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Neurologic Manifestations of Nutritional Disorders
Maintenance of medical and neurologic health requires adequate ingestion, absorption, and storage of vitamins and minerals. Nutritional deficiencies may result from inadequate intake or malabsorption of critical vitamins and micronutrients. Individuals at risk for deficient nutrient intake include the impoverished in developed and underdeveloped countries (where certain nutritional disorders may be endemic), individuals with eating disorders or engaging in fad or restrictive diets, those suffering from chronic alcoholism, and patients with chronic medical conditions that result in malabsorption or require prolonged parenteral nutrition. Malabsorption may result from gastrointestinal surgery, including bariatric surgery for obesity, and from chronic gastrointestinal disorders such as celiac disease, Whipple disease, bacterial overgrowth, and inflammatory bowel disease. Excessive ingestion of certain substances, including vitamins and micronutrients, may result in neurologic impairment directly (vitamin B 6 excess) or indirectly by interfering with absorption of certain vitamins (copper deficiency induced by hyperzincemia). Awareness of the characteristic clinical features of the various nutritional disorders and conditions associated with them facilitates more timely recognition and treatment, and directly impacts prognosis ( Table 15-1 ).
Table 15-1
Nutritional Disorders—Diagnosis and Treatment
| Vitamin | Diagnosis | Treatment |
|---|---|---|
| Vitamin B 12 deficiency | Serum cobalamin Serum methylmalonic acidSerum homocysteine | Intramuscular vitamin B 12 1000 μg×5 days; once monthly thereafter or vitamin B 12 1,000 μg daily orally |
| Nitrous oxide | Serum cobalamin (rendered inactive by N 2 O) | Cessation of nitrous oxide exposure; Intramuscular vitamin B 12 ; Oral methionine considered |
| Folate deficiency | Serum folate, homocysteine | Oral folate 1 mg tid initially; then 1 mg daily thereafter |
| Copper deficiency | Serum copper, ceruloplasmin; urinary copper | Discontinue zinc; oral copper 8 mg daily for 1 week; 6 mg daily for 1 week; 4 mg daily for 1 week; 2 mg daily thereafter |
| Vitamin E | Serum vitamin E; ratio serum vitamin E to serum lipids Cholesterol, triglycerides | Vitamin E—dose range 200 mg–200 mg/kg/day oral or intramuscular |
| Thiamine | Clinical diagnosis; brain MRI | Thiamine 100 mg IV followed by 50–100 mg IV/IM until nutritional status stable |
| Pyridoxine | Serum pyridoxal phosphate | Pyridoxine 50–100 mg daily |
| Niacin | Urinary excretion niacin metabolites | Nicotinic acid 25–50 mg oral/IM |
As is true with the evaluation of all suspected neurologic disorders, the identification of nutritional deficiencies requires a careful neurologic history and examination. A meticulous review of medication history, including prescription and over-the-counter medications, is necessary. Certain prescription and nonprescription medications may increase an individual’s risk of developing a vitamin deficiency (e.g., histamine H2 blockers and vitamin B 12 deficiency), and excessive ingestion of particular supplement medications may result in vitamin malabsorption (e.g., zinc-induced copper deficiency) and deficiency. A careful review of past medical and surgical history is critical, as a prior history of gastric bypass surgery, inflammatory bowel disease, celiac disease, and other medical and surgical conditions may compromise nutritional status. It is also essential in the evaluation of such patients to understand the time course over which various vitamin deficiencies may develop. For example, body stores of thiamine are limited, and thiamine deficiency may develop within weeks, whereas cobalamin (vitamin B 12 ) deficiency develops over years. Additionally, the identification of a particular vitamin deficiency should prompt a thorough laboratory evaluation for other vitamin deficiencies, as multiple vitamin deficiencies may occur in the same patient.
Vitamin B 12 Deficiency
Vitamin B 12 (cobalamin) deficiency is a common condition, with estimated prevalence rates ranging from 2 to 15 percent of the elderly, depending upon the population studied and diagnostic criteria used. Despite these high prevalence rates, there remains no consensus on how to diagnose and evaluate patients with suspected vitamin B 12 deficiency. Recognition of vitamin B 12 deficiency is critical, as the hematologic and neurologic manifestations are potentially reversible if diagnosed and treated in a timely manner. However, if treatment is initiated too late, the neurologic impairment resulting from vitamin B 12 deficiency may be irreversible.
