Ocular Toxicity of Ethambutol
Ethambutol hydrochloride is one of the first line agents
employed in the treatment of tuberculosis, which remains
an important infectious disease in Hong Kong, classified
by the World Health Organization as "place with
intermediate burden and a good health infrastructure".
Being a commonly used drug, ocular toxicity of
ethambutol has been described since its first use in
treatment of tuberculosis in 1960s1,2, manifesting as optic
neuritis in affected individuals. Data regarding this
potential side effect have been published, yet much
controversy remains, especially on the issue of prevention
of ocular toxicity of ethambutol.
The article aims to give a summary of literature published
on ethambutol ocular toxicity - background, clinical
presentation, toxicity characteristics, management,
monitoring and preventive measures.
We have performed a search in MEDLINE from 1962
through 2005, using the search formula: (ethambutol OR
myambutol) AND ( eye* OR ophthal* OR ocular ) AND (
adverse OR toxic ). All relevant publications in English
A lthough uncommonly seen in patients on standard
dosage, optic neuritis is the most important potential side
effect of ethambutol hydrochloride. Retrobulbar neuritis is
most common, with involvement of either axial fibres or
less commonly, periaxial fibres. Mixed pattern is possible.
3,4 Other rarer side effects of ethambutol include peripheral
neuropathy, cutaneous reactions (rash, pruritis, urticaria
etc.), thrombocytopenia and hepatitis. 5, 6
Exact mechanism of ocular neurotoxic effect of ethambutol
is yet to be identified. Animal studies have demonstrated
ethambutol toxicity on retinal ganglion neurons in rodents.
Hypotheses for its toxicity have been made, including zinc-
chelating effect of ethambutol and its metabolite 7, 8, 9, and
excitotoxic pathway 10.
The onset of ocular symptoms is usually delayed,
occurring months after therapy initiation, though rare
cases of toxicity occurring few days after initiation have
been reported, one on standard dosage of 15mg/kg/day,
another on 25mg/kg/day.11,12 No study has reported onset
after stopping ethambutol. Clinical course can be acute or
chronic and typically, progressive.
A ffected individuals may complain of bilateral
progressive painless visual blurring. Decreased colour
perception may also be experienced. Central vision is
most commonly affected, though other visual field loss
has also been described. Some individuals may be
asymptomatic with abnormalities detected only by vision
On physical examination, both eyes are usually affected
symmetrically. Physical findings can be very variable.
Pupils may be bilaterally sluggish to light with no relative
afferent pupillary defect. V isual acuity drop varies
greatly from nil or minimal reduction to no light
perception. Central scotoma is the most common visual
field defect, but bitemporal defects13 or peripheral field
constriction have been reported. Dyschromatopsia
(abnormal colour perception) may be the earliest sign of
toxicity14, classically documented to be red-green colour
changes. In contrary, the report by Polak et al stated that
blue-yellow defects were the most common and early
defect in patients without any visual symptoms15.
However, the subtle blue-yellow defects could only be
detected using the generally unavailable desaturated
panel of Lanthony and not Ishihara charts nor
Farnsworth-Munsell D-15 test. Fundoscopic examination
is usually normal.
Characteristics of ocular toxicity of
Classically, the ocular toxicity is described as dose and
duration related, and is largely reversible on drug
discontinuation. However, the issue of reversibility is
challenged by many recent studies.
Studies gave a reported incidence of ethambutol related
retrobulbar neuritis of 18% in patients receiving
>35mg/kg/day, 5-6% with 25mg/kg/day and <1% with
15mg/kg/day of ethambutol HCL for more than two
months.3,16No "safe dosage" for ethambutol was reported17,
with toxicity observed at a dose as low as 12.3 mg/kg18. In
Hong Kong, the usual daily dosage is 15mg/kg for adults
and children, therefore, ethambutol ocular toxicity is not
commonly seen in Hong Kong. As the major excretion
pathway of ethambutol is by the kidneys, patients with
poor renal function are at higher risk of ocular toxicities.
Other factors predisposing subjects to ethambutol toxicity
include diabetes and optic neuritis related to tobacco and
alcohol. 19, 20
Manifestation of ocular toxicity is usually delayed, which
Dr. Alvin Kwok MD(HKU), MD(CUHK), FRCS(Edin), FCSHK, FCOphthHK,
?FHKAM(Ophthalmology), PDip Biostat & Epidem(CUHK), MBBS(HKU)
President, Hong Kong Ophthalmological Society
Dr. Alvin Kwok
VOL.1 1 NO.2 FEBRUARY 2006