Metabolic and Toxic Myelopathies.12

Metabolic and Toxic REVIEW ARTICLE

Myelopathies C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Kathryn B. Holroyd, MD; Aaron L. Berkowitz, MD, PhD, FAAN
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ABSTRACT
OBJECTIVE: This article reviews the clinical presentation, diagnostic
evaluation, and treatment of metabolic and toxic myelopathies resulting
from nutritional deficiencies, environmental and dietary toxins, drugs of
abuse, systemic medical illnesses, and oncologic treatments.
LATEST DEVELOPMENTS: Increased use of bariatric surgery for obesity has led to
higher incidences of deficiencies in nutrients such as vitamin B12 and copper,
which can cause subacute combined degeneration. Myelopathies CITE AS:
CONTINUUM (MINNEAP MINN)
secondary to dietary toxins including konzo and lathyrism are likely to
2024;30(1, SPINAL CORD
become more prevalent in the setting of climate change leading to drought DISORDERS):199–223.
and flooding. Although modern advances in radiation therapy techniques
have reduced the incidence of radiation myelopathy, patients with cancer Address correspondence to
Dr Aaron L. Berkowitz, San
are living longer due to improved treatments and may require reirradiation Francisco VA Medical Center,
that can increase the risk of this condition. Immune checkpoint inhibitors are 4150 Clement St, San Francisco,
increasingly used for the treatment of cancer and are associated with a wide CA 94121, Aaron.
Berkowitz@ucsf.edu.
variety of immune-mediated neurologic syndromes including myelitis.
RELATIONSHIP DISCLOSURE:
ESSENTIAL POINTS: Metabolic and toxic causes should be considered in the Dr Holroyd reports no
disclosure. Dr Berkowitz has
diagnosis of myelopathy in patients with particular clinical syndromes, risk received personal
factors, and neuroimaging findings. Some of these conditions may be compensation in the range of
$500 to $4999 for serving as a
reversible if identified and treated early, requiring careful history,
content creator for The Clinical
examination, and laboratory and radiologic evaluation for prompt diagnosis. Problem Solvers and as an
editor, associate editor, or
editorial advisory board
member for the American
INTRODUCTION Academy of Neurology and
M
etabolic causes of myelopathy include nutritional deficiencies McGraw-Hill Education; in the
(eg, vitamin B12, copper, folate, and vitamin E). Toxic causes range of $5000 to $9999 for
serving as a consultant with
of myelopathy include dietary exposures (eg, bitter cassava Thieme Group; and in the range
root causing konzo, grass pea causing lathyrism), endogenous of $10,000 to $49,999 for serving
as an expert witness for various
toxins (eg, hepatic myelopathy), and drugs of abuse (eg, nitrous law firms. Dr Berkowitz has
oxide, heroin). Treatments for cancer such as intrathecal chemotherapy, immune received publishing royalties
checkpoint inhibitors (ICIs), and radiation therapy can cause myelopathy. This from publications relating to
health care.
article reviews the clinical, laboratory, and radiologic features of these conditions,
the risk factors for their development, and their treatment and prognosis. A UNLABELED USE OF PRODUCTS/
summary of the key aspects of these entities can be found in TABLE 9-1. INVESTIGATIONAL USE
DISCLOSURE:
Drs Holroyd and Berkowitz
VITAMIN B12 (COBALAMIN) DEFICIENCY report no disclosures.
Vitamin B12 is a water-soluble vitamin that serves as a cofactor for key enzymatic
reactions in amino acid synthesis, fatty acid metabolism, DNA synthesis, and © 2024 American Academy
myelin formation.1 Dietary sources of vitamin B12 include eggs, red meat, milk, of Neurology.
CONTINUUMJOURNAL.COM 199
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

METABOLIC AND TOXIC MYELOPATHIES
cheese, and some fortified grains. After cleavage by gastric acid in the stomach,
vitamin B12 binds to intrinsic factor in the duodenum and is absorbed in
the ileum.2
Vitamin B12 deficiency is more common in patients older than 60 years,
and prevalence increases with advancing age.2 The most common causes of
vitamin B12 deficiency include inadequate intake (eg, vegan diet), autoimmune
disease (eg, pernicious anemia), malabsorption (eg, gastric bypass, gastric or

ileal resection, inflammatory bowel disease, intestinal lymphoma, chronic
pancreatitis), and medications (eg, proton pump inhibitors and metformin).2
TABLE 9-1 Clinical Features of Metabolic and Toxic Myelopathies
Spinal cord
Population at risk syndrome MRI CSF Serum Treatment
Vitamin B12 Older than 60 years, Dorsal columns T2 hyperintensity Normal Macrocytic 1000 µg vitamin B12
deficiency vegan diet, pernicious and corticospinal of the dorsal anemia, serum IM weekly or oral
anemia, bariatric tracts (concurrent columns spanning vitamin B12 daily depending on
surgery, inflammatory neuropathy may multiple levels <200 pg/mL, cause of deficiency
bowel disease, be present) (“inverted V” or elevated (see text)
pancreatic “rabbit ears” on methylmalonic
insufficiency axial sections) acid and
homocysteine
Nitrous oxide Inhaled anesthetic for Dorsal columns T2 hyperintensity Normal Low serum Vitamin B12
medical and dental and corticospinal of the dorsal vitamin B12, repletion, stop
procedures, tracts columns elevated nitrous
recreational use methylmalonic oxide use
(“whippets”) acid and
homocysteine
Folate Alcohol use disorder, Dorsal columns T2 hyperintensity Normal Macrocytic Folic acid
deficiency meat-based diet, and corticospinal of the dorsal anemia, folate 5 mg/d 4 months
hematologic tracts (concurrent columns <3 ng/mL, red then 1 mg/d; may
malignancies, bariatric neuropathy may cell folate need up to
surgery, inflammatory be present) <150 μg/L, 30 mg/d
bowel disease increased
homocysteine
Vitamin E Cystic fibrosis, Dorsal columns T2 hyperintensity Normal Serum vitamin E Oral vitamin E 200-
deficiency abetalipoproteinemia, and of the dorsal < 5 μg/mL, ratio 300 mg/d; may
cholestatic and spinocerebellar columns of vitamin E to need up to
hepatobiliary tracts serum lipids 3000 mg daily
disorders, (concurrent <0.8 mg/g
inflammatory bowel neuropathy may
disease, small bowel be present)
resection
Copper Parenteral nutrition, Dorsal columns T2 hyperintensity Normal Pancytopenia, Oral copper
deficiency excessive zinc intake, and corticospinal of the dorsal serum copper 6 mg 1 week,
bariatric surgery, tracts (concurrent columns <0.75 μg/mL, 4 mg 1 week, then
nephrotic syndrome, neuropathy may ceruloplasmin 2 mg daily
Menkes disease, be present) <21.5 mg/dL
penicillamine
Konzo Cassava root Dorsal columns Normal, but Normal Elevated serum Supportive care
consumption in and corticospinal few reports and urine
drought-prone tracts thiocyanate
regions
CONTINUED ON PAGE 201
200 F E B R U A R Y 2 0 24

Nitrous oxide use can also lead to secondary vitamin B12 deficiency
(as discussed in the Nitrous Oxide section).
Clinical Presentation
Vitamin B12 deficiency is associated with subacute combined degeneration,
a condition affecting the posterolateral spinal cord (ie, dorsal columns and
corticospinal tracts).2 Vitamin B12 deficiency myelopathy presents subacutely

to chronically, with large case series reporting a median time from symptom
onset to clinical evaluation of 4 to 14 months,3 although symptoms may progress
CONTINUED FROM PAGE 200
Spinal cord
Population at risk syndrome MRI CSF Serum Treatment
Lathyrism Consumption of Dorsal columns Normal, but Normal Not applicable Supportive care
grass pea, protein and corticospinal few reports
malnutrition, more tracts
common in men
Heroin Resumption of heroin Transverse, Longitudinally Usually normal Not applicable Unknown,
use after period of dorsal columns extensive T2 corticosteroids
abstinence from may be spared in hyperintensity, used in some cases
chronic use some cases patchy
enhancement may
be seen
Hepatic Portacaval shunting Subacute lower Normal Normal Elevated liver Liver
(spontaneous, surgical, extremity function tests, transplantation,
or transjugular paraparesis; ammonia TIPS occlusion
intrahepatic sensory or
portosystemic shunt sphincter
[TIPS]) involvement rare
Intrathecal Patients receiving Arachnoiditis Arachnoiditis: Elevated Decreased Unknown, folate

chemotherapy intrathecal (causing cauda equina protein, folate with metabolites and
methotrexate or lumbosacral clumping or elevated myelin intrathecal dextromethorphan
cytarabine radiculitis) or enhancement; basic protein methotrexate have been used in
transverse myelopathy: some cases
longitudinally
extensive T2
hyperintensity
Immune Preexisting Transverse Longitudinally Elevated Not applicable Discontinuation

checkpoint paraneoplastic or extensive T2 protein, of checkpoint
inhibitors other autoantibodies hyperintensity, lymphocytic inhibitor; steroids
against neural antigens patchy pleocytosis, with escalation
may increase risk enhancement may autoantibodies to IV immunoglobulin
be seen detected in (IVIg), plasma
some cases exchange, or other
immunomodulatory
treatment if
refractory
Radiation Radiation for cancers Early: isolated Early: normal Early: normal Not applicable Unknown, steroids,
of head or neck, Lhermitte sign Late: longitudinally Late: normal or anticoagulation,
thorax, upper abdomen; Late: Brown- extensive T2 elevated protein hyperbaric oxygen,
spinal metastases Séquard hyperintensity, and bevacizumab
with total dose or syndrome T1 hypointensity, have been used
fraction exceeding or transverse focal patchy or ring
recommended limits; enhancement
reirradiation of spine

rapidly over weeks.4 Paresthesia and sensory ataxia of all four limbs are the
predominant symptoms (CASE 9-1). Weakness is uncommon early in the
condition, although upper motor neuron findings such as hyperreflexia and the
Babinski sign are common on examination. In long-standing untreated cases,
weakness can develop.3,5,6 Bowel and bladder symptoms are seen in less than
15% of patients.3
Peripheral neuropathy occurs in 15% to 30% of patients with vitamin B12

deficiency and may be concurrent with subacute combined degeneration,
CASE 9-1 A 65-year-old man with a history of Crohn disease presented with several
weeks of bilateral hand and foot paresthesia. He also reported feeling off
balance, needing to hold on to the handrails when using the stairs to avoid
falling. A recent flare in his Crohn disease had led to reduced food intake
for the past 2 weeks.
On examination, there was absent vibration sense and proprioception
at the big toe and ankle bilaterally with preserved pain sensation. His
reflexes were absent at the ankles and brisk at the knees and in the upper
extremities. The Babinski sign was present bilaterally. He had a Romberg
sign and wide-based gait.
MRI demonstrated longitudinal T2 hyperintensity in the posterior
spinal cord (FIGURE 9-1). Complete blood cell count was notable for a
hemoglobin of 9 g/dL and a mean corpuscular volume of 110 fL. Serum
vitamin B12 was 110 pg/mL. Serum folate, copper, and vitamin E were
within normal limits.
The patient was diagnosed with vitamin B12 deficiency myelopathy and
started on IM cyanocobalamin 1000 μg weekly for 2 weeks, followed by
monthly injections. Over the course of the next 6 months, he noted
almost complete improvement in his neurologic symptoms, with only
mild paresthesia in his feet remaining.
COMMENT The patient’s risk factors for vitamin B12 deficiency included age and
inflammatory bowel disease. He likely had low baseline vitamin B12 levels
due to malabsorption that were further reduced due to a flare of
inflammatory bowel disease leading to both decreased oral intake and
decreased absorption. His neurologic examination findings of dorsal
column dysfunction and mixed upper and lower motor neuron signs were
consistent with myeloneuropathy with posterolateral spinal dysfunction, a
common pattern in vitamin B12 deficiency that may also be seen in copper
or folate deficiency.
202 F E B R U A R Y 2 0 24

causing a myeloneuropathy with both upper and lower motor neuron signs on
examination.3,7 Long-standing untreated vitamin B12 deficiency commonly
causes cognitive impairment8 and can more rarely cause autonomic neuropathy
and optic neuropathy.9,10 Systemic symptoms of generalized fatigue,
constipation, and urinary frequency and examination findings such as glossitis
and skin hyperpigmentation may be clues to the diagnosis of vitamin B12
deficiency, although they may be absent.5 Of these systemic signs, glossitis may
be the most common, seen in 87% of 136 patients in one series.11
FIGURE 9-1
T2-weighted MRI of the cervical spine of the
patient in CASE 9-1. A, Sagittal view shows
longitudinally extensive hyperintensity in the
dorsal columns. B, Axial view shows
hyperintensity in bilateral dorsal columns in the
classic “inverted V” or “rabbit ears” pattern
(arrow), characteristic of the myelopathy
associated with vitamin B12 deficiency.

