CASE REPORT

Case Report: Nutritional and Toxic Optic Neuropathy:

A Diagnostic Dilemma
Clara Monferrer-Adsuara, MD,1* Carolina García-Villanueva, MD,1 Lucía Mata-Moret, MD,1 Miguel Ortiz-Salvador, MD,1
Lidia Remolí-Sargues, MD,1 and Enrique Cervera-Taulet, PhD1

SIGNIFICANCE: Nutritional and toxic optic neuropathies are rare disorders characterized by visual impairment due
to optic nerve damage by a toxin, usually with coexisting nutritional deficiencies. Its pathophysiology is still unclear,
and multiple mechanisms implicated act synergistically to bring about this condition. The decline in its incidence and
its confusing clinical appearance make diagnosing nutritional and toxic optic neuropathies challenging.
PURPOSE: This is an observational clinical case report of an atypical clinical case of a nutritional and toxic optic
neuropathy with a subacute presentation and papilledema at the time of diagnosis. The patient provided written
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informed consent for medical information and images to be published.

CASE REPORT: A 47-year-old man presented with progressive, painless bilateral decrease in central vision over
15 days. The patient had a long-standing history of alcohol abuse and was a heavy smoker. The examination revealed
dyschromatopsia, 20/400 visual acuity on both eyes, and no relative afferent pupillary defect. Funduscopy revealed
bilateral papilledema. A visual field test showed generalized depression with centrocecal involvement in the left eye.
Laboratory studies evidenced decreased vitamin B12/B1 and red blood cell folate levels, increased acute phase reac-
tants, hypertransaminasemia, and macrocytic anemia. Serologies and methanol in urine were negative. After the dis-
continuation of tobacco use and alcohol accompanied by vitamin supplementation, our patient's visual field, visual
acuity, and papilledema improved remarkably. After 5 months, visual acuity and funduscopy were normal.
Author Affiliations:
CONCLUSIONS: Although some hallmark signs were visible in this case, its subacute presentation and the presence of 1
Department of Ophthalmology,
papilledema at diagnosis caused some diagnostic uncertainty. Nutritional and toxic optic neuropathy is a rare and chal- Consorcio Hospital General Universitario
lenging diagnosis because of a lack of biomarkers. Eye care clinicians should consider nutritional and toxic optic neurop- of Valencia, Valencia, Spain
athies to prevent severe and irreversible visual damage resulting from underdiagnosis and mismanagement. *clara_cma@hotmail.com

Optom Vis Sci 2020;97:477–481. doi:10.1097/OPX.0000000000001531

Copyright © 2020 American Academy of Optometry

Nutritional and toxic optic neuropathies, previously known as
tobacco-alcohol amblyopias, are uncommon disorders characterized
by visual impairment due to optic nerve damage caused by a toxin
and usually present with coexisting nutritional deficiencies.1–3 The
latter is thought to play a critical role in triggering or enhancing the
toxic effects of cyanide and tobacco's free radicals while causing
secondary damage to ganglion cell axons.1 Nevertheless, its patho-
physiology is still unclear, and multiple mechanisms implicated
act synergistically to bring about this condition.4
Although considered an epidemic during times of famine, the
incidence of nutritional and toxic optic neuropathies has declined
dramatically in modern times because of the improvements in nutri-
tion. This observation is suggestive of vitamin deficiency being a key
etiological sign.1–4 The main differences with other toxic amblyopias
are its more insidious onset and the reversibility of symptoms. The de-
cline in its incidence and its confusing clinical appearance make diag-
nosing nutritional and toxic optic neuropathies challenging.
CASE REPORT
A 47-year-old man presented with progressive, painless bilat-
eral decrease in central vision over 15 days. The patient had a
long-standing history of alcohol abuse (>100 g of alcohol per day
over the last 4 years) and was a smoker of one pack of cigarettes
per day for at least 25 years on average with no previous history
of ophthalmologic problems. The patient's medications included
atypical antipsychotics such as quetiapine (300 mg/d) and
paliperidone (6 mg) orally once daily and antidepressants such as
duloxetine (60 mg/d) and trazodone (150 mg) orally once daily
for the last year.
The ocular examination revealed bilateral sluggishly reactive
isochoric pupils, no relative afferent pupillary defect, and normal
ocular motility. Ishihara plates performed monocularly showed
dyschromatopsia (1/14 right and left eye). Visual acuity was 20/400
in both eyes. Funduscopy revealed hyperemic optic disc with pa-
pilledema and peripapillary hemorrhage in both eyes (Figs. 1 and 2).
Optical coherence tomography (Cirrus HD-OCT 4000; Carl Zeiss
Meditec Inc., Dublin, CA) displayed increased retinal nerve fiber layer
thickness (Fig. 3) and macular ganglion cell layer atrophy in both eyes.
The visual field test results are shown in Fig. 3, demonstrating
centrocecal involvement with generalized hemifield loss in the left
eye; the right eye presents a generalized depression.
A brain and orbit computed tomography scan displayed no path-
ological changes. Posterior gadolinium-enhanced brain MRI ex-
cluded conditions such as vascular, demyelinating, inflammatory,
or compressive processes.
Laboratory studies were performed evidencing hypertransaminasemia
(aspartate aminotransferase, 62 IU/L [reference range, 12 to 38 IU/L];

