Review Article

Medication, Toxic, and

Address correspondence to
Dr Vinay Chaudhry, Johns
Hopkins University School of
Medicine, 601 N. Caroline St,

Vitamin-Related 5072A, Baltimore, MD 21287,

vchaudh@jhmi.edu.
Relationship Disclosure:

Neuropathies Dr Morrison receives research

support from Biogen-Idec for
the study of novel compound
in ALS. Dr Chaudhry serves as
Brett Morrison, MD, PhD; Vinay Chaudhry, MD, MBA, FRCP, FAAN a consultant for Novartis
Pharmaceuticals Corporation
and is a member of The
Neurologist Editorial Board.
ABSTRACT Dr Chaudhry receives license
Purpose of Review: Although medication, toxic, and vitamin-related neuropathies fee payments or royalty
are rare causes of neuropathy, they are important to recognize because they are payments from Abbott
Laboratories and Johnson &
treatable and preventable. It is often difficult to conclusively demonstrate that a Johnson Services, Inc., and
particular agent is the cause of neuropathy, but understanding the specific electro- license fee payments through
diagnostic and clinical patterns produced by these agents is critical for making these Johns Hopkins University for
the Total Neuropathy Score.
assessments. Dr Chaudhry receives
Recent Findings: The clinical and electrodiagnostic features for many of these research support from Nutricia
neuropathies have been well established. The exact mechanism by which some of for a study of ketogenic diet
in ALS. Dr Chaudhry has
these agents produce neuropathy is only now beginning to be revealed. These served as a medical record
mechanisms are critical for both understanding the normal function of nerves as reviewer and provided expert
well as eventually devising specific treatments. witness testimony for the
Department of Justice Injury
Summary: A large number of medications and toxins can produce neuropathy. This Compensation Program, and
article reviews the clinical characteristics, electrodiagnostic features, and mechanism has also given a deposition in
of action (when known) of those agents that produce the most severe, or perhaps a legal case.
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Copyright * 2012,
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INTRODUCTION ing for neuropathy, constant evaluation reserved.
In the differential diagnosis of peripheral of risks and benefits, and alternative op-
neuropathy, toxic neuropathies caused tions are critical strategies. Often two
by medications, food contaminants, en- toxic chemotherapeutic agents are used
vironmental exposure, or vitamin over- in combination, producing synergistic
dose or deficiencies are infrequently toxicity. A preexisting neuropathy from
the underlying cause. However, they diabetes, alcohol abuse, paraneoplastic
are, to varying degrees, treatable, and process, or inherited neuropathy may
this makes them important to recog- also contribute to worsening the sever-
nize. The possible toxin is often a ity of a toxic neuropathy. A set of criteria
medication that the patient has been for establishing causality should be ap-
prescribed to treat another condition. plied to each potential peripheral nerve
The decision to take a patient off a toxic drug. To determine causality for
medicine for ‘‘possible’’ toxic neurop- a potential toxin, a list of principles,
athy should not be made lightly, be- termed the ‘‘Bradford Hill Criteria,’’
cause the medication may be the best, have been outlined (Table 7-1).1 Apply-
first-line, or only treatment for the medi- ing these principles to neuropathies
cal condition. This is best exemplified is challenging, however, because defin-
by chemotherapy-induced neuropathy, ing the onset of neuropathy is often
in which dose reduction, close monitor- imprecise, making direct correlation of
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 Toxic Neuropathies

KEY POINT
h Toxic neuropathies are
defined by their clinical
and electrodiagnostic
characteristics, including
the specific fiber types
affected, the pattern of
the neuropathy, the
dosing information, and
the electrodiagnostic
features.
TABLE 7-1 Modified Bradford Hill Criteria to Establish Causation in
the Case of Peripheral Nerve Toxins
b Dose-response relationship
b Consistent manifestations related to biological activity of toxin if known
b Proximity of symptoms to exposure
b Stabilization or improvement following drug cessation
b Reproduction of pathology in animal models
b Epidemiologic studies or case reports
b Exclusion of other causes
Data from Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58(5):295Y300.

the neuropathy to a toxic exposure as distal weakness, loss of sensation,

difficult. In addition, many toxic neu-
ropathies have apparent ‘‘coasting pe-
riods,’’ where the symptoms appear to
continue to worsen weeks to months
after discontinuation of the offending
agent. Finally, the exact mechanism of
neurotoxicity is often unknown and
therefore difficult to establish conclu-
sively. For all these reasons, the deci-
sion to remove a potential peripheral
nerve toxin, particularly when it is a
medication, is not easy and requires a
careful weighing of the potential bene-
fits of the medication versus the evi-
dence of a toxic property.
Toxic neuropathies are identified not
only by their temporal relationships but
also by clinical and electrodiagnostic
characteristics, including the following:
& The specific fiber type affected. Small
fibers present as burning dysesthesia
and show loss of pinprick and tem-
perature sensibility; large sensory fi-
bers present as sensory ataxia and
show loss of vibration and proprio-
ception; motor fibers present as weak-
ness; and autonomic fibers present as
gastroparesis, syncope, sweating, and
bladder or erectile dysfunction.
& The pattern of neuropathy. Length-
dependent stocking-glove neurop-
athy (distal axonopathy) presents
and loss of ankle jerks; length-
independent neuropathy is sugges-
tive of neuronopathy.
& Dosing information. The relationship
of acute dose, dose duration, and cu-
mulative dose to the incidence and
severity of neuropathy.
& Electrodiagnostic features. Whether
the neuropathy is axonal, demy-
elinating, or neuronal.
A summary of electrodiagnostic fea-
tures of toxic neuropathies is provided
in Table 7-2. Most toxic neuropathies
are reversible (except for those that
cause sensory neuronopathy [dorsal
root ganglia injury]), provided they are
recognized early and the offending
agent can be removed. The informa-
tion in this article will assist clinicians
in assessing the potential of a specific
agent to produce a toxic neuropathy.
TOXIC NEUROPATHY
Pharmaceuticals
Antimicrobials. Although critical for
combating viruses, bacteria, protozoa,
and other infectious agents, several an-
timicrobials have clear toxic properties
to peripheral nerves (Table 7-3). For-
tunately, most antimicrobials are used
only for short periods of time, so
the neuropathies are often mild and

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TABLE 7-2 Toxic Neuropathies by EMG Characteristics

b Conduction Slowing—Motor Leflunomide

and/or Sensory
Misonidazole
Amiodarone Nitrous oxide
Arsenic Nucleoside analogs (zalcitabine,
Buckhorn didanosine, stavudine, fialuridine,
lamivudine)
Chloroquine and hydroxychloroquine
Statins
Ciguatera toxin
Taxanes
Diphtheria toxin
Thalidomide
Disulfiram
Vitamin B6 (pyridoxine) toxicity
Gold
Vitamin B6 deficiency
Hexacarbons
Vitamin B12 (cobalamin) deficiency
Perhexiline
Vitamin E deficiency
Procainamide
b No Conduction Slowing—Mixed
Saxitoxin and brevetoxin B (red tide) Sensorimotor
Suramin Arsenic
Tacrolimus (FK506) Ethanol
Tetrodotoxin (puffer fish) Ethylene glycol
b No Conduction Slowing— Fluoroquinolones
Predominantly Motor
Hydralazine
Dapsone
Mercury
Lead (high exposure)
Metronidazole
Tick paralysis
Mitotic spindle inhibitors (ie,
b No Conduction Slowing— vinblastine, vincristine, paclitaxel)
Predominantly Sensory
Nitrofurantoin
Almitrine
Organophosphates
Bortezomib
Statins
Chloramphenicol
Thallium
Colchicine
Copper deficiency
DNA-binding chemotherapies
(ie, cisplatin, carboplatin, oxaliplatin) Vitamin B1 (thiamine) deficiency

