Nutritional Disorders of the Nervous System1



Nutritional Disorders of the Nervous System1


Gustavo C. RomÁn





Brain function is unavoidably dependent on a constant dietary supply of appropriate nutrients. Regrettably, large segments of the world population have limited access to basic foodstuffs. Despite increases in agricultural production, hunger remains a widespread worldwide problem as a result of poverty, war, population displacement, and social unrest. Hunger creates a vicious cycle of poor health, lack of energy, and mental impairment that reduces people’s ability to work thereby increasing poverty.

According to the United Nations Food and Agriculture Organization (FAO), nearly 30% of the world population, some 777 million people worldwide, are malnourished (1). This represents more than 35% of tropical Africa’s population, about 25% of the people in India, and 5% to 20% of Lätin America and Caribbean populations. Of them, 150 million children worldwide are underweight, and 182 million are physically and cognitively stunted. Moreover, protein-energy malnutrition contributes to 5 million child deaths per year.

Less recognized, however, are the effects of malnutrition on the nervous system. These may range from isolated involvement of the peripheral nervous system that produces blindness, deafness, paralysis, or sensory deficits to complex lesions of the spinal cord and central nervous system (CNS) that lead to mental retardation, cognitive dysfunction, and gait limitations. Nutritional deficiencies affecting the nervous system are not restricted to developing nations, however. Selected groups in the developed world also suffer from the neurologic consequences of nutritional deficiencies as a result of meager diets. Populations at risk include the poor, the homeless, people addicted to alcohol and substance abusers, some patients with chronic psychiatric conditions, and demented elderly persons. Also affected are persons with restrictive dietary habits such as strict vegans or those suffering from eating disorders such as bulimia and anorexia nervosa, as well as patients with impaired absorption of nutrients from intestinal malabsorption syndromes.

A rampant form of malnutrition peculiar to developed nations is obesity, frequently accompanied by metabolic syndrome, hypertension, and diabetes that may manifest with secondary neurologic signs and symptoms as a result of stroke, obstructive sleep apnea, and peripheral neuropathy. According to the FAO, obesity is also beginning
to affect developing nations, a situation resulting in the coexistence in the same population of undernutrition and obesity. This problem is called “the double burden of malnutrition” (1).


NUTRITION AND COGNITIVE FUNCTION

A constant dietary supply of appropriate nutrients including glucose, amino acids, fatty acids, vitamins, and minerals is required for normal brain function (2). Food is also needed to maintain the integrity of cellular membranes in the brain and the production of neurotransmitters (3). Although the brain represents only 2% of the body mass, it consumes 20% of the energy provided by the diet and 20% of the oxygen inhaled. Children consume twice more glucose than adults do, and the newborn brain requires 60% of the energy provided by the diet. Therefore, the effects of prolonged hypoglycemia can be devastating for newborns and children, given that the brain is totally dependent on dietary glucose, and glycogen reserves are limited. Many of the fatalities and permanent sequelae resulting from cerebral malaria in children are caused by the severe hypoglycemia induced by the malarial infection and quinine treatment (4), in addition to the direct damage induced by the parasite (5). In elderly persons, decreased cognitive performance occurs with relatively mild hypoglycemia (6). Similarly, cognitive dysfunction worsens the outcome of treatment in patients with type 2 diabetes (7).

Appropriate dietary supply of amino acids is needed to synthesize proteins and neurotransmitters in the nervous system. The quality of dietary proteins influences brain protein formation. Tryptophan, a precursor of serotonin (5-hydroxytryptamine)—the neurotransmitter involved in appetite and satiety, sleep, blood pressure, pain sensitivity, and mood—is particularly important because 5-hydroxytryptamine cannot cross the blood-brain barrier. Metabolically active brain sites such as hippocampus, basal ganglia, and hypothalamus are particularly sensitive to the effects of malnutrition, loss of energy, and amino acid supply.

