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Research Article

Visual field changes in patients receiving antitubercular therapy: A prospective cross-sectional study from South India

[version 1; peer review: 1 not approved]
PUBLISHED 01 Jul 2024
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This article is included in the Manipal Academy of Higher Education gateway.

This article is included in the Eye Health gateway.

Abstract

Objective

Tuberculosis is a global health challenge with one-third of the world’s population infected by it. Although ocular side effects of Anti-tubercular drugs are well known, the patients generally report late in the course which can result in irreversible vision loss. The purpose of this study was to study the visual field changes during the time course of anti-tubercular therapy (ATT).

Methods

A total of 48 patients were studied in this prospective type of study. All patients newly diagnosed with TB and started on treatment were included in the study. Baseline examination which included visual acuity, color vision, anterior segment, IOP, Amsler grid, fundus, and visual field test were performed before starting ATT and at 6-month follow-up.

Results

The mean age of the study population was 35.90 ± 10.2 years. 35 (72.9%) were males and 13 (27.1%) females. 32(66.6%) had pulmonary TB and the rest 16 (33.3%) had extrapulmonary TB. MDR TB was diagnosed in 27 (56.3%) of the patients with the rest 21 (43.8%) being drug sensitive. The baseline examination was normal in all 48 patients. 3(6.3%) out of 45 patients presented with visual complaints after the treatment initiation. Altogether 7 patients out of 48, had visual field defects at the 6-month follow-up. The incidence of visual field defects in our study was 14.6% with the value being significant (0.016). 8.3% had peripheral constriction of visual fields, 2.1% with Severe generalized depression of visual fields and 2.1% with central scotoma. Out of the 45 patients with no visual complaints at 6-month follow-up, 4 (8.33%) showed peripheral field constriction.

Conclusion

Visual field defects caused by ATT can precede clinical symptoms. Visual field evaluation can be an important tool for the early detection of optic neuropathy in patients receiving ATT in clinical settings where Visual evoked potential testing and RNFL-OCT are not available.

Keywords

Mycobacterium tuberculosis, Drug toxicity, DOTS, visual field defects, toxic optic neuropathy, Ethambutol, Linezolid

Introduction

Tuberculosis (TB) is one of the ancient diseases known to mankind that has co-evolved with humans for many decades1 and is a global health challenge.2 Among the world’s population, one-third are infected by it, and that makes TB, a public health concern.24 TB is one of the top three infectious killing diseases in the world1 and is also the leading cause of death from a single infectious agent.2 According to the India TB Report 2022, there is a 19% increase in cases (new and relapse) in 2021 from 2020.5 Interrupting its transmission is central to achieving the reduction in its incidence required to meet the End TB targets.5

DOT (Directly observed therapy) is widely accepted and followed in many other countries and is the most effective.3 It is the fastest expanding and most extensive growing strategy and the second largest based on people initiated on treatment and population coverage, respectively.1 The standard treatment plan for tuberculosis usually is six months however, for resistant cases, it may even extend to 2 years with less potent and less toxic drugs1with treatment change based on the drug resistance.

The first line of drugs includes ethambutol, isoniazid, pyrazinamide, and rifampicin, and these are part of DOTS (Directly Observed Treatment Short course). Despite the increased availability of medical treatment, new challenges have developed with the growing incidences of drug-resistant tuberculosis that include DR-TB (drug-resistant), MDR-TB (multidrug-resistant), and XDR-TB (extensively drug-resistant).6

ATT-associated ocular toxicity was first established in the 1960s.7 Ethambutol and linezolid are the most common anti-TB drugs responsible for ocular side effects.4,8 Rare cases of Isoniazid-induced toxic optic neuropathy have also been reported.9,10 The toxic neuropathies associated with Ethambutol and linezolid account for about 1% and normally occur after 4-6 months of treatment.11 Optic nerve head and retinal nerve fiber layer changes are minimal in the early stages.7 The most common visual field defects associated with ethambutol and linezolid are central and centro-caecal scotomas,12 whereas bitemporal hemianopic scotomas with isoniazid.9

Timely detection of ATT-induced optic neuropathy is essential since sight-threatening complications can be reversed if the drug causing the toxicity is discontinued at the earliest. The purpose of this study was to evaluate visual function in patients receiving ATT and to evaluate the visual field changes caused due to ATT.

