eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Vitamin B-12 Associated Neurological Diseases: Differential Diagnoses & Workup

Author: Niranjan N Singh, MD, DNB, Fellow in Neurophysiology, Department of Neurology, St Louis University School of Medicine
Coauthor(s): Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Associate Program Director, Associate Professor, Departments of Neurology, Molecular Virology, and Molecular Microbiology and Immunology, St Louis University School of Medicine; Alan L Diamond, DO, Movement Disorder Fellow, Department of Neurology, Baylor College of Medicine; René Diamond, DO, Resident, Internal Medicine, Saint Louis University School of Medicine
Contributor Information and Disclosures

Updated: Jan 29, 2008

Differential Diagnoses

HIV-1 Associated Vacuolar Myelopathy
Lyme Disease
Multiple Sclerosis
Neurosyphilis
Toxic Neuropathy
Tropical Myeloneuropathies

Other Problems to Be Considered

Human T-cell leukemia virus type 1 (HTLV-1) myelopathy
Folate deficiency
Copper deficiency myeloneuropathy

Workup

Laboratory Studies

  • Clinical evidence of vitamin B-12 deficiency
    • Serum cobalamin levels are the initial test.
    • Two assays exist: radioassay and the nonradioisotopic assay, chemiluminescence, which is becoming more popular because of improved automation, safety, and cost. Chemiluminescence has a higher reference range value, from 250-1100 pg/mL versus 170-900 pg/mL for radioassay. Using the radioassay and elevated HC and MMA as criterion standards, levels are less than 200 pg/mL in 90-95% of patients, 200-300 pg/mL in 5-10%, and greater than 300 pg/mL in 0.1-1%. Be aware of the assay used and how the reference range was determined. A serum cobalamin level that is within the reference range does not exclude cobalamin deficiency.
  • Abnormally low vitamin B-12 levels: Test for PA by measuring antibodies against IF.
    • Antiparietal cell antibodies are present in 90% of PA cases. In patients older than 70 years, 10% have false-positive abnormal antibody levels.
    • IF antibodies are present in 60% of patients. These are more specific but less sensitive.
    • If either antibody is positive, the diagnosis of PA is confirmed and further testing is not required.
    • If antibodies are negative, obtain a serum gastrin level to test for achlorhydria, which is associated with PA. If these are elevated, the diagnosis is likely PA. If these results are normal, perform a Schilling test.
  • Borderline vitamin B-12 level and clinical features of vitamin B-12 deficiency: Measure MMA and HC.
    • Both folate and vitamin B-12 deficiency can lead to metabolite elevation.
    • In vitamin B-12 deficiency, MMA and HC are elevated, although HC elevation occurs by itself. MMA is more sensitive than HC.
    • In folate deficiency, MMA is within the reference range and HC is elevated.
    • MMA and HC are considered abnormal when greater than 3 standard deviations above the mean. Reference range values are not age dependent for MMA and are 70-350 nM/L. For patients younger than 60 years, reference range values are 5-15 µM/L for HC. In people older than 60 years, the cutoff for HC is 20 µM/L.
    • If both metabolites are within the reference range, vitamin B-12 deficiency is effectively ruled out. Only 0.2% of 400 patients with low serum vitamin B-12 had normal metabolite levels, and 10% of 98 patients with folate deficiency had metabolite levels within the reference range. False-positive elevations in MMA and HC occur in inborn errors of metabolism, renal disease, and deficiencies of folate. If either metabolite is elevated, test for PA or use the Schilling test.
  • Schilling test: The Schilling test is used to determine the etiology of vitamin B-12 deficiency in patients with normal IF antibodies.
    • Stage 1: Administer radiolabeled cobalamin 0.5-2.0 mCi PO to fasted patients. One to 6 hours later, administer unlabeled cobalamin 1000 mcg IM to saturate transcobalamin and flush hepatic storage. Measure the percentage of radiolabeled cobalamin in a 24-hour urine specimen. Urinary excretion within the reference range is 10-35% over 24 hours. Reduced urinary excretion of cobalamin, ie, less than 7-9% based on individual laboratory reference range values, in persons with normal renal function supports decreased absorption of oral cobalamin. If excretion is low, proceed to stage 2.
    • Stage 2: Stage 1 is repeated with coadministration of porcine IF 60 mg. If the absorption of cobalamin is normalized, the presumptive diagnosis is PA. If poor absorption persists after administration, proceed to stage 3.
    • Stage 3: Tetracycline is administered for 5 days prior to reperformance of stage 1 to exclude blind loop as the etiology.
    • Stage 4: Pancreatic enzymes are administered with repetition of stage 1 to test for pancreatic disease.
    • Caveats: If vitamin B-12 is administered 48 hours before the Schilling test, dilution of the radiolabeled cobalamin and spuriously low apparent urinary excretion and false-positive results occur. False-negative values occur in food-bound malabsorption due to achlorhydria. True negative results are from dietary deficiencies (vegan) and cobalamin binding–protein abnormalities.
  • Routine hematologic and chemistry tests
    • Hematologic abnormalities may be absent at the time of neurologic presentation.
    • Vitamin B-12 deficiency produces the classic picture of macrocytic anemia, with a mean corpuscular value (MCV) greater than 100 fL. The MCV correlates with estimated vitamin B-12 level:
      • MCV of 80-100 fL (normal) indicates less than 25% probability of vitamin B-12 deficiency.
      • MCV of 115-129 fL indicates a 50% probability.
      • MCV greater than 130 fL indicates a 100% probability.
    • Peripheral blood smear shows macro-ovalocytosis, anisocytosis, and poikilocytosis, as well as basophilic stippling of the erythrocytes and Howell-Jolly bodies. Reticulocyte count can be within the reference range or low. Hypersegmentation (>5% of neutrophils with > 5 lobes or 1% with > 6 lobes) of polymorphonuclear cells may occur without anemia. Thrombocytopenia is observed in approximately 50% of patients, and platelets often have bizarre size and shape.
    • Serum indirect bilirubin and lactate dehydrogenase (LDH) may be elevated because PA can have a hemolytic component.
    • Achlorhydria is present in many patients with PA.
  • Laboratory parameters after administration of vitamin B-12
    • Anemic patients
      • Reticulocytosis starts in 3-4 days and peaks at 1 week.
      • Hemoglobin concentration rises in 10 days and returns to the reference range in 8 weeks.
      • LDH falls within 2 days.
      • Hypersegmented neutrophils disappear in 1-2 weeks.
    • Patients with severe anemia and borderline-to-low iron stores
      • Serum iron level falls within 24 hours because of increased erythropoiesis.
      • Hypokalemia may develop because of increased potassium utilization in hematopoiesis.

