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Review Article
The Role of Vitamin B
12
in the Management
and Optimization of Treatment in Patients
With Degenerative Cervical Myelopathy
Aria Nouri, MD, MSc
1,2
, Kishan Patel, BA
1
, Julio Montejo, BA
1
,
Rani Nasser, MD
2
, David A. Gimbel, MD
2
, Daniel M. Sciubba, MD
3
,
and Joseph S. Cheng, MD, MS, FAANS, FACS
1,2
Abstract
Study Design: Narrative review.
Objectives: To discuss the relationship between degenerative cervical myelopathy (DCM) and vitamin B
12
deficiency. Specifi-
cally, it is the aim to outline the rational for future research into assessment and therapeutic optimization of vitamin B
12
in the
treatment of DCM.
Methods: Literature review.
Results: DCM is the commonest cause of spinal cord impairment, with an average age of presentation in the sixth decade.
Patients at this age have also been reported to have a high prevalence of vitamin B
12
deficiency, with estimates of up to 20% in the
elderly. Vitamin B
12
deficiency can result in subacute combined degeneration of the spinal cord (SACD), and several case reports
have pointed to patients with both DCM and SACD. Both SACD and reversible compressive injury due to DCM necessitate
remyelination in the spinal cord, a process that requires adequate vitamin B
12
levels. Basic science research on nerve crush injuries
have shown that vitamin B
12
levels are altered after nerve injury and that vitamin B
12
along with dexamethasone or nonsteroidal
anti-inflammatory drugs can reduce Wallerian degeneration. Furthermore, it has been suggested that a combination of B-vitamins
can reduce glutamate-induced neurotoxicity.
Conclusions: Given the high prevalence of clinical and subclinical vitamin B
12
deficiency in the elderly, the role of vitamin B
12
in
myelination, and vitamin B
12
deficiency as a differential diagnosis of DCM, it is important to investigate what role vitamin B
12
levels play in patients with DCM in terms of baseline neurological function and whether optimization of vitamin B
12
levels can
improve surgical outcome. Furthermore, the routine assessment of vitamin B
12
levels in patients considered for DCM surgery
should be considered.
Keywords
nutrition, anemia, subacute combined degeneration, spinal cord, nitrous oxide, cobalamin
Introduction
Degenerative cervical myelopathy (DCM) encompasses a
set of age-related changes of the cervical spine that result in
spinal cord impairment through static and dynamic injury
mechanisms.
1
Patients with DCM typically present with vari-
able degrees of upper and lower limb neurological deficits,
including numbness, clumsiness, gait impairment, and motor
weakness. Additionally, objective myelopathic signs such as
Hoffmann’s sign, Babinski’s reflex, and ankle clonus may be
1
Department of Neurosurgery, Yale University, New Haven, CT, USA
2
Department of Neurosurgery, University of Cincinnati, Cincinnati, OH, USA
3
Department of Neurosurgery, Johns Hopkins University, Baltimore, MD,
USA
Corresponding Author:
Joseph S. Cheng, Department of Neurosurgery, University of Cincinnati
College of Medicine, 260 Stetson Street, Suite 2200, Cincinnati, OH 45219,
USA.
Email: chengj6@ucmail.uc.edu
Global Spine Journal
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ªThe Author(s) 2018
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observed.
2,3
One of the potential differential diagnoses to con-
sider in these patients is cobalamin or vitamin B
12
(B
12
) defi-
ciency. Neurological deficits encountered with B
12
deficiency
include peripheral neuropathy, myelopathy, mental status
changes, optic neuropathy, or a combination of these.
4,5
Patients with both DCM and B
12
deficiency are most frequently
diagnosed above the age of 50 years, and it has been estimated
that the prevalence of B
12
deficiency is about 20%in indus-
trialized countries.
4
Furthermore, many more patients may
have subclinical B
12
deficiency.
6
Given this high prevalence
of B
12
deficiency in elderly population, it would seem intuitive
that many patients with DCM are also affected. Indeed, there
have been some case reports describing patients with DCM
and superimposed B
12
deficiency.
