Medscape is available in 5 Language Editions – Choose your Edition here.


Vitamin B-12 Associated Neurological Diseases Clinical Presentation

  • Author: Niranjan N Singh, MD, DM; Chief Editor: Selim R Benbadis, MD  more...
Updated: Nov 23, 2015


Clinical course

The neurologic features are attributable to pathology in the peripheral and optic nerves, posterior and lateral columns of the spinal cord (subacute combined degeneration), and in the brain. Interestingly, hematologic and neurologic manifestations are occasionally dissociated.[14, 15] An inverse correlation in the severity of both manifestations has been suggested. In patients with neuropsychiatric abnormalities, 28% lack anemia or macrocytosis.

Clinical manifestations due to vitamin B-12 deficiency are unrelated to etiology. In a prospective comparative study between antiparietal cell antibody positive and negative patients, no significant difference was shown in clinical, electrodiagnostic, and radiological features.[16]

Although the clinical features of vitamin B-12 deficiency may consist of a classic triad of weakness, sore tongue, and paresthesias, these are not usually the chief symptoms.

Onset is subacute or gradual, although more acute courses have been described, in particular after N 2 O exposure. In 1986, Schilling described 2 patients with unrecognized vitamin B-12 deficiency who developed paresthesias and poor manual dexterity 1-3 months after brief N 2 O exposure.[17] In 1995, Kinsella and Green described a 70-year-old man with paresthesias and hand clumsiness after 2 exposures to N 2 O over 3 months.[18]

Onset is often with a sensation of cold, numbness, or tightness in the tips of the toes and then in the fingertips, rarely with lancinating pains. Simultaneous involvement of arms and legs is uncommon, and onset in the arms is even rarer.

Paresthesias are ascending and occasionally involve the trunk, leading to a sensation of constriction in the abdomen and chest.

Untreated patients may develop limb weakness and ataxia.

In 1991, Healton et al performed detailed neurologic evaluations of 143 patients with vitamin B-12 deficiency; 74% presented with neurologic symptoms.[19]

  • Isolated numbness or paresthesias were present in 33%.
  • Gait abnormalities occurred in 12%.
  • Psychiatric or cognitive symptoms were noted in 3%.
  • Visual symptoms were reported in 0.5%. Symptoms include subacute progressive decrease in visual acuity, usually caused by bilateral optic neuropathy and rarely pseudotumor cerebri or optic neuritis.
  • Rare autonomic features include orthostasis, sexual dysfunction, and bowel and bladder incontinence.
  • Other symptoms include lightheadedness and impaired taste and smell.
  • Asymptomatic neurologic manifestations can be detected using somatosensory evoked potentials (SSEP); see below.
  • Nonneurologic symptoms, some of which may also reflect autonomic nervous system involvement, were present in 26%.
    • Constitutional symptoms, including anorexia and weight loss occurred in 50%. Low-grade fever that resolves with treatment occurred in 33% of cases. Other symptoms include fatigue and malaise.
    • Cardiovascular symptoms include syncope, dyspnea, orthopnea, palpitations, and angina.
    • Gastrointestinal symptoms include heartburn, flatulence, constipation, diarrhea, sore tongue, and early satiety.

In a prospective study of 57 patients with vitamin B-12 deficiency neurological syndrome, common presenting syndromes included myeloneuropathy (25), myelopathy (14), myeloneuroencephalopathy (13), myeloencephalopathy (4), and behavioral (1).[126]



Most patients exhibit signs of peripheral nervous system (PNS) or spinal cord involvement, but the extent of PNS involvement remains unclear, in part because both neuropathy and myelopathy can cause impaired vibration sense, ataxia, and paresthesias. Either can be affected first in the early stages. Objective sensory abnormalities usually result from posterior column involvement and less often from PNS disease.