Imaging Studies

  • Because of the increased incidence of gastric cancer in PA, gastric radiographic series are suggested at the first visit.
  • In patients with myelopathy, MRI may reveal regional T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensities mainly in the thoracic posterior columns with possible extension into the brain stem. In patients with chronic disease, atrophy of the spinal cord is observed.
  • Brain MRI may show T2 and FLAIR hyperintensities in the cerebral white matter and around the fourth ventricle.
  • Brain MRI of infants with vitamin B-12 deficiency may show delayed myelination.

Other Tests

  • Abnormal evoked potentials may be the first electrodiagnostic finding, even in asymptomatic patients with normal neurologic examination findings. The abnormalities are often referable to a central conduction defect; however, peripheral nerves are also affected.
  • Somatosensory evoked potentials (SSEP) may reveal prolongation of L3-P27 latency, reflecting a defect in conduction in the large-fiber sensory pathway between the cauda equina and the contralateral sensory cortex.
  • Visual evoked potential (VEP) findings are as follows:
    • VEP findings may be abnormal even without visual symptoms or signs.
    • Prolongation of the P100 waveform can be unilateral or bilateral.
    • P100 may normalize after cobalamin replacement.
  • Nerve conduction study (NCS)/EMG findings are as follows:
    • In 1943, Dynes and Norcross found evidence of neuropathy in 23% of patients with PA.15
    • In a recent study, up to 65% of untreated patients had peripheral neuropathy.
    • Axonal sensorimotor polyneuropathy is present in up to 80%. Demyelinating or mixed forms are less frequent.
    • Typical features are decreased conduction velocities and motor or sensory amplitude and denervation on EMG.
    • In 1991, Healton et al found decreased motor nerve conduction velocities (NCV), absent or reduced sensory potentials, and fibrillations in the distal muscles indicating mixed demyelinating-axonal disease in 7 of 9 cases of vitamin B-12 deficiency and neuropathy.13
    • In 1998, Steiner et al described 5 patients with demyelinating polyneuropathy.16
    • Sensory nerves are usually more affected than motor nerves and are more severely affected distally than proximally. Proximal focal conduction block has been reported, which reversed on treatment.
  • Electroencephalography (EEG) findings may be normal or show nonspecific slowing. Follow-up EEG findings may be improved in response to treatment.