Studies in experimental animals and in humans have demonstrated the importance of appropriate nutrition during crucial—and relatively brief—periods of brain growth (8, 9, 10, 11, 12). Neurons and glia are formed and begin migration by 22 weeks of gestation; and by late pregnancy, marked axonal and neural proliferation result in substantial brain growth. Brain weight at birth is about 350 g, increasing during the first year of life to about 1100 g or 70% of the adult brain weight. In 1969, Winick and Rosso (13, 14) demonstrated that early malnutrition stunts brain growth and development. Children dying of severe malnutrition during pregnancy and from marasmic malnutrition in early life had smaller head circumferences, decreased brain weight, and lower brain content of total protein, DNA and RNA compared with normal controls. Early malnutrition also affects processes involved in brain maturation such as neurogenesis, neuronal and glial migration, number of synapses, and degree of myelination.

These changes are largely irreversible and cause permanent cognitive deficiencies (11, 15, 16). The extent of the cognitive and neurologic damage depends on factors such as severity and duration of the nutritional deficiency, the stage of brain development, and associated diseases such as diarrhea from Giardia lamblia (17) and other causes, as well as familial, social, cultural, and economic factors. Nonetheless, substantial evidence indicates that reduced breast-feeding, low birth weight, iron and iodine deficiency, and protein-energy malnutrition are associated with long-term deficits in psychomotor brain function (12). Follow-up studies of perinatal malnutrition showed, 15 and 20 years later, residual deficits in brain size, cognition, and psychosocial achievements (6, 11). Ivanovic et al (18) and Leiva et al (19) demonstrated, among high school students in Chile, residual effects of early malnutrition manifested by smaller head circumferences and brain volumes determined by magnetic resonance imaging. Lower IQ and more severe learning difficulties resulted in worse school performance, higher school desertion, and lower enrollment in higher education institutions in those with history of early malnutrition, compared with classmates from a common socioeconomic background who had a normal nutritional history.

Similar, although less severe, problems also occur in premature and low birth weight infants (20). In clinical trials comparing breast milk with preterm formula alone or as a supplement to maternal milk, in preterm infants weighing less than 1200 g, children fed banked breast milk took longer to reach 2000 g than did infants fed a preterm formula. Lucas et al (21) found that IQs, shortterm memory, and attention at 8 years of age were better in children fed maternal milk than in controls, even after adjustment for maternal education and social class. Breast milk lowers low-density lipoprotein (LDL) cholesterol and C-reactive protein, findings indicating decreased risk of atherosclerosis late in life (22).

Maternal milk contains certain factors, particularly lipids, that promote brain maturation in periods of rapid growth. The brain is 60% structural lipid and depends on dietary lipids. Lack of both linoleic acid and α-linolenic acid (ALA) is incompatible with life. Of major dietary importance are ω-3 fatty acids of the ALA family (2). Arachidonic acid and docosahexaenoic acid (DHA) are large contributors to nonmyelin membranes and must be provided by the diet. Differentiation and functioning of cultured brain cells, oligodendrocytes, and astrocytes require ALA and ω-3 fatty acids. Brain, retinä, and visual development are affected by diets with insufficient amounts of essential fatty acids, such as those found in soy oil-based formula products (20).

In adults, decreased dietary levels of ω-3 fatty acids (particularly from fish consumption) increase the risk of cardiovascular disease and stroke (23), depression (24),
in particular postpartum depression, as well as cognitive decline and dementia (25, 26). An appropriate dietary provision of ω-3 fatty acids during aging may prevent abnormal phospholipid metabolism, thus ensuring membrane maintenance and preventing cognitive decline (27, 28).


MICRONUTRIENT DEFICIENCIES AND COGNITIVE FUNCTION

From the public health viewpoint, iodine is the most important micronutrient for the prevention of brain disorders causing lower intellectual functioning, psychomotor delay, and mental retardation (29). Universal salt iodization may solve the worldwide problem of iodine deficiency disorders (IDDs). The World Health Organization considers that 50 million people have some degree of mental impairment caused by IDDs (30, 31).

