The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Allison R. Bond, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors

Case 35-2017: A 57-Year-Old Woman

with Hypoesthesia and Weakness
in the Legs and Arms
Michael P. Bowley, M.D., Ph.D., William S. David, M.D., Ph.D.,
Tracey A. Cho, M.D., and Anand S. Dighe, M.D., Ph.D.​​

Pr e sen tat ion of C a se

Dr. Daniel B. Rubin (Neurology): A 57-year-old-woman was admitted to this hospital From the Departments of Neurology
because of progressive hypoesthesia, paresthesia, and weakness in the arms and legs. (M.P.B., W.S.D., T.A.C.) and Pathology
(A.S.D.), Massachusetts General Hospi‑
The patient had been in her usual health until 18 months before this admission, tal, and the Departments of Neurology
when paresthesia developed in the feet. Sixteen months before this admission, the (M.P.B., W.S.D., T.A.C.) and Pathology
patient underwent lumbar surgery, including laminectomy and facetectomies at (A.S.D.), Harvard Medical School —
both in Boston.
L3–L4 and bilateral foraminotomies at L4. After surgery, she reported that the
symptoms in the feet had diminished. N Engl J Med 2017;377:1977-84.
DOI: 10.1056/NEJMcpc1710564
Nine months before this admission, hypoesthesia and weakness recurred in the Copyright © 2017 Massachusetts Medical Society.
feet; over a period of several months, they spread to involve the legs and hands.
The patient had several falls at home and began to use a cane and then a wheel-
chair. Eight months before this admission, she was evaluated at an outpatient
neurology clinic, and electromyography and nerve-conduction studies were per-
formed. A presumptive diagnosis of chronic inflammatory demyelinating polyneu-
ropathy (CIDP) was made, and intravenous immune globulin (IVIG) was adminis-
tered; the patient reported transient improvement in sensation and strength in her
legs and hands. During the next 6 months, IVIG was administered every 4 weeks,
but hypoesthesia and weakness progressed to involve both arms. When she was
no longer able to transfer safely into a wheelchair, she presented to the emergency
department of another hospital for evaluation.
In the emergency department of the other hospital, the patient reported incon-
sistent bowel and bladder continence and progressive hypoesthesia and weakness
in her legs and arms. She had a history of chronic low-back pain (which had been
treated with opioids), fibromyalgia, headaches, and depression. Surgeries included
appendectomy, cholecystectomy, and hysterectomy in the distant past, as well as
Roux-en-Y gastric bypass approximately 4 years earlier. Medications included
controlled-release morphine sulfate, hydrocodone with acetaminophen, gabapentin,

