Ophthalmologic Findings Related to Tuberculosis

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Overview of Tuberculosis

Tuberculosis (TB) is the world’s leading infectious disease killer, with one-fourth of the world’s population infected.[1] The intracellular pathogen responsible for causing TB, Mycobacterium tuberculosis, is transmitted via inhalation of respiratory droplets containing the bacteria.[1][2] In the lungs, the primary site of infection, cells of the innate immune system phagocytose the bacteria. Interferon- γ (INF- γ) production leads to the formation of granulomas, a hallmark of the disease, which can become a nidus for long-term infection.[2] A wide variety of pulmonary manifestations can be seen with TB, leading to both airflow obstruction and restrictive ventilatory defects.[3] Primary TB involves infection and formation of a granuloma (Ghon complex) within the middle and lower lobes of the lung. However, symptoms are often non-specific and therefore primary infection goes undiagnosed in most cases.[4] Upon reactivation, typically secondary to an immunosuppressive event, fever, night sweats, weight loss, and a persistent cough can develop.[3][4] Approximately 15% of TB is characterized as extra-pulmonary, with common locations involving the lymph nodes, pleura, and CNS.[5] Another such specific location is the eyes, with TB being found in the eye, around the eye, and on the ocular surface.[6] This manuscript reviews the ophthalmic manifestations of TB.

Ocular TB

Ocular TB is uncommon and represents only 1-2% of TB in the United States.[7] It can present as a primary or secondary disease. In primary disease, the eye is the entry point of the mycobacterium and often has a predilection for the eyelids, conjunctiva, cornea, and sclera. The secondary disease results from the hematogenous spread of infection and preferentially targets the uvea, retina, and optic nerve; TB is a great masquerader and can manifest with any symptoms and signs, and some of the common manifestations are discussed in this brief.[6] Ocular TB can be categorized into extraocular, which includes structures around and on the eye, and intraocular, related to structures within the eye.[8]

Extraocular TB

• Orbit: With orbital TB involvement, proptosis, chemosis, headache, and decreased vision can result.[9] See below for further information regarding extraocular muscle involvement secondary to nerve dysfunction.

• Eyelids/Lacrimal Glands: TB with a predilection for the eyelids can present as “apple-jelly” nodules (lupus vulgaris). Lid abscesses and chalazions can also be seen. Lacrimal glands, although technically differentiated from the lids, can also harbor TB and present as infection as well.[10]

• Conjunctiva/Cornea: Phlyctenular keratoconjunctivitis, which presents as an inflammatory nodule located at the limbus, causes redness, tearing, photophobia, and epithelial erosions. Specifically for the cornea, TB can present with interstitial keratitis with associated stromal infiltrates.[11]

• Sclera: Isolated TB scleritis may result from either direct inoculation by the bacterium or through an immune-mediated inflammatory reaction. There is often predilection for the posterior sclera.[12]

Intraocular TB

• Anterior Uveitis: TB-related anterior uveitis usually presents as granulomatous uveitis, commonly exhibiting iris granulomas. These granulomas are often in conjunction with Koeppe (located at the pupillary border) and Busacca (directly on the iris surface) nodules. The composition of the nodule includes typical granulomatous features such as epitheloid and giant cells with surrounding lymphocytes.[13]

• Posterior Uveitis: The most common presentation of ocular TB is posterior uveitis. Choroidal tubercles can be seen, with a predilection for the posterior pole of the eye. Posterior uveitis due to TB classically produces a serpiginous-like lesion that spares the fovea and causes vitreal inflammation.[7][14]

o For more information regarding tuberculous uveitis, see: https://eyewiki.aao.org/w/index.php?title=Tuberculosis_Uveitis&oldid=74174

• Endophthalmitis: Any active TB lesion within the eye can seed the vitreous fluid and lead to TB endophthalmitis. TB endophthalmitis can be sight-threatening and delay in diagnosis and anti-TB therapy can result in significant and permanent loss of vision.[15]

• Retina: Retinal involvement in TB is typically secondary to choroidal infection with the bacterium. As with uveitis, tubercles may be present. TB vasculitis of the retina can lead to neovascularization and eventual retinal hemorrhages.[16]

• Cranial Nerves: Optic nerve involvement in TB can result from both primary disease and secondary disease. Similar to other infectious or inflammatory causes of optic neuropathy, TB optic neuropathy may present with optic nerve edema, disc granuloma, or may be retrobulbar. TB papillitis can be associated with optic nerve tubercles and anterior or posterior TB uveitis.[17] Other cranial nerve involvement, particularly the abducens nerve, is common and found in over one-third of patients with TB meningitis. TB can also involve the brain parenchyma, the brainstem, cerebellum, or cavernous sinus.[18] TB has also been reported to cause third, fourth, or sixth cranial nerve palsy.

