Neuropsychiatric symptoms of B12 deficiency: not just in the elderly and often without anaemia

Vitamin B12 is an essential nutrient, needed for the function of many systems in the body. As a result of a B12 deficiency haematological, neurological, gastro-intestinal and psychiatric problems can develop.
The psychiatric symptoms can precede the other symptoms, among which the well known anaemia, in some cases even with years. These psychiatric symptoms include: irritability, mood changes, depression, disorientation, confusion, memory problems, concentration problems, sleep disorders, hallucinations, paranoia and apathy. Psychiatric disorders that are diagnosed in B12 deficient patients are, among others: dementia, depression, delirium, bipolar disorder, panic disorder, psychosis and phobias.
The fact that many symptoms can precede the development of anaemia, and even cause permanent damage before anaemia develops, has been known for over a century, attested by many scientific articles.
A summary of some of those articles:


  • In 1905 (!) Langdon 1 wrote in The Journal of the American Medical Association about a group of patients in which the development of mental and neurologic symptoms preceded anaemia and he described a large variety of neurotic and psychic symptoms.
  • McAlpine 2 wrote in 1929: “Mental changes occur not uncommonly in pernicious anaemia. They range from states of depression accompanied by loss of mental energy to definite psychoses. They, like the nervous symptoms, may precede the characteristic changes in the blood by many months. It must be emphasized that the cerebral symptoms, like those due to lesions in the spinal cord, may precede the appearance of anaemia for long periods, sometimes for years, and that they may occur in the presence of a completely normal blood picture and bone marrow and even in the absence of spinal lesions.”
  • In 1933 Greenfield and O’Flynn8 stated that 14% of patients with combined degeneration of the spinal cord have normal blood values.
  • In 1956 Holmes 4 wrote in the British Medical Journal: “The great difficulty in establishing the diagnosis of vitamin-B12 deficiency with involvement of the nervous system is the lack of correlation between the haematological and neurological manifestations. There is also a similar lack of correlation between the spinal and cerebral symptoms of the syndrome. Early diagnosis is essential if treatment is to be effective, for the reversibility of neurological symptoms is largely dependent on their duration. The brain lesions which form part of the neurological syndrome of vitamin-B12 deficiency, although they have been recognized for more than half a century, are still much less familiar than those which occur in the spinal cord and peripheral nerves, to which by long usage the term “subacute combined degeneration” has been applied. The end-result of unrecognized and untreated cerebral lesions may be a severe dementia, even more crippling than the paraplegia produced by the spinal lesions, but early treatment will produce complete remission. The cerebral symptoms preceded the appearance of Addisonian anaemia or of spinal and peripheral nerve involvement by several years in some instances.”
  • And in 1960 The British Medical Journal published A.D.M Smith’s ‘Megaloblastic Madness’ 10 He wrote: “The occurrence of subacute combined degeneration of the cord prior to the onset of anaemia is well recognized and clinicians are now fully alive to this possibility.” “The time-lag may be considerable and may give rise to diagnostic difficulty unless this situation is constantly borne in mind. Owing to the many tragedies that have resulted from unawareness, with subsequent irreversible cord damage, it is now unusual to come across cases of this nature.” “The necessity for making the correct diagnosis cannot be overstressed, as delay is extremely dangerous and the condition eminently treatable, provided cerebral demyelination has not occurred.”
  • In 1988 when ‘Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis’ 5 was published in the New England Journal of Medicine. They showed that the neurologic symptoms of a B12 deficiency can occur without hematologic abnormalities and even with a low-normal serum B12.
  • In 1990 the same Lindenbaum et al published: “Clinical spectrum and diagnosis of cobalamin deficiency” 4 in which they showed that 44% of the patients with a B12 deficiency in their study did not have anemia, 36% did not have macrocytosis and 43% did not have an elevated LDH value.
  • And in 1992 from the same authors5: “We have shown that the clinical spectrum of Cbl deficiency is much broader and varied than previously believed and that neuropsychiatric abnormalities occur frequently in the absence of the classic hematologic abnormalities.”


That psychiatric symptoms due to a B12 deficiency can occur in the elderly is well known. But that even (young) children can have these symptoms is hardly known, and almost always overlooked. The following cases illustrate the importance of checking B12 in children with neuropsychiatric symptoms:

Case one 7: Boy,12 years old.

