123

Metabolic and Toxic Myelopathies

Neeraj Kumar, M.D. 1

1 Department of Neurology, College of Medicine, Mayo Clinic, Address for correspondence and reprint requests Neeraj Kumar,
Rochester, Minnesota M.D., Department of Neurology, College of Medicine, Mayo Clinic,
200 First Street SW, Rochester, MN 55905
Semin Neurol 2012;32:123–136. (e-mail: Kumar.Neeraj@mayo.edu).

Abstract The myelopathies discussed in this article have an underlying metabolic or toxic
etiology. They have many clinical, electrophysiologic, and neuropathologic similarities.
Preferential involvement of the dorsal columns and/ or corticospinal tracts is commonly
seen. Variable degrees of peripheral nerve and/ or optic nerve involvement may be
present. In the presence of clinical or electrophysiologic evidence of peripheral nerve
involvement, the term myeloneuropathy is commonly used.
The metabolic and toxic myelopathies discussed here are divided into three
categories: disorders due to an identified nutrient deficiency such as the subacute

Downloaded by: Karolinska Institutet. Copyrighted material.

Keywords combined degeneration of cobalamin/ vitamin B12 or copper deficiency, disorders that
► myelopathy have a geographical predilection and are due to a suspected toxin such as lathyrism, and
► metabolic disorders due to a possible toxin but without a geographical predilection such as hepatic
► toxic myelopathy (►Table 1).

Metabolic Myelopathies due to a
Nutrient Deficiency
Vitamin B12 (Cobalamin/ Cbl) Deficiency
Cbl deficiency is particularly common in the elderly and is
likely due to the high incidence of atrophic gastritis and
associated achlorhydria-induced food-Cbl malabsorption.1,2
Food-Cbl malabsorption is insidious in onset and is rarely
associated with clinically significant deficiency. Though con-
troversial, there has been concern that low Cbl levels in the
elderly might cause nervous system damage, but studies have
not consistently demonstrated improvements in neurologic
function following therapy. This concern, and sensitivity of
the available metabolic tests for Cbl deficiency, has led to the
development of the concept of subclinical or subtle Cbl
deficiency.1,3 Many patients with clinically expressed Cbl
deficiency have intrinsic factor- (IF-) related malabsorption
such as that seen in pernicious anemia (PA). PA is associated
with IF antibodies. Cbl deficiency is commonly seen following
gastric surgery (gastrectomy and bariatric surgery).4 Other
causes of Cbl deficiency include conditions associated with
malabsorption, certain infections and medications, and he-
reditary enzymatic defects and mutations in genes encoding
endocytic receptors involved in ileal absorption and cellular
Cbl uptake (►Fig. 1). These and other causes of Cbl deficiency
are noted in ►Table 2. Cbl deficiency is only rarely the
consequence of diminished dietary intake. Strict vegetarians
may rarely develop mild Cbl deficiency after years. The low
Cbl levels noted in vegetarians is often without clinical
consequences. Not infrequently the cause of Cbl deficiency
is unknown.1,2 ►Figure 2 illustrates the absorption and
metabolism of Cbl.5
Neurologic manifestations may be the earliest and often
the only manifestation of Cbl deficiency.6–8 They may be
unaccompanied by hematologic manifestations of Cbl defi-
ciency such as anemia, macrocytosis, neutrophil hyperseg-
mentation, or megaloblastic marrow changes. Neurologic
manifestations may include a myelopathy (subacute com-
bined degeneration) with or without an associated neuropa-
thy, cognitive impairment, optic neuropathy, autonomic
dysfunction, and paresthesias without abnormal signs.7 The
myelopathy is characterized by a symmetric spastic para-
paresis, extensor plantar response, and impaired perception
of position and vibration. Accompanying peripheral nerve or
rarely optic nerve involvement may be present. Clinical,
electrophysiologic, and pathologic involvement of the pe-
ripheral nervous system has been described with Cbl defi-
ciency.9 Clues to possible Cbl deficiency in a patient with
polyneuropathy included a relatively sudden onset of symp-
toms, findings suggestive of an associated myelopathy, onset

Issue Theme Myelopathies; Guest Editor, Copyright © 2012 by Thieme Medical DOI http://dx.doi.org/
John W. Engstrom, M.D. Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0032-1322583.
New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
124 Metabolic and Toxic Myelopathies Kumar
Table 1 Causes of Metabolic Myelopathies
Metabolic myelopathies due to a nutrient deficiency
B12 deficiency
Nitrous oxide toxicity
AIDS-associated myelopathy (AIDS associated with
impaired B12 metabolism)
Folate deficiency
Copper deficiency
Vitamin E deficiency
Metabolic myelopathies due to a possible toxin
(geographical predilection)
Cassava toxicity
Lathyrism
Fluorosis
Subacute myelo-optico neuropathy (clioquinol toxicity)
Tropical myeloneuropathies
Metabolic myelopathies due to possible toxins
(without a geographical predilection)
Chemotherapy-related myelopathy
Hepatic myelopathy
Heroin myelopathy
Organophosphate toxicity
AIDS, acquired immunodeficiency syndrome.
of symptoms in the hands, concomitant involvement of upper
and lower limbs, macrocytic red blood cells, and the presence
of a risk factor for Cbl deficiency.
Cord magnetic resonance imaging (MRI) abnormalities in
Cbl deficiency include a signal change in the posterior and
lateral columns.10 Associated contrast enhancement may be
present. Other reported findings include cord atrophy and
anterior column involvement.11,12 Rarely diffuse white mat-
ter abnormalities (supratentorial and very rarely infratento-
rial) suggestive of a leukoencephalopathy may be seen.13
Electrophysiologic abnormalities include nerve conduction
studies suggestive of a sensorimotor axonopathy, and abnor-
malities on evoked potentials (somatosensory, visual, and
motor).
Though a widely used screening test, serum Cbl measure-
ment has technical and interpretive problems and lacks
sensitivity and specificity for the diagnosis of Cbl deficiency
(►Table 3).1,3,14,15 A proportion of Cbl-deficient patients may
have Cbl levels that are on the lower side of the normal range
and a proportion of patients with low Cbl levels are not Cbl
deficient. Levels of serum methylmalonic acid (MMA) and
plasma total homocysteine (Hcy) are useful as ancillary
diagnostic tests.16,17 They too have significant limitations.18
The specificity of MMA is superior to that of Hcy. Though Hcy
is a very sensitive indicator of Cbl deficiency, its major
limitation is its poor specificity. ►Table 3 indicates causes
other than Cbl deficiency that can result in abnormal levels of
Cbl, MMA, and Hcy. Some authors suggest that low Cbl and
Seminars in Neurology Vol. 32 No. 2/2012
increased MMA or Hcy levels may not be sensitive markers of
Cbl-responsive disorders; MMA and Hcy may be normal in
some patients with neurologic or hematologic abnormalities
responsive to Cbl.14 Further, short-term fluctuations of Cbl,
MMA, and Hcy may obscure Cbl deficiency and lead to
erroneous conclusions regarding response to therapy.14 To
determine the cause of Cbl deficiency, tests directed at
determining the cause of malabsorption are undertaken.
Concerns regarding cost, accuracy, and radiation exposure
have led to a significant decrease in the availability of the
Schilling’s test. Further, the Schilling’s test is based on ab-
sorption of crystalline Cbl (with and without intrinsic factor)
and does not detect food-Cbl malabsorption. An elevated
serum gastrin and decreased pepsinogen I is seen in 80 to
90% of patients with PA, but the specificity of these tests is
limited. Elevated gastrin levels are a marker for hypochlo-
rhydria or achlorhydria, which are invariably seen with PA.
Elevated serum gastrin levels may be seen in up to 30% of the
elderly. Anti-IF antibodies are specific (over 95%), but lack
sensitivity and are found in 50 to 70% of patients with PA.
Downloaded by: Karolinska Institutet. Copyrighted material.
Antiparietal cell antibodies may not be seen as commonly as
was earlier believed and therefore have limited utility. Fur-
ther, false-positive results for the gastric parietal cell anti-
body are common. They may be seen in 10% of people over age
70 and are also present in other autoimmune endocrinopa-
thies. A common approach is to combine the specific but
insensitive IF antibody test with the sensitive but nonspecific
serum gastrin or pepsinogen level in patients with Cbl
deficiency.15
The goals of treatment are to reverse the signs and
symptoms of deficiency, replete body stores, ascertain the
cause of deficiency, and monitor response to therapy. With
normal Cbl absorption, oral administration of 3 to 5 μg may
suffice. In patients with food-bound Cbl malabsorption, 50 to
100 μg cyanocobalamin given orally may be adequate. The
more common situation is one of impaired absorption where
parenteral therapy is required (►Table 4). A short course of
daily or weekly therapy is often followed by monthly main-
tenance therapy (►Table 4). If the oral dose is large enough,
even patients with an absorption defect, including PA, may
respond to oral Cbl.1,19 The role of oral therapy in patients
with severe neurologic disease has not been well studied.19
Patients with PA have a higher risk of gastric cancer and
carcinoids and therefore should get an endoscopy. Patients
with PA also have a higher frequency of thyroid disease,
diabetes, and iron deficiency and should be screened for
these conditions. Response to treatment may relate to
extent of involvement and delay in starting treatment.
Response of the hematologic derangements is prompt
and complete. Response of the neurologic manifestations is
variable and often incomplete.7,15 If an elevated MMA or Hcy
is due to Cbl deficiency, these values will normalize after
1 to 2 weeks of replacement therapy.20 Cbl and holoTC levels
rise after injection regardless of the benefit. Hence, MMA
and Hcy are more reliable ways for monitoring response
to therapy.3 Anemia due to Cbl deficiency often responds
to folate therapy, but the response is incomplete and
transient.
 Metabolic and Toxic Myelopathies Kumar 125

Downloaded by: Karolinska Institutet. Copyrighted material.

