Review
Involuntary movements due to vitamin B12 deficiency Aaron de Souza1,2, M. W. Moloi1 1
Department of Internal Medicine, University of Botswana School of Medicine, Gaborone, Botswana, 2Princess Marina Hospital, Gaborone, Botswana
Deficiency of vitamin B12 produces protean effects on the nervous system, most commonly neuropathy, myelopathy, cognitive and behavioural symptoms, and optic atrophy. Involuntary movements comprise a relatively rare manifestation of this readily treatable disorder. Both adults and infants deficient in vitamin B12 may present with chorea, tremor, myoclonus, Parkinsonism, dystonia, or a combination of these, which may precede diagnosis or become apparent only a few days after parenteral replacement therapy has begun. The pathogenesis of these movement disorders shows interesting parallels to certain neurodegenerative conditions. The clinical syndrome responds well to vitamin B12 supplementation in most cases, and an early diagnosis is essential to reverse the haematological and neurological dysfunction characteristic of this disorder. In this article, we elucidate the association of vitamin B12 deficiency with movement disorders in adults and in infants, discuss the pathogenesis of this association, review previously reported cases, and present a young adult male with severe generalized chorea that showed a salutary response to vitamin B12 supplementation. Keywords: Vitamin B12, Cobalamin, Movement disorders, Chorea, Tremor, Myoclonus, Megaloblastic anaemia
Introduction Vitamin B12 deficiency is a condition that is readily amenable to treatment, but its protean manifestations make diagnosis difficult in certain circumstances. Early recognition is essential to reversing the haematologic and neurologic dysfunction characteristic of this disorder by means of vitamin supplementation.1 The variable neurological manifestations of vitamin B12 deficiency have been known for over 150 years: indeed, Addison’s initial description of pernicious anaemia in 1849 noted disturbances of cognitive function; and progressive myelopathy (first described by Lichtheim in 1887) was named sub-acute combined degeneration in 1900.2–4 The nervous system may be affected at multiple locations: symptoms attributed to vitamin B12 deficiency include large fibre neuropathy, myelopathy, dementia, optic atrophy, psychosis, recurrent seizures, and mood disorders.5–8 In 1962, Jadhav et al. reported a series of patients with ‘infantile tremor syndrome’ due to nutritional cobalamin deficiency.9 A number of movement disorders have since been reported to respond to treatment with vitamin B12, particularly in children,10–13 and some have been precipitated by supplementation with this vitamin.14–23 Cerebellar ataxia and extrapyramidal Correspondence to: Aaron de Souza, Department of Internal Medicine, Princess Marina Hospital, Hospital Way, Gaborone, Botswana. Email: [email protected]
ß W. S. Maney & Son Ltd 2014 DOI 10.1179/1743132814Y.0000000396
manifestations like dystonia and chorea have been documented infrequently in adults.1,7,8,24–30 Vitamin B12 deficiency is a rare cause of chorea in adults, with vitamin supplementation resulting in striking improvement in the involuntary movements (Table 1).7,27,31 In this article, we review the association of vitamin B12 deficiency with various movement disorders in children and adults, discuss the possible pathogenetic mechanisms underlying this association, and present a young adult male with severe generalized chorea that showed a salutary response to vitamin B12 supplementation.
Pathophysiology and Pathogenesis Vitamin B12 deficiency Vitamin B12 (cobalamin) is an essential vitamin and needs to be supplied in the diet, mainly through foods such as meat, fish, eggs, milk, and liver.15 The daily requirements for vitamin B12 are 0.3–0.5 mg in infants, 0.7–1.4 mg in children, 2 mg in adults, and 2.6 mg in pregnant women and lactating mothers.32 As vitamin B12 is not synthesized by humans and is only found in food of animal origin, strict vegetarian, vegan, or macrobiotic diets may lead to a deficiency. As adults store 2–3 mg in their bodies, several years of dietary deficiency are usually necessary before the condition is clinically apparent. Storage is much lower in infants and young children, around 25 mg.18,33,34 During the first month of life, about 0.1 mg/day is needed for tissue
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Figure 1 Role of cobalamin as a cofactor in essential metabolic reactions. CoA: coenzyme A.
synthesis. Disregarding losses, it was estimated that the body stores of a normal newborn would last for 8 months.35 Usually caused by inadequate intake, vitamin B12 deficiency may also be due to intrinsic factor deficiency (congenital or acquired pernicious anaemia), selective vitamin B12 malabsorption, gastric or distal ileal surgical interventions, and increase in consumption of the vitamin (Diphyllobothrium latum infections). The most important cause of vitamin B12 deficiency in infants is maternal dietary deficiency, either due to strict dietary restrictions or to socio-economic factors.36 As mentioned above, the dietary intake of vitamin B12 should increase from 2 to 2.2 mg/day during pregnancy.36 Cobalamin is actively transported across the placenta in foetuses of deficient mothers, and they are haematologically normal at birth. However, their cobalamin stores are low, and because the level of cobalamin in their mother’s breast milk corresponds closely with those in her serum, the scene is set for the development of cobalamin deficiency with the growth of the baby if it is exclusively breast-fed.18,23 Infants born to vitamin B12-deficient mothers have a very limited hepatic stock of cobalamin and can develop symptoms after a few months of a vitamin B12deficient diet, typically between the ages of 4 and 12 months.18,36–38 As vitamin B12 is essential for development of the central nervous system (CNS), severe neurological impairment may follow.39 Aside from the CNS, tissues with fast mitotic activity, such as the haematopoietic system and digestive tract epithelium are affected.37 Such symptoms appear late in the first year of life, when a relationship to maternal nutritional deficiency seems remote.
Neuronal dysfunction in vitamin B12 deficiency Cobalamin exists as two biochemically active forms in the human body: methylcobalamin is involved as a cofactor in the methylenetetrahydrofolate reductase (MTHFR) reaction converting homocysteine to methionine (also called the methionine synthase reaction) and adenosylcobalamin acts as a cofactor aiding the isomerization of L-methylmalonyl-coenzyme A (CoA) to succinyl-CoA via the enzyme methylmalonyl-CoA mutase (Fig. 1). The methyl group in the MTHFR
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reaction is donated by 5-methyltetrahydrofolate, this reaction being a point of convergence of cobalamin and folate metabolism, and deficiency of this reaction leads to a derangement of folate metabolism. Two crucial intermediates, methionine and tetrahydrofolate generated by this reaction are respectively involved in the production of s-adenosylmethionine (SAM) and in the transfer of single carbon units in the formation of purines, pyrimidines, and formates. s-Adenosylmethionine functions as a methyl donor to a wide variety of molecules, including catecholamines and other biogenic amines, fatty acids, phospholipids, proteins, nucleic acids, polysaccharides, and porphyrins.23,27,40 The exact mechanism by which cobalamin deficiency causes neurological problems is unknown, but studies of children with inborn errors of homocysteine remethylation implicate an abnormality of the MTHFR reaction as the main cause. The patients have clinical findings similar to nutritional cobalamin deficiency, presenting with developmental delay, lethargy or coma, hypotonia, and seizures. Cerebral atrophy and delayed or abnormal myelination are consistent neuroimaging findings, possibly due to deficient conversion of phosphatidylethanolamine to phosphatidylcholine leading to incorporation of non-physiological fatty acids into myelin. s-Adenosylmethionine plays the role of a methyl donor in this reaction, and Surtees et al.41 demonstrated that the restoration of normal SAM levels improved in myelination in children with inborn errors of cobalamin metabolism. Abnormal myelination is responsible for long tract dysfunction as well as axonal neuropathy. Cortical dysfunction has been implicated in infants with vitamin B12 deficiency. Low cerebrospinal fluid levels of vitamin B12 and its transporter protein, transcobalamin II have been demonstrated in such children.42 Furthermore, phosphatidylcholine is believed to decrease the microviscosity of cell membranes, thus improving neurotransmission. The sudden improvement in alertness seen almost immediately after treatment in most cases of infantile cobalamin deficiency might be explained by increased amounts of phosphatidylcholine improving neurotransmission.18,23,27,40,41,43–47 Accumulation of guanidoacetate, homocysteine, and methylmalonic acid (MMA) as a result of cobalamin deficiency have also been postulated to contribute to neurotoxicity in the form of demyelination, axonal degeneration, and neuronal death.37