Procedures

  • Bone marrow aspiration may be performed for histologic examination.

Histologic Findings

The CNS is better characterized than the PNS in vitamin B-12 deficiency. The classic picture is subacute combined degeneration of the spinal cord involving the dorsal columns and corticospinal tracts. Lesions are concentrated in the cervical and upper thoracic cord and the cerebrum.

Spinal cord findings

  • Macroscopic: It may be shrunken in anteroposterior diameter. The posterior and lateral columns may be gray-white in color.
  • Microscopic: Multifocal vacuolated and demyelinated lesions exist in the white matter of the posterior and lateral columns. Early in the course, myelin sheaths are swollen, but axons appear normal; the largest fibers are predominantly affected. Demyelination starts in the center of the posterior columns of the upper thoracic cord. Then, lesions spread laterally and cranially to the lateral corticospinal tracts in the cervical segments and the medulla. Myelin breakdown, foamy macrophages, and occasional lymphocytes are characteristic, predominantly in a perivascular location. As demyelination and vacuolation increase, axons degenerate. Gliosis may be present in older lesions.
    • Electronic microscopic findings have only been used in nonhuman primates, not in humans. In the rhesus monkey model, the posterior and lateral spinal cord shows myelin degeneration characterized by separation of myelin lamellae and formation of intramyelin vacuoles leading to complete destruction of the myelin sheath and later to degeneration and loss of axons and gliosis.
    • Vitamin B-12 deficiency myelopathy is virtually indistinguishable from vacuolar myelopathy in AIDS, which is also characterized by vacuolation between the myelin sheaths accompanied by macrophage infiltration. However, the presence of multinucleated giant cells is characteristic of AIDS and not of vitamin B-12 deficiency.

Brain findings

  • Macroscopic: The brain appears normal.
  • Microscopic: Findings resemble the spinal cord pathology with scanty small perivascular foci of demyelination within the white matter featuring myelin swelling and axon degeneration. The optic nerve typically shows degeneration, predominantly in the papillomacular bundles.

Peripheral nervous system findings

  • Unlike EMG/NCS findings, which indicate predominantly axonal or mixed axonal-demyelinating neuropathy, histologic examination suggests either primary demyelinating or axonal neuropathy with secondary demyelination. However, most studies were performed before the introduction of semithin, teased fiber, and electron microscopy analysis.
    • A biopsy of the anterior tibial nerve recorded loss of myelin sheath and no loss of axons.17
    • A sural biopsy revealed loss of myelinated fibers and no demyelination in teased fibers, indicating secondary demyelination.18
    • In 1959, Coers and Woolf found endplate and preterminal axon abnormalities in muscle biopsies of patients with cobalamin deficiency, suggesting axonal damage.19
  • The pathology is better described in animal models. In cobalamin-deficient rats, electron microscopy revealed intramyelin and endoneural edema, with no or minimal axonal damage (reversible on administration of cobalamin) in nerves, dorsal root ganglia, and the ventral and dorsal roots.

Nonneurologic findings

  • Bone marrow hyperplasia
  • Mild-to-moderate splenomegaly
  • Increased iron deposits in the reticuloendothelial system
  • Atrophy in all layers of the stomach, sparing the pyloroduodenal region

More on Vitamin B-12 Associated Neurological Diseases

Overview: Vitamin B-12 Associated Neurological Diseases
Differential Diagnoses & Workup: Vitamin B-12 Associated Neurological Diseases
Treatment & Medication: Vitamin B-12 Associated Neurological Diseases
Follow-up: Vitamin B-12 Associated Neurological Diseases
Multimedia: Vitamin B-12 Associated Neurological Diseases
References
[ CLOSE WINDOW ]

References

  1. Gardner W, Osler W. A case of progressive pernicious anemia (Idiopathic of Addison). Can Med Surg J. 1877;5:385-404.

  2. Leichtenstein O. Uber progressive perniciose anamie bei tabeskranken. Deutsche Medizinische Wochenschrift. 1884;10:849.

  3. Lichtheim L. Zur kenntniss der perniziosen anamie. Muchen. Schweiz med wochenschr. 1887;34:300.

  4. Minnich W. Kenntnis der im Verlaufe der perniciosen anamie beobachteten spinalerkrankungen. Zeitschrift fur Klinische Medizin. 1892;21:264-314.

