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Year : 2016 | Volume : 4 | Issue : 2 | Page : 89 - 92  


Original Articles
A Prospective evaluation of visual function for early detection of ethambutol toxicity

Raghu V1, Rajender M2, Kiran Beesam3, Nithin Reddy4

1 Professor & HOD, Department of Ophthalmology, Chalmeda Anand Rao Institute of Medical Sciences, Karimnagar

2 Professor & HOD, Department of Pulmonary Medicine, Chalmeda Anand Rao Institute of Medical Sciences, Karimnagar

3 Postgraduate, Department of Ophthalmology, Chalmeda Anand Rao Institute of Medical Sciences, Karimnagar

4 Postgraduate, Department of Pulmonary Medicine, Chalmeda Anand Rao Institute of Medical Sciences, Karimnagar

Corresponding Author:

Dr. Raghu V

Email: veladandaraghu@gmail.com

 

Abstract:

Background and objectives: India is among the largest countries to implement the RNTCP. This program provides intermittent regimens to the patients, where doses of isoniazide and ethambutol are more as compare to the daily regimen. The present study was undertaken to explore the early detection of ethambutol toxicity in the patients registered under this program.

Methods: This was a prospective study of 180 eyes of 90 patients being with ethambutol in the Directly observed Treatment Strategy Centre (Chalmeda Anand Rao Institute Of Medical Sciences, Karimnagar, Telangana, India).In this study visual acuity, colour vision, fundus changes and visual fields were assessed. Examinations were done before the start of therapy, after 1 month and 2 months of treatment and 1 month after stopping ethambutol.

Results: No visual functional defect was noted at baseline. On follow up, following changes were observed, decrease visual acuity seen in 10% (18/180) of the eyes (p=0.02). Color vision 12.2% (22/180)of the eyes(p=0.049),among them 6 eyes developed defect in Red-Green color perception and 16 eyes developed defect in Blue-yellow colour perception. Fundus changes were seen in 6.1% (11/180) of the eyes (p=0.032). Visual field defects developed in 5.5% (10/180) of the eyes (p=0.047). Patients with ocular symptoms were advised to stop ethambutol and they showed improvement in visual acuity and colour vision after follow up of one to two months.

Conclusion: Visual acuity, color vision, fundus changes and visual field examinations are sensitive tests to detect early toxicity. The early recognition of ocular symptoms is important to prevent delay in diagnosis and probable irreversible visual loss.

Key words: Ethambutol toxicity, visual acuity, color vision, visual field

INTRODUCTION:

 

India is among the countries that carry highest burden for TB. To control this problem a revised National Tuberculosis Control Programme (RNTCP) has been implemented. Under this program patients receive intermittent treatment under supervision, thrice weekly. Ethambutol is a bacteriostatic drug developed in 1960 since then toxic neuritis may be reversible or irreversible and axial or peri-axial has been reported 1,2,3,4. Ethambutol can cause decreased visual acuity, impairment of color vision and development of visual field defects depending on dose and duration of treatment. Due to limited medical literature regarding early recognition of ethambutol related ocular symptoms given as in intermittent therapy under RNTCP, this study was planned.

MATERIAL AND METHODS

 

Study design:

Registered RNTCP DOTS centre Prospective single centre cohort study of category 1 patients between Aug 2014 to JULY 2015.

Setting:

Study was done at the department of ophthalmology with the help of pulmonary medicine at the Chalmeda Anand Rao Institute of Medical Sciences, a tertiary care referral hospital and a teaching medical institution, after approval from the institutional ethics committee.

Patient selection:

All patients of category 1 coming to the RNTCP DOTS centre, after their informed consent, are selected for study. Category 1 regimen is followed as 2 months of intensive phase with rifampicin (450 mg), isoniazid (600 mg), ethambutol (1200 mg), pyrazinamide (1500 mg), thrice weekly, followed by continuation phase with rifampicin and isoniazid of the same dose for 4 months.