Methods

This was a prospective observational study done in a tertiary health care center, in south India, conducted from December 2020 to October 2022. The study was approved by the Institutional Ethics Committee (Kasturba Medical College, Mangalore affiliated to Manipal Academy of Higher Education, Manipal, India Approval No: IEC KMC MLR 12-2020/441) and abided by the tenets of the Helsinki Protocol. Patients above 15 years of age, newly diagnosed with TB who were started on anti-tubercular therapy were included in the study. A written informed consent was taken from all the patients. Patients who were previously on Anti Tubercular Therapy, patients with a previous history of the retina and optic nerve pathologies, and those with previously documented visual field defects were excluded.

The following tests were done at baseline (beginning of ATT) and at 6 months from the date of starting ATT. Baseline ocular examination which included best corrected visual acuity using Snellen chart and Jaeger chart, color vision using Ishihara plates, Slit amp examination, IOP with Goldman Applanation Tonometer, Amsler grid, Dilated fundus examination using slit lamp biomicroscopy and indirect ophthalmoscopy, and Humphrey visual field analysis 30-2 were done. Patients were advised to continue with their ATT and to review immediately in case of any visual symptoms. At the onset of visual symptoms, the drug responsible was identified and stopped.

The data was analyzed using IBM SPSS version 25. The nominal variables-type of color vision and fields at baseline and follow-up were compared using the Mc Nemer test for nominal variables; whereas the visual acuity was compared at baseline and follow-up using the Wilcoxon sign rank test for ordinal variables. A p-value of <0.05 was considered significant for all analyses.

Results

A total of 48 patients were part of this study. The mean age of the study population was 35.90 years ± 10.2 years. Among the 48 patients, 4 (8.3%) were 15-20 years of age, 13 (27%) in the age group of 21-30 years, and 8 (16.6%) in the age group of 31-40. Rest 23 (47.9%) patients are in the age group of 41-50 years.35 (72.9%) out of 48 were male and 13 (27.1%) were female.

Of the total 48 patients included, 32(66.6%) patients had a diagnosis of pulmonary tuberculosis. Out of the 15 patients with extrapulmonary tuberculosis 4(8.3%) had disseminated tuberculosis, 4(8.3%) with TB lymphadenitis, 6(12.5%) with pleural effusion, 1(2.1%) with abdominal tuberculosis and 1(2.1%) with pott’s spine (Figure 1).

7a223ba7-363f-425e-9367-96ba4b7a4150_figure1.gif

Figure 1. Pi chart showing various indications in the study population for receiving ATT.

TB REGIMEN: MDR tuberculosis, mainly rifampicin-resistant tuberculosis was found in 27(56.3%) at the time of their diagnosis and the rest 21 (43.8%) were drug-sensitive.

Of the 27 with drug resistance, 2(4.2%) were initiated on a shorter bedaquiline regimen and 3(6.3%) on all oral longer MDR TB regimens (Table 1).

Table 1. Treatment regimen followed among the study group.

SensitivityDrug sensitiveMDR TB Rifampicin resistantShorter bedaquilineLonger MDR TB regimen
Number212223
Percentage43.8%45.8%4.2%6.3%

Visual acuity at baseline for all the 48 patients included in the study was 6/6. 3(6.3%) out of 45 patients presented with visual complaints after the treatment initiation. 1 patient (2.1%) had vision of 6/18 with the other two patients (4.2%) below 6/60 (Table 2).

Table 2. Visual acuity at baseline and at follow-up.

