Oral Presentation - 18th Asia Pacific Optometry Congress, Singapore

1. Visual Function in Patients on
Ethambutol Therapy for
Tuberculosis
Himal Kandel
Optometrist
himal@eyecare.com.mv
18th Asia Pacific Optometry Congress
Singapore (Nov 24-26)
1

2. Introduction
• Ethambutol toxicity in eye can occur even at the lowest
recommended dosage levels. (Melamud A et al . 2003)
• Severe visual impairment due to Ethambutol has been
reported after just three days of treatment, whilst the
longest reported interval is over 12 months. (Kumar A et al, 1993)
• Vision loss can be severe and permanent. (Rong-Kung T et al, 1997)
2

3. … … Introduction
• The incidence of Ethambutol toxicity has been reported
to vary from 0.62 % to 63% in different studies. (Polak BCP et
al, 1985; Narang RK et al, 1979)
• Ocular symptoms are usually preceded by sub clinical
color vision impairment, electrophysiological changes and
other visual function changes. (Mathur SS et al, 1981)
3

4. Rationale
• There are many unresolved issues related to
ocular toxicity of ethambutol and screening.
• International guidelines on prevention and early
detection of ethambutol-induced ocular toxicity
have been published,
– but views on the use of regular vision tests for
early toxicity detection are still divided. (Menon V et
al, 2009)
• The organ most prominently affected by
ethambutol toxicity is the eye. (Schmidt, 1966)

5. … … Rationale
 Early detection and immediate therapy
discontinuation are the only effective management
that can halt the progression of vision loss and
allow recovery of vision. (Chan RYC et al, 2003)
 In Nepal, there is a lack of proper referral for
regular eye evaluation for patients under
ethambutol therapy and patients usually visit the
eye practioners when it is too late.
 To our knowledge, no study on the effects of
ethambutol therapy in the eye has been done in
Nepal.

6. Specific Objectives
• To determine the effects of ethambutol therapy on visual
acuity.
• To determine the effects of ethambutol therapy on
contrast sensitivity.
• To determine the effects of ethambutol therapy on
colour vision.
• To study the effects of ethambutol therapy on visual
field.
• To determine the effects of ethambutol therapy in
electroretinography findings.

7. Materials and Methods
Place of study:
– BP Koirala Lions Centre for ophthalmic
Studies (BPKLCOS)
• Referred cases from DOTS Centre
TUTH
Study design : Prospective, Longitudinal,
Hospital based
Study duration : 1 Year (1st September 2009 to
30th August 2010)

8. Materials & Methods
• Complete ocular Examination was performed before and
after two months of starting of Ethambutol therapy
which includes:
– Visual acuity, Refraction, Colour vision, Fundus
examination, Slit-lamp examination, Pupil reflex
evaluation, IOP measurements, mfERG and Automated
Perimetry.

9. Inclusion Criteria
 All Clinically diagnosed cases of Primary
Tuberculosis receiving Ethambutol therapy
(Category I)

10. Exclusion Criteria
• Any other ocular and systemic diseases that may affect
the parameters being evaluated.
• Best corrected visual acuity less than 0.18 Log-MAR.
• Pre-existing colour vision defects
• Intake of any other drugs known to cause optic
neuropathy / Maculopathy
• Children below 15 years of age

11. Tools
– Assessment of Visual Acuity
• Unaided, pinhole and best corrected visual
acuity
• Bailey Lovie Log-MAR chart
– Assessment of Contrast sensitivity (CS)
• Pelli-Robson CS chart at one metre
• monocularly and binocularly.

12. – Refraction
• Objective refraction was done by using a streak
retinoscope (Heine, Beta 200).
• The final refraction was done by subjective means.
– Assessment of Colour vision
• Colour vision was tested using Farnsworth D15
test under monocular viewing conditions in the same
room under similar lighting conditions in both visits.

