Nutrition and nervous system

Brain function is unavoidably dependent on a constant dietary supply of appropriate nutrients.

The effects of malnutrition on the nervous system 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.

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.

A constant dietary supply of appropriate nutrients including glucose, amino acids, fatty acids, vitamins, and minerals is required for normal brain function. Food is also needed to maintain the integrity of cellular membranes in the brain and the production of neurotransmitters. 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.

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, the neurotransmitter involved in appetite and satiety, sleep, blood pressure, pain sensitivity, and mood, is particularly important because it cannot cross the blood–brain barrier.

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. 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.

IDDs occur in areas of the earth where iodine was leached from the soil by the effects of rain, 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. 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.

Endemic cretinism is a congenital disorder of the CNS manifested by deaf-mutism, mental retardation, spastic diplegia, squint, and signs of bulbar damage. 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.

Numerous staple foods in the tropics contain large amounts of cyanogenic glycosides. These include cassava, yam, sweet potato, corn, millet, bamboo shoots, and beans. Tobacco smoke also contains considerable amounts of cyanide. 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.

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.

Dietary zinc deficiency is a common nutritional disorder around the world. 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.

Copper is an essential cofactor for numerous enzymes such as copper-zinc superoxide dismutase, ceruloplasmin ferroxidase, and cytochrome oxidase. Copper deficiency may result also from total parenteral nutrition (TPN), prior vitamin B12 deficiency, intestinal malabsorption from gastric resection or bariatric surgery, and zinc overload, particularly with use of zinccontaining adhesive denture creams. Copper deficiency may mimic cobalamin deficiency manifesting with anemia from myelodysplasia, spinal cord involvement with subacute combined degeneration (SCD), peripheral neuropathy, optic neuropathy, and periventricular white matter lesions. Oral copper supplementation improves functional activities of daily living in patients with copper 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, where it is needed for the synthesis of RNA and glycoproteins in cornea and conjunctiva. Clinical manifestations of vitamin A deficiency include night blindness, conjunctival xerosis, Bitot spots, and corneal xerosis that may lead to corneal ulceration and keratomalacia. Vitamin A deficiency also affects metabolic and immune functions, thus worsening morbidity and mortality in children. Vitamin A attenuates the severity of diarrhea and measles.

Excessive intake of vitamin A produces increased intracranial pressure, with irritability, anorexia, confusion, headache, vomiting, lethargy, malaise, abdominal pain, hepatomegaly, and myalgias. Funduscopic examination reveals papilledema, consistent with pseudotumor cerebri in the absence of focal neurologic signs. In addition to pharmaceutical preparations, foods rich in vitamin A include polar bear liver and halibut liver. Excessive vitamin A intake increases the risk of cleft palate, harelip, macroglossia, eye abnormalities, and hydrocephalus. Retinoids are vitamin A derivatives used in dermatology. Isotretinoin (Accutane) increases blood lipids and has substantial teratogenic effects estimated at 15% to 45% of exposures in utero, mainly in the first trimester of pregnancy; risks persist up to 1 month after discontinuation of the drug. Malformations involve the face, the ears, the CNS, and the heart; there is also a 20% to 30% rate of spontaneous abortion.

The main manifestations of thiamin deficiency are a sensorimotor axonal peripheral neuropathy (dry beriberi) and a cardiac form (Shoshin beriberi) also called wet beriberi because of edema secondary to congestive heart failure. Beriberi was major cause of morbidity and mortality in populations depending on polished rice for their staple diet (China, Japan, Indonesia, the Philippines), but it also occurred among poorly nourished children and adults in the Indian subcontinent, the Far East, Africa and tropical South America. In the tropics, beriberi occurs under conditions of low thiamin intake, carbohydrate-rich diets, and high energy expenditure. Thiamin is not stored in the body, and signs of thiamin depletion occur in just 18 days with a thiamindeficient diet or with TPN.

Thiamin is required for energy production in all metabolically active tissues and is found in high concentrations in skeletal muscle, heart, liver, kidneys, and brain. Thiamin serves as a coenzyme for the mitochondrial enzyme complex and transketolase.