Diagnosis

Pulmonary TB can be divided into active or latent TB. Latent TB may have a positive TB skin test (TST) or a positive Interferon-Gamma Release Assay (IGRA) but the chest x-ray is negative for active TB (i.e., no hilar lymphadenopathy or cavitary lung lesions).[19] Active TB, on the other hand, shows active lesions on chest x-ray and a sputum sample stained for acid-fast bacteria may be diagnostic.[19]

In contrast, ocular TB is more difficult to diagnose. Fluid collected from the eye is often negative for TB on both culture and PCR, especially when posterior structures of the eye are affected.[20] To date, promising diagnostic technologies include IGRAs sampled directly from ocular fluid, as well as further advancement of PCR techniques.[20][21] Especially in resource-limited countries where ocular TB is most prominent, access to such diagnostics is scarce and many clinicians are forced to presume a diagnosis of ocular TB when other systemic signs of TB are present in conjunction with expected TST and chest x-ray findings as described above. Additionally, clinical ophthalmic improvement with antti-TB medications has often been used as a retro-diagnostic tool for ocular TB.[20]

Treatment

As with pulmonary TB, ocular TB often requires multi-drug TB therapy (e.g., rifampin, isoniazid, pyrazinamide, and ethambutol).[22] Treatment for ocular TB is similar to pulmonary TB and may require four-drug therapy for up to two months followed by two-drug therapy (rifampin and isoniazid) for up to four months.[23] The role of steroids for ocular TB (systemic or topical) remains controversial.[23]

In addition, TB treatment with ethambutol can cause visual loss as a side effect. Ethambutol-induced optic neuropathy can mimic ocular TB (e.g., decreased visual acuity, visual field defects, and dyschromatopsia).[24] Additionally, isoniazid has reportedly been associated with optic neuropathy, retrobulbar optic neuritis, and optic atrophy, although with less of a frequency than with ethambutol.[25]

A meta-analysis showed that multi-drug anti-TB therapy resulted in 92% improvement in ocular inflammation with 69% improved visual acuity, and 84% without recurrence of their TB after treatment.[23]

Summary

Clinicians should be aware of the ocular (e.g., anterior or posterior uveitis) and neurologic manifestations of TB (e.g., meningitis, optic neuritis, cranial neuropathy, encephalitis). Anti-TB therapy might require multi-drug therapy. Some anti-TB treatments have visual side effects (e.g., ethambutol, isoniazid).

References

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  3. 3.0 3.1 Ravimohan S, Kornfeld H, Weissman D, Bisson GP. Tuberculosis and lung damage: from epidemiology to pathophysiology. Eur Respir Rev. 2018;27(147):170077. Published 2018 Feb 28. doi:10.1183/16000617.0077-2017
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  5. Rodriguez-Takeuchi SY, Renjifo ME, Medina FJ. Extrapulmonary Tuberculosis: Pathophysiology and imaging findings. RadioGraphics. https://pubs.rsna.org/doi/10.1148/rg.2019190109. Published November 7, 2019. Accessed May 22, 2022.
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  7. 7.0 7.1 Tsai J, Prabhu S, Read R, Al-Falah M, Palestine A, Cao J. Tuberculosis uveitis. EyeWiki. https://eyewiki.aao.org/w/index.php?title=Tuberculosis_Uveitis&oldid=74174. Published November 1, 2021. Accessed May 23, 2022.
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  14. M A, El-Asrar A, Abouammoh M, Al-Mezaine HS. Tuberculous uveitis. Middle East Afr J Ophthalmol. 2009;16(4):188-201. doi:10.4103/0974-9233.58421
  15. Antaki F, Javidi S, Touma S, Aubin MJ. Endogenous Tuberculous Endophthalmitis and Panophthalmitis: A Systematic Review of Case Reports and Case Series. Clin Ophthalmol. 2020;14:3075-3096. Published 2020 Oct 7. doi:10.2147/OPTH.S265521
  16. Dalvin LA, Smith WM. Intraocular manifestations of mycobacterium tuberculosis: A review of the literature. J Clin Tuberc Other Mycobact Dis. 2017;7:13-21. Published 2017 Feb 17. doi:10.1016/j.jctube.2017.01.003
  17. Davis EJ, Rathinam SR, Okada AA, et al. Clinical spectrum of tuberculous optic neuropathy. J Ophthalmic Inflamm Infect. 2012;2(4):183-189. doi:10.1007/s12348-012-0079-5
  18. Sharma P, Garg RK, Verma R, Singh MK, Shukla R. Incidence, predictors and prognostic value of cranial nerve involvement in patients with tuberculous meningitis: a retrospective evaluation. Eur J Intern Med. 2011;22(3):289-295. doi:10.1016/j.ejim.2011.01.007
  19. 19.0 19.1 Ryu YJ. Diagnosis of pulmonary tuberculosis: recent advances and diagnostic algorithms. Tuberc Respir Dis (Seoul). 2015;78(2):64-71. doi:10.4046/trd.2015.78.2.64
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  21. Kurup SK, Buggage RR, Clarke GL, Ursea R, Lim WK, Nussenblatt RB. Gamma interferon assay as an alternative to PPD skin testing in selected patients with granulomatous intraocular inflammatory disease. Can J Ophthalmol. 2006;41(6):737-740. doi:10.3129/i06-068
  22. Thompson MJ, Albert DM. Ocular tuberculosis. Arch Ophthalmol. 2005;123(6):844-849. doi:10.1001/archopht.123.6.844
  23. 23.0 23.1 23.2 Kee AR, Gonzalez-Lopez JJ, Al-Hity A, et al. Anti-tubercular therapy for intraocular tuberculosis: A systematic review and meta-analysis. Surv Ophthalmol. 2016;61(5):628-653. doi:10.1016/j.survophthal.2016.03.001
  24. Lee N, Nguyen H. Ethambutol. [Updated 2021 Nov 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559050/
  25. Gan, N., Teoh, S. Isoniazid-related bilateral choroidal effusions. Eye 24, 1408–1409 (2010). https://doi.org/10.1038/eye.2010.57
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