n engl j med 377;20 nejm.org  November 16, 2017 1977

The New England Journal of Medicine
Downloaded from nejm.org on November 15, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
diazepam, cyclobenzaprine, valproic acid, citalo-
pram, cyanocobalamin, and cholecalciferol. The
patient was married, lived with her husband in
New England, and did not smoke tobacco, drink
alcohol, or use illicit drugs. There was no family
history of autoimmune disease; her father had a
history of bladder cancer.
On examination at the other hospital, the
temperature was 36.6°C, the blood pressure
138/66 mm Hg, the pulse 64 beats per minute,
the respiratory rate 18 breaths per minute, and
the oxygen saturation 100% while the patient was
breathing ambient air. The oropharynx had no
erythema or exudate; the patient was edentulous,
with a normal-appearing oral mucosa and tongue.
Results of cranial-nerve examinations were nor-
mal (although the first cranial nerve was not
tested). Strength was 0–1 out of 5 in the legs and
3 out of 5 in the arms. Sensation to pinprick was
decreased in both legs, from the toes to the hips.
Negative inspiratory force at functional residual
capacity and vital capacity were normal. A stage 2
pressure ulcer was present over the sacrum. The
remainder of the examination was normal.
Blood levels of electrolytes, glucose, vitamin B12
(cobalamin), and vitamin B9 (folate) were normal,
as were results of kidney- and liver-function tests.
Blood tests for human immunodeficiency virus
(HIV) type 1 p24 antigen and antibodies to HIV
types 1 and 2 and hepatitis C virus were nega-
tive. The blood level of valproic acid was 15.3 μg
per milliliter (therapeutic range, 50 to 100). Uri-
nalysis was unremarkable. Other laboratory test
results are shown in Table 1. Magnetic reso-
nance imaging (MRI) of the head was performed
without the administration of contrast material;
T2-weighted images showed mild abnormalities
in the periventricular white matter, a finding
consistent with a chronic small-vessel ischemic
process. Valproic acid was stopped, high-dose
methylprednisolone was administered, and the
patient was transferred to the neurology depart-
ment of this hospital for evaluation.
On examination at this hospital, results of a
mental-status examination (including tests of
language, attention, and memory) were normal.
There was no voluntary movement in the legs;
there was atrophy of the calf and foot muscles.
Weakness was more severe in the hands than in
the proximal arms. Deep-tendon reflexes were
2+ at the ankles, 3+ at the patellas, and 3+ at the
biceps. Perception of vibration, light touch, and
1978 n engl j med 377;20 nejm.org  November 16, 2017
The New England Journal of Medicine
Downloaded from nejm.org on November 15, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
pinprick was absent in the legs and diminished
in the arms. Sensation to pinprick was impaired
caudal to the T4 level. The plantar reflex was
absent bilaterally. A blood test for antinuclear
antibodies was positive at a titer of 1:40, with a
speckled pattern. Serum protein electrophoresis
revealed a normal pattern, with a moderate, dif-
fuse increase in immune globulin. Screening tests
for antitreponemal antibodies and for antibodies
to Borrelia burgdorferi and human T-lymphotropic
virus (HTLV) types 1 and 2 were negative. Other
laboratory test results are shown in Table 1.
Nerve-conduction studies and needle electromy-
ography were performed.
Dr. William S. David: The nerve-conduction stud-
ies revealed normal sensory responses, apart from
a mildly reduced amplitude of the right ulnar
nerve. Fibular motor responses could not be
elicited in the extensor digitorum brevis muscle
in either leg; fibular motor responses were se-
verely reduced in the tibialis anterior muscle in
both legs, as were posterior tibial motor respons-
es in the abductor hallucis muscle. Distal motor
latencies and velocities were normal. Needle elec-
tromyography revealed scattered fibrillation po-
tentials and positive sharp waves in two muscles
in the right arm and two muscles in the right
leg. The patient was unable to activate units in
several muscles in the arms and legs. In other
muscles, there was a reduced number of normal-
appearing motor units and slow firing of those
units, findings suggestive of impaired activation.
Dr. Rubin: MRI of the cervical, thoracic, and
lumbar spine, performed with and without the
administration of intravenous contrast material,
revealed mild scattered degenerative changes of
the spine, with no evidence of cord compression,
nerve-root impingement, or a demyelinating pro-
cess. A lumbar puncture was performed for
analysis of the cerebrospinal fluid (CSF); results
are shown in Table 1. Hypoesthesia and weak-
ness in the arms and legs did not improve, and
the results of a neurologic examination were
unchanged from those obtained on admission.
Dr. David: On the fifth hospital day, studies
for somatosensory evoked potentials were per-
formed. The right median somatosensory evoked
potential was normal; the left side was not
studied. The P37 scalp waveform was absent in
the right tibial somatosensory evoked potential,
a finding that suggested a disruption of central
conduction.
 Case Records of the Massachuset ts Gener al Hospital

Table 1. Laboratory Data.