Pathogenesis of movement disorders due to vitamin B12 deficiency The association of movement disorders with cobalamin deficiency has been explained in terms of elevated serum levels of homocysteine and methyltetrahydrofolate consequent to the impaired MTHFR reaction.27,48 Cobalamin deficiency is the commonest cause of hyperhomocysteinaemia, which represents an independent,
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graded risk factor for atherosclerotic disease in the coronary, cerebral, and peripheral vessels.7,31,49,50 Homocysteine acts as an agonist at the N-methyl-Daspartate (NMDA) type of glutamate receptor through its metabolites L-homocysteate and L-homocysteine sulphinate, activating the basal ganglia by means of the thalamocortical pathway and leading to dystonia.25,51–55 An increase in excitatory amino acid concentration removes the magnesium-mediated blockade of the NMDA receptor and allows calcium flux through the ion channel, which disrupts cell polarity and has a number of downstream signalling effects which lead to cell death.56,57 Endothelial dysfunction is also seen in patients with elevated homocysteine levels, due to defective clearance of oxidant molecules. This homocysteine-induced endothelial dysfunction may further promote susceptibility to impaired mitochondrial energy metabolism.58 Cognitive dysfunction in cobalamin-deficient patients is also attributed to hyperhomocysteinaemia. Neuronal destruction has been linked to the elevated levels of methyltetrahydrofolate seen in vitamin B12 deficiency. Methyltetrahydrofolate acts as an agonist of kainic acid which has been experimentally shown to produce damage similar to that seen in patients with Huntington’s disease (HD).12,55,59 Methylmalonic acid levels are also elevated in cobalamin deficiency, and children with methylmalonic acidaemia present with severe extrapyramidal symptoms with symmetric involvement of the basal ganglia (particularly the globus pallidus) on MRI or at autopsy.60 A similar mechanism has been invoked to explain the rare occurrence of Parkinsonism responsive to cobalamin supplementation,26 supported by a case report of bilateral pallidal involvement in a cobalamin-deficient patient with cognitive decline and mild Parkinsonism. The clinical and imaging findings reversed with treatment of the vitamin deficiency.1 Non-specific interference with cleavage of glycine in patients deficient in cobalamin leads to hyperglycinaemia.22,61,62 Besides its inhibitory action in the spinal cord and brainstem, glycine acts as an NMDA-type receptor agonist and has been implicated by some authors in the genesis of involuntary movements.63,64 In non-ketotic hyperglycinaemia, an inborn error of glycine metabolism, similar involuntary movements are known.65 However, Emery and Homans did not find elevated levels of glycine in blood or urine before treatment or at a time when their patients were symptomatic with abnormal movements.22 Interestingly, degenerative movement disorders such as HD, Parkinson’s disease, and primary dystonia have also been associated with hyperhomocysteinaemia,25,54,58 thereby indirectly supporting a role for this amino acid in the pathogenesis of involuntary movements associated with cobalamin deficiency. o-methylation of levodopa via the enzyme catechol o-methyltransferase
Vitamin B 12 deficiency
results in hyperhomocysteinaemia, which has been implicated in the development of motor complications in patients with Parkinson’s disease.54 Homocysteine is elevated in patients with HD and is postulated to promote neurodegeneration.58 A positive correlation between homocysteine levels and the severity of untreated chorea in patients with HD supports this hypothesis.66 A neurotoxic excess of folates may accumulate in the brains of patients with HD, contributing to kainate-induced neuronal damage.12 The mutated huntingtin protein has been shown to bind specifically with the enzyme cystathionine beta-synthase, which catalyses the formation of cystathionine by condensation of homocysteine and serine. Huntingtin probably inhibits activity of this enzyme, either directly or by preventing processing of the enzyme to its active form.67 Absence of cystathionine beta-synthase activity is associated with homocystinuria,55,66 and excitotoxic mechanisms have been suggested to underlie the mental retardation, seizures, and cerebrovascular disease seen in this disorder.55 Genetic defects of MTHFR and cystathionine beta-synthase activity also result in dystonia with hyperhomocysteinaemia.68 Mu¨ller et al. demonstrated increased serum homocysteine levels in a group patients with primary dystonia, and the severity of the dystonia correlated with the serum homocysteine level. The authors concluded that homocysteine may play a role in the pathogenesis of dystonia, possibly due to its excitotoxic action at NMDA receptors as well as via atherosclerosis in striatal blood vessels with subsequent onset of differential susceptibility to energy metabolism and basal ganglia dysfunction.25 Increased plasma homocysteine levels may have important implications in patients affected by these movement disorders, by exerting neurotoxic effects, contributing to neurotransmitter imbalance in motor circuits, and increasing the risk for vascular insults and cognitive dysfunction.54 The appearance of involuntary movements soon after therapy with vitamin B12 has begun in infants with severe deficiency is less easily explained. GrattanSmith et al., who provided the initial description in 1997, hypothesized that the new symptoms represented exacerbations of a pre-existing, mild movement disorder that had not been readily appreciated because of obtundation. The sudden availability of vitamin B12 after a prolonged and severe shortage may have resulted in intense stimulation of cobalamin and folate pathways and produced a temporary imbalance of metabolic pathways, with local deficiencies or excesses occurring.23 Moreover, neurological deterioration after the commencement of cobalamin therapy has been reported in adult patients with pernicious anaemia and children with inborn errors of cobalamin metabolism.5 The complex pathways of cobalamin utilization in the CNS make it difficult to arrive at a
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M 2000 68 30
M: male; F: female; Hcy: homocysteine; MMA: methylmalonic acid; z: present. *: anaemia, macrocytosis, and/or pancytopenia.
Before 2
Hemichorea, blepharospasm, postural tremor Orthostatic tremor z
124 pg/ml (243–894) 132 ng/l (222–753) 2002 71 27
M
2004 55 2003 55 26 28
M M
2008 40 7
M
2010 51 29
M
Amantadine, tiapride Clonazepam
– –
Before After, 1 day later Before Parkinsonism Multifocal myoclonus z z
– Before Generalized chorea, ataxia z
– Before Blepharospasm z
– Before Generalized chorea 2
105 pM/l (150–650) 16 pM/l (150–650) 62.96 pg/ml (243–894) 5 pg/ml ,30 pg/ml 2011 62 31
M
z
Bradykinesia, hypomimia, delayed saccades
Before
Folic acid, haloperidol – Before Generalized chorea 2
M
Approximately half of all infants with vitamin B12 deficiency may develop involuntary movements either before or after parenteral vitamin replacement therapy (Table 2).18,19,22,37 In case series of patients with vitamin B12 deficiency, tremors and/or choreoathetosis were seen in 12–33% of patients.39,73–75 As discussed above, symptoms begin after 6 months of age with a peak at 9–12 months. A male preponderance is noted from the Table, similar to the situation for adults. The patients present with failure to thrive; haematological problems (anaemia,
2012 43
Infants
195 pg/ml (211–911) 254 pg/ml (200–900)
Movement disorders are a rare consequence of vitamin B12 deficiency in adults. Chorea, tremor, myoclonus, and dystonia have all been reported to respond to vitamin B12 supplementation in single case reports (Table 1).1,7,26–31 All the reported patients were male, and the movement disorder preceded therapy with cobalamin in all except for a single patient with undetectable serum levels of vitamin B12 who developed multifocal myoclonus 1 day after beginning parenteral vitamin replacement.28 This syndrome, commoner in infants, was felt to represent propriospinal myoclonus by the authors and resolved rapidly without treatment. The movement disorder is often a combination of various types of movements and may be associated with cognitive impairment, peripheral neuropathy, or long tract signs. Stroke was associated in two patients: one with acute middle cerebral artery territory ischaemia,7 and another with chronic subcortical infarcts (reported below). Two patients,30,31 in addition to our patient reported below, had normal haematological tests. It is well known that neurological symptoms can precede macrocytosis and anaemia. Anaemia is only one and probably a late sign of vitamin B12 deficiency.21,71,72 These cases also improved over variable periods of time after the vitamin deficiency was corrected: involuntary movements subsided in as little as 1 week in three patients, while in others it took up to 1 year.
Table 1 Movement disorders associated with vitamin B12 deficiency in adults reported in the English literature since 1997
Adults
M
The tables list the cases of involuntary movements associated with vitamin B12 deficiency reported in the English literature since 1997, in adults (Table 1) and children (Table 2).