Visual acuitybaseline6 month follow-upP value
6/648 (100%)45 (93.8%).102
6/18-6/900
6/36-6/1801 (2.1%)
<6/6002 (4.2%)

Color vision examination was normal in all 48 patients during baseline evaluation. 3(6.3%) developed color vision abnormalities at follow-up with all of them being red-green deficient (Table 3). P value was 0.250 which is not significant.

Table 3. Color vision at baseline and follow-up.

Color visionbaseline6-month follow-upP value
Normal48 (100%)45 (93.8%).250 (NS)
Red-green deficit03 (6.3%)

Anterior segment examination findings and IOP were normal in all patients at baseline and follow-up. Fundus examination was found to be within normal limits in all 48 patients at baseline. However, 3(6.3%) had abnormal findings at follow-up. 1(2.1%) had bilateral temporal disc pallor with the other two patients (4.2%) having bilateral hyperaemic disc (Figure 2).

7a223ba7-363f-425e-9367-96ba4b7a4150_figure2.gif

Figure 2. Fundus color photograph of a patient, 25-year-old male, showing bilateral disc edema (black arrow showing peripapillary hemorrhage) 5 months after starting ATT (right and left eye).

Visual fields at baseline for all 48 patients were normal. Out of the 45 patients with no visual complaints at 6-month follow-up, 4 (8.33%) showed peripheral field constriction. Out of the 8.33%, Constriction in one quadrant was observed in 2.1% whereas constriction in 2 quadrants was observed in 6.3%. 3(6.3%) patients developed visual symptoms during the treatment course, out of them, peripheral field constriction was noted in one patient (2.1%), one showed severe generalized depression of visual fields (2.1%) and the other patient had central scotoma (2.1%). p-value of 0.16 was calculated which was found to be significant (Table 4).

Table 4. Comparison of baseline visual field with 6month follow-up.

Visual fieldsBaseline6-month follow-upP value
Normal48 (100%)41 (85.4%).016 (sig)
Central scotoma01 (2.1%)
Peripheral constriction in only 1 quadrant01 (2.1%)
Peripheral constriction in 2 quadrants03 (6.3%)
Peripheral constriction in all 4 quadrants01 (2.1%)
Severe generalized depression of visual fields01 (2.1%)

All three of these patients with visual complaints were on linezolid as part of their all-oral long bedaquiline regimen. The three patients with visual symptoms were immediately advised to stop the linezolid and even the TB center had been notified of the same.

To confirm the diagnosis in the three patients with visual symptoms VEP and RNFL OCT was done which showed prolonged P100 latency and thinning of the RNFL layer.

The visual acuity, color vision, and visual field defects improved in two of the three patients within 1-2 months with the average being 1.5 months post-stopping linezolid. Visual symptoms of one patient however did not improve even after stopping linezolid which can be attributed to a longer duration of drug intake.

Discussion

Baseline visual acuity was normal in all patients, however, 3 (6.3%) patients complained of visual symptoms with 2 reported vision less than 6/60. This is similar to Garg et a13 at 8.69%, Ashraf et al,14 at 10.6%, Panchal et al,4 7.44%, and Goyal et al,15 at 3.3% incidence of visual complaints. However, no patient in studies done by Saxena et al,16 Menon et al,17 Kandel et al,18 Kim et al,19 Jin et al,8 had any visual complaints.

Color vision abnormality was noted in 6.3% of our patients similar to 5.32% as seen in a study done by Panchal et al.4 All our patients had Red-Green deficiency in contrast to the study by Ashraf et al,14 who had 23.23% of people with color vision abnormalities with the maximum being blue-yellow deficient.

Out of 48 people in our study on fundus examination, 4.2% had disc edema and 2.1% had temporal disc pallor. The findings in these patients were bilateral. Similar findings were noted by Panchal et al4 who had 2.12% with bilateral disc edema and 2.12% with bilateral disc pallor. A study done by Ambika et al,20 showed 44.14% with disc pallor and <1% showed disc edema.