Also of major public health importance is the deficiency of other micronutrients capable of affecting the nervous system; these include deficiencies of iron, copper, zinc, and selenium, as well as vitamin B12, folate, and vitamin A. The magnitude of these problems is staggering (31): for example, 2 billion people—more than 30% of the world’s population—suffer from iron deficiency anemia, most often in developing countries in association with malaria and hookworm infections. Anemia contributes to 20% of all maternal deaths of pregnant women. Between 100 and 140 million children have vitamin A deficiency, and of these, 250,000 to 500,000 become blind every year, and half of them die prematurely. Multinutrient food fortification appears to be a cost-effective treatment (32).


Iodine Deficiency Disorders

IDDs occur in areas of the earth where iodine was leached from the soil by the effects of räin, glaciations, and flooding waters. These areas typically include flood plains and mountainous regions such as the Alps, the Balkans, the Andes, the Himalayas, and the New Guinea Highlands (33). The populations of these regions suffer from high prevalence of endemic cretinism, goiter, short stature, and deafness. The neurologic importance of IDDs resides in the definite risk of fetal brain damage resulting from thyroid hormone deficiency during critical periods of brain development, both in utero and in the early postpartum period (34, 35).

Normal pregnancy causes a progressive increase of serum thyroid-stimulating hormone (TSH) along with a corresponding rise of serum thyroglobulin. In areas with moderate dietary iodine deficiency, a steady decrease of free thyroxine (T4) occurs during gestation; TSH increases, resulting in a 20% to 30% enlargement of the thyroid volume that leads to goiter (35). Serum TSH and thyroglobulin values are even higher in neonates born to mothers with iodine deficiency. These changes in neonatal TSH frequently occur with levels of maternal iodine deficiency that would not affect the thyroid function in nonpregnant adults.

In areas with moderate iodine deficiency (iodine ingestion = 20 to 49 μg/day), clinically euthyroid children and adults often have definite abnormalities of psychomotor and intellectual development including lower IQ, slower visual-motor performance, loss of fine-motor skill, deficits in perceptual and neuromotor abilities, apathy, and low developmental quotients (35). A metaanalysis of 19 studies from 8 countries included 2676 subjects ranging in age from 2 to 30 years who were living in iodine-deficient regions. Iodine deficiency resulted in a mean loss of 13.5 IQ points at global population level; that is, 82% of children with normal iodine intake scored better than iodine-deficient children (36). Loss of intellectual capacity and deafness from IDDs constitute public health problems with a major impact on socioeconomic development.


Endemic Cretinism and Other Forms of Iodine Deficiency Disorders

Endemic cretinism is a congenital disorder of the CNS manifested by deaf-mutism, mental retardation, spastic diplegia, squint, and signs of bulbar damage (37). Partial manifestations include isolated deafness or deaf-mutism and mental retardation without pyramidal tract signs. In some endemic places (New Guinea, Thailand, Indonesia, the Andes), the usual signs of childhood myxedema—coarse puffy skin, macroglossia, umbilical hernia, short stature, and skeletal disproportion—occur rarely, whereas these signs predominate in other endemic areas (China, Congo). Therefore, two forms of the syndrome of endemic cretinism are recognized: neurologic and myxedematous.

Endemic cretinism is different from congenital hypothyroidism, which occurs in 1 in 3500 newborns (38). Congenital hypothyroidism results from deficient thyroid function in the fetus and the newborn, resulting from endocrine factors unrelated to dietary iodine deficiency.

Halpern et al (39) studied the neurologic features associated with both types of endemic cretinism in 104 persons with myxedematous cretinism from China and in 35 persons from central Java (Indonesia), who had the predominantly neurologic form. Both types of endemic cretinism had a similar pattern of neurologic involvement with mental retardation, proximal pyramidal and extrapyramidal signs, squint, deafness, primitive reflexes, and typical gait with laxity and deformities of joints. Those with serious hypothyroidism had calcification of basal ganglia on cerebral computed tomography. Therefore, both forms of endemic cretinism represent the most severe degree of brain damage from in utero maternal and fetal hypothyroidism, resulting from dietary iodine deficiency. The myxedematous type is explained by continuing postnatal thyroid hormone deficiency with impaired growth, skeletal retardation, and sexual immaturity. Thiocyanate toxicity from cassava consumption plays a role in myxedematous endemic cretinism. The combined effect of iodine and selenium deficiency is also relevant.


