Deficiency Diseases of the Nervous System

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Chapter 57 Deficiency Diseases of the Nervous System

Malnutrition causes a wide spectrum of neurological disorders (Table 57.1). Despite socioeconomic advances, nutritional deficiency diseases such as kwashiorkor and marasmus are still endemic in many underdeveloped countries. The problem in Western countries is usually the result of dietary insufficiency from chronic alcoholism or malabsorption due to gastrointestinal (GI) diseases. The B vitamins (thiamine, pyridoxine, nicotinic acid, and vitamin B12), vitamin E, and perhaps folic acid are important for normal function of the nervous system. Emerging evidence also supports important roles of vitamin D and copper.

Table 57.1 Neurological Manifestations in Deficiency Diseases

Neurological Manifestations Associated Nutritional Deficiencies
Dementia, encephalopathy Vitamin B12, nicotinic acid, thiamine, folate
Seizures Pyridoxine
Myelopathy Vitamin B12, vitamin E, folate, copper
Myopathy Vitamin D, vitamin E
Peripheral neuropathy Thiamine, vitamin B12, and many others
Optic neuropathy Thiamine, vitamin B12, and many others

Most causes of nutritional deficiency, whether dietary or malabsorptive, do not selectively deplete a single vitamin. This is especially true among the malnourished populations in underdeveloped countries where the diet may lack more than one nutrient, and overlapping neurological syndromes are the result. Individual vitamin requirements are influenced by many factors. The daily need for thiamine and nicotinic acid, important compounds in energy metabolism, increases proportionally with increasing caloric intake and energy need. For example, symptoms of thiamine deficiency may occur in at-risk patients during periods of vigorous exercise and high carbohydrate intake. Other factors such as growth, infection, and pregnancy may also worsen deficiency states.

Cobalamin (Vitamin B12)

The terms vitamin B12 and cobalamin are used interchangeably in the literature. Cobalamins are abundant in meat, fish, and most animal byproducts. Although vegetables are generally devoid of the vitamin, strict vegetarians seldom develop symptoms because only 1 mg is needed per day, and an adequate amount is available in legumes. Intestinal absorption of cobalamin requires the presence of intrinsic factor, a binding protein secreted by gastric parietal cells. Cobalamin binds to intrinsic factor, and the complex is transported to the ileum where it is absorbed into the circulation. A small amount of free cobalamin, about 1% to 5%, is also absorbed through the entire intestine without intrinsic factor. Once absorbed, cobalamin binds to a transport protein, transcobalamin, for delivery to tissues. As much as 90% of total body cobalamin (1-10 mg) is stored in the liver. Even when vitamin absorption is severely impaired, many years are needed to deplete the body store. A clinical relapse in pernicious anemia after interrupting cobalamin therapy takes an average of 5 years to be recognized.

Two biochemical reactions depend on cobalamin. One involves methylmalonic acid as precursor in the conversion of methylmalonyl coenzyme-A (co-A) to succinyl co-A. The importance of this to the nervous system is unclear. The other is a folate-dependent reaction in which the methyl group of methyltetrahydrofolate is transferred to homocysteine to yield methionine and tetrahydrofolate. The reaction depends on the enzyme methionine synthase, which uses cobalamin as a cofactor. Methionine is converted to S-adenosylmethionine (SAM), which is used for methylation reactions in the nervous system.

Causes of Deficiency

The classic disease, pernicious anemia, is caused by defective intrinsic factor production by parietal cells, leading to malabsorption. These patients may have demonstrable circulating antibodies to parietal cells or lymphocytic infiltrations of the gastric mucosa, suggesting an underlying autoimmune disorder. Another common cause of malabsorption is food-cobalamin malabsorption (Dali-Youcef and Andres, 2009). Under some clinical settings, the normal digestive process fails to release cobalamin from food or intestinal transport protein. Cobalamin remains bound and cannot be absorbed even in the presence of available intrinsic factors. Predisposing factors include atrophic gastritis and hypochlorhydria, and malabsorption may be seen with Helicobacter pylori infection, gastrectomy or other gastric surgeries, intestinal bacterial overgrowth, and prolonged use of H2 antagonists, proton pump inhibitors, or biguanides (e.g., metformin). Patients with human immunodeficiency virus (HIV) are often observed to have a low serum cobalamin level, usually with normal homocysteine and methylmalonic acid. The significance of this association is unknown.