Reference Range, Reference Range,

Adults, Other On Presentation, Adults, This On Admission,
Variable Hospital Other Hospital Hospital* This Hospital
Blood
Hematocrit (%) 37–47 31.7 36–46 31
Hemoglobin (g/dl) 12–16 10.4 12–16 9.9
White-cell count (per mm3) 4500–10,900 1800 4500–11,000 3960
Differential count (%)
Neutrophils 47–80 64 40–70 77
Band forms 0–7 0 0–10 0
Lymphocytes 14–46 20 22–44 18
Monocytes 5–12 12 4–11 5
Eosinophils 0–5 2 0–8 0
Basophils 0–1 0 0–3 0
3)
Platelet count (per mm 130,000–400,000 302,000 150,000–400,000 293,000
Red-cell count (per mm3) 4,200,000–5,400,000 3,660,000 4,000,000–5,200,000 3,540,000
Red-cell distribution width (%) 11.5–14.5 15.8 11.5–14.5 15.9
Mean corpuscular volume (fl) 81–99 86.6 80–100 87.6
Mean corpuscular hemoglobin (pg) 27–31 28.4 26–34 28
Mean corpuscular hemoglobin concentration (g/dl) 33–37 32.8 31–37 31.9
IgG (mg/dl) 614–1295 2780
IgA (mg/dl) 69–309 162
IgM (mg/dl) 53–334 42
Cerebrospinal fluid
Color Colorless Colorless
Turbidity Clear Clear
Xanthochromia None None
Red-cell count (per mm3)
Tube 1/4 0–5 1
Tube 4/4 0–5 0
Total nucleated cells (per mm3)
Tube 1/4 0–5 15
Tube 4/4 0–5 7
White-cell differential count in tube 4/4 (%)
Neutrophils 0 96
Lymphocytes 0–100 0
Monocytes 0–100 4
Macrophages or lining cells 0 0
Unclassified cells 0 0
Glucose (mg/dl) 50–75 47
Protein (mg/dl) 5–55 45

* Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results.
They may therefore not be appropriate for all patients.

