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1
Dr R P Centre for Ophthalmic
Sciences, AIIMS, New Delhi,
India; 2 Department of Medicine,
AIIMS, New Delhi, India
Correspondence to:
Dr R Saxena, Squint and Neuro-
Ophthalmology Section, Dr R P
Centre for Ophthalmic Sciences,
All India Institute for Medical
Sciences, New Delhi-110029,
India; rohitsaxena80@yahoo.
com
Accepted 7 May 2009
Published Online First
11 June 2009
Br J Ophthalmol 2009;93:1251–1254. doi:10.1136/bjo.2008.148502
Prospective evaluation of visual function for early
detection of ethambutol toxicity
V Menon,1 D Jain,1 R Saxena,1 R Sood2
ABSTRACT
Aim: The aim of the study was to evaluate various visual
parameters for early detection of ethambutol toxicity.
Method: This was a prospective study of 104 eyes of 52
patients being treated with ethambutol in the Directly
Observed Treatment Strategy Centre (Dr R P Centre for
Opthalmic Sciences, New Delhi, India). Visual acuity,
visual fields, visual evoked responses (VER), stereoacuity
and retinal nerve fibre layer (RNFL) thickness on optical
coherence tomography (OCT) were assessed.
Examinations were done before the start of therapy, after
1 and 2 months of treatment, and 1 month after stopping
ethambutol.
Results: No visual functional defect was noted at baseline.
On follow-up, visual acuity, colour vision, contrast
sensitivity, fundus and stereoacuity were not affected in
any patient. Visual field defects developed in 7.69% (8/104)
of the eyes. Pattern-VER showed an increased mean
latency of the P100 wave after 1 and 2 months of therapy
(p,0.001 for both) with 14.42% (15/104) of eyes showing
more than 10 ms increase in latency. On OCT, significant
loss of mean temporal RNFL thickness was detected in
2.88% (3/104) of eyes individually. Overall, 19.23% (20/
104) of the studied eyes showed sub-clinical toxicity.
Reversal of this observed toxicity on pattern-VER and visual
fields was seen in 80% of eyes after 1 month of stoppage
of ethambutol; however, mean VER latency remained
delayed (p = 0.002).
Conclusion: Pattern-VER and visual field examinations
are sensitive tests to detect early toxicity. Together with
OCT, they may help to identify patients who are likely to
develop clinical toxicity.
Ethambutol hydrochloride is one of the first-line
drugs employed in the treatment of tuberculosis.
The drug is well tolerated, except for its potential
to cause toxic optic neuropathy. The cause of this
ocular toxicity is uncertain. The reported incidence
of the toxicity varies widely in different studies,
ranging from 0.5% to more than 35%.1–3 The
toxicity is dose-related, and the incidence varies
from 18% in patients receiving more than 35
mg/kg per day, 5–6% with 25 mg/kg per day, to
less than 1% with 15 mg/kg per day of the drug
when taken for at least 2 months.4 The toxicity is
considered reversible on discontinuation of the
therapy, although this remains controversial.5–7
There are also several reports of permanent visual
damage due to ethambutol.8 9 Permanent visual
impairment has been reported within a follow-up
period ranging from 6 months to 3 years after
discontinuation of the drug.5 6
Reversibility of the toxicity depends on early
detection. Visual acuity, colour vision and visual
fields, which are the usual tests recommended to
Clinical science
evaluate ocular effects, may not detect cases of
early and subclinical toxicity. Therefore, other
visual parameters, such as contrast sensitivity,
visual evoked responses (VER) and so on might
be used to detect early toxicity.1 10 This study
evaluated the role of various modalities for early
detection of ethambutol optic nerve toxicity.
METHODS
This was a prospective study of 52 consecutive
patients with tuberculosis (104 eyes) treated with
anti-tubercular therapy, which included ethambu-
tol given at a dose of 15–20 mg/kg per day for
2 months. The other drugs in the treatment
regimen included isoniazid, rifampicin and pyrazi-
namide. Patients were recruited from the Directly
Observed Treatment Strategy (DOTS) Centre (Dr
R P Centre for Opthalmic Sciences, New Delhi,
India) and outpatient department of our hospital.
The patients had to take the drugs from a single