2013 31
Clinical Features
Present case 1
Notes
definite conclusion, and other theories that have been advanced to explain neurological worsening after initiation of vitamin B12 replacement therapy include ‘denervation supersensitivity’,28 hyperglycinaemia,16 cerebral thromboembolism,15 an imbalance of excitatory versus inhibitory activity,17 dysfunction along fibre tracts during recovery from myelin degradation,69 and the toxic effects of the cyanide moiety in cyanocobalamin, the commonly used therapeutic form of vitamin B12.70
Reduction in chorea over Mild elevation in Hcy, Marfanoid 3 months habitus, chronic subcortical strokes Improved over 1 week Cognitive/pyramidal/proprioceptive dysfunction, normal serum folate, elevated serum Hcy and MMA Improved over 3 months Serum folate normal, elevated serum Hcy and MMA Improved over 9 months Proprioceptive dysfunction, serum folate normal, elevated serum Hcy Reduction in chorea and Stroke with Wernicke aphasia, ataxia over 2 months elevated serum Hcy Improved over 1 week Serum folate normal Improved over 1 week Sensorimotor neuropathy, serum folate normal Improved over 11 Sensory neuropathy, serum folate months normal, elevated serum Hcy Improved over 1 year —
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Whether before or after Other treatment Vitamin B12 level Haematological Response to treatment Reference Year Age Sex (reference range) involvement* Type of movement disorder vitamin supplementation administered
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12 months 20 months
1997 10 months
7 months
1997 10 months
F M
M
M
M
37 pM/l (150–600) 85 pM/l (150–600)
35 pM/l (150–700)
28 pg/ml (250–1100)
41 pg/ml (200–900)
50 pM/l (150–600)
36 pM/l (150–600)
Undetectable
13 pM/l (138–781)
120 ng/l (90–900)
65 pg/ml
44 pg/ml (190–980)
80 pg/ml (190–980)
40 pg/ml (190–980)
10 pM/l (150–750)
,83 pg/ml (180–1100) 69 pg/ml (180–914)
51 pg/ml (190–980)
42 pg/ml (190–980)
48 pM/l (200–1200)
Vitamin B12 level (reference range)
z z
z
z
z
z
z
z
z
z
z
z
z
z
z
z z
z
z
z
Haematological involvement*
Tremor, myoclonus Unilateral tremor
Tremor, myoclonus
Myoclonus, chorea
Tremor
Tremor
Tremor, myoclonus
Tremor
Generalized tremors, myoclonus Tremor, myoclonus
Unilateral ‘twitching’
Tremor
Tremor
Tremor
Tremor, myoclonus
Tremor, myoclonus Tremors
Unilateral tremor/chorea Chorea
Tremor
Type of movement disorder
After, 2 days later Before
After, 2 days later
After, 3 days later
After, 3 days later
After, 2 days later
After, 3 days later
After, 3 days later
Before
After, 3 days later
Before
After, 4 days later
After, 5 days later
After, 1 day later
After, 3 days later
After, 5 days later Before
After, 3 days later
After
After, 3 days later
Improved 3 weeks Improved 2 weeks Improved 2 weeks Improved 3 weeks
Improved 5 days Improved 3 months Improved 12 days Improved 1 month ?
Improved 15 days Improved 1 week Improved 3 days ? Improved 3 months Improved 1 week Improved 10 days Improved .1 week
over
over
over
over
over
over
over
over
over
over
over
over
over
Response to treatment
Serum folate normal
Serum Hcy and urinary MMA increased Serum Hcy and urinary Hcy/MMA increased MRI: delayed myelination and frontoparietal cerebral atrophy
Serum folate normal
Serum folate normal
Serum folate normal
Serum folate normal
– Serum folate normal, urine MMA z Serum folate normal
Serum folate normal
Elevated serum Hcy and MMA Serum folate normal
Notes
–
over
Serum folate normal, urinary Hcy z – over Serum folate normal, elevated serum Hcy and urinary MMA – Improved over Serum folate normal, 6 weeks elevated urinary MMA and Hcy, MRI: delayed myelination, cerebral atrophy – Improved – Phenobarbitone, Improved over 3 weeks Seizuresz, Serum folate carbamazepine normal, CT scan: diffuse cerebral atrophy, bilateral subdural hygromas
Clonazepam
Clonazepam
–
–
–
Haloperidol
Clonazepam, propranolol, piracetam Clonazepam
Clonazepam
Clonazepam
– –
Clonazepam
Clonazepam
Clonazepam
Whether before or after Other treatment vitamin supplementation administered
M: male; F: female; Hcy: homocysteine; MMA: methylmalonic acid; z: present. *: anaemia, macrocytosis, and/or pancytopenia; ?: not reported.
23
22
F
11 months
M
F
2003 16 months
20
F
M
F
2001 12 months
2003 9 months
13
19
2005 6 months
21
F
16 months
2006 11 months
M
14 months
12
M
2008 13 months
16
M
2008 6 months
18
F M
2012 11 months 2009 7 months
M
16 months
17 11
F
2013 13 months
14
M
Sex
2013 9 months
Age
15
Reference Year
Table 2 Movement disorders associated with vitamin B12 deficiency in infants reported in the English literature since 1997
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macrocytosis, or pancytopenia); vomiting, lethargy and feeding difficulties; hypotonia, developmental regression, irritability, apathy, tremors, and seizures; and optic atrophy.10,15,16,18,21,23,27,39,73 Although such patients may even present without anaemia, all patients reported with movement disorders did manifest the haematological features of vitamin B12 deficiency. The type of movement disorder varies considerably: tremor, myoclonus, chorea, rolling movements or a combination of these and may last up to 1 month.22,73,76 They can be asymmetric11,25,38 and may or may not persist in sleep.16,19,76 Movements that begin after initiation of vitamin B12 replacement are usually more severe, become more intense with tactile stimulation, and on arousal. These movements have a hyperkinetic character; shaking movements, myoclonus, tremor, chorea, twitching, protrusion or tremor of the tongue, and wandering eyes are described in the literature.17 A distinction from seizures, which are also reported in vitamin B12 deficiency in infants, may be difficult.23 An electroencephalogram is often required: it is characterized by a slowing of the background activity, consistent with the lethargic and hyporeactive state of the child, without any epileptiform activity.17 Cerebral atrophy, thinning of the corpus callosum, and delayed myelination are seen on neuroimaging studies.21,73 Satisfactory clinical and imaging improvement usually follows vitamin B12 repletion, but permanent sequelae may be seen in children with severe and prolonged symptoms before diagnosis.37,77 von Schenck et al.35 summarized the clinical descriptions of 24 infants who had been reported up to 1997 with neurologic abnormalities due to infantile vitamin B12 deficiency; of the 16 infants for whom a follow-up was available 6 still had an abnormal neuro-developmental status years afterwards. These children had been diagnosed later (mean age 13 months) than those who improved with treatment (mean age 10 months).
Illustrative Case As an illustration, we present a 31-year-old Motswana man who presented with severe generalized chorea of 5 years’ duration. He had had an acute right hemiparesis 2 years prior to the onset of chorea, and a CT scan at the time showed a left caudate infarct. No further workup was done. The hemiparesis resolved nearly completely within 6 months. There were no systemic symptoms, no family history of chorea, and no psychiatric illness in the patient or his family. He denied intake of any drugs other than aspirin. At presentation, he had generalized chorea involving all the limbs – more prominently on the left side – as well as the axial musculature and face. Minimal pyramidal weakness was noted in the right
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upper and lower limbs. A mental status examination was normal, as were ocular movements (including saccades and antisaccades). The patient was cognitively normal and showed no signs of peripheral neuropathy or proprioceptive dysfunction, thus pseudoathetosis causing the abnormal movements was considered unlikely. Systemic examination was remarkable for a Marfanoid habitus with increased arm span to height ratio, high arched palate, and positive ‘wrist sign’ and ‘thumb sign’. No cataracts or lens subluxation were seen. Cardiac examination was normal, and there were no bruits. Laboratory tests revealed serum vitamin B12 levels of 195 pg/ml (reference range, 211–911), with serum homocysteine levels of 16.75 (reference range, 9–14). An MRI of the brain showed chronic infarcts in the left caudate nucleus and the right putamen. Blood counts with red cell indices, echocardiogram, human immunodeficiency virus serology, antinuclear antibodies, antineutrophil cytoplasmic antibodies, and thyroid function tests were within normal limits. Serum MMA levels, Schilling test, antiparietal cell antibody testing, and genetic testing for mutations in the MTHFR and huntingtin genes were not done due to logistic constraints. The patient had been on regular treatment with haloperidol (15 mg/day) for 3 years with no benefit. This was continued and a course of intramuscular cyanocobalamin (1000 mg daily for 10 days, then weekly for 1 month, and subsequently monthly) along with folic acid (5 mg/day) was initiated. After 3 months, a significant reduction in chorea was seen. Haloperidol was then tapered to 7.5 mg/day with no worsening of symptoms. This patient presents with generalized chorea which improved with vitamin B12 and folic acid supplementation. Although chorea may possibly be a result of neuronal reorganization following stroke, the generalized distribution of the movements as well as the lack of temporal relationship to the hemiparesis argues against this. The therapeutic benefit of vitamin B12 and folic acid therapy is striking and supports a role for vitamin deficiency in the genesis of this movement disorder. Although a Marfanoid habitus suggested homocystinuria, the mild elevation of homocysteine and lack of a family history and of other physical signs suggested that the primary factor was a deficiency of vitamin B12 rather than an inherited disorder of homocysteine metabolism.
