Elsevier

The Lancet Neurology

Volume 5, Issue 11, November 2006, Pages 949-960
The Lancet Neurology

Review
Vitamin B12, folic acid, and the nervous system

https://doi.org/10.1016/S1474-4422(06)70598-1Get rights and content

Summary

There are many reasons for reviewing the neurology of vitamin-B12 and folic-acid deficiencies together, including the intimate relation between the metabolism of the two vitamins, their morphologically indistinguishable megaloblastic anaemias, and their overlapping neuropsychiatric syndromes and neuropathology, including their related inborn errors of metabolism. Folates and vitamin B12 have fundamental roles in CNS function at all ages, especially the methionine-synthase mediated conversion of homocysteine to methionine, which is essential for nucleotide synthesis and genomic and non-genomic methylation. Folic acid and vitamin B12 may have roles in the prevention of disorders of CNS development, mood disorders, and dementias, including Alzheimer's disease and vascular dementia in elderly people.

Section snippets

Historical background

In the late 19th century, Leichtenstern1 and Lichtheim2 wrote the earliest accounts of the neurological associations of megaloblastic anaemia; they described typical lesions in the posterior and lateral columns of the spinal cord of which Russell and colleagues3 soon coined the term “subacute combined degeneration of the cord” (SCD). In the first third of the 20th century, before the availability of liver therapy, the neuropsychiatry and neuropathology of megaloblastic anaemia was thoroughly

Vitamin B12 and folate metabolism

Reviews of the structure, binding, absorption, transport, metabolism, function, and interaction of vitamin B12 and folates, and the polymorphisms of folate-related enzymes can be found elsewhere.12, 13, 17, 21, 24, 25, 26, 27 A key interaction is that between vitamin B12 and folate in the synthesis of methionine from homocysteine by methionine synthase, in which both 5-methyl-tetrahydrofolate and methyl-vitamin-B12 are cofactors (figure 1), a reaction that can be inhibited by nitrous oxide. The

Neurology of vitamin-B12 deficiency

Kinnier Wilson wrote the best review of the older detailed description of the overlapping syndromes of peripheral neuropathy, SCD, autonomic dysfunction, optic atrophy, mood and behaviour changes, psychosis, memory impairment, and cognitive decline.6 Recent studies have concentrated on early diagnosis and treatment based on the modern techniques for the separation of the megaloblastic anaemias.

Patients may present to haematologists and physicians with megaloblastic anaemia or to neurologists

Neurology of folic-acid deficiency

The first reports of megaloblastic anaemia due to folate deficiency associated with spinal-cord, peripheral-nerve, and mental disorders appeared in the mid-1960s.51, 52 These were soon followed by accounts of folate-responsive neuropsychiatric disorders in patients deficient in folate with or without anaemia or macrocytosis.53, 54, 55, 56

The reported neuropsychiatric effects of folate deficiency are remarkably similar to those described for vitamin-B12 deficiency. Shorvon and colleagues29

Vitamin-B12 deficiency

Two-thirds of patients with vitamin-B12 deficiency and neurological complications are still functionally independent at the time of diagnosis, and only about 10% are severely disabled.31, 32 The severity of the neurological disorder correlates with the duration of symptoms but also inversely with the haemoglobin concentration.31

The treatment of neuropsychiatric disorders is empirical, based mainly on haematological experience rather than neurological study.7, 32 Although remission of

Neural-tube defects

Inadequate maternal folate intake and status is one of several well-established factors that can increase the risk of neural-tube defects, especially spina bifida and anencephaly.14, 114, 117, 118 Impaired vitamin-B12 status and high plasma homocysteine are also suspected to be additional or related risk factors.119, 120 Periconceptional preventive treatment with 400 μg folic acid significantly reduces the risk of such defects but at least a third of neural-tube defects are not preventable with

Dissociation

An issue that has puzzled many for a century is the lack of association between the haematological and neuropsychiatric manifestations of vitamin-B12 or folate deficiencies.6, 7, 8, 10, 29, 30, 31 This dissociation has led to repeated suggestions that the nervous-system disorders must have a different mechanism to the megaloblastic anaemia.7, 10, 30, 31 To some extent, the dissociation is illusory, reinforced by the relatively early modern diagnosis of these disorders. In the first third of the

Conclusions

Vitamin-B12 and folic-acid deficiency and related inborn errors of metabolism may result in similar megaloblastic anaemias and overlapping neuropsychiatric complications. In the early stages there is often dissociation between the neuropsychiatric and haematological manifestations, as occurs in other general metabolic disorders that affect the CNS. The occurrence of CNS complications is influenced by the duration as well as the severity of either deficiency, by predisposing genetic factors,

Search strategy and selection criteria

References for this review were identified through searches of PubMed most recently done on June 1, 2006, and of the authors' files from 1966. The search terms were “vitamin B12”, “folic acid”, “folate”, “nervous system”, “neuropathy”, “dementia”, “epilepsy”, “multiple sclerosis”, “nitrous oxide”. Relevant textbooks were also used. The final reference list was generated on the basis of originality and relevance to each of the subtopics reviewed.

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