Acta Ophthalmologica 2015

Review Article

Toxic optic neuropathies: an updated review

Andrzej Grzybowski,1,2 Magdalena Zulsdorff,€1 Helmut Wilhelm3 and Felix Tonagel3
1
Department of Ophthalmology, Poznan City Hospital, Poznan, Poland
2
Departtment of Ophthalmology, University of Warmia and Mazury, Olsztyn, Poland
3Centre 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 through unknown and probably different sub-
different toxins, including drugs, metals, organic solvents, methanol and carbon stances affect the optic nerve in differ-ent
dioxide. A similar clinical picture may also be caused by nutritional deficits, ways. It is generally accepted that the
including B vitamins, folic acid and proteins with sulphur-containing amino acids. common pathway, for at least some of
This review summarizes the present knowledge on disease-causing factors, the toxins, is mitochondrial injury and
clinical presentation, diagnostics and treatment in TON. It discusses in detail imbalance of intracellular and
known and hypothesized relations between drugs, including tuberculostatic drugs, extracellular-free radical homoeostasis
antimicrobial agents, antiepileptic drugs, antiarrhythmic drugs, disulfi-ram, (Wang & Sadun 2013). This may explain
some similarities with Leber’s hereditary
halogenated hydroquinolones, antimetabolites, tamoxifen and phosphodi-esterase
optic neuropathy (LHON). It is argued
type 5 inhibitors and optic neuropathy.
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
Introduction patients, for example, both factors usu- and use of a systemic medication; social
ally play a synergistic role contributing to history and habits (e.g. amount and sort
The optic nerve is susceptible to dam-age the TON. Clinical pictures of both of tobacco and alcohol used), diet (e.g.
from toxins, including drugs, metals (e.g. disorders, nutritional optic neuropathy any special diets used), anorexia nervosa,
lead, mercury and thallium), organic (NON) and TON, are also very similar, gastrointestinal dis-ease or surgery or
solvents (ethylene glycol, tolu-ene, and they usually cannot be differenti-ated anaemia. Some metabolic diseases,
styrene and perchloroethylene), based on clinical signs and symp-toms. including diabetes mellitus, kidney
methanol, carbon dioxide and probably Both disorders are rare in economically failure and thyroid disease, might
some sort of tobacco. This group of influence TON due to the accumulation
developed countries. They are more
disorders is named toxic optic neurop- of toxins.
prevalent in developing coun-tries,
athy (TON) and is characterized by because of people’s greater expo-sure to A family history should also be taken
bilateral visual loss, papillomacular toxic substances in environment and into account to identify hints on
bundle damage, central or cecocentral food, and coexisting malnutrition. No hereditary optic nerve disorders. On the
scotoma, and reduction of colour vision. racial, gender and age-dependent other hand, if alcohol or drug addiction is
Toxic optic neuropathy might be predilections have been shown. suspected, information from family
triggered or just enhanced by nutri-tional members or friends might contribute.
deficits, including the vitamins thiamine Review of symptoms should include
(B1), riboflavin (B2), niacin (B3),
Pathology sensory disturbances in the extremities
pyridoxine (B6), cobalamin (B12), folic In most of the cases of TON, the primary and gait problems, indicating toxic
acid and proteins with sulphur-containing lesion is not limited to the optic nerve peripheral neuropathy and/or toxic effect
amino acids (Phillips 2005). Among and may possibly originate in the retina, upon the cerebel-lum. Patients’
malnourished and intoxicated chiasm or even the optic 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? Yes
Papilledema ? Yes
Peripapillary telangiectasia?
Preserved pupillary light Yes 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
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 nerve
Yes Adequate therapy
but also probably other retinal elements
based upon abnormal mfERG findings
(Kardon et al. 2006).
MRI Opticne uritis? The ocular toxicity is dose and
duration dependent; thus, early recog-
Raised ICP? nition of TON and prompt cessation of
Basal ganglia necrosis? the therapy is important in pre-venting
MRI Bilateral AION? further progression of vision loss.
Amiodarone? Standard methods for monitoring
ethambutol use include visual acuity
assessment, visual field testing, fun-
Family history
gene analysis LHON? duscopy, colour vision testing, con-trast
sensitivity measurement, OCT and VEP.
It was shown that the use of 3D
computer-automated threshold Amsler
Yes See parents Hereditary disease? grid testing with 0.5° grid spacing
colour vision testing ADOA (tritan defect)? revealed relative scotomas that had been
gene analysis
missed by both standard visual field
testing methods and 3D-
MRI
Infitrative or paraneoplastic
fundus auto fluorescence CTAG with 1° grid spacing (Kim et al.
disease (e.g. MAR/CAR)?
electrophysiology 2008). Visual acuity and colour vision
testing are the easiest tests that can also
Wolfram syndrome, other be performed by non-oph-thalmologists,
Yes Gene analysis hered. neuropathy? 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-ture
Toxic mitochondrial are presented in Table 1.
Yes neuropathy? Stop drugs if possible
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 1969; 2006; Kulkarni et al. 2010). However,
Kedar et al. 2011). the few published reports show a rather
Visual problems do usually not occur favourable outcome, better than in
during the first 2 months of ethambutol ethambutol. As with other drugs, patients
treatment, and they gen-erally appear with hepatic or renal disease are at higher
between 4 and 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 the Methanol is metabolized to formic acid,
risk of TON was higher at that dosages which is responsible for its toxicity
of of 25 mg/kg/day or more. In such a case, (Hayreh et al. 1977; Martin-Amat et al.
the dosage should be reduced to 15 1977, 1978). This origi-nates from a
mg/kg/day, which is considered both combined effect of met-abolic acidosis
relatively safe and effective. However, and an intrinsic toxicity of the formiate
even with much anion itself.