Laboratory and Radiology Findings

Vitamin B12 deficiency can cause macrocytic anemia, although up to 25% of
individuals with vitamin B12 deficiency–associated myelopathy will not have a
concurrent anemia of any kind.5 Hypersegmented neutrophils may be seen on
blood smear. A serum vitamin B12 level below 200 pg/mL (148 pmol/L) is
considered deficient,1 and levels greater than 300 pg/mL (221 pmol/L) are
considered normal. If the serum vitamin B12 level is between 200 pg/mL to
300 pg/mL (148 pmol/L to 221 pmol/L) or if clinical suspicion for vitamin B12
deficiency is high despite a vitamin B12 level within the laboratory reported
normal range, serum methylmalonic acid and homocysteine levels should be

evaluated. Elevation in both of these laboratory values (greater than 270 nmol/L
and 15 μmol/L, respectively)2 is consistent with vitamin B12 deficiency. If low
vitamin B12 is identified without clear dietary-related or medication-related
etiology, evaluation for pernicious anemia with serum anti–intrinsic factor
antibodies should be performed.1 Of note, serum vitamin B12 may be low without
clinical deficiency during pregnancy (due to hemodilution), so methylmalonic
acid and homocysteine evaluation should be considered in that setting to assess
for biochemical evidence of functional vitamin B12 deficiency.12
MRI classically demonstrates T2 hyperintensity in the dorsal columns
spanning multiple levels, with an “inverted V” or “rabbit ears” appearance on
axial sections, although MRI is normal in 60% to 85% of patients in large case
series (FIGURE 9-1).3,13 The cervical and thoracic portions of the spinal cord are
most commonly affected.3,14 Rarely reported radiologic findings include mild
cord swelling10,13 and subtle, linear contrast enhancement of the dorsal columns.14
Abnormal MRI findings have been associated with a shorter course of disease
prior to presentation (median, 7 months versus 20 months),3 suggesting that
MRI abnormalities may normalize over time with longer delays to diagnosis.
Pathophysiology
Autopsy studies of patients with subacute combined degeneration of the spinal
cord demonstrate myelin sheath swelling, vacuolization, and secondary axonal
degeneration of the posterior and lateral white matter tracts.15 Although the
mechanism by which vitamin B12 deficiency leads to myelin degeneration is not
fully understood, in vitro studies suggest the accumulation of methylmalonic
acid or disrupted fatty acid metabolism as potential causes.5
Treatment and Prognosis

Patients with neurologic manifestations of vitamin B12 deficiency should be
treated with IM vitamin B12 1000 μg 1 to 3 times weekly for 2 weeks, or until the
serum level surpasses 300 pg/mL, followed by 1000 μg monthly.1 If the cause of
vitamin B12 deficiency is not malabsorption, treatment with oral vitamin B12
1000 μg daily is considered as effective as intramuscular administration.16 Repeat
measurement of serum vitamin B12 is not required in the setting of clinical
improvement but is often performed after 3 to 4 months of repletion to
ensure normalization.
Vitamin B12 repletion halts symptom progression in vitamin B12 deficiency
myelopathy, but improvement in neurologic symptoms may take weeks to
months and may be incomplete in patients with severe or long-standing
symptoms. Complete resolution occurs in approximately 20% to 40% of
patients.5,10 Factors associated with worse prognosis include older age, greater
204 F E B R U A R Y 2 0 24

disability at diagnosis, and more extensive spinal cord involvement on KEY POINTS
imaging.3,5,13 MRI abnormalities resolve in 60% to 90% of cases after
● The most common causes
treatment.10,13 of vitamin B12 deficiency
include inadequate intake
NITROUS OXIDE (vegan diet), autoimmune
Nitrous oxide is an inhaled anesthetic used in dental and medical procedures. It is disease (pernicious anemia),
malabsorption (gastric
also a drug of abuse due to its euphoric and hallucinogenic psychotropic effects
bypass, gastric or ileal
(“laughing gas”), most commonly consumed via inhalation from pressurized resection, inflammatory
whipped cream containers (“whippets”). Inhaled nitrous oxide inactivates bowel disease, intestinal
vitamin B12, causing functional vitamin B12 deficiency which can lead to subacute lymphoma, chronic
pancreatitis), and
combined degeneration. An estimated 26% of patients who use nitrous oxide
medications (proton pump
recreationally develop myelopathy.17 inhibitors and metformin).
Clinical Presentation ● Vitamin B12 deficiency is

Nitrous oxide myelopathy can present subacutely in patients who chronically associated with subacute
combined degeneration, a
abuse nitrous oxide, but may also occur acutely after a single exposure condition affecting the
(recreational or in the context of anesthesia) in patients with preexisting vitamin posterolateral spinal cord
B12 deficiency.17,18 As with vitamin B12 deficiency, the dorsal columns and (ie, dorsal columns and
corticospinal tracts are preferentially affected, causing paresthesia, unsteady gait, corticospinal tracts).
sensory ataxia, and weakness.17 Sphincter dysfunction is rarely reported.19,20
● Peripheral neuropathy
More than 20% of patients with nitrous oxide exposure will develop a concurrent occurs in 15% to 30% of
demyelinating polyneuropathy.17 In several reported cases of nitrous oxide patients with vitamin B12
myelopathy, cognitive impairment has been reported, particularly affecting deficiency and may be
concurrent with subacute
short-term memory.21,22
combined degeneration,
causing a myeloneuropathy
Laboratory and Radiology Findings with both upper and lower
In most cases of nitrous oxide myelopathy that develop after weeks to months of motor neuron signs on
nitrous oxide exposure, serum vitamin B12 is low (>70% of patients) and examination.
methylmalonic acid and homocysteine levels are elevated (>90% of patients).17,18 ● Vitamin B12 deficiency can
However, these tests may be normal, particularly in acute nitrous oxide cause macrocytic anemia,
intoxication.17,21 MRI of the spine in nitrous oxide myelopathy was abnormal in although up to 25% of
68% of cases in one series, with findings similar to those described in vitamin individuals with vitamin B12
deficiency–associated
B12 deficiency.17 myelopathy will not have a
concurrent anemia of any
Pathophysiology kind.
Neurologic complications of nitrous oxide exposure are thought to be
● If the serum vitamin B12
secondary to inactivation of vitamin B12 by nitrous oxide. The mechanism
level is between 200 pg/mL
of myelopathy is therefore thought to be the same as described above for to 300 pg/mL (148 pmol/L to
vitamin B12 deficiency.17 221 pmol/L) or if clinical
suspicion for vitamin B12
Treatment and Prognosis deficiency is high despite a
vitamin B12 level within the
Treatment involves cessation of nitrous oxide use and repletion of vitamin B12 as laboratory reported normal
described above. At least partial clinical improvement was observed after range, serum methylmalonic
treatment in more than 90% of patients in one small series,18 although recovery acid and homocysteine
can take months to years. Younger age and less severe symptoms at presentation levels should be evaluated.
are associated with a more favorable prognosis.18–20
FOLATE (VITAMIN B9) DEFICIENCY

Folate is a water-soluble vitamin that serves as a cofactor in DNA synthesis,
protein metabolism, and the breakdown of amino acids. Primary dietary sources

of folate include legumes, citrus fruits, leafy green vegetables, and fortified white
flour. Folate is absorbed mainly in the jejunum, after which it is metabolized to
its active form of tetrahydrofolate.23
The most common causes of folate deficiency include inadequate dietary intake
(eg, primarily grain-based and meat-based diets, alcohol use disorder), increased
folate requirement (eg, pregnancy, sickle cell disease, hematologic malignancies),
and impaired absorption (eg, bariatric surgery, inflammatory bowel disease,

intestinal resection). Medications such as methotrexate or trimethoprim can
also lead to folate deficiency if appropriate concurrent supplementation is not
provided.1,23 Myelopathy due to folate deficiency is currently rare because of

widespread dietary fortification programs and should be suspected only when
other causes of myelopathy have been thoroughly excluded.23
Case reports of definitive folate deficiency myelopathy describe a pattern of
sensorimotor dysfunction similar to subacute combined degeneration secondary
to vitamin B12 deficiency but are more often chronically progressive over
years.24,25 In long-standing untreated cases, other neurologic manifestations of
folate deficiency can be seen including peripheral neuropathy, optic neuropathy,
and progressive cognitive decline.23 Clues to folate deficiency as a cause of
neurologic dysfunction include glossitis, angular stomatitis, and
hyperpigmentation of the hands and feet.

Macrocytic anemia may be present as in vitamin B12 deficiency. Serum folate
greater than 5 ng/mL excludes folate deficiency as the cause of neurologic
symptoms. Although serum folate deficiency is often defined as less than
3 ng/mL, up to 5% of healthy, asymptomatic individuals may have serum folate
below this level, so low serum folate does not confirm folate deficiency as the
cause of neurologic symptoms.1 If a very high clinical suspicion for folate
deficiency is present but serum folate is normal, red blood cell folate can be
evaluated, which is an approximation of folate ingestion over 3 months. A level
less than 150 μg/L is consistent with folate deficiency.1 Although homocysteine is
elevated in folate deficiency as it is in B12 deficiency, methylmalonic acid is
normal as folate is not involved in metabolism of methylmalonic acid. Low serum
folate takes 3 to 6 months to normalize with adequate supplementation.2
Rare reports of MRI findings in folate myelopathy describe findings similar to
those seen in vitamin B12 deficiency (as described in the Vitamin B12 [Cobalamin]
Deficiency section).26
Pathophysiology
After absorption in the small intestine, folate is converted to tetrahydrofolate, its
biologically active form, which is an essential cofactor for DNA synthesis,
epigenetic methylation, and the conversion of homocysteine to methionine.
Neurologic dysfunction in folate deficiency has been theorized to be due to the
disruption of cellular replication and hyperhomocysteinemia.23

Treatment of folate deficiency myelopathy is oral folate replacement: 5 mg of
folic acid daily for 4 months (or until term if related to pregnancy) followed by
206 F E B R U A R Y 2 0 24

