Nervous System and Cobalamin Deficiency

Abstract

Cobalamin or Vitamin B12 deficiency is common and underdiagnosed in adults. It should be looked for, in addition to the classical hematological presentation, in patients with suggestive neurological signs such ataxia, paresthesia or cognitive impairment, particularly in populations at risk, such as elderly, alcoholic, vegetarian or malnourished. The main causes of this deficiency are the food cobalamin malabsorption syndrome, Biermer's disease and, less frequently, intestinal malabsorption and lack of intake. The understanding of the metabolism of this vitamin, not to mention the mechanism of neurological damage, is essential but still incomplete. However, current knowledge makes it possible to develop diagnostic and therapeutic approaches. The diagnosis is retained either by a biochemical test expressing the decrease in vitamin B12 stores, or retrospectively after improvement under substitution treatment based on vitamin B12 supplementation.

Full text

Citation: Khellaf S, Boulefkhad A, Boudraa B, Semra H, Serradj F, et al. (2019) Nervous system and Cobalamin deciency. Curr Res
Psychiatry Brain Disord: CRPBD-100005
1Volume 2018; Issue 01
Current Research in
Psychiatry and Brain Disorders
Review Article Khellaf S, et al. Curr Res Psychiatry Brain Disord: CRPBD-100005
Nervous System and Cobalamin Deciency
Khellaf S1*, Boulefkhad A2, Boudraa B2, Semra H2, Serradj F2, Boumala N2, Benhamada S2, Fekraoui BS2, Si Y2, Zahem AM2,
Hamri A2 and Bouali F1
1Internal Medicine department, Khelil Amrane University Hospital Center, 06000, Bejaia, Algeria
2Neurology department, Dr Benbadis University Hospital Center, 25000, Constantine, Algeria
*Corresponding author: Khellaf S, Internal Medicine department, Khelil Amrane University Hospital Center, 06000, Bejaia, Algeria,
Tel: +213795082200; E-mail: saddek.khellaf@gmail.com
Citation: Khellaf S, Boulefkhad A, Boudraa B, Semra H, Serradj F, et al. (2019) Nervous system and Cobalamin deciency. Curr Res
Psychiatry Brain Disord: CRPBD-100005
Received date: 05 December, 2019; Accepted date: 12 December, 2019; Published date: 19 December, 2019
Volume 2019; Issue 01
1
Abstract
Cobalamin or Vitamin B12 deciency is common and underdiagnosed in adults. It should be looked for, in addition to the
classical hematological presentation, in patients with suggestive neurological signs such ataxia, paresthesia or cognitive impairment,
particularly in populations at risk, such as elderly, alcoholic, vegetarian or malnourished. The main causes of this deciency are the
food cobalamin malabsorption syndrome, Biermer’s disease and, less frequently, intestinal malabsorption and lack of intake. The
understanding of the metabolism of this vitamin, not to mention the mechanism of neurological damage, is essential but still incomplete.
However, current knowledge makes it possible to develop diagnostic and therapeutic approaches. The diagnosis is retained either by
a biochemical test expressing the decrease in vitamin B12 stores, or retrospectively after improvement under substitution treatment
based on vitamin B12 supplementation.
Keywords: Anemia; Cobalamin; Nervous System Diseases;
Subacute Combined Degeneration; Vitamin B12
Introduction
Cobalamin or vitamin B12 deciency is dened according
to several different denitions in the absence of standardized and
reproducible criteria, see (Table 1) [1]. This deciency is quite
common among adults and often underdiagnosed because of its
insidious clinical presentations; its prevalence would be about 15
to 20% in the general population [2], ranging between 5 and 60%
depending on the denition used, it is higher among the elderly
(30 to 40%) [3]. Although the most suggestive clinical picture is
Subacute Combined Degeneration (SCD), many cases of deciency
have little or no symptoms. requiring the practitioner to have a
thorough knowledge of various vitamin B12 deciency symptoms
to best prevent the potentially serious consequences.
Vitamin B12 < 200 pg/mL (or 150 pmol /L), twice
Vitamin B12 < 160 pg / ml
Vitamin B12 < 200μg/ml
and Total Homocysteine < 13μmol /L or Methyl Malonic > 0.4μmol
/ L
(without renal insufciency or folate and vitamin B6 deciency nor a
mutant of methyltetrahydrofolate reductase).