Figure 1 Cbl and folate metabolism. In the stomach, Cbl bound to food is dissociated from proteins in the presence of acid and pepsin. The
released Cbl binds to haptocorrin/HC (encoded by the TCN1 gene). In the small intestine, pancreatic proteases partially degrade the Cbl-HC
complex at neutral pH and release Cbl, which then binds with intrinsic factor/IF (encoded by the GIF gene). The Cbl-IF complex binds to a specific
receptor in the ileal mucosa called cubulin/CUB (encoded by the CUBN gene) and is then internalized. The internalization of cubulin with Cbl-IF is
facilitated by amnionless/AMN (encoded by the AMN gene), an endocytic receptor protein. The megalin/MAG receptor (encoded by the LRP-2
gene) may play a role in the stability of the cubilin/AMN complex. Like MAG, the receptor associated protein/RAP can interact with CUB. The Cbl-IF
complex enters the ileal cell where IF is destroyed. In addition to the IF-mediated absorption of ingested Cbl, there is a nonspecific absorption of
free or crystalline Cbl that occurs by passive diffusion at all mucosal sites. TransCbl/TC (encoded by the TCN2 gene) carries 10 to 30% of the total
Cbl. TC-bound Cbl (holotransCbl/holoTC) represents the active form of Cbl. TC binds to and transports the newly absorbed Cbl in the distal ileum to
cells throughout the body where it is internalized by receptor-mediated cellular uptake. Following internalization, the Cbl-TC complex is degraded
by the lysosome and the receptor is recycled to the plasma membrane. Intracellular lysosomal degradation releases Cbl (hydroxoCbl) for
conversion to methylCbl in the cytosol or adenosylCbl in the mitochondria. MethylCbl is a cofactor for a cytosolic enzyme, methionine synthase in
a methyl-transfer reaction that converts homocysteine to methionine. Methionine is adenosylated to S-adenosylmethionine/SAM, a methyl group
donor required for neuronal methylation reactions involving proteins, nucleic acids, neurotransmitters, myelin, and phospholipids. Decreased
SAM production possibly leads to reduced myelin basic protein methylation and white matter vacuolization in Cbl deficiency. The biologically
active folates are in the tetrahydrofolate/THF form. MethylTHF is the predominant folate and is required for the Cbl-dependent remethylation of
Hcy to methionine. During the process of methionine formation methylTHF donates the methyl group and is converted into THF, a precursor for
purine and pyrimidine synthesis. Methionine also facilitates the formation of formylTHF, which is involved in purine synthesis. Impaired DNA
synthesis could interfere with oligodendrocyte growth and myelin production. Methylation of deoxyuridylate to thymidylate is mediated by
methyleneTHF. Impairment of this reaction results in accumulation of uracil, which replaces the decreased thymine in nucleoprotein synthesis and
initiates the process that leads to megaloblastic anemia. AdenosylCbl is a cofactor for mitochondrial L-methylmalonyl coenzyme A (CoA) mutase
that catalyzes the conversion of L-methylmalonyl CoA to succinyl CoA in an isomerization reaction. Accumulation of methylmalonate and
propionate may provide abnormal substrates for fatty acid synthesis. Folate functions as a coenzyme or cosubstrate by modifying, accepting, or
transferring one carbon moieties in single-carbon reactions involved in the metabolism of nucleic and amino acids. The biologically active folates
are in the THF form. MethylTHF is the predominant folate and is required for the Cbl-dependent remethylation of Hcy to methionine. Methylation
of deoxyuridylate to thymidylate is mediated by methyleneTHF. Impairment of this reaction results in accumulation of uracil, which replaces the
decreased thymine in nucleoprotein synthesis and initiates the process that leads to megaloblastic anemia. Cbl, cobalamin; HC, haptocorrin; IF,
intrinsic factor; CUB, cubilin; AMN, amnionless; MAG, megalin; RAP, receptor-associated protein; TC, transcobalamin; TCblR, transcobalamin
receptor; CH3, methyl; THF, tetrahydrofolate; MS, methionine synthetase; AT, adenosyl transferase; SAM, S-adenosylmethionine; CoA, coenzyme
A. Copyright Mayo Foundation.

Seminars in Neurology Vol. 32 No. 2/2012

126 Metabolic and Toxic Myelopathies Kumar

Table 2 Clinical Settings Associated with Cobalamin Deficiency

Elderly Related to atrophic gastritis-related hypochlorhydria induced food-Cbl malabsorption

Gastrointestinal disease or
surgery
Hereditary enzymatic defects and
mutations in genes encoding
endocytic receptors involved in
ileal absorption and cellular Cbl
uptake
Infections
Intrinsic factor-related
malabsorption
Medications
Bariatric surgery, gastrectomy, ileal disease or resection, intestinal tuberculosis or
lymphoma, celiac disease, Whipple’s disease, inflammatory bowel disease, radiation
enteritis, graft-versus-host disease, pancreatic disease, and tropical sprue, bacterial
overgrowth (jejunal diverticulosis, enteroanastomosis, strictures, fistulas), Zollinger-Ellison
syndrome (high acidity causes inactivation of pancreatic trypsin and prevents Cbl release
from HC)
Mutations in CUBN and AMN (selective Cbl malabsorption and proteinuria: Imerslund-
Gräsbeck syndrome), mutations in GIF (intrinsic factor) or TCN2 (transcobalamin) leading to
absence of the protein or presence of abnormal protein, disorders of intracellular processing
and utilization of Cbl, disorders involving the synthesis of Cbl cofactors (cblA to cblG)
Helicobacter pylori, Diphyllobothrium latum, human immunodeficiency virus
Pernicious anemia, mutations in the gene encoding for the gastric IF (GIF)
Antacids, H2 blockers, metformin, sunitinib, nitrous oxide, others

Downloaded by: Karolinska Institutet. Copyrighted material.

Figure 2 Copper metabolism. (A) Copper absorption occurs primarily in the small intestine. The Menkes P-type ATPase (ATP7A) is responsible for
copper trafficking to the secretory pathway for efflux from enterocytes and other cells. Absorbed copper is bound to albumin and transported via
the portal vein to the liver where it is incorporated into ceruloplasmin and released into the plasma. 95% of the copper is bound to ceruloplasmin.
Ceruloplasmin binds to its receptors on the cell surface; copper is then released from its binding protein and enters the cell. Excretion of copper
into the gastrointestinal tract is the major pathway that regulates copper homeostasis and prevents deficiency or toxicity. The Wilson P-type
ATPase (ATP7B) is responsible for copper trafficking to the secretory pathway for ceruloplasmin biosynthesis and for endosome formation prior to
biliary secretion. Biliary copper is adjusted to maintain balance. Urinary excretion is normally very low, less than 0.1 mg/day. Excretion of copper
into the gastrointestinal tract is the major pathway that regulates copper homeostasis and prevents deficiency or toxicity. Excessive zinc ingestion
is a well recognized cause of copper deficiency. The zinc-induced inhibition of copper absorption could be the result of competition for a common
transporter or a consequence of induction of metallothionein in enterocytes. Metallothionein has a higher binding affinity for copper than for zinc.
Copper is retained within the enterocytes and lost as the intestinal cells are sloughed off. Failure to mobilize absorbed copper from intestinal cells
forms the basis of Menkes’ disease (1). In Wilson’s disease there is decreased incorporation of copper into ceruloplasmin (A) and impaired biliary
excretion of copper (B). Copper is a component of enzymes that have a critical role in the structure and function of the nervous system. It
permits electron transfer in key enzymatic pathways. These include cytochrome-c-oxidase for electron transport and oxidative phosphorylation,
copper/zinc superoxide dismutase for antioxidant defense, dopamine β-hydroxylase for catecholamine biosynthesis, peptidylglycine α-amidating
monooxygenase for neuropeptide and peptide hormone processing, monoamine oxidase for serotonin synthesis, and ceruloplasmin for brain iron
homeostasis. Cu, copper; Zn, zinc; Cp, ceruloplasmin; M, metallothionein; alb, albumin; SOD, superoxide dismutase; cyt c ox, cytochrome c
oxidase. Copyright: Mayo Foundation.

