Acta Ophthalmologica 2015

Review Article

Toxic optic neuropathies: an updated review

Andrzej Grzybowski,1,2 Magdalena Z€
ulsdorff,1 Helmut Wilhelm3 and Felix Tonagel3
1
Department of Ophthalmology, Pozna n City Hospital, Pozna
n, Poland
2
Departtment of Ophthalmology, University of Warmia and Mazury, Olsztyn, Poland
3
Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany

ABSTRACT. tracts. The pathophysiology of TON is

Toxic optic neuropathy (TON) is caused by the damage to the optic nerve unknown and probably different sub-
through different toxins, including drugs, metals, organic solvents, methanol and stances affect the optic nerve in differ-
carbon dioxide. A similar clinical picture may also be caused by nutritional ent ways. It is generally accepted that
deficits, including B vitamins, folic acid and proteins with sulphur-containing the common pathway, for at least some
amino acids. This review summarizes the present knowledge on disease-causing of the toxins, is mitochondrial injury
factors, clinical presentation, diagnostics and treatment in TON. It discusses in and imbalance of intracellular and
detail known and hypothesized relations between drugs, including tuberculostatic extracellular-free radical homoeostasis
drugs, antimicrobial agents, antiepileptic drugs, antiarrhythmic drugs, disulfi- (Wang & Sadun 2013). This may
explain some similarities with Leber’s
ram, halogenated hydroquinolones, antimetabolites, tamoxifen and phosphodi-
hereditary optic neuropathy (LHON).
esterase type 5 inhibitors and optic neuropathy.
It is argued that TONs are acquired
mitochondrial optic neuropathies.
Key words: adalimumab optic neuropathy – antitumor necrosis factor alpha optic neuropathy –
cuban epidemic optic neuropathy – ethambutol optic neuropathy – infliximab optic
neuropathy – Leber’s hereditary optic neuropathy – nutritional optic neuropathy – tobacco-
alcohol amblyopia – toxic optic neuropathy Examination
Acta Ophthalmol. 2015: 93: 402–410 History
ª 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Drug/toxin exposure: in a workplace
doi: 10.1111/aos.12515 (e.g. heavy metals, fumes and solvents),
ingestion of materials/food, alcohol
and use of a systemic medication;
Introduction patients, for example, both factors usu-
social history and habits (e.g. amount
ally play a synergistic role contributing
The optic nerve is susceptible to dam- to the TON. Clinical pictures of both and sort of tobacco and alcohol used),
age from toxins, including drugs, metals disorders, nutritional optic neuropathy diet (e.g. any special diets used),
(e.g. lead, mercury and thallium), (NON) and TON, are also very similar, anorexia nervosa, gastrointestinal dis-
organic solvents (ethylene glycol, tolu- and they usually cannot be differenti- ease or surgery or anaemia. Some
ene, styrene and perchloroethylene), ated based on clinical signs and symp- metabolic diseases, including diabetes
methanol, carbon dioxide and probably toms. Both disorders are rare in mellitus, kidney failure and thyroid
some sort of tobacco. This group of economically developed countries. They disease, might influence TON due to
disorders is named toxic optic neurop- are more prevalent in developing coun- the accumulation of toxins.
athy (TON) and is characterized by tries, because of people’s greater expo- A family history should also be
bilateral visual loss, papillomacular sure to toxic substances in environment taken into account to identify hints
bundle damage, central or cecocentral and food, and coexisting malnutrition. on hereditary optic nerve disorders. On
scotoma, and reduction of colour No racial, gender and age-dependent the other hand, if alcohol or drug
vision. Toxic optic neuropathy might predilections have been shown. addiction is suspected, information
be triggered or just enhanced by nutri- from family members or friends might
tional deficits, including the vitamins contribute. Review of symptoms
thiamine (B1), riboflavin (B2), niacin
Pathology should include sensory disturbances in
(B3), pyridoxine (B6), cobalamin (B12), In most of the cases of TON, the the extremities and gait problems,
folic acid and proteins with sulphur- primary lesion is not limited to the indicating toxic peripheral neuropathy
containing amino acids (Phillips 2005). optic nerve and may possibly originate and/or toxic effect upon the cerebel-
Among malnourished and intoxicated in the retina, chiasm or even the optic lum. Patients’ complaints include the