13. – Visual Field
• Visual field examination was done using
– Octopus –Automated Perimetry
– Anterior and posterior segment
• Slit-lamp biomicroscopy
• Fundus evaluation under mydriasis (FEUM) was
done with a 90D Volk lens and Direct
ophthalmoscopy

14. – Multifocal elctroretinography
• Multifocal elctroretinography was performed using
Roland-RETIscan system under the guidelines given by
the International Society for Clinical Electrophysiology
for Vision (ISCEV) wherever possible. (Hood DC et al 2007)
• DTL-thread electrodes (Roland Consult) were used as the
active electrodes.
• Less than 5 KΩ impedance was achieved in all cases.

15. • Data were analyzed using Statistical Package for
Social Sciences-14 (SPSS -14) software.
• Paired t test was used to compare the findings
before and after the therapy. p value less than 0.05
was considered as significant.

16. Results
• The total number of subjects included in the study
was 44 (88 eyes)
• Mean Age: 26.48 9.50 years
– Age range = (16 – 59) years

17. Age distribution
4% 16-30
14%
31-45
45-60
82%

18. Form of TB
57%
Pulmonary
43%
Extra-pulmonary

19. Visual Acuity
Mean Visual Mean Visual Acuity p value
Acuity (Before (After therapy) (Paired t test)
therapy)
0.00 ± 0.08 0.08 ± 0.18 <0.05
Log-MAR Log-MAR

20. Contrast Sensitivity
Before After p value
therapy therapy (paired t
test)
Mean contrast sensitivity – 1.83± 0.03 1.75± 0.08 <0.05
Right eye (N = 44)
Mean contrast sensitivity – 1.84± 0.03 1.75± 0.07 <0.05
Left eye (N = 44)
Mean monocular contrast 1.80 ± 0.26 1.75 ± 0.08 <0.05
sensitivity (N = 88)
Mean binocular contrast 1.96 ± 0.02 1.88 ± 0.06 <0.05
sensitivity (N = 44)

21. Anterior and Posterior Segments Findings
• Anterior and posterior segments findings were
similar pre and post therapy.
Colour Vision
• Colour vision finding was normal in every subject.

22. Visual Field Parameters
Before After P value
therapy Therapy
Mean sensitivity 28.33 ± 1.62 27.84 ± 0.485
(dB) 1.84
Mean deviation 0.90 ± 1.64 1.37 ± 1.78 0.475
(dB)
Loss variance 3.71 ± 2.40 4.88 ± 4.85 0.445
(dB2)

23. Multifocal ERG
• There was no significant change in N1 amplitudes
and N1 latencies in any of the rings after the
therapy.

24. P1 Amplitude (nv/deg2)
100
90
80
70
60
50 Before Therapy
After Therapy
40
30
20
10
Paired t
test
0 p < 0.05
Ring 1 Ring 2 Ring 3 Ring 4 Ring 5 Ring 6

25. P1 Amplitude (µV)
0.9
0.8
0.7
0.6
0.5
Before Therapy
0.4 After Therapy
0.3
0.2
0.1
Paired t
test
0
Ring 1 Ring 2 Ring 3 Ring 4 Ring 5 Ring 6 p < 0.05

26. P1 Implicit time (ms)
50
48
46
44
Before Therapy
After Therapy
42
40
38
Paired t
test
36
Ring 1 Ring 2 Ring 3 Ring 4 Ring 5 Ring 6 p < 0.05
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27. Discussion
• None of the patients developed clinical symptoms
– as reported in a prospective study done by Menon V et
al (2009).
• Subclinical toxicity was seen in the form of visual acuity
loss, contrast sensitivity loss, and reduction of P1
amplitude with increased latency of ERG waves.

28. • There are no clear risk factors for irreversible visual
damage due to the drug, but old age, renal insufficiency
and chronic smoking are said to increase the risk of
toxicity. (Menon V et al, 2009)
• None of these risk factors were found in the subjects
with the observed subclinical defects.

29. • Contrast sensitivity as measured on Pelli-Robson chart
was affected in most of the patients unlike demonstrated
earlier (Sadun AA et al, 2000).

