The health of the peripheral nervous system depends on an adequate supply of nutrients. Peripheral neuropathy can be the predominant or only manifestation of certain nutrient deficiencies. Cognitive difficulties or involvement of other parts of the central nervous system, such as the optic nerve and spinal cord, may accompany nutritional peripheral neuropathies. In most patients, nutritional deficiency may have a single predominant cause, but in some cases, multiple causes may coexist. Obesity, for unclear reasons, can be associated with nutrient deficiencies. The rising rates of bariatric surgery and the incidence of nutrient deficiencies following bariatric surgery becomes relevant to heed.
Chronic alcoholism leads to malnutrition.
Patients with chronic illnesses, unusual diets (vegans) and bariatric surgery, malabsorption states, medication effects (INH, hydralazine, Vit B6 deficiency), (metformin, PPI, H2 blockers - Vit B12 deficiency). result in vitamin deficiencies.
The B-complex vitamins (nomenclature): Vitamin B1 (thiamine), vitamin B3 (niacin), vitamin B6 (pyridoxine), vitamin B9 (folate), and vitamin B12 (cobalamin). vitamin B5 (pantothenic acid) and vitamin B7 (biotin).
Vitamin B6 toxicity can cause a sensory neuronopathy.
Vitamin B1 (thiamine) deficiency can result in acute and chronic neuropathy, central nervous system manifestations (Wernicke-Korsakoff syndrome) are a hallmark of thiamine deficiency.
Myopathy is perhaps the most characteristic neurologic manifestation of vitamin D deficiency.
Vitamin A toxicity has been implicated in pseudotumor cerebri. Vitamin A deficiency causes impaired vision (night blindness).
Copper deficiency is the only relevant mineral deficiency that can affect the peripheral nerves and spinal cord. Copper and vitamin B12 deficiencies can coexist after bariatric surgery. Copper deficiency may be caused by reduced absorption following bariatric surgery and by the prolonged use of oral zinc supplements.
Neurologic involvement is generally a late manifestation of malnutrition except for manifestations caused by thiamine and folate deficiency
Vitamin B12, folate, vitamin E, and copper deficiencies often have spinal cord involvement associated with neuropathy.
Nutrient deficiencies are seen not only with malnutrition but also with obesity.
Malabsorption states: Pernicious anemia, IBD, Whipple disease, celiac disease, intestinal infections and infestations, cystic fibrosis, tropic sprue, bacterial overgrowth. liver disease, pancreatic insufficiency, prior abdominal radiation,
Fat soluble vitamins: Vit A, D, E, K.
Pernicious anemia may be accompanied by iron deficiency, increased risk of gastric cancer or carcinoid, and other autoimmune diseases such as autoimmune thyroiditis, Addison disease, vitiligo, and type 1 diabetes.
Acute nutritional axonal neuropathy (ANAN) is a severe, symmetric, length-dependent, acute or subacute axonal polyneuropathy that occurs in the setting of nutritional deficiency (e.g., alcoholism, extreme dieting/anorexia, postgastrectomy) with marked weight loss, vomiting, or diarrhea. Hospitalized patients with ANAN cannot walk without aide, are areflexic, have marked sensory or motor deficits, and neuropathic pain. Electrodiagnostic testing confirms axonal physiology, and the CSF is typically normal. When tested before supplementation, levels of micronutrients with short half-lives are low, most importantly thiamine, along with vitamin B6, folate, vitamin E, or copper.
The spectrum of ANAN is wide, ranging from:
A pure sensory neuropathy with areflexia, limb and gait ataxia, neuropathic pain, and unevocable sensory responses.
A motor axonal neuropathy with low-amplitude motor responses without conduction slowing, block, or dispersion,
A mixed sensorimotor axonal polyneuropathy.
Specific micronutrient deficiencies or risk factors do not predict neuropathy subtype.
The subgroup of patients with ANAN with documented thiamine deficiency also range from pure sensory to pure motor, and only a minority have Wernicke encephalopathy. We do not know whether coexistent micronutrient deficiencies may help explain the wide clinical spectrum of thiamine-deficient ANAN.
The prognosis of ANAN is guarded due to residual neuropathic pain and slow recovery of independent ambulation. Therefore, early recognition of patients at risk is important.
Laboratory data: MCV, prealbumin, LFTs, potassium, CSF when available, thiamine (whole blood HPLC), vitamin B6 (fasting), B12, and E, folate, and copper.
Predominantly women (83%)
History of weight loss over on average of 4 months.
Alcohol use disorder.