1 mg daily in patients with normal absorption, or up to 15 mg to 30 mg daily in KEY POINTS
patients with malabsorption.1 In patients with concurrent vitamin B12 deficiency,
● MRI in patients with
treatment with folic acid alone may worsen neurologic symptoms, so serum vitamin B12 deficiency
vitamin B12 level should be evaluated prior to treatment and concurrent repletion classically demonstrates T2
of vitamin B12 may be necessary.27 hyperintensity in the dorsal
Improvement in myelopathic symptoms has been reported in treated patients, columns spanning multiple
levels, with an “inverted V”
even in cases of symptom progression for many years prior to treatment,

or “rabbit ears” appearance
although recovery may be incomplete.24,25,28 Repeat measurement of serum on axial sections, although
folate is not required but may be considered after several months of repletion if MRI is normal in 60% to 85%
there is a lack of clinical improvement. In cases of severe malabsorption, IV folic of patients in large case
series.
acid (1:1 dosing equivalent with oral regimens) can be considered.
● Patients with neurologic
VITAMIN E DEFICIENCY manifestations of vitamin B12
Vitamin E is a fat-soluble vitamin that functions as an antioxidant, free radical deficiency should be
scavenger, and enzyme activity regulator. Foods high in vitamin E include nuts, treated with IM vitamin B12
1000 μg 1 to 3 times weekly
seeds, and leafy green vegetables. After ingestion, vitamin E requires pancreatic for 2 weeks, or until serum
lipase for adequate absorption in the small intestine, after which it is transported level surpasses 300 pg/mL,
in the bloodstream in very-low-density lipoprotein particles and low-density followed by 1000 μg
lipoprotein particles.29 monthly.
Vitamin E deficiency secondary to dietary insufficiency is rare, occurring
● Nitrous oxide myelopathy
more commonly in the context of malabsorption. Conditions that increase the can present subacutely in
risk of vitamin E deficiency include cystic fibrosis (due to deficits in pancreatic patients who chronically
enzyme production), abetalipoproteinemia (a genetic deficit of lipoprotein abuse nitrous oxide but may
also occur acutely after a
metabolism), ataxia with vitamin E deficiency (a genetic condition affecting
single exposure
vitamin E binding to very-low-density lipoprotein particles), cholestatic and (recreational or in the
hepatobiliary disorders, inflammatory bowel disease, and surgical resection of context of anesthesia) in
the small intestine.29,30 patients with preexisting
vitamin B12 deficiency.
Clinical Presentation ● The most common causes

Vitamin E deficiency is a rare cause of a subacute to chronic myelopathy of folate deficiency include
predominantly affecting the dorsal columns. The spinocerebellar tracts and inadequate dietary intake
peripheral nerves may also be affected. In severe cases and those caused by (eg, primarily grain-based
and meat-based diets,
inherited disorders of vitamin E absorption, ophthalmoplegia, ptosis, dysarthria, alcohol use disorder),
retinopathy, and myopathy31 may occur.30,32 increased folate
requirement (pregnancy,
Laboratory and Radiology Findings sickle cell disease,
hematologic malignancies),
Vitamin E deficiency is defined as a serum level less than 5 μg/mL. However,
and impaired absorption
in malabsorption secondary to cholestasis, serum lipid levels may be elevated, (bariatric surgery,
leading to a falsely normal serum vitamin E level. In these cases, the ratio inflammatory bowel
of serum vitamin E to total serum lipids can be evaluated, with a ratio less disease).
than 0.8 mg/g considered low.29 In cases of abetalipoproteinemia, serum
● Although folate
vitamin A levels will also be low.30 MRI of the spine may show T2 deficiency is often defined
hyperintensity in the dorsal columns similar to vitamin B12 deficiency,32 or as less than 3 ng/mL, up to
it may be normal.30 5% of healthy, asymptomatic
individuals may have serum
folate below this level, so
Pathophysiology low serum folate does not
Although the exact cause of neuronal damage in vitamin E deficiency is not confirm folate deficiency as
known, it may be related to the loss of antioxidant effect and damage of the cause of neurologic
myelinated axons from increased free radicals.29 Pathologic studies have symptoms.
demonstrated swollen and degenerated posterior and spinocerebellar tracts in

the absence of inflammation or demyelination. Axonal loss in the cerebellum and

peripheral sensory nerves has also been observed.29

Oral vitamin E repletion can be used except in cases of severe malabsorption,
in which IM or IV vitamin E should be considered. The precise dose for repletion
varies based on the cause of vitamin E deficiency. In adults with fat

malabsorption due to intestinal disease or resection, repletion is usually initiated
at 200 mg/d to 300 mg/d and adjusted as needed to obtain normalization of
serum vitamin E levels; doses up to 3000 mg daily have been used.29 In patients
with cystic fibrosis, oral vitamin E 100 mg/d can be used to prevent deficiency.
Neurologic improvement in vitamin E myelopathy can vary from minimal to
full recovery and often depends on the etiology and severity of vitamin E
deficiency. In one study of 132 children with a genetic cause of vitamin E
deficiency, vitamin E repletion stabilized neurologic symptoms in close to
one-third of patients and improved symptoms in about one-half of patients.30
COPPER DEFICIENCY
Copper is essential for aerobic metabolism, protection of cellular membranes
against free-radical damage, and red blood cell and neurotransmitter synthesis.
Copper is predominantly found in shellfish, nuts, seeds, red meat, and whole
grains and is absorbed primarily in the stomach and duodenum.33
Given that dietary requirement for copper is low, copper deficiency secondary
to insufficient intake is rare. Conditions predisposing to copper deficiency
include parenteral nutrition (without copper supplementation), nephrotic
syndrome, gastrectomy or gastric bypass surgery (the most common cause in the
United States),34 jejunectomy, celiac disease, and Menkes disease (genetic
disorder of copper transport). Copper deficiency can also be caused by excessive
zinc intake (eg, oral zinc supplements or zinc-containing denture cream) or the
medication penicillamine (rarely used to treat rheumatoid arthritis or prevent
kidney stones).34
Copper deficiency can cause a neurologic presentation indistinguishable from
vitamin B12 deficiency: subacute combined degeneration of the dorsal columns
and corticospinal tracts that may be accompanied by peripheral neuropathy. In
cases resulting from gastrointestinal surgeries, neurologic signs of copper
deficiency may emerge as late as 10 to 20 years after surgery.33

Copper deficiency is diagnosed by decreased serum copper (below 0.75 μg/mL)
and ceruloplasmin (below 21.5 mg/dL). Low urine copper is also commonly
present (below 20 μg per 24 hours). Anemia, leukopenia, or thrombocytopenia is
seen in more than 75% of patients.33 MRI of the spine most commonly
demonstrates T2 hyperintensities in the posterior columns, but may be normal in
approximately one-half of cases.33
Pathophysiology
The precise pathophysiology of copper deficiency myelopathy has not been
elucidated. Hypotheses include copper-dependent dysfunction in cytochrome c
208 F E B R U A R Y 2 0 24

oxidase, the methylation cycle, or methionine synthase causing secondary KEY POINTS
damage to the dorsal columns and corticospinal tracts.33 In rare pathologic
● Treatment of folate
descriptions of copper deficiency myelopathy, demyelination of the spinal cord deficiency myelopathy is
white matter and wallerian degeneration of axons are seen.35 oral folate replacement:
5 mg of folic acid daily for
Treatment and Prognosis 4 months (or until term if
related to pregnancy)
Patients with normal absorption are generally treated with 2 mg daily of
followed by 1 mg daily in
elemental copper, although an induction approach with dosing of 6 mg/d for patients with normal
1 week, 4 mg/d for 1 week, and 2 mg/d thereafter has also been suggested.35 A absorption, or up to 15 mg to
dose of up to 8 mg daily may be required in patients with malabsorption.35 IV 30 mg daily in patients with
malabsorption.
copper may be considered in cases caused by surgical small bowel or gastric
resection. Adequate copper repletion should lead to stabilization of neurologic ● Conditions that increase
symptoms and prevention of further decline. Although neurologic recovery may the risk of vitamin E
occur over days to weeks, it is often incomplete. Less severe symptoms at the deficiency include cystic
time of diagnosis generally indicate a more favorable prognosis.33,35–37 Serum fibrosis,
abetalipoproteinemia,
copper testing is generally reevaluated after 3 to 6 months of repletion to assess ataxia with vitamin E
for normalization.34 deficiency, cholestatic and
hepatobiliary disorders,
KONZO inflammatory bowel
disease, and surgical
Konzo is an acute spastic myelopathy caused by cyanide toxicity secondary to resection of the small
ingestion of the bitter cassava root.38,39 Cassava is a dietary staple in parts of intestine.
Africa and Southeast Asia, and outbreaks of konzo have been reported on the
African continent.39–41 Konzo is most commonly seen in periods of drought due ● Vitamin E deficiency is a
rare cause of a subacute to
to the increased cyanide content of cassava root in dry growing conditions.42
chronic myelopathy
Protein malnutrition appears to be a risk factor for konzo, which has most predominantly affecting the
frequently been described in children and young women, although it can affect dorsal columns.
individuals of all ages.39
● Oral vitamin E repletion
can be used except in cases
Clinical Presentation of severe malabsorption, in
Myelopathy in konzo is acute in onset, with symptoms reaching a nadir within which IM or IV vitamin E
hours to days. Onset commonly occurs after physical exertion such as a long walk should be considered. The
or manual labor. Symptoms of lower extremity cramping, sometimes precise dose for repletion
varies based on the cause of
accompanied by paresthesia and myalgias, rapidly progress to spasticity with vitamin E deficiency.
scissoring gait. There is no flaccid phase,39 and sphincter and sexual function are
preserved.43 Rarely, patients may develop dysphagia, dysarthria, nystagmus, ● Conditions predisposing
optic neuropathy,40 or neurocognitive impairment.44 to copper deficiency
include parenteral nutrition
(without copper
Laboratory and Radiology Findings supplementation), nephrotic
Because konzo outbreaks have historically occurred in regions with limited syndrome, gastrectomy or
capacity for advanced diagnostics, clinical criteria have been created by the gastric bypass surgery (the
World Health Organization, requiring (1) cassava as a staple food, (2) sudden- most common cause in the
United States), jejunectomy,
onset leg weakness (less than 1 week), (3) nonprogressive course, (4) symmetric, and Menkes disease
spastic gait, and (5) hyperreflexia.45 Diagnostic testing with MRI and CSF are (genetic disorder of copper
generally normal in affected patients, with the exception of one report of MRI transport).
demonstrating T2 hyperintensity in the dorsal columns46; however, these
tests are often unavailable in endemic regions. Elevated levels of thiocyanate
(a cyanide metabolite) in urine or plasma have been observed in patients with
konzo.47 However, not all individuals with elevated blood or urine thiocyanate
develop konzo, and additional risk factors such as protein malnutrition, genetic
predisposition, or other environmental toxins may also play a role.39

Pathophysiology
Cassava contains linamarin, which is converted to cyanide by gut flora after
ingestion. The severity of neurologic damage from cyanide toxicity is thought to
be dose dependent, but the mechanism by which cyanide causes myelopathy is
not known. It is hypothesized that chronic elevations in blood cyanide may cause
toxicity to long myelinated tracts.38 No human autopsy studies have been
performed, but an animal model demonstrated demyelination, glial

proliferation, and cytoplasmic granules in glial cells of the corticospinal tracts
after 6 weeks of cyanide exposure.38

Although konzo is irreversible, it is not progressive after the early period, with
initial deficits remaining static for up to decades after the inciting event.40,47,48
There is no known effective cure for the condition, and symptomatic treatments
for spasticity such as botulinum toxin, antispasmodics, and surgical tendon
release are often unavailable in endemic regions. Therefore, care is often
supportive with walking aids and physical therapy.40,47
Public health efforts focused on the prevention of konzo have taught a
cassava “wetting” method (involving longer soaking time during processing)
that has been shown to effectively reduce cassava cyanide content, reduce
blood thiocyanate levels, and prevent konzo outbreaks in high-prevalence
areas.49,50
LATHYRISM
Lathyrism refers to myelopathy caused by chronic ingestion of grass pea
(Lathyrus sativus, also known as chickling pea), a drought-resistant and
flood-resistant legume most often ground to flour. Lathyrism is most commonly
seen in Southeast Asia and North Africa. Similar to konzo, lathyrism is seen more
commonly in the setting of protein malnutrition.39,51 In contrast to konzo,
lathyrism predominantly affects adult men.
Lathyrism causes subacute spastic paraparesis evolving over weeks that emerges
several months after significant dietary consumption of grass pea. Sensation and
sphincter function are generally spared. Spasticity is usually out of proportion to
weakness, which may be mild.52 Rarely, a concurrent distal symmetric sensory
polyneuropathy can be seen.53 Similar to konzo, onset may be triggered by
significant physical activity. In some cases, mild improvement in initial
symptoms has been reported prior to the establishment of permanent disability.53