People who abuse nitrous oxide may develop a clinical syndrome of myeloneuropathy indistinguishable from that of cobalamin deficiency. The mechanism appears to be an interference with the cobalamin-dependent conversion of homocysteine to methionine. The other pathway, conversion of methylmalonyl co-A to succinyl co-A, is unaffected by nitrous oxide. Prolonged exposure to nitrous oxide is necessary to produce neurological symptoms in normal individuals. By contrast, patients who are already deficient in cobalamin may experience neurological deficits after only brief exposures during general anesthesia. Symptoms appear subacutely after surgery and resolve quickly with cobalamin treatment (Singer et al., 2008).

Laboratory Studies

Serum assays of vitamin B12 and cobalamin-dependent metabolites provide direct measures of cobalamin homeostasis, although there are important limitations (Solomon, 2005). Blood cobalamins are bound to two transport proteins, transcobalamin and haptocorrin. The cobalamin bound to transcobalamin, known as holotranscobalamin, is the fraction that is available to tissues, although it accounts for only 10% to 30% of the serum level measured by standard laboratory methods. Serum levels are influenced by conditions that affect the concentrations of these transport proteins. Myeloproliferative and hepatic disorders may raise the concentration of haptocorrin and cause a falsely normal serum level. A misleadingly high serum level also may result from the presence of an abnormal cobalamin-binding protein. In contrast, pregnancy and contraceptives may give falsely low measurements in the absence of deficiency. Folate deficiency also causes a falsely low cobalamin serum level that corrects after folate replacement. These confounding factors diminish the sensitivity and specificity of the commonly used assay of total serum cobalamin in the diagnosis of deficiency state. Although measurement of holotranscobalamin is better in theory, available data suggest that its diagnostic accuracy is approximately equivalent to that of total serum cobalamin (Miller et al., 2006).

Homocysteine and methylmalonic acid are precursors of cobalamin-dependent biochemical reactions. These metabolites accumulate during deficiency state. Measuring these metabolites is useful in settings of nitrous oxide abuse and in inherited metabolic disorders in which cobalamin-dependent pathways are impaired despite normal serum level. Homocysteine and methylmalonic acid assays are also useful when the cobalamin concentration is in the lower range of normal, between 200 and 350 pg/mL. Homocysteine level should be measured either at fasting or after an oral methionine load. The blood sample should be refrigerated immediately after collection because the level increases if whole blood is left at room temperature for several hours. Elevated levels of homocysteine and methylmalonic acid are not specific for cobalamin deficiency, as there are many other causes of increase in these metabolites (Box 57.1). In cobalamin-deficient patients, these levels typically normalize within 2 weeks of treatment.

In patients with autoimmune gastritis and intrinsic factor deficiency, antibodies against parietal cell and intrinsic factor may be elevated. Anti–parietal cell antibodies are nonspecific and are present in other autoimmune endocrinopathies as well as occasional normal individuals. Anti–intrinsic factor antibodies are less sensitive (50%–70%) but are specific for pernicious anemia. Elevated serum gastrin level is a marker of atrophic gastritis and hypochlorhydria and is a sensitive (up to 90%) but nonspecific indicator of pernicious anemia. The Schilling test measures intestinal cobalamin absorption using radiolabeled cobalamin and intrinsic factor but has fallen out of favor, in part because the labeled cobalamin is not readily available. In food-cobalamin malabsorption, the routine Schilling test is normal, but a modified Schilling test using protein-bound cobalamin may show impaired absorption.

The classic hematological manifestation of pernicious anemia is a macrocytic anemia. Erythrocyte or bone marrow macrocytosis or hypersegmentation of polymorphonuclear cells may be present without anemia. Hematological abnormalities may be absent at the time of neurological presentation and are thus insufficiently sensitive for use in diagnosis.

Because most patients present with clinical features suggesting a myelopathy or encephalopathy, imaging studies are necessary to exclude structural causes. Results of magnetic resonance imaging (MRI) may be normal, or T2-signal abnormalities may be seen in the lateral or posterior columns in patients with subacute combined degeneration (Kumar and Singh, 2009) (Fig. 57.1). Both gadolinium enhancement and spinal cord swelling have been described. Patients with encephalopathy or dementia often have multiple foci of T2 signal abnormalities in the deep white matter that may become confluent with disease progression. Radiographic improvement is seen within a few months after initiation of treatment. Nonspecific abnormalities of electroencephalography, as well as visual and somatosensory evoked responses, are present in most patients with neurological abnormalities. Nerve-conduction studies show small or absent rural nerve sensory potentials in approximately half of patients, providing evidence for an axonal polyneuropathy.


The term subacute combined degeneration of the spinal cord describes the pathological process seen in this disorder. Microscopically, spongiform changes and foci of myelin and axon destruction are seen in the white matter of the spinal cord. The most severely affected regions are the posterior columns at the cervical and upper thoracic levels (Fig. 57.2). Pathological changes also are seen commonly in the lateral columns, whereas the anterior columns are involved in only a small number of the advanced cases. The pathological findings of the peripheral nervous system are those of axonal degeneration, but in some cases there is evidence of demyelination. Involvement of the optic nerve and cerebral white matter also occurs.