Thiocyanate Toxicity. Numerous staple foods in the tropics contain large amounts of cyanogenic glycosides. These include cassava (Manihot esculenta Crantz: yuca in Spanish, manioc in French), yam, sweet potato, corn, millet (Sorghum sp.), bamboo shoots, and beans such as Phaseolus vulgaris (40). Tobacco smoke (Nicotiana tabacum) also contains considerable amounts of cyanide (150 to 300 μg per cigarette). Hydrolysis of plant glycosides releases cyanide as hydrocyanic acid. Acute intoxication occurs by rapid cyanide absorption through the gastrointestinal tract or the lungs. Detoxification is mainly to thiocyanate in a reaction mediated by a sulfurtransferase (rhodanase) converting thiosulfate into thiocyanate and sulfite. The sulfurcontaining essential amino acids—cystine, cysteine, and methionine—provide the sulfur for these detoxification reactions. Also important is vitamin B12 with conversion of hydroxocobalamin to cyanocobalamin.

Thiocyanate from cassava is goitrogenic (41); it inhibits thyroid peroxidase and prevents the incorporation of iodine into thyroglobulin (42). Thiocyanate may also form thiourea. These mechanisms explain the damaging neurologic effects of cyanide, diets poor in sulfur-containing amino acids, and low dietary iodine intake.

Selenium. In 1990, Vanderpas et al (43) found combined iodine and selenium deficiency associated with cretinism in northern Congo. Selenium is present in high concentrations in the normal thyroid (34) and in glutathione peroxidase and superoxide dismutase, the enzymes for detoxification of toxic oxygen radicals. It is also present in deiodinase, the enzyme for peripheral conversion of T4 to triiodothyronine (T3). Selenium deficiency decreases T4 catabolism and allows excessive production of peroxide (H2O2), with thyroid cell destruction, fibrosis, and thyroid failure (34).


Pathogenesis of Brain Lesions Induced by Iodine Deficiency

Thyroid hormones affect neuronal differentiation, migration, neural networking, and synaptogenesis through binding of T3 to nuclear receptors regulating gene expression in different brain regions (44). Thyroid hormone receptors are present in the human fetus by 8 weeks of gestation and increase about 10-fold between 10 and 18 weeks of gestation. Kester et al (45) found that T3 is required by the human cerebral cortex before midgestation. T4 from the mother is the only source and correlates with deiodinase (D2) activity in the cortex. For these reasons, even moderately low T4 maternal levels may be damaging to the fetus. Haddow et al (46) found, in mothers with increased TSH during the second trimester of pregnancy, that the strongest predictor of infant mental development was the mothers’ free T4 levels at 12 weeks of gestation. Furthermore, low levels of free T4 at both 12 and 32 weeks of gestation resulted in worse infant cognitive outcome.

Lavado-Autric et al (47) and Ausó et al (48) produced in the rat an experimental model of transient maternal hypothyroxinemia—low T4 but normal T3—demonstrating that transient and mild thyroid function deficits in the mother during early gestation produced permanent abnormalities in cortical cytoarchitecture, with presence of heterotopic neuronal migration in hippocampus and somatosensory cortex. Migration of cortical neurons along the scaffolding provided by radial glia is regulated by the reelin-dab signaling system. Reelin is an extracellular protein secreted by Cajal-Retzius neurons that binds to membrane receptors on migrating neurons, phosphorylating the disabled homolog 1 (Dab1) to guide cells to their destination. Hypothyroidism reduces reelin expression and enhances Dab1 expression and could explain these migratory abnormalities (49, 50). Based on the foregoing mechanisms, Román (51) proposed that early maternal hypothyroxinemia could induce autism.