Symptoms: aphasia, tremors, nervousness, during 2 years. Became introverted, sometimes stopped eating for days, was angry, talked and laughed with himself, couldn’t walk or sleep anymore.
B12 < 111 pmol/L, folate 5.8 nmol/L, Hb 8.4 mmol/L, MCV 98.
Diagnosis: psychosis and extrapyramidal symptoms due to B12- and folate deficiency.
Treatment: B12 injections (1000mcg a day) and folic acid 5mg twice a week.
After one week clear improvement, no more tremors, started to walk and talk again, and functioning independently.

Case two 8: Girl, 16 years old.

Symptoms: hypertension, depression, hallucinations, epileptic seizures, nervousness, couldn’t walk or sleep, and wasn’t capable of answering questions.
B12 < 111 pmol/L, folate 18 nmol/L, Hb 9.4, MCV 94.
Only treatment: B12 injections 5 x daily, followed by 2 a week for 2 weeks.
Within one week improvement of symptoms. Blood pressure normalized, hallucinations, depressive mood and psychosis symptoms disappeared and she could eat and talk normally again. After 3 weeks her B12 blood value was 728 pmol/L. At 6 months follow-up symptoms were gone, blood pressure remained normal, no more epileptic seizures.

Case three 9: Boy, 16 years old.

Symptoms (among others): memory problems, irritability, sleeplessness, apathy, hallucinations, delusions, concentration problems, crying, ataxia, shoulder and elbow rigidity, coordination problems, diminished thinking capability, glossitis
B12 122 pmol/L, Hb 6.2, MCV 98.
Treatment: low dose Risperidon 0.5 mg/day + B12-injections 500mcg a day. Risperidon was stopped in the second week, B12-injecties maintained monthly. Symptoms did not come back in the following six months.


It has to be emphasized again that neuropsychiatric symptoms, like other symptoms, can precede the development of anaemia, sometimes even with years, and that they can occur with a normal complete blood count.
It is, to say the least, remarkable, that in 2013, more than 50 years after A.D.M Smith’s ‘Megaloblastic Madness’ , this knowledge has been lost, and many physicians do not consider a B12 deficiency as a possible cause for symtoms, or do not want to test B12 when there is no anaemia present.

Psychiatric symptoms of a B12 deficiency are common and can be severe. With an early diagnosis and treatment, further development of symptoms can be prevented, before psychosis, dementia and severe depression can develop. The treatment is simple and effective and often gives very good results in these symptoms, when it is given in time.

In short: test for a possible B12 deficiency when neuropsychiatric symptoms are present. In old and young, with or without anaemia.



1. Langdon, F.W. (1905) J. Amer. med. Ass., 45, 1635.
2. McAlpine, D. (1929) Lancet, 2, 643.
3. Greenfield J.G. and O’Flynn, E. (1933) Lancet, 2, 62.
4. J. MacDonald Holmes, Cerebral Manifestations of vitamin B12 deficiency. Dec. 15, 1956 British Medical Journal
5. J Lindenbaum, EB Healton, DG Savage, JC Brust, TJ Garrett, ER Podell, PD Marcell, SP Stabler, and RH Allen. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. NEJM Volume 318:1720-1728
6. Voedingsnormen: vitamine B6, foliumzuur en vitamine B12. Den Haag: Gezondheidsraad, 2003; publicatie nr 2003/04.
7. Murat Dogan, Osman Ozdemir, Ertan A. Sal, S. Zehra Dogan, Pinar Ozdemir, Yasar Cesur, and Huseyin Caksen. Case Report: Psychotic Disorder and Extrapyramidal Symptoms Associated with Vitamin B12 and Folate Deficiency. J Trop Pediatr (2009) 55 (3): 205-207
8. Dogan M, Ariyuca S, Peker E, Akbayram S, Dogan ŞZ, Ozdemir O, Cesur Y.
Psychotic disorder, hypertension and seizures associated with vitamin B12 deficiency: a case report. Hum Exp Toxicol. 2012 Apr;31(4):410-3
9. Ali Evren Tufan, Rabia Bilici, Genco Usta and Ayten Erdoğan.
Mood disorder with mixed, psychotic features due to vitamin b12 deficiency in an adolescent: case report. Child Adolesc Psychiatry Ment Health. 2012; 6: 25.
10. Smith, A.D.M. (1960) Megaloblastic Madness. British Medical Journal, dec 24, 1840.

February 2013

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