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Nutritional and Alcohol-Related Neurologic Disorders
Vitamins and minerals, which are essential to cellular function, must be obtained from the environment because the body cannot produce them. They are necessary for embryonic and early development as well as the subsequent maintenance of metabolic function of both the central and peripheral nervous systems. Deficiencies can cause a variety of neurologic syndromes ( Table 384-1 ), each with a well-described constellation of symptoms that are dependent on the location of the pathology within the nervous system, the duration of the deficiency, and the potential presence of multiple deficiencies or other risk factors, such as excess alcohol use.
TABLE 384-1
VITAMIN AND MINERAL DEFICIENCIES
| VITAMIN AND MINERAL DEFICIENCIES | NEUROLOGIC SYNDROME(S) | SUPPORTING TESTS | TREATMENT ∗ REPLETION/SUPPLEMENTATION |
CAUSES (OTHER THAN MALNUTRITION) |
|---|---|---|---|---|
| A (retinol) | Blindness from retinal or corneal damage, especially at night; ageusia | Visual fields, visual acuity Serum level <30-65 µg/dL |
30,000 IU vitamin A daily × 1 wk or 60,000 µg × 2 days, repeated in 2 wk; then 5000-10,000 IU daily | Hypothyroidism, diabetes, renal or liver failure, bariatric surgery |
| B 1 (thiamine) | Wernicke encephalopathy: ataxia, nystagmus, ophthalmoparesis, confusion, delirium Korsakoff syndrome: amnesia, confabulation, impaired learning Beri-beri: axonal neuropathy with paresthesias, numbness, loss of distal reflexes |
MRI: symmetrical lesions of midbrain (periaqueductal area), pons, hypothalamus, thalamus, cerebellum MRI: necrosis of mamillary bodies, dorsomedial and anterior thalamus Nerve conduction tests: decreased amplitude Serum thiamine level <20 ng/dL Decreased erythrocyte transketolase |
Prevent by 100 mg PO daily before and after bariatric surgery, 100 mg IV before glucose administration or refeeding after starvation Treat Wernicke encephalopathy with 5 days of thiamine, 500-1000 mg IV or IM daily, until improvement stabilizes, then 250 mg daily for 3-5 days; then PO 100 mg daily or 100 mg IM monthly |
Alcoholism, bariatric or other major GI surgery, prolonged vomiting, hemodialysis, diuretic treatment of heart failure, cachexia, 5-fluorouracil, other blockers of thiamine phosphate production |
| B 3 (niacin) | Pellagra: confusion, dementia, weakness, ataxia, spasticity, myoclonus, glossitis, dermatitis, photosensitivity | Erythrocyte NAD, plasma niacin, urinary N1-methylnicotinamide | Nicotinic acid, 50 mg PO tid or 25 mg IV tid; nicotinamide, 50-100 mg IM or 250-500 mg daily PO | Alcoholism, corn- or cereal-based diet, Hartnup syndrome, carcinoid syndrome |
| B 5 (pantothenic acid) | Dysesthesias, foot paresthesias, cramps, poor coordination | Deficient coenzyme A | 5 mg PO daily | Severe malnutrition |
| B 6 (pyridoxine) | Neuropathy, sensory ataxia, depression, irritability Infantile and adult pyridoxine-deficient epilepsy |
Plasma PLP <27 nmol/L; urinary 4-pyridoxic acid <3 nmol ↑ Homocysteine after methionine loading challenge ↑ α-AASA in urine, plasma, CSF |
50-100 mg PO daily for neuropathy (preventive use if taking B 6 antagonist) 100 mg IV; then 15-30 mg/kg lifelong PO daily for infants, 100-200 mg PO daily for adult epilepsy |
Diverticulosis, isoniazid, some anti-seizure medications, cycloserine, other antagonists Genetic defects in ALDH7A1 gene for antiquitin (aldehyde dehydrogenase), pyridoxal synthesis Renal failure, homocystinuria |
| B 12 (cobalamin) | Myelopathy with spastic paraparesis and sensory ataxia, peripheral neuropathy, optic neuropathy, memory loss, dementia; indirect contributor to stroke | Blood level <200 pg/mL ↑ Methylmalonic acid >145 nmol/L Intrinsic factor antibodies Megaloblastic anemia (bone marrow) Delayed somatosensory evoked potentials ↑ Homocysteine, total >12.5 µmol/L |