Cognitive Effects of Iron Deficiency

Iron is an essential cofactor for numerous proteins involved in neuronal function. Both iron deficiency anemia and excessive iron accumulation in the brain are associated with neurologic disturbances. The brain has limited access to plasma iron because of the blood-brain barrier (56). Apathy and poverty of movement have been observed in iron-deficient children. A review by Grantham-McGregor and Ani (57) showed that anemic children usually have poor cognition and lower school achievement than nonanemic children. With treatment, most but not all of them tend to improve; however, school achievement generally remains lower in children with prior iron deficiency anemia than in nonanemic controls. Lozoff and Brittenham (58) showed that severe and chronic iron deficiency in infancy continues to cause developmental and behavioral delay more than 10 years after iron treatment. Iron deficiency causes lower cognitive, motor, attentional, and developmental scores, including failure to respond to test stimuli, short attention span, unhappiness, increased fearfulness, withdrawal, and increased body tension. In adults, anemia limits maximal physical performance, endurance, and spontaneous activity.

With aging, there is accumulation of iron-containing molecules in the brain, particularly in Alzheimer and Parkinson diseases, perhaps caused by enhanced generation of reactive oxygen species (ROS) and higher neuronal vulnerability. Iron accumulation also occurs in other neurologic diseases, such as congenital aceruloplasminemia, Friedreich ataxia, Hallervorden-Spatz disease, neuroferritinopathy, neurodegeneration with brain iron accumulation, and restless legs syndrome (56).


Cognitive Effects of Zinc Deficiency

Dietary zinc deficiency is a common nutritional disorder around the world (29). Zinc treatment of deficient children improves growth, immunity, and motor development in infants and toddlers. Zinc deprivation during periods of rapid growth impairs brain and sexual development. There are few studies in children on the cognitive, motor, and behavioral changes associated with zinc deficiency and supplementation (59, 60).


Neurologic Effects of Copper Deficiency

Copper is an essential cofactor for numerous enzymes such as copper-zinc superoxide dismutase, ceruloplasmin ferroxidase, and cytochrome oxidase. Menkes disease and Wilson disease are congenital metabolic copper abnormalities resulting from mutations of two related genes, MNK and WND, which encode proteins belonging to P-type adenosine triphosphatase (ATPase) cation transporters (61). Menkes disease is caused by mutations of the ATP7A gene resulting in abnormally low intestinal absorption of copper, low ceruloplasmin, and secondary deficiency in copper-dependent mitochondrial enzymes in brain, skin, hair (“kinky hair”), blood vessels, and other organs. In contrast, Wilson disease (hepatolenticular degeneration) results from mutations of the ATP7B gene with decreased plasma ceruloplasmin and excessive copper in blood and urine, as well as excessive copper deposition in brain, liver, eyes, and other organs. Treatment includes low-copper diet and use of chelating agents (penicillamine, trientine) or inhibitors of intestinal absorption (zinc acetate).

Copper deficiency may result also from total parenteral nutrition (TPN), prior vitamin B12 deficiency, intestinal malabsorption from gastric resection or bariatric surgery (62), and zinc overload, particularly with use of zinccontaining adhesive denture creams (63). Copper deficiency may mimic cobalamin deficiency manifesting with anemia from myelodysplasia (64), spinal cord involvement with subacute combined degeneration (SCD) (65), peripheral neuropathy, optic neuropathy, and periventricular white matter lesions (66). Oral copper supplementation improves functional activities of daily living in patients with copper deficiency (67).


NUTRITIONAL NEUROPATHIES AND MYELONEUROPATHIES

The polyneuropathies observed in association with alcoholism are usually considered nutritional, although a specific vitamin cannot be identified as causal. Alcohol may play a secondary neurotoxic role, but it also displaces food in the diet, increases the metabolic demands for B-group vitamins, and decreases absorption of thiamin, folic acid, and liposoluble vitamins because of impaired pancreatic function. Symptoms vary from weakness, dysesthesias, and pain to the asymptomatic patient with absent ankle reflexes. Sensory and motor deficits predominate distally and symmetrically in the legs; the face and trunk are not involved. Sensitivity to pressure palsies is often present. On neuropathologic examination, the nutritional neuropathies show predominantly sensory axonal degeneration.