7-9
Investigation of this rela-
tionship is important since deficiency of B
12
may not only
exacerbate myelopathic symptoms in DCM but may also
hinder neurological recovery, since B
12
is essential for mye-
lination.
10
In this review, the mechanism of action, causes of
deficiency, and presentation of B
12
deficiency will be briefly
described and will be followed by the role of routine B
12
assessment and its potential role in optimizing surgical
outcome in patients with DCM.
Vitamin B
12
: Mechanism of Action
Vitamin B
12
is synthesized exclusively by anaerobic bacteria,
and it is obtained in foods of animal origin. Uptake of B
12
in the
gastrointestinal system requires binding of a glycoprotein
called intrinsic factor, which is secreted by gastric parietal
cells. The B
12
-intrinsic factor complex binds to “cubam” recep-
tors expressed on enterocytes in the distal ileum and is
absorbed via receptor-mediated endocytosis. Given the critical
role of intrinsic factor in B
12
uptake, deficiencies in the glyco-
protein due to an autoimmune gastritis known as “pernicious
anemia” leads to a severe B
12
deficiency, with hematological
and neurological manifestations.
11
Intracellular B
12
is stored as 2 active coenzymes: methylco-
balamin and deoxyadenosylcobalamin. Methylcobalamin acts
as a coenzyme for cytoplasmic methionine synthase, which
catalyzes the methylation of homocysteine to methionine. This
transmethylation reaction also involves folate (vitamin B
9
) and
is therefore critical for nucleic acid synthesis. Deoxyadenosyl-
cobalamin is a cofactor for methylmalonyl-CoA mutase, which
catalyzes the conversion of methylmalonyl-CoA to succinyl-
CoA in the mitochondria. Succinyl-CoA subsequently enter the
Krebs cycle and is important for the synthesis of lipids and
carbohydrates
12
(Figure 1).
Methylcobalamin is also important for the synthesis and
maintenance of the myelin sheath. A number of studies report
the development of white-matter lesions or retarded myelina-
tion in patients with B
12
deficiency.
13-15
Although the precise
molecular mechanisms underlying methylcobalamin-mediated
myelination are unknown, a number of models have been sug-
gested, including increased synthesis of lecithin (the primary
component of myelin sheath lipids)
16,17
; downregulation of
Erk1/2 and upregulation of myelin basic protein
18
; increased
synthesis of myelinotrophic cytokines and growth factors, such
as IL-6 and EGF
19
; upregulation of neurotrophic gene fac-
tors
20
; and regulation of normal prion protein concentration
in the central nervous system.
21
Vitamin B
12
Deficiency: Anemia,
Neuropathy, and Myelopathy
Vitamin B
12
deficiency is a significant health concern in the
United States; it is estimated that 5%to 40%of the elderly
population have low serum B
12
levels.
4,22-24
Due to enterohe-
patic circulation and kidney reabsorption, humans have exten-
sive stores of B
12
and require several years of inadequate intake
to present with a clinical deficiency. As a result, with the
exception of unsupplemented populations of vegans, B
12
defi-
ciency occurs primarily through gastrointestinal malabsorp-
tion.
11,25
The most direct measurement of B
12
status is the
measurement of total serum B
12
. Laboratory ranges for normal
(>221 pmol/L), low (148-221 pmol/L), and acute deficiency
(<148 pmol/L) have been established and are used in most
clinical settings.
22
However, a major limitation of this assay
is that it assesses total circulating B
12
, about 80%of which is
bound to haptocorrin, a transcobalamin protein, and not bioa-
vailable.
25
Furthermore, a number of studies have shown that
serum B
12
does not reliably represent levels of cellular B
12
.As
a result, assessing serum B
12
alone does not allow for an accurate
diagnosis of deficiency.