source, the DOTS centre, which provided free anti-
tubercular drugs under the revised National
Tuberculosis Control Programme of the
Government of India. The patients took the
medicines in front of the DOTS centre personnel,
which ensured 100% compliance with the therapy.
All the patients were examined at our centre.
The exclusion criterion were:
c Presence of any other disease causing optic
neuropathy.
c Intake of any other drug known to cause optic
neuropathy except the first-line anti-tubercular
drugs.
c Ocular/central nervous system tuberculosis.
c Any ocular disease affecting the parameters
that were being evaluated.
c Pre-existing colour vision defects.
Patient evaluation
A detailed clinical history was taken, including the
history of present illness, occupation and history of
smoking. A complete general physical and systemic
examination was carried out. A thorough ophthal-
mic examination was done, including cycloplegic
refraction, slit-lamp examination for anterior seg-
ment and pupillary reactions. Specific ophthalmic
tests were done with the appropriate spectacle
correction. Visual acuity was assessed on ETDRS
charts. Colour vision was noted using Ishihara
pseudoisochromatic plates and with the Oculus
Heidelberger anomaloscope (Oculus, Wetzlar,
Germany), as it specifically picks up red-green
defects, which are known to be more common
with ethambutol toxicity.11 Contrast sensitivity
was measured using the Pelli–Robson chart.
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Clinical science
Fundus examination was done with the direct and indirect
ophthalmoscopes to rule out ocular tuberculosis and other
ocular pathology. Intraocular pressure was measured using
Goldmann’s applanation tonometer. The Amsler’s grid chart
was used to look for any central scotoma and the Goldmann
kinetic perimeter was used to evaluate the peripheral visual
fields. Stereoacuity was measured using a standard test booklet
(The Netherlands Organization for Applied Scientific Research
(TNO)).
Pattern-reversal VER were noted on a Nicolet Bravo EP with
1015 visual stimulator and monitor (Nicolet Biomedical,
Madison, Wisconsin, USA). Monocular, whole-field stimulation
with a checkerboard pattern (reversal time of 500 ms) was used.
All the patients were tested with the same machine, from a
distance of 1 m, in standard ambient conditions.
Retinal nerve fibre layer (RNFL) thickness was assessed using
optical coherence tomography (Zeiss Optical Coherence
Tomographer, Model 3000 OCT-3; Carl Zeiss Meditec,
Dublin, California, USA). Pupils of both eyes were dilated with
tropicamide 1% eye drops. When the pupil was at least 5 mm in
diameter, OCT scans were taken using the ‘‘Fast RNFL
thickness’’ protocol of the machine. Peripapillary RNFL thick-
ness was measured in each of the four quadrants. The quadratic
and average RNFL thickness was noted for both eyes separately.
The first examination was done as a baseline just before
starting the drug. Thereafter, examinations were done each
month, concluding 1 month after stopping the ethambutol
therapy. OCT examination was done before the start of therapy
and at 1 month after stopping the drug.
Statistical analysis was performed using the Student’s t test.
A p value of ,0.05 was considered significant.
RESULTS
There were 29 men and 23 women with ages ranging from 11 to
56 years (mean age 28.1 years). Pulmonary tuberculosis was
present in 39 (75%) of patients; the remainder had extra-
pulmonary disease, including seven (13%) patients with uterine
tuberculosis, five (10%) with lymph node tuberculosis and one
(2%) with skeletal tuberculosis. None had renal tuberculosis,
known to be a risk factor for optic neuropathy.
No patient complained of diminution or blurring of vision or
any other ocular problem at any time during the study. No
change was seen in visual acuity of any of the patients on
ETDRS charts.
Colour vision and contrast sensitivity were normal in all the
patients. No change in the fundus or the intraocular pressure
was observed at any point of time during the study. Amsler’s
grid charting was normal at all the visits. Assessment of
stereoacuity with the TNO test did not show any significant
change in any of the patients.