It appears pointless to incriminate one particular factor as the cause of polyneuropathy seen in conditions of severe dietary restriction, alcoholism, or widespread malabsorption. Nevertheless, B-group vitamin deficiencies have long been thought to be the main cause of nutritional disorders, particularly when they are associated with alcoholism.

Neurologic signs occur relatively late during malnutrition. Symptoms appear when a combination of factors finally leads to a deficiency of essential nutrients that is severe enough to injure the nervous system or when protective nutrients—such as sulfur-containing amino acids and antioxidant carotenoids such as lycopene—become unavailable. The most sensitive elements are highly active metabolic neurons, such as dorsal root ganglia, large myelinated distal axons, bipolar retinal neurons, and cochlear neurons. These are the first to suffer damage
and to manifest symptoms. Axons require active transport mechanisms to maintain the integrity of neurotubules and to secure axonal flow. Neurotransmitter precursors, glycoproteins, lipids, and amino acids are transported from the soma to the distal axon at rates of 200 to 410 mm/day. There is also a retrograde transport system. Nutritional deficiencies and toxic products disrupt adenosine triphosphate (ATP) production, and axonal flow begins to fail in the typical “dying back neuropathy” pattern. The distal ends of the longest and largest axons are the first to display pathologic changes; the clinical consequences are the stocking-and-glove distribution of sensory and motor symptoms.

In addition to alcoholism, nutritional neuropathies are also observed with dietary restriction (vegans and food faddists), with malabsorption (sprue, pernicious anemia, gastrointestinal tract resections, bariatric surgery), antivitamins (isoniazid), excessive use of pyridoxine, and prolonged inadequate parenteral therapy. A nutritional origin has also been postulated in tropical neuropathies and myeloneuropathies (68, 69). These include Strachan Jamaican neuropathy (1888) characterized by sensory symptoms of feet and hands, ataxic gait, absent knee reflexes, and decreased sight and hearing; and Mádan’s Cuban retrobulbar optic neuropathy (1898), considered to be identical to tobacco-alcohol amblyopia in nondrinking malnourished patients (70). Nutritional neuropathies and myeloneuropathies were common among prisoners of war (POWs) interned in Japanese prison camps in tropical and subtropical regions, mainly in the Far East, during World War II (71). A similar condition was Peraita’s Spanish Civil War neuropathy (1939).

More recently, in 1993 to 1994, an epidemic of nutritional neuropathy in Cuba affected more than 50,000 people and constituted one of the worst nutritional neurologic epidemics of the last century (72). This phenomenon emphasizes the pervasiveness and importance of nutrition as a cause of neurologic problems.


Cuban Epidemic Neuropathy

The epidemic of neuropathy in Cuba (70, 72, 73, 74, 75, 76, 77) began as an outbreak of optic neuropathy; however, other nutritional syndromes affecting peripheral nerves and spinal cord were also observed (Table 95.1).


Epidemiology

A total of 50,862 patients were diagnosed and treated in the island during the epidemic for an incidence rate of 462 per 100,000, with balanced rates for predominantly optic forms (242 per 100,000) and peripheral forms (219 per 100,000). Few cases occurred in children, adolescents, and elderly persons. Most cases (87%) occurred between the ages of 25 and 64 years. Optic forms predominated in men aged 45 to 64 years and peripheral forms in women aged 25 to 44 years. The geographic west-to-east pattern of decreasing incidence showed the highest rates in the tobacco-growing province of Pinar del Rio. Risk factors included irregular diet, weight loss, cigar smoking, alcohol, and excessive sugar consumption (76).