n engl j med 377;20 nejm.org  November 16, 2017 1979

The New England Journal of Medicine
Downloaded from nejm.org on November 15, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
Dr. Rubin: A diagnostic test was performed.
Differ en t i a l Di agnosis
Dr. Michael P. Bowley: The first step in construct-
ing a differential diagnosis in this case is to de-
termine the location of the disease process in
the nervous system. This patient had reduced
sensation to pinprick on the trunk below the T4
level. This finding, which indicates disruption of
the ascending spinothalamic fibers at the ap-
proximate level of the thoracic spinal cord, is a
clinical hallmark of spinal cord dysfunction. In
addition, she had weak limbs accompanied by
hyperreflexia, a finding that indicates dysfunc-
tion of upper motor neurons or their descending
projections in the corticospinal tracts. Finally, she
had a history of bladder incontinence, a symptom
that can be seen with injury of the central ner-
vous system, typically between the pons and
sacral spinal cord. Taken together, the sensory
loss, hyperreflexia, and bladder incontinence in
this patient help to localize the disease process
to a central origin. Because the results of her
mental-status and cranial-nerve examinations
were normal, it is likely that her neurologic con-
dition was caused by primary spinal cord dys-
function, also known as myelopathy.
The results of electrophysiological investiga-
tions further support this localization. First, the
patient had marked sensory symptoms, and the
nerve-conduction studies revealed normal sensory
responses but marked attenuation in motor-
response amplitudes. This pattern is inconsistent
with a polyneuropathy (e.g., CIDP) and indicates
a preganglionic localization of neurologic dys-
function that affects the dorsal roots or ascend-
ing sensory tracts in the spinal cord or brain.
Second, her arm weakness was out of proportion
to the normal motor responses observed on the
nerve-conduction studies; this finding further
suggests dysfunction of upper motor neurons or
their descending projections in the corticospinal
tracts. Third, the reduced number of normal-
appearing motor units and the slow firing of
those units in most muscles on needle electro-
myography indicate impaired activation of motor
units. This pattern of activation indicates a cen-
tral origin; the poor muscle activation may be due
to dysfunction of upper motor neurons or their
descending projections in the corticospinal tracts
1980 n engl j med 377;20 nejm.org  November 16, 2017
The New England Journal of Medicine
Downloaded from nejm.org on November 15, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
or to poor effort of the patient during testing.
Finally, the right tibial somatosensory evoked
potential with central slowing in combination
with a normal median somatosensory evoked
potential supports dysfunction of the dorsolat-
eral columns in the thoracic or lumbar region of
the spinal cord. After considering these find-
ings, we can conclude that this patient has a
diffuse myelopathy involving the cervical, thorac-
ic, and lumbosacral spinal cord.
Myelopathy
The differential diagnosis of myelopathy is broad
and includes infectious, structural, inflammatory,
autoimmune, vascular, hereditary, and metabolic
causes. The chronic and progressive nature of this
patient’s illness rules out many acute or subacute
causes of myelopathy. The negative HIV test rules
out the chronic vacuolar myelopathy seen in ad-
vanced HIV infection. The negative test for anti-
bodies to HTLV type 1 and the absence of travel
argue against the chronic myelopathy seen in
tropical spastic paraparesis. The negative test for
antitreponemal antibodies and the atypical symp-
toms rule out tertiary syphilis (tabes dorsalis),
and the absence of infectious symptoms and of
clinically significant abnormalities on CSF analy-
sis makes other infectious causes of chronic
myelopathy (e.g., Tropheryma whipplei infection,
brucellosis, and schistosomiasis) unlikely.
Structural spondylosis, autoimmune causes
(e.g., primary progressive multiple sclerosis), and
inflammatory causes (e.g., neurosarcoidosis,
Behçet’s disease, or Sjögren’s syndrome) would
be expected to result in abnormalities on imag-
ing studies of the spine. The absence of such
abnormalities makes these diagnoses unlikely in
this case.
Could this patient have myelopathy due to a
spinal dural arteriovenous fistula? A spinal dural
arteriovenous fistula is a direct communication
between a spinal artery and a spinal vein without
an intervening capillary bed, and it leads to ve-
nous congestion, edema, and ischemia of the
cord parenchyma. Patients with a spinal dural
arteriovenous fistula classically present with non-
specific spinal cord dysfunction, chronic and
progressive sensory loss, weakness, and inconti-
