European Journal of Cardiovascular Medicine

Tuberculosis (TB) is a “Great imitator of diseases” owing to its varied presentation. Mycobacterium tuberculosis is the causative organism and the diagnosis can be confirmed only by direct visualisation of this acid-fast bacilli under direct microscope. But due to inaccessibility of organs it is quite difficult to retrieve these bacilli. Indirect evidences can be in form of Mantoux test, or Interferon gamma release assay (IGRA). Although the sensitivity and specificity of these tests are not reliable, yet we have to rely on these results after a clinical diagnosis has been made so that the Anti Tuberculosis Treatment can be started early. [1,2] Tuberculosis of eye can present either as extraocular or intraocular lesion. In the external eye it may present as a lid abscess or manifest as chronic blepharitis or atypical chalazions. It can present as a mucopurulent conjunctivitis with regional lymphadenopathy. It can also present as a phlyctenule (an inflammatory nodule at the junction of the cornea and sclera), infectious keratitis, inflammation within the cornea stroma (interstitial keratitis), or as an infectious scleritis. Intraocular lesions pose a much greater challenge in the form of uveitis, retinitis, choroiditis, optic neuritis etc. [3]

Ocular tuberculosis, one of the rare presentations of tuberculous bacteria, has a very difficult diagnosis.[4] So, the diagnosis is presumed on the basis of clinical features, haematological and immune tests. Early start of ATT is important in such patients because the disease may affect other organs once the immunity lowers. This is important because the burden of TB is very high in India, levelling to endemic proportions. Thus, ATT helps in decreasing the overall morbidity and mortality.

Prior approval of institutional ethics committee was sought and the study complies with the declaration of Helsinki. Informed consent was taken from all participants and their guardians in case of minors. This retrospective cohort study was carried out in a tertiary medical college. The medical record data were retrieved from January 2022 to June 2023 for a period of 18 months under the assessment of a single ophthalmologist.

Inclusion criteria

All patients with a presumed diagnosis of ocular tuberculosis on the basis of ocular findings keeping a high index of suspicion and a positive Mantoux /IGRA and prompt response/non relapse to ATT were included in the study

Aim:

To demonstrate the spectrum of presentation of ocular tuberculosis with its demographic distribution, course and response to treatment.

Objective

To study the morbidity associated with disease and its treatment

A total of sixteen cases presented during the duration of study, with twenty-one eyes and nine different presentations. All patients underwent complete ophthalmic examination including visual acuity, colour vision, intraocular pressure, pupillary reaction, slit lamp biomicroscopic and dilated fundus examination. A complete haematological investigation including complete blood count, CRP, ESR, liver function test, renal profile, blood sugar, RA factor, serum ACE, Mantoux test, interferon gamma release assay (IGRA), VDRL, Viral markers and chest X-Ray. The investigations were customized according to specific cases. The patients with positive Mantoux were referred to chest and TB department for any further work up and initiation of ATT, where they were kept under constant follow up. ATT was given for 6- 9 months in all the cases. The quadruple regimen for 2 months and isoniazid and rifampicin for 4 to 7 months were prescribed. All warning signs of adverse effect were clearly explained to the patient.

The diagnosis was made on the basis of clinical presentation, a positive Mantoux or IGRA test and the response to ATT within a month. For ocular diseases topical steroids were prescribed in all the cases. In cases like vasculitis, choroiditis, orbital cellulitis and optic neuritis, systemic steroids in form of oral preparations and intravenous drip were started at least 3 days to a week after initiation of ATT under physician guidance, after ruling out any other infectious component.

Nine different presentations were noted during the period of study in which five patients had bilateral presentations and eleven had unilateral lesions as shown in Figure 1.

Phyctenular conjunctivitis was most frequent in four of the cases. One case of bilateral dacryoadenitis had a history of tuberculous meningitis and ATT in childhood and the patient with orbital cellulitis had concurrent pulmonary tuberculosis and was on ATT regimen when he presented to us.