IM B 12 , 1000 µg daily for 1 wk, then weekly for 1 mo, then monthly; or oral B 12 , 1000 µg daily; or nasal B 12 , 500 µg weekly for lifetime if abnormal absorption, 50-100 µg daily if normal absorption | Achlorhydria, pernicious anemia, gastric or ileal resection, blind loop syndrome, sprue, HIV infection, nitrous oxide anesthesia (especially abuse), fish tapeworm, vegan diet |
| D (calciferol) | Proximal myopathy, often painful; cognitive impairment Secondary compression of spinal cord, plexus, or peripheral nerves from rickets or osteomalacia |
25-(OH) vitamin D 3 level <10 ng/mL in urine Serum calcium ↑ PTH >54 pg/mL Osteopenia/osteoporosis on bone densitometry |
Daily supplementation with 400 IU cholecalciferol (D 3 ) or 50,000 IU ergocalciferol (D 2 ) 1-3 times per week if malabsorption; use blood level to guide dosing or urine calcium excretion (should be >100 mg/day) | Lack of exposure to sunlight, including sunblock protection; chronic antiepileptic drug use |
| E (tocopherol) | Spinal and cerebellar ataxia, Babinski sign, ophthalmoplegia, peripheral neuropathy, retinitis pigmentosa | Vitamin E level <2.5 mg/L (normal, 6-15 with normal lipid level) ↑ A-β-lipoprotein levels, antigliadin antibodies Genetic analysis to rule out other spinocerebellar ataxias such as Friedreich ataxia |
Supplement with 6-800 IU or 10-40 mg/kg daily, for ataxia of genetic causes. Water-soluble 20 mg/kg/day PO or 50-100 mg/wk IM α-tocopherol to normal serum level for malabsorption; 300 mg PO daily after bariatric surgery |
Biliary atresia, celiac sprue, Genetic: ↓ α-tocopherol transport protein (8q13), microsomal triglyceride transfer protein |
| Folate | Dementia, B 12 deficiency, stroke | ↑ Homocysteine, plasma level <2.5 µg/L | 1 mg 3 times daily until normal level, then maintenance of 1 mg/day Pregnancy: 1-4 mg/day during first trimester if taking a folate antagonist or at risk of neural tube defects |
Malabsorption or use of antagonist (methotrexate) or antiepileptic medication |
| K (phytonadione) | Intracranial hemorrhage | INR or PT elevation | IM phytonadione at birth, maternal vitamin K for last month of pregnancy | Medication use that increases metabolism (e.g., phenytoin) |
| Copper | Myelopathy, neuropathy | Serum Cu <75 µg/dL, ↓ urinary Cu, ceruloplasmin <23 mg/dL MRI: ↑ T2 signal in cervical cord, dorsal column Mutation in ATP7A gene (Menkes disease) |
Elemental Cu, 8 mg/day PO or 2 mg/day IV wk 1, 6 mg/day wk 2, 4 mg/day wk 3, 2 mg/day ongoing malabsorption Menkes disease: 250 mg copper histidine SQ bid, 1-2 mg in a multivitamin postbariatric surgery |
Wilson disease, Menkes disease, alcoholism, malabsorption, gastric bypass, zinc toxicity |
| Magnesium | Seizures, encephalopathy | Serum magnesium <1.5 mg/dL, correct for low albumin | Magnesium sulfate IV or PO to normal level Avoid magnesium-wasting drugs |
Alcoholism, especially beer Diuretic use |
| Potassium | Muscle weakness, chronic, acute | Serum potassium <3.5 mEq/L, ECG | IV or PO KCl until normalized | Diuretic use, bulimia |
AASA = aminoadipic semialdehyde; bid = twice daily; CSF = cerebrospinal fluid; Cu = copper; ECG = electrocardiography; GI = gastrointestinal; HIV = human immunodeficiency virus; IM = intramuscular; INR = international normalized ratio; IV = intravenous; KCl = potassium chloride; MRI = magnetic resonance imaging; NAD = nicotinamide adenine dinucleotide; PLP = pyridoxal-5-phosphate (active coenzyme of pyridoxine); PO = by mouth; PT = prothrombin time; PTH = parathyroid hormone; SQ = subcutaneous; tid = three times daily.
