**5. Endogenous mycobacterial endophthalmitis**

*Mycobaterium tuberculosis*, a rod shaped, aerobic bacterium, is known to infect around one third of the world's population [125]. Individuals are infected by inhalation of small airborne droplets containing the mycobacteria. The immune system is usually capable of containing the infection in immunocompetent patients; however, if that protective mechanism fails, mycobacteria are able to disseminate by hematogenous and lymphatic spread and seed in organs beyond the lungs, leading to extrapulmonary tuberculosis (TB) [126]. The eye is one of the organs that can be affected and represents 2–18% of extrapulmonary tuberculosis cases [127, 128]. *Mycobacterium tuberculosis* is an aerobic bacterium that has increased affinity to organs with high oxygen tension. The choroid is one of the tissues with the highest oxygen tension in the human body, making it especially vulnerable to seeding by mycobacteria.

The diagnosis of intraocular tuberculosis can be challenging, as it may have no pathognomonic eye findings. Instead, it has a protean presentation, which can appear similar to non-tubercular infections. Patients with HIV are more likely to develop intraocular TB than HIV-negative patients [3, 126]. However, severe intraocular TB can also occur in healthy individuals, which may cause a delay in diagnosis and treatment resulting in profound visual and organ loss [129, 130].

Uveitis is the most common ocular manifestation and can take the form of granulomatous anterior uveitis (12–36%), intermediate uveitis, posterior uveitis (11–20%) and most commonly, panuveitis (34–42%) [128]. Retinal manifestations can include multi-focal choroiditis, chorioretinitis, serpiginous-like choroiditis and choroidal tubercles [131–136]. Ocular tuberculosis can even be severe enough to cause panophthalmitis [137].

Identifying *M. tuberculosis* from body tissues and fluids is the gold standard for diagnosis. In the case of intraocular TB, this may require a major intervention such as enucleation, which may be clinically undesirable [138–140]. Moreover, most patients with intraocular TB present without signs of systemic manifestation, and tuberculin skin test (TST) can be negative in patients with disseminated TB [141, 142]. A recent review of endogenous TB endophthalmitis found that the majority of patients (63%) did not have a prior history of tuberculosis, and ocular manifestations were their presenting sign [141, 142]. Furthermore, half of the presenting patients denied any systemic symptoms such as fever, chills or hemoptysis prior to presentation at the eye clinic. The most common presenting symptom was decreased vision (90%), followed by pain (58%), eye redness (32%), and proptosis (6.5%), all of which are nonspecific signs [141, 142].

Together, these factors make accurate diagnosis of intraocular TB challenging. Nevertheless, certain ophthalmic findings can increase the likelihood of establishing the correct diagnosis. A study found that broad-based posterior synechiae, retinal vasculitis with or without choroiditis, and serpiginous-like choroiditis demonstrate a high likelihood of intraocular TB being present; however, the absence of these signs does not rule out the disease [143]. Moreover, retinal vasculitis in intraocular TB mainly involves the veins with perivascular cuffing and vitritis, and focal choroiditis lesions tend to be under the vessels [131, 144]. A presumed intraocular TB diagnosis can be made when these signs are present in addition to a positive tuberculosis test such as Tuberculin Skin Test (TST), QuantiFERON-TB Gold, chest radiograph, or computed tomography of the chest.

Being aware of the limitations of each diagnostic test is vital. As mentioned previously, TST can produce false negative results in some patients. These patients typically have anergy as result of immunosuppression or disseminated TB, hence TST should not be used to rule out TB when suspicion is high [145]. Moreover, spiral chest computed tomography is more sensitive in the detection of pulmonary TB and should be used in cases with normal radiography and high suspicion of the disease [146]. PPV can be an important diagnostic and therapeutic intervention, as it was found to have a higher yield than vitreous tap in returning positive for mycobacteria (87.5% vs. 14.3%, respectively) [142]. Moreover, PPV may have a similar role in improving

#### *Endogenous Endophthalmitis: Etiology and Treatment DOI: http://dx.doi.org/10.5772/intechopen.96766*

visual outcomes and reducing the possibility of enucleation in intraocular TB as was demonstrated in EBE cases. PCR also has a high diagnostic value and can be more accurate than cultures in diagnosing intraocular TB [142].

In the absence of confirmatory tests such as direct visualization of the mycobacteria, positive response to antitubercular therapy (ATT) supports the diagnosis of presumed intraocular tuberculosis. In fact, any delay in treatment to establish a definitive diagnosis is discouraged. One study found that systemic antibiotics were started in 47.6% of endophthalmitis of unknown etiology cases prior to establishing a definitive diagnosis [142]. Antitubercular therapy comprises a four-drug regimen: isoniazid, rifampicin, ethambutol, and pyrazinamide. The role of steroids as part of ATT remains controversial. Some studies have found that steroids can be effective in reducing TB-associated mortality and recurrences of uveitis as well as treating macular edema [141, 147], while another multi-center study found the use of steroids was associated with higher treatment failure rates [148]. Failure rates were higher when steroid treatment was started prior to initiation of ATT compared to after [148]. Therefore, judicious use of steroids is recommended as part of ATT. In fact, there might be two different pathophysiological mechanisms behind the intraocular inflammation: an active mycobacterial infection of the eye and an immunological response to the pathogen located elsewhere in the body [3, 143]. Thus, steroids may be more beneficial in the latter case. Higher treatment failure rates were also observed in patients with choroidal involvement and associated vitreous haze [148]. Caution and close observation of patients on ATT is required as isoniazid and ethambutol can cause toxic optic neuropathy [149]. Nevertheless, TB-associated endophthalmitis has a very poor outcome. The majority of cases (83.7%) end in either evisceration, enucleation or exenteration of the eye [142]. Of note, this figure is significantly higher than for EBE which is reported to be 20% [3].

Nontuberculous mycobacteria (NTM) have also been shown to cause endogenous endophthalmitis [150]. They can be divided into slow and rapid growers [151]. The latter group comprises the most cases of overall ocular infections and carries worse visual outcomes [152, 153]. However, rapid growers are mainly associated with exogenous endophthalmitis and can occur in healthy individuals [150]. On the other hand, endogenous endophthalmitis is typically secondary to infection by slow growers and occurs almost exclusively in immunocompromised patients. The source of infection is often unknown but disseminated infections have been documented [150, 154]. Some of the NTM slow growers implicated in endogenous endophthalmitis include *Mycobacterium avium* (the most common), *Mycobacterium kansasii, Mycobacterium triplex and Mycobacterium haemophilum*. A case of a rapid grower NTM, *Mycobacterium chelonae,* has also been documented to cause endogenous endophthalmitis as has the slow-growing *Mycobacterium bovis* [155, 156]. NTM endophthalmitis is often misdiagnosed as fungal or bacterial infection as it can present as a chronic intraocular inflammation [152, 157]. Therefore, an infection by NTM should be suspected in any immunocompromised patient with chronic granulomatous intraocular inflammation and poor response to anti-inflammatory drugs. Guidelines for treatment of NTM infection have yet to be established; however, slow grower NTM can usually be treated by the standard ATT, while rapid grower NTM are more sensitive to macrolides, aminoglycosides and fluoroquinolones [158].