402

following: loss of visual acuity (acute
or chronic), reduced contrast percep-
tion, a blur in the centre when reading
(continuously and slowly progressing),
faded colours (particularly red) or a
general loss of colour perception. All of
aforementioned symptoms are not
accompanied by any ocular pain.
Physical Examination
The loss of visual acuity is usually
progressive, painless and bilateral. It
starts with the blur at the point of
fixation (a relative scotoma) and is
followed by a progressive decline. It
varies from minimal reduction to no
light perception (NLP) in rare cases
(e.g. methanol ingestion). Most
patients reach 20 of 200 or better.
Relative afferent pupillary defect
(RAPD) is usually not present because
the optic neuropathy is virtually always
bilateral and symmetric. Only to strong
light, the pupils often react bilaterally
with an adequate constriction, but they
usually respond normally to near stim-
ulation. Clinically, pupillary reaction
does not differ visibly from a normal
population in most cases. Dyschroma-
topsia is a typical feature that can be
tested with colour vision tests such as
Ishihara plates or, still better because
also blue deficits are included, Panel D
15 test. However, it has to be kept in
mind that at least 7% of men and 0.3%
of women have a congenital colour
vision defect. In those cases, the anom-
aloscope frequently shows typical
results, different from those seen in
acquired colour vision deficits that
cannot be assigned to a classical con-
genital colour vision disorder.
In the early stages, most patients
have normal-appearing optic discs, but
disc oedema and hyperaemia may
occur in some acute poisonings. Disc
haemorrhages may also be present.
Thereafter, papillomacular bundle loss
and optic atrophy develop, initially
visible as temporal pallor of the optic
disc.
Visual field (VF) test is of major
importance in any patient suspected of
having TON. It reveals symmetrically
central or cecocentral scotoma, ini-
tially as relative scotoma, with preser-
vation of the peripheral field. Defects
are characterized by soft margins,
which are easier to plot for coloured
targets, such as red, than for white
stimuli.
Lab studies include CBC, blood
chemistries, urinalysis and a serum
lead level; identification of a specific
toxin (such as methanol) or its metab-
olites in the patient’s tissues or fluids;
screening of the blood and urine for
other toxins if exposure to a particular
one is not identified on history (e.g.
heavy metal screening). To exclude
NON test serum B-12 (pernicious
anaemia) and red cell folate levels
(marker of general nutritional status)
need to be obtained. Other tests reveal-
ing nutritional imbalance include direct
or indirect vitamin assays, serum pro-
tein concentrations and antioxidant
levels. Serologic testing for syphilis is
recommended. Liver enzymes may
indicate alcoholism. It is advisable to
contact a legal medical and/or indus-
trial medical centre experienced with
toxicological tests.
Imaging studies include MRI of the
optic nerves, chiasm with and without
gadolinium enhancement is usually
performed to exclude a compressive
lesion, and it is normal in typical
TON. In methanol intoxication, it
may show a degeneration of the basal
ganglia.
Electrophysiological tests, including
visual-evoked potentials (VEP) and the
pattern electroretinography (PERG),
might be useful. VEP can be useful in
patients with early or subclinical optic
neuropathy, also to differentiate from
demyelinating disease. VEP usually
reveals normal or near normal latency
with significantly reduced amplitude of
P100. However, in most cases, demye-
linating disease would become visible
in MRI as well. The P50 and N95
components of PERG reflect macular
and retinal ganglion cell function,
respectively. PERG can be useful in a
patient with abnormal VEP to identify
a macular lesion. ERG or still better
multifocal ERG may be used to
exclude a retinal disease. ERG,
contrast sensitivity (CS) measurements
and retinal nerve fibre layer thickness
by OCT are also suggested to early
detect subclinical toxicity of drugs,
such as antibiotic, antimetabolite or
antituberculosis medicines in an early
stage. Diagnosis is based on the iden-
tification of a toxic factor and exclu-
sion of other pathologies giving a
similar clinical picture. Differential
diagnosis includes nutritional optic
neuropathies, LHON, dominantly
inherited optic neuropathy, compres-
Acta Ophthalmologica 2015
sive or infiltrative lesion of optic chiasm,
bilateral inflammatory or demyelinative
optic neuropathy, maculopathies/mac-
ular dystrophies, retinal degenerations
such as cone dystrophy, syphilitic optic
neuritis, Graves disease, radiation optic
neuropathy, diabetic papillopathy and
non-organic visual loss (hysteria/malin-
gering).
Toxic optic neuropathy is a diagno-
sis of exclusion. For that reason, the
procedures necessary for the diagnostic
approach could not be easily specified.
Figure 1 shows a flow chart concerning
strategies for the evaluation of bilateral
visual loss.
Treatment includes removing the
toxic substance (e.g. discontinuation
of the drug), stopping smoking or
consumption of alcohol.
Check-up examinations should be
continued initially every 4–6 weeks and
include visual acuity, colour vision,
visual field, pupil reaction and optic
disc examination.
Prognosis depends on the dosage
and duration of exposure to toxic
substance. Usually, after discontinua-
tion, vision improves to normal over
