Laboratory Studies
The neuropathy first must be characterized as a polyneuropathy, mononeuropathy, mononeuropathy multiplex disease, or plexopathy; motor, sensory, sensorimotor, motor-sensory, or autonomic; acute or chronic; and of demyelinating or axonal pathophysiology. Readily apparent clues in the history can often suggest that the peripheral neuropathy might be secondary to nutritional problems; they are as follows:
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Excessive consumption of alcohol
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History of bariatric surgery, especially gastrectomy and intestinal shortening
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History of GI syndromes indicating a predisposition toward malabsorption
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History of using medications known to be associated with a vitamin deficiency (e.g., isoniazid)
Once the neuropathy is suspected to be nutritional in origin, the physician should first assess a possible vitamin B 12 deficiency (remembering that a CBC is not a good indicator). Documenting other B vitamin deficiencies is not as important because treatment replaces these vitamins anyway.
If history—which is the key to diagnosing a nutritional neuropathy—and physical are unrevealing, check CBC, urinalysis, thyroid-stimulating hormone (TSH), glucose, renal and hepatic functions, vitamin B 12 level, erythrocyte sedimentation rate (ESR), and serum protein electrophoresis, then order other tests, such as copper, as needed. Electrophysiologic findings can confirm the impression of polyneuropathy but rarely provide the diagnosis.
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Alcohol neuropathy: CBC may show low platelet counts and a megaloblastic anemia due to decreased folate levels.
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Thiamine (vitamin B 1 ) deficiency: A serum thiamine (vitamin B 1 ) level is not a good index because it responds quickly to dietary supplementation and because it is a poor indicator of total body stores. Urinary excretion of < 65 mg/g of creatinine is abnormal. A pyruvate level of >1 mg/dL is a reliable indicator of deficiency. The best test is erythrocyte transketolase activity; a concentration of < 0.017 U/dL indicates deficiency.
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Pyridoxine (vitamin B 6 ) deficiency: The CBC shows a microcytic, hypochromic anemia with normal iron levels. Serum pyridoxine levels are < 25 mg/mL, and serum homocysteine and cysathioprine values should be elevated. A tryptophan-loading test (not commonly performed) reveals urinary xanthurenic acid excretion of >50 mg/d.
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Folate deficiency: Serum folate levels are low.
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Niacin (vitamin B 3 ) deficiency: Urinary excretion of N -methylnicotinamide + N -methyl-6-pyridone-3-carboxamide is < 2 mg, or urinary excretion of N -methylnicotinamide is < 0.5 mg/g creatinine. Performing a stress test is possible by giving niacin 10 mg and tryptophan 100 mg. If urinary excretion of niacin metabolites is < 3 mg, a deficiency is present.
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Cyanocobalamin (vitamin B 12 ) deficiency: The CBC may show mean corpuscular volume (MCV) >110 fL (ie, macrocytic anemia), anisocytosis, poikilocytosis, and large and oval erythrocytes with decreased reticulocyte, leukocyte, and platelet counts. However, the neuropathy may precede any hematologic abnormalities in 25% of patients. The serum cobalamin level is < 10 mg/dL but may be normal, even in those with a tissue cobalamin deficit. Serum homocysteine and methylmalonic acid levels are elevated, as is urinary methylmalonic acid excretion. Serum holotranscobalamin II is deficient. Intrinsic factor antibodies are specific for pernicious anemia but not very sensitive (40% negative). The traditional Schilling test is now rarely used.
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Pantothenic acid deficiency: Excretion is < 1 mg/d.
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Alpha-tocopherol (vitamin E) deficiency: The serum α -tocopherol (vitamin E) level is low, and the CBC shows acanthocytes. Normal serum α -tocopherol levels in an adult with symptoms consistent with Friedreich ataxia should prompt an investigation for an autosomal recessive defect in the tocopherol transporter protein gene on chromosome 8.
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Hypophosphatemia: Serum phosphate level is < 1 mg/dL.
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Gluten-sensitive neuropathy: Anti-gliadin antibodies, either IgM or IgA should be present. 90% have HLA DQ2. Intestinal biopsy is abnormal in only 35%.
Imaging Studies
Imaging studies are generally not useful. In thiamine deficiency, MRIs occasionally show abnormal signal intensity in periaqueductal gray matter and midline structures.
Radiographs of chronic peripheral neuropathies are often consistent with the picture of a diabetic foot.
Other Tests
Axonal loss manifests as a mild slowing of the nerve conduction velocity (NCV) with a disproportionate loss of amplitude. Demyelination, on the other hand, produces mild loss of amplitude with a disproportionate slowing of the NCV. In affected motor fibers, electromyography (EMG) shows fibrillations, positive sharp waves, and decreased motor unit potentials. EMG and NCV are useful to assess the degree of damage and monitor progression of the neuropathy.
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Thiamine (vitamin B 1 ) deficiency: EMG and nerve conduction studies reveal a generalized axonal sensorimotor polyneuropathy with denervation of the distal lower extremity musculature; at times some subtle demyelinating features may be present.
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Niacin (vitamin B 3 ): EMG and NCV show demyelination in mild cases and axonal degeneration in severe cases.
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Alpha-tocopherol (vitamin E) deficiency: Peripheral nerve conduction findings are normal. Sensory evoked potentials are low or absent. Somatosensory evoked potentials show a delay in central conduction. EMG findings are normal.
Sensorineural hearing loss: Audiometry shows high-tone hearing loss.
Alcohol: The CSF protein level on lumbar puncture is normal or slightly elevated.
Histologic Findings
A biopsy is not indicated unless the diagnosis is in doubt. If so, biopsy is indicated only if the neuropathy is multifocal or asymmetric, or if the patient has multiple mononeuropathies. The best nerve to biopsy is the sural nerve, lateral to the lateral malleolus. In general, sural nerve biopsy is of limited use in differentiating various types of nutritional neuropathy, but it can help in distinguishing hereditary neuropathy, neuropathy caused by organic solvents, leprosy, amyloidosis, polyarteritis nodosa, or sarcoidosis, and it is occasionally useful in evaluating Guillain-Barré syndrome. Nutritional neuropathies can result in either demyelinating or axonal peripheral nerve pathology.
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Pernicious anemia. Characteristic lemon-yellow–tinged pallor with raw-beef tongue lacking filiform papillae. Used with permission from Forbes and Jackson.
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Ischemic retinopathy caused by severe megaloblastic anemia.