Ethambutol b Mononeuropathy Multiplex

Isoniazid Dapsone

Lead (low exposure) Lead

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 Toxic Neuropathies

TABLE 7-3 Toxic Neuropathies Summary: Pharmaceuticals

Nerve Fiber Type

Medication or Affected Nerves Site of Injury Course
Antimicrobials
Nucleoside analogs Small fiber sensory Axonal Subacute,
(zalcitabine, didanosine, 9 large fiber chronic
stavudine, fialuridine, sensory 9 motor
lamivudine)
Isoniazid Pansensory 9 motor Axonal Chronic
Ethambutol Pansensory 9 motor Axonal Chronic
Dapsone Motor 9 pansensory, Axonal Subacute,
autonomic chronic
Chloramphenicol Pansensory Axonal Subacute
Nitrofurantoin Pansensory, motor Axonal Subacute
Fluoroquinolones Pansensory, motor Axonal Chronic
Metronidazole Pansensory, motor Axonal Subacute
Cardiovascular drugs
Amiodarone Pansensory, motor Demyelinating Chronic
Hydralazine Pansensory 9 motor Axonal Chronic
Procainamide Pansensory, motor Demyelinating Chronic
Perhexiline Pansensory, motor, Demyelinating Chronic
autonomic
Statins Pansensory 9 motor Axonal Chronic
Chemotherapy
Mitotic spindle drugs
Vinca alkaloids Pansensory, motor, Axonal Chronic
autonomic
Taxanes Pansensory 9 motor Axonal (neuronal) Chronic
DNA-binding drugs
Cisplatin/Carboplatin Large fiber 9 small Neuronal Chronic
fiber sensory
Oxaliplatin Large fiber 9 small Neuronal Chronic,
fiber sensory acute
Proteasome inhibitors Pansensory 9 motor Axonal Chronic
(bortezomib) (demyelinating)
Thalidomide Pansensory 9 motor Axonal (neuronal) Chronic
Suramin Pansensory 9 motor Axonal Chronic
(demyelinating)
Misoindazole Pansensory Axonal Chronic
Continued on next page

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 KEY POINT
Continued h Most antibiotics given
for a short period of
Nerve Fiber Type time (ie, 3 to 14 days)
Medication or Affected Nerves Site of Injury Course will not produce
neuropathy. Only
Immunosuppressives
antibiotics given for
Gold Pansensory 9 motor Demyelinating Acute or infections that require
(axonal) subacute lengthy treatment
Colchicine Pansensory 9 motor Axonal Chronic durations, such as
tuberculosis and HIV,
Chloroquine Pansensory 9 motor Demyelinating Chronic
or those given
(axonal)
prophylactically to
Tacrolimus Pansensory, motor Demyelinating Acute prevent infections will
Leflunomide Small fiber 9 large Axonal Chronic cause neuropathy.
fiber 9 motor
Other
Almitrine Small fiber 9 large Axonal Chronic
fiber 9 motor
Phenytoin Pansensory, motor Axonal Chronic
Pyridoxine Small fiber sensory, Neuronal Chronic
(vitamin B6) large fiber sensory,
autonomic

self-limiting. Antimicrobials that are usu-
ally given for long periods of time
(and thus have the potential to produce
more significant neuropathy) include
nucleoside analogs, used to treat HIV;
isoniazid and ethambutol, used to treat
tuberculosis; dapsone, used to treat lep-
rosy and prophylactically to prevent
opportunistic infections in immunosup-
pressed individuals; chloramphenicol,
used to prevent respiratory infections in
children with cystic fibrosis; nitrofuran-
toin, used to prevent recurrent urinary
tract infections; fluoroquinolones, used
to treat many bacterial infections; and
metronidazole, used to treat protozoan
and anaerobic bacteria.
Nucleoside analogs and other treat-
ments for HIV have dramatically ex-
tended the survival of patients with HIV.
These medicines must be taken for de-
cades, so symptoms of peripheral nerve
toxicities are important to recognize
early. Nucleoside analogs, which include
zalcitabine, didanosine, stavudine, fia-
luridine, and lamivudine, can produce
a moderate to severe, primarily sen-
sory axonal neuropathy.2 Both large
and small caliber sensory nerve fi-
bers are involved, and pain is the pri-
mary symptom reported. In addition,
lamivudine has been associated with
weakness from involvement of motor
nerves. Symptoms begin 6 to 8 weeks
after medication initiation and begin
to recede approximately 1 month af-
ter discontinuing the medication. The
mechanism of toxicity is the same
as the mechanism of action. These
compounds inhibit DNA polymerase
gamma, which is important for both
HIV replication and mitochondrial
DNA replication in neurons. Thus, the
presumed mechanism of degeneration
is energy failure to the axon. It is of-
ten difficult to separate the neuropathy
produced by these agents from neu-
ropathy caused by HIV itself. Serum
lactate may help distinguish between
these possibilities.3 Because nucleoside