Vitamin B 12 is a cofactor for the enzymes methionine synthase and L-methylmalonyl-coenzyme A mutase and is required for proper red blood cell formation, normal neurologic function, and DNA synthesis. Vitamin B 12 is necessary for the initial myelination, development, and maintenance of myelination within the central nervous system. Classically, vitamin B 12 deficiency results in a myelopathy, or “subacute combined degeneration,” which results from demyelination of the posterolateral columns of the cervical and thoracic spinal cord. Demyelination of cranial nerves, peripheral nerves, and brain may also occur and has been referred to as “combined-systems disease.” Vitamin B 12 deficiency may result in megaloblastic anemia, with macrocytosis, anisocytosis, hypersegmented neutrophils, leukopenia, thrombocytopenia, or pancytopenia.
Etiology
Vitamin B 12 is a water-soluble vitamin that exists in several forms, all of which contain cobalt, and are collectively referred to as cobalamins. Methylcobalamin and 5-deoxyadensoylcobalamin are the forms of vitamin B 12 that are active in human metabolism. Vitamin B 12 is contained in a number of animal proteins, in fortified breakfast cereals, and in some nutritional yeast products. Daily losses of vitamin B 12 are minimal, and even in cases of severe malabsorption, it may take 5 years or more to develop symptomatic vitamin B 12 deficiency.
Vitamin B 12 deficiency in elderly patients most commonly results from pernicious anemia, atrophic gastritis, and achlorhydria-induced cobalamin malabsorption ( Table 15-2 ). The incidence of atrophic gastritis increases with age and may at least partially explain the increased frequency of vitamin B 12 deficiency with aging. Achlorhydria results in impaired extraction of vitamin B 12 from food sources. Partial gastrectomy, bariatric surgery, and ileal resection may result in the malabsorption of vitamin B 12 , and partial gastrectomy has been associated with loss of intrinsic factor. Gastroenterologic disorders such as celiac disease, Crohn disease, ileitis, pancreatic disease, and bacterial overgrowth may also result in vitamin B 12 deficiency. Certain medications, such as histamine (H2) blocking agents, proton pump inhibitors, and glucophage may also increase one’s risk of developing vitamin B 12 deficiency. Vitamin B 12 deficiency rarely results from inadequate intake in vegetarians and would be expected to develop only after many years.
Table 15-2
Risk Factors for Vitamin B 12 Deficiency
| Pernicious anemia |
| Atrophic gastritis |
| Achlorhydria-induced food-cobalamin malabsorption |
| Partial gastrectomy |
| Ileal resection |
| Bariatric surgery |
| Histamine-2 (H2) receptor antagonists |
| Proton pump inhibitors |
| Glucophage |
| Bacterial overgrowth |
| Pancreatic disease |
| Celiac disease |
| Helicobacter pylori infection |
| Diphyllobothrium latum infection |
| Nitrous oxide |
| Dietary restriction |
Nitrous oxide alters the cobalt core of cobalamin, converting it into an inactive, oxidized form. Hence, nitrous oxide abuse may result in cobalamin deficiency, with most reported cases associated with low or borderline-low vitamin B 12 levels. A single exposure to nitrous oxide may be enough to precipitate neurologic impairment in an individual with unsuspected vitamin B 12 deficiency, with time to symptom onset ranging from immediate postexposure up to 2 months. Nitrous oxide remains one of the more commonly used anesthetic agents worldwide, and can also be obtained for abuse in the form of whipped cream canisters, and as “whippets,” which are small bulbs containing nitrous oxide.
Clinical Manifestations
Neurologic signs and symptoms of vitamin B 12 deficiency may be the initial manifestation of this condition. Paresthesias and ataxia are the most common initial symptoms in patients with vitamin B 12 deficiency. Classically, vitamin B 12 deficiency results in a myelopathy, which may be accompanied by a peripheral neuropathy. The myelopathy results from impairment in posterior column and lateral spinothalamic tract function, with a combination of pyramidal signs and posterior column sensory loss evident on examination. The peripheral neuropathy associated with vitamin B 12 deficiency is typically mild and is predominantly axonal on electrodiagnostic testing.
Neuropsychiatric manifestations range from memory impairment, change in personality, delirium, and even psychosis. Optic neuropathy, resulting in diminished visual acuity, optic atrophy, and centrocecal scotomas may be seen. Symptoms of orthostatic intolerance, resulting from orthostatic hypotension, are an uncommon manifestation of vitamin B 12 deficiency. Other much less commonly encountered neurologic conditions attributed to vitamin B 12 deficiency include cerebellar ataxia, orthostatic tremor, ophthalmoplegia, and vocal cord paralysis. A number of constitutional symptoms may accompany the neurologic signs and symptoms, including fatigue, weight loss, fever, dyspnea, and gastrointestinal symptoms.