nence, typically beginning in the fifth or sixth
decade of life.1 This patient’s presentation fits
with this description, and this diagnosis should
 Case Records of the Massachuset ts Gener al Hospital
be considered in any middle-aged person who
presents with symptoms or signs of chronic
myelopathy. However, several specific features of
her presentation lower the likelihood of a spinal
dural arteriovenous fistula. The most important
of these features is the extent of the myelopathy,
which involves the cervical, thoracic, and lumbo-
sacral spinal cord. In 80% of reported cases of
spinal dural arteriovenous fistulas, the myelopa-
thy affects the thoracolumbar segments between
T6 and L2. Cervical involvement (which is seen
in this patient) is rare.2 In addition, the absence
of abnormalities in the cord parenchyma on MRI
is possible but atypical in the context of a spinal
dural arteriovenous fistula.3
Because the patient had a history of bariatric
surgery, she is at increased risk for the develop-
ment of nutritional deficiencies and associated
neurologic dysfunction. The patient had under-
gone Roux-en-Y gastric bypass that resulted in
the creation of a small proximal stomach pouch
that was directly connected to the midjejunum
and thus bypassed most of the stomach, duode-
num, and proximal jejunum — the portion of
the digestive tract that is critical for fat and
mineral absorption. Therefore, the procedure
produced a malabsorptive state that can result in
numerous nutritional deficiencies, including de-
ficiencies in vitamins A, B1, B2, B6, B9, B12, D, and
E, as well as iron, copper, and other micronutri-
ents. After surgery, patients who have intractable
vomiting, cannot tolerate food, use alcohol ex-
cessively, lose more weight than expected, or do
not take vitamin supplementation as instructed
are at the greatest risk for the development of
nutritional deficiencies.4-6
Neurologic disorders occur as a complication
of bariatric surgery in 5 to 16% of patients5,7 and
are largely attributed to nutritional deficiencies.
Such disorders are classified according to the
time of onset (Table 2).8 Myelopathy is consid-
ered to be a late complication; it typically occurs
an average of 9 years after bariatric surgery.9
Nutritional deficiencies that are specifically as-
sociated with myelopathy include deficiencies in
vitamins B9, B12, and E and copper; deficiencies
in vitamin B12 and copper are reported most
often.9 The normal vitamin B9 level in this patient
argues against a vitamin B9 deficiency, and there-
fore, deficiencies in vitamin B12 and E and cop-
per are left as possible diagnoses.
n engl j med 377;20 nejm.org  November 16, 2017
The New England Journal of Medicine
Downloaded from nejm.org on November 15, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
Table 2. Neurologic Disorders and Associated Nutritional Deficiencies That
Complicate Bariatric Surgery, According to Time of Onset.
Neurologic Disorder Associated Deficiencies
Early (<1 yr after surgery)
Polyradiculoneuropathy Vitamin B1
Encephalopathy Vitamins B1 and B12
Late (≥1 yr after surgery)
Optic neuropathy Vitamins A and B1 and copper
Myelopathy Vitamins B9, B12, and E and copper
Polyneuropathy Vitamins B1, B6, B9, B12, and E and copper
Myopathy Vitamin D and copper
Vitamin B12 Deficiency
Does a vitamin B12 deficiency explain the myelopa-
thy in this patient? Vitamin B12 deficiency has
long been associated with subacute combined
degeneration, which is a myelopathic syndrome
characterized by dysfunction of the posterior
and lateral columns of the spine that results in
paresthesias, impaired perception of vibration,
loss of proprioception, ataxia, weakness, and
hyperreflexia,10 features consistent with this
patient’s symptoms. Other signs of vitamin B12
deficiency may include encephalopathy, optic
neuropathy, polyneuropathy, and hematologic
abnormalities, such as macrocytic anemia and
pancytopenia. Vitamin B12 deficiency is the most
commonly reported nutritional deficiency among
patients who undergo bariatric surgery,4 and it is
typically a late complication, since the body has
large natural stores of vitamin B12.
In this patient, the blood vitamin B12 level was
reported as normal, and this result possibly ar-
gues against vitamin B12 deficiency as the prin-
cipal cause of myelopathy. However, the exact
vitamin B12 level was not provided. In patients
with symptoms consistent with vitamin B12 defi-
ciency, a low normal or borderline level of vita-
min B12 may lead to further evaluation,11 such as
tests for methylmalonic acid and homocysteine,
which are sensitive markers of vitamin B12 defi-
ciency. Because the results of these tests are not
reported in this case and the precise blood vita-
min B12 level is not available, we are unable to
rule out vitamin B12 deficiency as the underlying
cause of this patient’s myelopathy.
1981
 The n e w e ng l a n d j o u r na l