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 Toxic Neuropathies
KEY POINTS
h Neuropathy caused by analogs reduce the number of mito-
nucleoside analogs chondria, there is reduced conversion
often produces of pyruvate to acetyl coenzyme A and
elevation of serum increased production of lactate. We
lactate due to therefore suggest that elevated serum
mitochondrial deficiency, lactate (greater than 2.2 mmol/L) in the
whereas neuropathy appropriate clinical context may distin-
produced by HIV itself guish nucleoside analog toxicity from
does not. This can be HIV neuropathy. In fact, this single cri-
used to distinguish terion was 90% sensitive and 90% spe-
between these clinically
cific in discriminating stavudine toxic
similar neuropathies
neuropathy from HIV distal sensory
in patients with HIV.
neuropathy. Thus far no treatments
h Dapsone can produce a have been proven to reduce the toxic-
motor-predominant or
ity to nerves, and this side effect is often
mononeuropathy
dose-limiting. Fortunately, the use of
multiplex pattern of
neuropathy, which is
neurotoxic antiretrovirals has markedly
unusual for decreased in the developed world,
medication-induced although they are still commonly used
neuropathy. in the developing world because of their
low cost.
Two agents used to treat tuberculo-
sis, isoniazid and ethambutol, can also
cause peripheral neuropathy.4 These
treatments are often given for many
months, so it is critical to evaluate pa-
tients for this potential toxicity. Both
isoniazid and ethambutol produce a
sensory-predominant axonal polyneur-
opathy, although their mechanisms of
toxicity are quite different. Isoniazid,
which often produces neuropathy af-
ter 4 to 6 months of use, depletes the
body of vitamin B6 (pyridoxine) by in-
creasing its excretion in the urine, thus
inhibiting vitamin B6Ydependent en-
zymes. In contrast, ethambutol appears
to inhibit mitochondrial protein syn-
thesis, which leads to energy failure
and nerve degeneration. Because of its
mechanism of action, nerve toxicity
from isoniazid can often be ameliorated
or avoided completely by cotreating pa-
tients with vitamin B6 supplements (rec-
ommended dose of 10 mg/d for every
100 mg/d of isoniazid treatment). As for
ethambutol, no treatments are available
to reduce its toxicity. Although the pe-
ripheral neuropathy caused by etham-
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butol is mild, retrobulbar optic neurop-
athy is a more concerning toxicity.
Dapsone is used to treat leprosy, an
infection caused by Mycobacterium lep-
rae, and also as a prophylactic agent to
prevent opportunistic infections in immu-
nosuppressed individuals. With respect
to leprosy treatment, dapsone is often
used along with rifampicin and clofa-
zimine. It is also a second-line treatment
to prevent immunosuppressed patients
who cannot tolerate cotrimoxazole from
developing toxoplasmosis and pneu-
mocystis pneumonia. Dapsone pro-
duces a nonYlength-dependent motor-
predominant neuropathy or even a
mononeuropathy multiplex neuropa-
thy that causes weakness in upper
more than lower extremities, which is
unusual for a toxic neuropathy.5 The
toxic neuropathy primarily occurs with
daily doses equal to or greater than
300 mg per day, and often takes weeks
to years to develop. The mechanism of
toxicity is unknown, and there are no
known preventive treatments.
Chloramphenicol, an antibiotic that
was previously used to treat frequent
pseudomonal infections in children
with cystic fibrosis, is now used less fre-
quently because of toxicities. The pri-
mary concern for toxicity with this
medication is not actually peripheral
neuropathy but rather bone marrow sup-
pression. Thus, other antibiotics are
often first-line choices. Chloramphenicol
can produce a mild distal painful periph-
eral neuropathy.6 It has also been as-
sociated with an optic neuropathy.
Nitrofurantoin, an antibiotic used
for urinary tract infections, may cause
length-dependent paresthesia and
weakness affecting the feet and
hands.7 The neuropathy is more likely
to occur with prolonged use of the
drug, in the elderly, and in those with
renal dysfunction. Nerve conduction
studies show an axonal neuropathy
with decreased amplitudes in sensory
February 2012
and motor fibers. Some patients have an
abrupt onset of symptoms following brief
exposure to nitrofurantoin, suggesting
an allergic reaction rather than the dose-
dependent phenomenon noted with
most toxic neuropathies, although the
precise mechanism of action is poorly
understood.
Fluoroquinolones are a commonly
used class of antibiotics used to treat
bacterial infections ranging from urinary
tract infections to pneumonia. In one
study of self-reported adverse events,
many patients taking these medications
reported neuropathic symptoms, par-
ticularly sensory symptoms.8 However,
this study was completely based on self-
reported symptoms, and there was no
physical examination, electrodiagnostic
study, or pathology to support a diag-
nosis of neuropathy. A single case of a
reversible sensorimotor axonal polyneu-
ropathy has been reported in a patient
taking pefloxacin for several months to
treat osteomyelitis.9 For now, it is most
accurate to say that the fluoroquinolones
may cause neuropathy but that more
definitive studies need to be completed.
The final antimicrobial associated
with significant peripheral neuropathy
is metronidazole. Metronidazole is a
commonly used medication for treat-
ing protozoan and anaerobic bacteria
infections. It is also used as an anti-
inflammatory medication for the treat-
ment of Crohn disease. It produces a
sensory-greater-than-motor axonal neu-
ropathy that involves both small and
large caliber nerve fibers.10 It appears
to be dependent on cumulative doses,
as those receiving greater than 30 g
total are at highest risk. Interestingly,
this toxic neuropathy has been associ-
ated with elevated CSF protein. Recov-
ery after discontinuing the medication
is often delayed for 6 to 12 months.
Cardiovascular drugs. Given the
vast array of medications used to treat
cardiovascular diseases, very few of
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them cause significant peripheral neu-
ropathy. Four medications that have
been linked to neuropathy are amio-
darone, procainamide, hydralazine,
and perhexiline. The statin class of
medications, which have clearly been
shown to cause myopathy, have also
been shown by some investigators to
cause a neuropathy, although this re-
mains quite controversial.
Two anti-arrhythmics, amiodarone
and procainamide, have been shown
to produce peripheral neuropathy.
Amiodarone is a commonly used anti-
arrhythmic drug that is used both
acutely as part of advanced cardiopul-
monary life support as well as chronically
to rate stabilize patients with atrial fibril-
lation and other arrhythmias. The medi-
cation has been associated with a sen-
sorimotor neuropathy, often with severe
motor symptoms, in approximately 6%
of patients.11 Electrophysiologically, the
neuropathy is characterized by demye-
inating features with prolonged distal la-
tencies, prolonged F waves, and reduced
conduction velocities. Symptoms often
improve with discontinuation or reduc-
tion of dose. The mechanism of action
is not known, but cytoplasmic intralyso-
somal inclusions are observed within
endothelial cells and nonmyelinating
Schwann cells. In contrast to amiodar-
one, which can cause mixed features of
demyelination and axonal degenera-
tion, procainamide selectively produ-
ces demyelination.12 This is unusual
for a toxic neuropathy and distin-
guishes procainamide from most other
agents. Nerve conduction studies clas-
sically show prolonged distal latencies
and prolonged conduction velocities
without reduced amplitudes. Nerve bi-
opsies of patients with procainamide
toxicity show perivascular inflammation,
demyelination, and ‘‘onion bulbs.’’ In
addition, CSF analysis reveals elevated
CSF protein. Chronic procainamide
toxicity is in the differential diagnosis
www.aan.com/continuum 145
 Toxic Neuropathies
KEY POINTS
h Vitamin B6Yresponsive for chronic inflammatory demyelinat-
neuropathies include ing polyneuropathy (CIDP).
isoniazid, hydralazine, Hydralazine is an older antihyper-
and, of course, vitamin tensive that is still used because of its
B6 deficiency. potency and rapid onset of action. In
h Mitotic spindle inhibitors standard doses, it rarely produces a
all produce an axonal sensory-predominant axonal neuropa-
dying-back neuropathy thy. This drug toxicity is important to
by disrupting recognize, however, because the neuro-
microtubule-dependent pathy is improved by treatment with
axonal transport. vitamin B6 (pyridoxine).13 Similar to iso-
niazid, hydralazine appears to increase
vitamin B6 excretion in the urine, thus
causing vitamin B6 deficiency.
Perhexiline is used for treatment of
angina pectoris in Europe and other
countries, but it is not approved by
the US Food and Drug Administration.
Sensory, motor, and autonomic nerve
fibers can be variably affected depend-
ing on the duration of treatment. Nerve
conduction studies show a predomi-
nantly demyelinating physiology. The
neuropathy is reversible, and symptoms
usually improve within a few weeks of
cessation of the drug.14
The final group of cardiovascular
medications that may produce periph-
eral neuropathy is statins. Statins, which
include simvastatin, atorvastatin, fluvas-
tatin, lovastatin, pitavastatin, pravastatin,
and rosuvastatin, are inhibitors of the en-
zyme $-hydroxy-$-methylglutaryl-CoA
reductase, which is critical in the forma-
tion of cholesterol. They are among the
most frequently prescribed medications
in the United States, and their associa-
tion with myalgias and myopathy is well
known. More controversial, however, is
their potential nerve toxicity. Some co-
hort studies show an effect15 whereas
others do not.16 Part of the controversy
may stem from the fact that triglycerides,
which themselves have been linked to
the development of neuropathy, are
elevated in virtually all patients taking
statins. If present, statins may cause an
axonal sensorimotor neuropathy, and
the onset of neuropathy has been de-
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scribed in patients taking the medication
from 1 to 7 years. Further clarification
of this issue is likely necessary. See the
review by Umapathi and Chaudhry for
a more detailed discussion.17
Chemotherapy-induced neuropathy.
For many types of cancers, advances
in cell and molecular biology have led
to the development of newer, less-
toxic pharmacologic treatments. De-
spite these advances, many of the older
chemotherapies, designed to disrupt
major intracellular processes, continue
to be used. These chemotherapies pro-
duce widespread toxicity, although the
toxicity to peripheral nerves is often
dose-limiting. For the purpose of this
article, cancer therapeutics will be
grouped by their mechanism of ac-
tion into mitotic spindle inhibitors,
DNA-binding compounds, proteasome
inhibitors, and others or unknown.
Mitotic spindle inhibitors. This class
of cancer therapeutics reduces the
capacity of tumor cells to replicate by
preventing mitosis. Unfortunately, all
of these compounds produce a dying-
back neuropathy by interfering with
the microtubule system, which is
critical for axonal transport. Specific
compounds in this class include vin-
blastine, vincristine, paclitaxel, and
docetaxel. Vinblastine and vincristine
are used primarily for hematologic
and lymphatic cancers. They bind
directly to tubulin, disrupting micro-
tubule formation. The axonal neuro-
pathy produced by vinblastine and
vincristine can involve sensory, motor,
autonomic, or cranial nerves, and is
often dose-limiting.18 The differential
diagnosis of neuropathy produced by
these compounds includes Guillain-
Barré syndrome (GBS) and malignant
infiltration of the nerve (Case 7-1).
Paclitaxel and docetaxel are taxoids and
are commonly called taxanes. They are
used to treat a number of different
types of cancers. They function to
February 2012
 KEY POINT