Dietary modifications: GI disturbances, or an eating disorder resulting in decreased food intake.
Diarrhea and vomiting were common
Associated clinical features were tachycardia, pain, Wernicke encephalopathy, optic atrophy, and myopathy.
Most of the patients need admission to the hospital.
Symmetric, length-dependent sensorimotor polyneuropathy with distal muscle weakness, large and small fiber sensory loss, and hyporeflexia, more evident in the legs than arms. Clinical features of a symmetric, length-dependent sensory polyneuropathy affecting legs more than arms with preserved muscle strength, but with distal deficits on sensory examination and reflexes.
EDx: Motor physiology was axonal with normal or only slightly prolonged distal and F wave latencies, normal or only slightly slowed conduction velocities, and with no conduction blocks or dispersion. Similarly, sensory responses also disclosed a length-dependent pattern of axon loss in the sensorimotor and pure sensory groups with absent responses more often seen with sural than ulnar or radial sensory conduction studies.
Background: Vitamin B12 is a water-soluble vitamin that acts as a cofactor in methylation reactions. The active coenzyme forms are methylcobalamin and adenosylcobalamin. Methylcobalamin is a cofactor for methionine synthase that converts homocysteine to methionine. Methionine is adenosylated to S-adenosyl methionine, which is a methyl group donor and is responsible for neuronal methylation reactions such as the methylation of myelin basic protein. Adenosylcobalamin is a cofactor for mitochondrial L-methylmalonyl coenzyme A mutase, which converts L-methylmalonyl coenzyme A to succinyl coenzyme A. Impairment of this reaction results in the accumulation of methylmalonate and propionate, which provide abnormal substrates for fatty acid synthesis. The primary dietary sources of vitamin B12 are meat, fish, and dairy.
Deficiency causes: Pernicious anemia is most commonly seen in older adults, but any age group can be affected. In pernicious anemia, immune-mediated destruction of gastric parietal cells occurs, which results in a lack of intrinsic factor required for the binding and subsequent transfer of ingested vitamin B12 to the distal ileum for absorption. Additionally, patients with pernicious anemia may have anti-intrinsic factor and antiparietal cell antibodies. An immune response directed against the gastric hydrogen-potassium ATPase accounts for the associated achlorhydria. Pernicious anemia may be accompanied by iron deficiency, increased risk of gastric cancer or carcinoid, and other autoimmune diseases such as autoimmune thyroiditis, Addison disease, vitiligo, and type 1 diabetes. Because an acidic environment in the stomach is essential for releasing food-bound vitamin B12, conditions that cause hypochlorhydria (eg, using antacids or proton-pump inhibitors, gastritis, and gastrectomy) can result in vitamin B12 deficiency. Food-bound vitamin B12 malabsorption is particularly common in older adults because of the high incidence of atrophic gastritis; however, this is often unaccompanied by clinical manifestations, and the precise significance of subclinical vitamin B12 deficiency and its management is poorly understood. Vegetarians have a higher incidence of vitamin B12 deficiency, but this is usually subclinical. Vitamin B12 secreted in the bile is reabsorbed along with vitamin B12 derived from sloughed intestinal cells. Therefore, vitamin B12 deficiency is not universal in those who do not eat any animal products. However, in the setting of an additional cause of vitamin B12 deficiency, vegetarians may develop symptomatic vitamin B12 deficiency more rapidly.
Although metformin can lower vitamin B12 levels, the clinical significance of this is unclear. Typically, it takes 4 to 5 years of malabsorption to develop clinically significant vitamin B12 deficiency because of large hepatic stores and minute daily losses. Gastrointestinal diseases, particularly those that involve the stomach or distal ileum, can result in vitamin B12 deficiency. Pancreatic proteases are required to release vitamin B12 bound to haptocorrin, a B12 binding glycoprotein secreted by the salivary and gastric glands, before vitamin B12 can bind to intrinsic factor; therefore, pancreatic disease can also result in vitamin B12 deficiency. Nitrous oxide (laughing gas) may be abused in the form of “whippets.” Nitrous oxide oxidizes the cobalt core of cobalamin and renders cobalamin inactive. In this setting, although low or low-normal vitamin B12 levels may be present, the pathophysiologic hallmark is a functionally inactive vitamin B12, leading to a syndrome typical of vitamin B12 deficiency.