  5. Russell JSR, Batten FE, Collier J. Subacute combined degeneration of the spinal cord. Brain. 1900;23:39.

  6. Minot GR, Murphy WP. Treatment of pernicious anemia by a special diet. JAMA. 1926;87:470-476.

  7. Castle WB. Extrinsic factor in pernicious anemia. American Journal of Medical Science. 1929;178:148.

  8. Lassen HCA, Henricksen E, Neukirch F. Treatment of tetanus: severe bone marrow depression after prolonged nitrous oxide anesthesia. Lancet. 1956;1:527-530.

  9. Sahenk Z, Mendell JR, Couri D. Polyneuropathy from inhalation of N2O cartridges through a whipped-cream dispenser. Neurology. May 1978;28(5):485-7. [Medline].

  10. Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet. Dec 9 1978;2(8102):1227-30. [Medline].

  11. Misra UK, Kalita J. Comparison of clinical and electrodiagnostic features in B12 deficiency neurological syndromes with and without antiparietal cell antibodies. Postgrad Med J. Feb 2007;83(976):124-7. [Medline].

  12. Kinsella LJ, Green R. 'Anesthesia paresthetica': nitrous oxide-induced cobalamin deficiency. Neurology. Aug 1995;45(8):1608-10. [Medline].

  13. Healton EB, Savage DG, Brust JC. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore). Jul 1991;70(4):229-45. [Medline].

  14. Woltmann HW. The nervous symptoms in pernicious anemia: an analysis of one hundred and fifty cases. American Journal of Medical Science. 1919;173:400-9.

  15. Dynes JB, Norcross JW. Peripheral neuritis as a complication of pernicious anemia. JAMA. 1943;122:586-8.

  16. Steiner I, Kidron D, Soffer D. Sensory peripheral neuropathy of vitamin B12 deficiency: a primary demyelinating disease?. J Neurol. Jan 1988;235(3):163-4. [Medline].

  17. Greenfield JG. Subacute spinocerebellar degeneration occurring in elderly patients. Brain. 1934;57:161-76.

  18. McCombe PA, McLeod JG. The peripheral neuropathy of vitamin B12 deficiency. J Neurol Sci. Oct 1984;66(1):117-26. [Medline].

  19. Coers C, Woolf AL. The Innervation of Muscle. Oxford, England: Blackwell Scientific; 1959:91.

  20. Vasconcelos OM, Poehm EH, McCarter RJ, Campbell WW, Quezado ZM. Potential outcome factors in subacute combined degeneration: review of observational studies. J Gen Intern Med. Oct 2006;21(10):1063-8. [Medline].

  21. Adachi H, Hirai Y, Fujiura Y. Plasma homocysteine levels and atherosclerosis in Japan: epidemiological study by use of carotid ultrasonography. Stroke. Sep 2002;33(9):2177-81. [Medline].

  22. Addison T. Anemia: Disease of the suprarenal capsules. London Med Gazette. 1849;8:517-518.

  23. Al-Shubaili AF, Farah SA, Hussein JM, et al. Axonal and demyelinating neuropathy with reversible proximal conduction block, an unusual feature of vitamin B12 deficiency. Muscle Nerve. Oct 1998;21(10):1341-3. [Medline].

  24. Allen RH, Stabler SP, Savage DG. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J. Nov 1993;7(14):1344-53. [Medline].

  25. Andres E, Noel E, Kaltenbach G. [Vitamin B12 deficiency with normal Schilling test or non-dissociation of vitamin B12 and its carrier proteins in elderly patients. A study of 60 patients]. Rev Med Interne. Apr 2003;24(4):218-23. [Medline].

  26. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-77. [Medline].

  27. Balducci L. Epidemiology of anemia in the elderly: information on diagnostic evaluation. J Am Geriatr Soc. Mar 2003;51(3 Suppl):S2-9. [Medline].

  28. Beach RS, Mantero-Atienza E, Shor-Posner G. Specific nutrient abnormalities in asymptomatic HIV-1 infection. AIDS. Jul 1992;6(7):701-8. [Medline].

  29. Berger JR, Quencer R. Reversible myelopathy with pernicious anemia: clinical/MR correlation. Neurology. Jun 1991;41(6):947-8. [Medline].

  30. Booth GL, Wang EE. Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care. CMAJ. Jul 11 2000;163(1):21-9. [Medline].

  31. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. Oct 4 1995;274(13):1049-57. [Medline].

