CHAPTER 109 VITAMIN DEFICIENCIES AND OTHER NUTRITIONAL DISORDERS OF THE NERVOUS SYSTEM
A vitamin is a substance that serves as a cofactor for a biochemical reaction and whose absence causes some derangement of function (Fig. 109-1). Thiamine is a classic example, required by three enzyme systems that are essential for glucose metabolism. However, the term vitamin deficiency is too restrictive to account for all disorders of nutrition with neurological consequences. A number of syndromes are associated with megadoses of vitamins (pyridoxine, zinc) and dietary supplements (Chinese herbal remedies, St. John’s Wort, ephedra) (Table 109-1). The recognition of mineral deficiencies such as copper myeloneuropathy, mineral excess disorders such as zinc-induced copper deficiency, and polynutritional disturbances such as postgastroplasty neuropathy requires that a discussion of “vitamin deficiency” be broadened to include other nutritional syndromes of the nervous system.
TABLE 109-1 Toxins Associated with Nutritional Syndromes
| Alcohol | Wernicke-Korsakoff syndrome, painful polyneuropathy |
| Zinc | Copper deficiency myelopathy |
| Pyridoxine | Large-fiber sensory neuropathy |
| Nitrous oxide | Cobalamin deficiency myelopathy |
| Methyltetrahydrofolate reductase (MTHFR) deficiency encephalopathy | |
| Vitamin A | Optic neuropathy, pseudotumor cerebri |
The diagnosis of a nutritional disorder of the nervous system may be challenging for a number of reasons. First, multiple deficiencies may coexist in the same patient, as in dietary malnutrition, postgastroplasty neuropathy, and malabsorption states. Some syndromes that manifest acutely may not be interpreted as nutritional (Tables 109-2 and 109-3). Instead of evolving in a slowly progressive manner, some deficiency states may have an explosive onset triggered by an environmental stressor or by a sudden increase in metabolic demands for the deficient nutrient.
TABLE 109-2 Acute and Subacute Manifestations of Nutritional Disorders
| Neurological Syndrome | Mechanism | Time Course |
|---|---|---|
| Acute post–gastric reduction surgery neuropathy | Excessive and prolonged vomiting, severe weight loss | Weeks to months after surgery |
| Wernicke-Korsakoff syndrome | IV glucose administration in a thiamine-deficient patient, inducing sudden demand for thiamine-dependent glycolytic enzymes | Hours |
| Wernicke-Korsakoff syndrome | Excessive and prolonged vomiting, severe weight loss (gastric surgery, hyperemesis gravidarum) | Weeks |
| Nitrous oxide–associated myeloneuropathy | N2O oxidizes cobalt core of cobalamin, affects vitamin B12–deficient patients acutely or vitamin B12–replete patients with multiple exposures | Hours |
| Pyridoxine neuropathy | Unknown, but probably multiple redox reactions | Hours to days |
IV, intravenous.
The underrecognition of nutritional disorders in industrialized countries has led to difficulties in diagnosis, and these deficiencies may be more common than has been clinically appreciated. Thiamine deficiency has been reported in up to 17% of hospitalized elderly individuals1 and is documented in 3% of autopsy series.2,3 One study of thiamine-deficient alcoholic subjects demonstrated that more than 50% were also riboflavin deficient, and 2% had a concomitant deficiency of pyridoxine.4 With the increasing popularity of obesity-related surgery, new neurological syndromes have emerged as a result of postoperative polynutritional deficiency states (such as acute post–gastric reduction surgery neuropathy, described later). Cobalamin deficiency occurs in 5% to 14% of ambulatory elderly persons,5,6 and up to 27% of hospitalized elderly people develop protein-energy malnutrition during their hospital stay.7
Finally, several inherited enzyme deficiency disorders, although not accompanied by a vitamin deficiency, may nonetheless be vitamin responsive (Table 109-4). Homocystinemia responds to pharmacological doses of folate, cobalamin, and pyridoxine, whereas methylmalonic acidemia responds to cobalamin. Patients with mitochondrial cytopathology may respond to large doses of thiamine (300 mg/day).
TABLE 109-4 Hereditary Disorders Responsive to Vitamin Therapy
| Thiamine | |
| Cobalamin, folate, pyridoxine | Methylmalonic acidemia |
| Homocystinemia | |
| Biotin | β-Methylcrotonyl glycinemia |
| Propionic acidemia | |
| Niacin | Hartnup’s disease (tryptophan metabolism) |
MELAS, mitochondrial encephalopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy associated with ragged-red fibers.