Diagnosis
Serum cobalamin is the initial screening test in patients with suspected vitamin B 12 deficiency ( Table 15-1 ), however limitations in cobalamin sensitivity must be recognized. Some patients with vitamin B 12 deficiency will have normal cobalamin levels. In patients with borderline low cobalamin levels, and particularly in those patients strongly suspected of vitamin B 12 deficiency, methylmalonic acid and homocysteine levels should be checked. Methylmalonic acid and homocysteine levels are increased in as many as one-third of patients with low-normal serum cobalamin levels and vitamin B 12 deficiency. However, these tests, particularly homocysteine, lack specificity ( Table 15-2 ).
Once a diagnosis of vitamin B 12 deficiency is established, diagnostic testing may be pursued in order to determine the cause. Antibodies to intrinsic factor are seen in only 50 to 70 percent of patients with pernicious anemia, but are highly specific. Antiparietal cell antibodies lack sensitivity and specificity and have limited utility. Gastrin antibodies are 70 percent sensitive and specific for pernicious anemia. Elevated serum gastrin and decreased pepsinogen I levels have been reported to be abnormal in 80 to 90 percent of patients with pernicious anemia, but the specificity of these tests may be limited. The Schilling test is rarely utilized presently due to concerns about radiation exposure, cost, and diagnostic accuracy.
Nerve conduction studies (NCSs) and needle electromyography (EMG) may confirm the presence of an axonal sensorimotor peripheral neuropathy. Somatosensory evoked potentials (SEPs) may show slowing in central proprioceptive pathways. Brain and spinal cord magnetic resonance imaging (MRI) studies may show signal change in subcortical white matter and in posterolateral columns.
Treatment
Treatment of neurologic impairment due to vitamin B 12 deficiency involves the administration of high-dose oral, sublingual, or intramuscular cobalamin. With malabsorption, 1000 μg of cobalamin is administered intramuscularly for 5 days and monthly thereafter. There is evidence to suggest that 1000 μg of oral or sublingual cobalamin, given daily, is as effective as intramuscular administration. Lifelong vitamin B 12 supplementation therapy is typically necessary, unless a potentially reversible cause is identified and treated. Hematologic recovery occurs within the first 1 to 2 months and is complete. The neurologic condition should stabilize and improvement may occur over the first 6 to 12 months following the initiation of treatment. Neurologic recovery may be incomplete, particularly in those with significant neurologic deficits prior to the initiation of therapy. Methylmalonic acid and homocysteine levels should be utilized to monitor response to therapy, and typically should normalize within 10–14 days.
Patients with pernicious anemia should undergo endoscopy, as they are at higher risk of developing gastric and carcinoid cancers. Upper endoscopy should be considered in other patients as well, including those with other gastrointestinal symptoms and those with other concomitant vitamin deficiencies.
Folate Deficiency
The active form of folate, tetrahydrofolic acid (THFA), is essential in the transfer of one-carbon units to substrates utilized in the synthesis of purine, thymidine, and amino acids. Methyl tetrahydrofolate (THF) is required for the cobalamin-dependent remethylation of homocysteine to methionine, and methylene THF methylates deoxyuridylate to thymidylate. While folate deficiency might be expected to result in similar complications as vitamin B 12 deficiency, neurologic manifestations of isolated folate deficiency are extremely uncommon.
Etiology
Folate is present in animal products, citrus fruits, and green, leafy vegetables. Normal body stores of folate range from 500 to 20,000 µg, and 50 to 100 µg are required daily. Serum folate falls within 3 weeks of diminished intake or malabsorption, and clinical signs of folate deficiency may occur within months. After ingestion, folate polyglutamates undergo hydrolysis to monoglutamates, which are absorbed in the proximal small intestine and ileum. Absorbed folate monoglutamates are then metabolized by the liver to 5-methyl-tetrahydrofolate (MTHF), the principal circulating form of folate. The cellular uptake of MHTF is mediated by four different carrier systems: a proton-coupled folate transporter, low-affinity high-capacity reduced folate carrier, and two high-affinity folate receptors.
Folate deficiency is one of the more common nutritional disorders worldwide. Risk factors for folate deficiency include malnutrition, conditions associated with increased folate requirements (e.g., pregnancy, lactation, and chronic hemolytic anemia), gastroenterologic disorders, and certain medications ( Table 15-3 ). Gastroenterologic conditions that affect folate absorption in the small bowel may result in folate deficiency, including tropical sprue, celiac disease, bacterial overgrowth syndrome, inflammatory bowel disease, and pancreatic insufficiency. Gastric surgeries or medications that reduce gastric secretions may also result in folate deficiency. A number of other medications, such as methotrexate, aminopterin, pyrimethamine, trimethoprim, and triamterene, inhibit dihydrofolate reductase and may result in folate deficiency. Mechanisms by which other medications such as anticonvulsants, sulfasalazine, oral contraceptives, and antituberculous drugs affect folate levels have not been established.