  32. Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med. May 27 1996;156(10):1097-100. [Medline].

  33. Carmel R. Reassessment of the relative prevalences of antibodies to gastric parietal cell and to intrinsic factor in patients with pernicious anaemia: influence of patient age and race. Clin Exp Immunol. Jul 1992;89(1):74-7. [Medline].

  34. Carmel R, Gott PS, Waters CH. The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and electrophysiologic abnormalities. Eur J Haematol. Apr 1995;54(4):245-53. [Medline].

  35. Carmel R, Johnson CS. Racial patterns in pernicious anemia. Early age at onset and increased frequency of intrinsic-factor antibody in black women. N Engl J Med. Mar 23 1978;298(12):647-50. [Medline].

  36. Carmel R, Johnson CS, Weiner JM. Pernicious anemia in Latin Americans is not a disease of the elderly. Arch Intern Med. Nov 1987;147(11):1995-6. [Medline].

  37. Chanarin I. The Megaloblastic Anemias. 2nd ed. Oxford, England: Blackwell Scientific; 1979.

  38. Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. Nov 1998;55(11):1449-55. [Medline].

  39. Cole M. Neurological manifestation of vitamin B12 deficiency. In: Goetz C, Aminoff M, eds. Handbook of Clinical Neurology. Vol 26. Systemic Diseases. Part II. 1998. Amsterdam, Holland: Elsevier Science BV; 367-405.

  40. Combe JJ. History of a case of anemia. Trans Med Chir Soc Edimb. 1822;1:194-204.

  41. Cunha UG, Rocha FL, Peixoto JM. Vitamin B12 deficiency and dementia. Int Psychogeriatr. Spring 1995;7(1):85-8. [Medline].

  42. Daly LE, Kirke PN, Molloy A, et al. Folate levels and neural tube defects. Implications for prevention. JAMA. Dec 6 1995;274(21):1698-702. [Medline].

  43. Dana CL. Subacute combined sclerosis of the spinal cord and its relation to anemia and to toxemia. J Nerv Ment Dis. 1899;26:1.

  44. Diaz-Arrastia R. Homocysteine and neurologic disease. Arch Neurol. Oct 2000;57(10):1422-7. [Medline].

  45. Ehrenpreis ED, Carlson SJ, Boorstein HL. Malabsorption and deficiency of vitamin B12 in HIV-infected patients with chronic diarrhea. Dig Dis Sci. Oct 1994;39(10):2159-62. [Medline].

  46. Fenwick S. On atrophy of the stomach. Lancet. 1870;ii:78-80.

  47. Fine EJ, Hallett M. Neurophysiological study of subacute combined degeneration. J Neurol Sci. Mar 1980;45(2-3):331-6. [Medline].

  48. Fine EJ, Soria E, Paroski MW. The neurophysiological profile of vitamin B12 deficiency. Muscle Nerve. Feb 1990;13(2):158-64. [Medline].

  49. Fowler B. Genetic defects of folate and cobalamin metabolism. Eur J Pediatr. Apr 1998;157 Suppl 2:S60-6. [Medline].

  50. Goodman BP, Chong BW, Patel AC, Fletcher GP, Smith BE. Copper deficiency myeloneuropathy resembling B12 deficiency: partial resolution of MR imaging findings with copper supplementation. AJNR Am J Neuroradiol. Nov-Dec 2006;27(10):2112-4. [Medline].

  51. Graham D, Lantos P. Vitamin Deficiencies. In: Greenfield's Neuropathology. 6th ed. London, England:. Arnold Publishers;1997:621-624.

  52. Grattan-Smith PJ, Wilcken B, Procopis PG. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord. Jan 1997;12(1):39-46. [Medline].

  53. Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin deficiency. Neurology. Aug 1995;45(8):1435-40. [Medline].

  54. Greenfield JG, Carmichael EA. Peripheral nerves in cases of subacute combined degeneration of the cord. Brain. 1935;58:483-91.

  55. Gueant JL, Saunier M, Gastin I. Decreased activity of intestinal and urinary intrinsic factor receptor in Grasbeck-Imerslund disease [corrected]. Gastroenterology. Jun 1995;108(6):1622-8. [Medline].

  56. Hamilton AS, Nixon CE. Sensory changes in the subacute combined degeneration of pernicious anemia. Arch Neurol Psychiatry. 1921;6:1.

  57. Hemmer B, Glocker FX, Schumacher M, et al. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry. Dec 1998;65(6):822-7. [Medline].