Vitamin E Deficiency
Vitamin E principally acts as a free radical that
protects nerve cells against oxidative damage.
Vitamin E absorption in the intestine is closely
tied to fat absorption. Therefore, vitamin E defi-
ciency has been associated with inherited and
acquired conditions and is sometimes associated
with surgical procedures (e.g., bariatric surgery12)
that may cause insufficient fat digestion and
steatorrhea. The neurologic symptoms and signs
of vitamin E deficiency vary, depending on the
underlying cause; ataxia, weakness, hyporeflexia,
and ophthalmoplegia are commonly reported. In
vitamin E deficiency, both the spinal cord and
the peripheral nerves are susceptible to injury
that causes a myeloneuropathy. Such a myelo-
neuropathy is almost always associated with
hyporeflexia or areflexia,12 and this feature was
not present in this case. Moreover, reports of
myelopathy due to vitamin E deficiency after
bariatric surgery are rare9; when such a condi-
tion is reported, it is often seen in combination
with more common nutritional deficiencies, in-
cluding vitamin B12 or copper deficiency.
Copper Deficiency
Copper is an essential daily micronutrient that is
found in foods such as dark chocolate, almonds,
and liver, and it serves an important role in re-
dox reactions, enzymatic function, and gene ex-
pression in the nervous system. Copper deficiency
occurs in a variety of disorders (e.g., celiac dis-
ease) and hereditary conditions (e.g., Menkes
disease). Copper is predominantly absorbed in
the duodenum, and thus copper deficiency is a
known complication of Roux-en-Y gastric bypass.
Does this patient have any additional risk fac-
tors that may contribute to copper deficiency?
An increased blood zinc level is associated with
copper deficiency, since zinc inhibits the absorp-
tion of copper by enterocytes. Zinc toxicity occurs
as a result of excess zinc in the diet or in dietary
supplements or as a result of the use of dental
adhesives that contain zinc. This patient was
noted to be edentulous, which raises the possi-
bility that she wore dentures and may have used
a dental adhesive that contains zinc. Further-
more, the patient was receiving valproic acid, an
antiseizure drug that has been shown to lower
blood copper levels through an unclear mecha-
nism.13 In addition to the history of gastric by-
pass, the use of valproic acid and the possible
1982 n engl j med 377;20 nejm.org  November 16, 2017
The New England Journal of Medicine
Downloaded from nejm.org on November 15, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
use of a dental adhesive may contribute to cop-
per deficiency in this patient.
Neurologic manifestations of copper defi-
ciency include myelopathy, polyneuropathy, optic
neuropathy, myopathy, and motor neuron dis-
ease. Copper deficiency myelopathy is a relatively
new phenomenon that was first described in
2001.14 It is characterized by symptoms similar
to those seen in this patient, including sensory
loss, ataxia, weakness that is more severe in the
legs than in the arms, and hyperreflexia. Copper
deficiency has also been associated with hema-
tologic abnormalities, including anemia (typically
normocytic, macrocytic, or sideroblastic), neutro-
penia, and in rare cases, thrombocytopenia.15 In
this patient, a complete blood count revealed
mild leukopenia and normocytic anemia, find-
ings consistent with copper deficiency.
The results of electrophysiological testing and
imaging studies of the spine further support a
diagnosis of copper deficiency in this patient.
Nerve-conduction studies may show a sensori­
motor polyneuropathy, although the sensory-
response abnormalities are typically mild and
insufficient to explain the degree of sensory loss
noted on examination,16 which underscores the
primary myelopathic quality of this syndrome.
On electrophysiological studies, abnormalities
may mimic those seen with amyotrophic lateral
sclerosis,17 as they did in this patient. Results of
MRI are abnormal in 47% of cases18 and appear
normal in the remainder of cases, as they did in
this patient. On laboratory testing, the hallmark
of copper deficiency is a low blood copper level;
45% of patients have a level lower than 0.10 μg
per milliliter (1.57 μmol per liter).19
This patient had multiple risk factors for cop-
per deficiency, including a history of Roux-en-Y
gastric bypass, the use of valproic acid, the pos-
sible use of dental adhesives, an established dif-
fuse myelopathy, anemia, characteristic features
on electrophysiological studies, normal imaging
studies of the spine, and no convincing evidence
of other common nutritional deficiencies. There-
fore, the most likely diagnosis in this case is
copper deficiency myelopathy, and the test result
that would most likely establish the diagnosis is
a low blood copper level.
Dr. Meridale V. Baggett (Medicine): Dr. Rubin,