∗ Treatment doses not same as RDA, recommended daily intake.
Acquired vitamin deficiency ( Chapter 199 ) can be caused by malnutrition ( Chapter 197 ), malabsorption ( Chapter 126 ), or increased demand owing to stress, sepsis ( Chapter 94 ), chronic inflammatory conditions, renal dialysis ( Chapter 117 ), infection, or other disease states. Even with adequate supply, inherited (genetic) conditions can produce neurologic dysfunction through various pathophysiologic mechanisms, including aberrant production of a necessary cofactor; impaired transport of a vitamin from the intestine, in the blood, or within the cell that needs it (e.g., mitochondria, neuron, glial cell); production of an enzyme from a vitamin cofactor, thereby resulting in metabolic dysfunction; or an epiphenomenon in a vitamin pathway. These gene disorders generally present early in life, even in neonates, although somewhat different presentations can occur in adolescence or adulthood. By comparison, acquired deficiency states may occur at any age and usually take months to years to develop. Exposure to alcohol, chemotherapy, cassava, or other neurotoxins in the setting of certain vitamin deficiencies (usually B 1 ) synergistically contributes to neuropathology. Genetic predisposition to variable metabolic rates also may explain why not all patients who consume the same food or ingest the same amount of alcohol develop deficiencies.
Malnutrition is the most common cause of vitamin deficiency in economically disadvantaged geographic locations, especially in seasons of famine due to drought or disease-induced crop failure or times of conflict or warfare. Overreliance on a single food source, particularly one that has lost its nutritional value—such as polished rice, untreated corn, or spoiled grain—can precipitate disease. In contrast, attempts to deal with obesity, such as consuming empty calories with little other nutritional value, following a fad diet, or undergoing restrictive bariatric surgery without guidance on the need for supplemental vitamins, can cause disease. Even when sufficient food supplies are readily available, malnutrition may be caused by inadequate consumption owing to mechanical obstruction from cancer of the mouth or gastrointestinal tract, unbalanced diets, fasting, anorexia, chronic nausea, or recurrent or persistent vomiting.
Iatrogenic causes include failure to feed patients who are comatose, patients who are not self-sufficient (from dementia [ Chapter 371 ], brain injury [ Chapter 368 ], or psychiatric illness [ Chapter 362 ]), or patients who have dysphagia, as can occur following a stroke or spinal cord injury. Vitamin deficiency can also result from failure to include adequate amounts of vitamin and mineral supplements when parenteral or liquid enteral diets are used for an extended period ( Chapter 198 ).
Malabsorption ( Chapter 126 ) over long periods can cause deficiency of fat-soluble vitamins such as vitamin E and even substances with higher body stores, such as vitamin B 12 and copper. As bariatric surgery has become more common in the treatment of morbid obesity ( Chapter 201 ), patients who do not maintain their vitamin supplementation after bypass-type procedures or who continue to limit intake after undergoing restrictive procedures (“lap band,” sleeve gastrectomy) are at high risk of vitamin deficiency syndromes, primarily early thiamine deficiency but also delayed cases of copper and B 12 deficiency.
Deficiency of Water-Soluble Vitamins
Thiamine (Vitamin B 1 ) Deficiency
Thiamine is converted to thiamine pyrophosphate, which is a coenzyme required in glucose and lipid metabolism for energy production and in the synthesis of neurotransmitters from branched-chain amino acids ( Chapter 199 ). Storage is exhausted after 2 to 3 weeks, and even sooner in conditions of high demand, such as pregnancy, lactation, or infection. Daily requirements of about 1 mg (0.33 mg per 1000 calories) can be obtained from food sources such as whole grains, legumes, meat, and fortified bread or cereals. Inherited dysfunction of thiamine transport mechanisms also can produce the same deficiency.