VITAMIN DEFICIENCIES
Thiamine
Pathogenesis and Pathophysiology
The metabolically active form of thiamine, thiamine pyrophosphate (TPP), is crucial in the intermediary metabolism of carbohydrate. TPP is involved in three enzyme systems: (1) pyruvate dehydrogenase, which converts pyruvate to acetyl coenzyme A; (2) α-ketoglutarate dehydrogenase, which catalyzes the conversion of α-ketoglutarate to succinate in the Krebs cycle; and (3) transketolase, which catalyzes the pentose monophosphate shunt (see Fig. 109-1). A deficiency of TPP leads to elevated levels of serum pyruvate and lactate, reduced red blood cell transketolase activity, and a corresponding increase in transketolase activity in response to added TPP (“TPP effect”).8
Pathologically, patients with Wernicke-Korsakoff syndrome show capillary proliferation and petechiae. Spongy degeneration of astrocytes with neuronal preservation occurs in midline structures of the brain, such as the medial thalamic nuclei, the mammillary bodies, the periaqueductal gray area of the mesencephalon, and the pontine tegmentum (Fig. 109-2). Degeneration of the superior cerebellar vermis is frequent. The lesions in the thalami and mammillary bodies probably account for the confusion, memory loss, and confabulation. The pontine tegmental lesions may cause the oculomotor palsies, and the truncal ataxia may result from the midline cerebellar degeneration.9 Cellular injury in these regions may be caused by inhibition of adenosine triphosphate synthesis and induction of abnormal carbohydrate metabolism. In thiamine deficiency polyneuropathy, nerves show axonal degeneration with secondary demyelination. The neuropathy of dry beriberi may be related to TPP deficiency–induced impairment of nerve excitability and conduction.10,11
Epidemiology and Risk Factors
Thiamine is most abundant in yeast, pork, legumes, cereal grains, and unpolished rice, and the recommended daily allowance of this vitamin is 0.5 mg/1000 kcal.12 The total body store is 30 to 100 mg, and thiamine is present in heart, skeletal muscle, liver, kidney, and brain tissue. Because the quantity stored is limited, the supply must be constantly replenished. The half-life of thiamine is approximately 2 weeks, and patients may suffer severe neurological complications and even death after 6 weeks of total thiamine depletion. Patients at high risk for deficiency include alcoholic persons, adults who derive most of their carbohydrate from white rice, and infants breastfed by malnourished mothers. Other potential causes of thiamine deficiency include prolonged total parenteral nutrition,13 defective baby formula,14 hyperemesis gravidarum,15 anorexia nervosa, gastric or jejunoileal bypass,16,17 intractable vomiting after gastric stapling for morbid obesity,18 and severe malabsorption. Thiamine deficiency is also found among prisoners of war19 and persons engaged in hunger strikes. In addition, thiamine deficiency has been reported after long-standing peritoneal or hemodialysis.20,21
Clinical Features and Associated Disorders
Wernicke-Korsakoff syndrome and polyneuropathy (dry beriberi) are the two neurological disorders resulting from thiamine deficiency. The classic triad of confusion, ataxia, and oculomotor palsies is uncommon in clinical practice. In Harper and colleagues’ autopsy series of 131 patients, only 16% had all three features premorbidly.3
The frequency of Wernicke-Korsakoff syndrome in autopsy series ranges from 0.8% to 2.8%. The disorder is probably underdiagnosed during life. Wernicke-Korsakoff syndrome is most common in alcoholic persons as a result of a combination of poor diet, inadequate intake, impaired absorption of thiamine, and overdependence on alcohol as a source of calories. Certain individuals may also have a genetic predisposition toward the development of this syndrome because of an abnormality of thiamine-dependent enzymes.22,23
Polyneuropathy is present in more than 80% of patients with Wernicke-Korsakoff syndrome, but most cases are probably caused by alcoholism. Koike and associates demonstrated that thiamine deficiency and alcohol-induced neuropathy are distinct entities.11 Thiamine deficiency may manifest acutely with prominent motor weakness and large-fiber sensory loss. In contrast, alcoholic neuropathy manifests with slowly progressive muscular weakness and with sensory and reflex loss, accompanied by burning sensation in the feet and lancinating pains. Calf tenderness is a prominent feature. Bilateral footdrop and even wristdrop may be present (Fig. 109-3). Half of Koike and associates’ patients had evidence of autonomic neuropathy with orthostatic hypotension.