several days or weeks.
Drugs and Toxic Optic
Neuropathy
It is known that TON is dose and
duration dependent and occurs more
often with antituberculosis drugs (eth-
ambutol and isoniazid), some antimi-
crobial agents (linezolid, ciprofloxacin,
cimetidine and chloramphenicol),
antiepileptic drugs (vigabatrin), disulfi-
ram (for chronic alcoholism), haloge-
nated hydroquinolones (amebicidal
medications), antimetabolites (e.g.
methotrexate, cisplatin, carboplatin,
vincristine and cyclosporin), tamoxifen
and sildenafil. In these cases, especially
when drugs are used for longer periods
or with higher dosage, patients should
be informed about possible toxicity
and educated to report any visual
problems immediately (Lloyd &
Fraunfelder 2007; Reeks & Ang
2010). In the following, the different
drugs are described in detail. Because
of the large number of ethambutol
cases, a table is enclosed that summa-
rizes the reported cases from April
2010 to 2012 (Table 1). The published
cases for the other drugs can be seen in
Tables S1–S4.
403
Acta Ophthalmologica 2015
AQUIRED BILATERAL VISUAL LOSS
Refractive error, media opacitiy,
macular problem?
Trauma or high dose radiotherapy?
Painful eye movement?
Papilledema ?
Peripapillary telangiectasia?
Preserved pupillary light
reflex in spite of bad vision?
Family history of
unexplained visual loss?
History of cancer
Yes
Ataxia, hearing loss
diabetes
Anemia, polyneuropathy
Alcohol, smoking,
transaminases high?
Potential toxic drugs
(e.g. ethambutol)
MRI – magnetic resonance imaging; ICP – intracranial pressure; AION – anterior ischemic optic neuropathy;
LHON – Lebers’ hereditary optic neuroptahy; ADOA – autosomal dominant optic atrophy.
Fig. 1. A flow chart concerning strategies for the evaluation of bilateral visual loss.
Ethambutol
Ethambutol is used in treatment
against tuberculosis and Mycobacte-
rium avium infections. Optic nerve tox-
icity belongs to most serious adverse
effects related to ethambutol use
(Fraunfelder et al. 2006a,b; Sharma &
Sharma 2011). It occurs in up to 6% of
patients who taking the drug. The
clinical picture is similar to other toxic
optic neuropathies in general, including
early occurrence of dyschromatopsia.
Less common field defects include
peripheral constriction (Choi & Hwang
1997), altitudinal field defects, and
404
lower doses, cases of vision loss have
been reported. The exact pathophysi-
ology mechanism of ethambutol TON
is unknown. However, it was shown
that this affects not only the optic
Yes Adequate therapy
nerve but also probably other retinal
elements based upon abnormal
mfERG findings (Kardon et al. 2006).
Yes MRI Opticne uritis? The ocular toxicity is dose and
duration dependent; thus, early recog-
Raised ICP? nition of TON and prompt cessation
Basal ganglia necrosis? of the therapy is important in pre-
Yes MRI
Bilateral AION? venting further progression of vision
Amiodarone? loss. Standard methods for monitoring
ethambutol use include visual acuity
assessment, visual field testing, fun-
Family history
Yes gene analysis LHON? duscopy, colour vision testing, con-
trast sensitivity measurement, OCT
and VEP. It was shown that the use
See parents
of 3D computer-automated threshold
Yes Hereditary disease?
colour vision testing ADOA (tritan defect)? Amsler grid testing with 0.5° grid
gene analysis spacing revealed relative scotomas that
had been missed by both standard
MRI visual field testing methods and 3D-
Infitrative or paraneoplastic CTAG with 1° grid spacing (Kim
fundus auto fluorescence
disease (e.g. MAR/CAR)?
electrophysiology et al. 2008). Visual acuity and colour
vision testing are the easiest tests that
Wolfram syndrome, other can also be performed by non-oph-
Yes Gene analysis
hered. neuropathy? thalmologists, especially important in
countries where only few specialists
are available.
Yes Vitamin B12 Nutritive optic neuropathy? Cases of ethambutol-induced optic
neuropathy have been reported since
1963 (Harada 1963). A great number of
Yes Toxic mitochondrial
Stop nicotine and alcohol cases are reported in the literature. The
neuropathy?
reported cases from 2010 to April 2012
described in English-language litera-
Toxic mitochondrial ture are presented in Table 1.
Yes Stop drugs if possible
neuropathy?
Isoniazid
This is another antitubercular drug
able to evoke TON. This TON may
be associated with bilateral optic disc
swelling with concurrent bitemporal
hemianopic scotomas (Kocabay et al.
bitemporal field defects (Asayama 2006; Kulkarni et al. 2010). However,
1969; Kedar et al. 2011). the few published reports show a rather
Visual problems do usually not favourable outcome, better than in
occur during the first 2 months of ethambutol. As with other drugs,
ethambutol treatment, and they gen- patients with hepatic or renal disease
erally appear between 4 and are at higher risk.
12 months. Renal dysfunction might
shorten this period by reducing the
Methanol
excretion of the drug and increasing
its serum levels. It was proposed that Methanol is metabolized to formic
the risk of TON was higher at that acid, which is responsible for its
dosages of 25 mg/kg/day or more. In toxicity (Hayreh et al. 1977; Martin-
such a case, the dosage should be Amat et al. 1977, 1978). This origi-
reduced to 15 mg/kg/day, which is nates from a combined effect of met-
considered both relatively safe and abolic acidosis and an intrinsic
effective. However, even with much toxicity of the formiate anion itself.
 Acta Ophthalmologica 2015