Beri-Beri
In developing countries, the most common manifestation of thiamine deficiency is beri-beri, which is characterized by a peripheral sensorimotor axonal neuropathy with numbness, paresthesias, or burning pain, occasionally accompanied by peripheral edema from heart failure (“wet beri-beri”). Other causes of thiamine deficiency include reliance on foods in which the vitamin has been inactivated by processing (e.g., polished rice) or overcooking, or eating foods that contain thiaminase-producing bacteria (e.g., raw fish). Deficiency also contributes to the neuropathy caused by chemotherapy.
“Dry” beri-beri does not produce heart failure but has a prominent neuropathy that affects all nerve types (motor, sensory and autonomic) and produces subacute distal (because of its length-dependent process) weakness and burning pain that can mimic Guillain-Barré syndrome ( Chapter 388 ). Progression usually occurs over weeks and can become advanced; rarely, a more insidious presentation can develop over months. Alcohol abuse can contribute to the nutritional deficiency but is not a required prerequisite.
Wernicke Encephalopathy
Thiamine deficiency also can result in Wernicke encephalopathy, a syndrome characterized by the development and progression over days to weeks of confusion or delirium, abnormal eye movements, and ataxia as early as 2 weeks after thiamine stores have been depleted, especially in seriously ill patients. Wernicke encephalopathy occurs most often in the setting of poor nutrition or prolonged vomiting in patients with chronic alcohol abuse. Based on pathologic changes discovered at autopsy, only about 25% of cases are detected before death. Other at-risk patients include those with excessive vomiting from any cause, including bariatric surgery ; patients with the acquired immunodeficiency syndrome (AIDS) or cancer; patients with cachexia and poor nutrition; or people who are chronically malnourished. The symptoms and signs of Wernicke encephalopathy reflect the preferential dysfunction of brain regions that have a high demand for thiamine, a cofactor in energy-producing cycles, including the blood-brain barrier, anterior and centromedian thalamus, mamillary bodies, periaqueductal gray matter, superior and inferior colliculi, and floor of the fourth ventricle. The most common pathologic changes in these regions include neuronal swelling and microscopic hemorrhages, followed by gliosis. Rarely, the cerebral cortex and hypothalamus may be involved as well. Deficiency of α-ketoglutamate dehydrogenase activity in astrocytes leads to microglial activation and glutamatergic toxicity.
Clinical Manifestations and Diagnosis
The full triad of mental status change (delirium or coma), abnormal eye movements, and ataxia occurs in only about one-third of cases. Acute symptoms may be provoked if intravenous (IV) glucose or food is given before thiamine has been replaced. Because a medical history may be unobtainable until the patient’s confusion clears, physical signs of chronic alcoholism (e.g., gynecomastia, skin angiomata, palmar erythema, Dupuytren contractures, ascites, jaundice; Chapters 132 and 138 ) or of cachexia must be sought.
Mental status changes range from mild memory impairment and inattention to delirium and coma, often with apathy or abulia. Eye movement abnormalities include nystagmus, dysconjugate gaze, and gaze palsies ( Video 384-1 and Video 384-2 ). Especially in alcoholic patients, ataxia can affect the limbs (legs more than arms), trunk, and gait. Nonalcoholic patients are more likely to have ocular dysfunction. Patients with Wernicke encephalopathy also can have autonomic and hypothalamic dysfunction, with bradycardia and hypothermia, as well as papilledema, optic neuropathy, seizures, and myoclonus.
In symptomatic patients, T2-weighted magnetic resonance imaging (MRI) can be normal but often demonstrates symmetrical increased signal owing to edema or hemorrhage in affected areas, most often periventricular thalamus, periaqueductal regions in the floor of the fourth ventricle or cerebellum, and in the mamillary bodies ( Fig. 384-1 ). Low thiamine levels (<50 mg/mL) are common, although levels may be normal in about 10% of cases. Because thiamine deficiency disrupts carbohydrate metabolism, serum levels of lactate and pyruvate can be elevated.