Lathyrism is a clinical diagnosis based on symptoms and signs in the context
of dietary history. There are no serum tests available to confirm the diagnosis.
MRI is generally less available in endemic regions, but when obtained has
been normal.54
Pathophysiology
The pathophysiology of lathyrism is not fully understood, but it is hypothesized
to be caused by toxicity to spinal neurons from β-N-oxalylamino-L-alanine, a
toxin present in the grass pea that can cause neuronal death in vitro and has led to
210 F E B R U A R Y 2 0 24

a spastic myelopathy in animal models.51,55 Limited pathologic studies have KEY POINTS
demonstrated degeneration of corticospinal tracts and anterior horn cells.53
● Copper deficiency may
be caused by excessive zinc
Treatment and Prognosis intake (eg, oral zinc
Similar to konzo, lathyrism is permanent and irreversible, although it is usually supplements or
not progressive unless there is significant ongoing ingestion of grass pea. zinc-containing denture
cream) or the medication

Treatment is supportive with walking aids, physical therapy, and
penicillamine (rarely used to
antispasmodics. A public health focus on prevention is imperative; alternative treat rheumatoid arthritis or
preparation methods of the grass pea (eg, soaking prior to cooking, avoiding clay prevent kidney stones).
cooking utensils, avoiding raw consumption, mixing with other grains) have
been associated with a reduced risk of lathyrism,56 but widespread education ● Copper deficiency can
cause a neurologic
about these methods has not yet been implemented.39,53 presentation
indistinguishable from
HEROIN MYELOPATHY vitamin B12 deficiency:
Heroin (diacetylmorphine) is an opioid derived from chemical processing of subacute combined
degeneration of the dorsal
morphine. Routes of administration include IV injection, insufflation (snorting), columns and corticospinal
or inhaling vapors from heroin heated over a flame (called chasing the dragon). tracts that may be
According to the National Survey on Drug Use and Health conducted by the accompanied by peripheral
US Department of Health and Human Services, more than 900,000 individuals neuropathy.
in the United States older than 12 years used heroin in 2020.57
● MRI of the spine in
patients with copper
Clinical Presentation deficiency most commonly
Heroin-associated myelopathy most commonly occurs in patients with a history demonstrates T2
hyperintensities in the
of prior chronic extensive heroin use who resume heroin consumption after
posterior columns but may
several months of abstinence,58–63 although myelopathy may occur with chronic be normal in approximately
use without a period of abstinence64 or rarely after first-time use.65 Patients one-half of cases.
typically awaken from a heroin-induced stupor with acute paraplegia, although
myelopathy may also rarely develop over weeks of heroin use.60 Heroin- ● Konzo is an acute spastic
myelopathy caused by
associated myelopathy is usually a complete transverse myelopathy (affecting cyanide toxicity secondary
motor, sensory, and sphincter function), although dorsal column function is to ingestion of the bitter
spared in some cases.62 cassava root.
● Cassava is a dietary staple

in parts of Africa and
MRI typically demonstrates cord expansion with longitudinally extensive Southeast Asia, and
T2 hyperintensity spanning the cervical region, thoracic region, or both. Signal outbreaks of konzo have
change is most commonly transverse58 but may involve gray matter only66 or been reported on the
African continent.
may be limited to the corticospinal tracts and posterior columns.60 Patchy
enhancement has been reported in some cases58,59,67 but may be absent; diffusion ● Myelopathy in konzo is
restriction has been reported in one case.67 In one reported case in which spinal acute in onset, with
angiography was performed, irregular vessel caliber was observed, suggesting symptoms reaching a nadir
vasculopathy.67 within hours to days.
CSF is generally unremarkable, but a significant inflammatory response with ● The onset of konzo
elevated CSF white blood cell count and protein has been described in one case67 commonly occurs after
and elevated CSF levels of glial fibrillary acidic protein (GFAP) and physical exertion such as a
neurofilament light chain in another.59 long walk or manual labor.
Pathophysiology
The underlying mechanism of heroin-induced myelopathy is unknown.
Hypotension (due to opiate effect or hypersensitivity reaction to cutting agent),
the direct toxic effect of heroin or a contaminant, vasculitis, and hyperextension

injury (due to prolonged stupor in a fixed position) have been proposed.62–64,68,69

Hypotension as the sole mechanism has been challenged since reported cases do
not have concurrent watershed strokes in the brain as may be expected with a
state of global hypoperfusion.58,59 Inflammatory CSF or pathologic findings
appear rare in reported cases, making vasculitis or another inflammatory
mechanism less likely. In one case following inhalation that affected the posterior
columns and corticospinal tracts specifically, the release of nitrous oxide was
postulated.60
Autopsy specimens of the spinal cord in heroin-associated myelopathy
have most commonly shown necrosis predominantly affecting the gray matter
without inflammation.62,63 In one case, parenchymal and vascular inflammation
were seen with refractile particles in vessel walls suggesting vasculitis attributed
to an adulterant.61

Patients often make a partial or complete recovery over weeks to months,
although some patients do not recover. A short course of high-dose IV
corticosteroids has been used to treat patients in some reports with variable
results.60,66,67
HEPATIC MYELOPATHY
Hepatic myelopathy is a relatively rare complication of liver disease,
occurring in an estimated 2% of patients with severe liver failure.70 It occurs in
patients with cirrhosis leading to portosystemic (portacaval) shunting that
causes the systemic circulation to bypass the liver. Such shunting may occur
spontaneously in patients with severe portal hypertension or may be surgically
created (via vascular anastomoses or endovascular transjugular intrahepatic
portosystemic shunt [TIPS] procedure) as treatment of portal hypertension to
prevent variceal bleeding.
Hepatic myelopathy can develop several months to 10 or more years after
shunting.71–73 It most often occurs in patients with liver disease severe enough to
cause recurrent episodes of hepatic encephalopathy, although cases of patients
developing hepatic myelopathy without encephalopathy
(or who subsequently develop encephalopathy after presenting with
myelopathy) have been reported.71,73,74 Patients most commonly present with
subacute progressive paraparesis without upper extremity weakness, sensory
involvement, or sphincter dysfunction, although these findings have been
reported in rare cases.72,73

Serum ammonia is often elevated and other laboratory evidence of hepatic
dysfunction is usually present (elevated aspartate transaminase [AST] and
alanine transaminase [ALT], decreased albumin). MRI of the spine and CSF
analysis are normal. MRI of the brain may reveal T1 hyperintensity in the globus
pallidus and substantia nigra, features of acquired hepatocerebral degeneration
that are not specific to hepatic myelopathy.75 In one case of hepatic myelopathy,
MRI of the brain demonstrated T2 hyperintensity in the corticospinal tracts
that improved after liver transplantation.76
212 F E B R U A R Y 2 0 24

Pathophysiology KEY POINTS
The exact mechanism of hepatic myelopathy is unknown. Hypotheses include toxic
● Although konzo is
unmetabolized substances bypassing the liver, deficiency in a nutrient normally irreversible, it is not
produced or processed by the liver, or hypoperfusion of the spinal cord due to progressive after the early
shunt-induced hemodynamic changes.72,73 Pathologic studies have demonstrated period, with initial deficits
demyelination of the lateral corticospinal tracts, with axonal loss reported in remaining static for up to
decades after the inciting

advanced cases.72,73 Rarely, additional involvement of the anterior (ventral)
event.
corticospinal tracts, dorsal columns, and spinocerebellar tracts has been reported.72,73
● Lathyrism refers to
Treatment and Prognosis myelopathy caused by

Liver transplantation has been reported to lead to significant improvement chronic ingestion of grass
pea (Lathyrus sativus, also
and appears to be most effective when performed early in the course of the known as chickling pea), a
condition.76,77 In patients who develop hepatic myelopathy after TIPS, drought-resistant and
endovascular occlusion of the TIPS may lead to clinical improvement.71,78 flood-resistant legume most
Ammonia-lowering interventions that can treat hepatic encephalopathy often ground to flour.
(eg, lactulose, protein restriction) are generally ineffective. ● Lathyrism is most
commonly seen in Southeast
MYELOPATHY ASSOCIATED WITH CANCER TREATMENT Asia and North Africa.
Neurologic conditions in patients with cancer can be caused by the invasion or
● Lathyrism causes
compression of neurologic structures (due to primary tumors or metastases),
subacute spastic
paraneoplastic disorders, and toxicity of cancer treatment (chemotherapy and paraparesis evolving over
radiation therapy). Myelopathy in the first scenario is discussed in the article weeks that emerges several
“Neoplasms of the Spinal Cord” by J. Ricardo McFaline-Figueroa, MD, PhD,79 months after significant
in this issue of Continuum. Paraneoplastic myelopathies are reviewed in the dietary consumption of
grass pea.
article “Immune-Mediated Myelopathies” by Michael Levy, MD, PhD,
FAAN,80 also in this issue. Here, myelopathy due to intrathecal chemotherapy, ● Heroin-associated
ICIs, and radiation therapy is discussed. myelopathy most commonly
occurs in patients with a
history of prior chronic
Myelopathy Associated With Intrathecal Chemotherapy extensive heroin use who
Intrathecal methotrexate and cytarabine are used in the treatment of and resume heroin consumption
prophylaxis for central nervous system metastases, most commonly in the setting after several months of
of hematologic malignancies such as leukemia and lymphoma. Intrathecal abstinence, although
myelopathy may occur with
chemotherapy can cause arachnoiditis, myelopathy, or both.81-83 Both
chronic use without a period
complications occur in less than 1% of patients.82 of abstinence or rarely after
Although systemic chemotherapy with platinum-based therapies may cause first-time use.
the Lhermitte sign classically associated with cervical myelopathy, normal spine
MRI, lack of evidence of dorsal column dysfunction on somatosensory evoked ● Heroin-associated
myelopathy is usually
potential testing, and decreased peripheral nerve refractoriness on transverse (affecting motor,
electrophysiologic evaluation in these patients has led to the hypothesis that the sensory, and sphincter
mechanism is likely hyperexcitability of peripheral nerves, dorsal root ganglia, or function), although dorsal
both, rather than true myelopathy.84 column function is spared in
some cases.
CLINICAL PRESENTATION. Arachnoiditis due to intrathecal chemotherapy presents ● Hepatic myelopathy may
within days of administration with lumbosacral radiculopathy causing occur in patients with
paraplegia, saddle anesthesia, and bowel or bladder incontinence.81,82 cirrhosis leading to
portosystemic (portacaval)
Myelopathy due to intrathecal chemotherapy typically presents weeks to
shunting that causes the
months following initiation of treatment, occurring after a median of 17 cycles of systemic circulation to
intrathecal chemotherapy (range, 3 to 36 cycles).83 Myelopathy in this context bypass the liver.
tends to predominantly affect the lower extremities and is usually transverse,
causing deficits in motor, sensory, and sphincter function.82,83

