This historical review addresses major
neurological disorders associated with deficiencies of water-soluble
B vitamins:
beriberi,
Wernicke-Korsakoff syndrome,
pellagra,
neural tube defects, and
subacute combined degeneration of the spinal cord.
Beriberi:
Beriberi was known for millennia in Asia, but was not described by a European until the 17th century when Brontius in the Dutch East Indies reported the progressive sensorimotor
polyneuropathy. The prevalence of
beriberi increased greatly in Asia with a change in the milling process for rice in the late 19th century. In the 1880s, Takaki demonstrated the benefits of
dietary modification in sailors, and later instituted dietary reforms in the Japanese Navy, which largely eradicated
beriberi from the Japanese Navy by 1887. In 1889 Eijkman in Java serendipitously identified dietary factors as a major contributor to "chicken
polyneuritis," which he took to be an animal model for
beriberi; the
polyneuritis could be cured or prevented by feeding the chickens either unpolished rice or rice polishings. By 1901, Grijns, while continuing studies of
beriberi in Java, suggested a dietary deficiency explanation for
beriberi after systematically eliminating deficiencies of known dietary components and excluding a toxic effect.
Wernicke-Korsakoff syndrome: In the late 1870s, Wernicke identified a clinicopathological condition with
ophthalmoparesis, nystagmus,
ataxia, and
encephalopathy, associated with punctate
hemorrhages symmetrically arranged in the grey matter around the third and fourth ventricles and the aqueduct of Sylvius. In the late 1880s, Korsakoff described a spectrum of
cognitive disorders, including a confabulatory
amnestic state following an agitated
delirium, occurring in conjunction with peripheral
polyneuropathy. Beginning around 1900, investigators recognized the close relationship between Korsakoff's
psychosis,
delirium tremens, and
Wernicke's encephalopathy, but not until several decades later were
Wernicke's encephalopathy, Korsakoff's
psychosis, and
beriberi all linked to the deficiency of a specific dietary
factor, i.e.
thiamin.
Thiamin:
Thiamin was crystallized from rice polishings by Jansen and Donath in 1926, and synthesized by Williams and Cline in 1936. In the late 1930s and early 1940s, characteristic pathological changes of
Wernicke-Korsakoff syndrome were produced in animal models, the biochemical roles of
thiamin in intermediary carbohydrate metabolism were elaborated by Peters and others, and the therapeutic benefits of
thiamin for
Wernicke-Korsakoff syndrome and
beriberi were demonstrated. By the 1950s synthetic forms of the
vitamin were produced cheaply, allowing both therapeutic administration and prevention with food enrichment.
Pellagra and
niacin:
Pellagra was unknown prior to the introduction of maize into Europe from the New World. In the 18th century, Casàl and Frapolli described the clinical features of
pellagra in Europe, and linked it with poverty and subsistence on nutritionally marginal corn-based diets. In the United States,
pellagra became epidemic among poor Southerners in the early 20th century, in part because of economically-driven reliance on monotonous, nutritionally inadequate diets, combined with new manufacturing methods that removed
vitamins from processed grain. From 1914-1929, Goldberger completed well-designed epidemiologic investigations, tested theories with human experiments, and utilized an animal model ("
black tongue" in dogs) - all strongly supporting a dietary deficiency explanation for
pellagra over prevailing toxic and infectious theories. Initial prevention and treatment approaches proved inadequate because of complex social issues linked to poverty, even after Goldberger and colleagues established that dried brewer's yeast could cure or prevent
pellagra less expensively than
dietary modification. During the depression, the collapse of cotton as an economically viable crop facilitated crop diversification, which contributed to an abrupt decline in
pellagra mortality in the early 1930s. In 1937 Elvehjem isolated the P-P (
pellagra preventive) factor, identified it as
nicotinic acid (
niacin), and demonstrated that
nicotinic acid and
nicotinic acid amide cure
black tongue in dogs. Although clinical trials soon confirmed dramatic
therapeutic effects in individual people, therapeutic administration of
niacin had relatively little impact on population-level morbidity and mortality.
Vitamin fortification of foodstuffs during World War II ultimately eradicated endemic
pellagra in the United States. In the 1940s and 1950s, with expanded biochemical knowledge,
pellagra was reformulated as a
deficiency disease due to inadequate
niacin and its
amino acid precursor
tryptophan.
Neural tube defects and
folate:
Folate deficiency was initially recognized clinically as a
macrocytic anemia in the 1920s, and only clearly separated from
pernicious anemia by the mid-20th century. When
folic acid was isolated and synthesized in the 1940s, it was shown to correct the
macrocytic anemia associated with
pernicious anemia, while the
neurological manifestations progressed. In the 1950s and 1960s, the biochemical role of folates in transferring single
carbon units was elucidated. Beginning in the 1960s,
folate deficiency was increasingly recognized as the major cause of preventable
neural tube defects. In the early 1990s well-designed randomized trials established that
folate supplementation could prevent
neural tube defects. Trial data, collectively indicating that periconceptual
folate administration reduces both the occurrence and recurrence risks of
neural tube defects by at least 70%, helped establish governmental recommendations concerning
folic acid intake and health policy concerning
vitamin fortification of foodstuffs. When
dietary modification and supplementation strategies proved inadequate,
folic acid food fortification was legally mandated in the US in the late 1990s, which significantly improved population
folate status and produced an abrupt decline (20%-27%) in the prevalence of
neural tube defects at birth. Recent studies have established
genetic predispositions for
neural tube defects, including both infant and maternal gene polymorphisms for
enzymes involved in
folate-dependent
homocysteine metabolism, which help explain how the genotype of the mother, the genotype of the unborn child, and environmental factors (e.g.
folate intake) can all impact on the risk of
neural tube defects.
Subacute combined degeneration and B(12) deficiency:
Pernicious anemia was recognized clinically in the mid-19th century by Addison, but the most important
neurological manifestation -
subacute combined degeneration of the spinal cord - was not recognized clinically and linked with
pernicious anemia until the end of the 19th century, particularly by Lichtheim, Putnam, and Dana. At the beginning of the 20th century,
pernicious anemia and the associated
subacute combined degeneration of the spinal cord were considered, by many investigators, to result from infectious or toxic causes. During the first quarter of the 20th century, various
therapies were employed, but, with the possible exception of transfusion, were largely ineffective. In the 1920s, Minot and Murphy showed that large quantities of ingested liver could be used to effectively treat
pernicious anemia, and specifically could improve or prevent progression of
neurological manifestations, and could extend life expectancy beyond 2 years. Beginning in the late 1920s, Castle demonstrated that a substance elaborated by the gastric mucosa ("
intrinsic factor") was essential for the absorption of a dietary factor ("extrinsic factor," later shown to be
vitamin B(12)) needed to prevent
pernicious anemia. Over two decades, from the late 1920s until the late 1940s, increasingly potent
liver extracts were manufactured that could be given either intramuscularly or intravenously. In 1947,
vitamin B(12) was isolated by Folkers and colleagues, and nearly simultaneously by Smith. Shortly thereafter the therapeutic efficacy of
vitamin B(12) on
subacute combined degeneration was demonstrated by West and Reisner and others. By 1955, Hodgkin determined the molecular structure of
cyanocobalamin using computer-assisted x-ray crystallography, allowing complete chemical synthesis of
vitamin B(12) in 1960 by an international consortium. Beginning in the late 1950s, the absorption and biochemistry of
vitamin B(12) were elaborated, and several lines of evidence converged to support an autoimmune basis for
pernicious anemia.