Nutritional Neuropathy

Updated: Sep 25, 2017
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Overview

Background

The first study of the relationship between nutrition and peripheral neuropathy began in the 19th century, when polyneuropathy and heart failure from beriberi reached epidemic proportions. In 1897, Dr. Eijkman cured the disease in pigeons by feeding them the nutrient-rich rice husks that were stripped from the polished rice produced by the grain mills of the time. Most of the work on vitamins goes back to 1900s. The use of thiamin and its disulfide derivatives in particular is often neglected in Western medicine.

Beriberi was described in the 17th century when Brontius reported cases of sensorimotor polyneuropathy in the Dutch East Indies. The mystery ingredient was christened "vitamine" in 1911 and then changed to "thiamine" in 1936 because it is not an amine and the sulfur-containing molecular structure was characterized. Since then, outbreaks of nutritional neuropathy have occurred in World War II prisoner-of-war camps, Jamaican sugar-cane plantations, and Cuba following the collapse of Soviet food support in the 1990s. More recently, bariatric surgery has lead to increasing numbers of patients with nutritional deficiencies and consequent neurologic problems. [1, 2, 3, 4, 5, 6, 7, 8]

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Pathophysiology

Neuropathies occur in 2 forms: an isolated deficiency (usually of a B vitamin) or a complex deficiency resulting from several concurrent metabolic disorders (usually including malabsorption). The mechanisms of the discrete deficiencies are described below.

Alcohol exposure

Ethanol intercalates into cell membranes, increasing membrane fluidity. Alcohol also affects many signal-transduction proteins, including ion channels, secondary messengers, neurotransmitters, neurotransmitter receptors, G proteins, chaperonins, and regulators of genetic expression. [9, 10]

Peripheral neuropathy is often the earliest symptom of chronic alcohol dependence, and generally occurs after consumption of at least 100 g/d for several years. Peripheral nerve damage results from 3 processes, and it is controversial which is the most important. The first is nutritional deficiency, especially thiamine deficiency, as ethanol interferes with thiamine absorption in the intestine. Other deficiencies may involve niacin, folate, or protein. The second is direct toxicity from abnormal products (eg, phosphatidyl ethanol, fatty acid ethyl esters) and from metabolites (eg, acetaldehyde that reacts with proteins to form adducts). The third is indirect toxicity (ie, neuropathy from hepatic dysfunction).

Likely, the direct toxic effects of ethanol and its metabolites are involved in the pathogenesis of the pure form of alcoholic neuropathy but this can be modified by a superimposed thiamine deficiency.

Thiamine deficiency

Thiamine (vitamin B 1 ) is found in wheat germ, or the outer layer of seeds, nuts, and most vegetables. Thiamine pyrophosphate is essential for the proper transfer of the aldehyde groups, and it is an essential coenzyme for glycolytic and pentose pathways of glucose metabolism. Four enzymes need thiamine: pyruvate dehydrogenase, α -ketoglutarate dehydrogenase, transketolase, and branched-chain α -ketoacid dehydrogenase.

Body tissues store about 30 mg but use about 1-2 mg daily. The United States recommended daily allowance (RDA) for men is 1.5 mg. Daily intake of less than 0.2 mg causes a discontinuous degeneration of the axonal sheath with subsequent impairment of the axon, producing a polyneuropathy in about 3 months. The vagal nerve is affected particularly, causing symptoms in the distributions of the cardiac, laryngeal, and recurrent nerves.

Thiamine deficiency can cause wet beriberi, for which congestive heart failure is the primary symptom, or dry beriberi, in which a peripheral neuropathy is the primary symptom, depending on the percentage of carbohydrates in the diet; wet beriberi is associated with high carbohydrate intake. Deficiencies preferentially affect the nervous and cardiac tissue because thiamine pyrophosphate is bound less strongly there than elsewhere. Essa et al describe a case in which cardiac MRI revealed myocardial edema associated with wet beriberi. [11]

Niacin deficiency

Niacin (vitamin B 3 ) is found in yeast, beef, pork, and chicken. The active form of this coenzyme, nicotinamide adenine dinucleotide (NAD), is essential for electron and acyl-group transfer in glycolysis. A deficiency of niacin causes pellagra. The US RDA for men is 20 mg.

Pyridoxine deficiency and excess

Pyridoxine (vitamin B 6 ) widely occurs in plant and animal tissues, such as muscle meats, liver, vegetables, and whole-grain cereals. Vitamin B 6 consists of pyridoxine, pyridoxal, and pyridoxamine. It is involved in primary carboxylation and transamination, playing a role in metabolizing tryptophan, glycine, serotonin, and glutamate, as well as sulfur-containing amino acids. Pyridoxine is used in the synthesis of both heme and γ -aminobutyric acid (GABA). Deficiencies are usually associated with increased excretion due to isoniazid ingestion and cause a sensorimotor neuropathy and seizures. Pyridoxine deficiency is rarely associated with a vasculitic mononeuropathy multiplex. A high-protein diet increases pyridoxine requirements, for which the US RDA for men is 2 mg.