Neurological manifestations: The classic neurologic manifestation of vitamin B12 deficiency is the subacute combined degeneration of the spinal cord. Peripheral neuropathy may coexist or be independently present. The concomitant onset of hand and foot paresthesia, disproportionate and severe dorsal column dysfunction, brisk knee jerks with reduced ankle reflexes, and Lhermitte signs all indicate myelopathy accompanying the neuropathy. The neuropathy is typically a sensory-predominant axonal neuropathy, although a pure sensory neuropathy (large or small fiber) and autonomic dysfunction have all been described. Vitamin B12 deficiency can result in neuropsychiatric manifestations such as depression, cognitive impairment, and psychosis, but these have been poorly characterized. Because low vitamin B12 levels are commonly seen in older adults, the specific cause and effect can be hard to establish in patients with peripheral neuropathy or memory impairment. The presence of other biochemical biomarkers for a metabolically significant vitamin B12 deficiency (elevated methylmalonic acid and homocysteine), the presence of a cause for vitamin B12 deficiency, and associated hematologic manifestations caused by vitamin B12 deficiency (megaloblastic anemia, macrocytosis, hypersegmented polymorphonuclear cells) can help establish an association between the laboratory finding and clinical context. Neurologic manifestations of vitamin B12 deficiency are often unaccompanied by hematologic derangement. An acute onset may prompt consideration of nitrous oxide inhalation since vitamin B12 stores in the liver take years to deplete.
Laboratory features: Holotranscobalamin (transcobalamin-bound cobalamin) represents the metabolically active vitamin B12, and its measurement can be particularly useful in equivocal cases; however, the test has limited worldwide availability. The range of normal serum vitamin B12 is rather broad: 180 ng/L to 914 ng/L, with levels between 150 ng/L and 399 ng/L considered borderline. The presence of elevated methylmalonic acid and homocysteine levels are important indications for metabolically significant vitamin B12 deficiency; the former is more specific than the latter because homocysteine can also be elevated in folate deficiency.
Health care providers should obtain a baseline methylmalonic acid level to monitor a patient’s response to treatment. Tests to identify underlying pernicious anemia could include serum gastrin, pepsinogen I, antiparietal cell antibodies, and anti-intrinsic factor antibodies. Elevated serum gastrin and decreased serum pepsinogen I are common in pernicious anemia. A lack of serum gastrin elevation should bring into question the diagnosis of pernicious anemia. Anti-intrinsic factor antibodies are specific but not extremely sensitive. Antiparietal cell antibodies are nonspecific and can also be elevated in 10% of individuals over 70 years of age. A common approach to diagnosing pernicious anemia is combining the specific but insensitive intrinsic factor antibody test with the sensitive but nonspecific serum gastrin level test.
Particularly in the presence of prominent neurologic manifestations, parenteral vitamin B12 replacement therapy is generally preferred over oral therapy because of concerns regarding a slower response with oral therapy. While a high enough oral dose (1000 μg/d to 2000 μg/d) may lead to adequate vitamin B12 absorption, oral therapy is generally reserved for patients with no neurologic manifestations or for maintenance after the initial response to parenteral therapy in those with neurologic manifestations. The neurologic response is slower and less predictable than the response of hematologic derangements.
Also, consider copper deficiency as it manifests in a virtually identical manner as vitamin B12 deficiency. Suspect when patients have sudden onset of symptoms, symptoms beginning in the hands in case of only peripheral neuropathy without myelopathy. If upper motor neuron signs are present suspect myelopathy.
EDx: NCS revealed absent or reduced SNAP amplitudes with CMAP amplitudes that are normal or slightly reduced. Motor and sensory distal latencies and conduction velocities are normal or mildly abnormal. SSEP may reveal a prolongation of the central conduction time. MRI scans of the cervical cord and revealed increased signal in T2 images in the posterior column.
Treatment: Vitamin B12 1000 mcg IM daily for 5 days, then weekly for 1 month, followed by 1000 mcg IM monthly thereafter for life. Check vitamin B12 and MMA and homocysteine as follow-up. In addition to neurological symptoms resolution. The response to treatment of vitamin B12 deficiency polyneuropathy, separate from other neurological complications of vitamin B12 has not been well studied. Patients with vitamin B12 deficiency polyneuropathy/myelopathy probably do not show an immediate response to treatment and may not respond at all.
Reference daily intake: 2.4 μg
Major dietary sources: Meat, poultry, fish, eggs, dairy products, fortified soymilk, cereals
Deficiency causes: Pernicious anemia, advanced age (atrophic gastritis), vegan and vegetarian diets, poor nutrition (as with alcohol use disorder), gastrointestinal surgery (gastrectomy, bariatric surgery, ileocecal resection), acid reduction therapy, gastrointestinal disease (Crohn disease, celiac disease), pancreatic disease, nitrous oxide toxicity.