Table 1: Different proposals for vitamin B12 deciency denition
[1].
Metabolism
Food intakes and reserves: Made exclusively from animal
products (offal, especially beef, sh, eggs and dairy products),
the daily intake of vitamin B12 varies between 5 and 7 µg for

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Citation: Khellaf S, Boulefkhad A, Boudraa B, Semra H, Serradj F, et al. (2019) Nervous system and Cobalamin deciency. Curr Res
Psychiatry Brain Disord: CRPBD-100005
Volume 2019; Issue 01
3
a recommended dose of 2.5 to 3 µg / d [4, 5]. Mainly stored in
the liver, its reserves are estimated between 2 and 5 mg, which
corresponds to about 1000 days of intake; this reserve contributes
to the diagnostic difculty of the serum cobalamin assay and
explains the delay between the intake decit and the beginning of
the cell decit [6].
Digestion and absorption: Intestinal absorption of vitamin B12
is performed through two separate systems, which highlight the
crucial roles of inadequacy, particularly the role of gastric and
exogenous pancreatic functions, as well as the integrity of the ileal
mucosa [6].
Intrinsic Factor (IF) Dependent System: Ingested cobalamin
detaches itself from dietary proteins in the stomach under the
action of gastric juice and pepsin, then it binds to a protein carrier
called haptocorrine, secreted by the salivary glands and gastric
cells. Then, in contact with the biliary and pancreatic secretions,
this complex is lysed in the duodenum. It is at this level that bile
secretion of the enterohepatic cycle occurs. Finally, IF secreted by
gastric cells binds to vitamin B12, unlike haptocorrine, IF protects
cobalamin from ileal bacterial catabolism and binds specically
to the terminal ileal cell by a receptor called cubuline. It follows a
calcium-dependent mechanism of internalization by endocytosis.
It is clear that this specic and efcient absorption system is
however saturable [6].
IF independent system: Allows the diffusional absorption of 1 to
5% of the ingested dose of vitamin B12, it is insufcient to provide
the body with the daily required dose during a balanced diet, but it
is non-saturable, allowing recourse to oral substitution [6].
Transport: Transcobalamin I, II and III participate in the
serum transport of vitamin B12. Only Holotranscobalamin II
(Transcobalamin) seems to have physiologically an important role,
thus allowing vitamin intake to the cell metabolism pathways. That
is why the serum dosage of Transcobalamin is more accurate than
the overall dosage of vitamin B12 [7].
In the cytoplasm: Vitamin B12 mainly acts as a coenzyme in the
form of methyl-cobalamin catalyzing the action of methionine
synthetase allowing the conversion of homocysteine (HC) to
methionine, but also the conversion of methyl-tetrahydrofolate to
tetrahydrofolate (THF) which can be used in the synthesis of purine
and pyrimidine bases. As a result, methyl-cobalamin deciency
will cause methionine deciency with an increase in HC, thus
blocking DNA replication by decreasing THF, leading to a nucleo-
cytoplasmic maturation asynchronism expressing megaloblastosis
on myelogram [8, 9].
In the mitochondria: In the form of intra-mitochondrial
adenosyl-B12 which allows the conversion of propionyl-CoA to
methylmalonyl-CoA and nally succinyl-CoA, an intermediate of
the Krebs cycle. Whose consequences of deciency are, in addition
to succinyl CoA deciency, the accumulation of methyl malonic
acid (MMA) [8, 9].
MMA and HC, thus constitute two metabolic markers which
will increase in case of cellular deciency in vitamin B12.
Elimination: Elimination of serum cobalamin excess is renal
[10]. Serum levels are modulated by liver reserve utilization, renal
tubular reabsorption and enterohepatic circulation [10, 11].
Pathophysiology: The neurological signs related to vitamin B12
deciency are linked to complex and still imperfectly understood
mechanisms. they would be due to a disorder of the methylation
of the myelin sheaths with abnormalities of the nerve conduction,
either by decrease of methionine, and thus of its metabolite
S-adenosyl methionine (SAM) which participates in basic myelin
protein composition, or by accumulation of methylmalonic acid,
which is a toxic fatty acid for myelin [12-14].