Case 7-1 h DNA-binding

compounds, such as
A 29-year-old woman with a diagnosis of ataxia telangiectasia since the age
cisplatin, carboplatin,
of 6 was diagnosed with non-Hodgkin lymphoma for which she received
and oxaliplatin, produce
vincristine 1.5 mg/m2 (total of 2 mg), doxorubicin 30 mg/m2, and
a neuronopathy by
cyclophosphamide 750 mg/m2. Within a week of receiving one dose of
binding to and
vincristine, she developed severe weakness and required hospitalization
damaging DNA. Dorsal
because she was unable to take care of herself. Examination showed severe
root ganglia, and thus
distal sensory loss (to pin, vibration, and proprioception), severe distal
sensory neurons, are
weakness, and absent reflexes. Nerve conduction studies revealed absent
particularly vulnerable
sural, median, ulnar, and radial sensory nerve action potentials, absent
because of the relative
motor responses (compound muscle action potentials [CMAPs]) in the legs,
leakiness of the
and reduced CMAP amplitudes in the upper limbs. CSF analysis was normal.
blood-brain barrier
The patient continued to worsen for several weeks prior to stabilization. Her
around ganglia as
neuropathy gradually improved over the subsequent 2 years, although she
compared to the
continued to have numbness and weakness distally in her lower extremities.
spinal cord.
Comment. This case illustrates an example of an acute sensory and motor
toxic neuropathy secondary to vincristine treatment. As demonstrated in
this case, the presentation is often very similar to Guillain-Barré syndrome,
so a careful medication history is required for all patients presenting with
acute neuropathy. This case also exemplifies the slow, but significant,
recovery in peripheral nerve function that can occur even in severe cases
of axonal neuropathy. This improvement is due to the regrowth of
peripheral nerves following removal of the toxic agent.

stabilize the microtubule subunit, pro-
moting assembly of disordered micro-
tubules in dorsal root ganglia, axons,
and Schwann cells, which interferes
with axonal transport. They produce a
sensory-greater-than-motor peripheral
neuropathy, particularly at doses greater
than 200 mg/m2. Fortunately, the symp-
toms are rarely dose-limiting; however,
individual high doses of taxanes
(greater than 300 mg/m2) have been
reported to cause a syndrome of sen-
sory neuronopathy (ganglionopathy)
with severe disabling ataxia. Several
preventive treatments, including gluta-
mine, acetyl-L-carnitine, neurotrophins,
vitamin E, and alpha lipoic acid, have
been tried, but none has proven effec-
tive (Case 7-2).
DNA-binding compounds. The pri-
mary chemotherapeutics in this class are
the platinum compounds cisplatin, car-
boplatin, and oxaliplatin. They are used
to treat several solid organ cancers, in-
cluding testicular, ovarian, lung, breast,
and colon cancer. The compounds func-
tion as cancer treatments by binding to
and injuring DNA, thus causing apop-
tosis. All three compounds produce a
sensory neuronopathy by direct damage
to the dorsal root ganglia.19 Patients re-
port severe paresthesia, pain, and loss
of balance. The differential diagnosis
includes other causes of sensory neu-
ronopathy, such as paraneoplastic gan-
glionopathy and Sjögren syndrome. In
general, neuronopathy is associated with
total cumulative dose. Of the three, car-
boplatin is less toxic, unless it is com-
bined with other chemotherapeutic
agents, such as paclitaxel. In addition
to the sensory neuronopathy, oxalipla-
tin can also cause acute onset of cold-
induced paresthesia, throat and jaw
tightness, and muscle cramps. These
symptoms are associated with repeti-
tive synchronous discharges and neu-
romyotonia on EMG.20
Proteasome inhibitors. The pro-
teasome complex is responsible for

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 Toxic Neuropathies

Case 7-2
A 74-year-old man with diabetes on metformin and glyburide was
evaluated for diabetic neuropathy prior to receiving chemotherapy for
mesothelioma of the pleural cavity. He had numbness on the bottom of
both feet but required no neuropathic pain medications. Examination
showed distal sensory loss to pinprick, absent ankle jerks, and mild distal
weakness. Sural and peroneal responses were absent. Chemotherapy
with paclitaxel for mesothelioma (125 mg/m2 every 2 weeks for four cycles)
and later carboplatin followed by cisplatin for recurrent squamous cell
carcinoma of the neck (40 mg/m2 for eight such cycles) was given over
7 months. After 4 months on the cisplatin, the patient developed severe
pain, numbness, and tingling in his extremities. He also had problems with
balance and dexterity. Examination showed distal loss of sensation to
pinprick up to the level of the midthigh, absent vibration sense up to the
knees, loss of proprioception in the toes, loss of kinesthetic sense in the
feet and hands, positive Romberg sign, normal strength, and absent
reflexes. Nerve conduction studies showed absent sensory responses and
preserved motor responses.
Comment. This patient developed typical sensory-greater-than-motor
neuropathy following administration of paclitaxel, a mitotic spindle
inhibitor, and carboplatin and cisplatin, DNA-binding drugs. In addition to
developing the typical toxic neuropathy from these medications, this
patient also exemplifies the additive risk of using multiple medications
toxic to the peripheral nerve or having neuropathy (in this case due to
diabetes) prior to administration of agents.

breaking down most of the proteins frequently cause toxic neuropathy.

marked for degradation within the cell.
Therefore, inhibitors of this process
disrupt multiple cellular pathways. The
most commonly used proteasome
inhibitor in cancer treatment is borte-
zomib. It is used primarily for recur-
rence of myeloma and functions to
inhibit the 26s proteasome, preventing
the normal degradation of nuclear
factor-.B (NF.B) and reducing cell di-
vision and proliferation. Approximately
30% of patients on this medication
develop a painful sensory neuropathy
involving small-greater-than-large cali-
ber nerve fibers.21 Symptoms gradually
improve after discontinuing the medi-
cine. A demyelinating neuropathy re-
sembling GBS or CIDP has also been
described.22
Other cancer drugs. Suramin, thali-
domide, and misonidazole are three
other chemotherapeutic agents that
148 www.aan.com/continuum
Suramin is used to treat Kaposi sar-
coma, a connective tissue tumor most
commonly seen in immunosuppressed
patients. Neuropathy is a common side
effect of treatment; 15% to 40% of pa-
tients develop evidence of neuropathy.
The neuropathy can manifest with axo-
nal or demyelinating features and often
leads to elevated CSF protein; there-
fore, the differential diagnosis includes
GBS.23 The mechanism of toxicity is
unknown but may involve blocking
nerve growth factor receptor or in-
creasing ceramide. Thalidomide, used
to treat multiple myeloma, graft versus
host reaction, and discoid lupus,
causes a length-dependent, axonal,
sensory-greater-than-motor neuropa-
thy with cumulative doses greater than
20 g, although significant neuropathy
is only seen with cumulative dosages
up to 100 g.24 Thalidomide has also
February 2012