Table 15-3
Causes of Folate Deficiency
| Malnutrition (e.g., in alcoholism, premature infants, adolescents) |
| Increased folate requirement (e.g., pregnancy, lactation, chronic hemolytic anemia) |
| Dietary restriction (e.g., phenylketonuria) |
| Malabsorption (e.g., tropical sprue, celiac disease, bacterial overgrowth, inflammatory bowel disease, giardiasis) |
|
| Medications that inhibit dihydrofolate reductase (e.g., aminopterin, trimethoprim, methotrexate, pyrimethamine, triamterene) |
| Medications with unclear mechanism (e.g., anticonvulsants, antituberculous drugs, sulfasalazine, oral contraceptive agents) |
| Inborn errors of folate metabolism (e.g., hereditary folate malabsorption, cerebral folate transporter deficiency, glutamate formiminotransferase deficiency, severe methylenetetrahydrofolate reductase (MTHFR) deficiency, dihydrofolate reductase deficiency, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protein deficiency, functional methionine synthase deficiency) |
Eight inborn errors of folate absorption have been described, including hereditary folate malabsorption, cerebral folate transporter deficiency, glutamate formiminotransferase deficiency, severe methylenetetrahydrofolate reductase (MTHFR) deficiency, dihydrofolate reductase deficiency, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protein deficiency, and functional methionine synthase deficiency. Clinical manifestations of these disorders may include megaloblastic anemia, mental retardation, seizures, movement disorders, and peripheral neuropathy. Early identification and treatment with folate may result in clinical improvement in certain forms of these disorders. Methylenetetrahydrofolate deficiency is the most common of these disorders, with variable neurologic and vascular manifestations, including mental retardation, seizures, motor and gait disorders, schizophrenia, and thromboses, with laboratory studies showing hyperhomocysteinemia and homocystinuria.
Clinical Manifestations
Maternal folate deficiency during or around the time of conception has been reported to result in more than 50 percent of neural tube defects. Myeloneuropathy, peripheral neuropathy, and megaloblastic anemia have been associated with folate deficiency. These potential manifestations of folate deficiency are clinically indistinguishable from those of vitamin B 12 deficiency, although as previously mentioned they are much less common. Preliminary reports suggest that folate deficiency may be associated with an increased risk of peripheral vascular disease, coronary artery disease, cerebrovascular disease, and cognitive impairment, although these preliminary reports await further confirmatory research.
Diagnosis
Serum folate, red blood cell folate, and homocysteine levels may be used to evaluate an individual with suspected folate deficiency. Results depend upon methods and laboratories where these studies are performed. Serum folate levels fluctuate considerably and do not always accurately reflect tissue stores. Red blood cell folate levels may more accurately predict tissue stores, but there is considerable laboratory assay variability. Homocysteine levels have been demonstrated to be elevated in 86 percent of patients with clinically significant folate deficiency. Typically, a serum folate level of 2.5 μg/L has been utilized as the cutoff for folate deficiency; however, it has been suggested that a range of 2.5 to 5 ng/mL may reflect mildly compromised folate status.
Treatment
Vitamin B 12 levels should also be assessed with suspected folate deficiency, and if low, vitamin B 12 supplementation should be initiated immediately. Oral administration of folic acid may be adequate, typically 1 mg three times daily followed by maintenance dosing of 1 mg daily. Parenteral administration of folic acid may be considered in acutely ill patients, and particularly in patients with malabsorption. Folate supplementation, 0.4 mg daily, is recommended in women of childbearing age with epilepsy.
Copper Deficiency
Copper is a trace element involved in a number of metalloenzymes, critical in the development and maintenance of nervous system structure and function. These enzymes include cytochrome c-oxidase (electron transport, oxidative phosphorylation), copper/zinc superoxide dismutase (antioxidant defense), tyrosinase (melanin synthesis), dopamine β-hydroxylase (catecholamine synthesis), lysl oxidase (cross-linking collagen and elastin), and others.
Copper deficiency in animals was first recognized in sheep in 1937, manifesting as an enzootic ataxia (also known as swayback), and then subsequently was noted to affect other animals similarly. Hematologic abnormalities were the first signs of acquired copper deficiency recognized in humans, with anemia, neutropenia, and sideroblastic anemia evident in some but not all patients with copper deficiency. The neurologic manifestations of acquired copper deficiency have been defined over the past several years.