Korsakoff Syndrome
Korsakoff syndrome becomes apparent in up to 80% of patients who survive Wernicke encephalopathy. It is more likely to follow in the setting of alcoholism than in pure nutritional deficiency, thereby implying a synergistic mechanism that may be due to repeated episodes of alcohol withdrawal with associated glutamate neurotoxicity, compounded by lack of thiamine. The primary pathologic findings occur in the limbic system, especially the mamillary bodies, amygdala, and dorsomedial and anterior thalamus. Cortical involvement may be related to alcohol neurotoxicity rather than thiamine deficiency.
As the mental status changes of Wernicke syndrome improve, the delirious, confused state is followed by an amnestic state in which patients are often unaware of their memory impairment. Korsakoff syndrome can be reliably identified only when patients can cooperate with neuropsychological testing. It is characterized by retrograde and anterograde episodic amnesia, confabulation, and hallucinations. Occasionally, Korsakoff psychosis is present clinically or pathologically without documented episodes of Wernicke encephalopathy, perhaps because Wernicke encephalopathy went unrecognized.
The memory deficit, which precludes learning new information or acquisition of new memories, is disproportionately severe in relation to other aspects of cognitive function. For example, alertness, attention, social interactions, and motor learning (procedural memory) are generally well preserved. There may be mild disorientation with respect to time and place, and sometimes apathy and other emotional changes are present. Confabulation, in which the intrusion of errors in response to questions leads to fabrication of answers without the intention to deceive, is sometimes present spontaneously in the first weeks after Wernicke encephalopathy. Since it is most likely a compensatory mechanism, it usually lessens over time. Neuropsychological testing frequently demonstrates emotional changes and mild problems in executive function, which are indicative of frontal lobe involvement.
Treatment
Prophylactic treatment (i.e., >100 mg daily of thiamine replacement) of anyone at risk due to vomiting, starvation, bariatric surgery, and dialysis (see Table 384-1 ) can prevent Wernicke encephalopathy as well as beri-beri. In the acute setting, especially in intensive care units, all patients should receive replenishment with high-dose IV or IM thiamine (500 to 1000 mg daily for 3 to 5 days) prior to any glucose administration to circumvent any problems with swallowing or absorption. Treatment will lead rapidly, often within hours, to complete resolution of nystagmus and oculomotor paresis, followed by resolution of the ataxia and eventually of the mental status changes attributable to thiamine deficiency. Magnesium ( Chapter 105 ) and sodium also must be replaced if deficient.
Prognosis
The cognitive function in Korsakoff tends to be stable, but many alcoholic patients may have residual ataxia and cognitive impairment, including memory dysfunction, owing to the toxic effects of alcohol itself. As a result, about 50% of treated patients die within 8 years. Because Korsakoff syndrome does not respond to thiamine replacement, prevention by timely recognition of Wernicke encephalopathy is essential. Untreated, Wernicke encephalopathy is fatal in 90% of cases, and the mortality rate can be as high as 20% even in treated patients.
Cobalamin (Vitamin B 12 ) Deficiency
Cobalamin is involved in methionine pathways that regulate the formation of myelin during development and maintain myelin throughout life ( Chapter 199 ). Deficiency results in combined system disease (peripheral neuropathy and spinal cord degeneration) or subacute combined degeneration of the dorsal (sensory) and lateral (motor) tracts (i.e., myelopathy). The spinal cord tracts that are dysfunctional result in impaired position and vibratory sensation and spastic paraparesis. Impairment of cognitive function is not as closely correlated with B 12 deficiency.