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been reported to cause a nonreversible
neuronopathy (ganglionopathy). It
appears to act on multiple myeloma
by inhibiting NF.B activation. The
exact pathogenesis of neuropathy is
unknown, but neuropathy is very com-
mon and virtually 100% of patients
develop this side effect by 9 months.
The final chemotherapeutic agent that
produces significant neuropathy is
misonidazole. It is actually not toxic
to tumors at all but rather acts as a
radiosensitizer to increase the effec-
tiveness of radiation treatment. Thirty
percent of patients taking the medica-
tion develop a painful pansensory
neuropathy characterized electrophy-
siologically by axonal features with
secondary demyelination.25
Immunosuppressive medications.
Immunosuppressive medications are
used to treat rheumatologic and auto-
immune diseases and to prevent re-
jection following organ transplant. The
medications are often prescribed for
years, and several of them have been
associated with neuropathy. Peripheral
neuropathy has been associated with
older medications such as gold, colchi-
cine, and chloroquine, as well as newer
medications such as tacrolimus and
leflunomide.
Organic gold salts, including gold so-
dium thiomalate and thioglucose, are in-
jectable treatments primarily used for
rheumatoid arthritis and other inflam-
matory arthritides. The neuropathy is
a mixed axonal and demyelinating sen-
sory and motor neuropathy that appears
to be dependent on total cumulative
dose.26 Rapidly progressive weakness,
areflexia, and stocking-glove sensory
loss may occur. A predominantly sen-
sory neuropathy has also been re-
ported. Patients who have been treated
with more than 1 g of gold salt are at the
greatest risk. The neuropathy may be
associated with elevated CSF protein
and occasionally myokymia on needle
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KEY POINT
EMG. In addition to peripheral neuro- h Tacrolimus produces
pathy, patients often develop cranial a demyelinating
neuropathies. Nerve biopsies show seg- neuropathy that mimics
mental demyelination. The exact mecha- Guillain-Barré syndrome
nism of neuropathy is unknown. and responds to
Colchicine is a first-line treatment treatment with IV
for an acute attack of gout. It disrupts immunoglobulin or
microtubules, causing both a pan- plasmapheresis.
sensory axonal polyneuropathy and a
vacuolar myopathy.27 Of the two, the
myopathy is usually more severe. The
neuropathy rapidly improves after dis-
continuing colchicine.
Chloroquine and hydroxychloro-
quine are used to treat a number of au-
toimmune disorders as well as malaria.
Like colchicine, the major toxicity of the
medicine is myopathy, and the neurop-
athy symptoms are usually more mild.28
The peripheral neuropathy is a mixed
demyelinating and axonal neuropathy
of both sensory and motor nerves, and,
similar to gold salts, CSF protein is of-
ten elevated. The mechanism of neu-
rotoxicity appears to be disruption of
lysosomal function and the develop-
ment of Schwann cell toxicity.
Tacrolimus is a very potent immuno-
suppressive agent used to prevent trans-
plant organ rejection and to treat severe
autoimmune diseases. It can cause sig-
nificant CNS toxicity but produces pe-
ripheral neuropathy in fewer than 1% of
patients who take the medicine. Symp-
tomatically, patients develop distal pain
first, followed by a sensorimotor poly-
neuropathy. A predominantly motor
neuropathy with flaccid quadriparesis
and areflexia can also occur. The neu-
ropathy has primarily demyelinating
features, and interestingly has been suc-
cessfully treated with IV immunoglobu-
lin or plasmapheresis.29 The etiology is
unclear, but it may be a form of GBS
caused by abnormal T-cell activation or
autoantigen response.
Leflunomide is a new immuno-
suppressive agent used to treat rheu-
matoid arthritis. The mechanism of
www.aan.com/continuum 149
 Toxic Neuropathies

KEY POINT
h Pyridoxine-induced
neuropathy is becoming
increasingly common
because of the number
of supplements
containing pyridoxine
marketed to patients
with neuropathy.
action is inhibition of pyrimidine syn-
thesis. The medication produces a
painful axonal, sensory-greater-than-
motor neuropathy with onset 3 to 6
months following drug initiation.30
The mechanism of neurotoxicity is
unknown.
Other drugs. Almitrine bismesylate
is used to improve blood gas concen-
trations, although it is not approved
for use in the United States. Altmitrine
can cause progressive dysesthesia in a
stocking-glove pattern. Neurologic exami-
nation reveals distal sensory loss and
areflexia with preserved strength. Nerve
conduction studies show reduced sen-
sory and motor amplitudes with preser-
vation of conduction velocities.31
Phenytoin, historically the most com-
monly prescribed antiepileptic drug, has
been associated with a mild predomi-
nantly sensory neuropathy. In most
cases, the neuropathy is only detected
by noting absent reflexes and distal sen-
sory loss on clinical examination, al-
though clinically symptomatic neuropa-
thy may develop with sustained high
levels of exposure. Nerve conduction
study shows an axonal pattern with
reduction in sensory and motor ampli-
tudes. The mechanism of this neuropathy
is not understood, but it is reversible
after discontinuing the medication.32
Pyridoxine (or vitamin B6) is mar-
keted to patients as a treatment for neu-
ropathy. Although some patients do
develop neuropathy from lack of pyr-
idoxine (see below section on vitamin
deficiencies), most patients do not re-
quire the supplement and can present
with pyridoxine toxicity if it is taken
in excess (Case 7-3). Acute pyridoxine
toxicity produces severe sensory neu-
ronopathy, whereas chronic pyridox-
ine toxicity, which can be caused by
as little as 50 mg/d of pyridoxine sup-
plements, produces diffuse paresthe-
sia, proximal and distal sensory loss,

Case 7-3
A 30-year-old man self-diagnosed his intermittent hand pain as carpal tunnel syndrome and
self-administered over-the-counter 500 mg pyridoxine (vitamin B6) pills, increasing the dose to 20 pills a
day when his symptoms did not improve with lower doses. Over a period of 4 weeks, he developed
severe burning pain, allodynia, and numbness progressing from his feet through his knees, and his
hands through his elbows. These symptoms impaired his manual dexterity such that he could not cut his
food or button his shirts. His gait became progressively unsteady because of the absence of feeling in
his feet, and he became wheelchair dependent within 6 weeks of initiating pyridoxine treatment.
Examination revealed profound loss of perception to pin, temperature, vibration, and proprioception
in all four limbs, from the feet to the iliac crests and from the hands to the elbows. Deep tendon reflexes
were absent. Strength and autonomic functioning were preserved. Nerve conduction studies revealed
absent sensory responses in all upper and lower extremity nerves. A sural nerve biopsy demonstrated
severe reduction in the density of large myelinated fibers. Skin biopsy showed severe reduction in fiber
density that was worse in the feet and wrists than in the thigh and elbow.
Following pyridoxine cessation, the patient continued to feel worse for another 2 months. His
condition then stabilized, and he improved over the next year, although objective findings on
examination, skin biopsy, and nerve conduction did not improve dramatically.
Comment. This case exemplifies both the clinical scenario and progression of symptoms typically
seen in a case of severe pyridoxine toxicity. As expected, the sensory system, particularly the dorsal
root ganglia, is most severely affected, whereas the motor nerves are spared. This case also
demonstrates the phenomenon of coasting (further progression of symptoms even after cessation
of the toxic agent), which is common in many toxic neuropathies. As is typical with toxic sensory
neuropathies involving the dorsal root ganglia, the patient had little objective evidence of
improvement, although he subjectively felt somewhat better.