Seminars in Neurology Vol. 32 No. 2/2012

 Metabolic and Toxic Myelopathies Kumar 127

Table 3 Common Causes, Other than Cbl Deficiency, for Abnormal Cbl, MMA, and Hcy Levels

Cbl MMA Hcy

Decrease (falsely low) Increase
Pregnancy (third trimester) Renal insufficiency
Haptocorrin deficiency (also seen in sickle Volume contraction
cell disease) (possible)
Folate deficiency Bacterial contamination
of gut (possible)
Other diseases: HIV infection and myeloma MMCoA mutase
(abnormalities in Cbl binding proteins) deficiency
Drugs: Anticonvulsants, oral contraceptives, Other MMA-related
radionuclide isotope studies enzyme defects
Idiopathic Infancy, pregnancy
Increase (falsely normal) Decrease
Renal failure Antibiotic-related
Increase
Renal insufficiency
Volume contraction
Folate deficiency
Vitamin B6 deficiency
Other diseases: Hypothyroidism,
renal transplant, leukemia,
psoriasis, alcohol abuse
Inappropriate sample collection
and processing
Drugs: Isoniazid, colestipol, niacin,
L-dopa, diuretics
Enzyme defects: Cystathionine
β-synthase deficiency, MTHFR

Downloaded by: Karolinska Institutet. Copyrighted material.

reductions in bowel
flora deficiency
Intestinal bacterial overgrowth (measurement of Increased age, males, caffeine
biochemically inert B12 analogues) consumption, increased
muscle mass
Increase haptocorrin concentration Decrease
(seen in liver disease and Drugs: Estrogens, tamoxifen, statins
myeloproliferative disorders like
polycythemia vera, chronic
myelogenous leukemia,
chronic myelofibrosis)

Cbl, cobalamin; MMA, methylmalonic acid; Hcy, homocysteine; HIV, human immunodeficiency virus; MTHFR, methylene tetrahydrofolate reductase.

Nitrous-Oxide Toxicity AIDS-Associated Myelopathy and

Nitrous oxide (N2O; “laughing gas”) is a commonly used
inhalational anesthetic agent that has been abused because
of its euphoriant properties. It is a potent oxidizing agent that
produces irreversible oxidation of the cobalt core of cobala-
min and renders methylCbl inactive. Earlier reports of N2O
toxicity were among dentists, and medical or nursing staff
working in poorly ventilated surgeries. More recently the
practice has been seen among university students.21 Neuro-
logic manifestations may result from chronic exposure or
after a single exposure in individuals with unsuspected Cbl
deficiency.22 They may be seen despite a normal Cbl level.
Signs and symptoms appear relatively rapidly with N2O
toxicity. Less commonly, symptoms may be delayed up to
2 months after acute exposure. Neurologic manifestations
may include a myelopathy, neuropathy, myeloneuropathy,
and mental status changes. MRI findings include hyperin-
tense T2-signal in the dorsal and lateral column.23 A myelo-
neuropathy due to N2O should be considered when dealing
with patients who develop neurologic symptoms following
surgical or dental procedures. It is preventable by prophylac-
tic Cbl given weeks before surgery in individuals with a
borderline Cbl level who are expected to receive N2O
anesthesia.
Cobalamin Deficiency
Increased prevalence of Cbl deficiency has been recognized in
human immunodeficiency virus- (HIV-) infected patients
with neurologic symptoms, but the precise significance of
this is unclear.24 The histopathology of acquired immunode-
ficiency syndrome- (AIDS-) associated myelopathy resembles
that of subacute combined degeneration. The pathogenesis of
AIDS-associated myelopathy is possibly not related to direct
HIV infection of the spinal cord.25 In AIDS-associated
myelopathy the Cbl and folate dependent transmethylation
pathway is depressed. Possible benefit of administration of
L-methionine in AIDS-associated myelopathy was suggested
by a pilot study, but not confirmed in a subsequent double-
blind study.25
Folate Deficiency
Daily folate losses may approximate 1 to 2% of body stores.
Clinically significant depletion of normal folate stores may be
seen within 3 months – more rapidly with low stores or
coexisting alcoholism. Folate deficiency rarely exists in the
pure state. It is often associated with conditions that affect
other nutrients and can coexist with other nutrient deficien-
cies. Hence, attribution of neurologic manifestations due to

Seminars in Neurology Vol. 32 No. 2/2012


Table 4 Summary of Sources, Causes of Deficiency, Neurologic Significance, Laboratory Tests, and Treatment for Metabolic Myelopathies Related to Nutrient Deficiencies (Cobalamin,
Folate, Copper, and Vitamin E)
Nutrient Sources Major Causes of
Deficiency
Seminars in Neurology
Cobalamin Meats, egg, milk, Pernicious anemia, elderly
fortified cereals (due to atrophic gastritis
and achlorhydria-induced
Vol. 32
food-cobalamin
malabsorption), gastric
surgery, acid reduction
therapy, gastrointestinal
No. 2/2012
disease, parasitic
infestation by fish
tapeworm, hereditary
enzymatic defects, N2O
toxicity; rarely strict
vegetarianism; often
unknown cause
Folate In virtually all foods Alcoholism,
(grains and cereals gastrointestinal disease,
are fortified with folic folate antagonists (e.g.,
acid). aminopterin,
methotrexate,
pyrimethamine, trimetho-
prim, triamterene), errors
of folate metabolism.
Folate deficiency generally
coexists with other nutrient
deficiencies.
Copper Widely distributed in Gastric surgery, zinc
foods (organ meats, toxicity, gastrointestinal
seafood, nuts, beans, disease, total parenteral
legumes, chocolate, nutrition and enteral
cocoa, whole grain feeding; rarely acquired
products, dietary deficiency; often
mushrooms) unknown
Vitamin E Vegetable oils, leafy Chronic cholestasis
vegetables, fruits, (particularly in children),
meats, nuts, pancreatic insufficiency,
unprocessed cereal gastrointestinal disease,
grains ataxia with vitamin E
deficiency, homozygous
hypobetalipoproteinemia,
abetalipoproteinemia,
chylomicron retention
disease
Cbl, cobalamin; MMA, methylmalonic acid; Hcy, homocysteine; IM: intramuscular; MRI, magnetic resonance imaging; AIDS, acquired immunodeficiency syndrome; RBC, red blood cell.
128
Neurologic Sequelae Laboratory Tests Treatment (Commonly Used Additional Comments
Regimens)
Myelopathy or Serum Cbl, serum MMA, plasma IM B12 1000 μg daily for the Even in the presence of severe
myeloneuropathy, total Hcy, hematologic tests first week, followed by malabsorption, 2–5 years may
peripheral (anemia, macrocytosis, monthly thereafter; cyanoCbl pass before cobalamin deficiency
neuropathy, neutrophil hypersegmentation, is the form commonly used in develops.
neuropsychiatric megaloblastic marrow), serum the U.S., hydroxoCbl is the Disturbance in cobalamin
manifestations, optic gastrin, IF and parietal cell form preferred in parts of metabolism in AIDS-associated
neuropathy, auto- antibodies, increased signal on Europe: it requires less myelopathy
nomic dysfunction T2-weighted MRI involving dorsal frequent injections and may be Advantages of delivering Cbl by
column more allergenic the nasal or sublingual route are
Metabolic and Toxic Myelopathies
(Not routinely used: Schilling’s unproven.
test, urinary MMA excretion, Oral preparations of intrinsic
deoxyuridine suppression, holoTC factor are not reliable.
concentration)
Kumar
Neurologic Serum folate, RBC folate (more Oral folate 1 mg three times a Higher requirements in
manifestations are reliable indicator of tissue stores day followed by a maintenance pregnancy, lactation
rare and indistin- than serum folate), plasma total dose of 1 mg/d (initial Folate in foods have a
guishable from those homocysteine parenteral for acutely ill bioavailability of less than 50%,
due to cobalamin patients: 1–5 mg/d); folic acid supplements are in the
deficiency. supplementation with 0.4 mg/ monoglutamate form and have
d in women in child bearing as a bioavailability approaching
for prophylaxis against neural 100%.
tube defects. The reduced folates in food are
labile and readily lost under
certain cooking conditions such
as boiling.
Myelopathy or Serum and urinary copper, serum Oral elemental copper: 8 mg/d Hyperzincemia of indeterminate
myeloneuropathy ceruloplasmin, serum and urinary for a week, 6 mg/d for the cause may be present even in the
zinc, hematologic parameters second week, 4 mg/ d for the absence of excess zinc ingestion
(anemia, neutropenia, third week and 2 mg/d Speculative if copper deficiency
vacuolated myeloid precursors, thereafter may have been responsible for
ringed sideroblasts, iron- subacute myelo-optic neuropathy
containing plasma cells) (secondary to clioquinol)
Spinocerebellar Serum vitamin E, Vitamin E ranging from 200 Vitamin E deficiency is virtually
syndrome with ratio of serum vitamin E to sum of mg/d to 200 mg/kg/d (oral, never the consequence of a
peripheral serum cholesterol and intramuscular) dietary inadequacy
neuropathy, triglycerides Neurologic findings are rare in
ophthalmoplegia, vitamin E-deficient adults with
pigmentary chronic cholestasis
retinopathy
Downloaded by: Karolinska Institutet. Copyrighted material.

