Delhi Journal of Ophthalmology

Visual Loss following Daily Dose Regimen of Anti Tubercular Treatment

Silni Chandra, Ranjini K. Christie Sarah Mathew
Department of Ophthalmology, Government Medical College Kozhikode, Kerala, India

Corresponding Author:

Silni Chandra
Assistant Professor, Department of Ophthalmology,
Government Medical College, Kozhikode, Kerala, India
Email: drsilni@gmail.com

Received: 08-JAN-2020

Accepted: 03-MAY-2020

Published Online: 20-DEC-2020

DOI:http://dx.doi.org/10.7869/djo.595

Abstract
This article is to report on the increasing trend of visual loss following daily regimen of Anti Tubercular treatment. Review of 15 patients who presented with varying degrees of visual loss after starting Anti Tubercular treatment was done. The patients had variable time of presentation ranging from few weeks to 3 months. Pupillary reaction was bilaterally brisk but ill sustained in 80% cases. Fundus examination showed optic disc changes only in 20% cases. Ethambutol was stopped in all cases. 46.6% patients were given systemic steroids. Patients who presented early had better visual prognosis. No treatment was found to be effective in reversing the optic neuropathy except stopping of Ethambutol. Only early diagnosis could prevent total visual loss. Till the time the causes and risk factors get better elucidated it would be prudent to have a regular Ophthalmological evaluation of all patients who are started on daily regimen of anti-tubercular treatment.

Keywords :Tuberculosis, Visual Loss, Daily Dose Regimen

Introduction
Tuberculosis, an infectious disease caused by Mycobacterium Tuberculosis has seen a resurgence since last few years. The presence of multi drug resistant Tuberculosis has also shown an upswing. In India, the diagnosis and treatment of tuberculosis is based on the Revised National Tuberculosis control program which was started in 1997, by the Government of India. Earlier all new patients received an initial intensive phase of four medications for eight weeks. It included Isoniazid, Rifampicin, Pyrazinamide and Ethambutol. It was followed by continuation phase of two medications for sixteen weeks. This was under the WHO approved DOTS Regime (Directly observed Treatment, short course). The treatment was provided for three days a week and all drugs were given separately. This regimen was later found to promote relapse and generated drug resistant strains and the relapsed cases were also found to be difficult to treat.
In 2014 RNTCP recognized the need for daily dosing and the new regimen was implemented from February 2017. Under the new daily drug regimen Patients are given fixed dose combinations (FDC) of 4 drugs according to patients’ weight, in a single pill on a daily basis. This is followed for 6-8 months. The patients are supervised by the DOTS strategy. They are given a combination of Isoniazid 5 mg/kg/day, Rifampicin 10 mg/kg/day, Ethambutol 14.5-21.4 mg/kg/day and Pyrazinamide 18.2-26.3 mg/kg/day. Maximum recommended dose of Ethambutol is 1500mg/day. Ethambutol toxicity has been identified as dose related. So patients receiving higher doses of ethambutol according to the new regimen of RNTCP should be at greater risk of developing Ethambutol induced adverse effects the most common of which is Optic neuropathy 

Methods
This study is a retrospective chart review of 15 patients who developed visual loss after treatment with the daily regimen of Anti Tubercular Treatment (ATT)for a period ranging from 1 month to 1 year. They presented to the outpatient department of Ophthalmology of Government Medical College, Kozhikode, Kerala, India between January2018 to June 2019. Details regarding the age, gender, duration of ATT taken, comorbidities, renal status, smoking or alcohol dependence, time when the visual symptoms were noticed after starting ATT were noted. Clinical features included visual acuity, anterior segment findings, pupillary reaction, color vision, visual field, fundus findings at presentation and in last follow up, visually evoked potential(VEP), treatment given, fundus picture and visual acuity at last follow up and the time period that the patient has been on follow up were noted. Only those patients whose visual symptoms developed after the initiation of daily regimen of ATT and in whom the symptoms could be attributed to the Anti tubercular treatment and had been on follow up for at least 6 months were included in the study