25
A more effective method of diagnosis
is to use serum B
12
measurements in conjunction with other
biomarkers, namely, homocysteine (Hcy), methylmalonic acid
Figure 1. Vitamin B
12
coenzyme function. B
12
acts as a coenzyme in
the conversion of homocysteine to methionine in the cytosol, and the
conversion of methylmalonyl-CoA to succinyl-CoA in the mitochon-
drion. The cytoplasmic reaction requires folate, as the methyl group
that is added to homocysteine is removed from 5-methyl tetrahy-
drofolate. Tetrahydrofolate is a precursor in the synthetic pathway for
purines and pyrimidines, while succinyl-CoA enters the Krebs cycle
and is important for lipid and carbohydrate synthesis. Reprinted with
permission from Springer: Nature Reviews Gastroenterology and Hepa-
tology (Nielsen et al
11
).
2Global Spine Journal
(MMA), and holo-transcobalamin (holo-TC). Hcy and MMA
accumulation occurs as a result of inactivation of the 2 B
12
-
dependent enzymes, methionine synthase and methylmalonyl-
CoA mutase, respectively. Most studies set the upper limit of
normal plasma Hcy to 15 mmol/L; higher levels are indicative
of a nutritional deficiency.
26
However, since the conversion of
Hcy to methionine via methionine synthase also depends on
the availability of folate, nutritional deficiencies in either
folate or B
12
could result in increased levels of Hcy. MMA,
on the other hand, is not affected by other vitamins and is
therefore considered a more specific biomarker of B
12
defi-
ciency. Serum levels of MMA that are greater than 260 nmol/
L indicate an elevated reading
26
(Table1).Notably,certain
pathologies such as renal dysfunction may also present with
increased levels of MMA; as a result, the use of this marker in
elderly patients with renal disease should be done cau-
tiously.
27
Last, Holo-TC, in contrast to haptocorrin, is the
readily bioavailable form of B
12
transport, and is therefore a
more accurate biomarker of B
12
status. The normal range of
holo-TC is 20 to 125 pmol/L.
28
An algorithm for the diagnosis
of B
12
deficiency using these 3 biomarkers in addition to
serum B
12
was presented by Hannibal et al.
25
The Schilling test, an assay for pernicious anemia in which
radiolabeled vitamin B
12
is ingested and its excretion measured
in urine, is now rarely used in the United States. Two studies
have shown that elevated levels of Hcy and MMA were detect-
able in 15%to 33%of patients with normal Schilling tests,
indicating the increased specificity of laboratory measurements
in diagnosing B
12
deficiency.
29,30
Magnetic resonance imaging
(MRI) is not normally indicated for patients with B
12
deficiency,
but some reports have noted characteristic V-shaped hyperinten-
sity on T2-imaging when present in the cervical cord and
“bumbell” or bilateral nodular shape when present in the thor-
acic cord in patients with severe myelopathy
31,32
(Figure 2).
The clinical presentations of B
12
deficiency include megalo-
blastic anemia and neurological deficits. Megaloblastic anemia
is characterized by enlarged red blood cell precursors with asyn-
chronous maturation of the nucleus and cytoplasm. The clinical
picture of megaloblastic anemia develops slowly, and symptoms
include weakness, palpitations, dyspnea on exertion, fatigue,
light-headedness, jaundice, and shortness of breath. These symp-
toms typically do not arise until the anemia is quite severe, as
cardiopulmonary adaptations can alleviate hypoxia.
33
Common neurological symptoms include myelopathy,
neuropathy, and, less frequently, optic nerve atrophy.
12
The
best characterized form of myelopathy is known as subacute
combined degeneration (SACD). SACD is caused by damage
to dorsal and lateral columns and is characterized by sym-
metric dysesthesia, abnormal proprioception, loss of vibratory
sensation, positive Romberg sign, and spastic paraparesis or
tetraparesis. Oftentimes, patients initially report sensory loss,
presenting as lower limb paresthesia associated with ataxia. In
late-stage disease, lateral corticospinal tracts can be involved,
leading to impairment of fine motor function and abnormal
reflexes.