TABLE 95.1 CLINICAL SYNDROMES OBSERVED DURING THE EPIDEMIC OF NUTRITIONAL NEUROPATHY IN CUBA AND POSSIBLE CAUSES

















































CLINICAL MANIFESTATIONS


POSSIBLE CAUSE


Optic neuropathy



Decreased visual acuity


Folate-vitamin B12 deficiency and methanol



Cecocentral scotoma



Dyschromatopsia


Cyanide


Dorsolateral myelopathy



Proprioceptive loss


Vitamin B12 deficiency



Pyramidal tract weakness


Sensorineural deafness



High-frequency (4-8 kHz) loss


Folate-vitamin B12 deficiency


Peripheral neuropathy



Stocking-and-glove sensory loss


Thiamin deficiency



Areflexia


Burning feet


Deficiencies of niacin, pantothenic acid, thiamin, and pyridoxine


Myeloneuropathy


Multivitamin deficiency including vitamin E



Clinical Manifestations

Neurologic symptoms were preceded by weight loss, anorexia, chronic fatigue, lack of energy, irritability, sleep disturbances, and difficulties with concentration and memory.

Optic Neuropathy. Patients complained of blurred vision, photophobia, decreased visual acuity, and loss of color vision for red and green. Examination showed central and cecocentral scotomata, loss of axons in the maculopapillary bundle, and temporal disc pallor in advanced cases (73). One third of patients also presented cheilosis, glossitis, dermatitis, peripheral neuropathy, or funicular spinal cord involvement, and 20% had hearing loss. Vision improved with parenteral B-group vitamins and folic acid treatment.

Dorsolateral Myelopathy. Patients had leg weakness, difficulty walking, increased urinary frequency, impotence in men, and brisk knee reflexes with crossedadductor responses contrasting with decreased ankle reflexes, but spasticity and Babinski sign were usually absent. Proximal motor weakness was present in one third of these cases, with loss of position sense in the feet, positive Romberg sign, and sensory ataxia in severe cases. Vitamin B12 deficiency was probably responsible for most of these cases that resembled SCD.

Sensorineural Deafness. Patients had high-pitch tinnitus and bilateral and symmetric high-frequency (4 to 8 kHz) hearing loss. No associated vestibular symptoms were reported. Hearing loss has been associated with folate-cobalamin deficiency in elderly persons.


Peripheral Neuropathy. Symptoms included painful dysesthesias of the soles and palms, “burning feet,” numbness, cramps, paresthesias, and sensitivity of nerves to pressure, but with minimal motor involvement. Objective signs were often mild and included loss or decreased perception of vibration, light touch, and pinprick distally in the limbs in a glove-and-stocking pattern. Achilles tendon reflexes were decreased or absent. Motor nerve conduction velocities were normal, and sensory nerve potential amplitudes were decreased only in severe cases. Some patients presented with hot skin and excessive sweating or coldness and hyperhidrosis of hands and feet. Sural nerve biopsies in 34 patients (74) showed an axonal neuropathy with predominant loss of myelinated large-caliber fibers and a less important loss of small-caliber fibers.

Myeloneuropathy. Patients had a combination of peripheral distal sensory polyneuropathy and funicular spinal cord involvement, manifested by spastic-ataxic gait, sphincter disturbances, brisk knee reflexes, and absent ankle reflexes.



NEUROLOGIC DISORDERS ASSOCIATED WITH SPECIFIC VITAMINS


Vitamin A


Vitamin A Deficiency

The causes of vitamin A deficiency include defective intake of preformed vitamin A (retinyl esters) of animal origin or of fruits and vegetables containing provitamin A carotenoids, altered intestinal absorption such as in intestinal parasitic infections (giardiasis, ascaridiasis, and strongyloidiasis), or, more rarely, abetalipoproteinemia or after biliopancreatic bypass surgery. Raw soybeans contain the enzyme lipoxidase, which oxidizes and destroys carotene.

The main manifestations of vitamin A deficiency occur in the eye (77, 78, 79), where it is needed for the synthesis of RNA and glycoproteins in cornea and conjunctiva. Retinal is the essential chromophore that combines with both rod and cone opsins to form rhodopsin for phototransduction. Clinical manifestations of vitamin A deficiency include night blindness, conjunctival xerosis, Bitot spots, and corneal xerosis that may lead to corneal ulceration and keratomalacia (78, 79). Vitamin A deficiency also affects metabolic and immune functions, thus worsening morbidity and mortality in children (80, 81). Vitamin A attenuates the severity of diarrhea and measles (82).

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