Definition
Most nutritional disorders with deleterious effects on the central and peripheral nervous system are secondary to vitamin deficiencies, particularly those of the B group. Many of these disorders occur in the setting of malnutrition associated with alcoholism.
A detailed discussion of all vitamin B deficiencies is beyond the scope of this article. However, four of the more common vitamin B deficiencies—thiamine (B1), cobalamin (B12), niacin (B3), and folate (B9)—are reviewed.
Thiamine (vitamin B1)
Thiamine is a water-soluble vitamin required for carbohydrate metabolism. Thiamine diphosphate, the biologically active form of thiamine, is a required cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, two important enzymes in the Krebs cycle, and for transketolase, a key enzyme involved in the pentose phosphate pathway. Thiamine deficiency results in impaired carbohydrate and lipid metabolism, altered mitochondrial activity, decreased energy stores, reduced neurotransmitter synthesis, and altered cellular membrane functions. [1, 2, 3]
Thiamine deficiency can result in disorders that affect both the central and peripheral nervous systems. Wernicke encephalopathy (WE) is an acute, life-threatening but potentially reversible central nervous system disorder. If WE is not treated, the condition progresses to Korsakoff syndrome (KS), with resulting permanent brain damage. Wernicke-Korsakoff syndrome (KWS) has been used to describe the spectrum of clinical and pathologic changes associated with thiamine deficiency. [4]
Thiamine deficiency can also cause beriberi. Dry beriberi is a peripheral nervous system disorder associated with peripheral neuropathy. Wet beriberi is a cardiovascular disorder associated with cardiac manifestations and edema secondary to congestive heart failure. [5] Infantile beriberi can occur in breastfed infants secondary to inadequate thiamine levels in the mother's breast milk.
Cobalamin (vitamin B12)
Cobalamin is found exclusively in animal products. It is required cofactor for two enzymatic reactions in humans. Methylcobalamin is required for methionine synthase, which converts homocysteine to methionine while simultaneously transforming 5’-methyltetrahydrofolate (5-MTHF) to tetrahydrofolate (THF). Adenosylcobalamin is necessary for methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA within mitochondria. [6, 7]
Cobalamin deficiency leads to reduced DNA synthesis, altered cell metabolism, and impaired myelin maintenance. Clinical features of cobalamin deficiency include myelopathy, peripheral neuropathy, optic neuropathy, glossitis, neuropsychiatric changes, and hematologic manifestations including megaloblastic anemia. [8]
Niacin (vitamin B3, nicotinic acid)
Niacin is a water-soluble vitamin and an essential component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), coenzymes required for oxidation-reduction reactions. [9] Niacin can be found in the diet or can be synthesized during tryptophan metabolism. Niacin deficiency results in pellagra, a condition characterized by diarrhea, dermatitis, dementia and, eventually, death.
Folate (vitamin B9)
Folate is a water-soluble essential vitamin found in green leafy vegetables and the liver. Folate is converted into THF, the active form involved in single-carbon transfers in a variety of metabolic reactions. [10] THF is required for the conversion of homocysteine to methionine (which also requires cobalamine), the synthesis of thymine and purine bases, and the metabolism of serine and glycine.
Folate deficiency is most commonly associated with megaloblastic anemia. Pregnant women with low folate intake have an increased risk of neural tube defects (NTDs); folic acid supplementation reduces the risk of NTDs. [11, 12] In rare cases, folate deficiency may be associated with subacute combined degeneration of the spinal cord.
Epidemiology
Thiamine (vitamin B1)
The prevalence of Wernicke encephalopathy (WE) in the general population is estimated to be 0.8%-2.8%. [13] In developed countries, WE occurs most frequently in the setting of alcoholism, with an incidence of up to 12.5%. [1] Up to 80% of patients with WE who survive will progress to Korsakoff syndrome (KS). [4, 14] Beriberi is rare in Western countries, but it can be seen in alcoholics, malnourished adults, and pregnant women with hyperemesis gravidarum. [5, 15]
Cobalamin (vitamin B12)
The prevalence of cobalamin deficiency in the United States and the United Kingdom is approximately 6% in those younger than 60 years; in adults older than 60 years, the prevalence is approximately 20%. African and Asian countries have a much higher prevalence of cobalamin deficiency. [8]
Niacin (vitamin B3, nicotinic acid)
Although endemic pellagra has nearly been eradicated in Western countries due to the fortification of grains and cereals, [16] niacin deficiency still occurs in setting of alcoholism and malnutrition, even in developed nations. [17] One autopsy series reported a prevalence of 27% in their cases of chronic alcoholism. [18]
Folate (vitamin B9)
The frequency of folate deficiency varies among countries and age groups. [19] In countries with folic acid fortification programs, folate deficiency has dramatically decreased. One study found an overall 0.1% US prevalence of folate deficiency after the implementation of folic acid fortification of enriched cereal grains in 1998. [20]
Etiology
Thiamine (vitamin B1)