In 1919, Woltmann found features of PNS disease in 4.9% of patients with PA, including distal hyporeflexia or areflexia; 80% of these also had evidence of cord involvement.[20]

In 1991, Healton summarized his experience with a large group of patients as follows:[19]

  • Isolated neuropathy was reported in 25% of patients.
  • Myelopathy occurred in 12% of cases.
  • A combination of neuropathy and myelopathy was noted in 41%.
  • Neuropsychiatric manifestations, such as recent memory loss with reduced attention span and otherwise normal cognition, depression, hypomania, paranoid psychosis with auditory or visual hallucinations (megaloblastic madness), violent behavior, personality changes, blunted affect, and emotional liability, were reported in 8% of patients.
  • Ocular findings included a cecocentral scotoma and occurred in 0.5% of cases. Others have described optic atrophy, nystagmus, small reactive pupils, and chiasmatic lesion causing bitemporal hemianopia.
  • Normal findings were noted on neurologic examination in 14% of patients despite paresthetic symptoms.

Early in the course, poor joint position and vibration sense predominate. Typically, the legs are affected before the arms. Rarely are all limbs affected simultaneously. A Romberg sign is commonly found. The gait may be wide based.

On presentation, 50% of patients have absent ankle reflexes with relative hyperreflexia at the knees. Plantars are initially flexor and later extensor. A Hoffman sign may be found.

As the disease progresses, ascending loss of pinprick, light touch, and temperature sensation occurs. Later, depending on the predominance of posterior column versus cortical spinal tract involvement, ataxia or spastic paraplegia predominates. Then, PNS involvement causes distal limb atrophy.

Cognitive testing may reveal mild impairment or frank dementia.

Nonneurologic manifestations include the following:

  • General - Lemon-yellow waxy pallor, premature whitening of hair, flabby bulky frame, mild icterus, and blotchy skin pigmentation in dark-skinned patients
  • Cardiovascular - Tachycardia, congestive heart failure
  • Gastrointestinal - Beefy, red, smooth, and sore tongue with loss of papillae that is more pronounced along edges

Abnormal vitamin B-12 metabolism occurs in infants born to vitamin B-12–deficient mothers or those with hereditary diseases, including the Imerslünd-Grasbeck syndrome (cublin mutation resulting in decreased cobalamin transport from the intestinal lumen), transcobalamin II deficiency, and intracellular cobalamin abnormalities (classified as Cbl A though G with neurologic features in Cbl C and Cbl D, see below). Symptoms become prominent after exhaustion of vitamin B-12 stores acquired in utero. Infants present with developmental delay, failure to thrive, lethargy, poor feeding, mental retardation, seizures, listlessness, irritability, ataxia, hyporeflexia, hypotonia, pathologic reflexes, coma, tremor, and myoclonus. The latter may worsen transiently upon initiation of treatment.



Inadequate vitamin B-12 absorption is the major pathomechanism and may result from several factors.