what was your clinical impression when you
evaluated this patient?
Dr. Rubin: Although this patient had some defi-
 Case Records of the Massachuset ts Gener al Hospital
nite objective neurologic abnormalities, including
hyperreflexia, a functional neurologic disorder was
also suggested by variability and inconsistencies in
her examination results among examiners and
from day to day. The results of her nerve-conduc-
tion studies and electromyography included evi-
dence of clinically significant motor dysfunction,
but they could not fully account for the degree and
distribution of her sensory deficits. MRI of the
head and spinal cord did not reveal structural ab-
normalities that would account for the sensory
deficits. To better characterize the nature of her
apparent sensory impairment, studies for somato-
sensory evoked potentials were performed and re-
vealed prolonged central conduction. This finding
pointed us in the direction of copper deficiency
myelopathy, and further history was obtained from
the patient. She confirmed that she wore dentures.
When we asked her if she used denture cream,
she said, “Ever since I lost all that weight from my
gastric bypass, my dentures don’t fit at all. I have
to use about half a tube of cream a day.” Given the
evidence of spinal cord and peripheral-nerve dys-
function, along with the history of gastric bypass
and use of a denture cream that contains zinc, we
thought the most likely diagnosis was copper defi-
ciency myelopathy.
Cl inic a l Di agnosis
Copper deficiency myelopathy.
Dr . Mich a el P. Bow l e y ’s
Di agnosis
Copper deficiency myelopathy.
Pathol o gic a l Discussion
Dr. Anand S. Dighe: The diagnostic test result in
this case was a low total blood copper level of
0.12 μg per milliliter (1.89 μmol per liter; refer-
ence range, 0.75 to 1.45 μg per milliliter [11.80
to 22.81 μmol per liter]). In addition, the patient
had a low blood ceruloplasmin level of 9 mg per
deciliter (reference range, 20 to 60). In the ab-
sence of liver disease, the nephrotic syndrome,
or a genetic disorder that affects copper metabo-
lism, these results are consistent with a copper
deficiency that is caused by inadequate copper
intake or absorption.20 Although ceruloplasmin
is still produced by hepatocytes in the context of
n engl j med 377;20 nejm.org  November 16, 2017
The New England Journal of Medicine
Downloaded from nejm.org on November 15, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
copper deficiency, it is produced as an apoen-
zyme that lacks copper and is rapidly degraded.21
The anemia observed in this patient may be related
to the reduced level and function of copper-
dependent enzymes, including ceruloplasmin,
that affect iron transport and metabolism.22
The patient was further assessed for evidence
of concomitant vitamin deficiencies.23 Vitamin A,
K, and E levels were within normal limits. The
vitamin B12 level was 378 pg per milliliter (refer-
ence range, >250). Because a vitamin B12 level be-
tween 250 and 400 pg per milliliter may be con-
sidered to be borderline, the patient was assessed
for a vitamin B12 deficiency through measure-
ment of the blood level of methylmalonic acid, a
metabolite that is normally processed by a vita-
min B12–dependent enzyme. The blood methyl-
malonic acid level was 0.22 nmol per milliliter
(reference range, ≤0.40), a finding that effectively
ruled out vitamin B12 deficiency.
Zinc-induced copper deficiency appears to re-
sult from the competitive relationship between
zinc absorption and copper absorption in entero-
cytes, which is mediated by the protein metallo-
thionein.24 In this patient, the zinc level was ele-
vated at 1.32 μg per milliliter (20.19 μmol per
liter; reference range, 0.66 to 1.10 μg per milli-
liter [10.09 to 16.82 μmol per liter]), which pro-
vides evidence of the role of zinc, most likely
from the patient’s denture cream, in the ob-
served copper deficiency.
Discussion of M a nagemen t
Dr. Tracey A. Cho: Both malabsorption and increased
loss of copper due to zinc ingestion can contribute
to copper deficiency.25 In this patient, the use of
denture cream was discontinued, and she was
counseled to avoid any use in the future. In con-
sultation with our pharmacist, we intravenously
administered copper chloride at a dose of 2 mg
daily for 5 days and then orally administered cop-
per at a dose of 8 mg daily for 1 week, 6 mg daily
for 1 week, 4 mg daily for 1 week, and 2 mg daily
thereafter.26 Follow-up measurements of copper
levels were then used to determine the ongoing
need for oral supplementation. For treatment of
the neuropathic pain, we initially administered
gabapentin, but she had an inadequate response.
Pregabalin was used and had some benefit.
At a 6-month outpatient follow-up appoint-
ment, the patient had had clinically significant
1983
 Case Records of the Massachuset ts Gener al Hospital