LABORATORY AND RADIOLOGY FINDINGS. Serum folate may be decreased in

intrathecal methotrexate–associated neurotoxicity.83 MRI in intrathecal
chemotherapy–associated arachnoiditis can show clumping and enhancement of
lumbosacral nerve roots.81,82 In intrathecal chemotherapy–associated
myelopathy, MRI most commonly demonstrates longitudinally extensive T2
hyperintensity in the dorsal columns, as is seen in subacute combined
degeneration.82,83 Spinal cord enhancement is usually absent but has been rarely
reported in a minority of cases.83,85
CSF analysis in both conditions demonstrates elevated protein. A pleocytosis
has rarely been described with arachnoiditis.82 In cases of arachnoiditis, CSF

cytology and flow cytometry should be obtained to evaluate for leptomeningeal
spread of malignancy since the imaging appearance may be similar to that seen
in arachnoiditis. CSF myelin basic protein may be elevated in cases of
intrathecal chemotherapy–associated arachnoiditis and has therefore been
proposed as a potential marker to distinguish this condition from neoplastic
involvement.82,83
PATHOPHYSIOLOGY. Intrathecal chemotherapy–associated myelopathy and

arachnoiditis were initially attributed to preservatives in the diluents of
intrathecal chemotherapy, but these conditions have continued to occur in
patients receiving preservative-free agents.81,82,85 Pathogenesis of intrathecal
methotrexate–associated myelopathy is currently thought to be due to
methotrexate-induced folate deficiency via the mechanism discussed above for
folate deficiency myelopathy.81–83 On pathologic examination, one case
demonstrated axonal loss in the fasciculus gracilis with preservation of myelin;83
in another, complete transverse necrosis of the thoracic cord was observed with
relative preservation of central gray matter.82
TREATMENT AND PROGNOSIS. Improvement in myelopathy may be seen with the

discontinuation of intrathecal chemotherapy, but patients often subsequently
worsen due to complications of their underlying malignancy.82 A combination of
the folate metabolites S-adenosyl methionine, folinate, cyanocobalamin, and
methionine led to resolution of clinical deficits and imaging abnormalities in one
case.86 Dextromethorphan has led to improvement in methotrexate-associated
neurotoxicity affecting the brain,87 but has had mixed results when utilized in
patients with myelopathy.82,83 Overall, prognosis is generally poor due to the
severity of the underlying disease.82
Myelopathy Associated With Immune Checkpoint Inhibitors

ICIs have become a mainstay of treatment of melanoma, non–small cell lung
cancer, and other malignancies. Through inhibition of programmed cell death
protein 1 (PD-1; pembrolizumab, nivolumab), programmed cell death-ligand 1
(PD-L1; durvalumab, atezolizumab, avelumab), or cytotoxic T-lymphocyte
antigen-4 (CTLA-4; ipilimumab, tremelimumab), these agents lead to increased
immune activation against neoplastic cells, but may also cause autoimmune
adverse effects.88,89
Autoimmune neurologic complications of ICIs have been reported to occur in
1% to 12% of patients treated with these agents, with severe neurologic adverse
events in approximately 1%.88,89 Patients receiving combination therapy with
multiple ICIs have a higher risk of neurologic adverse events.89 ICI-associated
214 F E B R U A R Y 2 0 24

myelitis is relatively uncommon, accounting for 2% to 4.8% of ICI-associated KEY POINTS
neurologic complications.90,91
● Liver transplantation has
been reported to lead to
CLINICAL PRESENTATION. ICI-associated myelitis is typically acute and transverse, significant improvement in
affecting motor and all sensory modalities as well as sphincter function. It most hepatic myelopathy and
commonly affects the thoracic cord leading to paraplegia, although the upper appears to be most
effective when performed

extremities may rarely be involved.92 Concurrent meningitis, encephalitis,
early in the course of the
radiculitis, or neuropathy (including cranial neuropathy) may accompany condition.
myelitis.92 In a series of seven cases, myelitis occurred after a median of 7 cycles
of ICI treatment (range, 3 to 51 cycles).92 ● Intrathecal chemotherapy

can cause arachnoiditis,
myelopathy, or both.
LABORATORY AND RADIOLOGY FINDINGS. MRI most commonly demonstrates
longitudinally extensive T2 hyperintensity of the spinal cord with patchy ● Arachnoiditis due to
contrast enhancement, although shorter-segment lesions may occur and contrast intrathecal chemotherapy
enhancement may rarely be absent.92 CSF protein is typically increased (median, presents within days of
administration with
80 mg/dL to 183 mg/dL; range, 32 mg/dL to 520 mg/dL across two series) and a lumbosacral radiculopathy
lymphocytic pleocytosis is common (median, 24 cells/μL to 97 cells/μL; range, causing paraplegia, saddle
3 cells/μL to 900 cells/μL across two series).90,92 Unique CSF oligoclonal bands anesthesia, and bowel and
have been reported in some cases.90,92 In some patients, autoantibodies may be bladder incontinence.
present including anti–aquaporin 4, anti-GFAP, and other antibodies to
● Myelopathy due to
unknown neural antigens.92 intrathecal chemotherapy
typically presents weeks to
PATHOPHYSIOLOGY. The pathogenesis of ICI-associated neurologic toxicity is months following initiation
thought to be enhanced autoimmunity against nervous system structures. Some of treatment, occurring after
a median of 17 cycles of
ICI-associated neurologic complications may represent unmasking of an intrathecal chemotherapy
underlying paraneoplastic neurologic syndrome.93 In patients with a preexisting (range, 3 to 36 cycles).
paraneoplastic neurologic disorder, ICIs may lead to irreversible worsening,
leading some experts to recommend screening for neuronal autoantibodies ● In intrathecal
chemotherapy–associated
before ICI initiation in patients with unexplained neurologic symptoms or if the myelopathy, MRI most
patient’s cancer has a high risk of association with paraneoplastic syndromes (eg, commonly demonstrates
small cell lung cancer, thymoma).94 longitudinally extensive T2
hyperintensity in the dorsal
columns as is seen in
TREATMENT AND PROGNOSIS. For ICI-associated myelitis, treatment guidelines are
subacute combined
based on syndrome severity: for mild (grade 1) symptoms (defined as no degeneration.
interference with function and not concerning to the patient), ICIs may be
continued with close observation; for moderate (grade 2) symptoms (defined as ● Autoimmune neurologic
symptoms causing limitation in age-appropriate instrumental activities of daily complications of immune
checkpoint inhibitors (ICIs)
living), ICIs should be stopped and treatment initiated with prednisone 1 mg/kg have been reported to occur
daily tapered over 1 month; for severe (grades 3 and 4) symptoms (grade 3: in 1% to 12% of patients
defined as limiting self-care activities of daily living; grade 4: defined as treated with these agents,
life-threatening), ICIs should be permanently discontinued and treatment with severe neurologic
adverse events in
initiated with IV methylprednisolone (1 g/d) with escalation to intravenous approximately 1%.
immunoglobulin (IVIg) or plasma exchange if symptoms do not begin to
improve after 3 days.89 In patients with refractory symptoms, cyclophosphamide, ● ICI-associated myelitis is
infliximab, tocilizumab, and natalizumab have been used.92 Improvement or relatively uncommon,
accounting for 2% to 4.8% of
stabilization is seen in some patients, but others may not improve and relapses
ICI-associated neurologic
may occur.90,92 complications.
The decision to rechallenge a patient with an ICI after an ICI-associated
neurologic toxicity must balance the potential oncologic benefit with the risk of
triggering further neurologic autoimmunity.89,91,93 Data on rechallenging

patients with ICI-associated neurologic toxicity are limited. In one series, five
patients with mild-to-moderate (grades 2 and 3) neurotoxicity (one of whom had
myelitis) were rechallenged with the same or a different ICI regimen and did not
experience relapse of neurologic toxicity; all improved spontaneously or with
steroids and had only mild sequelae before rechallenge.91 In a larger series,
recurrence of neurologic toxicity after rechallenge occurred in 3 out of 19 patients
(16%) with ICI-associated neurologic toxicity, although no cases of myelitis

were included.95
Radiation-induced Myelopathy
Myelopathy can develop when the spinal cord is exposed to radiation therapy for
the treatment of primary spinal cord tumors, spinal metastases, or cancers of the
head and neck, mediastinum, chest, and upper abdomen in which the spinal cord
is in the radiation field. Although modern modalities of radiation delivery and
improved techniques for treatment planning have reduced the risk of radiation
myelopathy, patients with cancer are living longer due to advances in
chemotherapy and may therefore require reirradiation, increasing the risk of
radiation injury to the spinal cord.96
CASE 9-2 A 64-year-old woman presented with several months of difficulty

walking and hand clumsiness. She reported that her legs felt “stuck,”
causing several falls, and that she had numbness in her hands. There was
no bowel or bladder dysfunction. She had been treated 20 years prior for
Hodgkin lymphoma including mantle irradiation.
On examination, she had weakness in hip flexion, knee flexion, and
foot dorsiflexion bilaterally with diminished sensation to pinprick and
vibration, brisk reflexes, upgoing toes, and mild spasticity of the lower
extremities. She had normal strength in her upper extremities but
decreased sensation to pinprick and vibration and brisk reflexes. She
swayed but did not fall when evaluating for Romberg sign and had a
slightly spastic gait.
MRI demonstrated patchy longitudinally extensive T2 hyperintensity in
the spinal cord with T1 hyperintensity in the vertebral bodies in the
radiation field. Her serum vitamin B12 level was normal, and CSF analysis
was unremarkable. She was diagnosed with radiation myelopathy
(FIGURE 9-2).
Her spasticity was treated with baclofen with mild improvement, but
she continued to progress slowly over subsequent years, ultimately
requiring a wheelchair.
COMMENT Delayed radiation myelopathy may develop up to decades following radiation

therapy. Although the prevalence of radiation myelopathy has decreased
with advances in radiation therapy techniques, patients may have received
higher doses to larger radiation fields when treated in the past such as in the
case of mantle irradiation for lymphoma. Bevacizumab holds promise as a
potential treatment of radiation myelopathy, but data are limited.
216 F E B R U A R Y 2 0 24

The risk of permanent radiation damage to nervous system tissue correlates
with the total radiation dosage and the dose per fraction of radiation delivered.
Whether the volume of spinal cord exposed to radiation contributes significantly
to the risk of complications (as is the case for the brain) is debated.97,98
Recommended limits to the total dose and individual fractions and their
predicted risk of myelopathy have been published for conventional fractionated
external beam therapy for systemic cancers in which the spinal cord may be
exposed to radiation (eg, head and neck cancers in which the cervical spinal cord
is in the treatment field)97,98 and stereotactic body radiation therapy for spinal
metastases.99 Radiation myelopathy is uncommon with stereotactic radiosurgery

for spinal tumors, occurring in less than 0.6% of patients.100
CLINICAL PRESENTATION. Radiation can cause an early transient myelopathy within

weeks to months of treatment and a delayed myelopathy that may occur months
to years later.
Early radiation myelopathy is characterized by the Lhermitte sign in
isolation without other features of myelopathy, emerging from 2 weeks to
5 months (mean, 3 months) following completion of radiation therapy.101 It
FIGURE 9-2
Sagittal MRI of the spine showing radiographic changes characteristic of delayed radiation
myelopathy. A, T2-weighted image shows longitudinally extensive hyperintensity throughout
the cervical and thoracic spinal cord. B, Postcontrast T1-weighted image shows T1
hyperintensity in the vertebral bodies and contrast enhancement in the upper cervical and
upper thoracic regions of the spinal cord.
Reprinted with permission from Kara B, et al, J Pediatr Hematol Oncol.103 © 2020 Wolters Kluwer Health.