  • Intrinsic factor deficiency
    • PA accounts for 75% of cases of vitamin B-12 deficiency. It is an autoimmune attack on gastric IF. Antibodies are present in 70% of patients. They may block the formation of the cobalamin-IF complex or block its binding with cublin. Other antibodies are directed at parietal cell hydrogen-potassium adenosine triphosphatase (ATPase).
    • Juvenile PA results from inability to secrete IF. Secretion of hydrogen ions and the gastric mucosa are normal. Transmittance is autosomal recessive inheritance of abnormal GIF on chromosome arm 11q13.
    • Destruction of gastric mucosa can occur from gastrectomy or Helicobacter pylori infection. A Turkish study found endoscopic evidence of H pylori infection in more than 50% of vitamin B-12–deficient patients. Antibiotics alone eradicated H pylori in 31 patients, with resolution of vitamin B-12 deficiency.
  • Deficient vitamin B-12 intake: Intake may be inadequate because of strict vegetarianism (rare), breastfeeding of infants by vegan mothers, alcoholism, or following dietary fads.
  • Disorders of terminal ileum: Tropical sprue, celiac disease, enteritis, exudative enteropathy, intestinal resection, Whipple disease, ileal tuberculosis, and cublin gene mutation on chromosome arm 10p12.1 in the region designated MGA 1, which affects binding of the cobalamin-IF complex to intestinal mucosa (Imerslünd-Grasbeck syndrome), are disorders that affect the terminal ileum.
  • Competition for cobalamin: Competition for cobalamin may occur in blind loop syndrome or with fish tapeworm ( Diphyllobothrium latum).
  • Abnormalities related to protein digestion related to achlorhydria: Abnormalities include atrophic gastritis, pancreatic deficiency, proton pump inhibitor use, and Zollinger-Ellison syndrome, in which the acidic pH of the distal small intestine does not allow the cobalamin-IF complex to bind with cublin.
  • Medications: Medications include colchicine, neomycin, and p -aminosalicylic acid.
  • Transport protein abnormality: Abnormalities include transcobalamin II deficiency (autosomal recessive inheritance of an abnormal TCN2 gene on chromosome arm 22q11.2-qter resulting in failure to absorb and transport cobalamin) and deficiency of R-binder cobalamin enzyme.
  • Disorders of intracellular cobalamin metabolism: These disorders result in methylmalonic aciduria and homocystinuria in infants.
    • Isolated methylmalonic aciduria
      • Cbl A is due to deficiency of mitochondrial cobalamin reductase resulting in deficiency of adenosylcobalamin.
      • Cbl B is due to deficiency of adenosylcobalamin transferase resulting in deficiency of adenosylcobalamin.
    • Methylmalonic aciduria and homocystinuria
      • Cbl C is a combined deficiency of methylmalonyl CoA mutase and homocysteine:methyltetrahydrofolate methyltransferase. Patients have prominent neurologic features and megaloblastic anemia.
      • Cbl D is a deficiency of cobalamin reductase. Patients have prominent neurologic features.
      • Cbl F is a defect in lysosomal release of cobalamin.
    • Isolated homocystinuria
      • Cbl E is due to a defect in methionine synthase reductase located on chromosome arm 5p15.3-p15.2.
      • Cbl G is due to a defect in methyltetrahydrofolate homocysteine methyltransferase located on chromosome arm 1q43.
  • Increased vitamin B-12 requirement: Requirement is increased in hyperthyroidism and alpha thalassemia.
  • Other causes
    • In AIDS, vitamin B-12 deficiency is not infrequent. Although the exact etiology remains obscure, it is likely a multimodal process involving poor nutrition, chronic diarrhea, ileal dysfunction, and exudative enteropathy. Low vitamin B-12 levels may be more common in late than in early HIV disease.
    • N 2 O exposure can occur iatrogenically (ie, anesthesia) or through abuse ("whippets").
Contributor Information and Disclosures

Niranjan N Singh, MD, DM Associate Professor of Neurology, University of Missouri-Columbia School of Medicine

Niranjan N Singh, MD, DM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society

Disclosure: Nothing to disclose.


Florian P Thomas, MD, PhD, Drmed, MA, MS Director, National MS Society Multiple Sclerosis Center; Professor and Director, Clinical Research Unit, Department of Neurology, Adjunct Professor of Physical Therapy, Associate Professor, Institute for Molecular Virology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine

Florian P Thomas, MD, PhD, Drmed, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi

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, American Society of Neuroimaging

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nestor Galvez-Jimenez, MD, MSc, MHA The Pauline M Braathen Endowed Chair in Neurology, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, International Parkinson and Movement Disorder Society

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cyberonics; Eisai; Lundbeck; Sunovion; UCB; Upsher-Smith<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cyberonics; Eisai; Glaxo Smith Kline; Lundbeck; Sunovion; UCB<br/>Received research grant from: Cyberonics; Lundbeck; Sepracor; Sunovion; UCB; Upsher-Smith.

Additional Contributors

Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health

Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

  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. 1978 May. 28(5):485-7. [Medline].

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

  11. Nielsen MJ, Rasmussen MR, Andersen CB, Nexø E, Moestrup SK. Vitamin B12 transport from food to the body's cells--a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol. 2012 May 1. 9(6):345-54. [Medline].

  12. Leishear K, Ferrucci L, Lauretani F, Boudreau RM, Studenski SA, Rosano C, et al. Vitamin B12 and homocysteine levels and 6-year change in peripheral nerve function and neurological signs. J Gerontol A Biol Sci Med Sci. 2012 May. 67(5):537-43. [Medline]. [Full Text].