Conclusions Vitamin B12 deficiency may, in rare cases, produce movement disorders in addition to its better-known effects on the CNS. Both adults and infants deficient in vitamin B12 may present with chorea, tremor, myoclonus, Parkinsonism, dystonia, or a combination of these, which may precede diagnosis or become
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apparent only a few days after parenteral replacement therapy has begun. The pathogenesis of these movement disorders shows interesting parallels to certain neurodegenerative conditions. The clinical syndrome responds well to vitamin B12 supplementation in most cases, and an early diagnosis is essential to reverse the haematologic and neurologic dysfunction characteristic of this disorder.
Disclaimer Statements Contributors A. S. contributed to the concept of the article, literature review, writing of the first draft, and approval of the final manuscript. M. W. M. provided literature review, critical appraisal of the first draft, and approval of the final manuscript. Funding No funding was received from any source. Conflicts of interest The authors do not report any conflicts of interest. Ethics approval The article is a retrospective review of previously published works, therefore ethical clearance was not sought from the Institutional Review Board. The patient in the illustrative case report provided written informed consent for his clinical details to be published.
References 1 Sharieff AZ, Raffel J, Zee DS. Vitamin B12 deficiency with bilateral globus pallidus abnormalities. Arch Neurol. 2012;69(6):769–72. 2 Addison T. Anaemia: disease of the suprarenal capsules. Lond Med Gaz. 1849;43:517–8; (Quoted in ref. 23). 3 Lichtheim H. Zur Kenntniss der perniciosen Anamie. Munchen Med Med Wchnschr. 1887;34:301; (Quoted in ref. 23). 4 Russell JDR, Batten FE, Collier J. Subacute combined degeneration of the spinal cord. Brain. 1900;23:39–110. 5 Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore). 1991;70:229–45. 6 Kumar S. Recurrent seizures: an unusual manifestation of vitamin B12 deficiency. Neurol India. 2004;52:122–3. 7 Shyambabu C, Sinha S, Taly AB, Vijayan J, Kovoor JME. Serum vitamin B12 deficiency and hyperhomocysteinemia: a reversible cause of acute chorea, cerebellar ataxia in an adult with cerebral ischemia. J Neurol Sci. 2008;273:152–4. 8 Katsaros VK, Glocker FX, Hemmer B, Schumacher M. MRI of spinal cord and brain lesions in subacute combined degeneration. Neuroradiology. 1988;40:716–9. 9 Jadhav M, Webb JKG, Vaishnava S, Baker SJ. Vitamin B12 deficiency in Indian infants. Lancet. 1962;2:903–7. 10 Alawneh H, Batayneh A, Jaafreh M. Infantile dyskinesia and vitamin B12 deficiency. Middle East J Fam Med. 2006;4(5):42– 3. 11 Citak FE, Citak EC. Severe vitamin B12 deficiency in a breast fed infant with pancytopenia. J Trop Pediatr. 2011;57(1):69–70. 12 Brennan MJ, van der Westhuyzen J, Kramer S, Metz J. Neurotoxicity of folates: implications for vitamin B12 deficiency and Huntington’s chorea. Med Hypotheses. 1981;7:919– 29. 13 Rachmel A, Steinberg T, Ashkenazi S, Sela BA. Cobalamin deficiency in a breast-fed infant of a vegetarian mother. Isr Med Assoc J. 2003;5:534–6. 14 Carmen KB, Belgeman T, Yis U. Involuntary movements misdiagnosed as seizure during vitamin B12 treatment. Pediatr Emer Care. 2013;29:1223–4. 15 Patiroglu T, Unal E, Yildrim S. Infantile tremor syndrome associated with cobalamin therapy: a case report. Clin Neurol Neurosurg. 2013;115:1903–5. ¨ zdemir O ¨ , Baytan B, Gunes AM, Okan M. Involuntary 16 O movements during vitamin B12 treatment. J Child Neurol. 2010;25:227–30.
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17 Zanus C, Alberini E, Costa C, Colonna F, Zennaro F, Carrozzi M. Involuntary movements after correction of vitamin B12 deficiency: a video-case report. Epileptic Disord. 2012;14(2): 174–80. 18 Chalouhi C, Faesch S, Anthoine-Milhomme MC, Fulla Y, Dulac O, Cheron G. Neurological consequences of vitamin B12 deficiency and its treatment. Pediatr Emer Care. 2008;24(8): 538–41. 19 Ozer EA, Turker M, Bakiler AR, Yaprak I, Ozturk C. Involuntary movements in infantile cobalamin deficiency appearing after treatment. Pediatr Neurol. 2001;25:81–3. ¨ nal I. Involuntary movements and 20 Avci Z, Turul T, Aysun S, U magnetic resonance imaging findings in infantile cobalamin (vitamin B12) deficiency. Pediatrics. 2003;112(3):684–6. 21 Casella EB, Valente M, Medeiros de Navarro J, Kok F. Vitamin B12 deficiency in infancy as a cause of developmental regression. Brain Dev. 2005;27:592–4. 22 Emery ES, Homans AC. Vitamin B12 deficiency: a cause of abnormal movements in infants. Pediatrics. 1997;99:255–6. 23 Grattan-Smith PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord. 1997;12(1):39–46. 24 Ahn TB, Cho JW, Jeon BS. Unusual neurological presentations of vitamin B12 deficiency. Eur J Neurol. 2004;11:339–41. 25 Mu¨ller T, Woitalla D, Hunsdiek A, Kuhn W. Elevated plasma levels of homocysteine in dystonia. Acta Neurol Scand. 2000;101:388–90. 26 Kumar S. Vitamin B12 deficiency presenting with an acute reversible extrapyramidal syndrome. Neurol India. 2004;52: 507–9. 27 Pacchetti C, Cristina S, Nappi G. Reversible chorea and focal dystonia in vitamin B12 deficiency. N Engl J Med. 2002;347:295. 28 Celik M, Barkut IK, Oncel C, Forta H. Involuntary movements associated with vitamin B12 deficiency. Parkinsonism Relat Disord. 2003;10:55–7. 29 Edvardsson B, Persson S. Blepharospasm and vitamin B12 deficiency. Neurol India. 2010;58:320–1. 30 Benito-Leon J, Porta-Etessam J. Shaky-leg syndrome and vitamin B12 deficiency. N Engl J Med. 2000;342(13):981. 31 Edvardsson B, Persson S. Chorea associated with vitamin B12 deficiency. Eur J Neurol. 2011;18:e138–9. 32 Sachdev HPS, Shah D. Vitamin B12 (cobalamin). In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE, editors. Nelson’s textbook of paediatrics, 19th edn. Philadelphia: Elsevier; 2011. p. 197–8. 33 Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr. 2001;138:10–7. 34 Samuels MA. Neurological effects of malabsorption and vitamin deficiency. In: Samuels MA, Feske S, editors. Office practice of neurology. New York, NY: Churchill Livingstone; 1996. p. 1280. 35 von Schenck U, Bender-Gotze C, Koletzko B. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. Arch Dis Child. 1997;77:137–9. 36 Allen LH. Vitamin B12 metabolism and status during pregnancy, lactation and infancy. In: Allen LH, King J, Lonnerdal B, editors. Nutrient regulation during pregnancy, lactation, and infant growth. New York: Plenum Press; 1994. p. 173–86. 37 Graham SM, Arvela OM, Wise GA. Long-term neurologic consequences of nutritional vitamin B 12 deficiency in infants. J Pediatr. 1992;121:710–4. 38 Casterline JE, Allen LH, Ruel MT. Vitamin B12 deficiency is very prevalent in lactating Guatemalan women and their infants at three months postpartum. J Nutr. 1997;127:1966–72. 39 Taskesen M, Yaramis A, Katar S, Gozu Pirincioglu A, Soker M. Neurological presentations of nutritional vitamin B12 deficiency in 42 breastfed infants in Southeast Turkey. Turkish J Med Sci. 2011;41(6):1091–6. 40 Baldessarini RJ. Neuropharmacology of S-adenosyl-L-methionine. Am J Med. 1987;83(Suppl 5A):95–103. 41 Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid-S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet. 1991;338: 1550–4. 42 Garewal G, Narang A, Das KC. Infantile tremor syndrome: a vitamin B12 deficiency syndrome in infants. J Trop Pediatr. 1988;34(4):174–8.
