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Fundus examination was done with the direct and indirect persistent visual field defects even after 1 month of stopping
ophthalmoscopes to rule out ocular tuberculosis and other the therapy.
ocular pathology. Intraocular pressure was measured using Pattern-VER showed increase in the mean latency of the P100
Goldmann’s applanation tonometer. The Amsler’s grid chart wave component at 1 and 2 months of therapy (p,0.001 for
was used to look for any central scotoma and the Goldmann both) (table 1). There was marginal improvement in the mean
kinetic perimeter was used to evaluate the peripheral visual latency at 1 month after stoppage of the drug, but this was still
fields. Stereoacuity was measured using a standard test booklet significantly increased compared with the baseline mean
(The Netherlands Organization for Applied Scientific Research (p = 0.002). No significant change was found in the mean or
(TNO)). individual patient’s amplitude of the VER curve at any of the
Pattern-reversal VER were noted on a Nicolet Bravo EP with follow-up examinations.
1015 visual stimulator and monitor (Nicolet Biomedical, VER latency in each individual eye at 1- and 2-month follow-
Madison, Wisconsin, USA). Monocular, whole-field stimulation up visits and at 1 month after stopping the drug was compared
with a checkerboard pattern (reversal time of 500 ms) was used. with the baseline latency of that eye. A greater than 10 ms
All the patients were tested with the same machine, from a increase in latency was considered a significant increase in that
distance of 1 m, in standard ambient conditions. patient. Ten ms corresponded to 2 SD from the mean in baseline
Retinal nerve fibre layer (RNFL) thickness was assessed using VER latency (108.75 (SD 5.02) ms). At the 2 month visit, ten
optical coherence tomography (Zeiss Optical Coherence eyes showed an increase in VER latency of 10–15 ms, while five
Tomographer, Model 3000 OCT-3; Carl Zeiss Meditec, eyes showed an increase in latency of .15 ms. Of these 15 eyes
Dublin, California, USA). Pupils of both eyes were dilated with of 11 patients, four patients had increased latency in both of
tropicamide 1% eye drops. When the pupil was at least 5 mm in their eyes, and seven patients had increased latency in only one
diameter, OCT scans were taken using the ‘‘Fast RNFL eye. In the unilaterally affected cases, the other eye also showed
thickness’’ protocol of the machine. Peripapillary RNFL thick- an increased latency in six out of seven cases, but this increase
ness was measured in each of the four quadrants. The quadratic was not significant (ie ,10 ms).
and average RNFL thickness was noted for both eyes separately. VER examination 1 month after stopping the drug showed
The first examination was done as a baseline just before that out of the 15 eyes that had increased latency on previous
starting the drug. Thereafter, examinations were done each examination, 12 had recovered the latency to within 10 ms of
month, concluding 1 month after stopping the ethambutol their baseline values. Of the remaining three eyes, one of them
therapy. OCT examination was done before the start of therapy still had significantly increased latency (delay of 14 ms) and two
and at 1 month after stopping the drug. eyes had very significant increase (ie .15 ms).
Statistical analysis was performed using the Student’s t test. The mean of average and quadratic RNFL thickness at
A p value of ,0.05 was considered significant. 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
RESULTS
was significantly lower at 1 month follow-up compared with
There were 29 men and 23 women with ages ranging from 11 to
baseline (p = 0.011), while no significant change was observed
56 years (mean age 28.1 years). Pulmonary tuberculosis was
in the superior, inferior and nasal quadrants.
present in 39 (75%) of patients; the remainder had extra-
pulmonary disease, including seven (13%) patients with uterine OCT values of RNFL thickness in each eye were compared
tuberculosis, five (10%) with lymph node tuberculosis and one with the baseline value of that eye; a .20 mm decrease in the
(2%) with skeletal tuberculosis. None had renal tuberculosis, thickness was taken as significant. A thickness of 20 mm
known to be a risk factor for optic neuropathy. corresponded to a 2 SD difference from the mean of average
No patient complained of diminution or blurring of vision or thickness at baseline. Three eyes (2.88% of 104) of two patients
any other ocular problem at any time during the study. No showed significant decrease (.20 mm decrease in OCT values)
change was seen in visual acuity of any of the patients on in temporal quadrant RNFL thickness, while the same was not
ETDRS charts. observed in the other quadrants or in the average thickness in
any of the eyes. Visual function in all these three eyes was also
Colour vision and contrast sensitivity were normal in all the
affected at 1 month after stopping ethambutol, with all three
patients. No change in the fundus or the intraocular pressure
eyes demonstrating increase in latency on VER (.10 ms
was observed at any point of time during the study. Amsler’s
grid charting was normal at all the visits. Assessment of increase) and residual visual field defects.