folate deficiency requires exclusion of other potential causes.
Populations at increased risk of folate deficiency include
alcohol abusers, premature infants, and adolescents. Folate
deficiency may also result from restricted diets such as those
used to manage phenylketonuria. Folate deficiency is seen
with small bowel disorders associated with malabsorption.
Folate absorption may be decreased in conditions associated
with reduced gastric secretions such as gastric surgery,
atrophic gastritis, acid-suppressive therapy, and acid neutral-
ization by treatment of pancreatic insufficiency. Several drugs
act as folate antagonists and produce folate deficiency by
inhibiting dihydrofolate reductase (►Table 4).
Theoretically, folate deficiency could cause the same man-
ifestations as those seen with Cbl deficiency because of its
importance in the production of methionine and tetrahydro-
folate. For unclear reasons, neurologic and hematologic man-
ifestations due to folate deficiency, though similar to those
seen with Cbl deficiency, are rare, mild, and controver-
sial.26,27 Reported neurologic manifestations of folate defi-
ciency include a myelopathy, peripheral neuropathy, optic
neuropathy, and cognitive or behavioral manifestations.28,29
The megaloblastic anemia due to folate deficiency is indistin-
guishable from that seen in Cbl deficiency. A low folate level
may be seen in elderly asymptomatic individuals and in
individuals with psychiatric disease and Alzheimer’s demen-
tia.30 In recent years, there has been some evidence that
suggests that chronic folate deficiency may increase stroke
risk and cause cognitive impairment.31 A recent study noted
no effect on vascular outcomes in patients with stroke with
moderate reduction of Hcy levels with folate, Cbl, and vitamin
B6.32 The precise significance of these observations awaits
further studies. Folate deficiency causes increased frequency
of neural tube defects in babies born to folate-deficient
mothers.31
Serum folate levels between 2.5 and 5 μg/L may be
indicative of a mildly compromised folate status.33 Erythro-
cyte folate is more reliable than plasma folate because its
levels are less affected by short-term fluctuations in intake.34
Reticulocytes have a higher folate content than mature red
blood cells (RBCs). Their presence can affect RBC folate levels
as can blood transfusions. Plasma Hcy levels have been shown
to be elevated in many patients with clinically significant
folate deficiency.16
In women of childbearing age with epilepsy, a daily folate
supplement of 0.4 mg is recommended for prophylaxis
against neural tube defects. With documented folate defi-
ciency, higher doses are required (►Table 4). Daily doses as
high as 20 mg may be necessary in patients with malabsorp-
tion. Coexisting Cbl deficiency should be ruled out before
instituting folate therapy. Reduced folates such as folinic acid
(N5-formylTHF) is required only when folate metabolism is
impaired by drugs such as methotrexate or by an inborn error
of metabolism. Plasma Hcy is likely the best biochemical tool
for monitoring response to therapy; it decreases within a few
days of instituting folate therapy but does not respond to
inappropriate Cbl therapy.35 Because folate deficiency is
generally seen in association of a broader dietary inadequacy,
the associated comorbidities need to be addressed.
Metabolic and Toxic Myelopathies Kumar 129
Copper Deficiency
Because of copper’s ubiquitous distribution and low daily
requirement, acquired dietary copper deficiency is rare.
Copper deficiency since infancy results in Menkes’ disease.
The coexistence of multiple causes of copper deficiency
increases the chances of development of a clinically signifi-
cant deficiency state. The most common cause of acquired
copper deficiency is a prior history of gastric surgery (for
peptic ulcer disease or bariatric surgery).4,36–38 Typically
neurologic manifestations are delayed by years following
gastric surgery. Zinc is commonly used in the prevention or
treatment of common colds. Excessive zinc ingestion is a well-
recognized cause of copper deficiency.39–41 Unusual sources
of excess zinc have included patients who consumed exces-
sive amounts of denture cream for long periods,40,41 and
patients swallowing zinc-containing coins.42 Parenteral zinc
overloading during chronic hemodialysis has also been asso-
ciated with copper deficiency myelopathy.43 Overtreatment
of Wilson’s disease with zinc has only rarely been reported to
cause copper deficiency.44 Copper deficiency may occur in
Downloaded by: Karolinska Institutet. Copyrighted material.
premature infants and low-birth-weight or malnourished
infants. Copper deficiency has been reported in enteropathies
associated with malabsorption like cystic fibrosis, sprue,
bacterial overgrowth, and inflammatory bowel disease –
rarely in nephrotic syndrome and glomerulonephritis. Cop-
per deficiency may be seen in celiac disease and copper
deficiency-related neurologic manifestations may occur in
the absence of gastrointestinal symptoms.45,46 Copper defi-
ciency may be a complication of prolonged total parenteral or
enteral nutrition, particularly so when copper supplementa-
tion is withheld because of prolonged cholestasis.47 Not
infrequently, despite extensive investigations the cause of
copper deficiency may not be evident.48 The possibility of an
occult source of zinc ingestion (like excessive denture cream
use) should be looked into.41 Emerging knowledge about
copper transport may help clarify the etiology in some cases
of idiopathic hypocupremia.49
Copper deficiency-associated myelopathy has been well
described in various animal species; in particular in rumi-
nants (called swayback or enzootic ataxia). Acquired copper
deficiency has been recognized to cause a myelopathy or
myeloneuropathy in humans.39,48,50 Like the subacute com-
bined degeneration seen with Cbl deficiency, copper-defi-
ciency myelopathy presents with a spastic gait and
prominent sensory ataxia. The sensory ataxia is primarily
due to dorsal column dysfunction. Copper and Cbl deficiency
may coexist.51 A prior history of Cbl deficiency may be
present, particularly in patients with a prior history of gastric
surgery. Clinical or electrophysiologic evidence of an associ-
ated peripheral neuropathy is common. An accompanying
optic neuropathy may be present.52 Also reported is progres-
sive, asymmetric weakness or electrodiagnostic evidence of
denervation suggestive of lower motor neuron disease.40,53
Hematologic manifestations of acquired copper deficiency
include anemia and neutropenia.54,55 Typical bone marrow
findings include a left shift in granulocytic and erythroid
maturation with cytoplasmic vacuolization in erythroid and
myeloid precursors and the presence of ringed sideroblasts or
Seminars in Neurology Vol. 32 No. 2/2012
130 Metabolic and Toxic Myelopathies Kumar
hemosiderin-containing plasma cells. Neurologic manifesta-
tions of copper deficiency may not be accompanied by
hematologic derangement.
The most common abnormality on the spine MRI is
increased T2 signal involving the dorsal column, most com-
monly in the cervical cord.56,57 Additionally, signal change
involving the lateral column has also been reported.57 These
findings are similar to the spine MRI changes seen in patients
with Cbl deficiency. Also reported is extension of the pyra-
midal tract signal change into the brainstem.58 Evoked po-
tential studies may provide electrophysiologic evidence of
posterior column dysfunction.59 Axonal loss predominates on
nerve conduction studies.
Laboratory indicators of copper deficiency include a de-
crease in serum copper or ceruloplasmin, and in 24-h urinary
copper excretion. Changes in serum copper usually parallel
the ceruloplasmin concentration. Ceruloplasmin is an acute-
phase reactant and the rise in ceruloplasmin is probably
responsible for the increase in serum copper seen in con-
ditions like pregnancy, oral contraceptive use, liver disease,
malignancy, hematologic disease, myocardial infections,
smoking, diabetes, uremia, and various inflammatory and
infectious diseases. Copper deficiency could be masked under
these conditions. Serum zinc and 24-h urinary zinc excretion
levels should be obtained and an elevation in these should
prompt an aggressive search for an exogenous source of zinc.
A low serum copper or ceruloplasmin can be seen in Wilson’s
disease or in the Wilson’s disease heterozygote state. A
significant elevation in urinary copper excretion should
prompt consideration of Wilson’s disease or the Wilson’s
disease heterozygote state as a cause for low serum copper
levels. Serum ceruloplasmin is absent in aceruloplasminemia
and is low in carriers with a mutation in the ceruloplasmin
gene. Hence, the laboratory detection of a low serum copper
does not imply copper deficiency.60
In those patients in whom excess zinc ingestion is the likely
cause, stopping zinc supplementation may suffice and no
additional copper supplementation may be required. Copper
supplementation is generally started in addition to stopping
zinc supplementation. Despite a suspected absorption defect,
oral copper supplementation is generally the preferred route
for supplementation. In most cases, oral administration of
2 mg of elemental copper a day seems to suffice. Higher doses
may be used initially (►Table 4). At times prolonged oral
therapy may not result in improvement; parenteral therapy
may be required. Some have employed initial parenteral
administration followed by oral administration. Other situa-
tions in which parenteral therapy may be required include
severely depleted patients or significant malabsorption, par-
ticularly in context of gastrointestinal surgery, and in patients
with a jejunostomy tube. Response of the hematological
parameters (including bone marrow findings) is prompt
and often complete.48,50 Recovery of neurological signs and
symptoms is variable. Improvement in neurological symp-
toms is generally absent though progression is typically
halted. Improvement when present is often subjective and
involves sensory symptoms. There are reports of improve-
ment in the neurological deficits, nerve conduction studies,
Seminars in Neurology Vol. 32 No. 2/2012
evoked potential studies, and MRI signal change with nor-
malization of serum copper.
Vitamin E Deficiency
Vitamin E deficiency in adults may be due to gastrointestinal,
pancreatic, or hepatic disease (►Table 4). In addition to these
causes, particularly in children, vitamin E deficiency may be
seen due to genetic defects in α-TTP, apolipoprotein B, or
microsomal triglyceride transfer protein or due to chylomi-
cron synthesis and secretion (►Table 5). The physiology of
vitamin E metabolism is illustrated in ►Fig. 3.
Neurologic manifestations of vitamin E deficiency include
a progressive spinocerebellar syndrome and peripheral neu-
ropathy with resulting gait difficulty, hypo- or areflexia,
pyramidal signs, impaired position and vibration perception,
dysarthria, and gaze palsies.61 The phenotype is similar to
that of Friedreich ataxia. MRI may show high-signal lesions on
T2-weighted images in the posterior columns.62
Serum vitamin E levels are dependent on the concentra-
tions of serum lipids. Hyperlipidemia or hypolipidemia can
Downloaded by: Karolinska Institutet. Copyrighted material.
independently increase or decrease serum vitamin E without
reflecting similar alterations in tissue levels of the vitamin.
Effective serum vitamin E levels are calculated by dividing the
serum vitamin E by the sum of serum cholesterol and
triglycerides.63 Serum vitamin E concentrations may be in
the normal range in patients with vitamin E deficiency due to
cholestatic liver disease, a disorder that is also associated with
high lipid levels. In patients with neurological manifestations
due to vitamin E deficiency the serum vitamin E levels are
frequently undetectable.
Children with chronic cholestasis may require large oral
doses or intramuscular administration of dl- α-tocopherol.
The doses used in patients with homozygous hypobetalipo-
proteinemia, abetalipoproteinemia, and chylomicron reten-
tion disease are much higher than doses used in ataxia with
vitamin E deficiency (►Table 4). Supplementation of other
fat-soluble vitamins may be required; excess fat, particularly
in the form of long-chain fatty acids, should be avoided. An
empiric approach is to start with a lower dose, increase it
gradually, and based on the clinical and laboratory response,
consider a higher dose or parenteral formulation. Supple-
ments of bile salts may be of value in some patients.
Metabolic Myelopathies with a Geographical
Predilection and due to a Possible Toxin
Cassava Toxicity
Weeks of high dietary cyanide exposure due to consumption
of insufficiently processed cassava in parts of Africa results in
Konzo: a distinct tropical myelopathy characterized by the
abrupt onset of spastic nonprogressive paraparesis.64 The
upper limbs and visual pathways may be involved. There is
absence of sensory or autonomic disturbance. Years of cassava
consumption has also been implicated in a syndrome of
slowly progressive ataxia, peripheral neuropathy, and optic
atrophy seen in parts of Africa.65 Drought increases the
natural occurrence of cyanogenic glucosides in the cassava
roots. Further, due to food shortage, the processing procedure
 Metabolic and Toxic Myelopathies Kumar 131

