Introduction

Vitamin B12 deficiency in its early stages is asymptomatic. Afterwards macrocytic anaemia and/or a typical (neuro) psychiatric symptom pattern may arise (Carmel, 2000; Lindenbaum et al., 1988). Hence, the nature and severity of the symptoms are very diverse (Heil et al., 2012).

Diagnosing B12 deficiency is quite a challenge, since very often there is the (unjustified) assumption that anaemia is a required criteria for the diagnosis. A number of studies have shown, however, that neurological symptomology may be more severe among patients without anaemia (Healton et al., 1991).

There is a danger that the diagnosis – and thus B12 deficiency treatment –  will be delayed, which may have a large impact on the patient. Consequently, rapid diagnosis and treatment are very important. There is a chance that a lot of people may have chronic symptoms, considering the severity of the disease (Hunt et al., 2014).

All symptoms listed below may occur. Sometimes one of the symptoms is clearly manifest, sometimes there are multiple, more or less severe, symptoms. Patients have told us that their condition has been gradually deteriorating over the years. As early as 1901 this was reported (Hunt et al., 2014), when nobody yet knew which illness they were dealing with.

General symptoms

  • Exhaustion (strange ‘drained’feeling), general unwellness
  • dizziness (alsof in upright position), fainting
  • headache, migraine
  • loss of hair, prematurely turning gray
  • brittle nails
  • increased susceptibility to infection (urinary system, sinuses)
  • shortness of breath or COPD-like phenomena (especially upon exertion), fast high intake of breath
  • hoarseness, signs of paralysis in vocal cords (seldom)
  • muscle weakness and pains
  • increased pulse (tachycardia)
  • palour
  • tinnitus
  • sensitiveness to cold (especially of hands and feet)
  • feverish symptoms, feelings of coming down with the flu
  • misunderstood fever

Neurological symptoms

Central nervous system

Neuropsychiatry (from the brain)

  • cognitive decline
    • memory (especially short term memory)
    • concentration problems
    • problems in finding the proper words (aphasia)
    • desorientation
  • (mild to severe) depression, moodswings, suicidal tendencies, lability (weeping a lot), quickly irritated, outbursts of anger
  • anxiety, delirium, delusions, paranoia, manic behaviour, hallucinations, psychosis, catatonia, bipolar disorder, obsessive-compulsive personality disorder
  • altered mental condition, personality changes, sense of alienation, brainfog
  • dementia (prefrontal cortex), Alzheimer-like symptoms

Neurological (from the spinal cord, a.o. subacute combined degeneration of the spinal cord)

  • tingling in hands and feet
  • disturbed perception of the skin, numbness of the skin (paresthesia)
  • spastic and instability of gait (ataxia), (e.g. coordination of walking movement, people may knock objects from tables, walk into doorposts; clumsiness)
  • muscle weakness arms and legs (collapsing)
  • symptoms of paralysis
  • spasticity
  • abnormal reflexes
    • positive Romberg test
    • positive signs of Lhermitte
    • Babinski’s reflex
  • Parkinson-like symptoms
  • unvoluntary movements

Peripheral nervous system

Somatic nervous system (perception senses from the eyes, ears, skin (tactile) and sense of smell )

  • tingling hands and feet
  • numbness of hands and feet (feeling as if they are ‘asleep’)
  • muscle tremors on the skin (e.g. eyelid)
  • reduced capability to perceive the body position in a room
  • blurred vison (focus decreases), optic atrophia
  • infection and degeneration optic nerve
  • hearing problems, distortion, tinnitus
  • reduced sense of smell, taste, touch

Autonomous nervous system 

  • pattern of disturbed sleep rythm (unable to fall asleep, or to sleep throughout the night)
  • (harmless) cardiac arrythmias (sinusnode), rapid heartbeat
  • urinal or faecal incontinence
  • too low blood pressure (postural of orthostatic hypotension)

Digestive tract

  • lack of appetite, (unexplained) loss of weight 
  • nausea, throwing up, bloating
  • abdominal pain 
  • glossitis (red, sore, smooth tongue, sometimes infected)
  • burning mouth syndrom
  • inflammation of the oral mucosa (stomatitis)
  • often mouth ulcers
  • often bleeding gums
  • (sudden) diarrhea or constipation (sometimes alternating)

Gynaecology

  • atrophy of the vaginal mucosa (resulting in sore, sensitive vaginal wall)
  • chronic urinary tract and vagina infections
  • infertility (men and women)
  • repeated miscarriage
  • premature births
  • false positive PAP smear results (false pre-cervical cancer test results)
  • menstruation problems (heavy bleeding or missing periods)