Severe poisoning causes nausea, vom- 28 days. Usually, it is well tolerated

Talbert Estlin & Sadun (2010)

Detailed information in Tables S1–S4. Visual acuity: classification based on the worse eye; Modified ranking score: 0. normal and asymptomatic; 1. mild symptoms without disability, ambulant and
managing own affairs; 2. slightly disabled but can walk and do self-care without assistance; 3. moderately disabled, needing some help, but can walk unaided; 4. moderate to severe disability, unable to walk,
iting and abdominal pain and affects with only a few adverse effects. All
the central nervous system in a similar reported cases of linezolid-associated
Chatziralli et al. (2010)
Masvidal et al. (2010)
way as ethanol. toxic optic neuropathy have been asso-
Kazim et al. (2010)

It is believed that visual symptoms
Kho et al. (2011)
are related to mitochondrial damage
and suppression of oxidative metabo-
References
ciated with the long-term use of linezo-
lid (5–10 months), except for two that
occurred after 16 days (Azamfirei et al.

lism by inhibiting cytochrome oxidase
activity resulting in hyperaemia,
oedema and optic nerve atrophy (Sa-
dun 1998). It was also shown that
2 (MRS 4–5)
2007; Joshi et al. 2009). In most cases
after discontinuation of the therapy,
optic neuropathy improved, but a
residual deficit in central visual acuity

methanol causes retina damage (Baum- remained. The outcome is compara-

2 (1 NA)

bach et al. 1977), including change in tively favourable. Mitochondrial dys-

the molecular structure and orientation function is suspected as the cause of
>0.5

of rhodopsin in cell membranes of the neurotoxicity. Specifically, low folate

0
0
0

retina and an impairment of ERG levels cause the plasma homocysteine

3 (MRS 2–3)

(Gawad & Ibrahim 2011). level to increase, which may inhibit

needing help with activities of daily living; and 5. severely disabled, bed ridden, requiring constant care. CF: counting fingers, HM: hand motions.

Eye symptoms occur in half of the neuronal mitochondrial function (Ke-

0.3–0.5
Final visual acuity/MRS

patients. They may develop after 6 h or dar et al. 2011).

more after ingestion and include:
1
0
0
6

blurred vision; photophobia; visual

Antitumor Necrosis
0 (MRS 0–1)

hallucinations, such as ‘a snowstorm’,

partial to total visual loss and, rarely, Factor Alpha (TNF-a)
eye pain. Eye examination usually
Agents
<0.3

reveals normal to constricted visual

10
0
1
3

field, sluggish or non-reactive pupils, Antitumor necrosis factor alpha (TNF-

nystagmus, hyperaemic optic discs, pa- a) agents have been used in treatment
>0.5
Initial visual acuity

pilloedema, retinal oedema and haem- of a wide range of inflammatory dis-

0
0
0
0
0

orrhages and decreased to absent eases, including rheumatoid arthritis,

0.3–0.5

vision (Baumbach et al. 1977). The inflammatory bowel disease, psoriatic

most common acute field defect is a arthritis and refractory uveitis. Those
1
0
0
0
0

dense central scotoma (McKellar et al. licensed for clinical use are as follows:
<0.3

1997; Al Aseri & Altamimi 2009). etanercept, a dimeric fusion protein

19
5
1
1
3

Methanol poisoning is a life-threat- blocking the effect of TNF-a; inflix-

Pallor/atrophy

ening disease; therefore, its ocular imab, a chimeric monoclonal receptor

complications are usually of secondary antibody; and adalimumab, a human
Optic disc

importance. However, the visual symp- monoclonal TNF-a antibody.

toms help to make the diagnosis, thus There are numerous reports that
NA

13
0
1
2

leading to an early start of the appro- TNF-a inhibitors are associated with
priate therapy. Prognosis is best corre- demyelinating disorders, which are
Optic disc
Swelling

lated with the severity of the acidosis both central and peripheral (Li et al.
rather than with serum methanol con- 2010). Higher levels of TNF-a in the
1/6

centrations. The detailed diagnosis pro- CSF of patients with multiple sclerosis
0
0
0
0

cess of the disease and systemic correlate with severity and prognosis of
Table 1. Ethambutol TON cases since 2010 till April 2012.

Visual field

therapies are described elsewhere (Shu- this disease, while the advantage of
2 (1 NA)
Defects

kla et al. 2006; Al Aseri & Altamimi TNF-a inhibitors in the treatment of
2009). Besides the antidote therapy –
Yes
Yes

MS is currently studied (Li et al. 2010).

5/6

19

using fomepizole or ethanol to delay One of the central demyelinating dis-

the methanol metabolism – intravenous
TBC osteomyelitis

orders following TNF-a antagonists

Mycobact. Avium

steroid use was recently proposed (So- therapy is acute optic neuritis. The
Tuberculosis

Tuberculosis
Tuberculosis

dhi et al. 2001; Shukla et al. 2006; exact number of cases presenting optic
Indication

Abrishami et al. 2011). neuritis or other demyelinating disor-

der as an effect of TNF inhibitor
therapy is unknown but seems to be
Linezolid
much higher than described in the
M