More recent studies offer a very different explanation; the
clinical and histological manifestations of B12 deciency may
be the result of a regulatory phenomenon that will amplify the
neurotoxic effect of many cytokines but also negatively affect
the restorative action of certain neurotrophic factors [15, 16].
The resultant hyper homocysteinemia would be an independent
cerebrovascular risk factor, associated with atherosclerosis and
cerebrovascular accidents. However, the link is not yet well
documented and remains controversial [1, 17]
In general anesthesia, patients with sufcient body reserves
of vitamin B12 may maintain cellular functions after exposure to
nitrous oxide (N2). On the other hand, patients with limited or low
vitamin B12 reserves, oxidation of the core of vitamin B12 by
nitrous oxide (N2O) may be sufcient to render methyl cobalamin
inactive, to inhibit the conversion of HC to methionine and exhaust
the contribution of SAM [18, 19].
Finally, neurological disorders sometimes appear after
insufcient replacement therapy or following folate treatment.
This is the theory of “folate trap” where the contribution of folate
mobilize the last stocks of vitamin B12 in favor of the hematological
line rather than neurological, thus maintaining the synthesis of
nucleic acids to the detriment of the formation of methionine and
therefore myelin [20].
Etiologies
Etiologies of vitamin B12 deciency are intimately related
to the stages of its digestion and its metabolism (Figure 1). The
main causes of vitamin B12 deciency in adults are represented
by the Food-cobalamin malabsorption syndrome (60%), Biermer
disease (18%), intestinal malabsorption (6%) and lack of intake
(2%) [1, 21].

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Citation: Khellaf S, Boulefkhad A, Boudraa B, Semra H, Serradj F, et al. (2019) Nervous system and Cobalamin deciency. Curr Res
Psychiatry Brain Disord: CRPBD-100005
Volume 2019; Issue 01
Figure 1: Etiologies of vitamin B12 deciency corresponding to the different stages of its metabolism according [1,16].
Lack of intake: Outside a strict exclusion regime like vegan, or in
an elderly or already malnourished person, vitamin B12 deciency
is extremely rare in healthy adults [1].
Absorption abnormalities: The most common etiology of
cobalamin malabsorption in adults is decits in exocrine pancreatic
function following chronic pancreatitis (usually alcoholic) or after
pancreatectomy [22]. Other causes include gastrectomies and
surgical resection of the terminal small bowel (<5%), and even
more rarely (<2%): Crohn’s disease, lymphoma, tuberculosis,
amyloidosis, scleroderma, celiac disease; taking colchicine (by
inhibiting the expression of cubulin at the apical pole of the
enterocyte cell) [23] or cholestyramine [1].
Biermer disease: It is an autoimmune disease affecting the
gastric mucosa, especially fundic (classic autoimmune A-type
atrophic gastritis), and by the presence of various antibodies (AB),
especially in the blood plasma and gastric secretions. AB anti FI
(sensitivity: 50%, specicity:> 98%) and AB anti gastric parietal
cells (sensitivity:> 90%, specicity: 50%) [24]. This disease is
further characterized by the presence of a malabsorption of B12
corrected by the addition of FI during the Schilling test (specicity>
99%) which is no longer available [1]. Clinically, one of the
particularities of Biermer’s disease is to be associated with many
autoimmune disorders: vitiligo, dysthyroidism, Addison’s disease,
Sjögren’s syndrome, etc. Exceptional associations with chronic
hepatitis C (treated with interferon alfa) have also been reported
[1, 24]. Once the diagnosis is made, gastric broscopy with fundic
biopsies remains systematic and serves as a reference examination
for subsequent systematic follow-up (possible complication with
neoplasia).
Food-cobalamin malabsorption: This syndrome is characterized
by an inability to release B12 from food proteins and / or intestinal
transport proteins, especially in case of hypochlorhydria while
the absorption of B12 “unbound” is normal. In practice, the non-
availability of Schilling tests (standard and modied) makes
the Food-cobalamin malabsorption syndrome a diagnosis of
elimination which rests on two aspects:
Three criteria must be present: a serum vitamin B12 concentration
of less than 200 μg/ML, the absence of intrinsic factor antibodies
(or normal standard Schilling test with abnormal “modied”
Schilling test) and nally the absence of nutritional vitamin B12
deciency (intake > 2 μg per day) [1, 21].