Exclusion criteria:

Patients with systemic diseases like

  1. Diabetes
  2. Hypertension
  3. Renal failure
  4. Addictions

Ocular diseases like

  1. Diabetic retinopathy
  2. Sickle cell retinopathy
  3. Retinitis pigmentosa
  4. Previous retinal detachment
  5. Optic neuropathies
  6. Optic atrophy
  7. Cataract

Patients using medications like

  1. Digoxin
  2. OCP’s

All above patients were excluded from this study.

Clinical evaluation of patients:

It consists of detailed history, best corrected visual acuity by Snellen’s chart, color vision by Ichihara chart and Farnsworth panel D -15 hue test, anterior segment by slit lamp, fundus examination, visual fields by Humphrey field analyzer with C-30-2 threshold program.

All patients were examined before the start of ATT and after 1st and 2nd month of treatment. Decreased visual acuity is considered if there is difference more than two Snellen’s chart lines between before starting medication and 2 months after starting medication. Color vision assessment was done by using Ichihara color vision plates and Fransworth panel D-15 and they were tested binocularly with best correction. If a participant read nine or less than nine plates correctly his/her color vision was regarded as being deficit. The FD -15 test was done using color vision recorder software, version 4. In this, participant was offered a series of colors that needed to be sorted either in a sequence or in groups. The final diagnosis consists of either pass or fail, which was set by software.

RESULTS

 

There were 94 patients in that 4 patients lost their follow up after 1st month. 90 patients completed the prescribed number of follow ups, in that 59 were males, 31 were females of age of 10-60 years with a mean of 33.5+/-14.44 years. At the base line, visual acuity ranged from 6/6 to 6/60. Decreased visual acuity is seen in 18 eyes, 10 eyes after one month and 8 eyes after 2 months. On using chi-square test, there was statistically significant difference in visual acuity at the second month after the start of therapy (0.025).

Table.1. characteristics of the study subjects

Total no. of patients

90

Males

59

Females

31

Mean age

33.5+/-14.4

Total no . of eyes

180

 

Color vision abnormalities were noted in 22 eyes of 11 patients, 6 eyes showed impairment in red color perception and the others showed impairment in blue yellow perception. All abnormalities were noted by Fransworth panel D-15 test. This difference of color vision statistically significant (p=0.0489). Optic disc changes were noted in 11 eyes. All 11 eyes had temporal pallor only, these changes were statistically significant after two months of therapy (p= 0.0320). Visual field defects were seen in 10 eyes, 2 patients showed centrocaecalscotoma and others showed peripheral constriction on the Humphrey visual field. Visual field defect noted after 2 months showed the significance of 0.0479. patients who had ocular symptoms, they were advised to stop ethambutol and all showed improvement.

Table 2: Ophthalmological examination during follow up distributed category wise

Parameter examined

N=180

After 1st month

After 2nd month

Total

N(%)

P value

Visual acuity

10

8

18(10)

.0256

Color vision

14

8

22(12.22)

.0499

Fundus changes

2

9

11(6.1)

.0320

Visual field defects

3

7

10(5.5)

.0479

 Figure 1: Fundus picture showing temporal pallor

 

 

Figure 2: Humphrey visual field shows peripheral constriction of visual field

DISCUSSION

 

Ethambutol is being used to treat tuberculosis since the 1960s.The potential for visual impairment was recognized soon after its introduction. Ocular toxicity due to ethambutol usually develops after 2 months of therapy5 and is mainly related to dose 6 and duration, is also evident in this study. The dose related toxicity of this drug has been reported by LIEBOLDAND5 and BOBROWITZ6, it was 18% at 35 mg/kg body weight/day, 5% among patients on 25 mg/kg body weight/day, 3 % among those on 20/mg/kg/day, while very mild toxicity was seen with 15 mg/kg/day. In this present study patients received > 20 mg/kg body weight/day. Krishnaswamy 7 and mittal 8 et al did not find any case of retro-bulbar in their series, while Roy 9 et al and Sharma 10 et al found 3% toxicity in cases using 25 mg/kg/day of ethambutol. On the other hand Narang and Verma 11 in their study of 640 cases treated by ethambutol of 25 mg/kg/day of the drug, along with a companion drug came across only four cases, among which retrobulbar neuritis developed during six to eight months of therapy. Retrobulabar neuritis was reversible in all four cases after two to four months of withdrawal of the drug, as was seen in our case, and also where improvement, both in terms of visual acuity and fundus changes, was seen as early as one month of withdrawal of the drug.