Table 5 Summary of Disorders of Vitamin E Metabolism

Disease AVED Homozygous Abetalipoproteinemia Chylomicron

Hypobetalipoproteinemia (Bassen-Kornzweig Retention Disease
Disease)
Source of defect Mutations in a-TTP Defect in apolipoprotein B Genetic defect in Chylomicron
gene on gene (AD) microsomal triglyceride synthesis and
chromosome 8q13 transfer protein (AR) secretion
(AR)
Consequence Impaired incorpo- Apo-B containing Normal lipidation of apoB Impaired assembly
of defect ration of vitamin E lipoproteins secreted into is prevented and secre- and secretion of
into hepatic the circulation turnover tion of apoB-containing chylomicrons with
lipoproteins for rapidly lipoproteins is virtually chylomicron
tissue delivery nonexistent retention in intestinal
mucosa
Fat malabsorption Absent Present Present Present
Age of onset Generally first Early childhood Early childhood Early childhood
decade, adult onset
described
Other clinical Retinitis pigmen- Retinitis pigmentosa, acanthocytosis, retarded growth, Impacts growth and
features tosa, skeletal steatorrhea has gastrointestinal

Downloaded by: Karolinska Institutet. Copyrighted material.

deformities, manifestations but
cardiomyopathy acanthocytes are
essentially absent,
neuromuscular
manifestations are
less severe, and
ocular
manifestations are
subclinical
Laboratory Very low serum Low serum vitamin E and other fat soluble vitamins, low Hypocholesterole-
findings vitamin E (as low as to nondetectable circulating lipoproteins (apoB, mia, normal fasting
1/100 of normal) chylomicrons, VLDLs, or LDLs), serum cholesterol and triglycerides,
triglycerides are markedly reduced. (The ratio of free to reduced plasma LDL
esterified cholesterol in plasma is normal in apoprotein B,
hypolipoproteinemia and elevated in absence of
abetalipoproteinemia) chylomicrons after a
fat test meal
Treatment 800–1200 mg/d of 100–200 mg/kg of vitamin E 100–200 mg/kg of 100–200 mg/kg of
vitamin E (prompt vitamin E vitamin E
normalization of
plasma
a-tocopherol
concentration)

AVED, ataxia with vitamin E deficiency; AR, autosomal recessive; AD, autosomal dominant; VLDL, very low density lipoprotein; LDL, low density
lipoprotein.

normally used to remove cyanide before consumption is
shortened.
Lathyrism
Lathyrism is a self-limiting neurotoxic disorder that is en-
demic in parts of Bangladesh, India, and Ethiopia. It presents
as a subacute or insidious onset spastic paraparesis and
afflicts individuals who consume the environmentally toler-
ant legume lathyrus sativus (grass pea or chick pea) as a
dietary staple.66 Beta-N-oxalyl-amino-L-alanine (L-BOAA), an
excitotoxic amino acid in lathyrus sativus is the likely toxin.
The typical gait is a lurching scissoring gait characterized by
patients walking on the balls of their feet. In severely affected
individuals, pyramidal signs may be present in the upper
limbs also. Lower limb sensory symptoms may occur; sensory
signs are rare. In the early stages, there may be diffuse central
nervous system excitation of somatic motor and autonomic
function including the presence of bladder symptoms. An
early improvement in limb strength is seen and may be
substantial. Some patients stabilize in a subclinical, asymp-
tomatic stage with minimal deficits. Neurolathyrism may be
prevented by mixing grass pea preparations with cereals or
detoxification of grass peas through aqueous leaching.
Fluorosis
Fluorosis occurs when a large amount of fluoride, naturally
present in the earth and water in certain parts of the world,
are deposited in bones. The vertebral column is commonly

Seminars in Neurology Vol. 32 No. 2/2012

132 Metabolic and Toxic Myelopathies Kumar

Figure 3 Vitamin E metabolism. Vitamin E absorption from the gastrointestinal tract requires bile acids, fatty acids, and monoglycerides for

Downloaded by: Karolinska Institutet. Copyrighted material.