Thiamine deficiency can occur with inadequate nutrition, reduced thiamine absorption, impaired thiamine utilization, and excess thiamine use. [21] This condition is frequently seen in adults with chronic alcoholism. Alcohol increases thiamine utilization, reduces gastrointestinal uptake, and impairsthiamine phosphorylation. [22] Thiamine deficiency may also be seen in the pediatric and adolescent population [23] and in nonalcoholic conditions such as poor nutritional status, prolonged parenteral feeding, gastrointestinal diseases, prolonged diarrhea, recurrent vomiting, bariatric surgery, liver disease, malignancy, hyperemesis gravidarum, and hemodialysis. [4, 14, 24] Children with genetic defects in thiamine transport and metabolism are generally affected with primary thiamine deficiency. [25]
Cobalamin (vitamin B12)
Cobalamin must bind to intrinsic factor, a glycoprotein produced by parietal cells in the stomach, before it is absorbed in the terminal ileum. Cobalamin deficiency can result from reduced production of intrinsic factor and/or cobalamin malabsorption. Impaired intrinsic factor production can result from pernicious anemia, gastrectomy, and bariatric surgery. [8, 24, 26] Malabsorption may be seen with ileal resection, Crohn disease, tuberculous ileitis, celiac disease, tropical sprue, as well as Helicobacter pylori gastritis. Cobalamin deficiency may also occur with pancreatic insufficiency; malnutrition; strict vegetarian and vegan diets; and congenital disorders of cobalamin absorption, transport, metabolism or utilization; and also with the use of various drugs including protein pump inhibitors and H2-receptor antagonists. [6, 8] Infants exclusively breastfed by vitamin B12-deficient mothers are also at risk for cobalamin deficiency.
Niacin (vitamin B3, nicotinic acid)
Niacin deficiency may be associated with an insufficient dietary intake of niacin or tryptophan; chronic intestinal disorders with malabsorption, including Crohn disease and Hartnup disease; diets rich in leucine (eg, corn maize) as the primary carbohydrate source; carcinoid; hemodialysis; and isoniazid therapy. [5, 14, 18]
Folate (vitamin B9)
Folate deficiency is associated with malnutrition, malabsorption secondary to intestinal diseases (eg, celiac disease and tropical sprue), and rare inborn errors of folate metabolism. Medications with antifolate activity include methotrexate, trimethoprim, and various antiepileptic drugs (eg, phenytoin, carbamazepine, and barbiturates). Very rarely, folate deficiency may occur after bariatric surgery. [24]
Location
Thiamine (vitamin B1)
Wernicke encephalopathy and Korsakoff syndrome involve the bilateral mammillary bodies, medial hypothalamus, thalamus, periaqueductal gray matter, and the floor of the fourth ventricle. Dry beriberi affects the peripheral nervous system.
Cobalamin (vitamin B12)
Cobalamin deficiency results in a demyelinating disorder of the spinal cord.
Niacin (vitamin B3, nicotinic acid)
Niacin deficiency primarily affects neurons in the brainstem, cerebellar dentate nucleus, and spinal cord.
Folate (vitamin B9)
Folate deficiency may also result in a demyelinating disorder of the spinal cord.
Clinical Features and Imaging
Thiamine (vitamin B1)
Wernicke encephalopathy (WE) is clinically characterized by a classic triad of acute/subacute ataxia, altered mental status, and ocular motor abnormalities, including ophthalmoplegia and nystagmus. Korsakoff syndrome (KS) is characterized by the additional clinical features of anterograde and retrograde amnesia, disorientation, lack of insight, confabulation, and apathy. [1, 4]
Imaging features of WE and KS are similar. In acute WE, magnetic resonance imaging (MRI) shows symmetrical areas of hyperintensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the mammillary bodies, thalami, periaqueductal gray matter, and superior and inferior colliculi. [27] Patients with chronic Wernicke-Korsakoff syndrome (KWS) show shrinkage of the mammillary bodies. KS has been associated with more severe damage to the anterior thalamic nuclei, hypometabolism in the thalamus, and hippocampal volume deficits. [27, 28]
Dry beriberi is characterized by a symmetric, predominantly distal, sensorimotor polyneuropathy with dysesthesias, reduced distal reflexes, and muscle weakness. Wet beriberi is a cardiovascular disorder with high-output cardiac failure, peripheral edema, pulmonary edema, and orthopnea.
Cobalamin (vitamin B12)
Cobalamin deficiency results in megaloblastic anemia and subacute combined degeneration (SCD) of the spinal cord. SCD is characterized by progressive symmetrical sensorimotor disturbances of the lower limbs, followed by ataxia, spasticity, and loss of reflexes. MRI shows hyperintensities in the posterior columns of the spinal cord on T2-weighted images. [29] Infants with cobalamin deficiency demonstrate developmental delay, poor brain growth, hypotonia, failure to thrive, lethargy, and irritability. [6, 30] MRI may reveal dilated ventricles, a thin corpus callosum, delayed myelination, and/or brain atrophy. [30, 31, 32]
Niacin (vitamin B3, nicotinic acid)
As mentioned earlier, pellagra is classically characterized by "the three Ds": dermatitis, diarrhea, and dementia. Pellegrous encephalopathy is characterized by confusion, apathy, depression, impaired memory, abnormal gait, and spastic quadriplegia in severe cases. [5]
Folate (vitamin B9)
Folate deficiency is associated with elevated serum levels of homocysteine. Neurologic symptoms that occur with folate deficiency include cognitive impairment, dementia, and depression. In rare cases, subacute combined degeneration (SCD) of the spinal cord may occur. SCD due to folate deficiency clinically resembles the SCD associated with cobalamin deficiency.