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autonomic dysfunction, sensory ataxia,
and reduced reflexes. 33 Although
recovery following acute pyridoxine
toxicity is poor, recovery from chronic
toxicity is quite good.
Occupational, Biological, and
Environmental Agents
Heavy metals. Toxicity to heavy metals
can occur through occupational expo-
sure, contamination of living space, or

TABLE 7-4 Toxic Neuropathies Summary: Occupational, Biological,

and Environmental Agents

Nerve Fiber Type or

Toxin Affected Nerves Site of Injury Course
Heavy metals
Lead Motor 9 pansensory Axonal Chronic
Arsenic Pansensory, motor Axonal, Acute or
demyelinating chronic
Thallium Small fiber 9 large Axonal Chronic
fiber sensory, motor
Mercury Pansensory, motor Axonal Chronic
Seafood toxins
Ciguatera Pansensory, autonomic Demyelinating Acute
Red Tide Pansensory, motor Demyelinating Acute
Saxitoxin
Brevetoxin
Tetrodotoxin Pansensory, motor, Demyelinating Acute
autonomic
Environmental/occupational
Organophosphates Pansensory, motor Axonal Subacute
Ethylene glycol Pansensory, motor Axonal Acute
Hexacarbons Pansensory, motor Axonal, Subacute
demyelinating
Acrylamide Pansensory, motor, Axonal Subacute
autonomic
Vacor Pansensory, motor, Axonal Acute
autonomic
Alcohol Pansensory, Axonal Subacute
Disulfiram Pansensory, motor Demyelinating Subacute
Nitrous oxide Large fiber sensory Axonal Chronic
Other
Buckthorn Motor 9 pansensory Demyelinating Acute
Tick Motor, autonomic Axonal Acute
Diphtheria toxin Motor 9 pansensory Demyelinating Acute

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 Toxic Neuropathies
deliberate poisoning. Lead toxicity is the
most common heavy metal toxicity that
causes neuropathy, but arsenic, thal-
lium, and mercury can also cause toxic
peripheral neuropathy (Table 7-4).
Lead toxicity can occur through oc-
cupational contact with lead solder, but
it is more commonly seen with chronic
exposure to lead pipes, lead paint, or
lead shot. In adults, neuropathy is the
most common symptom, whereas chil-
dren are more likely to develop cog-
nitive problems.34 Children absorb a
higher percentage of lead through their
gastrointestinal system than adults, mak-
ing them more sensitive to low levels of
lead in food or drinking water. Lead
toxicity in children and adults has be-
come increasingly uncommon because
of recognition of its dangers and pro-
duction of pipes and paint without lead.
Subacute moderate- or high-level expo-
sure, which occurs primarily through in-
haling industrial aerosolized lead,
produces an axonal multifocal motor
neuropathy with minor sensory symp-
toms. Asymmetric finger and wrist drop,
resembling radial neuropathy, are
unique to lead toxicity, although more
diffuse weakness can also occur. Chronic
low-level exposure produces distal sym-
metric sensory loss. The pathogenesis
of neurotoxicity is believed to be dis-
ruption of mitochondrial oxidative phos-
phorylation. Associated symptoms are
abdominal pain, constipation, and ane-
mia. Although experimental models
show demyelinating neuropathy, the
prominent finding in humans is an axo-
nal neuropathy. Treatment is removal
of lead exposure and chelation therapy
with penicillamine.
Arsenic toxicity most often occurs
from contaminated water supply or ex-
posure to byproducts of copper and
lead smelting, although rare cases of
deliberate poisoning also occur. The
neuropathy produced by arsenic toxic-
ity is an axonal sensory and motor neu-
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ropathy.35 Both acute (GBS-like) and
chronic length-dependent neuropathy
can occur, depending on the severity
of the exposure. In addition to neu-
ropathy, acute toxicity also causes
nausea, vomiting, abdominal pain, di-
arrhea, psychosis, and seizures, while
chronic toxicity produces Mees lines,
hyperpigmentation, and palmar/solar
keratoses. Treatment of acute expo-
sure involves gastric lavage, aggres-
sive IV fluid replacement, and admin-
istration of chelating agents. The two
recommended chelating agents for
arsenic toxicity are 2,3-dimercapto-1-
propanesulfonate (DMPS) and meso-
2,3-dimercaptosuccinic acid (DMSA).
For chronic exposure, it is most impor-
tant to remove the exposing agent. In
addition, some evidence suggests that
DMPS may hasten the relief of systemic
symptoms of toxicity, although it does
not appear to impact recovery from
neuropathy, which is often incomplete
and delayed several months.
Thallium toxicity occurs either through
intentional poisoning or accidental in-
gestion. Acute toxicity causes a painful
sensory neuropathy with preserved
strength and reflexes and is associated
with alopecia.36 Chronic exposure
causes an axonal sensorimotor neu-
ropathy. Nerve biopsies demonstrate
swollen mitochondria and a distal
axonopathy; therefore, the presumed
mechanism of nerve degeneration is
energy failure from mitochondrial dys-
function. Treatment of acute ingestion
should include gastric lavage and admin-
istration of either intragastric Prussian
blue or activated charcoal. Chelating
agents have no role, but some physicians
recommend urgent hemodialysis.
Mercury is a metal used in many in-
dustries and is found in batteries and
fungicides. With the exception of a few
historical examples of mercury poi-
soning of a large population, most no-
tably the contamination of Minamata
February 2012