34
Furthermore, a minority of patients present with
autonomic disturbances, including bladder and erectile
dysfunction.
35
Peripheral neuropathy is seen in approximately 25%of
patients with B
12
deficiency.
5
Symptoms include paresthesias,
impaired sensation in a “glove and stocking” distribution, pain-
ful burning sensations, and muscle wasting.
36,37
Occasionally,
adult patients with B
12
deficiency will present with optic neu-
ropathy, characterized by symmetric, painless, and progressive
visual loss. Ophthalmologic findings include central and cen-
trocecal scotomas.
35
Although hematologic signs often precede neurological
symptoms, neurological symptoms may be the primary mani-
festation of B
12
deficiency in some patients. For example, stud-
ies by Lindenbaum et al
38
and Healton et al
5
showed that up to
28%of patients with neuropsychiatric symptoms of B
12
defi-
ciency can present with normal mean corpuscular volume
(MCV), hematocrit (HCT), or both. However, although HCT
and MCV were normal in these reports, other hematological
signs such as neutrophil hypersegmentation were found to be
abnormal on inspection of peripheral blood smear.
5,38,39
There
have been reports of B
12
-deficient patients with neurological
symptoms and normal MCV, HCT, peripheral blood smear,
and Hcy levels, although this is quite rare.
40
Table 1. Diagnostic Parameters, References Ranges, and Potential
Confounding Factors for Assessment of Vitamin B
12
Deficiency
a
.
Parameter Reference Range Confounding Factors
B
12
>148 pmol/L Renal insufficiency (")
Hcy <15 mmol/L Renal insufficiency(")
Folate deficiency (")
Vitamin B
6
deficiency (")
MMA <260 nmol/L Renal insufficiency (")
Age (")
Intestinal bacterial overgrowth (")
Abbreviations: B
12
, vitamin B
12
; Hcy, homocysteine; MMA, methylmalonic acid.
a
Adapted from Hermann W, Obeid R. Cobalamin deficiency. In: Stranger O, ed.
Water Soluble Vitamins: Clinical Research and Future Application. Berlin, Germany:
Springer; 2012:301-322.
Figure 2. Axial T2-wieghted MRI of a patients with degenerative
cervical myelopathy and concomitant B
12
deficiency. On the left, a
characteristic reverse V-shaped hyperintensity is visible in the pos-
terior column (arrow). On the right significant spinal cord compres-
sion is demonstrated. Reprinted with permission from Elsevier: The
Spine Journal (Miyazaki et al
8
).
Nouri et al 3
Pathophysiology of DCM
There are a number of pathophysiological factors that result in
DCM: (1) static compression of the spinal cord, (2) dynamic
injury resulting from mobile degenerative cervical spine ele-
ments compressing the cord, and (3) tethering of the cord or
altered cord tension due to changes in the cervical spine align-
ment or cord compression.
1,41
These various mechanisms con-
tribute to spinal cord dysfunction by causing reversible and
irreversible injury to neuronal tissue. Reversible tissue injury
includes demyelination, Wallerian degeneration, edema, and
inflammatory changes. Whereas irreversible injury manifests
after frank loss of neuronal tissue has occurred.
42
The under-
lying pathobiological mechanisms causing neuronal death are
multifold. Mechanical compression initiates an inflammatory
process that can be further exacerbated by disruption of blood
flow and the blood-spinal cord barrier. Disruption of blood
supply may result in variable degrees of cellular injury. This
may be caused by direct blood vessel compression, as well as
increased spinal cord tension, which may not only cause
stretching of nerve fibers but also flattening of blood ves-
sels.
1,41,43
The degree of injury is highly variable and is
affected by the degree of cord compression, the number of
levels involved, and whether the compression is static or
dynamic. Consequently, the natural history and clinical mani-
festations of DCM are highly variable. Clinically, patients typi-
cally present with problems using items with their hands and/or
problems with their gait.