Neurologic manifestations: Peripheral neuropathy, myelopathy, myeloneuropathy, neuropsychiatric manifestations, optic neuropathy, autonomic dysfunction.
Laboratory tests: Serum vitamin B12, serum methylmalonic acid, plasma homocysteine, serum holotranscobalamin, complete cell count (hemoglobin, mean corpuscular volume, peripheral smear), serum gastrin, intrinsic factor antibodies, parietal cell antibodies, tests for associated conditions (iron profile, upper endoscopy, thyroid disease, Addison disease); rule out coexisting nutrient deficiencies (particularly folate and copper)
Management: 1000 μg IM vitamin B12 given daily for 5 days, weekly for a month, and monthly thereafter.
Additional comments: Many years may elapse before the body’s vitamin B12 stores are depleted enough to cause clinical vitamin B12 deficiency. Neurologic manifestations may be unaccompanied by hematologic derangement.
Background: The term folate typically includes both the naturally occurring form of vitamin B9 (folate) and the synthetic form (folic acid). The primary biologically active forms of folate are dihydrofolate and tetrahydrofolate. The clinical features are similar to vitamin B12 deficiency. Subacute combined degeneration of the posterior column and corticospinal tracts, sensorimotor peripheral neuropathy, and altered mental status can develop. Methyltetrahydrofolate is required for the cobalamin-dependent remethylation of homocysteine to methionine. Methylenetetrahydrofolate is formed from tetrahydrofolate and is involved in uracil and thymine synthesis; formyltetrahydrofolate is involved in adenine and guanine synthesis. Impaired DNA synthesis caused by folate deficiency likely interferes with myelin production. Although it is found in a variety of foods, folate is easily destroyed by cooking.
Deficiency causes: Populations at increased risk of folate deficiency include people with alcohol use disorder, premature infants, and adolescents; increased folate requirements are seen in the setting of pregnancy, lactation, psoriasis, and chronic hemolysis. Folate deficiency may be seen in patients with small-bowel disorders associated with malabsorption; however, small intestinal bacterial overgrowth may be associated with elevated folate levels caused by bacterial synthesis. Gastric surgery, atrophic gastritis, and acid-suppressive therapy can decrease folate absorption. Methotrexate binds to dihydrofolate reductase, resulting in folate deficiency. Folate analogues such as trimethoprim and pyrimethamine can also result in folate deficiency. Numerous drugs can impair the absorption and distribution of folate. These include antimalarials, phenytoin, oral contraceptives, tetracyclines, penicillins, chloramphenicol, nitrofurantoin, and erythromycin. Folate deficiency can also be seen in obesity, the cause of which is unclear. Folate levels fall within weeks of decreased intake or absorption, and clinically significant depletion of folate stores is seen within months. Because it is rare to see folate deficiency in isolation, it is particularly important to screen for the deficiency of other nutrients when folate deficiency is detected.
Neurological manifestations: Theoretically, folate deficiency could cause the same clinical manifestations as vitamin B12 deficiency. For unclear reasons, such manifestations are rare. The neuropathy described with folate deficiency is typically a slowly progressive, sensory, axonal neuropathy. In some studies, folate deficiency has been associated with affective disorders, particularly depression. Some evidence also suggests that the elevated homocysteine accompanying folate deficiency may be associated with an increased risk of vascular complications. Although these associations are poorly understood and somewhat controversial, the association of neural tube defects in babies born to folate-deficient mothers is clear.
Investigations and management: Serum folate levels less than 4.0 μg/L suggest a deficient state. Patients with metabolically significant folate deficiency have elevated plasma homocysteine levels. Red blood cell folate is a more reliable indicator of folate status than plasma folate because it is less affected by short-term fluctuations in folate intake, although it can be technically challenging to determine. With documented folate deficiency, a commonly used replacement regimen is 1 mg of oral folate given 3 times a day. Once the folate levels normalize, a maintenance dose of 1 mg/d orally is used. Acutely ill patients or those with severe malabsorption may need parenteral administration or doses up to 20 mg/d. Patients with drug-induced folate deficiency need folinic acid for replacement; also known as leucovorin, folinic acid is used as a “rescue” agent with folate antagonist chemotherapeutic agents such as methotrexate. Clinicians should exclude coexisting vitamin B12 deficiency before instituting folate therapy. Plasma homocysteine levels are used to monitor patients’ response to therapy.