4
1
0
0
4

Linezolid belongs to the group of literature. After reviewing the manu-

oxazolidinone antibiotics and shows facturers’ clinical development pro-
Sex

15
2
0
1
3
F

activity against methicillin-resistant grams and postmarketing adverse

Staphylococcus species, penicillin- event reporting data, Li et al. sug-
35–46

72–81
23–84
Age

resistant Streptococcus species and gested as many as 13 new cases of

55
84

vancomycin-resistant enterococci. Rec- optic neuritis that had been reported in

19
6
1
1
3

ommended therapy duration extends to association with the use of etanercept

N

405
Acta Ophthalmologica 2015
by 2003 alone (Li et al. 2010). They
also described 130 reports categorized
as ‘optic neuritis’ associated with inf-
liximab, 205 associated with etanercept
and 101 associated with adalimumab,
from November 1997 to November
2009, according to their correspon-
dence with the FDA. There are also 3
cases of optic neuritis associated with
etanercept not described in the litera-
ture (Mohan et al. 2001) and at least 1
known case associated with ada-
limumab (Food & Drug Administra-
tion Center for Drug Evaluation &
Research 2003).
On the other hand, it is argued that
the association between TNF-a inhib-
itors therapy and subsequent demye-
lination disease could be coincidental.
There was no increased incidence of
demylinating disease in patients
exposed to TNF inhibitors compared
with the incidence of multiple sclerosis
in the general population (Magnano
et al. 2004). Also, several other studies
suggested that the higher rate of demy-
elination in patients undergoing TNF-
a inhibitors therapy could be second-
ary to an underlying predisposition
(Winthrop et al. 2013) or underlying
disease (Gupta et al. 2005). It was
shown that some inflammatory dis-
eases, in which TNF inhibitors are
used, pose a higher risk of demyelinat-
ing disease development by itself
(Magnano et al. 2004). Moreover, a
population-based cohort study of more
than 60 000 patients treated with anti-
TNF or non-biologic disease-modify-
ing antirheumatic drugs showed no
increased risk of optic neuritis (Prah-
alad et al. 2002).
In conclusion, the exact link between
TNF-a and demyelination disorders
remains controversial. It is not clear
whether TNF-a inhibitors cause these
disorders, unmask an underlying dis-
ease or occur irrespectively. However,
until the controversy is solved, moni-
toring of the development of ophthal-
mological symptoms in this group of
patients is recommended.
Other Drugs
Vigabatrin
This is an antiepileptic medicine used
for infantile spasms and refractory
complex partial seizures. Visual field
defects occur in 15–31% infants, 15%
children and 25–30% adults (Kedar
406
et al. 2011). They usually start as
bilateral nasal defects and progress to
concentric bilateral field constriction
with preservation of central vision.
Vigabatrin-associated visual field
defects may be irreversible. The time
of onset of visual field defects is age
and duration dependent: 3 months in
infants, 11 months in children and
9 months in adults (Kedar et al.
2011). Those visual field changes are
probably related to both retinal and
optic nerve toxicities. It is recom-
mended to monitor visual fields before
starting the treatment with vigaba-
trin and at regular 6-month intervals
thereafter (infants in 3-month inter-
vals). If the cumulative dosage of vig-
abatrin is more than 3 kg, the visual
field controls should be performed
more frequently because of the dos-
age–toxicity relationship (Viestenz
et al. 2003). There is a dispute if visual
field defects expand under continued
drug intake (Best & Acheson 2005).
Due to the unclear situation, in cases of
visual field constriction, the therapy
should be stopped if possible. There are
hints that concurrent taurine intake
and light protection (sunglasses) may
reduce this adverse effect of vigabatrin.
Taurine deficiency is a cause of vigaba-
trin-induced retinal phototoxicity
(Jammoul et al. 2009).
Ciprofloxacin
Ciprofloxacin is an antibiotic used to
treat a wide range of infections. Ocular
adverse effects are rare. Blurred vision,
changes in colour perception,
decreased visual acuity and eye pain
are noted to occur in <1% of cases
(Samarakoon et al. 2007). We noted
two cases of ciprofloxacin-induced
toxic optic neuropathy described in
the literature (Vrabec et al. 1990;
Samarakoon et al. 2007). The charac-
teristics of these cases are similar. Both
had an improvement in vision upon
ceasing ciprofloxacin. Both patients
also had a history of alcohol abuse
and some evidence of liver dysfunction.
It is uncertain whether the combination
of excessive alcohol use and ciproflox-
acin increased the risk of optic neurop-
athy. The mechanism of ciprofloxacin-
induced optic neuropathy remains
unknown. Being aware of adverse
effects including the possibility of toxic
optic neuropathy is important, partic-
ularly in those patients who are on high
dose or prolonged treatment courses.
After discontinuation of ciprofloxacin
therapy, a 6-month testing of visual
acuity, visual field and colour vision is
recommended.
Dapsone
There are also two cases described in
the literature about dapsone-induced
optic neuropathy. In both cases, optic
atrophy and visual impairment per-
sisted after ceasing dapsone (Danesh-
mend & Homeida 1980; Chalioulias
et al. 2006).
Controversies
Amiodarone, an important antiar-
rhythmic drug, has been known for its
ocular side-effects (Gittinger & Asdou-
rian 1987; Palimar & Cota 1998; John-
son et al. 2004). The most common
side-effect, found in more than two-
thirds of patients, is a reversible verti-
cillate keratopathy. This does not have
any significant influence on vision. In
50–60% blue-white anterior subcapsu-
lar cataract may develop (Lloyd &
Fraunfelder 2007) leading to mild blue
colour vision defects (Reeks & Ang
2010). Moreover, it was shown in many
reports that the drug may be associated
with an optic neuropathy resembling
non-arteritic ischaemic optic neuropa-
thy (NAION). However, whereas NA-
ION usually is unilateral, this
neuropathy is bilateral in two-thirds
of the amiodarone cases (Passman
et al. 2012). A recent review of amio-
darone toxic optic neuropathy (A-
TON) identified a total of 296 reported
cases: 214 from the FDA’s Adverse
Event Reporting System, 57 from
MEDLINE case reports and 23 from
adverse events reports for patients
enrolled in clinical trials (Passman
et al. 2012). However, only in 16 cases
together from MEDLINE and clinical
trials, the diagnosis of optic neuropa-
thy was complete, and in only 32 cases,
a complete association with amioda-
rone could be assigned. This was still
worse in the FDA database: no com-
plete diagnosis and no complete asso-
ciation were recorded. Among 80
published adverse event reports from
MEDLINE and clinical trials, 69%
described optic disc oedema in at least
one eye. Bilateral optic disc oedema
was observed in 12% of asymptomatic
patients, 64% of patients who pre-