KEY POINTS has been reported in 3.6% of patients who have received radiation for head
and neck cancers, occurring at total radiation doses to the cervical cord as low
● Concurrent meningitis,
encephalitis, radiculitis, or
as 36.5 Gy and more frequent at total doses greater than 50 Gy or radiation
neuropathy (including fractions higher than 2 Gy.101 Higher incidence (9%) was seen in the past
cranial neuropathy) may when mantle irradiation was widely used for the treatment of Hodgkin
accompany ICI-associated lymphoma.102
myelitis.
Delayed radiation myelopathy can occur in patients in whom the spinal cord is
● MRI in patients with exposed to radiation during treatment of cancers of the head and neck (cervical
cord) or of the lung, mediastinum, or upper abdomen (thoracic cord)
ICI-associated myelitis most

commonly demonstrates (CASE 9-2103). Patients typically develop a subacute to chronic progressive
longitudinally extensive T2 transverse myelopathy that may present initially as Brown-Séquard
hyperintensity of the spinal
cord with patchy contrast syndrome.104 In the largest reported series (35 patients who developed delayed
enhancement, although radiation myelopathy between 1955 and 1985), symptoms emerged 7 months to
shorter-segment lesions nearly 5 years (mean, 18.5 months) from the initiation of radiation, with a shorter
may occur and contrast latency to the development of myelopathy in patients who were reirradiated.105
enhancement may rarely be
absent.
All patients in this series received doses higher than currently recommended total
doses or dose fractions per day. In the same 30-year period there were no
● Some ICI-associated reported cases of delayed radiation myelopathy in patients whose radiation
neurologic complications dosage was below currently recommended limits.
may represent unmasking of
Rarely, a delayed pure motor syndrome has been reported months to decades
an underlying
paraneoplastic neurologic following radiation injury to the lumbosacral ventral nerve roots, most
syndrome. commonly associated with the treatment of testicular cancer.104,106 Acute spinal
cord hemorrhage decades following treatment has also been described,
● The decision to attributed to radiation-induced cavernous malformations.104,107
rechallenge a patient with
an ICI after an ICI-associated
neurologic toxicity must LABORATORY AND RADIOLOGY FINDINGS. CSF analysis and spine MRI in early
balance the potential radiation myelopathy are normal. In delayed radiation myelopathy, CSF may be
oncologic benefit with the normal or may demonstrate elevated protein (up to 98 mg/dL in one series in
risk of triggering further
neurologic autoimmunity.
which 9 out of 19 patients had elevated CSF protein).105
MRI in delayed radiation myelopathy demonstrates cord swelling and
● The risk of permanent longitudinally extensive T2 hyperintensity and T1 hypointensity that may be
radiation damage to nervous central, posterior, or transverse (FIGURE 9-2).108,109 Patchy or ring enhancement
system tissue correlates
of the spinal cord lesion has been seen in up to 45% of cases,109 and is usually
with the total radiation
dosage and the dose per more focal than the T2 hyperintensities.108-110 Contrast enhancement may persist
fraction of radiation for up to 22 months.109 Cord atrophy may appear as early as 10 months after
delivered. Whether the onset,111 and T1 hyperintensity of the vertebral bodies within the radiation field is
volume of spinal cord
also commonly observed.109
exposed to radiation
contributes significantly to
the risk of complications (as PATHOPHYSIOLOGY. Pathogenesis of radiation myelopathy is thought to be related
is the case for the brain) is to disruption of the blood-spinal cord barrier resulting in edema, upregulation of
debated. vascular endothelial growth factor (VEGF), and inflammation leading to
● Early radiation
demyelination.96 Radiation toxicity to oligodendrocytes and oligodendrocyte
myelopathy is characterized progenitor cells may also play a role.96 Autopsy studies have found
by Lhermitte sign in isolation demyelination with secondary axonal loss and necrosis as well as vascular
without other features of changes including hyaline thickening, telangiectasia, vascular occlusion, and
myelopathy, emerging from
2 weeks to 5 months (mean,
focal hemorrhage.96,112
3 months) following
completion of radiation TREATMENT AND PROGNOSIS. Early radiation myelopathy is typically transient,
therapy. lasting from less than 1 month to up to 22 months (mean, 6 months).101 It is not
associated with an increased risk of delayed radiation myelopathy.101 There is no
218 F E B R U A R Y 2 0 24

specific therapy, although a cervical collar may be considered to avoid KEY POINTS
provocation of the Lhermitte sign.101
● Early radiation
Treatments for delayed radiation myelopathy that have been described in case myelopathy is typically
reports and small series with varied success include corticosteroids, transient, lasting from less
anticoagulation, hyperbaric oxygen, and bevacizumab.96 Bevacizumab holds than 1 month to up to
particular promise for the treatment of radiation myelopathy based on 22 months (mean, 6 months).
extrapolation from a small randomized trial that demonstrated improvement in

● Early radiation
radiation-induced brain necrosis113 and a case report of significant clinical and myelopathy is not
radiologic improvement in one patient with radiation myelopathy.114
associated with an
Although the prognosis of delayed radiation myelopathy was historically poor increased risk of delayed
(14% survival at 5 years and a median survival time of 8.3 months in one series radiation myelopathy.
from the 1950s to the 1980s),105 45% of patients demonstrated some ● Delayed radiation
improvement in a more recent series.109 Given limited treatment options for myelopathy can occur in
delayed radiation myelopathy, the prevention of myelopathy through safe patients in whom the spinal
radiation dosing and administration is paramount. cord is exposed to radiation
during treatment of cancers
of the head and neck
(cervical cord) or of the lung,
CONCLUSION mediastinum, or upper
A wide variety of metabolic and toxic causes of myelopathy have been described. abdomen (thoracic cord).
The recognition of risk factors and neuroimaging findings is essential to
● MRI in patients with
diagnosis, noting that MRI may be normal in some entities. Therefore, patients delayed radiation
with undiagnosed causes of myelopathy should be asked about diet, medications, myelopathy demonstrates
drug use, and prior cancer treatment since the early recognition and treatment of cord swelling and
many metabolic and toxic causes of myelopathy is associated with an longitudinally extensive T2
hyperintensity and T1
improved prognosis. hypointensity that may be
central, posterior, or
transverse.
REFERENCES
1 Devalia V, Hamilton MS, Molloy AM, British 6 Hemmer B, Glocker FX, Schumacher M,
Committee for Standards in Haematology. Deuschl G, Lücking CH. Subacute combined
Guidelines for the diagnosis and treatment of degeneration: clinical, electrophysiological, and
cobalamin and folate disorders. Br J Haematol magnetic resonance imaging findings. J Neurol
2014;166(4):496–513. doi:10.1111/bjh.12959 Neurosurg Psychiatry 1998;65(6):822–827.
doi:10.1136/jnnp.65.6.822
2 Stabler SP, Allen RH, Savage DG, Lindenbaum J.
Clinical spectrum and diagnosis of cobalamin 7 Ahmed MA, Muntingh G, Rheeder P. Vitamin B12
deficiency. Blood 1990;76(5):871–881. deficiency in metformin-treated type-2 diabetes
patients, prevalence and association with
3 Cao J, Su ZY, Xu SB, Liu CC. Subacute combined
peripheral neuropathy. BMC Pharmacol Toxicol
degeneration: a retrospective study of 68 cases
2016;17(1):44. doi:10.1186/s40360-016-0088-3
with short-term follow-up. Eur Neurol 2018;
79(5-6):247–255. doi:10.1159/000488913 8 Jatoi S, Hafeez A, Riaz SU, et al. Low vitamin B12
levels: an underestimated cause of minimal
4 Pandey S, Holla VV, Rizvi I, Qavi A, Shukla R.
cognitive impairment and dementia. Cureus
Can vitamin B12 deficiency manifest with acute
2020;12(2):e6976. doi:10.7759/cureus.6976
posterolateral or posterior cord syndrome?
Spinal Cord Ser Cases 2016;2:16006. doi:10.1038/ 9 Ata F, Bint I, Bilal A, et al. Optic neuropathy as a
scsandc.2016.6 presenting feature of vitamin b-12 deficiency: a
systematic review of literature and a case report.
5 Healton EB, Savage DG, Brust JC, Garrett TJ,
Ann Med Surg 2012 2020;60:316–322. doi:10.1016/
Lindenbaum J. Neurologic aspects of cobalamin
j.amsu.2020.11.010
deficiency. Medicine (Baltimore) 1991;70(4):
229–245. doi:10.1097/00005792-199107000-00001 10 Vasconcelos OM, Poehm EH, McCarter RJ,
Campbell WW, Quezado ZMN. Potential
outcome factors in subacute combined
degeneration: review of observational studies.
J Gen Intern Med 2006;21(10):1063–1068.
doi:10.1111/j.1525-1497.2006.00525.x

11 Zhou P, Hua H, Yan Z, Zheng L, Liu X. Diagnostic 24 Okada A, Koike H, Nakamura T, Watanabe H,
value of oral “beefy red” patch in vitamin B12 Sobue G. Slowly progressive folate-deficiency
deficiency. Ther Clin Risk Manag 2018;14: myelopathy: report of a case. J Neurol Sci 2014;
1391–1397. doi:10.2147/TCRM.S159889 336(1-2):273–275. doi:10.1016/j.jns.2013.10.032
12 Kumar N. Neurologic presentations of nutritional 25 Lever EG, Elwes RD, Williams A, Reynolds EH.
deficiencies. Neurol Clin 2010;28(1):107–170. Subacute combined degeneration of the cord
doi:10.1016/j.ncl.2009.09.006 due to folate deficiency: response to methyl
folate treatment. J Neurol Neurosurg Psychiatry
13 Jain KK, Malhotra HS, Garg RK, et al. Prevalence

1986;49(10):1203–1207. doi:10.1136/jnnp.49.10.1203
of MR imaging abnormalities in vitamin B12
deficiency patients presenting with clinical 26 Ramalho J, Nunes RH, da Rocha AJ, Castillo M.
features of subacute combined degeneration of Toxic and metabolic myelopathies. Semin
the spinal cord. J Neurol Sci 2014;342(1-2):162-166. Ultrasound CT MR 2016;37(5):448–465. doi:

doi:10.1016/j.jns.2014.05.020 10.1053/j.sult.2016.05.010
14 Locatelli ER, Laureno R, Ballard P, Mark AS. MRI in 27 Dickinson CJ. Does folic acid harm people with
vitamin B12 deficiency myelopathy. Can J Neurol vitamin B12 deficiency? QJM Mon J Assoc
Sci J Can Sci Neurol 1999;26(1):60–63. Physicians 1995;88(5):357–364.
15 Risien Russell JS, Batten FE, Collier J. Subacute 28 Pincus JH, Reynolds EH, Glaser GH. Subacute
combined degeneration of the spinal cord. Brain combined system degeneration with folate
1900;23(1):39–110. doi:10.1093/brain/23.1.39 deficiency. JAMA 1972;221(5):496–497.
16 Eussen SJPM, de Groot LCPGM, Clarke R, et al. 29 Sokol RJ. Vitamin E and neurologic deficits. Adv
Oral cyanocobalamin supplementation in older Pediatr 1990;37:119–148.
people with vitamin B12 deficiency: a
30 El Euch-Fayache G, Bouhlal Y, Amouri R, Feki M,
dose-finding trial. Arch Intern Med 2005;165(10):
Hentati F. Molecular, clinical and peripheral
1167–1172. doi:10.1001/archinte.165.10.1167
neuropathy study of Tunisian patients with ataxia
17 Oussalah A, Julien M, Levy J, et al. Global burden with vitamin E deficiency. Brain J Neurol 2014;
related to nitrous oxide exposure in medical and 137(Pt 2):402–410. doi:10.1093/brain/awt339
recreational settings: a systematic review and
31 Kleopa KA, Kyriacou K, Zamba-Papanicolaou E,
individual patient data meta-analysis. J Clin Med
Kyriakides T. Reversible inflammatory and
2019;8(4):551. doi:10.3390/jcm8040551
vacuolar myopathy with vitamin E deficiency in
18 Patel KK, Mejia Munne JC, Gunness VRN, et al. celiac disease. Muscle Nerve 2005;31(2):260-265.
Subacute combined degeneration of the spinal doi:10.1002/mus.20144
cord following nitrous oxide anesthesia: A
32 Vorgerd M, Tegenthoff M, Kühne D, Malin JP.
systematic review of cases. Clin Neurol
Spinal MRI in progressive myeloneuropathy
Neurosurg 2018;173:163–168. doi:10.1016/j.
associated with vitamin E deficiency.
clineuro.2018.08.016
Neuroradiology 1996;38 Suppl 1:S111–113. doi:
19 Strauss J, Qadri SF. Myelopathy secondary to 10.1007/BF02278134
vitamin B12 deficiency induced by nitrous oxide
33 Jaiser SR, Winston GP. Copper deficiency
abuse. Cureus 2021;13(10):e18644. doi:10.7759/
myelopathy. J Neurol 2010;257(6):869–881. doi:
cureus.18644
10.1007/s00415-010-5511-x
20 Dong X, Ba F, Wang R, Zheng D. Imaging
34 Kumar N, Crum B, Petersen RC, Vernino SA,
appearance of myelopathy secondary to nitrous
Ahlskog JE. Copper deficiency myelopathy. Arch
oxide abuse: a case report and review of the
Neurol 2004;61(5):762–766. doi:10.1001/
literature. Int J Neurosci 2019;129(3):225–229. doi:
archneur.61.5.762
10.1080/00207454.2018.1526801
35 Kumar N. Copper deficiency myelopathy (human
21 Yuan JL, Wang SK, Jiang T, Hu WL. Nitrous oxide
swayback). Mayo Clin Proc 2006;81(10):1371–1384.
induced subacute combined degeneration with
doi:10.4065/81.10.1371
longitudinally extensive myelopathy with
inverted V-sign on spinal MRI: a case report and 36 Kumar N, Gross JB, Ahlskog JE. Copper deficiency
literature review. BMC Neurol 2017;17:222. doi:10. myelopathy produces a clinical picture like
1186/s12883-017-0990-3 subacute combined degeneration. Neurology
2004;63(1):33–39. doi:10.1212/01.
22 Shen Q, Lu H, Wang H, Xu Y. Acute cognitive
wnl.0000132644.52613.fa
disorder as the initial manifestation of nitrous
oxide abusing: a case report. Neurol Sci Off J Ital 37 Prodan CI, Rabadi M, Vincent AS, Cowan LD.
Neurol Soc Ital Soc Clin Neurophysiol 2021;42(2): Copper supplementation improves functional
755–756. doi:10.1007/s10072-019-04183-w activities of daily living in adults with copper
deficiency. J Clin Neuromuscul Dis 2011;12(3):
23 Reynolds EH. The neurology of folic acid
122–128. doi:10.1097/CND.0b013e3181dc34c0
deficiency. Handb Clin Neurol 2014;120:927–943.
doi:10.1016/B978-0-7020-4087-0.00061-9 38 Tylleskär T, Howlett WP, Rwiza HT, et al. Konzo: a
distinct disease entity with selective upper
motor neuron damage. J Neurol Neurosurg
Psychiatry 1993;56(6):638–643.
220 F E B R U A R Y 2 0 24