  13. Pflipsen MC, Oh RC, Saguil A, Seehusen DA, Topolski R. The prevalence of vitamin B(12) deficiency in patients with type 2 diabetes: a cross-sectional study. J Am Board Fam Med. 2009 Sep-Oct. 22(5):528-34. [Medline].

  14. Nachum-Biala Y, Troen AM. B-vitamins for neuroprotection: narrowing the evidence gap. Biofactors. 2012 Mar-Apr. 38(2):145-50. [Medline].

  15. Leishear K, Ferrucci L, Lauretani F, Boudreau RM, Studenski SA, Rosano C, et al. Vitamin B12 and homocysteine levels and 6-year change in peripheral nerve function and neurological signs. J Gerontol A Biol Sci Med Sci. 2012 May. 67(5):537-43. [Medline]. [Full Text].

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

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

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

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

  20. 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.

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

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

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

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

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

  26. Dalla Torre C, Lucchetta M, Cacciavillani M, Campagnolo M, Manara R, Briani C. Reversible isolated sensory axonal neuropathy due to cobalamin deficiency. Muscle Nerve. 2012 Mar. 45(3):428-30. [Medline].

  27. van Loon M, Postels DG, Heikens GT, Molyneux E. Severe pernicious anaemia in an 8-year-old African girl. Ann Trop Paediatr. 2009 Sep. 29(3):231-4. [Medline].

  28. Lahner E, Annibale B. Pernicious anemia: new insights from a gastroenterological point of view. World J Gastroenterol. 2009 Nov 7. 15(41):5121-8. [Medline]. [Full Text].

  29. 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].

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

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

  32. 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. 1998 Oct. 21(10):1341-3. [Medline].

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

  34. 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. 2003 Apr. 24(4):218-23. [Medline].

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

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

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

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

  39. 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. 2000 Jul 11. 163(1):21-9. [Medline].

  40. 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. 1995 Oct 4. 274(13):1049-57. [Medline].

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

  42. 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. 1992 Jul. 89(1):74-7. [Medline].

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

  44. 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. 1978 Mar 23. 298(12):647-50. [Medline].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  59. 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. 2006 Nov-Dec. 27(10):2112-4. [Medline].

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

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

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

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

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

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

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

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

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

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

  70. 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. 1999 Mar. 69(3):482-9. [Medline].

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

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

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

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

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

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

  77. 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. 1990 Sep. 47(9):1008-12. [Medline].

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

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

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

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

  82. 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. 1997 Jan. 62(1):99-100. [Medline].

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

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

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

  86. 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. 1990 Jun. 34(2):99-107. [Medline].

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

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

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

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

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

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

  93. 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].

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

  95. 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. 2000 Oct. 17(10):749-51. [Medline].

  96. 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. 1991 Apr 25. 266(12):7860-3. [Medline].

  97. 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. 2001 Nov-Dec. 47(6):324-9. [Medline].

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

  99. 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.

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

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

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

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

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

  105. 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].

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

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

  108. 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].

  109. 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].

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

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

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

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

  114. 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. 1999 Nov. 70(5):911-9. [Medline].

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

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

  117. 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. 1996 Mar 1. 124(5):469-76. [Medline].

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

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

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

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

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

  123. 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].

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

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

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

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

  128. 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].

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

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

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

Vitamin B-12–associated neurological diseases. Cobalamin and folate metabolism. TS = thymidylate synthase, DHFR = dihydrofolate reductase, SHMT = serine methyl-transferase.
Vitamin B-12–associated neurological diseases. Cobalamin deficiency leads to reduced adenosylcobalamin, which is required for production of succinyl-CoA. D-methylmalonyl-CoA is converted to methylmalonic acid.
Vitamin B-12–associated neurological diseases. Pernicious anemia. Characteristic lemon-yellow pallor with raw beef tongue lacking filiform papillae. Photo from Forbes and Jackson with permission.
Vitamin B-12–associated neurological diseases. Fluid attenuated inversion recovery (Flair) MRI sequence in a patient with cobalamin deficiency and neuropsychiatric manifestations. Discrete areas of hyperintensities are present in the corona radiata.
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.