sented with monocular visual loss and
68% of patients with bilateral visual
loss. It was shown that the mean
duration of amiodarone therapy before
vision loss was 9 months (range 1–
84 months). After drug discontinua-
tion, 58% had improved visual acuity,
21% were unchanged, and 21% wors-
ened even after amiodarone medication
was discontinued. Optic disc oedema
seems to resolve slower as in typical
NAION. It was also reported that legal
blindness (<20/200) was noted in at
least one eye in 20% of cases (Passman
et al. 2012). Purvin et al. recom-
mended a systematic approach to dif-
ferentiate the A-TON from NAION,
including assessment of bilaterality,
mode of onset, degree of optic nerve
dysfunction, structure of the unin-
volved optic disc in unilateral cases
and systemic toxic effects (Purvin et al.
2006).
On the other hand, the prospective,
controlled, double-blind study by Min-
del et al. of more than 1600 patients
followed for a median 45.5 months
failed to show an association between
amiodarone and bilateral toxic vision
loss (Mindel et al. 2007). According to
this study, the maximum possible
annual incidence rate of bilateral vision
loss from amiodarone in all 837 sub-
jects, medium age of 60, receiving a
mean daily dose of 3.7 mg/kg
(300 mg), was 0.13%. This rate is not
far from estimate ranges for idiopathic
NAION from 0.01% to 0.03% per
year, especially if the higher ischaemic
risk of patients receiving amiodarone
treatment is considered (Johnson &
Arnold 1994; Hattenbauer et al.
1997). Mindel et al. also suggested that
the A-TON is in fact a NAION occur-
ring with the same incidence as in
general population. Hayreh argued
that in the multifactorial scenario of
NA-AION, it is the systemic cardio-
vascular risk factors rather than the
amiodarone that cause NA-AION.
Patients who take amiodarone have
cardiovascular disorders, arterial
hypertension, diabetes mellitus, hyper-
lipidemia and ischaemic heart disease,
which are per se well-established risk
factors for the development of NA-
AION (Hayreh 2011).
In conclusion, the issue if amioda-
rone might separately produce A-TON
and NAION is still controversial and
needs to be elucidated. At present,
although these complications are rare,
they might lead to serious visual loss,
but on the other hand, an important
antiarrhythmic therapy might be dis-
continued without clear evidence.
Therefore, ophthalmologic examina-
tions in this group of patients are
recommended.
Phosphodiesterase Type
5 (PDE5) Inhibitors
This group of drugs, including sildena-
fil (Viagra), tadalafil (Cialis) and var-
denafil (Levitra), is commonly used in
the treatment of erectile dysfunction. It
is estimated that in some countries, the
population of users is as big as 2% of
all males aged above 65, which adds up
to millions of users all over the world.
Recently, sildenafil was proposed in the
treatment of pulmonary arterial hyper-
tension and was approved for this
indication in several countries world-
wide, including USA and European
Union. By increasing cGMP concen-
trations, sildenafil enables systemic
arterial smooth muscle relaxation and
vasodilatation.
The most common visual problems
related to PDE5 inhibitors were dose
dependent and reversible colour vision
problems in the blue-green to blue-
purple range and increased sensitivity
to light (Kerr & Danesh-Meyer 2009;
Laties 2009). Other rare ophthalmic
complications included central serous
chorioretinopathy (Fraunfelder et al.
2006a,b), branch retinal artery occlu-
sion, third nerve palsy, non-arteritic
ischaemic optic neuropathy (NAION)
(Felekis et al. 2011; Hayreh 2011)
(Pomeranz & Bhavsar 2005) and per-
manent vision loss, which was not
further specified (Fraunfelder et al.
2006a,b; Kerr & Danesh-Meyer 2009;
Laties 2009). The relation between
PDE5 inhibitors and NAION is, how-
ever, a controversial issue.
In one of the reviews, including case
descriptions of PDE5-selective inhibi-
tor-associated optic neuropathy events
reported between 1998 and 2005, 39
cases of optic neuropathy in sildenafil-
or tadalafil-treated patients were iden-
tified as case reports (n = 18) or in
FDA databases (n = 21) (Pomeranz &
Bhavsar 2005). It was, however, indi-
cated that the quality of the case
reports in the FDA database was
suboptimal given that they often lacked
important information on the duration
Acta Ophthalmologica 2015
of PDE5-selective inhibitor use, time
since ingestion of the most recent dose,
identification of the affected eye and
fundoscopic examination findings
(McKoy et al. 2009).
It was shown that PDE5-selective
inhibitor therapy was noted in 19% of
the FDA reports of drug-associated