micelle formation. Following uptake by enterocytes, all forms of dietary vitamin E are incorporated into chylomicrons. The chylomicrons are
secreted into the circulation, where lipolysis by lipoprotein lipase takes place. During lipolysis various forms of vitamin E are transferred to
high-density lipoproteins or other circulating lipoproteins and subsequently to tissues. The chylomicron remnants are taken up by the liver. In the
liver, the α-tocopherol transfer protein (TTP) incorporates α-tocopherol into very low density lipoproteins (VLDLs), which are secreted into plasma.
Lipolysis of VLDL results in enrichment of circulating lipoproteins with RRR-α-tocopherol that is delivered to peripheral tissue. Most ingested
vitamin E is eliminated by the fecal route. The majority of vitamin E in the human body is localized in the adipose tissue. Analysis of adipose tissue
α-tocopherol content provides a useful estimate of long-term vitamin E intake. Over 2 years are required for adipose tissue α-/γ-tocopherol ratios
to reach new steady-state levels in response to changes in dietary intake. Copyright: Mayo Foundation.

involved. This results in back pain and stiffness with limited
spine mobility. Neurologic manifestations are delayed and are
seen in 10% of patients with skeletal fluorosis. These include
cord compression and less commonly, radiculopathy.67
The spastic paraparesis may be accompanied by some sensory
manifestations and lower motor neuron involvement. Sphinc-
ter disturbance may be present. A sensory level is not seen.
Some patients may have decreased hearing due to compres-
sion of the auditory nerves in the sclerosed auditory canal.
Due to bony deformities, entrapment neuropathies may be
seen. The typical radiologic findings are osteosclerosis and
ligamentous calcification. A characteristic finding is calcifica-
tion of the interosseous membrane of the forearm. Laboratory
studies show elevation of alkaline phosphatase and parathor-
mone levels with normal calcium and phosphorus. Estima-
tion of urinary fluoride levels is not reliable.
Subacute Myelo-Optico Neuropathy
Subacute myelo-optico neuropathy (SMON) is a myeloneur-
opathy with optic nerve involvement that affected individu-
als in Japan and elsewhere between 1955 and 1970.68
Epidemiologic studies have suggested that SMON was due
to toxicity from the antiparasitic drug clioquinol. SMON was
characterized by subacute onset of lower limb paresthesias
and spastic paraparesis with optic atrophy. The precise
mechanism of action of clioquinol has been unclear. Clioqui-
nol is a copper chelator. Identification of a myelopathy
resulting from acquired copper deficiency has led to the
speculation that clioquinol-induced neurotoxicity could
have been a consequence of copper deficiency.69,70
Tropical Myeloneuropathies
The term tropical myeloneuropathies has been used to de-
scribe multifactorial conditions seen in several developing
countries. Associations have included malnutrition, cyanide
intoxication due to cassava consumption, lathyrism, organo-
phosphate neurotoxicity, malabsorption, and vegetarian di-
ets.71 From 1991 to 1994, an epidemic in Cuba affected more
than 50,000 persons and caused optic neuropathy, sensori-
neural deafness, dorsolateral myelopathy, dysautonomia,
bulbar dysfunction, and axonal sensory neuropathy.72 Iden-
tified risk factors included irregular diet, weight loss, smok-
ing, alcohol, and excessive sugar consumption. Patients
responded to B-group vitamins and folic acid. Overt malnu-
trition was not present. The term tropical ataxic neuropathy
was originally used to describe an ataxic neuropathy seen in
Nigeria that was related to cassava consumption. Tropical
spastic paraparesis (TSP) is a myelitis now known to be due to
HTLV-I or HTLV-II. It has been referred to as HTLV-associated
myelopathy (HAM) in Japan. HAM and TSP are now believed
to be identical syndromes. The hybrid designation HAM/TSP
is commonly used. A broader HTLV-1-related neurologic
spectrum is increasingly being recognized.73
Metabolic Myelopathies due to Possible
Toxins but Without a Geographical
Predilection
Chemotherapy-Induced Myelopathy
Myelopathy has been reported following administration of
certain chemotherapeutic agents (►Table 6), particularly so