Evaluation
Serum thiamine levels lack sufficient sensitivity and specificity to be used alone. Red blood cell transketolase activity, with or without TPP challenge, is the most accurate assessment tool,8 but the test has become commercially unavailable. Magnetic resonance imaging may reveal abnormal signal in the midline nuclei corresponding to the pathological lesions described (Fig. 109-4).24
Niacin and Nicotinic Acid
Niacin includes both nicotinic acid and nicotinamide, which form the metabolically active nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), an end product of tryptophan metabolism. More than 200 enzymes are dependent on NAD and NADP to carry out oxidation and reduction reactions, and these enzymes are involved in the synthesis and breakdown of carbohydrates, lipids, and amino acids. Although niacin is endogenously produced in humans, exogenous intake is necessary to prevent deficiency.
Pellagra, or rough skin, continues to occur in parts of Africa and Asia, especially in populations dependent on corn as the principle source of carbohydrate. When corn is first soaked in lime water, as is done in Mexico when tortillas are prepared, niacin is liberated, and deficiency occurs less commonly. In the United States, niacin deficiency is seen in alcoholic persons and in patients taking isoniazid. Pregnant women are protected from niacin deficiency because of their enhanced ability to convert tryptophan to niacin endogenously, particularly in the third trimester.
Pellagra affects the skin, the gastrointestinal system, and the central nervous system; hence, the classic triad of the “three Ds”: dermatitis, diarrhea, and dementia. In industrialized countries, particularly among alcoholic persons, niacin deficiency may manifest only with encephalopathy.25–27 Patients may have altered sensorium, diffuse rigidity of the limbs, and grasping and sucking reflexes. Dementia and confusion are the most constant findings, followed by diarrhea (50%), and dermatitis (30%).27 Spinal cord and peripheral nerve defects have also been reported, particularly in prisoners of war.19 Coexisting deficiencies of thiamine and pyridoxine are common, especially in alcoholic persons.
Cobalamin (Vitamin B12)
Pathogenesis and Pathophysiology
Vitamin B12 deficiency produces neurological and hematological symptoms by impairing two enzyme systems (Fig. 109-5).5,28 Methylcobalamin is a cofactor of methionine synthase, a cytosolic enzyme that catalyzes the conversion of homocysteine and methyltetrahydrofolate to produce methionine and tetrahydrofolate. Methionine is further metabolized to S-adenosylmethionine, which is necessary for the methylation of myelin sheath phospholipids and proteins. Tetrahydrofolate is the required precursor for purine and pyrimidine synthesis. In the mitochondria, adenosylcobalamin catalyzes the conversion of L-methylmalonyl–coenzyme A to succinyl–coenzyme A.
In deficiency states, serum levels of homocysteine and methylmalonic acid rise. Although the mechanism of megaloblastic changes in both folate and cobalamin deficiency is reasonably well understood, the biochemical basis of the neurological damage that occurs in cobalamin deficiency remains uncertain. Of the two reactions that require cobalamin, the methionine synthase reaction is considered more likely to play a critical role in nervous system function. In rare cases, neurological complications have also been reported in folate deficiency, because methionine synthase also requires this cosubstrate.29 It has been proposed that the accumulation of methylmalonate and propionate provides abnormal substrates for fatty acid synthesis, resulting in abnormal odd-carbon and branched-chain fatty acids, so-called funny fatty acids, which may be incorporated into the myelin sheath and interfere with impulse conduction.
Vitamin B12 deficiency results in demyelination of the posterior columns, corticospinal tracts, and white matter of the cerebral hemispheres (Fig. 109-6).30 Less commonly, a sensorimotor and autonomic neuropathy that is axonal and demyelinating in nature may also be present.31,32 These lesions lead to a constellation of symptoms, including cognitive and affective disorders, ataxia, spasticity, and paresthesias.
Epidemiology and Risk Factors
In the Framingham Heart Study, 5% of elderly subjects had serum vitamin B12 levels less than 148 pmol/L, 40.5% had values less than 258 pmol/L, and 15% had serum methylmalonic acid levels greater than 376 nmol/L.33 Therefore, 15% of the elderly population demonstrate biochemical evidence of vitamin B12 deficiency. Folate deficiency is far more common in alcoholism than is cobalamin deficiency. Of all cases of folate deficiency, 87% occur in alcoholic persons, whereas only 11% to 13% of cobalamin-deficient patients are alcoholic.34,35 For unclear reasons, vitamin B12 deficiency is uncommon in alcoholics. Anemia and macrocytosis (mean cell volume >100 fL) occur in 72% and 83%, respectively, of patients with vitamin B12 deficiency and in 100% and 75%, respectively, of those with folate deficiency.35
Approximately 50% to 78% of patients with vitamin B12 deficiency have autoimmune parietal cell dysfunction (pernicious anemia).36 Another 10% to 40% have food-bound cobalamin malabsorption, caused by achlorhydria.37