Bay from a factory spill in 1961, sub-
acute mercury poisoning occurs pri-
marily through occupational exposure.
Whether clinically significant mercury
toxicity can occur from eating fish high
in mercury, old dental fillings, or injec-
tions of thimerosal, which is a preser-
vative found in most vaccinations, is
controversial.37 Mercury primarily causes
cognitive and behavioral changes as
well as ataxia, but neuropathy can oc-
cur. Subacute exposure to metallic
mercury vapor clearly produces motor
axonal neuropathy, whereas chronic ex-
posure produces a painful axonal sen-
sorimotor polyneuropathy. Treatment
of subacute or acute toxicity involves
gastric lavage, activated charcoal, and
chelating agents. For chronic exposure,
removal of the offending agent is the
primary treatment. The pathogenesis
of mercury neurotoxicity is unclear, al-
though some authors have suggested
glutamate excitotoxicity.38
Seafood toxins. Seafood toxins can
be produced by algae, plankton, or cer-
tain fish. When consumed, these toxins
produce acute, and sometimes chronic,
toxicity to nerves. Toxins from algae or
plankton are concentrated in bivalve
mollusks or fish, which then produce
human disease after being ingested.
Ciguatera toxin is produced by micro-
algae within dinoflagellates (plankton)
located in the Caribbean, Indo-Pacific
region, and Australia. It is concentrated
first in herbivorous fish that consume
the plankton and later in carnivorous
fish. Human disease results from con-
sumption of a contaminated fish. It is
relatively common; 10,000 to 50,000
cases occur worldwide annually. Twelve
to 48 hours after ingestion, patients de-
velop a prodrome of gastroenteritis,
followed by perioral and distal paresthe-
sia that lasts from days to months. Addi-
tional symptoms include paradoxical
disturbances of temperature sensation,
myalgias, insomnia, prominent auto-
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KEY POINT
nomic signs, and sensory neuropathy.39 h Seafood toxins (ie,
Death due to shock may occur in up to ciguatera, red tide, or
20% of patients. A chronic syndrome tetrodotoxin) cause
consisting of fatigability, depression, neuropathy by binding
and weakness occurs in some patients. to voltage-gated sodium
The subacute syndrome is characterized channels and produce a
by a primarily demyelinating neuropa- prodrome of perioral
thy with slowed conduction velocities paresthesia.
and prolonged F waves. Ciguatera toxin
binds to voltage-gated sodium channels
leading to increased nerve membrane
excitability, but the mechanism for
causing neuropathy is unknown.
Saxitoxin, also called Northeast or
Northwest red tide, and brevetoxin B,
also termed Caribbean red tide, are two
seafood toxins produced by algae and
concentrated by bivalve mollusks. Both
toxins bind to sodium channels and
lead to conduction block and paraly-
sis.40 In the case of saxitoxin, patients
experience perioral tingling followed
by limb/trunk paresthesia, weakness,
incoordination, and eventually respira-
tory failure. If they receive appropriate
supportive care, patients often recover
within 1 week. Brevetoxin is actually the
most common shellfish poison in the
world.40 It is present in warmer waters
than saxitoxin. Following exposure, pa-
tients develop symptoms of gastroen-
teritis that are followed by paresthesia,
dysesthesia, and incoordination with-
out weakness.
The final seafood toxin that produces
neuropathy is tetrodotoxin. Tetrodo-
toxin is produced by the puffer fish or
fugu, which is considered a delicacy in
Japanese cuisine. Tetrodotoxin is con-
centrated in the skin, liver, and viscera
of the fish, and these areas must be
carefully removed from the fish during
preparation. Similar to saxitoxin and bre-
vetoxin B, tetrodotoxin is a potent so-
dium channel blocker. Ingestion of a
small amount of toxin produces perioral
tingling, while larger amounts produce
widespread paresthesia, weakness, au-
tonomic failure, and even coma and
www.aan.com/continuum 153
 Toxic Neuropathies
death.41 In fact, 50 deaths from tetro-
dotoxin poisoning occur each year in
Japan alone. If the patient receives timely
and appropriate intensive care, often in-
cluding ventilation and blood pressure
support, recovery will often occur in
4 to 5 days.
Organophosphates. Organophos-
phates are present in insecticides, pe-
troleum additives, and nerve gases.
Acute toxicity leads to cholinergic crisis
through cholinesterase inhibition. Clini-
cally, this produces meiosis, muscle
cramps, pulmonary edema, bradycar-
dia, and increased lacrimation and sali-
vation. The neuropathy, which often
occurs 7 to 10 days after exposure, is
characterized electrodiagnostically and
pathologically as a length-dependent
sensorimotor axonal neuropathy.42 In
addition to the neuropathy, patients
develop a delayed myelopathy. The
neuropathy slowly improves, but the
myelopathy does not. An example of
widespread organophosphate poison-
ing occurred in the 1930s during Pro-
hibition when bootleggers replaced
the ginger in the patent ethanol-based
medicine Jamaica ginger extract (also
known as ‘‘Jake’’) with the organo-
phosphate triorthocresyl phosphate
to make it more palatable. The wide-
spread consumption of this product
afflicted 50,000 to 100,000 people with
combined spinal cord and axonal de-
generation and was commonly referred
to as ‘‘Jake leg.’’
Ethylene glycol. Ethylene glycol is
present in antifreeze, paints, and deter-
gents. Toxicity results from accidental
ingestion, suicide attempt, or alcohol-
ism. Ethylene glycol is itself not toxic,
but in the digestive tract it is broken
down into glycolate, glyoxylate, and oxa-
late, which leads to acidosis and deposi-
tion of oxalate crystals. Clinically, patients
experience CNS depression, then cardio-
pulmonary toxicity, and finally renal
toxicity, all within the first 3 days. The
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cranial and peripheral nerve dysfunction
can occur as early as 5 days and as late as
20 days following exposure. The periph-
eral neuropathy is characterized as a
severe axonal sensorimotor polyneurop-
athy.43 The toxicity is treated with cor-
rection of acidosis, hemodialysis, and
alcohol dehydrogenase inhibitors.
Hexacarbons. Hexacarbons, such
as n-hexane, n-butyl ketone, and 2,5-
hexanedione, are present in glues and
solvents. Toxic exposure occurs secon-
dary to work-related accidents or rec-
reational abuse. Patients develop early
sensory symptoms that are followed by
weakness and areflexia. In acute expo-
sure, the neuropathy is a mixed de-
myelinating and axonal sensorimotor
polyneuropathy, whereas in chronic ex-
posure it is primarily an axonal sensory
neuropathy.44 Pathologic evaluation re-
veals giant axonal swellings composed
of disorganized neurofilaments just
proximal to nodes of Ranvier. Patients
have slow recovery months after re-
moval of hexacarbon exposure.
Acrylamide. Acrylamide is used in
the creation of grouting agents, adhe-
sives, and flocculators. Chronic inha-
lation or skin exposure can lead to a
length-dependent sensorimotor axonal
polyneuropathy. Distal sensory loss,
distal weakness, and loss of reflexes
can occur along with autonomic dys-
function. Sensory ataxia can be prom-
inent. Nerve conduction studies reveal
axonal neuropathy. The mechanism of
toxicity appears to be disruption of axo-
nal transport and subsequent dying-
back neuropathy.45
Vacor. Vacor (N-3-pyridylmethyl-N-
p-nitrophenylurea; PNU; pyriminil) is
used as a rat poison. Rapid onset of
quadriparesis may occur after inten-
tional or accidental ingestion of large
doses of vacor.46 Cranial nerve dys-
function and autonomic dysfunction
may also occur. Nerve conduction
studies show an axonal neuropathy.
February 2012

Diabetes mellitus can develop be-
cause vacor is structurally related to
alloxan and streptozocin, compounds
known to experimentally induce diabe-
tes in rats. Treatment with niacinamide
within 2 hours of ingestion may pre-
vent toxicity.
Ethanol and disulfiram. Ethanol
commonly causes a peripheral distal
sensorimotor polyneuropathy that is
primarily axonal with only rare demyeli-
nating features. Given the comorbid nu-
tritional deficits in people with chronic
alcoholism, it has been difficult to
definitively separate the direct effects
of ethanol from the indirect effects of
nutritional/vitamin deficiencies (particu-
larly thiamine deficiency). Two studies
attempted to separate these effects.
The first demonstrated that neuropathy
still occurred even in well-nourished
persons with alcoholism who received
alcohol supplemented with thiamine
and pyridoxine.47 The second demon-
strated that alcohol consumption alone
(ie, patients with normal thiamine lev-
els) produced a pure sensory neurop-
athy, whereas thiamine deficiency (ie,
thiamine deficiency in those without al-
coholism) produced a mixed motor and
sensory neuropathy.48 Related to alco-
hol abuse, disulfiram, which produces
nausea when combined with alcohol
and is used by persons with alcoholism
to reduce the urge to drink, also pro-
duces a sensorimotor axonal neuropa-
thy when taken at doses of 250 mg/d,
but not at doses of 125 mg/d.49 Electro-
physiologically, nerve conduction stud-
ies show conduction block and slowed
conduction velocities. Similar to hex-
acarbon toxicity, pathologic evaluation
of nerves often demonstrates dis-
tended axons with increased neurofila-
ment deposition.
Nitrous oxide. Nitrous oxide con-
tinues to be used as a dental anesthetic,
and most toxicity results from re-
creational abuse. Toxicity produces a
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KEY POINT
myeloneuropathy involving the dorsal h Ethanol toxicity alone
columns of the spinal cord and large produces a pure sensory
sensory nerve fibers. Small sensory neuropathy, whereas
nerve fibers and spinothalamic spinal thiamine deficiency, as
cord pathways are generally preserved. can sometimes be seen
Predominant loss of vibration and pro- in persons with
prioceptive loss are partially caused by alcoholism, causes a
neuropathy and partly due to dorsal mixed motor and
column degeneration as part of the sub- sensory neuropathy.
acute combined degeneration. Weak-
ness is related to myelopathy rather
than motor neuropathy. The pathogen-
esis of the neurotoxicity is inactivation
of cobalamin.50 Treatment involves ces-
sation of nitrous oxide inhalation and
cobalamin supplementation.
Other toxins. Buckthorn neuropa-
thy occurs from ingestion of buckthorn
fruit (Karwinskia humbodtiana) that is
found in the southwestern United States
and in Mexico. A rapidly progressive,
GBS-like, symmetric, motor-greater-
than-sensory neuropathy leading to
quadriparesis and respiratory and bul-
bar weakness occurs within 5 to 20
days of ingestion of the buckthorn
fruit. Nerve conduction studies have
been reported to show demyelination,
although axonal loss with secondary
demyelination has been described in
experimental studies. CSF is normal.
Treatment is supportive and most pa-
tients recover over 3 to 12 months.51
Tick paralysis occurs from a neuro-
toxin in the saliva of three female ticks
(Dermacentor andersoni, Dermacen-
tor variabilis, and Ixodes holocyclus).
The tick is usually found in the scalp
of affected children between the ages
of 1 and 6 years. A few days after tick
attachment to skin, rapidly progressive
weakness with bulbar and respiratory
compromise and areflexia ensue. Auto-
nomic symptoms in the form of tachy-
cardia and hypertension may occur, but
sensory pathways are spared. Nerve
conduction studies reveal reduction
of motor amplitudes. Removal of the
tick results in rapid resolution of the
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 Toxic Neuropathies