The existence of a predisposing factor for this deciency: such
as atrophic gastritis, chronic infection with Helicobacter pylori,
gastrectomy, gastric bypass, vagotomy; Exocrine pancreatic
insufciency (chronic ethylism, cystic brosis); Taking anti-
acids (antihistamines 2 or proton pump inhibitors) or biguanides
(metformin); microbial overgrowth Sjögren’s syndrome,
Scleroderma, age-related “Idiopathic” deciency or homozygous
haptocorin congenital deciency [1, 25, 21].

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Citation: Khellaf S, Boulefkhad A, Boudraa B, Semra H, Serradj F, et al. (2019) Nervous system and Cobalamin deciency. Curr Res
Psychiatry Brain Disord: CRPBD-100005
Volume 2019; Issue 01
5
Figure 2: Neuroimaging aspects of Cobalamin deciency [9, 49, 60].
A and B: T2 Medullary MRI showing the V-inverted sign as a hypersignal of the posterior cords on axial (A) and an extended medullary
cervical hypersignal on sagittal (B) [60].
C and D: T2 FLAIR Brain MRI axial sections. Showing symmetrical hypersignals of the dorsolateral brainstem regions (C) [49]. And
diffuse and symmetrical hypersignal of the periventricular white matter in a 45-year-old woman with progressive cognitive decline (D)
[9].
Iatrogenic causes: Nitrogen protoxide (NO) used in anesthesia
is a strong oxidizing agent that irreversibly oxidizes the cobalt
atom of vitamin B12, rendering methyl-cobalamin inactive
[19]. Similarly, vitamin C supplementation is reported to induce
cobalamin deciency by a similar mechanism [26, 27]. Finally,
when the patient’s prescription mentions a folate substitution.
Without a vitamin B12 substitution, the mechanism of the
folic trap must be strongly evoked in the presence of any compatible
clinical sign, despite the absence of anemia or macrocytosis [28,
29].
Hereditary diseases of vitamin B12 metabolism: These decits
are neonatal revelation and usually do not affect adults, such as
deciency in IF (in the form of juvenile and familial forms of
Biermer disease), in cubuline (as in Imerslund-Gräsbeck disease)
or in transcobalamin II, and exceptionally decits in intracellular
enzymes involved in the biosynthesis of the active forms of
cobalamins: adenosyl- and methyl-cobalamin [1].
Clinical presentations
Cobalamin deciency is very common in specic groups of
the population. In fact, the risk of vitamin B12 deciency is high
among vegetarians, malnourished, infants, pregnant and lactating
mothers, as well as among the elderly and institutionalized persons
[30, 3]. This deciency can take several years to reveal itself.
Twenty-six to sixty-six percent of patients develop neurological
and extra neurological manifestations that may be present even in
the absence of anemia. The main manifestations are the Subacute
Combined Degeneration (SCD), peripheral neuropathies,
dysautonomic disorders, dementia and other rarer disorders [31,
32]. These different syndromes can be associated in the same
patient, including SCD and peripheral neuropathies in about 50%
of cases [33].
Subacute Combined Degeneration: Represents the most classic
presentation, though rarely seen today [21]. It associates posterior
cordial syndrome (PCS) and pyramidal syndrome. The rst signs

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Citation: Khellaf S, Boulefkhad A, Boudraa B, Semra H, Serradj F, et al. (2019) Nervous system and Cobalamin deciency. Curr Res
Psychiatry Brain Disord: CRPBD-100005
Volume 2019; Issue 01
are those of the PCS, with paresthesia (tingling, numbness and
pain) predominating in the lower limbs and sometimes in the trunk
and upper limbs, a sign of Lhermitte, a proprioceptive ataxia with
sometimes isolated apallesthesia. This PCS in extension is followed
by the occurrence of a pyramidal syndrome manifested by tetra or
paraparesis, spastic hypertonia especially in the lower limbs, vivid
tendinous reexes and a Babinski sign. It is sometimes difcult
to clinically distinguish these 2 syndromes, the contribution of
evoked potentials and medullary magnetic resonance imaging
(MRI) is of great help in this case [34].