improvement in strength and sensation in her Fina l Di agnosis

proximal arms and legs. She could walk with a
walker. She continued to have notable weak- Copper deficiency myelopathy.
ness in the distal hands and legs, along with
This case was presented at Neurology Grand Rounds.
sensory impairment in a stocking–glove distri- No potential conflict of interest relevant to this article was
bution and ongoing moderate neuropathic pain. reported.
The blood copper level was normal, and oral Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
supplementation was discontinued, with a plan We thank Dr. Tom Byrne for assistance in organizing this
for ongoing laboratory monitoring. conference.

References
1. Fugate JE, Lanzino G, Rabinstein AA.
Clinical presentation and prognostic fac-
tors of spinal dural arteriovenous fistulas:
an overview. Neurosurg Focus 2012;​32(5):​
E17.
2. Krings T, Geibprasert S. Spinal dural
arteriovenous fistulas. AJNR Am J Neuro-
radiol 2009;​30:​639-48.
3. Saraf-Lavi E, Bowen BC, Quencer RM,
et al. Detection of spinal dural arteriove-
nous fistulae with MR imaging and con-
trast-enhanced MR angiography: sensitiv-
ity, specificity, and prediction of vertebral
level. AJNR Am J Neuroradiol 2002;​23:​
858-67.
4. Becker DA, Balcer LJ, Galetta SL. The
neurological complications of nutritional
deficiency following bariatric surgery.
J Obes 2012;​2012:​608534.
5. Thaisetthawatkul P, Collazo-Clavell
ML, Sarr MG, Norell JE, Dyck PJ. A con-
trolled study of peripheral neuropathy af-
ter bariatric surgery. Neurology 2004;​63:​
1462-70.
6. Thaisetthawatkul P, Collazo-Clavell
ML, Sarr MG, Norell JE, Dyck PJ. Good
nutritional control may prevent polyneu-
ropathy after bariatric surgery. Muscle
Nerve 2010;​42:​709-14.
7. Abarbanel JM, Berginer VM, Osimani A,
Solomon H, Charuzi I. Neurologic compli-
cations after gastric restriction surgery for
morbid obesity. Neurology 1987;​37:​196-200.
8. Landais A. Neurological complications
of bariatric surgery. Obes Surg 2014;​24:​
1800-7.
9. Juhasz-Pocsine K, Rudnicki SA, Archer
RL, Harik SI. Neurologic complications of
gastric bypass surgery for morbid obesity.
Neurology 2007;​68:​1843-50.
10. Pearce JM. Subacute combined degen-
eration of the cord: Putnam-Dana syn-
drome. Eur Neurol 2008;​60:​53-6.
11. Langan RC, Prieto PA, Sherry RM,
et al. Assessment of ovarian function after
preparative chemotherapy and total body
radiation for adoptive cell therapy. J Im-
munother 2011;​34:​397-402.
12. Sokol RJ. Vitamin E deficiency and
neurologic disease. Annu Rev Nutr 1988;​
8:​351-73.
13. Kaji M, Ito M, Okuno T, et al. Serum
copper and zinc levels in epileptic chil-
dren with valproate treatment. Epilepsia
1992;​33:​555-7.
14. Schleper B, Stuerenburg HJ. Copper
deficiency-associated myelopathy in a 46-
year-old woman. J Neurol 2001;​248:​705-6.
15. Williams DM. Copper deficiency in
humans. Semin Hematol 1983;​20:​118-28.
16. Goodman BP, Bosch EP, Ross MA,
Hoffman-Snyder C, Dodick DD, Smith BE.
Clinical and electrodiagnostic findings in
copper deficiency myeloneuropathy. J Neu-
rol Neurosurg Psychiatry 2009;​80:​524-7.
17. Weihl CC, Lopate G. Motor neuron
disease associated with copper deficiency.
Muscle Nerve 2006;​34:​789-93.
18. Kumar N, Ahlskog JE, Klein CJ, Port
JD. Imaging features of copper deficiency
myelopathy: a study of 25 cases. Neurora-
diology 2006;​48:​78-83.
19. Jaiser SR, Winston GP. Copper defi-
ciency myelopathy. J Neurol 2010;​257:​869-
81.
20. Milne DB. Assessment of copper nutri-
tional status. Clin Chem 1994;​40:​1479-84.
21. Sato M, Gitlin JD. Mechanisms of cop-
per incorporation during the biosynthesis
of human ceruloplasmin. J Biol Chem
1991;​266:​5128-34.
22. Gulec S, Collins JF. Molecular media-
tors governing iron-copper interactions.
Annu Rev Nutr 2014;​34:​95-116.
23. Chhetri SK, Mills RJ, Shaunak S, Emsley
HC. Copper deficiency. BMJ 2014;​ 348:​
g3691.
24. Plum LM, Rink L, Haase H. The essen-
tial toxin: impact of zinc on human health.
Int J Environ Res Public Health 2010;​7:​
1342-65.
25. Kumar N, Gross JB Jr, Ahlskog JE.
Copper deficiency myelopathy produces a
clinical picture like subacute combined
degeneration. Neurology 2004;​63:​33-9.
26. Goodman BP. Metabolic and toxic
causes of myelopathy. Continuum (Min-
neap Minn) 2015;​21:​84-99.
Copyright © 2017 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference
material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.

1984 n engl j med 377;20 nejm.org  November 16, 2017

The New England Journal of Medicine

Downloaded from nejm.org on November 15, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.