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Nutritional and Toxic Optic Neuropathy — Monferrer-Adsuara et al.

FIGURE 1. Clinical timeline: a 47-year-old white man diagnosed and medically treated for subacute nutritional and toxic optic neuropathy. CT = computed
tomography; GCL = ganglion cell layer; OCT = optical coherence tomography; RAPD = relative afferent pupillary defect; RNFL = retinal nerve fiber layer;
VA = visual acuity; VF = visual field.

FIGURE 2. Funduscopy revealed hyperemic optic disc with papilledema and peripapillary hemorrhage in both eyes.

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 Nutritional and Toxic Optic Neuropathy — Monferrer-Adsuara et al.

FIGURE 3. Optical coherence tomography at the diagnosis displaying increased retinal nerve fiber layer thickness. The visual field test at diagnosis dem-
onstrating generalized depression in both eyes; centrocecal involvement, but obscured with generalized hemifield loss in the left eye. Right eye pattern
deviation not shown for the severely depressed field; refer to total deviation.

alanine aminotransferase 48 IU/L [7 to 41 IU/L]; and γ-glutamyl
transferase, 230 IU/L [5 to 58 IU/L]), increased acute phase reac-
tants, and decreased levels of red blood cell folate (60 ng/mL [140
to 628 ng/mL]), vitamin B 1 (1.5 ng/mL [2.5 to 7.5 ng/mL]),
vitamin B12 (100 ng/mL [200 to 900 ng/mL]), and its metabolites.
Macrocytic anemia (hemoglobin, 10 g/dL [13.5 to 17.5 g/dL];
mean corpuscular volume, 139.6 fL [80 to 100 fL]) was also dem-
onstrated with normal intrinsic factor and parietal cell antibody
levels. Serologies and antinuclear antibodies were negative, as well
as methanol in urine.
In consequence, the diagnosis established was subacute
nutritional and toxic optic neuropathy, and the treatment plan
consisted of permanent cessation of smoking and alcohol con-
sumption with adequate psychotherapy aimed at abstinence
and relapse prevention, accompanied by vitamin supplementation
(multivitamin tablets and hydroxocobalamin injections) and nutri-
tional counseling.
After 3 months of therapeutic compliance, the patient's visual
acuity improved remarkably, revealing 20/40 in both eyes alongside
the visual field examinations (Fig. 4). After the 5-month follow-up,
visual acuity was 20/20 in both eyes, and funduscopy was normal.
One year after discharge, visual acuity remained stable.
DISCUSSION
Nutritional and toxic optic neuropathies are optic neuropathies
of uncertain etiology, better understood now as primarily nutritional
deficiencies with possible relation to tobacco or other toxic sub-
stances that respond well to vitamin supplementation.4 The grad-
ual accumulation of cyanide from tobacco abuse and formic acid
resulting from vitamin B12 and folic acid deficiencies leads to the
inhibition of mitochondrial oxidation mechanisms and adenosine
triphosphate production resulting in secondary damage of the
papillomacular bundle, with maculopathy or chiasmopathy pro-
posed as sites of primary involvement.5,6
Mitochondrial damage and intracellular and extracellular free
radical homeostasis imbalance are considered the common pathway

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Nutritional and Toxic Optic Neuropathy — Monferrer-Adsuara et al.