peripheral neuropathies: They account for 30 to 50% of the
neurological complications of B12 deciency [31, 35, 34, 32]
and are present in 6-8% of cases in cohort studies for all causes
of neuropathies combined [33, 36]. These are mainly sensory
neuropathies, of moderate intensity, acute or subacute, non-
ataxiant, symmetrical and length dependent. Sometimes they are
sensory-motor polyneuritis, electrically axonal polyneuropathy,
rarely demyelinating or mixed, usually dominated by paresthesia
and deep sensibility disorders. According to Franques et al. [Table
2], Several contextual elements with acute or subacute sensory
neuropathy and independently of biological markers, should evoke
a cobalamin deciency in order to start substitution therapy as soon
as possible. case of effectiveness will be the strongest argument in
favor of this hypothesis [37].
Context
Elderly
Undernutrition, vegetarianism
Isolated prescription of folic acid without vitamin
B12
General anesthesia by nitrous oxide
Pancreatic insufciency
Crohn’s disease
Prescription of proton pump inhibitor or Biguanides
Syndrome
Axonal neuropathy, sensitive, acute or subacute
Subacute Combined Degeneration
Biological
disorder
Normo-, macro- or microcytic anemia (iron
deciency)
Signicant elevation of homocysteinemia (not very
specic)
Elevation of serum or urinary methyl malonic acid
Biermer’s autoantibodies or hypergastrinemia
Therapeutic
response
Clinical improvement within 3 months after the
introduction of 2000 mg / day of oral vitamin B12.
Table 2: Elements for vitamin B12 deciency neuropathy despite
normal serum assay; according to [37].
Dysautonomic disorders: Dysautonomia is not uncommon
during B12 deciency as it is estimated at 22% of cases and it is
inaugural once in two [38]. It is mainly orthostatic hypotension or
genitourinary sphincter disorders [39].
Other neurological signs: Cobalamin deciency could be
the most commonly organic disease associated with dementia.
Nearly 40% of patients with dementia, Alzheimer’s disease in
particular, have low serum vitamin B12 levels [40]. In France
the high health authority recommends the dosage of vitamin B12
in the balance sheet of Alzheimer’s disease [41]. Other authors
propose to extend these recommendations to the assessment of
all dementias. However, in the work of Andres et al., 30% of
neuropsychiatric manifestations do not respond to well-conducted
cobalamin therapy. [25, 1]. Painful spinothalamic syndrome,
cerebellar ataxia or retrobulbar optic neuritis are also possible.
Other manifestations, such as Parkinson syndrome, depression,
manic states, psychoses, obsessive-compulsive disorder and sleep
disorders, have been described, but the causal relationship has not
yet been demonstrated [21].
Extra neurological manifestations
Manifestations Certain link Probable link
Hematological
Megaloblastic anemia -
thrombocytopenia -
leukopenia -
pancytopenia -
Intramedullary haemolysis -
Thrombotic
Pseudomicroangiopathy
(rare)
-
Epithelial
Hunter’s glossite Digestive
disorders
- Vaginal atrophy
-Urinary tract
infections
-Cutaneous
ulcers
Vascular
Deep vein thrombosis Atherosclerosis
Others
- low fertility
-Abortions
Table 3: shows the main events reported in the literature [21].

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Citation: Khellaf S, Boulefkhad A, Boudraa B, Semra H, Serradj F, et al. (2019) Nervous system and Cobalamin deciency. Curr Res
Psychiatry Brain Disord: CRPBD-100005
Volume 2019; Issue 01
7
Complementary exams
Biology
Blood Formula Count: Vitamin B12 deciency is commonly
responsible for megaloblastic anemia, characterized in its historical
and booklet form by frank macrocytic anemia (mean corpuscular
volume, MCV, greater than 110 μm3), normochromic, arterenative
with megaloblastosis medullary (giving a «Blue marrow»).
Leukopenia and moderate thrombocytopenia are associated [1, 42,
43]. However, the haematological picture of vitamin B12 deciency
is most often incomplete, sometimes even severe (deep anemia <6
g / dl, pancytopenia) that may be life-threatening, or even atypical
(haemolytic anemia, pseudo thrombotic microangiopathies) [12].