3
In more severe cases, urine incon-
tinence may also manifest. While diagnosis of DCM is based
on clinical examination, imaging evidence of spinal cord com-
pression or cord tethering on MRI is required to confirm the
diagnosis (Table 2).
On MRI, patients typically present with one or more levels
of cord compression. The direction of the compressive force
typically originates from the anterior or anterior and posterior
(pincer effect). In most, but not all patients, T2-weighted
hyperintensity will approximate the site of cord compression,
representing nonspecific inflammatory changes ranging from
edema to cavitation depending on the signal intensity and
appearance.
42
T1-weighted hypointensity changes can occur
in approximately one fifth of DCM patients at the site of
T2-weighted hyperintensity, indicating cavitation and that
frank neuronal tissue loss has occurred.
42
Rationale for Investigating B
12
Deficiency
in DCM
On the Basis of Epidemiology
Both B
12
deficiency and DCM are most prevalent in the
elderly, and with estimates of 20%of B
12
deficiency, even a
proportional prevalence among DCM patients would indicate a
high rate of potential deficiency among the DCM population.
Clinically, reports of patients with known B
12
deficiency and
superimposed DCM have shown that patients appear with a
degree of neurological impairment out of proportion of what
would be expected based on imaging, and that treatment with
B
12
can optimize neurological recovery.
7-9
In other case
reports, patients with suspected diagnosis of DCM, but under-
lying SACD, experienced a resolution of symptoms after B
12
administration.
44-46
These findings have the following impli-
cations: patients with definitive DCM and concomitant B
12
deficiency require treatment for both conditions to optimize
neurological recovery, but care should be taken for patients
with mild cord compression and possible B
12
deficiency prior
to surgical treatment, as cord compression may be a false pos-
itive finding and treatment with B
12
may resolve symptoms.
A high index of suspicion for B
12
deficiency among DCM
patients should be placed among patient with history of gastro-
intestinal resection or comorbidities, such as atrophic gastritis
and irritable bowel disease, which may be an underlying cause
for unrecognized B
12
deficiency.
47
When suspected, laboratory
findings of megaloblastic anemia, low B
12
levels, and high
levels of homocysteine may be helpful.
On the Basis of Pathophysiology
The average patient receiving surgical treatment for DCM has
moderate to severe neurological impairment at presentation,
48
and nonoperative management has been shown to result in
neurological deterioration in 20%to 62%of patients at 3 to
6 years of follow-up.
49
When surgical treatment is undertaken,
the average patient experiences meaningful neurological recov-
ery.
48
However, not all patients experience significant
improvement, others maintain their preoperative levels of func-
tion, and less commonly, patients experience neurological
deterioration. The occurrence of suboptimal recovery can be
expected since it is known that DCM can have elements of
reversible and irreversible neuroanatomic changes—the bal-
ance of which influences the degree of functional recovery.
50
Approximately 80%of patients with DCM present with either
no significant changes or only T2-weighted hyperintensity sig-
nal on conventional MRI,
50
and these MRI findings suggest
that most patients have a large component of nonspecific
Table 2. Clinical Findings That May Appear on Examination in
Patients With DCM.
Clinical Symptoms Clinical Signs MRI Findings
Corticospinal motor
deficits
Hoffmann sign Cord compression
Numbness of hands L’Hermitte’s
phenomenon
Cord flattening
Atrophy of hand
muscles
Ankle clonus Cord torsion
Hyperreflexia and
spasticity
Babinski sign T2WI Cord
hyperintensity
Gait disturbances
(broad based)
Romberg sign T1WI cord
hypointensity
Clumsy hands
Weakness
Paraesthesia
Urinary incontinence
(in severe cases)
4Global Spine Journal
inflammatory changes, including Wallerian degeneration, that
are potentially reversible. Reversible neurological function,
however, is partly attributable to remyelination, which requires
B
12
.
10
While there have been no direct clinical studies looking
at B
12
and DCM, basic science research has shown that per-
ipheral nerve crush injury alter the levels of B
12
at the nerve,
51
and it has been suggested that B
12
with dexamethasone or
nonsteroidal anti-inflammatory drugs can be used to treat
peripheral nerve crush injury and reduce Wallerian
degeneration.