FIGURE 4. Optical coherence tomography and visual field test 3 months after therapeutic compliance.

for some toxins. Thus, toxic optic neuropathies are considered
acquired mitochondrial optic neuropathies, which explain some
similarities with Leber hereditary optic neuropathy.7 The prevail-
ing theory behind the Cuban epidemic optic neuropathy in the
early 1990s was mitochondrial mutations carried by the affected
population, which predisposed them to the optic neuropathy
brought on by malnutrition.1 Although Leber hereditary optic neu-
ropathy in patients presenting for the first time at advanced stages
of the disease and without a family history can be difficult to dis-
tinguish from other optic nerve etiologies, the patient's recovery
after treatment compliance discarded it.
The most common clinical presentation that consists of symmetric
insidious and painless bilateral vision loss, dyschromatopsia, central
or cecocentral scotomas on visual field examinations, and its symmet-
ric optic nerve involvement results in no relative afferent pupillary de-
fect. Optic nerves appear normal or mildly hyperemic in the early
stages of the disease, leading to a bilateral temporal optic disc pallor
if exposure to the toxic agent continues; eventually, a diffuse pallor
and total optic atrophy appear.1
It is a challenging diagnosis of exclusion because of a lack of bio-
markers and is an uncommon occurrence because the procedures
necessary for its approach are difficult to specify.
The required laboratory studies include vitamin assays (perni-
cious anemia), liver enzymes (alcoholism indicator), and red blood
cell folate levels (general nutritional status marker). Identification
of a specific toxin (such as methanol) is required when suspected.
Targeted serological testing, especially syphilis, is essential, and
occasionally, lumbar puncture should be performed alongside ge-
netic tests to exclude hereditary optic neuropathies.1,2 Although
increased cyanide and decreased cyanocobalamin levels have
been considered diagnostic criteria in the appropriate clinical set-
ting,8 normal results in several cases emphasize the lack of reliable
laboratory markers for the disease.
Other differential diagnoses include chiasmatic compressive/
infiltrative lesions, radiation/inflammatory/demyelinating optic
neuropathy, macular or retinal degenerations, Graves disease,
diabetic papillopathy, and nonorganic visual loss (hysteria/
malingering). Thus, a thorough eye examination and neuroimag-
ing are crucial.2
All the aforementioned information emphasizes the importance
of a detailed and thorough history to make the diagnosis, particu-
larly exposure to drugs, alcohol/tobacco use, dietary intake, pro-
fessional background, and family history (hereditary optic nerve
disorders).

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 Nutritional and Toxic Optic Neuropathy — Monferrer-Adsuara et al.

Although some nutritional and toxic optic neuropathy signature
signs were well represented in our case, it stood out from the gen-
eral clinical picture because of the broad initial differential dia-
gnoses of its subacute presentation and papilledema at the
diagnosis, an atypical sign in nutritional and toxic optic neurop-
athies, but frequently found in the ischemic and infectious neu-
ropathies dismissed in this patient. The papilledema may also
occur in some acute poisonings, this being the reason behind
considering methanol poisoning in our patient, a life-threatening
condition with ocular complications of secondary importance, but
crucial for making a proper diagnosis and a timely initiation of
the appropriate therapy.2
The patient's progressive signs and symptoms improved after
therapeutic compliance, with this reversibility being a remarkable
feature of toxic optic neuropathies. Nevertheless, the prognosis is
usually variable, depending on the nature of the substance in-
volved, degree of exposure before cessation, and visual acuity at
the diagnosis that could be further complicated by a certain level
of damage irreversibility over time and severity of the affection.3
In conclusion, the relative paucity of recent literature is making
nutritional and toxic optic neuropathy diagnosis a challenging pro-
cedure, as this disease is often underdiagnosed or detected at a
late stage, making the full recovery of visual acuity difficult. Eye
care specialists and primary eye care practitioners should consider
toxic optic neuropathies, whose diagnosis is mainly clinical and
warrants exclusion of other entities, to prevent severe and irrevers-
ible visual damage resulting from misdiagnosis and management
mistakes. Early diagnosis and treatment are mandatory and a good
prognostic indicator. Thus, we emphasize the importance of a thor-
ough history.

ARTICLE INFORMATION REFERENCES 4. Syed S, Lioutas V. Tobacco-alcohol Amblyopia: A Di-

Submitted: July 22, 2019
Accepted: February 21, 2020
Funding/Support: None of the authors have reported
funding/support.
Conflict of Interest Disclosure: No financial conflicts of
interest exist for any author.
Author Contributions: Conceptualization: CM-A, CG-V,
LR-S, EC-T; Data Curation: MO-S; Formal Analysis:
LR-S; Writing – Original Draft: LM-M; Writing – Review
& Editing: CM-A.
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