Seminars in Neurology Vol. 32 No. 2/2012


Table 6 Salient Clinical Features of Some Additional Metabolic Myelopathies and Myeloneuropathies
Disease Clinical Clues
Nitrous oxide toxicity Among dentists, medical or
nursing staff
Consider when neurologic
symptoms develop after
surgical procedures
Symptoms may be delayed
after exposure
Resembles subacute combined
degeneration seen with
vitamin B12 deficiency
Cassava toxicity Consumption of insufficiently
processed cassava in parts of
Africa leads to abrupt onset of
spastic paraparesis
Chronic cassava consumption
associated with slowly
progressive ataxia and
peripheral neuropathy
Lathyrism Consumption of lathyrus
sativus as a staple
Subacute or insidious onset
spastic paraparesis
Fluorosis Consumption of large amounts
of fluoride that is naturally
present in water in some parts
of the world
Back pain, limited spine mo-
bility, cord compression,
radiculopathy
Chemotherapy-induced Immediate and transient or
myelopathy progressive
Particularly with intrathecal
use (methotrexate,
doxorubicin, vincristine,
cytarabine, vinorelbine,
carmustine, cisplatin)
Hepatic myelopathy Complication of chronic liver
disease
Progressive spastic paraparesis
Heroin myelopathy Acute or progressive
myelopathy
Organophosphate Acute (cholinergic),
toxicity intermediate (neuromuscular
junction), delayed
(organophosphate induced
delayed neurotoxicity)
manifestations
Progressive leg weakness that
may be associated with mild
sensory symptoms and upper
limb involvement
MRI, magnetic resonance imaging; RBC, red blood cell.
Metabolic and Toxic Myelopathies
Laboratory/Imaging Features
Evidence of vitamin B12
deficiency
Increased signal on T2-weighted
MRI involving dorsal column
Serum thiocyanate is a biomarker
for dietary cyanide exposure
— Preventable by mixing grass
Osteosclerosis and ligamentous
calcification on x-ray
Calcification of the interosseous
membrane of the forearm
Lateral column or peripheral cord
enhancement
Elevated serum manganese
Increased pallidal signal on
T1-weighted cranial MRI
Increased cervical cord signal on
T2-weighted MRI
Acute: MRI resembles transverse
myelitis
Chronic: MRI shows selective
involvement of lateral and
posterior columns
RBC cholinesterase activity is a
measure of chronic exposure to
organophosphates
Seminars in Neurology
Kumar 133
Treatment/Commons
Cessation of chronic exposure
Prophylactic vitamin B12 prior
to surgery in individuals with a
borderline vitamin B12 who are
expected to receive nitrous
oxide anesthesia
Intramuscular vitamin B12 with
acute nitrous oxide poisoning
Possible role of methionine
supplementation
Improvement in food
processing
Downloaded by: Karolinska Institutet. Copyrighted material.
pea with cereals, or
detoxification through
aqueous leaching
Prevention
Surgery may be required for
cord compression.
Avoid multiple intrathecal
therapy
Possible benefit of early liver
transplantation
Mechanism: Hypersensitivity
reaction (acute myelopathy),
direct toxicity (progressive
myelopathy)
Prevented by use of gloves and
protective clothing
Pralidoxime and atropine for
acute toxicity
Vol. 32 No. 2/2012
134 Metabolic and Toxic Myelopathies Kumar
with intrathecal administration. Paraparesis following intra-
thecal chemotherapy may be related to toxicity of the preser-
vative used.74 Two clinical patterns of paraparesis have been
recognized.74 A transient, flaccid, areflexic paraparesis with
pain and anesthesia may occur soon after the intrathecal
injection. Rarely, the paralysis may ascend with respiratory
compromise and death. This form localizes to the spinal root.
A less common form is a progressive spastic-ataxic para-
paresis with sphincteric dysfunction that is seen after weeks
of a series of intrathecal treatments. MRI in patients with
intrathecal chemotherapy-induced myelopathy may show
contrast enhancement limited to the lateral columns.75 To
prevent intrathecal chemotherapy-induced paralysis preser-
vative containing chemotherapeutic agents or diluents
should not be used intrathecally.74 Multiple and frequent
intrathecal therapy should be avoided.
Hepatic Myelopathy
Hepatic myelopathy (portosystemic myelopathy) is a rare
complication of chronic liver disease. It is associated with
cirrhosis and/ or extensive portosystemic shunting.76 Porto-
systemic myelopathy can be induced by portosystemic shunt-
ing of all types: surgical, angiographic, or spontaneous.
Preceding portosystemic encephalopathy is often, but not
invariably present. It has been suggested that the neurotoxic-
ity may be a consequence of ammonia or other metabolites
bypassing the liver. Also reported is hepatic myelopathy with
increased serum manganese and MRI evidence of manganese
deposition in the basal ganglia without extrapyramidal man-
ifestations or clinical evidence of decompensated cirrhosis.77
There is symmetric demyelination of the lateral corticospinal
tract and less commonly in the ventral pyramidal tracts,
posterior columns, and spinocerebellar tracts. The hallmark
of hepatic myelopathy is progressive spastic paraparesis.
Sensory disturbance, upper limb involvement, and sphincter-
ic dysfunction are minimal or absent. Variable results have
been reported following liver transplantation.
Heroin Myelopathy
Acute myelopathy is a recognized complication of insufflation
of heroin or intravenous heroin abuse. MRI resembles that
seen in transverse myelitis.78 Inhalation of heroin vapor
(“chasing the dragon”) has been shown to result in a progres-
sive myelopathy with selective involvement of the ventral
pons, lateral, and posterior columns.79 Proposed mechanisms
for heroin myelopathy include embolism of adulterants,
hypotension with border zone infarction, vasculitis, direct
toxicity, or hypersensitivity reaction. Hypersensitivity as a
possible mechanism is suggested by the fact that the myelop-
athy may occur after a period of abstinence followed by single
use.
Organophosphate Toxicity
The signs and symptoms of acute organophosphate toxicity
are due to acetylcholinesterase inhibition and resulting mus-
carinic and nicotinic dysfunction. Pralidoxime is a reactivator
of inhibited acetylcholinesterase and is the specific antidote.
It is used in conjunction with atropine in the acute stages. In
Seminars in Neurology Vol. 32 No. 2/2012
some patients, after resolution of the cholinergic crisis an
intermediate syndrome develops.80 This is likely a neuromus-
cular junction defect characterized by weakness of neck
flexors, proximal limbs, and respiratory muscles. Organo-
phosphate-induced-delayed neurotoxicity (OPIDN) is a com-
plication of some organophosphorus compounds and is
possibly due to phosphorylation and subsequent aging of
neurotoxic esterase (NTE) in the nervous system.81 It occurs 1
to 3 weeks after acute exposure and after a more uncertain
duration after chronic exposure. OPIDN may occur in the
absence of the cholinergic or intermediate phase. The symp-
toms include distal paresthesias, progressive leg weakness
and wasting, and cramping muscle pain. There may be
evidence of upper limb involvement and pyramidal tract
dysfunction. Sensory loss when present is mild. The RBC
cholinesterase activity is less rapidly depressed than the
serum cholinesterase activity and is a measure of chronic
exposure to organophosphates.
Downloaded by: Karolinska Institutet. Copyrighted material.
References
1 Carmel R. Current concepts in cobalamin deficiency. Annu Rev
Med 2000;51:357–375
2 Andrès E, Affenberger S, Vinzio S, et al. Food-cobalamin malab-
sorption in elderly patients: clinical manifestations and treatment.
Am J Med 2005;118(10):1154–1159
3 Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobala-
min, folate, and homocysteine. Hematology (Am Soc Hematol Educ
Program) 2003:62–81
4 Juhasz-Pocsine K, Rudnicki SA, Archer RL, Harik SI. Neurologic
complications of gastric bypass surgery for morbid obesity. Neu-
rology 2007;68(21):1843–1850
5 Kumar N. Neurological aspects of cobalamin (B12) deficiency. In:
Biller J, ed. Handbook of Clinical Neurology: Systemic Diseases.
Amsterdam: Elsevier; 2011 (in press)
6 Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric
disorders caused by cobalamin deficiency in the absence of anemia
or macrocytosis. N Engl J Med 1988;318(26):1720–1728
7 Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neuro-
logic aspects of cobalamin deficiency. Medicine (Baltimore)
1991;70(4):229–245
8 Carmel R, Melnyk S, James SJ. Cobalamin deficiency with and
without neurologic abnormalities: differences in homocysteine
and methionine metabolism. Blood 2003;101(8):3302–3308
9 Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in the
identification of cobalamin-deficiency polyneuropathy. Arch Neu-
rol 2003;60(9):1296–1301
10 Locatelli ER, Laureno R, Ballard P, Mark AS. MRI in vitamin B12
deficiency myelopathy. Can J Neurol Sci 1999;26(1):60–63
11 Bassi SS, Bulundwe KK, Greeff GP, Labuscagne JH, Gledhill RF. MRI
of the spinal cord in myelopathy complicating vitamin B12 defi-
ciency: two additional cases and a review of the literature.
Neuroradiology 1999;41(4):271–274
12 Karantanas AH, Markonis A, Bisbiyiannis G. Subacute combined
degeneration of the spinal cord with involvement of the anterior
columns: a new MRI finding. Neuroradiology 2000;42(2):115–117
13 Su S, Libman RB, Diamond A, Sharfstein S. Infratentorial and
supratentorial leukoencephalopathy associated with vitamin
B12 deficiency. J Stroke Cerebrovasc Dis 2000;9(3):136–138
14 Solomon LR. Cobalamin-responsive disorders in the ambulatory
care setting: unreliability of cobalamin, methylmalonic acid, and
homocysteine testing. Blood 2005;105(3):978–985
15 Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood
2008;112(6):2214–2221

