Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body. The disease has become rare in high income countries, but is still a major public health problem in low- and middle-income countries [1]. 

In 2019, India notified 24 lakh tuberculosis (TB) patients and the estimated TB incidence was 199 patients per 100,000 persons accounting for about 26% of the global incident cases.  TB control depends on early diagnosis of TB cases and their treatment with a full course of anti-tuberculosis drugs [2]. 

With the aim of elimination of TB by 2025, the Revised National Tuberculosis Control Programme (RNTCP) was revamped in 2016 with changes in the protocol for the management of TB cases. The three times a week regimen was changed to a daily regimen and ethambutol was made a part of both the intensive as well as the continuation phase (CP) of the treatment [3].

As per the new RNTCP guidelines- newly diagnosed TB patients are treated with eight weeks of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol in daily dosages as per four weight band categories during intensive phase. Pyrazinamide is stopped in CP, while the other three drugs continued for another 16 weeks as daily dosages [4]. 

Although this is expected to enhance compliance and reduce drug resistance, there is an apprehension that unless closely monitored, incidence of optic neuropathy can increase multifold and result in significant visual impairment due to increased exposure to ethambutol.

The incidence of ethambutol toxicity has been reported as varying from 0.5-4.3% [5-7]. Toxicity with Ethambutol is quite rare and can occur after two months of therapy although the average time is around seven months. Prognosis is good following the cessation of the drug but recovery may take up to 12 months and a minority of patients may have residual visual impairments.        

Review of Literature

Ethambutol (EMB) is an antibiotic used to treat infection by Mycobacterium species, particularly Mycobacterium tuberculosis and non- tubercular infections like M. avium complex and M. kansasii. EMB in combination with other medications is a commonly prescribed regimen for treatment of tuberculosis [8].

Clinical Presentation

Affected individuals may complain of bilateral progressive painless diminution of vision. Visual acuity drop varies greatly from minimal reduction to no perception of light. 

Pathogenesis

Retrobulbar neuritis is the most common form of EON. While the exact mechanism of the ocular neurotoxic effect of ethambutol is unknown, chelating properties of ethambutol have been hypothesized to contribute to its neurotoxicity. It causes a calcium flux into the mitochondria and excitotoxicity [9].

Dose related

Liebold JE [10] and Bobrowitz ID [11] reported dose related ocular toxicity of ethambutol, 18% in patients receiving 35 mg/kg/day, 5-6% with 25 mg/kg/day and 1% with 15 mg/kg/day of ethambutol for more than two months.

Duration related

Manifestation of ocular toxicity is usually delayed. Melamud et al. [12] reported toxicity does not develop until after treatment for at least 1.5 months. Variable mean interval three to five months between onset of therapy and toxic effects were reported. Manifestations of toxicity as late as 12 months after therapy initiation were reported.

Reversibility

Views on the issue of reversibility of ethambutol toxicity are divided. Although classically described as reversible on discontinuation of ethambutol (with visual acuity recovery over period of weeks to months), Tsai et al. [13] have reported only five patients (50%) experienced visual improvement after a period of 12 months to 3 years follow-up.

Aim and Objectives

To study the incidence of visual defect in patients treated with Antitubercular drugs under RNTCP in newly diagnosed TB patients (category one).

Study design

Prospective single centre cohort study of newly diagnosed tuberculosis patients registered at the RNTCP-DOTS centre at Dr RPGMC Kangra (Tanda) over the period of one year.

Selection Criteria

• Newly diagnosed TB patients coming to the institution’s RNTCP-DOTS centre, after their informed consent

• All patients are above 18 years of age

Setting

The study was done in Department of Ophthalmology, Dr RPGMC Tanda, with support of Department of Pulmonary Medicine, Dr RPGMC Tanda, after approval from institutional ethical committee.

Exclusion criterion

• Patients with other systemic diseases like renal failure, diabetes, hypertension, demyelinating diseases etc

• Addiction: tobacco, alcohol etc

• Ocular diseases: affecting visual acuity, or may contribute to colour vision defect

• Patients on medications causing colour vision defects like oral contraceptives, digoxin, indomethacin etc

• Patients having colour vision defect /visual field defect, at the baseline examination were excluded from the study

Methodology

The patients were examined on day-15 of ATT as baseline investigations, later there was a follow up at 2-months and 6-months of treatment and in between if patient complaint of decreased vision.

The patients were evaluated with special reference to

• Demographic information like name, age, sex (male/female), occupation, address

• Detailed history of symptoms including defective vision for distant and near, headache, double vision, transient visual obscuration, altered sensorium, nausea, vomiting

• History of hypertension, diabetes, and any other systemic illness

• History of head injury, brain tumour

• Past history of ocular infection, surgery or trauma

Examination findings including general physical examination, pulse, blood pressure and thorough ophthalmic examination including- Distant uncorrected visual acuity of all patients using Snellen’s chart of both eyes along with corrected visual acuity using pinhole was done.