Folate Deficiency and Homocysteine

Folate deficiency may produce the same neurological deficits as those seen in cobalamin deficiency because of its central role in the biosynthesis of methionine, SAM, and tetrahydrofolate (see Cobalamin Deficiency). Overt neurological manifestations are rare in folate deficiency, probably owing to alternative cellular mechanisms that are available to preserve SAM levels in times of folate scarcity.

Clinical Features

The majority of patients with laboratory evidence of folate deficiency do not have overt neurological findings. The classic syndrome of folate deficiency is similar to subacute combined degeneration seen in cobalamin deficiency. Presenting symptoms are limb paresthesias, weakness, and gait unsteadiness. These patients have megaloblastic anemia, impaired position and vibration sense, pyramidal signs, and possibly dementia. Chronic folate deficiency may result in mild cognitive impairment or increased stroke risk in adults, and in increased frequency of neural tube defects in babies born to folate-deficient mothers. Since 1998, the U.S. Food and Drug Administration mandates fortification of grain products with folate. The level of supplement, on the average, increases the dietary folate intake of adults by 100 mg/day.

Serum homocysteine is an important surrogate marker for folate metabolism, although there are other causes of elevated homocysteine levels. Hyperhomocysteinemia is a risk factor for vascular diseases and venous thrombosis. For cerebrovascular disease, the association is strongest for multi-infarct dementia and white-matter microangiopathy, but there is little or no association with cardioembolic or large-artery disease. Even a modestly increased serum level, in the range of 15 to 20 mmol/L, engenders a recognizable increase in vascular risk. On the other hand, it is as yet unclear whether folate supplementation can provide any reduction in vascular adverse outcomes.

Although low folate level is present in many elderly asymptomatic people, the prevalence seems to be higher in the psychiatric and Alzheimer disease populations. Moreover, a low folate level appears to correlate with depression and cognitive impairment. Even in healthy older adults, a low folate level is associated with subtle deficits in neuropsychological test performance.

Clinical observations in two inborn errors of metabolism reinforce our understanding of the role of homocysteine in neurological diseases. Hereditary deficiency of cystathionine β-synthase leads to hyperhomocysteinemia and hyperhomocysteinuria. The homozygous form presents with markedly elevated homocysteine levels, mental retardation, premature atherosclerosis, and seizures. Heterozygous individuals have milder elevations of homocysteine and also have increased risk of vascular disease. A much more common condition is a C-to-T substitution at codon 677 in the gene coding for N5, N10-methylenetetrahydrofolate reductase (MTHFR). Some 5% to 10% of the white population are homozygotes for this C677T mutation. These individuals have mildly elevated homocysteine levels and increased risk of vascular disease.

Vitamin E

Vitamin E refers to a group of tocopherols and tocoretinols, of which α-tocopherol is the most important. It is a free-radical scavenger and an antioxidant, and has attracted attention for its potentials in the prevention and treatment of a wide range of neurological diseases. Unfortunately, the value of vitamin E for these indications has yet to be proven. We limit discussion here to the neurological manifestations of vitamin E deficiency.

Like other fat-soluble compounds, vitamin E depends on the presence of pancreatic esterases and bile salts for its solubilization and absorption in the intestinal lumen. Neurological symptoms of deficiency occur most commonly in patients with fat malabsorption (Box 57.2). A reduced bile salt pool may be caused either by reduced hepatic excretion, as in congenital cholestasis, or by interruption of the enterohepatic reabsorption of bile, as in patients with extensive small-bowel resection. Pancreatic insufficiency contributes to malabsorption. Another setting is cystic fibrosis.

A rare familial form of fat malabsorption is abetalipoproteinemia (Bassen-Kornzweig syndrome), a disorder in which impaired chylomicron and lipoprotein synthesis is partly responsible for the impaired fat absorption. In addition to a neurological syndrome similar to that seen in other vitamin E-deficient states, spiky red blood cells (acanthocytes) and retinal pigment changes are characteristic. Another hereditary cause of vitamin E deficiency may be a genetic defect in the assembly or secretion of chylomicrons, leading to a chylomicron retention disease that is demonstrable in the intestinal mucosa (Aguglia et al., 2000). A syndrome of ataxia with isolated vitamin E deficiency (AVED) occurs in patients without GI disease or generalized fat malabsorption. Mutations in the α-tocopherol transfer protein gene (TTPA) on chromosome 8q13 are responsible (Mariotti et al., 2004

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