Beriberi may manifest as alcoholic ketoacidosis, characterized by increased levels of lactate from the anaerobic glycolysis of pyruvate as a result of the blockage of the oxidative decarboxylation of pyruvate. Unexplained lactic acidosis from thiamin deficiency may also occur in patients in intensive care settings with serious systemic diseases, liver failure, hemodialysis, severe vomiting, gastric malignancy, intestinal obstruction, pyloric stenosis, severe gastritis, after gastrectomy, or receiving TPN with insufficient thiamin.

The typical presentation in patients with alcoholism is high-output cardiac failure with tachycardia and wide pulse pressure. Cardiomegaly, pedal edema, and pulmonary edema are common. Cardiac beriberi may manifest in Western hospitals with intractable cardiac failure, collapsed peripheral circulation, lactic acidosis, and shock. With intravenous thiamin, cardiac failure responds dramatically, with massive diuresis, correction of acidosis, reduction in pulmonary capillary wedge pressure, and hemodynamic normalization.

Wernicke Encephalopathy - This disorder is characterized by acute onset of nystagmus, abducens, and conjugate gaze palsies; gait ataxia; and mental confusion from lesions of nuclei at the level of the third and fourth ventricle and in the periaqueductal gray. The disease may begin with ataxia, followed by nystagmus and confusion. The typical ocular abnormalities are horizontal and vertical nystagmus, bilateral lateral rectus palsy, and weakness of conjugate gaze. Internuclear ophthalmoplegia is common, and patients with advanced cases may exhibit complete ophthalmoplegia. Ataxia is severe, with wide-based stance and slow, hesitant, short-stepped gait; tandem walking may be impossible. Intention tremor is absent. Drowsiness, confusion, apathy, and loss of executive function, attention, and memory occur in the acute stage. The ocular signs and confusion respond rapidly to intravenous thiamin, but the ataxia and memory deficits may fail to improve.

Korsakoff Syndrome - This syndrome is considered a chronic phase of Wernicke encephalopathy. Usually, patients are completely amnesic of events that occurred during the acute phase of the illness. The memory loss affects both new learning (anterograde amnesia) and past memories (retrograde amnesia). The most severe deficits are those of learning and storage of new information. Patients also exhibit executive dysfunction, loss of spatial organization, and problems with visual and verbal abstractions. Korsakoff syndrome is associated not only with memory impairment but also with global and executive deficits indicative of impairment of frontal lobe connections. Interruption of the hippocampomammillothalamic tract at several levels (mammillary bodies, dorsal medial, and anterior thalamic nuclei) explains the severe amnesia. Other behavioral and cognitive deficits result from interruption of the prefrontal corticosubcortical circuits that underlie executive function and attention.

Vitamin B2 (Riboflavin) Deficiency - Ariboflavinosis is associated with nonspecific signs such as angular cheilosis, glossitis (beefy-red tongue), scaling dermatitis, normochromic normocytic anemia, and superficial interstitial keratitis. Recommended treatment is with vitamin B complex that usually contains a mixture of riboflavin, thiamin, niacin, folic acid, vitamin B12, pantothenic acid, and biotin. In the presence of a deficiency syndrome with interstitial keratitis, vitamin A is also recommended.

Niacin Deficiency (Pellagra) - Dermatitis, diarrhea, and dementia characterize the clinical manifestations of pellagra. The dermatitis typically occurs in areas exposed to sunlight, including the neck. The dermatitis of acute pellagra begins as an erythema that resembles sunburn with slow tanning and exacerbation by sunlight. Oral scalding, burning sensations of the tongue, glossitis, anorexia, abdominal pain, and recurrent bouts of diarrhea also occur. The dementia is preceded by insomnia, fatigue, nervousness, irritability, and depression. Suicide by drowning was said to be a common occurrence. The cognitive deficits include confusion, mental dullness, apathy, and memory impairment. Typical neuropathologic lesions of pellagra affect Betz cells in the motor cortex, smaller pyramidal cortical neurons, large neurons of basal ganglia and motor cranial nuclei, dentate nucleus, and anterior horn cells. Affected neurons appear swollen, rounded, with eccentric nuclei and loss of Nissl particles. Some alcoholic patients have similar brain lesions in the absence of overt pellagra. Pellagra neuropathy is indistinguishable from beriberi neuropathy, but it fails to respond to niacin treatment alone, and B-complex vitamin treatment is recommended.