Figure 2 phlyctenular conjunctivitis (pretreatment and post treatment day 3)

The youngest patient was a female child of 13 years who presented with acute phlyctenular conjunctivitis of right eye as shown in figure 2 and the oldest was of 60 years who presented with orbital cellulitis   of both eyes after    pulmonary tuberculosis.

The mean and median age were almost very close to 30 years as shown in Table 1.

Table 1 Age distribution

Four of the five patients who presented with bilateral lesions were males. However, the males and females considering the laterality were almost equal as shown in figure 3

Figure 3 laterality among genders (uni11- unilateral 11 cases, Bi5- bilateral 5 cases)

Comorbidities in the form of malnutrition/underweight, obesity, hypothyroidism, tobacco and alcohol addiction were seen in five patients as shown in figure 4

Figure 4 comorbidities (malnutrition, obesity, hypothyroidism, tobacco and alcohol addiction)

Fourteen out of sixteen patients were started on ATT.  The one with dacryoadenitis had a previous course of ATT for 9 months for brain TB, and the other one with anterior uveitis did not give consent for ATT.

Among 14 out of 16 patients’ complete resolution of lesion was seen, rest two were lost to follow up.

Sequelae to disease was seen in 3 out of 5 patients who were started on systemic steroids and 1 patient with anterior uveitis on topical steroid later presented with macular oedema. Optic atrophy was seen in the patients who presented with choroiditis, optic neuritis (figure 5) and orbital cellulitis.

Figure 5 bilateral optic neuritis

No relapse was observed in one year follow up among 13 patients except one with bilateral optic neuritis who is still being followed.

One patient underwent TB gold and was positive. Rest of them could not afford this test due to high cost and difficult availability.

Tuberculosis has been known to be a very deadly disease in mankind. According to world health organisation TB is the leading cause of death from a single infectious agent.^[5] It is a great masquerader and can have different presentations. About one-third of world population is suffering from TB   and 85% of this is curable by a just 6 months ATT regimen. Unrestrained transmission of latent infection and fear of recurrence in those inadequately treated pose daunting challenges in TB control. Breaking the transmission cycle by early diagnosis, detection and adherent treatment is the only way out. Detection of mycobacterium tuberculosis (acid fast bacilli) is the mainstay of confirmatory TB. But, the inaccessibility of organs as well as organisms makes the detection of extrapulmonary TB extremely tricky. Ocular TB is one of such situations where this paucibacillary infection needs invasive biopsy. So, a good way to deal with it is to start ATT on basis of presumption based on high degree of clinical suspicion and to shift this into “Ocular TB” category only after strong response to ATT and/or no relapse of the ocular lesion.

India has the highest burden of TB. We are still lagging behind in data due to low notification rates. “National TB programme (NTP) “was the 1^st effort towards fighting TB, launched by government of India in 1962.^[6] RNTCP was launched in 1997 which was in lines with global policies. Since then, there has been major changes and India has vowed to eliminate TB by 2025 which is 5 years ahead of WHO target of 2030.^[7]

In our study, the mean age of presentation was 30 years as shown in previous studies, indicating the active immune response mechanism and sufficient exposure. Except two cases, the one with orbital cellulitis who had active pulmonary tuberculosis and the other one of dacryoadenitis who has history of ATT regimen in past, the rest 14 cases had no active tuberculous lesion and were suspected to have latent tuberculosis manifesting as ocular tuberculosis.

India is an endemic country for tuberculosis, so, history of contact was not taken assuming that each one of us at some points of time are exposed to tubercle bacilli. No significant difference was seen in unilateral and bilateral presentations and there was no gender bias as opposed to previous studies. In literature review, the commonest manifestation of ocular tuberculosis was uveitis whereas in our study phlyctenular conjunctivitis was by far the most common.^[8] Comorbid conditions like obesity, malnutrition/underweight, hypothyroidism, polycystic ovarian syndrome, tobacco and alcohol addiction were present in only five of the cases which was inconclusive.