30. Visual field defects
• The incidence of visual field defects is highly
variable among the various studies and these
were found to be central, peripheral or both.
• There was no change in visual field parameters
in this study.
• Our study supports the view given by Citron KM
(1969) that visual field test during the
treatment serves no useful purpose as it fails
to detect ocular toxicity before the symptoms
appear.

31. Multifocal ERG
 In our study, the P1 amplitude was found to be
significantly lower and and P1 latency were significantly
increased in the ethambutol treated patients compared to
their baseline data.
 The source of the multifocal ERG signals is thought to be
from the outer retina with very little contribution from
the inner retina (ganglion cell layer). (Marmor MF et al, 2003)
 Therefore, for a disease to decrease the amplitude of
the mfERG, the cone driven bipolar cells must be
abnormal.

32. Conclusions
• In our study, anterior and posterior segment findings
remained the same after ethambutol therapy.
• However, the therapy caused statistically significant
loss of visual acuity, contrast sensitivity, reduction of
b-wave ERG amplitudes and increased b-wave ERG
latencies in sub-clinical stages.
• There were no significant changes in visual field
parameters, colour vision, latencies and a-wave
amplitudes in mfERG.

33. … … Conclusion
• Our study suggests that ethambutol usage is associated
with a risk of ethambutol toxicity.
• Hence, we conclude that visual acuity, contrast
sensitivity, multifocal ERG can be important tools in
detecting early ocular toxicity.

34. Limitations
• Less sample size
• Short follow-up duration
• Eight patients lost follow-up. We might have
missed some cases with some sort of ocular
toxicity.

35. Recommendations
 All patients commencing treatment with
ethambutol should have a baseline (pre-
treatment) ocular examination along with visual
acuity, contrast sensitivity and multifocal ERG.
 Regular ophthalmological monitoring is required.
 All patients treated with ethambutol should be
educated on its side effects.

36. • Further large scale studies with longer follow-
up examinations may be required to explore the
effect of ethambutol in eye.

37. References
• Hood DC, Bach M, Brigell M, Keating D, Kondo M, Lyons JS et al. ISCEV guidelines for
clinical multifocal electroretinography. 2007 edition [cited 2011 Oct 23]; Available from
www.ISCEV.org/standards
• Kumar A, Sandramouli S, Verma L, Tewari HK, Khosla PK. Ocular ethambutol toxicity: is it
reversible? J Clin Neuroophthalmol. 1993;13:15-7.
• Marmor MF, Hood DC, Keating D, et al. Guidelines for basic multifocal
electroretinography (mffERG). Doc Ophthalmol 2003;106:105–15.
• Melamud A, Kosmorksy GS, Lee MS. Ocular ethambutol toxicity. May Clin Proc 2003;78
(11):1409-11.
• Mathur SS, Mathur GB. Ocular toxicity of Ethambutol. Ind. J. Ophthalmol 1981; 29 : 19-
21
• Menon V, Jain D, Saxena R, Sood R. Prospective evaluation of visual function for early
detection of ethambutol toxicity. Br J Ophthalmol 2009;93(9):1251-4.
• Narang RK, Varma BMD. Ocular Toxicity of Ethambutol (a clinical study). Ind J
Ophthalmol 1979; 1: 37-40.
• Polak BC, Leys M, van Lith GH. Blue-yellow colour vision changes as early symptoms of
ethambutol oculotoxicity. Ophthalmologica 1985;191:223-6.
• Rong-Kung T, Ying-Hsun L. Reversibility of ethambutol optic neuropathy. J Ocul Pharmacol
Ther. 1997 Oct;13(5):473-7.
• Sadun AA, Win PH, Ross-Cisneros FN, et al. Leber’s hereditary optic neuropathy
differentially affects smaller axons in the optic nerve. Trans. Am. Ophthalmol Soc
2000;98:223-32.
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38. Pokhara, Nepal