16 Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum
methylmalonic acid and total homocysteine determinations for
diagnosing cobalamin and folate deficiencies. Am J Med 1994;
96(3):239–246
17 Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin
deficiency. Neurology 1995;45(8):1435–1440
18 Chanarin I, Metz J. Diagnosis of cobalamin deficiency: the old and
the new. Br J Haematol 1997;97(4):695–700
19 Andrès E, Fothergill H, Mecili M. Efficacy of oral cobalamin
(vitamin B12) therapy. Expert Opin Pharmacother 2010;11(2):
249–256
20 Stabler SP. Screening the older population for cobalamin (vitamin
B12) deficiency. J Am Geriatr Soc 1995;43(11):1290–1297
21 Ng J, Frith R. Nanging. Lancet 2002;360(9330):384
22 Kinsella LJ, Green R. ’Anesthesia paresthetica’: nitrous oxide-
induced cobalamin deficiency. Neurology 1995;45(8):1608–1610
23 Marié RM, Le Biez E, Busson P, et al. Nitrous oxide anesthesia-
associated myelopathy. Arch Neurol 2000;57(3):380–382
24 Kieburtz KD, Giang DW, Schiffer RB, Vakil N. Abnormal vitamin
B12 metabolism in human immunodeficiency virus infection.
Association with neurological dysfunction. Arch Neurol 1991;
48(3):312–314
25 Di Rocco A, Werner P, Bottiglieri T, et al. Treatment of AIDS-
associated myelopathy with L-methionine: a placebo-controlled
study. Neurology 2004;63(7):1270–1275
26 Green R, Miller JW. Folate deficiency beyond megaloblastic ane-
mia: hyperhomocysteinemia and other manifestations of dysfunc-
tional folate status. Semin Hematol 1999;36(1):47–64
27 Reynolds EH. Benefits and risks of folic acid to the nervous system.
J Neurol Neurosurg Psychiatry 2002;72(5):567–571
28 Reynolds EH, Rothfeld P, Pincus JH. Neurological disease associated
with folate deficiency. BMJ 1973;2(5863):398–400
29 Parry TE. Folate responsive neuropathy. Presse Med 1994;23(3):
131–137
30 Reynolds EH. Benefits and risks of folic acid to the nervous system.
J Neurol Neurosurg Psychiatry 2002;72(5):567–571
31 Diaz-Arrastia R. Homocysteine and neurologic disease. Arch Neu-
rol 2000;57(10):1422–1427
32 Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine
in patients with ischemic stroke to prevent recurrent stroke,
myocardial infarction, and death: the Vitamin Intervention for
Stroke Prevention (VISP) randomized controlled trial. [see com-
ment]JAMA 2004;291(5):565–575
33 Brouwer DA, Welten HT, Reijngoud DJ, van Doormaal JJ, Muskiet
FA. Plasma folic acid cutoff value, derived from its relationship
with homocyst(e)ine. Clin Chem 1998;44(7):1545–1550
34 Lucock M, Yates Z. Measurement of red blood cell methylfolate.
Lancet 2002;360(9338):1021–1022, author reply 1022
35 Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum
J. Elevation of total homocysteine in the serum of patients with
cobalamin or folate deficiency detected by capillary gas chroma-
tography-mass spectrometry. J Clin Invest 1988;81(2):466–474
36 Kumar N, McEvoy KM, Ahlskog JE. Myelopathy due to copper
deficiency following gastrointestinal surgery. Arch Neurol
2003;60(12):1782–1785
37 Kumar N, Ahlskog JE, Gross JB Jr. Acquired hypocupremia
after gastric surgery. Clin Gastroenterol Hepatol 2004;2(12):
1074–1079
38 Winston GP, Jaiser SR. Copper deficiency myelopathy and subacute
combined degeneration of the cord - why is the phenotype so
similar? Med Hypotheses 2008;71(2):229–236
39 Kumar N, Gross JB Jr, Ahlskog JE. Myelopathy due to copper
deficiency. Neurology 2003;61(2):273–274
40 Nations SP, Boyer PJ, Love LA, et al. Denture cream: an unusual
source of excess zinc, leading to hypocupremia and neurologic
disease. Neurology 2008;71(9):639–643
41 Hedera P, Peltier A, Fink JK, Wilcock S, London Z, Brewer GJ.
Myelopolyneuropathy and pancytopenia due to copper deficiency
Metabolic and Toxic Myelopathies Kumar 135
and high zinc levels of unknown origin II. The denture cream is a
primary source of excessive zinc. Neurotoxicology 2009;30(6):
996–999
42 Pawa S, Khalifa AJ, Ehrinpreis MN, Schiffer CA, Siddiqui FA. Zinc
toxicity from massive and prolonged coin ingestion in an adult. Am
J Med Sci 2008;336(5):430–433
43 Yaldizli O, Johansson U, Gizewski ER, Maschke M. Copper deficien-
cy myelopathy induced by repetitive parenteral zinc supplemen-
tation during chronic hemodialysis. J Neurol 2006;253(11):
1507–1509
44 Foubert-Samier A, Kazadi A, Rouanet M, et al. Axonal sensory
motor neuropathy in copper-deficient Wilson’s disease. Muscle
Nerve 2009;40(2):294–296
45 Halfdanarson TR, Kumar N, Hogan WJ, Murray JA. Copper
deficiency in celiac disease. J Clin Gastroenterol 2009;43(2):
162–164
46 Goodman BP, Mistry DH, Pasha SF, Bosch PE. Copper deficiency
myeloneuropathy due to occult celiac disease. Neurologist 2009;
15(6):355–356
47 Shike M. Copper in parenteral nutrition. Gastroenterology
2009;137(5, Suppl):S13–S17
48 Kumar N, Gross JB Jr, Ahlskog JE. Copper deficiency myelopathy
produces a clinical picture like subacute combined degeneration.
Downloaded by: Karolinska Institutet. Copyrighted material.
Neurology 2004;63(1):33–39
49 Mercer JF, Llanos RM. Molecular and cellular aspects of copper
transport in developing mammals. J Nutr 2003;133(5, Suppl 1):
1481S–1484S
50 Kumar N. Copper deficiency myelopathy (human swayback). Mayo
Clin Proc 2006;81(10):1371–1384
51 Prodan CI, Bottomley SS, Vincent AS, Cowan LD, Holland NR, Lind
SE. Hypocupremia associated with prior vitamin B12 deficiency.
Am J Hematol 2007;82(4):288–290
52 Pineles SL, Wilson CA, Balcer LJ, Slater R, Galetta SL. Combined
optic neuropathy and myelopathy secondary to copper deficiency.
Surv Ophthalmol 2010;55(4):386–392
53 Weihl CC, Lopate G. Motor neuron disease associated with copper
deficiency. Muscle Nerve 2006;34(6):789–793
54 Kumar N, Elliott MA, Hoyer JD, Harper CM Jr, Ahlskog JE, Phyliky RL.
“Myelodysplasia,” myeloneuropathy, and copper deficiency. Mayo
Clin Proc 2005;80(7):943–946
55 Halfdanarson TR, Kumar N, Li CY, Phyliky RL, Hogan WJ. Hemato-
logical manifestations of copper deficiency: a retrospective re-
view. Eur J Haematol 2008;80(6):523–531
56 Kumar N, Ahlskog JE, Klein CJ, Port JD. Imaging features of copper
deficiency myelopathy: a study of 25 cases. Neuroradiology
2006;48(2):78–83
57 Ferrara JM, Skeen MB, Edwards NJ, Gray L, Massey EW. Subacute
combined degeneration due to copper deficiency. J Neuroimaging
2007;17(4):375–377
58 Kumar G, Goyal MK, Lucchese S, Dhand U. Copper deficiency
myelopathy can also involve the brain stem. AJNR Am J Neuro-
radiol 2011;32(1):E14–E1510.3174/ajnr.A2261
59 Goodman BP, Bosch EP, Ross MA, Hoffman-Snyder C, Dodick DD,
Smith BE. Clinical and electrodiagnostic findings in copper defi-
ciency myeloneuropathy. J Neurol Neurosurg Psychiatry 2009;
80(5):524–527
60 Kumar N, Butz JA, Burritt MF. Clinical significance of the laboratory
determination of low serum copper in adults. Clin Chem Lab Med
2007;45(10):1402–1410
61 Sokol RJ. Vitamin E deficiency and neurologic disease. Annu Rev
Nutr 1988;8:351–373
62 Vorgerd M, Tegenthoff M, Kühne D, Malin JP. Spinal MRI in
progressive myeloneuropathy associated with vitamin E deficien-
cy. Neuroradiology 1996;38(Suppl (1):S111–S113
63 Sokol RJ, Heubi JE, Iannaccone ST, Bove KE, Balistreri WF. Vitamin E
deficiency with normal serum vitamin E concentrations in chil-
dren with chronic cholestasis. N Engl J Med 1984;310(19):
1209–1212
Seminars in Neurology Vol. 32 No. 2/2012
136 Metabolic and Toxic Myelopathies Kumar
64 Howlett WP, Brubaker GR, Mlingi N, Rosling H. Konzo, an epidemic
upper motor neuron disease studied in Tanzania. Brain 1990;
113(Pt 1):223–235
65 Osuntokun BO. An ataxic neuropathy in Nigeria. A clinical, bio-
chemical and electrophysiological study. Brain 1968;91(2):
215–248
66 Ludolph AC, Hugon J, Dwivedi MP, Schaumburg HH, Spencer PS.
Studies on the aetiology and pathogenesis of motor neuron
diseases. 1. Lathyrism: clinical findings in established cases. Brain
1987;110(Pt 1):149–165
67 Misra UK, Nag D, Husain M, Newton G, Ray PK. Endemic fluorosis
presenting as cervical cord compression. Arch Environ Health
1988;43(1):18–21
68 Konagaya M, Matsumoto A, Takase S, et al. Clinical analysis of
longstanding subacute myelo-optico-neuropathy: sequelae of clio-
quinol at 32 years after its ban. J Neurol Sci 2004;218(1–2):85–90
69 Kumar N, Knopman DS. SMON, clioquinol, and copper. Postgrad
Med J 2005;81:227
70 Schaumburg H, Herskovitz S. Copper deficiency myeloneuropathy:
a clue to clioquinol-induced subacute myelo-optic neuropathy?
Neurology 2008;71(9):622–623
71 Román GC, Spencer PS, Schoenberg BS. Tropical myeloneuropa-
thies: the hidden endemias. Neurology 1985;35(8):1158–1170
72 Román GC. An epidemic in Cuba of optic neuropathy, sensorineu-
ral deafness, peripheral sensory neuropathy and dorsolateral
myeloneuropathy. J Neurol Sci 1994;127(1):11–28
Seminars in Neurology Vol. 32 No. 2/2012
73 Araujo AQ, Silva MT. The HTLV-1 neurological complex. Lancet
Neurol 2006;5(12):1068–1076
74 Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following intrathecal
chemotherapy. Neurology 1983;33(8):1032–1038
75 McLean DR, Clink HM, Ernst P, et al. Myelopathy after intrathecal
chemotherapy. A case report with unique magnetic resonance
imaging changes. [see comment]Cancer 1994;73(12):
3037–3040
76 Conn HO, Rössle M, Levy L, Glocker FX. Portosystemic myelopathy:
spastic paraparesis after portosystemic shunting. Scand J Gastro-
enterol 2006;41(5):619–625
77 Gospe SM Jr, Caruso RD, Clegg MS, et al. Paraparesis, hyper-
manganesaemia, and polycythaemia: a novel presentation of
cirrhosis. Arch Dis Child 2000;83(5):439–442
78 McCreary M, Emerman C, Hanna J, Simon J. Acute myelopathy
following intranasal insufflation of heroin: a case report. Neurol-
ogy 2000;55(2):316–317
79 Nyffeler T, Stabba A, Sturzenegger M. Progressive myelopathy with
selective involvement of the lateral and posterior columns after
inhalation of heroin vapour. J Neurol 2003;250(4):496–498
80 Senanayake N, Karalliedde L. Neurotoxic effects of organophos-
phorus insecticides. An intermediate syndrome. N Engl J Med
1987;316(13):761–763
Downloaded by: Karolinska Institutet. Copyrighted material.
81 Lotti M, Becker CE, Aminoff MJ. Organophosphate polyneurop-
athy: pathogenesis and prevention. Neurology 1984;34(5):
658–662