Visual field defects were found in 7.69% (eight out of 104) of
eyes of four patients (all were bilaterally affected) in the study
at 2 months of therapy. These were in the form of peripheral
isopter contraction. No abnormality in central fields was
detected. Four eyes in three patients still demonstrated
Table 1 Pattern-visual evoked response latency (n = 104)
1 month after
Baseline 1 month 2 months stopping
Mean latency (ms) 108.75 113.52 112.98 110.51
SD 5.02 7.11 6.01 5.36
p Value ,0.001 ,0.001 0.002
1252
persistent visual field defects even after 1 month of stopping
the therapy.
Pattern-VER showed increase in the mean latency of the P100
wave component at 1 and 2 months of therapy (p,0.001 for
both) (table 1). There was marginal improvement in the mean
latency at 1 month after stoppage of the drug, but this was still
significantly increased compared with the baseline mean
(p = 0.002). No significant change was found in the mean or
individual patient’s amplitude of the VER curve at any of the
follow-up examinations.
VER latency in each individual eye at 1- and 2-month follow-
up visits and at 1 month after stopping the drug was compared
with the baseline latency of that eye. A greater than 10 ms
increase in latency was considered a significant increase in that
patient. Ten ms corresponded to 2 SD from the mean in baseline
VER latency (108.75 (SD 5.02) ms). At the 2 month visit, ten
eyes showed an increase in VER latency of 10–15 ms, while five
eyes showed an increase in latency of .15 ms. Of these 15 eyes
of 11 patients, four patients had increased latency in both of
their eyes, and seven patients had increased latency in only one
eye. In the unilaterally affected cases, the other eye also showed
an increased latency in six out of seven cases, but this increase
was not significant (ie ,10 ms).
VER examination 1 month after stopping the drug showed
that out of the 15 eyes that had increased latency on previous
examination, 12 had recovered the latency to within 10 ms of
their baseline values. Of the remaining three eyes, one of them
still had significantly increased latency (delay of 14 ms) and two
eyes had very significant increase (ie .15 ms).
The mean of average and quadratic RNFL thickness at
1 month after stopping ethambutol were compared with the
baseline mean (table 2). No significant change in average
thickness was seen. RNFL thickness in the temporal quadrant
was significantly lower at 1 month follow-up compared with
baseline (p = 0.011), while no significant change was observed
in the superior, inferior and nasal quadrants.
OCT values of RNFL thickness in each eye were compared
with the baseline value of that eye; a .20 mm decrease in the
thickness was taken as significant. A thickness of 20 mm
corresponded to a 2 SD difference from the mean of average
thickness at baseline. Three eyes (2.88% of 104) of two patients
showed significant decrease (.20 mm decrease in OCT values)
in temporal quadrant RNFL thickness, while the same was not
observed in the other quadrants or in the average thickness in
any of the eyes. Visual function in all these three eyes was also
affected at 1 month after stopping ethambutol, with all three
eyes demonstrating increase in latency on VER (.10 ms
increase) and residual visual field defects.
In our study, no patient complained of any clinical
symptoms, which is an incidence of 0% to ,2%. Subclinical
toxicity was found in 19.23% (20/104) of the total eyes. This
toxicity has been detected in the form of increased latency of
pattern-VER, peripheral defects on visual field examination and
decreased temporal RNFL thickness.
Reversal of the observed subclinical defects was seen in 80%
of eyes after 1 month of stoppage of the drug.
DISCUSSION
The incidence of toxicity is variably reported in literature and it
appears to be ,1% at the presently used dose of 15–20 mg/kg
per day. In our study none of the patients developed clinical
symptoms, which is an incidence of 0 to ,2%. Subclinical
toxicity was seen in 19.23% of the total eyes, which was in the
Br J Ophthalmol 2009;93:1251–1254. doi:10.1136/bjo.2008.148502
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Clinical science