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43 Fenton WA, Rosenberg L. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease, 7th edn. New York: McGraw-Hill; 1995, p. 1423–50. 44 Hall CA. Function of vitamin B12 in the central nervous system as revealed by congenital defects. Am J Hematol. 1990;34:121– 7. 45 Clayton PT, Smith I, Harding B. Subacute combined degeneration of the cord, dementia and Parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry. 1986;49:920–7. 46 Hyland K, Smith I, Bottiglieri T. Demyelination and decreased s-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurology. 1988;38:459–62. 47 Codazzi D, Sala F, Parini R. Coma and respiratory failure in a child with severe vitamin B12 deficiency. Pediatr Crit Care Med. 2005;6:483–5. 48 Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. 1996;54:382–90. 49 Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31–62. 50 Herrmann W. Significance of hyperhomocysteinemia. Clin Lab. 2006;52(7–8):367–74. 51 Berardelli A, Thompson PD, Zaccagnini M. Two sisters with generalized dystonia associated with homocystinuria. Mov Dis. 1991;6:163–5. 52 Kempster PA, Brenton DP, Gale AN, Stern GM. Dystonia in homocystinuria. J Neurol Neurosurg Psychiatry. 1988;51:859– 62. 53 Vitek JL, Chokkan V, Zhang JY. Neuronal activity in basal ganglia with generalized dystonia and hemiballismus. Ann Neurol. 1999;46:22–35. 54 Zoccolella S, Martino D, Defazio G, Lamberti P, Livrea P. Hyperhomocysteinemia in movement disorders: current evidence and hypotheses. Curr Vasc Pharmacol. 2013;4(3):237–43. 55 Boutell JM, Wood JD, Harper PS, Jones AL. Huntingtin interacts with cystathionine b-synthase. Hum Mol Genet. 1998;7(3):371–8. 56 Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1:623–34. 57 Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron. 1995;15:961–73. 58 Andrich J, Saft C, Arz A, Schneider B, Agelink MW, Kraus PH, et al. Hyperhomocysteinaemia in treated patients with Huntington’s disease. Mov Disord. 2004;19(2):226–8. 59 Ruck A, Kramer S, Metz J, Brennan MJ. Methyltetrahydrofolate is a potent and selective agonist for kainic acid receptors. Nature. 1980;287:852–3. 60 Larnaout A, Mongalgi MA, Kaabachi N, Khiari D, Debbabi A, Mebazza A. Methylmalonic acidaemia with bilateral globus
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pallidus involvement: a neuropathological study. J Inherit Metab Dis. 1998;21:639–44. Higginbottom MC, Sweetman L, Nyhan WL. A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breastfed infant of a strict vegetarian. N Engl J Med. 1978;299(7):317–23. Kuhne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr. 1991;150(3):205–8. Biancheri R, Cerone R, Schiaffino MC. Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiological findings in 14 cases. Neuropediatrics. 2001;32:14–22. Hamosh A, Johnston MV, Valle D. Non-ketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease, 7th edn. New York, NY: McGraw-Hill; 1995. p. 1337–46. Frazier DM, Summer GK, Chamberlin HR. Hyperglycinuria and hyperglycinemia in two siblings with mild developmental delays. Am J Dis Child. 1978;132(8):777–81. May PC, Gray PN. L-Homocysteic acid as an alternative cytotoxin for studying glutamate-induced cellular degeneration of Huntington’s disease and normal skin fibroblasts. Life Sci. 1985;37:1483–9. Skovby F, Kraus JP, Rosenberg LE. Biosynthesis and proteolytic activation of cystathionine b-synthase in rat liver. J Biol Chem. 1984;259:588. Kang SS, Wong PWK. Genetic and nongenetic factors for moderate hyperhomocyst(e)inemia. Atherosclerosis. 1996;119: 135–8. Stollhoff K, Schulte FJ. Vitamin B12 and brain development. Eur J Pediatr. 1987;146:201–5. Grasbeck R. Correspondence on ‘‘involuntary movements during vitamin B12 treatment’’: was cyanocobalamin perhaps responsible? J Child Neurol. 2010;25:794–5. Rowland LP, Pedley TA. Merritt’s neurology, 12th edn. Philadelphia: Lippincott Williams & Wilkins; 2010. Chanarin I, Metz J. Diagnosis of cobalamin deficiency: the old and the new. Br J Haematol. 1997;97:695–700. Incecik F, Herguner MO, Altunbasak S, Leblebisatan G. Neurologic findings of nutritional vitamin B12 deficiency in children. Turkish J Pediatr. 2010;52:17–21. Chandra J, Jain V, Narayan S, Sharma S, Singh V, Batra S, et al. Tremors and thrombocytosis during treatment of megaloblastic anaemia. Ann Trop Paediatr. 2006;26:101–5. Katar S, Ozbek MN, Yaramis A, Ecer S. Nutritional megaloblastic anemia in young Turkish children is associated with vitamin B12 deficiency and psychomotor retardation. J Pediatr Hematol Oncol. 2006;28:559–62. Yavuz H. Vitamin B12 deficiency, seizure, involuntary movements. Seizure. 2008;17:748–9. McPhee AJ, Davidson GP, Leahay M, Beare T. Vitamin B12 deficiency in a breast fed infant. Arch Dis Child. 1988;63:921–3
Involuntary movements due to vitamin B12 deficiency Aaron de Souza1,2, M. W. Moloi1 1
Department of Internal Medicine, University of Botswana School of Medicine, Gaborone, Botswana, 2Princess Marina Hospital, Gaborone, Botswana
Deficiency of vitamin B12 produces protean effects on the nervous system, most commonly neuropathy, myelopathy, cognitive and behavioural symptoms, and optic atrophy. Involuntary movements comprise a relatively rare manifestation of this readily treatable disorder. Both adults and infants deficient in vitamin B12 may present with chorea, tremor, myoclonus, Parkinsonism, dystonia, or a combination of these, which may precede diagnosis or become apparent only a few days after parenteral replacement therapy has begun. The pathogenesis of these movement disorders shows interesting parallels to certain neurodegenerative conditions. The clinical syndrome responds well to vitamin B12 supplementation in most cases, and an early diagnosis is essential to reverse the haematological and neurological dysfunction characteristic of this disorder. In this article, we elucidate the association of vitamin B12 deficiency with movement disorders in adults and in infants, discuss the pathogenesis of this association, review previously reported cases, and present a young adult male with severe generalized chorea that showed a salutary response to vitamin B12 supplementation. Keywords: Vitamin B12, Cobalamin, Movement disorders, Chorea, Tremor, Myoclonus, Megaloblastic anaemia
Introduction Vitamin B12 deficiency is a condition that is readily amenable to treatment, but its protean manifestations make diagnosis difficult in certain circumstances. Early recognition is essential to reversing the haematologic and neurologic dysfunction characteristic of this disorder by means of vitamin supplementation.1 The variable neurological manifestations of vitamin B12 deficiency have been known for over 150 years: indeed, Addison’s initial description of pernicious anaemia in 1849 noted disturbances of cognitive function; and progressive myelopathy (first described by Lichtheim in 1887) was named sub-acute combined degeneration in 1900.2–4 The nervous system may be affected at multiple locations: symptoms attributed to vitamin B12 deficiency include large fibre neuropathy, myelopathy, dementia, optic atrophy, psychosis, recurrent seizures, and mood disorders.5–8 In 1962, Jadhav et al. reported a series of patients with ‘infantile tremor syndrome’ due to nutritional cobalamin deficiency.9 A number of movement disorders have since been reported to respond to treatment with vitamin B12, particularly in children,10–13 and some have been precipitated by supplementation with this vitamin.14–23 Cerebellar ataxia and extrapyramidal Correspondence to: Aaron de Souza, Department of Internal Medicine, Princess Marina Hospital, Hospital Way, Gaborone, Botswana. Email: [email protected]
ß W. S. Maney & Son Ltd 2014 DOI 10.1179/1743132814Y.0000000396
manifestations like dystonia and chorea have been documented infrequently in adults.1,7,8,24–30 Vitamin B12 deficiency is a rare cause of chorea in adults, with vitamin supplementation resulting in striking improvement in the involuntary movements (Table 1).7,27,31 In this article, we review the association of vitamin B12 deficiency with various movement disorders in children and adults, discuss the possible pathogenetic mechanisms underlying this association, and present a young adult male with severe generalized chorea that showed a salutary response to vitamin B12 supplementation.