Reference daily intake: 400 μg of dietary folate equivalents
Major dietary sources: Green vegetables, legumes, fruits, beans, nuts, peas, eggs, milk, some meats, seafood, fortified grains, fortified cereals
Deficiency causes: Alcohol use disorder, gastrointestinal disease, folate antagonists (methotrexate, trimethoprim). Rare for folate deficiency to be present in isolation.
Neurologic manifestations: Indistinguishable from manifestations caused by vitamin B12 deficiency.
Laboratory tests: Serum folate, red blood cell folate (more reliable indicator of tissue stores than serum folate), plasma homocysteine; particularly important to rule out a coexisting nutrient deficiencies
Management: 1 mg oral folate given 3 times a day initially, followed by a maintenance dose of 1 mg/d (with severe malabsorption parenteral dosing or doses up to 20 mg/d may be needed).
Additional comments: Cooking destroys folate in food. Depletion of the body’s folate stores can occur in a few months. Oral folate supplementation with 0.4 mg/d is recommended as prophylaxis against neural tube defects for people who may become pregnant.
Background: The terms B1, vitamin B1, thiamin, and thiamine are used interchangeably. The metabolically active form of thiamine is thiamine diphosphate. Thiamine diphosphate is a cofactor for the pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase, and transketolase. Thiamine has a role in adenosine triphosphate synthesis and energy production. The pericarp of grain and yeast is particularly rich in thiamine. Heating food can reduce its thiamine content Stores of thiamine in the body are limited and its half-life is only 10-14 days. 1 to 1.5 mg of thiamine daily is needed in diet to avoid deficiency.
Deficiency: The body’s thiamine requirement is related to a person’s total caloric intake and to the proportion of calories provided as carbohydrates. Thiamine requirements increase during periods of high metabolic demand. Increased metabolic demand in the setting of marginal nutritional status is the typical scenario that precipitates thiamine deficiency. Often multiple contributing factors coexist. Alcohol use disorder is just one of the many causes of thiamine deficiency. It has been suggested that thiamine deficiency should be considered as a possible etiology for neurologic manifestations in any critically ill patient. A heavy dietary reliance on thiamine-poor carbohydrates such as polished rice or processed cassava is a risk factor for thiamine deficiency in some parts of the world. Thiamine has a short half-life, and the body can store only limited amounts; therefore, a continuous dietary supply of thiamine is necessary. A thiamine-deficient diet can result in clinically significant depletion of body stores in just 2 to 3 weeks.
Neurological manifestations: The term“thiamine deficiency disorders” is used to describe the broad clinical spectrum that results from thiamine deficiency and includes neurologic, cardiovascular, gastrointestinal, and metabolic derangements. The most characteristic neurologic disorders resulting from thiamine deficiency are Wernicke encephalopathy, Korsakoff syndrome or Korsakoff psychosis, and beriberi. Wernicke encephalopathy is characterized by changes in mental status, ocular abnormalities (notably ophthalmoparesis), and ataxia, but the classic triad is rarely seen. As Wernicke encephalopathy resolves, the Korsakoff psychosis evolves. Korsakoff syndrome is characterized by an amnestic-confabulatory state. Both anterograde and retrograde amnesia may be present. These disorders are often collectively referred to as Wernicke-Korsakoff syndrome. They typically result from short-term and severe thiamine deficiency. The gait and trunk ataxia seen in Wernicke encephalopathy is caused by cerebellar and vestibular dysfunction, but it may be complicated by a coexisting peripheral neuropathy. Peripheral neuropathy typically results from prolonged and mild to moderate thiamine deficiency. A rapid progression that mimics Guillain-Barré syndrome is a well-described neurologic manifestation of thiamine deficiency. In contrast to Guillain-Barré syndrome, thiamine deficiency-associated acute neuropathy lacks prominent autonomic manifestations or respiratory impairment. Beriberi exists in three forms: dry beriberi, wet beriberi, and infantile beriberi. Dry beriberi refers to a distal, sensorimotor, axonal neuropathy. Autonomic manifestations may be present. The term wet beriberi refers to when a high cardiac output heart failure causes an accompanying fluid overload. Infantile beriberi bears little resemblance to the adult form. Cardiac, aphonic, and pseudomeningitic forms are recognized.