Results
Demographic Characteristics- The age of the patients ranged from 34 to 75 years. 8 (53%) patients were male and 7(46.6%) patients were female. All patients presented with diminution of vision bilaterally which started after 1 month to 9 months of starting daily regimen of ATT treatment. They presented to the hospital within 15 days to 3 months of onset of symptoms. 5 patients (33%) had received ATT for pulmonary tuberculosis, 7 (46.6%) patients for Potts spine, 1 (6%) patient for laryngeal tuberculosis, 1 (6%) patient for intestinal tuberculosis and 1 patient (6%) for lupus vulgaris. 7(46.6%) patients had associated diabetes mellitus and hypertension, 1 (6%) patient had peripheral vascular disease, 1 (6%) patient had a seizure disorder, 1(6%) patient had a history of cerebrovascular accident and 1 (6%) patient had a chronic kidney disease. All diabetic patients had a normal renal profile. Only 3 (20%) patients had a history of smoking and alcohol consumption for many years.

Clinical features
Visual acuity- 7(46.6%) patients had a profound loss of vision in both eyes i.e. VA <3/60.3 (20%) patients had bilateral severe visual impairment (3/60 – 6/60). 4 patients (26.6%) had asymmetric presentation with one eye having profound vision loss and the other with a vision ranging from 6/60 to 6/18. 1 patient (6%) presented with visual acuity of 6/9 and 6/18 in RE and LE respectively with no further improvement. 6 (85.7%) patients out of 7 with profound loss of vision had presented late for ophthalmological evaluation at around 3 months. Rest of the patients presented between 2 weeks to less than 3 months. 1 patient with bilateral severe visual impairment did not reveal her history of ATT intake till 3 months even though she remained on continuous follow up for her diabetic retinopathy.
Anterior segment was unremarkable in all patients except 2(13.3%) who had nuclear sclerosis grade 2. Pupillary reaction was bilaterally brisk but ill sustained in 12 (80%) patients. 3 patients (20%) had Grade 1 relative afferent pupillary defect (RAPD) in the more severely affected eye while the other eye showed a sluggish pupillary reaction.
Color vision tested using Ishihara’s color plates, was defective bilaterally in 11 (73.3%) patients while in 3(20%) patients it could not be tested due to profound loss of vision. In 1 (6%) patient there was a loss of color vision in only the severely affected eye. 
Field examination showed a hemianopic field defect in 1 (6%) patient with profound loss of vision. Rest of the patients with profound loss of vision the field examination was not possible. Field examination showed central scotoma and centrocaecal scotoma (Figure 1) with peripheral field constriction in 9 (30%) eyes of 7 patients with bilateral severe visual impairment and patients with asymmetric loss of vision. 1 (6%) with minimal loss of vision did not have any visual field defect
12 eyes of 7 patients (40%) had minimal optic disc pallor at the time of presentation, 6 (20%) eyes of 4 patients had optic disc edema and 12 (40%) eyes of 7 patients had normal optic disc at presentation. 1 (6%) patient with normal optic disc had a macular scar bilaterally at the time of presentation and had a history of poor vision since young age. 1 (6%) had moderate non proliferative diabetic retinopathy with non-center involving macular edema in both eyes
VEP was done in 10 (66.6%) patients and it showed an absence of waves bilaterally in 8 patients (80%) and low amplitude with prolonged latency in BE of 2 patients (22.2%).
Magnetic resonance imaging of the brain was carried out in 3 patients (20%) which showed small vessel disease in 2 patients and an old infarct in the midbrain in 1 patient "Demographic and clinical features are further described in (Table 1)."