Pathophysiology and Pathogenesis Vitamin B12 deficiency Vitamin B12 (cobalamin) is an essential vitamin and needs to be supplied in the diet, mainly through foods such as meat, fish, eggs, milk, and liver.15 The daily requirements for vitamin B12 are 0.3–0.5 mg in infants, 0.7–1.4 mg in children, 2 mg in adults, and 2.6 mg in pregnant women and lactating mothers.32 As vitamin B12 is not synthesized by humans and is only found in food of animal origin, strict vegetarian, vegan, or macrobiotic diets may lead to a deficiency. As adults store 2–3 mg in their bodies, several years of dietary deficiency are usually necessary before the condition is clinically apparent. Storage is much lower in infants and young children, around 25 mg.18,33,34 During the first month of life, about 0.1 mg/day is needed for tissue
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Figure 1 Role of cobalamin as a cofactor in essential metabolic reactions. CoA: coenzyme A.
synthesis. Disregarding losses, it was estimated that the body stores of a normal newborn would last for 8 months.35 Usually caused by inadequate intake, vitamin B12 deficiency may also be due to intrinsic factor deficiency (congenital or acquired pernicious anaemia), selective vitamin B12 malabsorption, gastric or distal ileal surgical interventions, and increase in consumption of the vitamin (Diphyllobothrium latum infections). The most important cause of vitamin B12 deficiency in infants is maternal dietary deficiency, either due to strict dietary restrictions or to socio-economic factors.36 As mentioned above, the dietary intake of vitamin B12 should increase from 2 to 2.2 mg/day during pregnancy.36 Cobalamin is actively transported across the placenta in foetuses of deficient mothers, and they are haematologically normal at birth. However, their cobalamin stores are low, and because the level of cobalamin in their mother’s breast milk corresponds closely with those in her serum, the scene is set for the development of cobalamin deficiency with the growth of the baby if it is exclusively breast-fed.18,23 Infants born to vitamin B12-deficient mothers have a very limited hepatic stock of cobalamin and can develop symptoms after a few months of a vitamin B12deficient diet, typically between the ages of 4 and 12 months.18,36–38 As vitamin B12 is essential for development of the central nervous system (CNS), severe neurological impairment may follow.39 Aside from the CNS, tissues with fast mitotic activity, such as the haematopoietic system and digestive tract epithelium are affected.37 Such symptoms appear late in the first year of life, when a relationship to maternal nutritional deficiency seems remote.
Neuronal dysfunction in vitamin B12 deficiency Cobalamin exists as two biochemically active forms in the human body: methylcobalamin is involved as a cofactor in the methylenetetrahydrofolate reductase (MTHFR) reaction converting homocysteine to methionine (also called the methionine synthase reaction) and adenosylcobalamin acts as a cofactor aiding the isomerization of L-methylmalonyl-coenzyme A (CoA) to succinyl-CoA via the enzyme methylmalonyl-CoA mutase (Fig. 1). The methyl group in the MTHFR
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reaction is donated by 5-methyltetrahydrofolate, this reaction being a point of convergence of cobalamin and folate metabolism, and deficiency of this reaction leads to a derangement of folate metabolism. Two crucial intermediates, methionine and tetrahydrofolate generated by this reaction are respectively involved in the production of s-adenosylmethionine (SAM) and in the transfer of single carbon units in the formation of purines, pyrimidines, and formates. s-Adenosylmethionine functions as a methyl donor to a wide variety of molecules, including catecholamines and other biogenic amines, fatty acids, phospholipids, proteins, nucleic acids, polysaccharides, and porphyrins.23,27,40 The exact mechanism by which cobalamin deficiency causes neurological problems is unknown, but studies of children with inborn errors of homocysteine remethylation implicate an abnormality of the MTHFR reaction as the main cause. The patients have clinical findings similar to nutritional cobalamin deficiency, presenting with developmental delay, lethargy or coma, hypotonia, and seizures. Cerebral atrophy and delayed or abnormal myelination are consistent neuroimaging findings, possibly due to deficient conversion of phosphatidylethanolamine to phosphatidylcholine leading to incorporation of non-physiological fatty acids into myelin. s-Adenosylmethionine plays the role of a methyl donor in this reaction, and Surtees et al.41 demonstrated that the restoration of normal SAM levels improved in myelination in children with inborn errors of cobalamin metabolism. Abnormal myelination is responsible for long tract dysfunction as well as axonal neuropathy. Cortical dysfunction has been implicated in infants with vitamin B12 deficiency. Low cerebrospinal fluid levels of vitamin B12 and its transporter protein, transcobalamin II have been demonstrated in such children.42 Furthermore, phosphatidylcholine is believed to decrease the microviscosity of cell membranes, thus improving neurotransmission. The sudden improvement in alertness seen almost immediately after treatment in most cases of infantile cobalamin deficiency might be explained by increased amounts of phosphatidylcholine improving neurotransmission.18,23,27,40,41,43–47 Accumulation of guanidoacetate, homocysteine, and methylmalonic acid (MMA) as a result of cobalamin deficiency have also been postulated to contribute to neurotoxicity in the form of demyelination, axonal degeneration, and neuronal death.37
Pathogenesis of movement disorders due to vitamin B12 deficiency The association of movement disorders with cobalamin deficiency has been explained in terms of elevated serum levels of homocysteine and methyltetrahydrofolate consequent to the impaired MTHFR reaction.27,48 Cobalamin deficiency is the commonest cause of hyperhomocysteinaemia, which represents an independent,
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graded risk factor for atherosclerotic disease in the coronary, cerebral, and peripheral vessels.7,31,49,50 Homocysteine acts as an agonist at the N-methyl-Daspartate (NMDA) type of glutamate receptor through its metabolites L-homocysteate and L-homocysteine sulphinate, activating the basal ganglia by means of the thalamocortical pathway and leading to dystonia.25,51–55 An increase in excitatory amino acid concentration removes the magnesium-mediated blockade of the NMDA receptor and allows calcium flux through the ion channel, which disrupts cell polarity and has a number of downstream signalling effects which lead to cell death.56,57 Endothelial dysfunction is also seen in patients with elevated homocysteine levels, due to defective clearance of oxidant molecules. This homocysteine-induced endothelial dysfunction may further promote susceptibility to impaired mitochondrial energy metabolism.58 Cognitive dysfunction in cobalamin-deficient patients is also attributed to hyperhomocysteinaemia. Neuronal destruction has been linked to the elevated levels of methyltetrahydrofolate seen in vitamin B12 deficiency. Methyltetrahydrofolate acts as an agonist of kainic acid which has been experimentally shown to produce damage similar to that seen in patients with Huntington’s disease (HD).12,55,59 Methylmalonic acid levels are also elevated in cobalamin deficiency, and children with methylmalonic acidaemia present with severe extrapyramidal symptoms with symmetric involvement of the basal ganglia (particularly the globus pallidus) on MRI or at autopsy.60 A similar mechanism has been invoked to explain the rare occurrence of Parkinsonism responsive to cobalamin supplementation,26 supported by a case report of bilateral pallidal involvement in a cobalamin-deficient patient with cognitive decline and mild Parkinsonism. The clinical and imaging findings reversed with treatment of the vitamin deficiency.1 Non-specific interference with cleavage of glycine in patients deficient in cobalamin leads to hyperglycinaemia.22,61,62 Besides its inhibitory action in the spinal cord and brainstem, glycine acts as an NMDA-type receptor agonist and has been implicated by some authors in the genesis of involuntary movements.63,64 In non-ketotic hyperglycinaemia, an inborn error of glycine metabolism, similar involuntary movements are known.65 However, Emery and Homans did not find elevated levels of glycine in blood or urine before treatment or at a time when their patients were symptomatic with abnormal movements.22 Interestingly, degenerative movement disorders such as HD, Parkinson’s disease, and primary dystonia have also been associated with hyperhomocysteinaemia,25,54,58 thereby indirectly supporting a role for this amino acid in the pathogenesis of involuntary movements associated with cobalamin deficiency. o-methylation of levodopa via the enzyme catechol o-methyltransferase