In newly diagnosed TB patients, HRZE given for 2-months and HRE is given for next 4-months.

Injection streptomycin to be added in IP phase in previously treated drug sensitive patients Table 1.

Table 1: Drug dosage for adult TB under RNTCP

Observations and Results

The present study was aimed to evaluate the incidence of ocular complications in patients treated with ATT under RNTCP in newly diagnosed TB patients taking treatment at DOTS centre Tanda and nearby DOTS centres. During the study period, a total of 91 patients receiving ATT were included in the study; however, nine patients were lost to follow-up; hence, these patients were excluded from the final analysis. The final study included 82 patients (n =164 eyes). Results of the study are presented below (Table 2)

Table 2: Visual Defects

Visual defect

In our study, we observed that two eyes had deterioration of vision at second visit while eight eyes had visual defects at the time of the final visit.

Improvement of visual acuity

Our study observed that there were two patients with improvement in visual acuity two months after stopping ethambutol therapy.

One of the most common causes of Toxic optic neuropathy (TON) is the use of drugs. Ethambutol is used in the treatment of tuberculosis and M. avium infections. Optic nerve toxicity belongs to the most serious adverse effects related to ethambutol use. It occurs in up to 6% of patients who were taking the drug. The clinical picture is similar to other toxic optic neuropathies in general, including a decrease in vision [13].

Visual problems usually do not occur during the first 2 months of ethambutol treatment, and they generally appear between 4 and 12 months.

The risk of TON is higher at the dosages of 25 mg/kg/day or more. At lower doses, ≤15 mg/kg/day it is considered both relatively safe and effective. However, even with much lower doses, cases of vision loss have been reported [13].

The ocular toxicity is dose and duration-dependent; thus, early recognition of TON and prompt cessation of the therapy is important in preventing further progression of vision loss (Figure 1, 2).

Figure 1: Visual Defect

Figure 2: Line Diagram Showing Number of Eyes with Visual Defect at Different Time

In our study, two eyes (1.2%) at 2-months of starting the therapy (p = 0.156) and 8 eyes (4.9%) at 6-months of starting the therapy had decreased visual acuity (p = 0.042). Changes in visual acuity in our study were lower than reported by Garg et al. [14] and Indrayani et al. [15] but much higher than Mandal et al. [16] who reported no significant change in visual acuity at six months of ethambutol therapy. In the study by Garg et al. [14] a decrease in visual acuity was seen in 12 eyes (9.4%). In the study by Indrayani et al. [15] a decrease in visual acuity was reported in 23.3% of eyes. Mahrukh et al. [17] reported that 9.6% of eyes developed a decrease in visual acuity after 2 months of initiation of ethambutol. Kandel et al. [18] reported that mean visual acuity before starting therapy was 0.00±0.08 Log-MAR and after therapy was 0.08±0.18 Log-MAR. When the above studies were analyzed, it was found that the effects of ethambutol on the eye were highly unpredictable and idiosyncrasy also could play a part.

This study was an attempt to assess the incidence of ocular toxicity in patients on antitubercular treatment.  In the patients who received antitubercular treatment, there was a significant decrease in visual acuity. All the patients and especially the elderly on antitubercular treatment must be followed up regularly to detect these adverse effects early. However, studies with larger sample size and long-term follow-up are required to generalize the findings.

Financial disclosure

The study did not receive any financial assistance. The subjects included in the study were not provided any financial support and no financial burden was placed on the study subjects.

1. World Health Organization. “Tuberculosis.” WHO, https://www.who.int/news-room/fact-sheets/detail/tuberculosis. Accessed December 2021.

2. Government of India. India TB Report 2020. Central Tuberculosis Division, annualreport.tbc.gov.in. Accessed December 2021.

3. Revised National Tuberculosis Control Programme. “Revised National Tuberculosis Control Programme.” National Health Portal, https://www.nhp.gov.in/revised-national-tuberculosis-control-programme_pg. Accessed December 2021.

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15. Indrayani, I.A.S. et al. “Characteristics of ethambutol optic neuropathy on tuberculosis treatment in Sanglah Hospital Denpasar.” International Journal of Medical Reviews and Case Reports, 2020, doi:10.5455/IJMRCR.neuropathy-ethambutol-tuberculosis.

16. Mandal, S. et al. “Prospective study to evaluate incidence and indicators for early detection of ethambutol toxicity.” British Journal of Ophthalmology, 2020, doi:bjophthalmol-2020-316897.

17. Mahrukh, et al. “Visual field changes in patients receiving antitubercular drug therapy at tertiary care hospital: An analytical observational study.” International Journal of Contemporary Medical Research, vol. 4, no. 2, 2017, pp. 346–349.

18. Kandel, H. et al. “Visual function in patients on ethambutol therapy for tuberculosis.” Journal of Ocular Pharmacology and Therapeutics, vol. 28, no. 2, 2012, pp. 174–178.