Etiology
Copper is present in a wide variety of foods, with shellfish, oysters, legumes, organ meats, chocolate, nuts, and whole-grain products being particularly rich in copper. The estimated daily requirement for copper is 0.70 mg, and the estimated total body copper content is 50 to 120 mg. Copper absorption occurs in the stomach and proximal small intestine via active and passive transport processes. The Menkes P-type ATPase (ATP7A) is responsible for copper efflux from enterocytes.
Malabsorption following prior gastric surgery and excessive, exogenous zinc ingestion are the most frequently identified causes of symptomatic copper deficiency. Copper deficiency may also occur in premature, low-birthweight, and malnourished infants, and may occur as a complication of total parenteral or enteral nutrition. Chronic gastrointestinal conditions such as celiac disease, cystic fibrosis, inflammatory bowel disease, and bacterial overgrowth may result in copper malabsorption. Patients should be queried about the use of zinc supplements, including denture creams, some of which have excessive zinc and may induce copper deficiency. Excessive zinc ingestion may also cause copper deficiency. It is hypothesized that excessive zinc ingestion upregulates intestinal enterocyte metallothionein production, which has a higher affinity for copper than zinc, resulting in retention of copper in intestinal enterocytes and loss of copper in the stool. Some patients will not have any identifiable cause for copper deficiency.
Menkes disease is a congenital disorder with clinical signs and symptoms that result from copper deficiency. This condition results from a mutation in the ATP7A gene, which leads to failure of intestinal copper transport across the gastrointestinal tract and subsequent copper deficiency. Wilson disease is a disorder of copper toxicity that results from an impairment in biliary copper excretion.
Clinical Manifestations
Hematologic abnormalities have been well described in copper deficiency, and include anemia and neutropenia, primarily. Failure to recognize hematologic derangements as resulting from copper deficiency has led to misdiagnoses such as myelodysplastic syndrome, aplastic anemia, and sideroblastic anemia. Patients with copper deficiency may develop a myeloneuropathy that resembles the syndrome of subacute combined degeneration associated with vitamin B 12 deficiency. Pyramidal signs, such as brisk deep tendon reflexes at the knees, and extensor plantar responses are typically present, along with impairment in posterior column sensory modalities. Sensory loss is characteristically severe, and frequently leads to a sensory ataxia. Neuropathic extremity pain may be reported, and distal lower limb weakness and atrophy may develop suggesting peripheral nerve involvement.
Diagnosis
Low serum copper and ceruloplasmin levels establish the diagnosis of copper deficiency. Twenty-four-hour urine copper levels will often be decreased, in contrast to an elevation in urinary copper seen with Wilson disease. Serum and 24-hour urine zinc levels should also be assessed. Ceruloplasmin is an acute-phase reactant and may be increased in various conditions, including pregnancy, oral contraceptive use, liver disease, malignancy, hematologic disease, smoking, diabetes, uremia, and other inflammatory and infectious diseases. In the presence of these conditions, copper deficiency may be masked. Serum copper and ceruloplasmin may be decreased in Wilson disease, hence laboratory evidence of copper deficiency does not necessarily indicate copper deficiency in the absence of clinical features consistent with the diagnosis.
Cervical MRI studies may show T2 hyperintensity involving the dorsal columns ( Fig. 15-1 ). Somatosensory evoked potentials often show slowing in central proprioceptive pathways, and NCS and needle EMG demonstrate findings consistent with an axonal sensorimotor peripheral neuropathy. Brain MRI studies may show diffuse T2 hyperintensities involving the subcortical white matter, suggesting demyelination.
Treatment
Treatment of copper deficiency involves discontinuation of zinc in those with excessive zinc consumption as well as copper supplementation. A recommended regimen is 8 mg of orally administered elemental copper administered daily for 1 week, followed by 6 mg daily for the next week, 4 mg daily during the third week, and 2 mg daily thereafter. Occasionally intravenous copper supplementation is necessary. Ongoing copper supplementation may not be necessary in patients with copper deficiency due to zinc excess (with cessation of zinc ingestion) or in those with a treatable gastrointestinal condition resulting in copper malabsorption (such as celiac disease). Patients without an identifiable cause of copper deficiency or those with copper malabsorption due to gastric bypass surgery typically require lifelong copper supplementation.
Similar to vitamin B 12 deficiency, the hematologic abnormalities associated with copper deficiency normalize within 1 month of copper repletion. Neurologic deficits are expected to stabilize, but there may be little improvement in neurologic signs and symptoms, particularly in those with more severe neurologic impairment.
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