Table 2 Retinal nerve fibre layer thickness on optical coherence tomography (n = 104)
Average Superior Nasal Inferior Temporal
Base After Base After Base After Base After Base After
line stopping line stopping line stopping line stopping line stopping

Mean (mm) 97.23 96.93 126. 36 123.87 72.50 75.13 125.34 124.86 63.49 60.17
SD 9.63 9.37 17.03 16.14 16.67 19.31 17.63 18.04 11.14 9.25
p Value 0.548 0.061 0.082 0.564 0.021

form of delayed latency of pattern-VER, peripheral defects on
visual field examination and temporal RNFL thickness loss.
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. None of these
risk factors were found in the patients with the observed
subclinical defects.
All the patients recruited obtained the drug from a single
source, the DOTS Centre, which provides free anti-tubercular
drugs under the revised National Tuberculosis Control
Programme of the Government of India. This ensured that the
drug given to all the patients was of the same potency, thereby
avoiding the manufacturer-related bias. As per the DOTS
requirement, all the patients had to take the medicines in front
of the DOTS Centre personnel, which ensured 100% compli-
ance with the therapy.
Contrast sensitivity as measured on Pelli–Robson chart was
not affected in any of the patients, as has been demonstrated
earlier.3 Arden plates are affected by the ambient lighting
conditions, are observer-dependent and are also known to show
a high false-positive rate.12 The Pelli–Robson chart on other
hand is relatively unaffected by the ambient lighting conditions,
and also has high test–retest reliability.13
The incidence of visual field defects is highly variable among
the various studies and these were found to be central,
peripheral or both. In general, visual field defects tend to appear
with the use of higher dosage of the drug especially in cases with
obvious visual deficit.8 10 Visual field defects in our study were in
the form of peripheral isopter contraction and point defects. No
central field defects was detected.
Though VER is an objective tool for assessing optic nerve
function, there are very few reports of its use for early detection
of ethambutol-induced optic neuropathy with inconsistent
results. The most important finding in these studies was the
increased latency of the pattern-VER curve, although with
extremely variable incidence (0% to 42.8%).1 14 15 The results of
our study have shown an increase in latency in 14.4% of total
eyes with 2 months of therapy with reversal of the VER
findings in 80% of eyes after 1 month of stoppage of the drug.
In general, visual functional defects with ethambutol are
considered to be reversible in most of the cases as seen in our
study. Recovery may occur as late as 1 year after discontinua-
tion of ethambutol, although numerous reports of permanent
visual damage have been reported.2 6 8 9 Although the exact
mechanism of this ocular neurotoxic effect is largely unknown,
animal studies have shown ethambutol toxicity in the retinal
ganglion neurons of rodents.16 The peripapillary RNFL thickness
was assessed using OCT, which is a direct measure the
peripapillary RNFL thickness.17 Although the average thickness
of the four quadrants has not changed significantly, a significant
decrease in the mean peripapillary RNFL thickness in the
temporal quadrant was noted while no change was observed in
any of the other quadrants. On individual comparison of RNFL
thickness of each eye, 2.88% (three out of 104) of total eyes have
been found to have a significant RNFL thickness loss in the
temporal quadrant.
Recent studies on RNFL thickness on OCT in diagnosed cases
of ethambutol-induced optic neuropathy have observed sig-
nificant RNFL thickness loss in almost all the quadrants with
maximum involvement of the temporal quadrant.18 19 Moreover,
the amount of RNFL thickness-loss correlated with the severity
of clinically measured visual function deficit.18 In our study,
although only subclinical involvement was observed, significant
RNFL changes were seen only in the temporal quadrant. The
anatomical changes on OCT coincided with visual functional
defect and delayed conduction on VER, suggesting that these
findings were not just by chance. Our study suggests that the
macular fibres may be most sensitive to toxic damage and may
be the only long-term visible sign of a toxic insult. This appears
to be in agreement with the previous studies that have also
suggested that ethambutol has predilection for smaller papillo-
macular bundle, similar to other mitochondrial optic neuropa-
thies.3 Although none of the cases demonstrated classical central
visual field defects, it could be due to the early detection of these
cases. Intake of the drug over a longer time could result in
greater damage to the papillomacular bundle and present as
visual field defects.
From our study we recommend that apart from visual acuity,
colour vision, visual fields and contrast sensitivity, VER and
OCT should be added as important tools in detecting early
ethambutol toxicity. This is particularly important when
dosages .15–20 mg/kg per day are used or when ethambutol
is used for periods longer than 2 months.
Competing interests: The authors have no financial interest in the findings of the
paper. None declared.
Ethics approval: Obtained.
Patient consent: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed.
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1254 Br J Ophthalmol 2009;93:1251–1254. doi:10.1136/bjo.2008.148502

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Prospective evaluation of visual function for

early detection of ethambutol toxicity
V Menon, D Jain, R Saxena and R Sood

Br J Ophthalmol 2009 93: 1251-1254 originally published online June 11,

2009
doi: 10.1136/bjo.2008.148502

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