Vitamin B6 (Pyridoxine) - exists in three natural forms, pyridoxol, pyridoxal, and pyridoxamine. Ingested pyridoxol is phosphorylated and then oxidized to pyridoxal phosphate, an important coenzyme in the metabolism of amino acids, including the conversion of _-ketoglutarate to glutamate and of glutamate to GABA. Vitamin B6 deficiency may cause niacin deficiency as a result of impaired tryptophan metabolism. Increased homocysteine responds to pyridoxine, vitamin B12, or folate, depending on the type of depletion.

Pyridoxine is found in virtually all foods, thus making dietary deficiency unlikely, although increased requirements occur in pregnancy and lactation, estrogen use, hyperthyroidism, high-protein diets, and elderly persons. Faulty preparation may destroy pyridoxine in baby formula, with resulting infantile seizures. Infants of mothers deficient in vitamin B6 may also suffer neonatal seizures. The latter two mechanisms of seizure causation are different from pyridoxine dependency, a rare autosomal recessive disorder causing intractable seizures in neonates and infants.

Vitamin B12 (Cobalamin) - Diverse factors may cause cobalamin deficiency including absent dietary supply (vegans), decreased saliva (Sjögren syndrome), antibodies against IF (pernicious anemia), gastrectomy, antacids such as proton pump inhibitors and histamine (H2)-receptor antagonists, gastritis involving parietal cells in gastric fundus, malabsorption syndromes (tropical sprue), the diabetes medication metformin, surgical resection or bypass of distal ileum, competition for vitamin B12 (by bacterial proliferation in the intestine in the blind-loop syndrome, or by intestinal parasitism with the fish tapeworm Diphyllobothrium latum), and rare genetic enzyme deficiencies (methylmalonic aciduria).

Signs of neurologic involvement in vitamin B12 deficiency may occur before the development of megaloblastic anemia and, rarely, with normal serum levels of vitamin B12. More sensitive indicators of neural damage are increases in serum MMA, homocysteine, and methylcitric acid. The spinal cord, brain, optic nerves, and peripheral nerves may be affected by vitamin B12 deficiency.

Folic Acid - Folate deficiency produces megaloblastic anemia identical to that of vitamin B12 deficiency, but isolated folic acid deficiency rarely produces SCD and peripheral neuropathy. Folic acid deficiency may produce isolated increase of homocysteine.

Vitamin E - Vitamin E deficiency occurs with poor diets, malabsorption, short bowel and blind-loop syndromes, cystic fibrosis, celiac disease, and chronic cholestatic liver disease. There is a rare syndrome of isolated vitamin E deficiency with neurologic manifestations with onset in childhood, without fat malabsorption. Symptoms include tremor, tremulous dysarthric speech, gait ataxia from loss of vibratory sensation and proprioception, and global areflexia. Cerebellar deficits include dysmetria, slowed finger movements, and postural tremor. The gait is wide based, with prominent lordosis and genu recurvatum with pseudodystonic extension of the knees and inversion of the feet. Ophthalmoplegia, retinitis pigmentosa, dysarthria, generalized muscle weakness, and extensor plantar responses are present in some cases. The symptoms progress from hyporeflexia, ataxia, limitations in upward gaze, and strabismus to long-tract defects, weakness, and visual field constriction. Patients with severe, prolonged deficiency may develop complete blindness, dementia, and cardiac arrhythmias.