A study by MENON et al 12 done on patients treated with ethambutol under DOTS , showed no effect on visual acuity, color vision , fundus of any patients but visual field defects were seen in 7.69 % of eyes, with increased latency of the P wave in pattern VER after one and two months of therapy. In recent times KANDEL et 13 revealed a statistically significant change in the visual acuity as similar to this study.

The limitations of this study could be the ocular toxicity contributed by Isoniazid, as revealed by a study by sahin et al which was not taken in this study 14.

However, this recent study has been performed on an animal model and needs further evaluation in humans before its results can be recommended for the same.

CONCLUSION:

 

This study on the evaluation of visual functions in patients receiving DOTS therapy developed ocular toxicity related to dose and duration. Reversal of these toxic effects also seen if the drug was stopped. So thus early diagnosis using sensitive indicator like visual acuity, color vision, visual field changes is necessary and helpful in preventing irreversible visual loss. Based on this study routine ophthalmic examination in patients receiving ethambutol medication is advised and educate the patient about the ocular symptoms like blurring of vision, abnormalities of colour vision and scotoma in the visual fields.

REFERENCES:

 

  1. World Health Organization. Ethambutol efficacy and toxicity: Literature Review and recommendations for daily and intermittent dosage in children. Geneva: World Health Organization
  2. Inocencio FP, Castillo TR. Toxic optic neuropathy secondary to ethambutol. Philipp J Ophthalmol 1999;24:65-8
  3. Adel A. Ophthalmological side effects of ethambutol.Scand J Respir Dis Suppl 1969;69:55- 8.
  4. Schild HS, Fox BC. Rapid onset reversible ocular toxicity from ethambutol therapy. Am J Med 1991;90:404-6.
  5. Bobrowitz ID. Ethambutol in the re-treatment of pulmonary tuberculosis. Ann N Y AcadSci 1966;135:796-822.
  6. Leibold JE. The ocular toxicity of ethambutol and its relation to dose. Ann N Y AcadSci 1966;135:904-9.
  7. Krishnaswamy KV. Proceedings 24th National Cong. Tubercle and Chest Dis. Trivandrum: 1969. p. 254.
  8. Mittal OP, Narang RK, Sachan AS. Ethambutol in retreatment of pulmonary tuberculosis. Indian J Tuberc 1975;22:142-6.
  9. Roy DC, Sen PC, Bajpai BK. Ethambutol in the re-treatment of multi drug resistant advanced pulmonary tuberculosis (salvage cases). Indian J Chest Dis 1974;16:153-62.
  10. Sharma GS, Purohit SD, Lodha SC. Comparative study of isoniazid and ethambutol with isoniazid ethambutol and pyrazinamide in the re-treatment of pulmonary tuberculosis. Ind Med Gaz 1975;15:140.
  11. Narang RK, Varma BM. Occular toxicity of ethambutol (a clinical study). Indian J Ophthalmol 1979;27:37-40.
  12. Menon V, Jain D, Saxena R, Sood R. Prospective evaluation of visual function for early detection of ethambutol toxicity. Br J Ophthalmol 2009;93:1251-4.
  13. Kandel H, Adhikari P, Shrestha GS, Ruokonen EL, Shah DN. Visual function in patients on ethambutol therapy for tuberculosis. J Ocul PharmacolTher 2012;28:174-8.




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