  58. Hennerici M. Dissociated foveal and parafoveal visual evoked responses in subacute combined degeneration. Arch Neurol. Feb 1985;42(2):130-2. [Medline].

  59. Hsing AW, Hansson LE, McLaughlin JK, et al. Pernicious anemia and subsequent cancer. A population-based cohort study. Cancer. Feb 1 1993;71(3):745-50. [Medline].

  60. Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. Nov-Dec 1997;38(6):305-14. [Medline].

  61. Jacques PF, Rosenberg IH, Rogers G, et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr. Mar 1999;69(3):482-9. [Medline].

  62. Janson JJ, Galarza CR, Murua A. Prevalence of hyperhomocysteinemia in an elderly population. Am J Hypertens. May 2002;15(5):394-7. [Medline].

  63. Kagan BL, Sultzer DL, Rosenlicht N. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. May 1990;147(5):591-5. [Medline].

  64. Kang SS, Wong PW, Zhou JM, Cook HY. Total homocyst(e)ine in plasma and amniotic fluid of pregnant women. Metabolism. Oct 1986;35(10):889-91. [Medline].

  65. Kapadia CR. Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and transport. Gastroenterologist. Dec 1995;3(4):329-44. [Medline].

  66. Kaptan K, Beyan C, Ural AU. Helicobacter pylori--is it a novel causative agent in Vitamin B12 deficiency?. Arch Intern Med. May 8 2000;160(9):1349-53. [Medline].

  67. Karlsson FA, Burman P, Loof L. Enzyme-linked immunosorbent assay of H+,K+-ATPase, the parietal cell antigen. Clin Exp Immunol. Dec 1987;70(3):604-10. [Medline].

  68. Karnaze DS, Carmel R. Neurologic and evoked potential abnormalities in subtle cobalamin deficiency states, including deficiency without anemia and with normal absorption of free cobalamin. Arch Neurol. Sep 1990;47(9):1008-12. [Medline].

  69. Katsaros VK, Glocker FX, Hemmer B, Schumacher M. MRI of spinal cord and brain lesions in subacute combined degeneration. Neuroradiology. Nov 1998;40(11):716-9. [Medline].

  70. Kieburtz KD, Giang DW, Schiffer RB, Vakil N. Abnormal vitamin B12 metabolism in human immunodeficiency virus infection. Association with neurological dysfunction. Arch Neurol. Mar 1991;48(3):312-4. [Medline].

  71. Kirke PN, Molloy AM, Daly LE. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med. Nov 1993;86(11):703-8. [Medline].

  72. Krumholz A, Weiss HD, Goldstein PJ, Harris KC. Evoked responses in vitamin B12 deficiency. Ann Neurol. Apr 1981;9(4):407-9. [Medline].

  73. Larner AJ, Zeman AZ, Allen CM. MRI appearances in subacute combined degeneration of the spinal cord due to vitamin B12 deficiency. J Neurol Neurosurg Psychiatry. Jan 1997;62(1):99-100. [Medline].

  74. Lehmann M, Gottfries CG, Regland B. Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement Geriatr Cogn Disord. Jan-Feb 1999;10(1):12-20. [Medline].

  75. Lester-Smith E. Purification of antipernicious amaemia factors from liver. Nature. 1948;161:638-639.

  76. Lindenbaum J, Rosenberg IH, Wilson PW, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. Jul 1994;60(1):2-11. [Medline].

  77. Lindenbaum J, Savage DG, Stabler SP. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol. Jun 1990;34(2):99-107. [Medline].

  78. Magnaghi V, Veber D, Morabito A. Decreased GFAP-mRNA expression in spinal cord of cobalamin-deficient rats. FASEB J. 2002;16:1820-1822. [Medline].

  79. Marie RM, Le Biez E, Busson P, et al. Nitrous oxide anesthesia-associated myelopathy. Arch Neurol. Mar 2000;57(3):380-2. [Medline].

  80. Metz J. Cobalamin deficiency and the pathogenesis of nervous system disease. Annu Rev Nutr. 1992;12:59-79. [Medline].

  81. Metz J. Pathogenesis of cobalamin neuropathy: deficiency of nervous system S-adenosylmethionine?. Nutr Rev. Jan 1993;51(1):12-5. [Medline].

  82. Ozer EA, Turker M, Bakiler AR. Involuntary movements in infantile cobalamin deficiency appearing after treatment. Pediatr Neurol. Jul 2001;25(1):81-3. [Medline].