Vitamin D - Vitamin D receptors are present in the intestine and bone as well as in the brain, heart, stomach, pancreas, activated T and B lymphocytes, skin, and gonads.  Vitamin D is a natural immunoregulator with antiinflammatory action. Low vitamin D status has been implicated in the etiology of autoimmune diseases such as multiple sclerosis (MS).

MS occurs with lower prevalence in equatorial regions of the world that have significantly higher exposure to sunlight; Nordic countries with fewer days of sunlight have a much higher prevalence of MS.

Dietary and vitamin treatment in neurology

Numerous neurologic conditions, ranging from migraine, stroke, and hepatic encephalopathy to rare metabolic disturbances, respond to dietary treatment or to specific vitamins.

Migraine -  The most common dietary recommendations in neurology are given to patients with migraine; advice includes avoidance of ice-cold foods, hypoglycemia, nitrates, monosodium glutamate, and biogenic amines, in particular tyramine and phenylethylamine. Riboflavin supplementation helps to prevent recurrence of migraine.

Mediterranean Diet - Mediterranean diet is the generic name of the typical diet of people living in the olive-growing areas of the Mediterranean basin. Consequently, olive oil is the basic ingredient of this diet and the principal source of dietary fat, providing more calories than any other individual food. Other important components of the diet are of plant origin and include generous amounts of fruits and vegetables, legumes, grains, nuts, cereals cooked with species, and natural sweeteners such as honey and grape juice syrup. Wine, milk and dairy products, fish, and relatively small amounts of saturated fats, meat, and poultry are also characteristic of this diet. The Mediterranean diet has shown protective vascular effects in population-based studies and intervention trials. The main components of the Mediterranean diet include the following: olive oil; fish and seafood; probiotics in sour milk, yogurt, and other dairy products; and flavonoids and polyphenols in grains, vegetables, fruits, spices, and beverages such as red wine, tea, chocolate, and coffee. The Mediterranean diet is rich in fruits and vegetables, legumes, grains, nuts, and cereals, with minimal amounts of saturated fats, meat, and poultry providing a healthy balance of omega-6 and omega-3 fatty acids.

The Mediterranean diet lowers risk for cardiovascular disease, myocardial and cardiovascular mortality, stroke, obesity, arthritis, cancer, and, most recently, Alzheimer disease. The Mediterranean diet provides an appetizing and useful public health approach to prevention of stroke and cognitive dysfunction.

Stroke - Dietary advice for prevention of stroke and for poststroke treatment, as well as for patients with cardiovascular disease, includes recommendations to decrease the intake of saturated animal fats, trans-fats, and sodium to control hypertension, hyperlipidemia, and body mass index. The DASH diet (Dietary Approaches to Stop Hypertension diet) recommends lowering the dietary intake to 150, 100, or 50 mmol/day of sodium, according to the severity of hypertension and to increase consumption of fruits, juices and vegetables. As mentioned earlier, the Mediterranean diet is an excellent dietary approach to stroke prevention.

Orthostatic Hypotension - To increase the circulating volume, patients with orthostatic hypotension are advised to increase their sodium intake to 150 to 250 mEq/day of sodium (10 to 20 g of salt) and to raise their oral fluid intake to 20 oz/day, along with high potassium supplementation when they are taking fludrocortisone.

Idiopathic Intracranial Hypertension - is a syndrome characterized by headache, papilledema, and absence of focal neurologic signs. It may result from thrombosis of venous sinuses and from endocrine conditions. The two most common nutritional causes are obesity and hypervitaminosis A. Weight reduction, either by diet or by bariatric surgery, is effective in controlling the symptoms. A low-salt diet and fluid restriction help to alleviate the edema.

Childhood Epilepsy - The ketogenic diet has been used for many years for the treatment of childhood epilepsy, in particular for refractory cases such as the Lennox-Gastaut syndrome. It is important to maintain ketosis avoiding calorie and fluid restrictions. The ketogenic diet is also used in neonatal seizures resulting from glucose transporter deficiency and in some mitochondrial disorders (benign pyruvate dehydrogenase complex deficiency).