39 Baguma M, Nzabara F, Maheshe Balemba G, et al. 52 Misra UK, Sharma VP. Peripheral and central
Konzo risk factors, determinants and conduction studies in neurolathyrism. J Neurol
etiopathogenesis: What is new? A systematic Neurosurg Psychiatry 1994;57(5):572–577. doi:
review. Neurotoxicology 2021;85:54–67. doi: 10.1136/jnnp.57.5.572
10.1016/j.neuro.2021.05.001
53 Woldeamanuel YW, Hassan A, Zenebe G.
40 Kashala-Abotnes E, Okitundu D, Mumba D, et al. Neurolathyrism: two Ethiopian case reports and
Konzo: a distinct neurological disease associated review of the literature. J Neurol 2012;259(7):
with food (cassava) cyanogenic poisoning. Brain 1263–1268. doi:10.1007/s00415-011-6306-4
Res Bull 2019;145:87–91. doi:10.1016/j.

54 Bick AS, Meiner Z, Gotkine M, Levin N. Using
brainresbull.2018.07.001
advanced imaging methods to study
41 Siddiqi OK, Kapina M, Kumar R, et al. Konzo neurolathyrism. Isr Med Assoc J IMAJ 2016;18(6):
outbreak in the Western Province of Zambia. 341–345.

Neurology 2020;94(14):e1495–e1501. doi:10.1212/
55 Spencer PS, Roy DN, Ludolph A, et al. Lathyrism:
WNL.0000000000009017
evidence for role of the neuroexcitatory
42 Banea JP, Bradbury JH, Mandombi C, et al. Konzo aminoacid BOAA. Lancet Lond Engl 1986;2(8515):
prevention in six villages in the DRC and the 1066–1067. doi:10.1016/s0140-6736(86)90468-x
dependence of konzo prevalence on cyanide
56 Getahun H, Lambein F, Vanhoorne M, Van der
intake and malnutrition. Toxicol Rep 2015;2:
Stuyft P. Neurolathyrism risk depends on type of
609–616. doi:10.1016/j.toxrep.2015.03.014
grass pea preparation and on mixing with cereals
43 Tshala-Katumbay D, Eeg-Olofsson KE, Tylleskär T, and antioxidants. Trop Med Int Health TM IH
Kazadi-Kayembe T. Impairments, disabilities 2005;10(2):169–178. doi:10.1111/j.1365-
and handicap pattern in konzo–a 3156.2004.01370.x
non-progressive spastic para/tetraparesis of
57 Substance Abuse and Mental Health Services
acute onset. Disabil Rehabil 2001;23(16):731–736.
Administration. 2020 National Survey on Drug
doi:10.1080/09638280110055075
Use and Health (NSDUH) Releases. Accessed
44 Boivin MJ, Okitundu D, Makila-Mabe Bumoko G, November 3, 2023. https://www.samhsa.gov/
et al. Neuropsychological effects of konzo: a data/release/2020-national-survey-drug-use-
neuromotor disease associated with poorly and-health-nsduh-releases
processed cassava. Pediatrics 2013;131(4):
58 McCreary M, Emerman C, Hanna J, Simon J.
e1231–1239. doi:10.1542/peds.2012-3011
Acute myelopathy following intranasal
45 World Health Organization. Konzo, a distinct type insufflation of heroin: a case report. Neurology
of upper motor neuron disease. Wkly Epidemiol 2000;55(2):316–317. doi:10.1212/wnl.55.2.316-a
Rec 1996;71(30):225–232.
59 Sveinsson O, Herrman L, Hietala MA. Heroin-
46 Hedera P. Hereditary and metabolic induced acute myelopathy with extreme high
myelopathies. Handb Clin Neurol 2016;136: levels of CSF glial fibrillar acidic protein
769–785. doi:10.1016/B978-0-444-53486- indicating a toxic effect on astrocytes. BMJ Case
6.00038-7 Rep 2017;2017:bcr2017219903. doi:10.1136/bcr-
2017-219903
47 Howlett WP, Brubaker GR, Mlingi N, Rosling H.
Konzo, an epidemic upper motor neuron disease 60 Nyffeler T, Stabba A, Sturzenegger M.
studied in Tanzania. Brain J Neurol 1990;113(Pt 1): Progressive myelopathy with selective
223–235. doi:10.1093/brain/113.1.223 involvement of the lateral and posterior columns
after inhalation of heroin vapour. J Neurol 2003;
48 Cliff J, Nicala D. Long-term follow-up of konzo
250(4):496–498. doi:10.1007/s00415-003-1012-5
patients. Trans R Soc Trop Med Hyg 1997;91(4):
447–449. doi:10.1016/s0035-9203(97)90279-0 61 Judice DJ, LeBlanch HJ, McGarry PA. Spinal cord
vasculitis presenting as a spinal cord tumor in a
49 Mlingi NLV, Nkya S, Tatala SR, Rashid S, Bradbury
heroin addict. Case report. J Neurosurg 1978;
JH. Recurrence of konzo in southern Tanzania:
48(1):131–134. doi:10.3171/jns.1978.48.1.0131
rehabilitation and prevention using the wetting
method. Food Chem Toxicol Int J Publ Br Ind Biol 62 Richter RW, Rosenberg RN. Transverse myelitis
Res Assoc 2011;49(3):673–677. doi:10.1016/j. associated with heroin addiction. JAMA 1968;
fct.2010.09.017 206(6):1255–1257.
50 Banea JP, Bradbury JH, Mandombi C, et al. 63 Pearson J, Richter RW, Baden MM, Challenor YB,
Control of konzo by detoxification of cassava Brunn B. Transverse myelopathy as an illustration
flour in three villages in the Democratic Republic of the neurologic and neuropathologic features
of Congo. Food Chem Toxicol Int J Publ Br Ind of heroin addiction. Hum Pathol 1972;3(1):107–113.
Biol Res Assoc 2013;60:506–513. doi:10.1016/j. doi:10.1016/s0046-8177(72)80060-1
fct.2013.08.012
64 Ell JJ, Uttley D, Silver JR. Acute myelopathy in
51 Singh SS, Rao SLN. Lessons from neurolathyrism: association with heroin addiction. J Neurol
A disease of the past & the future of Lathyrus Neurosurg Psychiatry 1981;44(5):448–450. doi:
sativus (Khesari dal). Indian J Med Res 2013;138(1): 10.1136/jnnp.44.5.448
32–37.

65 Gupta A, Khaira A, Lata S, Agarwal SK, Tiwari SC. 78 Zhao H, Yue Z, Wang L, et al. Benefits of early
Rhabdomyolysis, acute kidney injury and treatment for patients with hepatic myelopathy
transverse myelitis due to naive heroin exposure. secondary to tips: a retrospective study in
Saudi J Kidney Dis Transplant Off Publ Saudi Cent northern China. Sci Rep 2018;8:15184. doi:10.1038/
Organ Transplant Saudi Arab 2011;22(6):1223–1225. s41598-018-33216-1
66 Eyas M, Jahinover M, Abhiram N, Michael TM. 79 McFaline-Figueroa J. Neoplasms of the spinal
Acute cervical-transverse myelitis following cord. Continuum (Minneap Minn) 2024;
intranasal insufflation of heroin. Radiol Case Rep 30(1, Spinal Cord Disorders):99–118.
2020;15(11):2136–2138. doi:10.1016/j.radcr.2020.07.039
80 M Levy. Immune-mediated myelopathies. Contin
67 Mahoney KW, Romba M, Gailloud P, Izbudak I, (Minneap Minn) 2024;30(1, Spinal Cord
Saylor D. Acute progressive paraplegia in Disorders):180–198.
heroin-associated myelopathy. J Clin Neurosci

