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Visual Function in Patients on Ethambutol Therapy for

Tuberculosis

Himal Kandel Optometrist

himal@eyecare.com.mv18th Asia Pacific Optometry Congress

Singapore (Nov 24-26)

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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)

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… … 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)

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)

… … RationaleEarly 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.

• 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.

Specific Objectives

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)

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.

Inclusion Criteria

All Clinically diagnosed cases of Primary Tuberculosis receiving Ethambutol therapy (Category I)

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

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.

– 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.

– 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

– 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.

• 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.

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

Age distribution

82%

14% 5%

16-30

31-45

45-60

Form of TB

57%

43%

Pulmonary

Extra-pulmonary

Visual Acuity

Mean Visual Acuity (Before

therapy)

Mean Visual Acuity (After therapy)

p value(Paired t test)

0.00 ± 0.08 Log-MAR

0.08 ± 0.18 Log-MAR

<0.05

Contrast Sensitivity

Before therapy

After therapy

p value(paired t

test)Mean contrast sensitivity – Right eye (N = 44)

1.83± 0.03 1.75± 0.08 <0.05

Mean contrast sensitivity – Left eye (N = 44)

1.84± 0.03 1.75± 0.07 <0.05

Mean monocular contrast sensitivity (N = 88)

1.80 ± 0.26 1.75 ± 0.08 <0.05

Mean binocular contrast sensitivity (N = 44)

1.96 ± 0.02 1.88 ± 0.06 <0.05

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.

Visual Field Parameters

Before therapy

After Therapy

P value

Mean sensitivity (dB)

28.33 ± 1.62 27.84 ± 1.84

0.485

Mean deviation (dB)

0.90 ± 1.64 1.37 ± 1.78 0.475

Loss variance (dB2)

3.71 ± 2.40 4.88 ± 4.85 0.445

Multifocal ERG

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

P1 Amplitude (nv/deg2)

Ring 1 Ring 2 Ring 3 Ring 4 Ring 5 Ring 60

10

20

30

40

50

60

70

80

90

100

Before TherapyAfter Therapy

Paired t testp < 0.05

P1 Amplitude (µV)

Ring 1 Ring 2 Ring 3 Ring 4 Ring 5 Ring 60

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Before TherapyAfter Therapy

Paired t testp < 0.05

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P1 Implicit time (ms)

Ring 1 Ring 2 Ring 3 Ring 4 Ring 5 Ring 636

38

40

42

44

46

48

50

Before TherapyAfter Therapy

Paired t testp < 0.05

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.

• 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.

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

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.

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.

• 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.

Conclusions

• 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.

… … Conclusion

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.

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.

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

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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.

Thank You !

Pokhara, Nepal