Dosage of Vitamin B12: As already mentioned, there are currently
no formal biological criteria for the diagnosis of vitamin B12
deciency. Nevertheless, most recent studies apply the criteria
listed in [Table 1] to diagnose vitamin B12 deciency [1]. Dosage
of cyanocobalamin (cobalamin bound to transport proteins) reects
the total level of vitamin B12 circulating in the blood. Only the
fraction bound to transcobalamin II, called transcobalamin, about
6 to 20%, is bioavailable and therefore biologically active. The
disadvantages of this method are the variations of the reference
intervals depending on the different immunoassays used. False
positives are possible if haptocorin is decreased (pregnancy) and
false negatives are possible when it is increased (myeloproliferative
neoplasia, hepatoma).
Dosage of methyl malonic acid:More sensitive than vitamin B12
with sensitivity close to 100%, but its specicity is also subject to
debate. While it also increases in case of kidney failure, MMA is
currently considered in research as the reference value. Its high
cost and limited availability make it not recommended in care
practice as rst intension [44].
Determination of homocysteine (HC): Increased in case of
vitamin B12 deciency, this marker is considered more sensitive
than the dosage of vitamin B12, however with a bad specicity.
False positives are possible during deciencies in folic acid
or vitamin B6. In addition, HC rate is increased in cases of
renal failure, active smoking, alcohol consumption and coffee
consumption [45].
Dosage of Transcobalamin: It is the Holotranscobalamin II-B12
complex, and represents the bioavailable part of vitamin B12. Its
values vary little during a day (measurement can be done fasting or
not) but faster than other biomarkers after a change in vitamin B12
intake (from 2 days). It increases in case of renal insufciency,
though to a lesser extent than the MMA and HC and it does not
vary during pregnancy [7].
Normal rate of vitamin B12: Opposing to popular belief, a normal
serum vitamin B12 test does not eliminate a cellular deciency.
In fact, 54% of responders clinically and biologically responding
to cobalamin substitution, had a pre-therapeutic dosage of normal
vitamin B12 [46]. In addition, vitamin B12 may even be increased
or falsely normal in case of deciency in certain situations such as
chronic renal failure, liver diseases, myeloproliferative syndromes
or intestinal colonization by certain bacteria producing vitamin B12
“like” substance [47,48]. Cell metabolites of B12, homocysteinemia
and serum methyl malonic acid can also be taken as the default, as
they are normal in 50 and 25% of cases respectively. Thus, if we
limit ourselves to biological markers, 63% of responder patients
would not be treated [46].
Neuroimaging : MRI may show a posterior cordial hyperintensity
in T2 (Figure 3); classically known by the inverted V sign in
axial section, most often cervicodorsal, associated or not with a
medullary edematous swelling in T1, sometimes interesting the
brainstem [49]. Images of diffuse leuko encephalopathy generally
symmetrical, however totally nonspecic are also described
[9]. The predominance of abnormalities in the white matter and
their nonspecic nature often raise the difculty of differential
diagnoses, including degenerative and /or demyelinating diseases
with bilateral posterior hyperintensity: infectious myelitis,
myocardial infarction, multiple sclerosis (MS), acute disseminated
encephalomyelitis (ADEM), acute transverse myelitis, and copper
deciency myelopathy [52]. However, several observations of
obvious clinical abnormalities with no evidence of detectable
MRI have been reported, which may indicate late radiologic
abnormalities [50, 51].
Figure 3: Diagnostic approach to vitamin B12 deciency [1, 25].
Neurophysiological explorations
Prolonged somatosensory evoked potentials, particularly
by lower limb stimulations indicative of posterior medullary cord
injury, are much more frequently observed than abnormalities of
peripheral sensory conduction strictly speaking [53, 54]. However,
electroneuromyographic (ENMG) results, according to several
studies, favor an axonal sensory involvement in 22 to 70% of
cases, demyelinating in 2 to 17% of cases, mixed in 18 to 67% of
cases [34, 35, 55].