Investigations and management: Serum or plasma thiamine and urinary thiamine levels do not accurately reflect tissue thiamine concentrations. Less than 10% of blood thiamine is contained in plasma. Measurements of erythrocyte thiamine diphosphate in the whole blood or erythrocyte transketolase activation assay are the preferred tests, but the latter has limited availability. Blood thiamine diphosphate levels of less than 70 nmol/L suggest thiamine deficiency. A normal thiamine level does not exclude thiamine deficiency as the cause of neurologic manifestations because thiamine levels normalize rapidly with oral intake. The blood draw should be done before the initiation of therapy. The presence of an anion gap metabolic acidosis and elevated lactate can be additional clues for a metabolically significant thiamine deficiency. MRI findings in Wernicke encephalopathy typically include an increased T2 or fluid-attenuated inversion recovery (FLAIR) signal in the paraventricular regions. Shrunken mamillary bodies may be seen in the chronic stages (Korsakoff syndrome).
Because parenteral glucose use in patients with a marginal thiamine status can consume the available thiamine and precipitate Wernicke encephalopathy at-risk patients should be given parenteral thiamine before administration of glucose or parenteral nutrition. Thiamine for parenteral use is diluted in 100 mL of normal saline or 5% glucose and infused over 30 minutes. A commonly used regimen for thiamine replacement is 200 mg IV every 8 hours; patients with Wernicke encephalopathy, severe malnutrition, or alcohol withdrawal should get higher doses. A commonly used regimen in these patients involves giving 500 mg thiamine IV 3 times a day for 2 to 3 days, followed by 250 mg thiamine IV or IM for 3 to 5 days. Long-term oral maintenance doses range from 50 mg/d to 100 mg/d. Comorbid conditions that may have precipitated manifestations of thiamine deficiency need to be identified and treated. With wet beriberi, thiamine administration results in a prompt improvement of heart failure but a slower improvement of neuropathy. Regarding the central manifestations, ocular signs improve promptly, but gait and memory improvement are delayed. Korsakoff syndrome does not respond to thiamine administration, but spontaneous improvement may occur over time.
Reference daily intake: 1.2 mg
Major dietary sources: Whole grains, meat, fish, fortified grains, fortified cereal.
Deficiency causes
Populations or settings with increased requirements: children, pregnant or lactating patients, critical illness, hyperthyroidism, malignancy, bone marrow transplantation, and systemic infection.
Marginal nutritional status: alcohol use disorder, anorexia nervosa, recurrent vomiting, starvation, extreme dieting, food fads, gastrointestinal surgery (particularly bariatric surgery), inadequate supplementation in parenteral or enteral nutrition, renal failure (particularly patients on dialysis), severe gastrointestinal disease, liver or pancreatic disease, magnesium deficiency
Neurologic manifestations: Wernicke encephalopathy, Korsakoff psychosis, beriberi (wet or dry), Guillain-Barré syndrome–like presentation.
Laboratory tests: Red blood cell thiamine diphosphate, erythrocyte transketolase assay, serum thiamine, urine thiamine
Management: 100 mg/d to 300 mg/d of thiamine (IV, IM, oral), significantly higher doses in some situations (Wernicke encephalopathy, alcohol use disorder, starvation)
Additional comments: Heating food can reduce the thiamine content.
A 35-year-old man presented with a 2-week history of ascending lower limb weakness and painful hand and foot paresthesia. The working diagnosis was Guillain-Barré syndrome. Soon after admission, he became confused. He had deficits in his mental status evaluation that included impaired recall and difficulty following complex commands. Cranial nerve examination showed bilateral impaired ocular abduction. He had mild, bilateral, proximal, and distal limb weakness. He had graduated impairment of pinprick and light touch perception to his knees and wrists. Muscle stretch reflexes were absent. Mild appendicular dysmetria and severe gait ataxia were present.
A brain MRI showed a T2-signal hyperintensity in the periaqueductal gray. Nerve conduction studies and EMG showed an axonal neuropathy with acute denervation. Blood thiamine diphosphate levels were on the lower side of the normal range. It was subsequently discovered that during the preceding 2 months he had been drinking 4 to 5 glasses of wine a day, experienced a 15-pound weight loss, and his oral food intake was limited.
With parenteral thiamine administration, the patient had a gradual clinical, neuroimaging, and electrophysiologic improvement.
