Fig. 2.1
(a) Granulomatous inflammation with giant cell reaction (arrow) (H&E ×100). (b) Higher magnification to show epithelioid cells (arrow) and lymphomononuclear surrounding the Langerhans giant cell (H&E ×200)
Ocular tuberculosis is a unique form of extrapulmonary tuberculosis which can present with several clinical manifestations based on the virulence of the organism and immune status of the individual. Both ocular and orbital tuberculosis are usually unilateral [8]. The most common clinical presentation is posterior uveitis followed by anterior uveitis, pan uveitis, and intermediate uveitis. Although granulomatous uveitis is common, it may be nongranulomatous. The diagnosis of intraocular TB is difficult prior to enucleation.
The eyelid involvement is very rare and is usually secondary to orbital TB and may appear as a small nodule simulating a chalazion or as a draining sinus (Fig. 2.2a, b). Rarely primary conjunctival and eyelid tuberculous granuloma may occur [8–11].
Fig. 2.2
(a) Subconjunctival necrotizing granuloma with giant cell reaction in a case of suspected eyelid tuberculosis (H&E ×100). (b) High-power view to show necrosis (arrow) in the center of granuloma (H&E ×200)
Orbital or lacrimal gland (Fig. 2.3a, b) and lacrimal sac granuloma may occur secondary to infection with M. tuberculosis [12, 13]. These may be associated with preauricular lymphadenopathy. Children can present as preseptal cellulitis with a fistula or as abducens nerve palsy [14].
Fig. 2.3
(a) Granulomatous inflammation (asterisk) in lacrimal gland (arrow shows lacrimal gland acini) (H&E ×100). (b) Higher magnification shows epithelioid cell granuloma (arrow) and adjoining lacrimal gland (LG) (H&E ×200)
Interstitial keratitis and phlyctenular keratoconjunctivitis represent a localized immunologic (hypersensitivity) response to the antigens of mycobacteria. Tuberculous scleritis presents as anterior scleritis mostly in the form of focal elevated nodules which may undergo necrosis and result in scleromalacia. Many of the cases of anterior segment are not associated with systemic manifestations of TB and appear localized to the eye [3, 10, 15].
Scleritis, both necrotizing and non-necrotizing, diffuse or nodular, may be associated with TB [16]. The diagnosis is often presumptive and rarely confirmed by histopathology or PCR following enucleation.
Anterior uveitis presents with insidious granulomatous uveitis which may be unilateral or bilateral. Iris lesions in tuberculosis appear as nodular areas at the pupillary margin, over the surface, or in the angle and are made up of epithelioid cells, giant cells, and lymphocytes with extensive caseation. Cyclitis is seen frequently and may cause caseating granulomas (Fig. 2.4a, b) [10, 17].
Fig. 2.4
(a) Tuberculous granuloma of the ciliary body with acute panophthalmitis. The vitreous shows necrotizing inflammatory reaction (H&E ×40). (b) Higher magnification to show granuloma with giant cell (arrow) and destroyed ciliary processes (asterisk) (H&E ×200)
Posterior segment involvement is more common and may include features of endophthalmitis or panophthalmitis simulating intraocular tumors including retinoblastoma (Fig. 2.5a–d) [18]. The retina and choroid are frequent targets with multifocal choroiditis being most common. Solitary choroidal tuberculoma (Fig. 2.6a) may occur in immunocompetent patients and in patients with disseminated tuberculosis [19–21]. Multifocal choroidal tubercles may occur anywhere in the posterior segment with retinal involvement. Vitritis is frequently associated with large choroidal tuberculomas. In the choroid these tuberculomas involve all the choroid layers including choriocapillaris (Fig. 2.6b). These are usually surrounded by choroidal vessels which get obliterated. The RPE initially is normal but can get disrupted in later stages. The granulomas are typical; however, the necrotic areas contain few bacilli.