Vitamin B 12 deficiency
results in hyperhomocysteinaemia, which has been implicated in the development of motor complications in patients with Parkinson’s disease.54 Homocysteine is elevated in patients with HD and is postulated to promote neurodegeneration.58 A positive correlation between homocysteine levels and the severity of untreated chorea in patients with HD supports this hypothesis.66 A neurotoxic excess of folates may accumulate in the brains of patients with HD, contributing to kainate-induced neuronal damage.12 The mutated huntingtin protein has been shown to bind specifically with the enzyme cystathionine beta-synthase, which catalyses the formation of cystathionine by condensation of homocysteine and serine. Huntingtin probably inhibits activity of this enzyme, either directly or by preventing processing of the enzyme to its active form.67 Absence of cystathionine beta-synthase activity is associated with homocystinuria,55,66 and excitotoxic mechanisms have been suggested to underlie the mental retardation, seizures, and cerebrovascular disease seen in this disorder.55 Genetic defects of MTHFR and cystathionine beta-synthase activity also result in dystonia with hyperhomocysteinaemia.68 Mu¨ller et al. demonstrated increased serum homocysteine levels in a group patients with primary dystonia, and the severity of the dystonia correlated with the serum homocysteine level. The authors concluded that homocysteine may play a role in the pathogenesis of dystonia, possibly due to its excitotoxic action at NMDA receptors as well as via atherosclerosis in striatal blood vessels with subsequent onset of differential susceptibility to energy metabolism and basal ganglia dysfunction.25 Increased plasma homocysteine levels may have important implications in patients affected by these movement disorders, by exerting neurotoxic effects, contributing to neurotransmitter imbalance in motor circuits, and increasing the risk for vascular insults and cognitive dysfunction.54 The appearance of involuntary movements soon after therapy with vitamin B12 has begun in infants with severe deficiency is less easily explained. GrattanSmith et al., who provided the initial description in 1997, hypothesized that the new symptoms represented exacerbations of a pre-existing, mild movement disorder that had not been readily appreciated because of obtundation. The sudden availability of vitamin B12 after a prolonged and severe shortage may have resulted in intense stimulation of cobalamin and folate pathways and produced a temporary imbalance of metabolic pathways, with local deficiencies or excesses occurring.23 Moreover, neurological deterioration after the commencement of cobalamin therapy has been reported in adult patients with pernicious anaemia and children with inborn errors of cobalamin metabolism.5 The complex pathways of cobalamin utilization in the CNS make it difficult to arrive at a
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M 2000 68 30
M: male; F: female; Hcy: homocysteine; MMA: methylmalonic acid; z: present. *: anaemia, macrocytosis, and/or pancytopenia.
Before 2
Hemichorea, blepharospasm, postural tremor Orthostatic tremor z
124 pg/ml (243–894) 132 ng/l (222–753) 2002 71 27
M
2004 55 2003 55 26 28
M M
2008 40 7
M
2010 51 29
M
Amantadine, tiapride Clonazepam
– –
Before After, 1 day later Before Parkinsonism Multifocal myoclonus z z
– Before Generalized chorea, ataxia z
– Before Blepharospasm z
– Before Generalized chorea 2
105 pM/l (150–650) 16 pM/l (150–650) 62.96 pg/ml (243–894) 5 pg/ml ,30 pg/ml 2011 62 31
M
z
Bradykinesia, hypomimia, delayed saccades
Before
Folic acid, haloperidol – Before Generalized chorea 2
M
Approximately half of all infants with vitamin B12 deficiency may develop involuntary movements either before or after parenteral vitamin replacement therapy (Table 2).18,19,22,37 In case series of patients with vitamin B12 deficiency, tremors and/or choreoathetosis were seen in 12–33% of patients.39,73–75 As discussed above, symptoms begin after 6 months of age with a peak at 9–12 months. A male preponderance is noted from the Table, similar to the situation for adults. The patients present with failure to thrive; haematological problems (anaemia,
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Infants
195 pg/ml (211–911) 254 pg/ml (200–900)
Movement disorders are a rare consequence of vitamin B12 deficiency in adults. Chorea, tremor, myoclonus, and dystonia have all been reported to respond to vitamin B12 supplementation in single case reports (Table 1).1,7,26–31 All the reported patients were male, and the movement disorder preceded therapy with cobalamin in all except for a single patient with undetectable serum levels of vitamin B12 who developed multifocal myoclonus 1 day after beginning parenteral vitamin replacement.28 This syndrome, commoner in infants, was felt to represent propriospinal myoclonus by the authors and resolved rapidly without treatment. The movement disorder is often a combination of various types of movements and may be associated with cognitive impairment, peripheral neuropathy, or long tract signs. Stroke was associated in two patients: one with acute middle cerebral artery territory ischaemia,7 and another with chronic subcortical infarcts (reported below). Two patients,30,31 in addition to our patient reported below, had normal haematological tests. It is well known that neurological symptoms can precede macrocytosis and anaemia. Anaemia is only one and probably a late sign of vitamin B12 deficiency.21,71,72 These cases also improved over variable periods of time after the vitamin deficiency was corrected: involuntary movements subsided in as little as 1 week in three patients, while in others it took up to 1 year.
Table 1 Movement disorders associated with vitamin B12 deficiency in adults reported in the English literature since 1997
Adults
M
The tables list the cases of involuntary movements associated with vitamin B12 deficiency reported in the English literature since 1997, in adults (Table 1) and children (Table 2).
2013 31
Clinical Features
Present case 1
Notes
definite conclusion, and other theories that have been advanced to explain neurological worsening after initiation of vitamin B12 replacement therapy include ‘denervation supersensitivity’,28 hyperglycinaemia,16 cerebral thromboembolism,15 an imbalance of excitatory versus inhibitory activity,17 dysfunction along fibre tracts during recovery from myelin degradation,69 and the toxic effects of the cyanide moiety in cyanocobalamin, the commonly used therapeutic form of vitamin B12.70
Reduction in chorea over Mild elevation in Hcy, Marfanoid 3 months habitus, chronic subcortical strokes Improved over 1 week Cognitive/pyramidal/proprioceptive dysfunction, normal serum folate, elevated serum Hcy and MMA Improved over 3 months Serum folate normal, elevated serum Hcy and MMA Improved over 9 months Proprioceptive dysfunction, serum folate normal, elevated serum Hcy Reduction in chorea and Stroke with Wernicke aphasia, ataxia over 2 months elevated serum Hcy Improved over 1 week Serum folate normal Improved over 1 week Sensorimotor neuropathy, serum folate normal Improved over 11 Sensory neuropathy, serum folate months normal, elevated serum Hcy Improved over 1 year —
Vitamin B 12 deficiency
Whether before or after Other treatment Vitamin B12 level Haematological Response to treatment Reference Year Age Sex (reference range) involvement* Type of movement disorder vitamin supplementation administered
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12 months 20 months
1997 10 months
7 months
1997 10 months
F M
M
M
M
37 pM/l (150–600) 85 pM/l (150–600)
35 pM/l (150–700)
28 pg/ml (250–1100)
41 pg/ml (200–900)
50 pM/l (150–600)
36 pM/l (150–600)
Undetectable
13 pM/l (138–781)
120 ng/l (90–900)
65 pg/ml
44 pg/ml (190–980)
80 pg/ml (190–980)
40 pg/ml (190–980)
10 pM/l (150–750)
,83 pg/ml (180–1100) 69 pg/ml (180–914)
51 pg/ml (190–980)
42 pg/ml (190–980)
48 pM/l (200–1200)
Vitamin B12 level (reference range)
z z
z
z
z
z
z
z
z
z
z
z
z
z
z
z z
z
z
z
Haematological involvement*
Tremor, myoclonus Unilateral tremor
Tremor, myoclonus
Myoclonus, chorea
Tremor
Tremor
Tremor, myoclonus
Tremor
Generalized tremors, myoclonus Tremor, myoclonus
Unilateral ‘twitching’
Tremor
Tremor
Tremor
Tremor, myoclonus
Tremor, myoclonus Tremors
Unilateral tremor/chorea Chorea
Tremor
Type of movement disorder
After, 2 days later Before
After, 2 days later
After, 3 days later
After, 3 days later
After, 2 days later
After, 3 days later
After, 3 days later
Before
After, 3 days later
Before
After, 4 days later
After, 5 days later
After, 1 day later
After, 3 days later
After, 5 days later Before
After, 3 days later
After
After, 3 days later
Improved 3 weeks Improved 2 weeks Improved 2 weeks Improved 3 weeks
Improved 5 days Improved 3 months Improved 12 days Improved 1 month ?