Severe poisoning causes nausea, vom-
iting and abdominal pain and affects the
–Tuberculosis5/61/6NA5100(MRS01)3(MRS23)2(MRS45) Kazim et al. (2010)Mycobact.AviumYes00100010Masvidaletal.(2010)TBCosteomyelitisYes01100100Chatzirallietal.(2010)Tuberculosis2(1NA)02300300TalbertEstlin&Sadun (2010)Tuberculosis1901319001062(1NA)Khoetal.(2011)
central nervous system in a similar way
as ethanol.
It is believed that visual symptoms are
related to mitochondrial damage and
suppression of oxidative metabo-lism by
inhibiting cytochrome oxidase activity
resulting in hyperaemia, oedema and
optic nerve atrophy (Sa-dun 1998). It
References3
was also shown that methanol causes
retina damage (Baum-bach et al. 1977),
including change in the molecular
structure and orientation of rhodopsin in
cell membranes of the retina and an
impairment of ERG (Gawad & Ibrahim
>–0.30.0.50.5
2011).
Eye symptoms occur in half of the
Final visual acuity/MRS
patients. They may develop after 6 h or
more after ingestion and include: blurred
vision; photophobia; visual
hallucinations, such as ‘a snowstorm’,
partial to total visual loss and, rarely, eye
pain. Eye examination usually reveals
normal to constricted visual field,
<
sluggish or non-reactive pupils,
nystagmus, hyperaemic optic discs, pa-
>–0.30.0.50.53
Initial visual acuity
pilloedema, retinal oedema and haem-
orrhages and decreased to absent vision
carewithoutassistance;3.moderatelydisabled,needingsomehelp,butcanwalkunaided;4.moderatetoseveredisability,unabletowalk,needin ghelpwithactivitiesofdailyliving;and5.severelydisabled,bedridden,requiringconstantcare.CF:countingfingers,HM:handmotions.
(Baumbach et al. 1977). The most
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 andmanagingownaffairs;2.slightlydisabledbutcanwalkanddoself-
common acute field defect is a dense
central scotoma (McKellar et al. 1997;
Al Aseri & Altamimi 2009).
<
Methanol poisoning is a life-threat-
ening disease; therefore, its ocular
Visual field Optic disc Optic discIndicationDefectsSwellingPallor/atrophy
complications are usually of secondary
importance. However, the visual symp-
toms help to make the diagnosis, thus
leading to an early start of the appro-
priate therapy. Prognosis is best corre-
lated with the severity of the acidosis
rather than with serum methanol con-
centrations. The detailed diagnosis pro-
cess of the disease and systemic
therapies are described elsewhere (Shu-
kla et al. 2006; Al Aseri & Altamimi
Ethambutol TON cases since 2010 till April 2012.Table1.
2009). Besides the antidote therapy –
using fomepizole or ethanol to delay the
methanol metabolism – intravenous
steroid use was recently proposed (So-
dhi et al. 2001; Shukla et al. 2006;
Abrishami et al. 2011).
–
Linezolid
–
2 4011030154
Linezolid belongs to the group of
F M
Sex
oxazolidinone antibiotics and shows
activity against methicillin-resistant
Staphylococcus species, penicillin-
–63546155184–37281–192384
resistant Streptococcus species and
AgeN
vancomycin-resistant enterococci. Rec-
ommended therapy duration extends to
Acta Ophthalmologica 2015
28 days. Usually, it is well tolerated with
only a few adverse effects. All reported
cases of linezolid-associated toxic optic
neuropathy have been asso-ciated with
the long-term use of linezo-lid (5–10
months), except for two that occurred
after 16 days (Azamfirei et al. 2007;
Joshi et al. 2009). In most cases after
discontinuation of the therapy, optic
neuropathy improved, but a residual
deficit in central visual acuity remained.
The outcome is compara-tively
favourable. Mitochondrial dys-function
is suspected as the cause of
neurotoxicity. Specifically, low folate
levels cause the plasma homocysteine
level to increase, which may inhibit
neuronal mitochondrial function (Ke-dar
et al. 2011).
Antitumor Necrosis
Factor Alpha (TNF-a)
Agents
Antitumor necrosis factor alpha (TNF-a)
agents have been used in treatment of a
wide range of inflammatory dis-eases,
including rheumatoid arthritis,
inflammatory bowel disease, psoriatic
arthritis and refractory uveitis. Those
licensed for clinical use are as follows:
etanercept, a dimeric fusion protein
blocking the effect of TNF-a; inflix-
imab, a chimeric monoclonal receptor
antibody; and adalimumab, a human
monoclonal TNF-a antibody.
There are numerous reports that TNF-
a inhibitors are associated with
demyelinating disorders, which are both
central and peripheral (Li et al. 2010).
Higher levels of TNF-a in the CSF of
patients with multiple sclerosis correlate
with severity and prognosis of this
disease, while the advantage of TNF-a
inhibitors in the treatment of MS is
currently studied (Li et al. 2010). One of
the central demyelinating dis-orders
following TNF-a antagonists therapy is
acute optic neuritis. The exact number of
cases presenting optic neuritis or other
demyelinating disor-der as an effect of
TNF inhibitor therapy is unknown but
seems to be much higher than described
in the literature. After reviewing the
manu-facturers’ clinical development
pro-grams and postmarketing adverse
event reporting data, Li et al. sug-gested
as many as 13 new cases of optic neuritis
that had been reported in association
with the use of etanercept
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 (Tubingen),€ 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.