Three of our patients who were on systemic steroids developed optic atrophy despite early start of ATT regimen. It could be either as a disease sequela or an adverse drug reaction to ATT. Although the known drugs for this like ethambutol and isoniazid were stopped early in the course and replaced by second line of treatment yet we could not save the optic nerve. So, close follow up and thorough counselling regarding the red flag signs of adverse drug effect to the patient is extremely necessary and needs special mention. We might be able to control and cease the infection but the eyes may be permanently lost. Similarly, we should strictly adhere to the criteria to screen for other organ damage during ATT regimen.

The complications of disease as well as that of treatment, both should be strictly followed and treated. Macular oedema developed in one of the patients with anterior uveitis after completion of   ocular treatment as shown in figure 6.

Figure 6 chronic anterior uveitis with macular oedema

Limitation

This case series is highly limited in terms of period of study which was a small duration of eighteen months as well as merely sixteen cases were studied. This retrospective study was further limited by the fact that the diagnosis of ocular TB was presumptive. Above all the criteria for diagnosis was Mantoux test which itself has high false positivity owing to exposure of mycobacterium in an endemic country like India. Moreover, many cases might be missed owing to non-confirmatory diagnosis of TB, another criteria was response to ATT which is confounded by treatment with steroids, moreover one and a half year is quite a short follow up to comment on recurrence and relapse.

This case series shows a wide spectrum of presumed ocular tuberculosis cases both extraocular and intraocular. Although most of the extraocular cases are naïve and self-limiting even without treatment, yet recurrence and relapse may prove to be a serious affair. Intraocular TB, on the other hand may be disastrous in term of disease sequelae as loss of vision. Early diagnosis depends on a high degree of suspicion and early treatment is the key. ATT itself has to be closely followed to look for drug reactions as some of these drugs are notorious for causing optic atrophy and other idiosyncratic reactions. New effective and confirmatory modalities of diagnosis and treatment for ocular TB is highly required, until India and the world is able to contain and eradicate tuberculosis.

1. Shahidatul-Adha, M., Zunaina E., Liza-Sharmini AT, Wan-Hazabbah WH, Shatriah I, Mohtar I, Azhany Y, Adil H. "Ocular Tuberculosis in Hospital Universiti Sains Malaysia - A Case Series." Annals of Medicine and Surgery (London), 13 Oct. 2017, vol. 24, pp. 25-30. doi: 10.1016/j.amsu.2017.10.003. PMID: 29062482; PMCID: PMC5647468.
2. Ang, Marcus, et al. "Diagnosis of Ocular Tuberculosis." Ocular Immunology and Inflammation, vol. 26, no. 2, 2018, pp. 208-216. doi: 10.1080/09273948.2016.1178304.
3. Alvarez, G.G., Roth, V.R., and Hodge, W. "Ocular Tuberculosis: Diagnostic and Treatment Challenges." International Journal of Infectious Diseases, vol. 13, no. 4, 2009, pp. 432–435.
4. Goyal, J.L., Jain, P., Arora, R., and Dokania, P. "Ocular Manifestations of Tuberculosis." Indian Journal of Tuberculosis, vol. 62, no. 2, Apr. 2015, pp. 66-73. doi: 10.1016/j.ijtb.2015.04.004. Epub 16 Jun. 2015. PMID: 26117474.
5. Global Tuberculosis Report 2019. Geneva: World Health Organization, 2019. License: CC BY-NC-SA 3.0 IGO.
6. Khanna, A., Saha, R., and Ahmad, N. "National TB Elimination Programme - What Has Changed." Indian Journal of Medical Microbiology, vol. 42, Mar-Apr. 2023, pp. 103-107. doi: 10.1016/j.ijmmb.2022.10.008. Epub 16 Nov. 2022. PMID: 36402676; PMCID: PMC9672688.
7. Gupta, A., and Chopra, V. "Evolution of Newer Regimens in TB from RNTCP to NTEP." Indian Journal of Tuberculosis, vol. 67, no. 4S, Dec. 2020, pp. S107-S110. doi: 10.1016/j.ijtb.2020.10.007. Epub 16 Oct. 2020. PMID: 33308654.
8. Neuhouser, A.J., and Sallam, A. "Ocular Tuberculosis." StatPearls [Internet], updated 5 Jan. 2023. StatPearls Publishing, 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559303/.