The toxic effect of long-term, excessive pyridoxine consumption on the dorsal root ganglions causes a pure sensory neuropathy. Pyridoxine inhibits methionine metabolism, causing an increase in S-adenosylmethionine, which in turn inhibits myelin synthesis. In general, exposure of 2 g/d is needed to cause the neuropathy, but cases due to longstanding use of as little as 200 mg/d have been reported. This is the only vitamin to cause a neuropathy when taken to excess.

Cyanocobalamin deficiency

Cyanocobalamin (vitamin B 12 ) is found in meats, especially liver and kidney, and in cheese, milk, eggs, and fish. This inactive precursor is converted into 2 active metabolites: methylcobalamin and adenosylcobalamin. Methylcobalamin is essential for folate metabolism and for the formation of choline-containing phospholipids, which are the building blocks of myelin. Adenosylcobalamin is required for the formation of succinyl coenzyme A, the lack of which causes impairment in the formation of neural lipids.

After its ingestion, cyanocobalamin binds with intrinsic factor secreted by parietal cells in the stomach, enabling it to resist proteolysis. Receptors in the distal ileum then facilitate digestion. The liver stores 4 mg of cyanocobalamin, representing a 3- to 6-year supply. Therefore, primary deficiencies are rare, except in strict vegetarians and nursing infants, but manifestations of cyanocobalamin deficiency occasionally complicate the presence of malabsorptive disorders. These lesions, which appear throughout the white matter, are a result of a focal disintegration of medullary sheath known as subacute combined degeneration. A single exposure to nitrous oxide may precipitate paresthesias in the hands and feet as well as features of a classic myeloneuropathy within days to weeks. The US RDA for men is 2 mg.

Pantothenic acid deficiency

Almost all foods contain this constituent of coenzyme A, the concentration of which in tissues is 10 times that of thiamine and 50% that of nicotinic acid. Deficiencies are rare because of this large amount of storage, though pantothenic acid has been implicated in the pathogenesis of burning-foot syndrome. The daily requirements are 6-10 mg.

Alpha-tocopherol deficiency

Alpha-tocopherol (vitamin E) is a lipid-soluble antioxidant. Its lack causes a syndrome resembling spinocerebellar degeneration, reversible in early stages but with devastating consequences if allowed to progress. The US RDA is 10 IU.

Gluten-sensitivity neuropathy (celiac disease)

Antibodies to gluten in wheat, barley, and oats in susceptible individuals also attack Purkinje cells and other neurons, leading to cerebellar ataxia, myoclonus, neuropathy, and neurologic symptoms. Adhering to a strict gluten-free diet may stabilize neurologic symptoms. [12, 13]

Multifactorial mechanism

This poorly characterized syndrome of neuropathy and visual and auditory deficits is common in prisoners of war camps [14] and in undernourished populations of tropical countries. Also known as "camp foot," "Jamaican neuritis," "camp dizziness," "Strachan syndrome," and other names, the neuropathy is probably due to a deficiency of B vitamins. Sensorineural deafness is postulated to result from deficiency in riboflavin or B-complex vitamins, and the amblyopia, too, may be from a complex deficiency, as it sometimes does not resolve with vitamin B 12 treatment alone.

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Epidemiology

Frequency

United States

About 10,000,000 (4%) Americans are dependent on alcohol. Because of this, alcohol is the most common cause of deficiency neuropathy. About 9-30% of people with alcoholism have clinically evident neuropathy, and more than 90% have electrophysiological evidence of neuropathy.

Approximately 4-15% of ambulatory elderly people (>65 y) will have cobalamin deficiency.

Nearly 10% of people taking isoniazid will have neuropathy.

The increasing incidence of obesity in the United States has led to increased rates of bariatric surgery and consequent malabsorption neuropathies. [15] Peripheral neuropathies are the most frequent complication and can affect up to 16% of patients who have undergone bariatric surgery. [3, 4]

International

Thiamine (vitamin B 1 ) deficiency is still endemic in the Far East; nutritional deficiencies and malnutrition are common in the developing nations.

Mortality/Morbidity

Morbidity and mortality rates vary by etiology.

Race

Racial differences in incidence are likely due to differing socioeconomic status and geographic location.

Sex

Alcoholic neuropathy affects men more than women, but women appear to be susceptible at lower doses.

Age

The incidence of neuropathy due to alcohol dependence peaks at the age of 40 years, although the primary disease may become established decades earlier.

Thiamine (vitamin B 1 ) deficiency predominantly occurs in adolescence and early adulthood.

Children are particularly prone to pyridoxine deficiency, which becomes apparent within a few days of birth.

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