Cobalamin deficiency is rarely due to inadequate dietary intake (e.g., a vegan diet for several years), because it is stored in fat and found in many foods, although more in animal proteins than vegetables. Failure to absorb the vitamin results in its deficiency, especially in individuals over age 60 years ( Chapter 150 ) because the prevalence of atrophic gastritis ( Chapter 125 ) with lack of intrinsic factor and achlorhydria rises in older individuals. Long-term use of proton pump inhibitors can also cause the same lack of gastric acid required for B 12 absorption. A more common cause in recent years is failure to maintain supplement use after bariatric surgery, with a higher risk after bypass (i.e., Roux-en-Y) than after restrictive surgery (i.e., sleeve gastrectomy or balloon placement). Reduced absorption can also occur with bacterial overgrowth, inflammatory bowel disease ( Chapter 127 ), and rarely, tapeworm infestation ( Chapter 315 ). Nitrous oxide (“laughing gas”) toxicity, usually from illicit use rather than administration as an anaesthetic, can cause cobalamin deficiency by inactivating the cobalamin-dependent enzyme methionine synthase. Long-term treatment of diabetes with metformin can lower B 12 levels. Low vitamin B 12 levels have been associated with increased homocysteine levels, but a relationship to vascular disease or vascular dementia is not established.
Clinical Manifestations
Demyelination of the dorsal columns causes proprioceptive loss that can result in sensory ataxia owing to loss of position sense in the feet. A positive Romberg sign (failure to maintain balance only after the eyes are closed) distinguishes sensory from cerebellar ataxia. A non–length-dependent axonal peripheral neuropathy causing numbness and tingling in the hands and feet is often present, but spinal cord disease is more prominent and less amenable to recovery. Motor nerve function eventually becomes impaired as well. The optic nerve is the most commonly involved cranial nerve, but vagal neuropathy also can occur. Signs of cerebral involvement include memory loss, personality changes, and occasionally hallucinations and psychosis. Although encephalopathy and dementia may be present, B 12 deficiency may be a secondary phenomenon in a patient with another cause of memory impairment, or both conditions may coexist without a causative relationship. Neurologic abnormalities may precede or be present without anemia, although the anemia is severe in 20% of patients with vitamin B 12 deficiency. Symptoms generally progress slowly, but they can appear rapidly after exposure to nitrous oxide anaesthesia in individuals who have preexisting subclinical cobalamin deficiency.
Diagnosis
Serum vitamin B 12 levels are usually low (<300 pg/mL) but can be normal in symptomatic patients. In such cases, serum levels of methylmalonic acid and homocysteine are useful ancillary tests because these levels are increased as a result of impaired cobalamin-dependent reactions. Pernicious anemia ( Chapter 150 ), an autoimmune disease diagnosed by measuring intrinsic factor antibodies, is severe in about 20% of patients. However, both the hematocrit and mean corpuscular volume are sometimes normal because the hematologic effects of cobalamin deficiency can be partially masked by folate supplementation. Inactivated cobalamin from nitrous oxide exposure cannot be detected by most assays; despite the normal B 12 level, methylmalonic acid levels are elevated.
Low cobalamin levels are sometimes present in normal people, especially the elderly, in which dementia, peripheral polyneuropathy, and myelopathy may be due to a myriad of unrelated causes. Therefore, a low cobalamin level may reflect poor nutrition or absorption rather than being the cause of these conditions. Causality is definitively confirmed by clinical improvement after cobalamin replacement, which usually begins only after several weeks and may continue for up to a year.
The myelopathy ( Chapter 369 ) may be difficult to distinguish from other causes. However, a magnetic resonance image (MRI) showing an increased T2 signal in the posterior and lateral columns of the spinal cord and in periventricular white matter can help exclude other causes of myelopathy.
Treatment
Treatment begins by repleting low B 12 levels with subcutaneous or IM injections of 1000 to 2000 µg of cobalamin daily for 1 week and then weekly for 1 month. After that time, oral supplementation continued indefinitely with 1000 µg daily of cyanocobalamin usually suffices in patients with achlorhydria, a history of bariatric surgery, pernicious anemia, or other causes of malabsorption. If no response in serum levels is seen with oral treatment, intramuscular monthly injections should be continued instead. Sublingual, transdermal patch, and nasal gel forms (500 µg weekly) have not been adequately studied. The anemia can be corrected by high-dose folate replacement, but the neurologic damage will progress unless vitamin B 12 is administered.