Figure 1: Central & Centrocaecal Scotoma in a patient with Asymmetric visual loss due to Ethambutol induced optic neuropathy

Treatment
All patients were advised to stop Ethambutol with immediate effect after consultation with their RNTCP physician. 2(13.3 %) patients with profound loss of vision who did not show any improvement even after stopping Ethambutol for 1-2 weeks were advised to stop Isoniazid. 7 patients (46.6%) were started on systemic steroid: 2 patients (13.3%) were given pulse therapy of methyl prednisolone 1 gram intravenously for 3 days and then oral steroids on tapering schedule. 2 patients (13.3%) were given injectable steroids 2cc intravenously twice a day for 5 days and then gradually tapered and 3 patients (20%) were given oral steroids 40- 60 mg twice daily for 5 days then tapered over a week. All were given methyl cobalamine and multi vitamin tablets. 
At the last follow up at 6 months, 6(20%) eyes of 4 patients with optic disc edema went into secondary optic atrophy, 10(33.3%) eyes of 6 patients with normal optic disc continued to have a similar fundus picture at last follow up at 6 months 2 eyes (6%)of a single patient with normal disc at presentation developed temporal disc pallor. 12 (40%) eyes of 7 patients had persistent or worsened temporal pallor at the time of last follow up.
Only 8 (26.6%) eyes of 4 patients showed any improvement of vision. 2 eyes of single patient with profound loss of vision bilaterally showed an objective improvement in vision from no perception of light (No PL) to 6/12 in BE. 4 eyes of 2 patients with bilateral severe visual impairment showed improvement from 3/60 in RE and 5/60 in LE to 6/60 and 6/36 in RE and LE respectively in 6 months. One patient with asymmetric visual loss showed improvement in vision from 6/60 to 6/12 in right eye and while in left eye there was only a marginal improvement from CFCF to 2/60. 
6 (20%) eyes of 3 patients showed deterioration of vision even after stopping ethambutol. 14 (46.6%) eyes of 7 patients showed stabilization of vision after stopping Ethambutol.

Discussion 
Ethambutol induced optic neuropathy is a well-recognized adverse effect which is dose and duration related.1 Prompt recognition of symptoms of diminution of vision could help in drastically reversing the optic neuropathy in 6.6% patients and marginally reversing it in 20% patients but rest of the patients did not show any improvement .The studies in the past have shown variability in the percentages of patients regaining their vision after stopping Ethambutol. This variability could be due to the difference in the follow up period of these patients apart from many known and unknown factors.2,3
The patients who recovered their vision came within 2 weeks to 1 month of their onset of visual symptoms.4 All patients who reported late after their visual symptoms started did not benefit by stopping of Ethambutol. 13.3 % of patients were also advised to stop Isonazid when stopping of Ethambutol was not found to be effective after 2-3 weeks. These patients did not show any improvement but further loss of vision could be prevented. 
In the patients who recovered their visual acuity 50% patients had no comorbidities while 50% were diabetic with normal renal functions.3 6% patients had chronic kidney disease and did not recover any vision even after cessation of Ethambutol. Renal disease has been a known risk factor for development of optic neuropathy following ATT. There were 46.6% diabetic patients and hypertensive patients all of whom had normal renal profile at the time of presentation and during follow up too. Patients with altered renal status require more frequent follow up with their ophthalmologists as the risk of Ethambutol induced optic neuropathy is found to be more in patients with reduced glomerular filtration rate since ethambutol is mainly excreted through kidney.2
None of these patients who recovered their vision had any history of smoking or alcohol consumption. Only 20% of patients in this group had history of smoking and alcohol intake. All of them maintained their visual acuity following stoppage of Ethambutol.
Among the patients who recovered vision 12.5% eyes had unilateral optic disc edema 50% eyes had a normal fundus at presentation while 37.5% eyes had a mild temporal pallor. This was in contrast to the findings in previous studies in which presence of optic disc pallor was a poor prognostic indicator. 
Only 25% patients among those who recovered vision were given systemic steroid intravenously which was gradually tapered while the other patients were given oral multivitamin and methycobalamine. Systemic steroids either orally or intravenously or as pulse therapy were given to 46.6% patients but only 14.2% patients out of these recovered some vision. Though Ethambutol induced optic neuropathy is supposed to be reversible but it was not found to be reversible in the majority of the patients in this group. 20% showed progression of visual loss even after stopping ethambutol. 
Creating awareness among patients and Ophthalmologists is the need of the hour since patients may not associate visual loss to the anti-tubercular treatment and thus may fail to inform the ophthalmologist regarding their ATT.5 This may result in unnecessary investigations and lead to loss of valuable time. 
This study has a few limitations. The number of patients has been very few to fully understand the risk factors, causes and treatment of ethambutol induced optic neuropathy. The role of Isoniazid has not been investigated. The relationship between the cumulative dose of Ethambutol, the weight of the individual and the severity of the visual loss has not been studied. The role of contrast sensitivity in early diagnosis of optic neuropathy has not been looked into.4 The follow up period is also a limiting factor in the study. The present daily dose regimen does not include tablet pyridoxine tablet which was earlier included in the regimen. Whether this had any role to play in the development of visual loss needs to be investigated.