stereoacuity with the TNO test did not show any significant In our study, no patient complained of any clinical
change in any of the patients. symptoms, which is an incidence of 0% to ,2%. Subclinical
Visual field defects were found in 7.69% (eight out of 104) of toxicity was found in 19.23% (20/104) of the total eyes. This
eyes of four patients (all were bilaterally affected) in the study toxicity has been detected in the form of increased latency of
at 2 months of therapy. These were in the form of peripheral pattern-VER, peripheral defects on visual field examination and
isopter contraction. No abnormality in central fields was decreased temporal RNFL thickness.
detected. Four eyes in three patients still demonstrated Reversal of the observed subclinical defects was seen in 80%
of eyes after 1 month of stoppage of the drug.
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 been found to have a significant RNFL thickness loss in the
visual field examination and temporal RNFL thickness loss. temporal quadrant.
There are no clear risk factors for irreversible visual damage Recent studies on RNFL thickness on OCT in diagnosed cases
due to the drug, but old age, renal insufficiency and chronic of ethambutol-induced optic neuropathy have observed sig-
smoking are said to increase the risk of toxicity. None of these nificant RNFL thickness loss in almost all the quadrants with
risk factors were found in the patients with the observed maximum involvement of the temporal quadrant.18 19 Moreover,
subclinical defects. the amount of RNFL thickness-loss correlated with the severity
All the patients recruited obtained the drug from a single of clinically measured visual function deficit.18 In our study,
source, the DOTS Centre, which provides free anti-tubercular although only subclinical involvement was observed, significant
drugs under the revised National Tuberculosis Control RNFL changes were seen only in the temporal quadrant. The
Programme of the Government of India. This ensured that the anatomical changes on OCT coincided with visual functional
drug given to all the patients was of the same potency, thereby defect and delayed conduction on VER, suggesting that these
avoiding the manufacturer-related bias. As per the DOTS findings were not just by chance. Our study suggests that the
requirement, all the patients had to take the medicines in front macular fibres may be most sensitive to toxic damage and may
of the DOTS Centre personnel, which ensured 100% compli- be the only long-term visible sign of a toxic insult. This appears
ance with the therapy. to be in agreement with the previous studies that have also
Contrast sensitivity as measured on Pelli–Robson chart was suggested that ethambutol has predilection for smaller papillo-
not affected in any of the patients, as has been demonstrated macular bundle, similar to other mitochondrial optic neuropa-
earlier.3 Arden plates are affected by the ambient lighting thies.3 Although none of the cases demonstrated classical central
conditions, are observer-dependent and are also known to show visual field defects, it could be due to the early detection of these
a high false-positive rate.12 The Pelli–Robson chart on other cases. Intake of the drug over a longer time could result in
hand is relatively unaffected by the ambient lighting conditions, greater damage to the papillomacular bundle and present as
and also has high test–retest reliability.13 visual field defects.
The incidence of visual field defects is highly variable among From our study we recommend that apart from visual acuity,
the various studies and these were found to be central, colour vision, visual fields and contrast sensitivity, VER and
peripheral or both. In general, visual field defects tend to appear OCT should be added as important tools in detecting early
with the use of higher dosage of the drug especially in cases with ethambutol toxicity. This is particularly important when
obvious visual deficit.8 10 Visual field defects in our study were in dosages .15–20 mg/kg per day are used or when ethambutol
the form of peripheral isopter contraction and point defects. No is used for periods longer than 2 months.
central field defects was detected. Competing interests: The authors have no financial interest in the findings of the
Though VER is an objective tool for assessing optic nerve paper. None declared.
function, there are very few reports of its use for early detection Ethics approval: Obtained.
of ethambutol-induced optic neuropathy with inconsistent
Patient consent: Obtained.
results. The most important finding in these studies was the
increased latency of the pattern-VER curve, although with Provenance and peer review: Not commissioned; externally peer reviewed.
extremely variable incidence (0% to 42.8%).1 14 15 The results of
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Clinical science
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These include:
References This article cites 19 articles, 2 of which you can access for free at:
http://bjo.bmj.com/content/93/9/1251#BIBL
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Notes