ocular toxicities, which makes it the
most commonly reported drug class
associated with this toxicity. On the
other hand, the drugs have been
administered to about 30 million men,
the majority of whom were older,
vasculopathic, and at risk of NAION
(i.e. a small optic cup-to-optic disc
ratio). Moreover, patients with vascul-
opathy also take antihypertensive med-
ications and may be at increased risk of
NAION due to nocturnal hypotension
(Rucker et al. 2004; McKoy et al.
2009).
Gorkin et al. (2006), using epidem-
iologic and clinical trial data, estimated
an incidence of 2.8 cases of NAION
per 100 000 patient-years of exposure
to sildenafil for the treatment of erectile
disorder. He pointed out that, com-
pared with estimates in general popu-
lation samples, this finding was similar
to those of Johnson and Arnold (2.52
per 100 000 men aged >50 years; 3.06
per 100 000 individuals [men and
women] aged >50 years when corrected
for missing respondents) but lower
than that of Hattenhauer et al. (11.8
cases per 100 000 men aged >50 years).
He concluded that the presented data
did not suggest an increased incidence
of NAION in men who took sildenafil
(Rucker et al. 2004).
Moreover, the most recent
randomized, double-masked, placebo-
controlled trial in 277 adults with a
mean age of 49 showed that sildenafil
in dosing up to 80 milligrams three
times daily is not related to ocular
adverse effects (Wirostko et al. 2012).
Following a series of similar case
reports, WHO and FDA have labelled
the link between use of PDE5 inhibi-
tors and risk of NAION as ‘possibly’
causal (Danesh-Meyer & Levin 2007).
There is an ongoing study trying to
establish the role of sildenafil as risk
factor. As NAION is not a toxic optic
neuropathy, it is questionable if this
debated side-effect of sildenafil should
be addressed in this review. But in
regard to all ongoing debates and the
frequent use of those drugs, we decided
to discuss this issue.
407
Acta Ophthalmologica 2015
Mixed Toxic and
Nutritional Optic
Neuropathy
In the years 1992–1993, an outbreak of
optic neuropathy in Cuba reached
epidemic proportions, involving nearly
50 000 people (Lincoff et al. 1993). The
studies of the Cuban Epidemic Optic
Neuropathy (CEON) confirmed that
there were multiple nutritional deficien-
cies and toxic exposures as risk factors.
Deficiencies of B2 and folic acid, as
well as exposure to cyanide and meth-
anol, were described (Sadun & Mar-
tone 1995; The Cuba Neuropathy Field
Investigation Team 1995; Torroni et al.
1995). The mtDNA mutations for
Leber’s were not found (Sadun &
Martone 1995). It was proposed that
the combination of poor nutrition,
leading to lower folic acid levels, and
even a small intake of methanol (such
as the 1% that was found as a con-
taminant in bootlegged rum) would be
expected to raise serum formate levels.
The authors were able to establish an
animal model that closely matched
several of the critical conditions and
biochemical values that were found
and described for CEON patients (Sa-
dun & Martone 1995).
The CEON is a good example of
common interactions between nutri-
tional deficits and toxic effects in the
pathogenesis of optic neuropathy.
Tobacco-Alcohol
Amblyopia – Misnomer
The term ‘tobacco-alcohol amblyopia’
is misleading. It is not an amblyopia
but an optic neuropathy and it has
never been proven that it is really
caused by an interaction or synergism
of alcohol and tobacco. However, there
are patients heavily smoking and alco-
hol addicted that develop a character-
istic optic neuropathy with bilateral
visual loss. In our own experience, this
is a rare disorder. In a large neuro-
ophthalmological clinic (T€
ubingen), we
are seeing approximately one new
patient per year. In the past, this
diagnosis was certainly more common.
One possibility is that a number of
early cases were probably misdiag-
nosed. For example, it was shown that
some patients diagnosed as tobacco
optic neuropathy carried a genetic
mutation characteristic for LHON
408
(Cullom et al. 1993; Johns et al.
1993; Mackey & Howell 1994). The
test for syphilis would not become
available until the early 20th century,
ischaemic optic neuropathy would not
be discovered until the mid 20th cen-
tury, and demyelinative optic neuritis
was just becoming recognized. In Ger-
many, cigarette consume has been
reduced in the last 10 years: starting
with nearly 400 million cigarettes a day
in 2002 to 230 million in the year 2010
(Federal Statistical Office, Wiesbaden).
Moreover, the nutritional status,
which may have contributed to the
development of optic neuropathy in
the past, is of minor importance at
present.
Because most heavy drinkers are