Conclusions
Adverse drug reactions to ATT has seen an increase following the daily regimen of Anti Tubercular treatment. This calls for a more rigid regimen of ophthalmological evaluation and follow up for all patients who are started on this new regimen. This would help in early detection of drug induced optic neuropathy and other adverse drug reactions which may help in saving the vision of the patient before irreversible damage has happened. This article is a small step in this direction to create awareness among all ophthalmologists regarding this drug induced optic neuropathy following daily regimen of anti-tubercular treatment.

References
  1.  Lee J-Y, Choi JH, Park K-A, Oh SY. Ganglion Cell Layer and Inner Plexiform Layer as Predictors of Vision Recovery in Ethambutol-Induced Optic Neuropathy: A Longitudinal OCT Analysis. Invest Ophthalmol Vis Sci [Internet]. 2018 Apr 1 [cited 2020 Apr 26];59(5):2104–9. Available from: https://iovs.arvojournals.org/article.aspx?articleid=2679335
  2. Lee EJ, Kim S-J, Choung HK, Kim JH, Yu YS. Incidence and Clinical Features of Ethambutol-Induced Optic Neuropathy in Korea. J Neuroophthalmol [Internet]. 2008 Dec [cited 2020 Jan 8];28(4):269. Available from: https://journals.lww.com/jneuro-ophthalmology/fulltext/2008/12000/Incidence_and_Clinical_Features_of.2.aspx
  3. Chen S-C, Lin M-C, Sheu S-J. Incidence and prognostic factor of ethambutol-related optic neuropathy: 10-year experience in southern Taiwan. Kaohsiung J Med Sci [Internet]. 2015 [cited 2020 Apr 26];31(7):358–62. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1016/j.kjms.2015.05.004
  4. Jin KW, Lee JY, Rhiu S, Choi DG. Longitudinal evaluation of visual function and structure for detection of subclinical Ethambutol-induced optic neuropathy. PLoS ONE [Internet]. 2019 Apr 17 [cited 2020 Apr 26];14(4). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469811/
  5. Mehta S. Patterns of Ethambutol Ocular Toxicity in Extended Use Therapy. Cureus [Internet]. [cited 2020 Apr 26];11(4). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559692/

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Chandra S, Mathew RKCSVisual Loss following Daily Dose Regimen of Anti Tubercular Treatment.DJO 2020;31:71-74

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Chandra S, Mathew RKCSVisual Loss following Daily Dose Regimen of Anti Tubercular Treatment.DJO [serial online] 2020[cited 2021 Jan 27];31:71-74. Available from: http://www.djo.org.in/articles/31/2/Visual-Loss-following-Daily-Dose-Regimen-of-Anti-Tubercular-Treatment.html