The incidence of visual field defects in our study was 14.6% with the value being significant (0.016). 2.1% had a peripheral constriction in all 4 quadrants, 2.1% with Severe generalized depression of visual fields, and 2.1% with central scotoma. In our study, 4 patients (8.3%) showed Peripheral field constriction in different quadrants making it the most common field defect similar to the study done by Ashraf et al,14 in which 13.3% had field defects with 8.15% being peripheral field defects in different quadrants. However, visual field defects in patients receiving anti-tubercular therapy varied in different studies. Bitemporal field defects were observed by Kho et al12 in his study, centro-caecal scotomas (2.12%) were observed by Panchal et al.4 Garg et al13 in their study concluded that 8.69% (8 eyes of 4 patients) with visual field defects with centro-caecal scotoma in one patient and the rest with peripheral constriction. Few studies like Kandel et al,18 Kim et al,19 Jin et al,8Saxena et al,16 observed no visual field changes in any of their patients on anti-tubercular therapy. The limitations of this study include that reaching a definite conclusion by extrapolation of results to the general population was not possible due to the small sample size. the patients were not followed up at shorter intervals, the accurate time of onset of the side effects could not be studied. Incidence of visual field defects was 14.6% in our study with 6.25% of them reporting visual symptoms.

Visual field defects caused by ATT can precede clinical symptoms. Visual field evaluation can be an important tool for the early detection of optic neuropathy in patients receiving ATT in clinical settings where visual evoked potential testing and RNFL-OCT are not available. Patients on ATT should be regularly screened for ocular adverse effects preferably every month. Routine examinations like visual acuity, color vision, and fundus examination must be carried out to look for any subclinical effects of the treatment and monitor their progression.

Chest physicians, ophthalmologists, and Health care workers need to be aware of potentially sight-threatening side effects of ATT. Prompt diagnosis and timely intervention are the keys to optimal visual outcomes in patients with toxic optic neuropathy due to ATT.

Declarations

Institutional Ethical committee clearance for the study was obtained.

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Pagadala T, Kamath G, Mendonca TM et al. Visual field changes in patients receiving antitubercular therapy: A prospective cross-sectional study from South India [version 1; peer review: 1 not approved]. F1000Research 2024, 13:719 (https://doi.org/10.12688/f1000research.149831.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Open Peer Review

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Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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Reviewer Report 12 Jul 2024
Karthik Vinay Mahesh, Department of Neurology, PGIMER, Chandigarh, Chandigarh, India 
Not Approved
VIEWS 31
The authors look into an important field of drug induced optic neuropathy in patients of tuberculosis, which is a public health concern.
However, there are several shortcomings in the methodology
1.) The most important factor is the offending ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Mahesh KV. Reviewer Report For: Visual field changes in patients receiving antitubercular therapy: A prospective cross-sectional study from South India [version 1; peer review: 1 not approved]. F1000Research 2024, 13:719 (https://doi.org/10.5256/f1000research.164337.r298163)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 01 Aug 2024
    Teena Mariet Mendonca, ophthalmology, Kasturba Medical College Hospital Mangalore, Mangalore, India
    01 Aug 2024
    Author Response
    Reviewer Comment:
    The authors look into an important field of drug-induced optic neuropathy in patients of tuberculosis, which is a public health concern.

    1.) The most important factor is ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 01 Aug 2024
    Teena Mariet Mendonca, ophthalmology, Kasturba Medical College Hospital Mangalore, Mangalore, India
    01 Aug 2024
    Author Response
    Reviewer Comment:
    The authors look into an important field of drug-induced optic neuropathy in patients of tuberculosis, which is a public health concern.

    1.) The most important factor is ... Continue reading

Comments on this article Comments (0)

Version 4
VERSION 4 PUBLISHED 01 Jul 2024
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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