Fig. 2.5
(a) Gross specimen of enucleated eye ball shows yellowish white mass in vitreous cavity. (b) Low-power view to show the entire vitreous cavity replaced by necrotizing inflammatory mass (asterisk). (c) Tubercular endophthalmitis. Low-power view of necrosis (asterisk) with adjacent chronic granulomatous inflammatory infiltrate (arrow) (H&E ×200). (d) Ziehl-Neelsen acid-fast stain demonstrates acid-fast bacilli (arrow) in necrotic tissue (×1000)
Fig. 2.6
(a) Choroidal granuloma (arrow) with lymphomononuclear infiltrate. Adjoining sclera (SC) (H&E ×200). (b) Tubercular retinitis . The retina (R) and choroid (CH) are replaced by intense chronic inflammatory cell infiltrate (H&E ×200). Inset shows RPE cells (double arrow) and Bruch’s membrane (arrow) (H&E ×400)
Tuberculosis may present with several manifestations including retinal vasculitis and serpiginous choroiditis. Retinal vasculitis may occur in the absence of choroiditis or retinitis. This form of phlebitis in patients with healed TB may represent immune-mediated reaction to tuberculoproteins. The inflammation may spread anteriorly to involve the anterior chamber angle, limbus, and cornea resulting in globe perforation.
Pathogenesis of Ocular Tuberculosis
Pathogenesis of extrapulmonary tuberculosis can be extended to ocular tuberculosis. Due to absence or rare isolation of MTB from ocular samples, the role of immune-mediated and direct bacterial-mediated inflammation is debated [22]. The mechanisms involved in pathogenesis include:
- (i)
Bacterial dissemination from the site of primary infection
- (ii)
Bacterial localization in ocular tissues
- (iii)
Bacterial reactivation and inflammation in these tissues
MTB is an obligate aerobic intracellular organism which invades tissues rich in oxygen. It enters the body through the respiratory system and spreads via the lymphatics or blood to other parts of the body [23]. Usually the bacteria are destroyed by alveolar macrophages or however they may grow destroying the alveolar macrophages resulting in initial nidus of developing tubercle [5].
An initial growth of MTB results in a delayed-type hypersensitivity response which is characterized by the formation of small necrotic lesions with solid caseous centers in infected area. After starting delayed-type hypersensitivity (DTH) and tubercle formation, stimulation of macrophages by CD4+ TDTH cells enables the macrophages to kill bacilli inside of the tubercle lesions [23]. The growth of the bacteria becomes limited, and the number of viable bacteria becomes stationary [5].
If the cell-mediated immune response is poor, bacilli start re-multiplying in nonactivated and partly activated macrophages. The T cells are primed followed by initiation of adaptive immunity which takes 5–7 days. During this latent period, macrophages carrying M. tuberculosis or even free bacteria may disseminate to the eyes or other organs. Once localized to the ocular tissues, M. tuberculosis may remain latent for long periods without apparent clinical disease [5, 24, 25]. The organism preferentially infects macrophages and other reticuloendothelial cells. Choroid is the most common site in the eye [1]. The RPE is the most suited among various ocular cell types to harbor MTB within the eye. It has alveolar macrophage-like properties like phagocytosis and expression of TLRs (Toll-like receptors) and complement receptors [22]. Although retina and uvea are involved by inflammation in tubercular pan uveitis, MTB localizes preferentially in RPE [26]. These organisms sequestered within RPE may cause recurrences.
TB choroidal granulomas in guinea pigs have shown evidence of tissue hypoxia with VEGF upregulation in RPE. However, AFB are rarely identified [27]. In most adults who are not HIV positive, ocular TB develops from postprimary reactivated lesion [5].
Although MTB evades killing if a good CMI develops, the bacteria are destroyed in the phagosomes on fusion with lysosomes, thereby exposing bacteria to acid pH, reactive nitrogen species, and lysosomal enzymes [26]. M. tuberculosis evokes an inflammatory response from the host to control the infection which may cause extensive tissue damage [1]. The progression of the lesion may get halted at subclinical stage.
The rare isolation of mycobacteria has led to the development of an alternative hypothesis in pathogenesis of intraocular TB. Garip et al. [28] have hypothesized that antigen mimicry between tubercular and retinal antigens could be a cause of uveitis in latent TB patients. Supporting features of this hypothesis include demonstration of significantly increased IL-6, rather than TNF-α, IL-12, and interferon gamma that characterize TB [22].
Immunopathogenesis of Ocular Tuberculosis (Fig. 2.7)
Initial immune response to M. tuberculosis results in the development of cell-mediated immunity and also hypersensitivity to mycobacterial antigens. Macrophages, T cells (CD4 and CD8), cytokines IFN γ, IL-12, TNF α, and IL-6 are most important in immune response to MTB.