  83. Paltiel O, Falutz J, Veilleux M. Clinical correlates of subnormal vitamin B12 levels in patients infected with the human immunodeficiency virus. Am J Hematol. Aug 1995;49(4):318-22. [Medline].

  84. Pant SS, Asbury AK, Richardson EP Jr. The myelopathy of pernicious anemia. A neuropathological reappraisal. Acta Neurol Scand. 1968;44:Suppl 5:1-36. [Medline].

  85. Penix LP. Ischemic strokes secondary to vitamin B12 deficiency-induced hyperhomocystinemia. Neurology. Aug 1998;51(2):622-4. [Medline].

  86. Perros P, Singh RK, Ludlam CA, Frier BM. Prevalence of pernicious anaemia in patients with Type 1 diabetes mellitus and autoimmune thyroid disease. Diabet Med. Oct 2000;17(10):749-51. [Medline].

  87. Platica O, Janeczko R, Quadros EV. The cDNA sequence and the deduced amino acid sequence of human transcobalamin II show homology with rat intrinsic factor and human transcobalamin I. J Biol Chem. Apr 25 1991;266(12):7860-3. [Medline].

  88. Postiglione A, Milan G, Ruocco A. Plasma folate, vitamin B(12), and total homocysteine and homozygosity for the C677T mutation of the 5,10-methylene tetrahydrofolate reductase gene in patients with Alzheimer''s dementia. A case-control study. Gerontology. Nov-Dec 2001;47(6):324-9. [Medline].

  89. Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc. Feb 1994;69(2):144-50. [Medline].

  90. Putnam JJ. A group of cases of systemic scleroses of the spinal cord, associated with diffuse collateral degeneration, occurring in enfeebled persons past middle life, especially in women: Studied with particular reference to etiology. J Nerv Ment Dis. 1891;16:69.

  91. Remacha AF, Cadafalch J. Cobalamin deficiency in patients infected with the human immunodeficiency virus. Semin Hematol. Jan 1999;36(1):75-87. [Medline].

  92. Renault F, Verstichel P, Ploussard JP. Neuropathy in two cobalamin-deficient breast-fed infants of vegetarian mothers. Muscle Nerve. Feb 1999;22(2):252-4. [Medline].

  93. Richmond J, Davidson S. Subacute combined degeneration of the spinal cord in non-Addisonian megaloblastic anaemia. Quarterly Journal of Medicine. 1958;27:517-531.

  94. Rickes EL, Brink NG, Koniuszy FR. Crystalline vitamin B 12. Science. 1948;107:396.

  95. Robertson KR, Stern RA, Hall CD. Vitamin B12 deficiency and nervous system disease in HIV infection. Arch Neurol. Aug 1993;50(8):807-11. [Medline].

  96. Sacco RL, Roberts JK, Jacobs BS. Homocysteine as a risk factor for ischemic stroke: an epidemiological story in evolution. Neuroepidemiology. 1998;17(4):167-73. [Medline].

  97. Savage DG, Lindenbaum J. Neurological complications of acquired cobalamin deficiency: clinical aspects. Baillieres Clin Haematol. Sep 1995;8(3):657-78. [Medline].

  98. Savage DG, Lindenbaum J, Stabler SP. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med. Mar 1994;96(3):239-46. [Medline].

  99. Scalabrino G, Carpo M, Bamonti F. High tumor necrosis factor-alpha [corrected] levels in cerebrospinal fluid of cobalamin-deficient patients. Ann Neurol. 2004;56:886-890. [Medline].

  100. Scalabrino G, Corsi MM, Veber D. Cobalamin (vitamin B(12)) positively regulates interleukin-6 levels in rat cerebrospinal fluid. J Neuroimmunol. 2002;127:37-43. [Medline].

  101. Scalabrino G, Mutti E, Veber D. Increased spinal cord NGF levels in rats with cobalamin (vitamin B12) deficiency. Neurosci Lett. Mar 27 2006;396(2):153-8. [Medline].

  102. Schilling RF. Is nitrous oxide a dangerous anesthetic for vitamin B12-deficient subjects?. JAMA. Mar 28 1986;255(12):1605-6. [Medline].

  103. Scott E. The prevalence of pernicious anemia in Britain. J Coll Gen Pract Res News. 1960;3:80-4.

  104. Scott JM. Folate and vitamin B12. Proc Nutr Soc. May 1999;58(2):441-8. [Medline].

  105. Selhub J, D'Angelo A. Hyperhomocysteinemia and thrombosis: acquired conditions. Thromb Haemost. Jul 1997;78(1):527-31. [Medline].