81 Bay A, Oner AF, Etlik O, Yilmaz C, Caksen H.
Off J Neurosurg Soc Australas 2018;51:69–71. doi:
Myelopathy due to intrathecal chemotherapy:
10.1016/j.jocn.2018.02.005
report of six cases. J Pediatr Hematol Oncol
68 Büttner A, Mall G, Penning R, Weis S. The 2005;27(5):270–272. doi:10.1097/01.
neuropathology of heroin abuse. Forensic Sci Int mph.0000162527.85024.e9
2000;113(1-3):435–442. doi:10.1016/s0379-0738
82 Cachia D, Kamiya-Matsuoka C, Pinnix CC, et al.
(00)00204-8
Myelopathy following intrathecal chemotherapy
69 Richter RW, Pearson J, Bruun B, et al. Neurological in adults: a single institution experience. J
complications of addiction to heroin. Bull N Y Neurooncol 2015;122(2):391–398. doi:10.1007/
Acad Med 1973;49(1):3–21. s11060-015-1727-z
70 Tryc AB, Goldbecker A, Berding G, et al. Cirrhosis- 83 Pinnix CC, Chi L, Jabbour EJ, et al. Dorsal column
related parkinsonism: prevalence, mechanisms myelopathy after intrathecal chemotherapy for
and response to treatments. J Hepatol 2013; leukemia. Am J Hematol 2017;92(2):155–160. doi:
58(4):698–705. doi:10.1016/j.jhep.2012.11.043 10.1002/ajh.24611
71 Conn HO, Rössle M, Levy L, Glocker FX. 84 Park SB, Lin CSY, Krishnan AV, et al. Oxaliplatin-
Portosystemic myelopathy: spastic paraparesis induced lhermitte’s phenomenon as a
after portosystemic shunting. Scand J manifestation of severe generalized
Gastroenterol 2006;41(5):619–625. doi: neurotoxicity. Oncology 2009;77(6):342–348. doi:
10.1080/00365520500318932 10.1159/000265940
72 Mendoza G, Marti-Fàbregas J, Kulisevsky J, 85 Watterson J, Toogood I, Nieder M, et al.
Escartín A. Hepatic myelopathy: a rare Excessive spinal cord toxicity from intensive
complication of portacaval shunt. Eur Neurol central nervous system-directed therapies.
1994;34(4):209–212. doi:10.1159/000117040 Cancer 1994;74(11):3034–3041. doi:10.1002/1097-
0142(19941201)74:11<3034::aid-cncr2820741122>3.
73 Nardone R, Höller Y, Storti M, et al. Spinal cord
0.co;2-o
involvement in patients with cirrhosis. World J
Gastroenterol WJG 2014;20(10):2578–2585. doi: 86 Ackermann R, Semmler A, Maurer GD, et al.
10.3748/wjg.v20.i10.2578 Methotrexate-induced myelopathy responsive
to substitution of multiple folate metabolites. J
74 Utku U, Asil T, Balci K, Uzunca I, Celik Y. Hepatic
Neurooncol 2010;97(3):425–427. doi:10.1007/
myelopathy with spastic paraparesis. Clin Neurol
s11060-009-0028-9
Neurosurg 2005;107(6):514–516. doi:10.1016/j.
clineuro.2004.10.002 87 Drachtman RA, Cole PD, Golden CB, et al.
Dextromethorphan is effective in the treatment
75 Rovira A, Alonso J, Córdoba J. MR imaging
of subacute methotrexate neurotoxicity. Pediatr
findings in hepatic encephalopathy. AJNR Am J
Hematol Oncol 2002;19(5):319–327. doi:
Neuroradiol 2008;29(9):1612–1621. doi:10.3174/
10.1080/08880010290057336
ajnr.A1139
88 Guidon AC, Burton LB, Chwalisz BK, et al.
76 Caldwell C, Werdiger N, Jakab S, et al. Use of
Consensus disease definitions for neurologic
model for end-stage liver disease exception
immune-related adverse events of immune
points for early liver transplantation and
checkpoint inhibitors. J Immunother Cancer 2021;
successful reversal of hepatic myelopathy with a
9(7):e002890. doi:10.1136/jitc-2021-002890
review of the literature. Liver Transplant Off Publ
Am Assoc Study Liver Dis Int Liver Transplant Soc 89 Schneider BJ, Naidoo J, Santomasso BD, et al.
2010;16(7):818–826. doi:10.1002/lt.22077 Management of immune-related adverse events
in patients treated with immune checkpoint
77 Weissenborn K, Tietge UJF, Bokemeyer M, et al.
inhibitor therapy: ASCO guideline update. J Clin
Liver transplantation improves hepatic
Oncol Off J Am Soc Clin Oncol 2021;39(36):
myelopathy: evidence by three cases.
4073–4126. doi:10.1200/JCO.21.01440
Gastroenterology 2003;124(2):346–351. doi:
10.1053/gast.2003.50062 90 Marini A, Bernardini A, Gigli GL, et al. Neurologic
adverse events of immune checkpoint inhibitors:
a systematic review. Neurology 2021;96(16):
754–766. doi:10.1212/WNL.0000000000011795
222 F E B R U A R Y 2 0 24

91 Plaçais L, Michot JM, Champiat S, et al. 103 Kara B, Seher N, Ucaryilmaz H, et al. Delayed
Neurological complications induced by immune radiation myelopathy in a child with hodgkin
checkpoint inhibitors: a comprehensive lymphoma and ARTEMIS mutation. J Pediatr
descriptive case-series unravelling high risk of Hematol Oncol 2021;43(3):e404-e407. doi:
long-term sequelae. Brain Commun 2021;3(4): 10.1097/MPH.0000000000001815
fcab220. doi:10.1093/braincomms/fcab220
104 DeAngelis LM, Posner JB. Side effects of
92 Picca A, Berzero G, Bihan K, et al. Longitudinally radiation therapy. In: Neurologic complications
extensive myelitis associated with immune of cancer. 2nd ed. Oxford University Press;
checkpoint inhibitors. Neurol Neuroimmunol 2008.

Neuroinflammation 2021;8(3):e967. doi:10.1212/
105 Wong CS, Van Dyk J, Milosevic M, Laperriere NJ.
NXI.0000000000000967
Radiation myelopathy following single courses
93 Graus F, Dalmau J. Paraneoplastic neurological of radiotherapy and retreatment. Int J Radiat

syndromes in the era of immune-checkpoint Oncol Biol Phys 1994;30(3):575–581.
inhibitors. Nat Rev Clin Oncol 2019;16(9):535–548. doi:10.1016/0360-3016(92)90943-c
doi:10.1038/s41571-019-0194-4
106 Esik O, Vönöczky K, Lengyel Z, Sáfrány G, Trón L.
94 Sechi E, Flanagan EP. Antibody-mediated Characteristics of radiogenic lower motor
autoimmune diseases of the CNS: challenges neurone disease, a possible link with a
and approaches to diagnosis and management. preceding viral infection. Spinal Cord 2004;
Front Neurol 2021;12:673339. doi:10.3389/fneur. 42(2):99–105. doi:10.1038/sj.sc.3101552
2021.673339
107 Jabbour P, Gault J, Murk SE, Awad IA. Multiple
95 Dolladille C, Ederhy S, Sassier M, et al. Immune spinal cavernous malformations with atypical
checkpoint inhibitor rechallenge after phenotype after prior irradiation: case report.
immune-related adverse events in patients with Neurosurgery 2004;55(6):1431.
cancer. JAMA Oncol 2020;6(6):865–871. doi:10.
108 Wang PY, Shen WC, Jan JS. MR imaging in
1001/jamaoncol.2020.0726
radiation myelopathy. AJNR Am J Neuroradiol
96 Wong CS, Fehlings MG, Sahgal A. Pathobiology of 1992;13(4):1049–1055; discussion 1056-1058.
radiation myelopathy and strategies to mitigate
109 Khan M, Ambady P, Kimbrough D, et al.
injury. Spinal Cord 2015;53(8):574–580. doi:
Radiation-induced myelitis: initial and follow-up
10.1038/sc.2015.43
MRI and clinical features in patients at a single
97 Schultheiss TE, Kun LE, Ang KK, Stephens LC. tertiary care institution during 20 years. AJNR Am
Radiation response of the central nervous J Neuroradiol 2018;39(8):1576–1581. doi:10.3174/
system. Int J Radiat Oncol Biol Phys 1995;31(5): ajnr.A5671
1093–1112. doi:10.1016/0360-3016(94)00655-5
110 Michikawa M, Wada Y, Sano M, et al. Radiation
98 Schultheiss TE. The radiation dose-response of myelopathy: significance of gadolinium-DTPA
the human spinal cord. Int J Radiat Oncol Biol enhancement in the diagnosis. Neuroradiology
Phys 2008;71(5):1455–1459. doi:10.1016/j.ijrobp. 1991;33(3):286–289. doi:10.1007/BF00588240
2007.11.075
111 Wang PY, Shen WC, Jan JS. Serial MRI changes in
99 Sahgal A, Chang JH, Ma L, et al. Spinal cord dose radiation myelopathy. Neuroradiology 1995;
tolerance to stereotactic body radiation therapy. 37(5):374–377. doi:10.1007/BF00588016
Int J Radiat Oncol Biol Phys 2021;110(1):124–136. doi:
112 Schultheiss TE, Stephens LC, Maor MH. Analysis
10.1016/j.ijrobp.2019.09.038
of the histopathology of radiation myelopathy.
100 Gibbs IC, Patil C, Gerszten PC, Adler JR, Burton Int J Radiat Oncol Biol Phys 1988;14(1):27–32. doi:
SA. Delayed radiation-induced myelopathy 10.1016/0360-3016(88)90046-6
after spinal radiosurgery. Neurosurgery 2009;
113 Levin VA, Bidaut L, Hou P, et al. Randomized
64(2 Suppl):A67–72. doi:10.1227/01.NEU.
double-blind placebo-controlled trial of
0000341628.98141.B6
bevacizumab therapy for radiation necrosis of
101 Fein DA, Marcus RB, Parsons JT, Mendenhall the central nervous system. Int J Radiat Oncol
WM, Million RR. Lhermitte’s sign: incidence and Biol Phys 2011;79(5):1487–1495. doi:10.1016/j.
treatment variables influencing risk after ijrobp.2009.12.061
irradiation of the cervical spinal cord. Int J Radiat
114 Chamberlain MC, Eaton KD, Fink J.
Oncol Biol Phys 1993;27(5):1029–1033. doi:
Radiation-induced myelopathy: treatment
10.1016/0360-3016(93)90519-2
with bevacizumab. Arch Neurol 2011;68(12):
102 Word JA, Kalokhe UP, Aron BS, Elson HR. 1608–1609. doi:10.1001/archneurol.2011.621
Transient radiation myelopathy (Lhermitte’s
sign) in patients with Hodgkin’s disease treated
by mantle irradiation. Int J Radiat Oncol Biol Phys
1980;6(12):1731–1733. doi:10.1016/0360-3016(80)
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Metabolic and Toxic REVIEW ARTICLE

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disease (eg, pernicious anemia), malabsorption (eg, gastric bypass, gastric or

TABLE 9-1 Clinical Features of Metabolic and Toxic Myelopathies

CONTINUED ON PAGE 201

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corticospinal tracts).2 Vitamin B12 deficiency myelopathy presents subacutely

CONTINUED FROM PAGE 200

Intrathecal Patients receiving Arachnoiditis Arachnoiditis: Elevated Decreased Unknown, folate

Immune Preexisting Transverse Longitudinally Elevated Not applicable Discontinuation

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Peripheral neuropathy occurs in 15% to 30% of patients with vitamin B12

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Laboratory and Radiology Findings

normal range, serum methylmalonic acid and homocysteine levels should be

Treatment and Prognosis

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Clinical Presentation ● Vitamin B12 deficiency is

FOLATE (VITAMIN B9) DEFICIENCY

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and impaired absorption (eg, bariatric surgery, inflammatory bowel disease,

provided.1,23 Myelopathy due to folate deficiency is currently rare because of

Laboratory and Radiology Findings

Treatment and Prognosis

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even in cases of symptom progression for many years prior to treatment,

Clinical Presentation ● The most common causes

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the absence of inflammation or demyelination. Axonal loss in the cerebellum and

Treatment and Prognosis

varies based on the cause of vitamin E deficiency. In adults with fat

Laboratory and Radiology Findings

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performed, but an animal model demonstrated demyelination, glial

Treatment and Prognosis

Laboratory and Radiology Findings

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cream) or the medication

● Cassava is a dietary staple

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injury (due to prolonged stupor in a fixed position) have been proposed.62–64,68,69

Treatment and Prognosis

Laboratory and Radiology Findings

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decades after the inciting

Treatment and Prognosis myelopathy caused by

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LABORATORY AND RADIOLOGY FINDINGS. Serum folate may be decreased in

has rarely been described with arachnoiditis.82 In cases of arachnoiditis, CSF

PATHOPHYSIOLOGY. Intrathecal chemotherapy–associated myelopathy and

TREATMENT AND PROGNOSIS. Improvement in myelopathy may be seen with the

Myelopathy Associated With Immune Checkpoint Inhibitors

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effective when performed

of ICI treatment (range, 3 to 51 cycles).92 ● Intrathecal chemotherapy

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(16%) with ICI-associated neurologic toxicity, although no cases of myelitis

CASE 9-2 A 64-year-old woman presented with several months of difficulty

COMMENT Delayed radiation myelopathy may develop up to decades following radiation

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metastases.99 Radiation myelopathy is uncommon with stereotactic radiosurgery