symptoms. The site of action is thought Vitamin B12 (Cobalamin)

to be the presynaptic neuromuscular
junction rather than the peripheral
nerve.52
Diphtheria toxin, produced by Cor-
ynebacterium diphtheriae, induces a
GBS-like syndrome, although the para-
lysis is more descending than ascend-
ing. After an incubation period of 2 to
5 days, patients, usually children, de-
velop palatal paralysis followed by
weakness. Unlike GBS, however, diph-
theritic neuropathy has a biphasic
slower course with palatal and adjacent
cranial nerve paralysis (first phase 1 to
3 weeks after infection) followed 8 to
12 weeks later by generalized descend-
ing weakness (second course). Nerve
conduction studies show demyelinating
features. Prompt treatment with diph-
theria antitoxin is critical in manage-
ment of diphtheria.
VITAMIN AND MINERAL
DEFICIENCY NEUROPATHY
Vitamin deficiencies, due either to poor
nutrition or incomplete absorption,
remain important causes of neuropathy
(Table 7-5). The vitamin deficiencies
most associated with peripheral neurop-
athy are B complex vitamins, vitamin E,
copper, and niacin.
Vitamin B12 deficiency is most com-
monly associated with malabsorption
due to intrinsic factor antibodies or prior
bariatric surgery. In addition, there is
some evidence that it may also occur
after chronic long-term use of metfor-
min.53 It produces subacute combined
degeneration of the spinal cord associ-
ated with sensory ataxia and loss of po-
sition and vibration sense (Case 7-4).54
Relative to the myelopathy, the symp-
toms from peripheral neuropathy are
actually quite mild and produce little
morbidity.
Vitamin B1 (Thiamine)
Vitamin B1 deficiency, also termed beri-
beri, most commonly occurs following
bariatric surgery or in persons with al-
coholism in association with Wernicke-
Korsakoff syndrome. Compared to the
acute CNS disorders, neuropathy from
vitamin B1 deficiency is chronic and is
often only noticeable after resolution
of cognitive toxicity. Enzymes depend-
ent on vitamin B1 include pyruvate
dehydrogenase, "-ketoglutarate dehy-
drogenase, and transketolase, all of
which are involved in cell metabolism;
thus, the pathogenesis of toxicity is
likely energy failure.55 Beriberi is often

TABLE 7-5 Vitamin and Other Deficiencies Summary

Nerve Fiber Type or Site of

Vitamin or Mineral Affected Nerves Injury Course
Cobalamin (vitamin B12) Large fiber sensory Axonal Chronic
Thiamine (vitamin B1) Small fiber 9 large fiber Axonal Chronic
sensory, motor
Pyridoxine (vitamin B6) Small fiber 9 large fiber 9 motor Axonal Chronic
Niacin (vitamin B3) Small fiber 9 large fiber, motor Axonal Chronic
Alpha tocopherol Large fiber sensory Axonal Chronic
(vitamin E)
Copper Pansensory, motor Axonal Chronic

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 Case 7-4
A 26-year-old woman developed progressive lower extremity numbness and
episodes of her legs ‘‘giving out.’’ She noted that the symptoms had been
getting worse over the past 1 to 2 years. She did not report any neck or
back pain or any change in bowel or bladder function. On examination, she
had loss of vibratory sense in the toes, ankles, and knees and loss of
proprioception in the toes. Her reflexes were normal at the ankles and
hyperreflexive with crossed adductors at the knees and spread in the upper
extremities. Electrodiagnostic testing revealed a mild sensory neuropathy
with reduced sural amplitudes bilaterally. There was no evidence of lumbar
radiculopathy. MRI studies of the brain and spinal cord were normal. On
laboratory testing, she had a vitamin B12 level of 100 pg/mL and a
methylmalonic acid level of 1600 nmol/L. Subsequent testing demonstrated
a positive intrinsic factor antibody and a macrocytic anemia.
Comment. This patient has typical symptoms, physical examination, and
laboratory findings for subacute combined degeneration secondary to
vitamin B12 deficiency. The preserved Achilles reflex and hyperreflexia
throughout despite reduced sural amplitudes is evidence of interruption of
corticospinal tract and myelopathy. Disruption of proprioception and
vibration can result from both large fiber sensory loss and myelopathy.
Given the intrinsic factor antibody, the patient has pernicious anemia and
will need to be on IM vitamin B12 shots for life.

divided into a dry form, in which Niacin

neuropathy is the major feature, and
a wet form, in which congestive heart
failure predominates. The neuropathy
is an axonal sensorimotor neuropathy,
and treatment is with aggressive thia-
mine repletion.
Vitamin B6 (Pyridoxine)
Because of the low level of vitamin B6
required by the body and the spectrum
of foods that contain this vitamin, it is
uncommon to see vitamin B6 deficiency
from nutritional deficits alone. Most
commonly, vitamin B6 deficiency occurs
among those with alcoholism, as a result
of medications (ie, isoniazid, hydrala-
zine, or penicillamine), or as a result of
bariatric surgery.56 The clinical symp-
toms of vitamin B6 deficiency are par-
esthesia, burning pain, and decreased
temperature sensation. Electrophysio-
logically, vitamin B6 deficiency produces
an axonal, sensory-greater-than-motor
neuropathy.
Continuum Lifelong Learning Neurol 2012;18(1):139–160
Niacin is a critical component of the
metabolic molecule nicotinamide ade-
nine dinucleotide, which determines
the reduction/oxidation state of cells.
Deficiencies cause pellagra, a systemic
disease characterized by skin lesions,
diarrhea, depression, and loss of appe-
tite. Niacin deficiency can occur as a
result of several medications, Hartnup
disease, carcinoid syndrome, or alco-
holism.57 A direct effect of niacin defi-
ciency on peripheral nerves has not
been shown, and most clinicians now
believe that neuropathy in patients
with pellagra is likely due to decreased
appetite and chronic diarrhea leading
to deficiencies of vitamins B6 or B1
rather than niacin deficiency itself.
Vitamin E (Alpha Tocopherol)
Vitamin E is a fat-soluble vitamin; there-
fore, deficiency can occur in diseases
of lipid malabsorption, such as abetali-
poproteinemia, or pancreatic enzyme
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 Toxic Neuropathies
KEY POINT
h Medication, toxic, and
vitamin neuropathies
that also produce
myelopathy include
organophosphates,
nitrous oxide, vitamin
B12 deficiency, and
copper deficiency.
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deficiencies, such as cystic fibrosis. Ad-
ditionally, vitamin E deficiency also oc-
curs following bariatric surgery. Vitamin
E deficiency primarily causes cerebellar
ataxia but can also cause sensory nerve
abnormalities. The sensory neuropathy
is primarily large caliber axons and leads
to a sensory ataxia.58 Pathologically, de-
generation of dorsal root ganglia neu-
rons is observed.
Copper
Copper deficiency can be acquired
or genetic. Acquired copper deficiency
occurs in patients requiring total
parenteral nutrition or secondary to
zinc toxicity or gastric bypass surgery.
Inherited copper deficiency can occur
as a component of Menkes disease,
which results from a defective copper
transporter.59 Copper deficiency can
produce a myelopathy, lower motor
neuronopathy, optic neuropathy, or an
axonal sensorimotor polyneuropathy.60
The specific mechanism of neurotox-
icity is unknown.
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