  106. Stabler SP, Allen RH, Fried LP, et al. Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women. Am J Clin Nutr. Nov 1999;70(5):911-9. [Medline].

  107. Stabler SP, Allen RH, Savage DG. Clinical spectrum and diagnosis of cobalamin deficiency. Blood. Sep 1 1990;76(5):871-81. [Medline].

  108. Stacy CB, Di Rocco A, Gould RJ. Methionine in the treatment of nitrous-oxide-induced neuropathy and myeloneuropathy. J Neurol. Aug 1992;239(7):401-3. [Medline].

  109. Sumner AE, Chin MM, Abrahm JL, et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery. Ann Intern Med. Mar 1 1996;124(5):469-76. [Medline].

  110. Surtees R. Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain. J Inherit Metab Dis. 1993;16(4):762-70. [Medline].

  111. Tan SV, Guiloff RJ. Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry. Jul 1998;65(1):23-8. [Medline].

  112. Tefferi A, Pruthi RK. The biochemical basis of cobalamin deficiency. Mayo Clin Proc. Feb 1994;69(2):181-6. [Medline].

  113. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med. Nov 13 1997;337(20):1441-8. [Medline].

  114. Tracey JP, Schiffman FJ. Magnetic resonance imaging in cobalamin deficiency. Lancet. May 9 1992;339(8802):1172-3. [Medline].

  115. Van der Mooren MJ, Wouters MG, Blom HJ, et al. Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women. Eur J Clin Invest. 24(11):733-6. [Medline].

  116. Victor M. Polyneuropathy due to nutritional deficiency and alcoholism. In: Dyck PJ, Thomas PK, Lambert EH, eds. Peripheral Neuropathy. 1975. Philadelphia, Pa: WB Saunders; 1030.

  117. Wadia RS, Bandishti S, Kharche M. B12 and folate deficiency: incidence and clinical features. Neurol India. Dec 2000;48(4):302-4. [Medline].

  118. Wang HX, Wahlin A, Basun H. Vitamin B(12) and folate in relation to the development of Alzheimer''s disease. Neurology. May 8 2001;56(9):1188-94. [Medline].

  119. Weir DG, Scott JM. Brain function in the elderly: role of vitamin B12 and folate. Br Med Bull. 1999;55(3):669-82. [Medline].

  120. Wilhelm H, Grodd W, Schiefer U. Uncommon chiasmal lesions: demyelinating disease, vasculitis, and cobalamin deficiency. Ger J Ophthalmol. 1993;2(4-5):234-40. [Medline].

  121. Wright JD, Bialostosky K, Gunter EW, et al. Blood folate and vitamin B12: United States, 1988-94. Vital Health Stat 11. Dec 1998;(243):1-78. [Medline].

  122. Yao Y, Yao SL, Yao SS. Prevalence of vitamin B12 deficiency among geriatric outpatients. J Fam Pract. Nov 1992;35(5):524-8. [Medline].

  123. Yoo JH, Chung CS, Kang SS. Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke. Dec 1998;29(12):2478-83. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

vitamin B-12 deficiency, cobalamin deficiency, subacute combined spinal degeneration, pernicious anemia, PA, vitamin B-12 associated neurologic diseases, vitamin B-12 associated neurological diseases

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Niranjan N Singh, MD, DNB, Fellow in Neurophysiology, Department of Neurology, St Louis University School of Medicine
Niranjan N Singh, MD, DNB is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Coauthor(s)

Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Associate Program Director, Associate Professor, Departments of Neurology, Molecular Virology, and Molecular Microbiology and Immunology, St Louis University School of Medicine
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

Alan L Diamond, DO, Movement Disorder Fellow, Department of Neurology, Baylor College of Medicine
Alan L Diamond, DO is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Osteopathic Association, and American Society of Neuroimaging
Disclosure: Nothing to disclose.

René Diamond, DO, Resident, Internal Medicine, Saint Louis University School of Medicine
René Diamond, DO is a member of the following medical societies: American Medical Student Association/Foundation and American Osteopathic Association
Disclosure: Nothing to disclose.

Medical Editor

Christopher Luzzio, MD, Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Nestor Galvez-Jimenez, MD, Program Director of Movement Disorders, Department of Neurology, Division of Medicine, Director of Neurology Residency Training Program, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.