COMMENT: Thiamine deficiency can present as a rapidly progressive ascending neuropathy that can mimic Guillain-Barré syndrome. The typical acute neurologic presentation of thiamine deficiency is changes in mental status, ophthalmoparesis, and ataxia (Wernicke encephalopathy), all of which this patient had. It is rare for the classic triad to present initially, although one or more components often develop over time. The presence of these manifestations, along with painful hand and foot paresthesia, were clues that thiamine deficiency was responsible for his rapidly progressive ascending weakness. His gait ataxia was more than what could be explained by the motor and sensory deficits and was likely because of cerebellar and possibly vestibular involvement. Thiamine deficiency (presenting as dry beriberi) should be included in the differential diagnosis of Guillain-Barré syndrome, particularly when a potential cause for thiamine deficiency is present. Blood thiamine diphosphate levels can rapidly normalize with oral intake or parenteral thiamine supplementation. Therefore, the possibility of neurologic disease caused by thiamine deficiency should not be excluded based on normal levels. Ancillary tests such as a brain MRI may show the classic neuroimaging findings seen in thiamine deficiency and provide a clue for the etiology of the weakness. The doses of parenteral thiamine are higher in the setting of alcohol use or severe malnutrition than for standard thiamine replacement.
Background: The common forms of niacin are nicotinic acid and nicotinamide. Niacin is converted into nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, coenzymes that have a role in carbohydrate metabolism. In humans, niacin is a product of tryptophan metabolism.
Deficiency causes: Niacin deficiency is common in populations that depend on corn as their primary carbohydrate because corn lacks niacin and tryptophan. Nonendemic deficiency is seen with alcohol use disorder and malabsorption. Chronic infections can increase niacin demand. In carcinoid syndrome, tryptophan is preferentially converted into serotonin, and niacin deficiency ensues. Vitamin B6 is required for the conversion of tryptophan to niacin, and vitamin B6 deficiency can result in niacin deficiency. Excess dietary amino acids compete with tryptophan absorption, and bacterial overgrowth converts dietary tryptophan into indoles. Hence, both of these conditions can decrease tryptophan absorption and cause subsequent niacin deficiency. Another cause of niacin deficiency is frequent dialysis. Hartnup syndrome is a metabolic disorder that affects amino acid transport and causes tryptophan deficiency, resulting in niacin deficiency.
Neurological manifestations: Coexisting nutrient deficiencies make it difficult to characterize the neurologic manifestations of niacin deficiency. Encephalopathy in people with alcohol use disorder that does not respond to thiamine replacement or to treatment of suspected withdrawal with benzodiazepines should prompt consideration of niacin deficiency. The peripheral neuropathy seen in niacin deficiency is similar to that seen with thiamine deficiency. Pellagra is the classic syndromic presentation of niacin deficiency. It involves the gastrointestinal tract, skin, and nervous system. The classic triad of diarrhea, dermatitis, and dementia is rarely seen; in nonendemic pellagra, the cutaneous and gastrointestinal manifestations are generally absent.
Investigations and management: No blood markers of niacin status are particularly reliable. Plasma nicotinamide levels from 5 ng/mL to 48 ng/mL are considered normal. Plasma metabolites of niacin, such as nicotinic acid and nicotinuric acid, can be measured. Other suggested markers include erythrocyte nicotinamide adenine dinucleotide and the urinary excretion of methylated niacin metabolites, but these are not in routine clinical use. In deficient and symptomatic patients, 25 mg to 100 mg of nicotinic acid can be given 3 times a day orally or by IM. Known adverse effects are pruritis and a burning sensation involving the face and chest. The response of neurologic manifestations is more variable than the otherwise prompt response of dermatologic and gastrointestinal manifestations.
Reference daily intake: 16 mg of niacin equivalents
Major dietary sources: Meat, poultry, fish, mushrooms, potatoes, nuts, legumes, grains, eggs, dairy products, enriched bread, fortified cereals, tryptophan-containing foods such as turkey.
Deficiency causes: Corn as a primary carbohydrate source, alcohol use disorder, carcinoid syndrome, Hartnup syndrome, vitamin B6 deficiency, excess neutral amino acids in the diet, frequent dialysis, gut bacterial overgrowth
Neurologic manifestations: Encephalopathy, peripheral neuropathy
Laboratory tests: Urinary excretion of niacin metabolites (used but is not very reliable)
Management: 25 mg to 100 mg of nicotinic acid given 3 times a day (IM, oral)
Additional comments: Nicotinic acid has a short half-life and must be given 3 times a day. The classic pellagra triad of dermatitis, dementia, and diarrhea is uncommon. In nonendemic pellagra, the dermatologic and gastrointestinal manifestations are typically absent.