Gross Findings
Thiamine (vitamin B1)
The acute phase of Wernicke encephalopathy shows bilateral, symmetric areas of softening, with petechial hemorrhages in the mammillary bodies, thalamus, medial hypothalamus, periaqueductal gray matter, floor of the fourth ventricle, and colliculi. In chronic Wernicke-Korsakoff syndrome, there is shrinkage and brown discoloration of the mammillary bodies accompanied by variable degrees of hydrocephalus.
Cobalamin (vitamin B12)
Cobalamin deficiency is characterized by atrophy and discoloration of the posterior columns (gracile fasciculi and cuneate fasciculi) and the lateral columns (the lateral corticospinal tracts more frequently than the lateral spinothalamic tracts) of the spinal cord.
Niacin (vitamin B3, nicotinic acid)
The brain and spinal cord are macroscopically normal in pellagra.
Folate (vitamin B9)
Folate deficiency may associated with atrophy and discoloration of the posterior and lateral columns of the spinal cord.
Microscopic Findings
Thiamine (vitamin B1)
Acute Wernicke encephalopathy (WE) is characterized by hypertrophy of vascular endothelial cells, edema, extravasation of erythrocytes, microglial activation, and variable intervening necrosis with sparing of neurons. In chronic WE, there is rarefaction and macrophage infiltration with a background of gliosis as well as loss of myelin and axons. Hemosiderin-laden macrophages may also be present. WE and Korsakoff psychosis may show neuronal loss in the mammillary bodies and mediodorsal thalamic nuclei. Only patients with Korsakoff psychosis have neuronal loss in the anterior thalamic nuclei. [33]
Early Wernicke encephalopathy. Note the prominent capillaries, microglial proliferation, and edema within the mammillary bodies (1 of 2).
Early Wernicke encephalopathy, with prominent capillaries, microglial proliferation, and edema within the mammillary bodies (2 of 2).
Beriberi peripheral neuropathy is characterized by axonal degeneration of large myelinated fibers with preservation of small myelinated and unmyelinated axons, and it is frequently accompanied by secondary segmental demyelination. [15]
Cobalamin (vitamin B12)
Subacute combined degeneration (SCD) of the spinal cord is characterized by spongy vacuolation and demyelination of the posterior and lateral columns of the spinal cord, particularly in the thoracic region. Swelling and ballooning of myelin, intramyelinic vacuoles, and separation of myelin lamellae may occur. In severe cases, there may be progression to axonal degeneration, infiltration of macrophages, and gliosis. [5, 8, 34]
Subacute combined degeneration of the spinal cord with spongy vacuolization and demyelination in the gracile funiculi of the posterior columns (A: hematoxylin & eosin [H&E] stain; B: stained with luxol fast blue/periodic acid-Shiff [LFB/PAS] stain).
Niacin (vitamin B3, nicotinic acid)
Pellagra is characterized by chromatolysis of neurons in the pontine nuclei and cerebellar dentate nuclei. Betz cells of the motor cortex may be involved in case induced by use of isoniazid therapy. [35] In severe cases, other brainstem nuclei and anterior motor neurons in the spinal cord may be affected.
Folate (vitamin B9)
Histologic features of SCD of the spinal cord due to folate deficiency are identical to those in cobalamin deficiency–associated SCD.
Differential Diagnosis
Thiamine (vitamin B1)
Based on neuropathologic findings, the main differential diagnosis for Wernicke-Korsakoff syndrome (WKS) is Leigh syndrome, a progressive neurometabolic disorder caused by mutations in mitochondria-related genes encoded by nuclear DNA or mitochondrial DNA. Leigh syndrome frequently presents in infancy, although pediatric and adult cases are reported. The topographic distribution and histology of central nervous system lesions in WKS and Leigh's disease are similar; however, mammillary bodies are typically spared in Leigh syndrome.
Cobalamin (vitamin B12)
Other causes of subacute combined degeneration of the spinal cord include human immunodeficiency virus (HIV)-associated myelopathy, nitrous oxide abuse, and folate deficiency. [19, 36]
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Subacute combined degeneration of the spinal cord with spongy vacuolization and demyelination in the gracile funiculi of the posterior columns (A: hematoxylin & eosin [H&E] stain; B: stained with luxol fast blue/periodic acid-Shiff [LFB/PAS] stain).
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Early Wernicke encephalopathy. Note the prominent capillaries, microglial proliferation, and edema within the mammillary bodies (1 of 2).
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Early Wernicke encephalopathy, with prominent capillaries, microglial proliferation, and edema within the mammillary bodies (2 of 2).