The Diagnostic approach
As shown in (Figure 3), this approach is intended primarily
realistic, especially in the elderly, avoiding invasive or systematic or
even “unnecessary” explorations, such as systematic myelogram or
gastroscopy of principle [1]. Indeed, in front of a neurological and
or extra neurological presentation evoking a cobalamin deciency,
especially in a population at risk (see above). It is desirable to
claim biologically this vitamin B12 deciency, by performing a
determination of vitamin B12 and homocysteine levels.

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Citation: Khellaf S, Boulefkhad A, Boudraa B, Semra H, Serradj F, et al. (2019) Nervous system and Cobalamin deciency. Curr Res
Psychiatry Brain Disord: CRPBD-100005
Volume 2019; Issue 01
Once the clinical or paraclinical picture of vitamin B12
deciency is strongly evoked (Table 1), it will be necessary to start
by looking for clinical and biological stigmas of undernutrition or
malabsorption (weight, albuminemia, dietary survey, diarrhea or
steatorrhea) as well as certain iatrogenic causes (see above) and
start the appropriate etiological and replacement treatments.
If this rst assessment is negative, then Biermer’s disease
should be mentioned, especially in the presence of a eld of
autoimmunity. It will be appropriate in the rst place, to look
for the presence of anti-IF antibodies and gastric parietal cells
serum, elevation of gastrinemia (or chromogranin A). Then and
only at this stage, perform a gastroscopy with systematic biopsies.
Lifetime substitute therapy will be offered if Biermer’s Disease is
conrmed.
Finally, if none of these etiologies is found, the diagnosis
of food-cobalamin malabsorption syndrome will be retained and
treated so, while looking for circumstances or contributing factors
(Table 2) or even retain its “idiopathic” character in case of good
response after one month of oral treatment test. (Figure 3)
Therapeutic management
Currently, there is no precise recommendation regarding
the treatment of Cobalamin deciency neurological disorders.
Although 2000 µg orally is as effective as 1000µg by intramuscular,
even in Biermer disease [56], the effectiveness of oral cobalamin
therapy on neurological manifestations has not been sufciently
documented to date, It is therefore always recommended to use
the parenteral route in this category of patients [21]. whatever the
route of administration, vitamin B12 substitution is not directly
toxic, but there are rare cases of anaphylaxis [57]. Not to mention
that the detection of vitamin B9 and iron deciency must be done
at the time of diagnosis because they are often associated. The
treatment consists of 2 phases :
Charge treatment: Parenteral (subcutaneous or intramuscular),
to bring vitamin B12 to already decient cells and to initiate a
reserve. At the dose of 1000µg / day for 7 days than 1000µg / week
for 1 month. If there is a diagnostic doubt about a vitamin B12
deciency, clinical evaluation can be used after a load treatment as
an additional aid. Sometimes it is enough to treat the cause without
charge treatment to correct the decit.
Maintenance treatment: The aim is to provide the body with the
equivalent of its vitamin B12 needs. At the dose of 1000 µg/month
until correction of the cause or for life in Biermer's disease. In
principle, no biological monitoring is necessary if the compliance
is good. However, it is important to draw attention to the potential
risk of long-term nonobservance and therefore to the need to
discuss the benets and risks of the oral route based on the patient's
prole and ability to adhere to treatment [25].
Evolution
The majority of patients respond within 3 months of
substitution [37], sometimes the state of some patients improves up
to 12 months or even 3 years. The risk of sequelae depends mainly
on the delay in the introduction of vitamin therapy [32]. Thus, 50%
of residual lesions due to axonal loss are reported in late diagnosis
forms [14]. Although complete healing of dementia seems possible
[58], data concerning the evolution of cognitive disorders under
treatment remain controversial [28]. Radiologically, the complete
reversibility of the images is correlated with a cure without
sequelae. However, at the too late stage of axonal degeneration
and gliosis, the lesions are irreversible and then abnormalities in
imaging persist.
Conclusion
Neurological disorders due to cobalamin deciency are
polymorphic and may occur outside any hematological context.
For this reason and independently of the etiology, the dosage of
vitamin B12 is suggested, and if necessary, that of its early markers
such as homocysteine or even methyl-malonic acid, without
justifying a diagnostic delay, and therefore a delay of vitamin
substitution, which represents the main prognostic factor of this
“benign” disease.
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