also smokers, it is difficult to differen-
tiate these two factors, and the term
‘tobacco-alcohol amblyopia’ is still
commonly used. It now seems likely
that there are two distinct disorders –
tobacco optic neuropathy and nutri-
tional optic neuropathy related to alco-
hol overconsumption. In the end of the
19th century, the role of nutritional
deficit in provoking optic neuropathy
was proposed, but it was in the middle
of the 20th century when Carroll pro-
vided what appears to be the conclusive
evidence (Carroll 1935, 1947, 1966); he
showed that patients with TON par-
tially or completely recovered their
vision following vitamin B supplemen-
tation despite continuing their usual
intake of alcohol and tobacco (Carroll
1966).
Tobacco optic neuropathy is most
often presented in elderly pipe-smoking
men; however, it was also reported in
cigar smokers, users of chewing
tobacco and users of snuff (Newman
1966). It is characterized by a bilateral
relative centro-coecal field defect, more
marked for a red or green target than
white, and a characteristic disturbance
of colour discrimination on the Farns-
worth-Munsell 100 Hue Test (Foulds
et al. 1974). Vision can improve to
normal or near normal over a period of
3–12 months if they stop smoking
(Harrington 1962; Foulds et al. 1974).
The visual field changes were postu-
lated as the most characteristic clinical
findings in TON (Traquair 1927, 1928,
1931; Harrington 1962).
It was proposed that smoking, espe-
cially in genetically susceptible
patients, might affect sulphur metabo-
lism, leading to chronic cyanide intox-
ication (Freeman 1988) and deficiency
of vitamin B12 (Heaton et al. 1958;
Wokes 1958). There are several reports
confirming the coexistence of tobacco
toxicity with deficiency of hydroxoco-
balamin (Heaton et al. 1958; Wokes
1958). On the other hand, most
patients with TON have B12 levels
within the normal range (Silvette et al.
1960). It was also proposed that genetic
susceptibility overlaps with toxic envi-
ronmental influences (Johns et al.
1993). As the clinical picture is not
definitive, the diagnosis should be
made after exclusion of the much more
common nutritional optic neuropathy,
other toxic optic neuropathies and
congenital optic neuropathies, mainly
LHON. Tobacco abstinence and oral
and intramuscular B vitamins, particu-
larly vitamin B1 and B12, were pro-
posed as appropriate therapy (Younge
1996).
By the end of the 20th century, a
paradox had become apparent: Despite
an increased use of tobacco products in
the general population, there was a
marked decrease in the incidence of
tobacco optic neuropathy.
Environmental Factors
and LHON Expression
Toxic and nutritional optic neuropa-
thies are often classified as acquired
mitochondrial optic neuropathies over-
lapping with congenital mitochondrial
optic neuropathies, including LHON
and dominant optic atrophy (DOA).
It should be noted that certain envi-
ronmental risk factors may be impor-
tant triggers of the conversion to active
LHON in unaffected carriers. One
study of a large Brazilian LHON
pedigree (332 individuals) showed a
doubling of the disease risk with high
consumption of either alcohol or
tobacco (Sadun et al. 2002, 2003).
Another multicenter survey of 402
LHON patients also reported a signif-
icant role of tobacco and alcohol use in
risk of disease outbreak (Kirkman
et al. 2009). It was also proposed that
smoking in general (not just tobacco
smoking) is able to trigger LHON, as
some reported cases have been associ-
ated with exposure to smoke from tire
fires or malfunctioning stoves (Sanchez
et al. 2006). There are, however, many
more substances that are under suspi-
cion to trigger LHON: cyanides, meth-

anol, pesticides, phosphodiesterase
type 5 inhibitors, antibiotics such as
ethambutol, chloramphenicol, linezo-
lid, aminoglycosides and antiretroviral
drugs (for HIV). The majority of these
are known for interfering with
mitochondrial respiratory function
(De Marinis 2001; Ikeda et al. 2006;
Cornish & Barras 2011).
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Received on April 16th, 2014.
Accepted on July 3rd, 2014.
Correspondence:
Andrzej Grzybowski, MD, PhD, MBA
Department of Ophthalmology
Poznan City Hospital
ul. Szwajcarska 3
61-285 Poznan
Poland
Tel/Fax: +4861-8739169
Email: ae.grzybowski@gmail.com
Supporting Information
Additional Supporting Information
may be found in the online version of
this article:
Table S1. Isoniazid – TON cases
reported since 2001.
Table S2. Linezolid-TON cases: all
reported cases.
Table S3. Anti-TNF-TON cases: all
reported cases.
Table S4. TON cases related to other
drugs: all reported cases.