52,53
Sun et al
52
suggested that upregulation of
brain-derived neurotrophic factor (BDNF) may be a mechan-
ism of action for this improvement.
Vitamin B
12
may also have a role in attenuating neurologi-
cal deterioration after surgery for DCM. While the occurrence
of deterioration is infrequent, not clearly understood, and dif-
ficult to anticipate, it has been suggested that reperfusion injury
and subsequent glutamate excitotoxicity after cord decompres-
sion may be responsible for this phenomenon.
54,55
It has been
shown that treatment with a combination of B-vitamins
(including B
1
,B
6
,B
12
) can reduce neuronal injury,
56
and it has
been suggested that B
12
potentially depresses glutamate-
induced neurotoxicity.
57
These studies suggest that in addition
to raising B
12
levels in those with suboptimal levels, higher
levels may also provide a therapeutic benefit to patients receiv-
ing surgery for DCM. This however remains speculative.
On the Basis of Preoperative Planning
An intriguing and clinical relationship between B
12
and myelo-
pathy that may be highly relevant for patients with DCM is also
interaction of nitrous oxide (N
2
O) during anesthesia with peri-
operative myelopathy development.
47
N
2
O irreversibly oxides
the cobalt ion at the center of B
12
, and impedes its crucial
cofactor function for methionine synthetase. This enzyme is
required for the formation of tetrahydrofolate (THF) and
methionine. THF is involved in thymidine synthesis and DNA
production, while methionine is required for the methylation of
myelin sheath phospholipids.
58
Consequently, patients with
already low levels of B
12
or methylene-tetrahydrofolate-
reductase deficiency are particularly at risk for perioperative
myelopathy due to N
2
O administration.
58
Although rare and an
underrecognized phenomenon, there have been numerous case
reports describing the development of SACD after anesthesia
with N
2
O administration.
47,59-62
Given that N
2
O can be used
during spine surgery, this points to the necessity of routinely
monitoring B
12
levels in patients with DCM to optimize surgi-
cal outcomes and prevent perioperative or postoperative neu-
rological deficit development. Recognition of this phenomenon
is important, as intramuscular injection of B
12
has been shown
to rapidly reverse SACD symptoms.
47
Conclusion
It is clear that B
12
is necessary for maintaining spinal cord
function, and deficiency can result in SACD. Given the high
prevalence of clinical and subclinical B
12
deficiency in the
elderly, the role of B
12
in myelination, and B
12
deficiency as
a differential diagnosis of DCM, there is considerable rationale
to conduct routine assessment of B
12
levels in patients with
DCM. Going forward, it will be necessary to assess additional
aspects of this relationship, including (1) whether DCM
patients with B
12
deficiency present differently on clinical
exam, (2) whether patients with B
12
deficiency and DCM have
suboptimal surgical outcomes, (3) whether patients with defi-
ciency who are supplemented with B
12
achieve optimal out-
comes, and (4) whether increasing B
12
levels in patients with
no deficiency improves surgical outcomes more than other-
wise expected. Since preoperative assessment includes rou-
tine blood work, this additional diagnostic measurement
would not unnecessarily burden the patient or substantially
increase costs. In the event that a patient appears to have
suboptimal levels or deficiency, treatment with B
12
would not
be costly, is unlikely to adversely affect the patient, and may
optimize surgical outcome. Further studies in this area are
needed and would be highly feasible given the fact that B
12
is an essential vitamin, cheap, and readily accessible. We
intend to investigate this relationship and will seek to report
on how to incorporate B
12
assessment into the clinical man-
agement of patients with DCM.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Dr Sciubba is a consultant for Medtronic, Depuy-Synthes,
Stryker, Nuvasive, and K2M. The other authors have no conflicts of
interest to declare.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Aria Nouri, MD, MSc http://orcid.org/0000-0002-4965-3059
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