Prognosis
Neurologic symptoms, especially paresthesias, typically improve to some extent within 3 months of achieving adequate B 12 serum levels. Numbness and areflexia often persist, especially if treatment is delayed. If there is no improvement whatsoever, causes other than vitamin B 12 deficiency are likely, such as copper deficiency or human immunodeficiency virus (HIV)–associated myelopathy. Similarly, vitamin B 12 supplementation does not affect cognitive performance in hyperhomocysteinemic elderly people without clinical signs of B 12 deficiency.
Folate Deficiency
Folate is an important coenzyme in the metabolism of nucleic and amino acids ( Chapter 199 ). Maternal deficiency accounts for 50% of babies born with neural tube defects and may cause more subtle neurologic problems, including autism. Inborn errors of folate metabolism cause seizures and intellectual disability. Other signs include psychomotor retardation, autism, dyskinesias, and irritability. In adults, neurologic symptoms of folate deficiency overlap with those of B 12 deficiency and include peripheral neuropathy, cognitive impairment, depression, and rarely, retrobulbar optic neuropathy. Folate deficiency also results in elevated levels of homocysteine, which is associated with an increased risk for ischemic heart disease and stroke, although replacement to correct homocysteine level does not prevent cardiovascular disease. Patients with genetic folate deficiency due to lack of methylenetetrahydrofolate reductase, which converts ingested folate to the active metabolic cofactor, have an increased risk of intracerebral hemorrhage.
The supplementation of flour with folate has greatly reduced the risk of folate deficiency, and pregnant women are now generally prescribed supplemental folate. Women of childbearing age should be treated even before pregnancy if they have any conditions that predispose to folate deficiency, such as the use of antiepileptic or other medications that induce folate metabolism.
Folate deficiency also can lead to megaloblastic anemia ( Chapter 150 ). Before correction of megaloblastic anemia with folate alone, vitamin B 12 levels should be checked to avoid ongoing neurologic injury from unrecognized cobalamin deficiency.
Treatment and Prognosis
Folate deficiency is treated orally with 1 mg three times daily for 1 month, followed by 1 mg daily; improvement takes many months. Return of folate and homocysteine serum levels to normal has not shown benefit for preventing progressive cognitive impairment, for preventing stroke, or for reducing adverse vascular events except in patients with classic homocysteinemia ( Chapter 193 ).
Pyridoxine (Vitamin B 6 ) Deficiency and Toxicity
Pyridoxine is a coenzyme in multiple reactions that involve gluconeogenesis, biosynthesis of neurotransmitters, and the metabolism of amino acids, nucleic acids, and lipids. Pyridoxine deficiency can be caused by genetic defects, such as defective antiquitin, that lead to increased utilization of pyridoxine. In adults, low serum pyridoxine levels are well tolerated, so symptomatic deficiency is rare, but it can occur in the setting of renal failure ( Chapter 116 ) or dialysis ( Chapter 117 ), cirrhosis ( Chapter 139 ), or with medications such as isoniazid for antitubercular therapy ( Chapter 299 ) or hydralazine for heart failure ( Chapter 46 ) if patients do not receive concurrent supplementation. Deficiency is also seen with extreme malnutrition, especially diets consisting predominantly of white rice. Pyridoxine deficiency in pregnancy can be caused by hyperemesis gravidarum ( Chapter 221 ).
Clinical Manifestations and Diagnosis
Pyridoxine Deficiency
Prolonged pyridoxine deficiency causes a painful peripheral axonal neuropathy that leads to weakness and sensory ataxia. Genetic defects can rarely present in adolescence or adulthood with neuropathy, but adult pyridoxine deficiency is almost always acquired, not genetic. Some patients have skin thickening, seborrheic dermatitis, or glossitis, which can resemble pellagra.
Serum levels of the active form of pyridoxine, pyridoxal 5′-phosphate, and urine levels of the metabolite 4-pyridoxic acid are low. Ancillary tests include nerve conduction studies, which show significantly reduced amplitudes in sensory and motor action potentials with normal conduction velocity times, typical of an axonal neuropathy. In the setting of seizures, which is predominately a neonatal manifestation, electroencephalography shows a highly disorganized pattern with excessive slow frequency activity and abundant multifocal and generalized spikes, similar to hypsarrhythmia.
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