Improved 15 days Improved 1 week Improved 3 days ? Improved 3 months Improved 1 week Improved 10 days Improved .1 week
over
over
over
over
over
over
over
over
over
over
over
over
over
Response to treatment
Serum folate normal
Serum Hcy and urinary MMA increased Serum Hcy and urinary Hcy/MMA increased MRI: delayed myelination and frontoparietal cerebral atrophy
Serum folate normal
Serum folate normal
Serum folate normal
Serum folate normal
– Serum folate normal, urine MMA z Serum folate normal
Serum folate normal
Elevated serum Hcy and MMA Serum folate normal
Notes
–
over
Serum folate normal, urinary Hcy z – over Serum folate normal, elevated serum Hcy and urinary MMA – Improved over Serum folate normal, 6 weeks elevated urinary MMA and Hcy, MRI: delayed myelination, cerebral atrophy – Improved – Phenobarbitone, Improved over 3 weeks Seizuresz, Serum folate carbamazepine normal, CT scan: diffuse cerebral atrophy, bilateral subdural hygromas
Clonazepam
Clonazepam
–
–
–
Haloperidol
Clonazepam, propranolol, piracetam Clonazepam
Clonazepam
Clonazepam
– –
Clonazepam
Clonazepam
Clonazepam
Whether before or after Other treatment vitamin supplementation administered
M: male; F: female; Hcy: homocysteine; MMA: methylmalonic acid; z: present. *: anaemia, macrocytosis, and/or pancytopenia; ?: not reported.
23
22
F
11 months
M
F
2003 16 months
20
F
M
F
2001 12 months
2003 9 months
13
19
2005 6 months
21
F
16 months
2006 11 months
M
14 months
12
M
2008 13 months
16
M
2008 6 months
18
F M
2012 11 months 2009 7 months
M
16 months
17 11
F
2013 13 months
14
M
Sex
2013 9 months
Age
15
Reference Year
Table 2 Movement disorders associated with vitamin B12 deficiency in infants reported in the English literature since 1997
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macrocytosis, or pancytopenia); vomiting, lethargy and feeding difficulties; hypotonia, developmental regression, irritability, apathy, tremors, and seizures; and optic atrophy.10,15,16,18,21,23,27,39,73 Although such patients may even present without anaemia, all patients reported with movement disorders did manifest the haematological features of vitamin B12 deficiency. The type of movement disorder varies considerably: tremor, myoclonus, chorea, rolling movements or a combination of these and may last up to 1 month.22,73,76 They can be asymmetric11,25,38 and may or may not persist in sleep.16,19,76 Movements that begin after initiation of vitamin B12 replacement are usually more severe, become more intense with tactile stimulation, and on arousal. These movements have a hyperkinetic character; shaking movements, myoclonus, tremor, chorea, twitching, protrusion or tremor of the tongue, and wandering eyes are described in the literature.17 A distinction from seizures, which are also reported in vitamin B12 deficiency in infants, may be difficult.23 An electroencephalogram is often required: it is characterized by a slowing of the background activity, consistent with the lethargic and hyporeactive state of the child, without any epileptiform activity.17 Cerebral atrophy, thinning of the corpus callosum, and delayed myelination are seen on neuroimaging studies.21,73 Satisfactory clinical and imaging improvement usually follows vitamin B12 repletion, but permanent sequelae may be seen in children with severe and prolonged symptoms before diagnosis.37,77 von Schenck et al.35 summarized the clinical descriptions of 24 infants who had been reported up to 1997 with neurologic abnormalities due to infantile vitamin B12 deficiency; of the 16 infants for whom a follow-up was available 6 still had an abnormal neuro-developmental status years afterwards. These children had been diagnosed later (mean age 13 months) than those who improved with treatment (mean age 10 months).
Illustrative Case As an illustration, we present a 31-year-old Motswana man who presented with severe generalized chorea of 5 years’ duration. He had had an acute right hemiparesis 2 years prior to the onset of chorea, and a CT scan at the time showed a left caudate infarct. No further workup was done. The hemiparesis resolved nearly completely within 6 months. There were no systemic symptoms, no family history of chorea, and no psychiatric illness in the patient or his family. He denied intake of any drugs other than aspirin. At presentation, he had generalized chorea involving all the limbs – more prominently on the left side – as well as the axial musculature and face. Minimal pyramidal weakness was noted in the right
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upper and lower limbs. A mental status examination was normal, as were ocular movements (including saccades and antisaccades). The patient was cognitively normal and showed no signs of peripheral neuropathy or proprioceptive dysfunction, thus pseudoathetosis causing the abnormal movements was considered unlikely. Systemic examination was remarkable for a Marfanoid habitus with increased arm span to height ratio, high arched palate, and positive ‘wrist sign’ and ‘thumb sign’. No cataracts or lens subluxation were seen. Cardiac examination was normal, and there were no bruits. Laboratory tests revealed serum vitamin B12 levels of 195 pg/ml (reference range, 211–911), with serum homocysteine levels of 16.75 (reference range, 9–14). An MRI of the brain showed chronic infarcts in the left caudate nucleus and the right putamen. Blood counts with red cell indices, echocardiogram, human immunodeficiency virus serology, antinuclear antibodies, antineutrophil cytoplasmic antibodies, and thyroid function tests were within normal limits. Serum MMA levels, Schilling test, antiparietal cell antibody testing, and genetic testing for mutations in the MTHFR and huntingtin genes were not done due to logistic constraints. The patient had been on regular treatment with haloperidol (15 mg/day) for 3 years with no benefit. This was continued and a course of intramuscular cyanocobalamin (1000 mg daily for 10 days, then weekly for 1 month, and subsequently monthly) along with folic acid (5 mg/day) was initiated. After 3 months, a significant reduction in chorea was seen. Haloperidol was then tapered to 7.5 mg/day with no worsening of symptoms. This patient presents with generalized chorea which improved with vitamin B12 and folic acid supplementation. Although chorea may possibly be a result of neuronal reorganization following stroke, the generalized distribution of the movements as well as the lack of temporal relationship to the hemiparesis argues against this. The therapeutic benefit of vitamin B12 and folic acid therapy is striking and supports a role for vitamin deficiency in the genesis of this movement disorder. Although a Marfanoid habitus suggested homocystinuria, the mild elevation of homocysteine and lack of a family history and of other physical signs suggested that the primary factor was a deficiency of vitamin B12 rather than an inherited disorder of homocysteine metabolism.
Conclusions Vitamin B12 deficiency may, in rare cases, produce movement disorders in addition to its better-known effects on the CNS. Both adults and infants deficient in vitamin B12 may present with chorea, tremor, myoclonus, Parkinsonism, dystonia, or a combination of these, which may precede diagnosis or become
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apparent only a few days after parenteral replacement therapy has begun. The pathogenesis of these movement disorders shows interesting parallels to certain neurodegenerative conditions. The clinical syndrome responds well to vitamin B12 supplementation in most cases, and an early diagnosis is essential to reverse the haematologic and neurologic dysfunction characteristic of this disorder.
Disclaimer Statements Contributors A. S. contributed to the concept of the article, literature review, writing of the first draft, and approval of the final manuscript. M. W. M. provided literature review, critical appraisal of the first draft, and approval of the final manuscript. Funding No funding was received from any source. Conflicts of interest The authors do not report any conflicts of interest. Ethics approval The article is a retrospective review of previously published works, therefore ethical clearance was not sought from the Institutional Review Board. The patient in the illustrative case report provided written informed consent for his clinical details to be published.
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