Pyridoxine (Vit B6 deficiency)
Vitamin B6 (pyridoxine) not only is neurotoxic when taken in large doses (2-10 gm/daily) which no one practically takes. daily allowance is 2 mg daily and a MVT pill has some Vit B6. Vit B6 toxicity is therefore very rare (as rare as hen's teeth). it can also be associated with sensorimotor polyneuropathy. It is normally associated with INH and hydralazine treatment. It may also be seen from malnutrition (chronic alcoholism) or in patients receiving chronic peritoneal dialysis. Affected individuals manifest with a sensory greater than motor polyneuropathy similar to most idiopathic neuropathies. It can cause sensory neuronopathy which may manifest in a non-length dependent manner, asymmetrically (may start in hands). Vitamin B6 levels can be measured in the blood. Patients who are deficient should be treated with vitamin B6 50 to 200 mg/day.
Vitamin E deficiency
Clinical features: Vitamin E deficiency can be caused by deficient fat absorption as seen in cystic fibrosis, chronic cholestasis, short bowel syndrome, and intestinal lymphangiectasia. They can be deficiency of fat transport as in abetalipoproteinemia, hypoalbuminemia hypoproteinemia, normal triglyceride to make abetalipoproteinemia, and chylomicrons retention disease. Also a genetically based abnormality of vitamin D metabolism can occur. Patients with vitamin D deficiency usually present with progressive difficulty ambulating and impaired coordination of the hands. Weakness and sensory loss cannot be present. Dysarthria can also occur. Physical examination is remarkable for ataxia of the trunk and upper and lower extremities. There is prominent loss of proprioception and vibration perception. Muscle stretch reflexes are reduced or absent. Muscle testing may be difficult secondary to the ataxia. Ocular examination may reveal ophthalmoplegia and retinopathy.
Laboratory features: Serum vitamin D levels. With hyperlipidemia, the vitamin D level may be normal. In such cases, the ratio of the serum vitamin D to the total serum lipids concentration is a more sensitive indicator of vitamin D deficiency. NCS reveals reduced amplitudes or absent snaps. Sensory nerve conduction velocities are normal or slightly reduced. SSEP demonstrates normal peripheral nerve potentials with marked slowing and attenuation of central responses consistent with slowing of central conduction with posterior column fibers. Motor NCS are normal. Mutations in the alpha-tocopherol transfer protein, TTPA located on 8q.13 resulting loss of vitamin E.
Treatment: Therapy is aimed at preventing progression but improvement in neurologic function may occur. In cases of isolated vitamin D deficiency patients are treated with 1500 to 6000 IU/day in divided doses. Patients with chronic cholestasis are initially treated with 50 IU units/kg/day and the dose was increased to 50 IU//kg increments up to a 200 IU/kg/day as required to obtain a normal serum tocopherol to lipid ratio. Patient with cystic fibrosis, receiving oral pancreatic enzyme therapy, required doses of 5 to 10 IU/kg/day. Those with short bowel syndrome are given 300 to 5400 IU/day. Abetalipoproteinemia is treated with vitamin D 150 to 300 IU/kg/day and vitamin A 15,000 to 20,000 IU/day
Myopathy is perhaps the most characteristic neurologic manifestation of vitamin D deficiency.
Copper deficiency is associated with unusual bilobar neuropathy, neutropenia, and sometimes pancytopenia. The clinical phenotype is similar to vitamin B12 deficiency. Most patients manifest with numbness and tingling in the legs, weakness, spasticity, and gait difficulties. Mild fiber sensory function is impaired, reflexes are brisk, and plantar responses are extensor. In some cases, light touch and pinprick sensation are affected and NCS indicate sensorimotor axonal polyneuropathy in addition to myelopathy. Severe motor axonopathy can also be seen. Weakness and sensory loss in some cases is primarily due to myelopathy. Demyelinating lesions may be appreciated on brain MRI and some patients have ocular dysmetria indicating brain involvement. Can also be increased signal abnormalities on MRI of the C-spine with or without contrast.
Laboratory features: No serum copper levels sometimes associated with high levels of zinc. Microcytic anemia and neutropenia. Occasionally that can be pancytopenia. Bone marrow biopsy may reveal abnormalities of the myelodysplastic syndrome. CSF fluid may be normal or show mildly elevated protein or immunoglobulin synthesis rate. MRI may demonstrate abnormal T2 weighted signal in the dorsal columns. NCS may reveal features of sensorimotor axonal polyneuropathy. SSEP demonstrate impaired conduction in the central pathway in those with myelopathy.
Treatment: Oral and intravenous copper replacement.
Zind gluconate: 50 to 150 mg/day PO day in 1 to 3 divided doses.
It has also been suggested that doses of zinc supplements should be 2 to 3 times the RDA to treat mild deficiency and 4 to 5 times the RDA to treat moderate to severe deficiency. Treatment for up to 6 months may be necessar