Other

  • back pains (lower extremities)
  • restless legs
  • hyperpigmentation of the skin or mucus membranes
  • vitiligo
  • pains in the joints
  • infected mucosa
  • allergies
  • angina pectoris
  • osteoporosis
  • unexplained chronic cough, hoarseness

Symptoms babies

  • neural tube defects
  • low birth weight, too small skull perimeter
  • frequent crying, nerve sensitivity
  • poor sucking and swallowing reflex
  • absence of smiling
  • throwing up, belching, refusing food
  • insufficient weight gain
  • developmental delays after initial progress (as a result of low milk supply mother)
  • apathy
  • hyperirritability, convulsions
  • overall weakness
  • crying a lot
  • abnormal movement (arms and legs)
  • ataxia
  • insulin resistance

Symptoms children, adoloscents

  • behaviour probems (mild to severe)
  • depression (mild to severe)
  • cognitive deterioration (memory and concentration problems)
  • nausea, no appetite
  • growth defects
  • absence of smiling or laughing
  • involuntary movement
  • anorexia

How often do these symptoms occur?

In 2014 Hooper et al. described a vitamin B12 deficiency related symptomatology  (Hooper et al., 2014). In a survey with a response rate of approximately one thousand patients in England, published in The British Journal of Nursing, patients with a B12 deficiency diagnosis prove to have a large variation of symptoms.

The most general symptoms

  • 96% of patients show (unusual) fatigue
  • 87% wake up tired
  • 34% have glossitis
  • 30% have loss of hair, mouth ulcers or blurred vision

Neurological symptoms

  • 78% suffer from memory loss
  • 75% show a lack of concentration
  • 73% experience shortness of breath
  • 66% experience clumsiness or ataxia
  • 59% have dizzy spells
  • 56% have arrythmias
  • 50% have aphasia

All symptoms listed above are also included in a survey by Stichting B12-tekort (Visser et al., 2013). This survey has a response rate of more than 1500 and gives a clear insight into the clinical phenomena and delays in recognition and treatment of B12 deficiency. Both surveys show a significant overlap between fibromyalgia, ME/CFS and somatic unexplained physical symptoms.

Present-day cutting points and standard values can easily lead to misdiagnosis (Carmel, 2011; Iqtidar & Chaudary, 2012). Based on her practitioner experience and joined by Jeffrey Stuart M.D, the American nurse Sally Pacholok wrote an accessible book about practice bottlenecks and case studies, underpinned by lots of references (Pacholok, 2014 edition 2).

The symptoms listed above are also described in multiple articles and in the research literature listed below.

© 2016 Clara Plattel, B12 Institute Nederland, Rotterdam

References

Allen, L. H. (1994). Vitamin B12 metabolism and status during pregnancy, lactation and infancy. (0065-2598 (Print)). doi:D – PIP: 105629

Carmel, R. (2000). Current Concepts in Cobalamin Deficiency. Annual Review of Medicine, 51(1), 357-375. doi:10.1146/annurev.med.51.1.357

Carmel, R. (2011). Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. The American Journal of Clinical Nutrition, 94(1), 348S-358S.

Clarfield, A. (2003). The decreasing prevalence of reversible dementias: an updated meta-analysis. Arch Intern Med, 163, 2219 – 2229.

Clarke, R. (2006). Vitamin B12, folic acid, and the prevention of dementia. The New England journal of medicine, 354(26), 2817-2819.

COLE, M. G., & PRCHAL, J. F. (1984). LOW SERUM VITAMIN B12 IN ALZHEIMER-TYPE DEMENTIA. Age and Ageing, 13(2), 101-105. doi:10.1093/ageing/13.2.101

Emmanuel Andrès, M., Laure Federici, M., & Stéphan Affenberger, M. (2007). B12 deficiency: A look beyond pernicious anemia. The Journal of family practice, 56(7), 6.

Farkas, M., Keskitalo, S., Smith, D. E. C., Bain, N., Semmler, A., Ineichen, B., et al. (2013). Hyperhomocysteinemia in Alzheimer’s Disease: The Hen and the Egg? Journal of Alzheimer’s Disease, 33(4), 1097-1104.

Ford, A., & Almeida, O. (2012). Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials. J Alzheimers Dis, 29, 133 – 149.

Gezondheidsraad, N. (2003). Voedingsnormen: vitamine B6, foliumzuur en vitamine B12. Publicatie nr: 2003/04.

Goedhart, G., Wal, v. d., van Eijsden, M., & Bonsel, G. J. (2011). Maternal vitamin B-12 and folate status during pregnancy and excessive infant crying. (1872-6232 (Electronic)).

Green, R., Kara, N., & Cocks, H. (2011). Vitamin B12 deficiency: an unusual cause of vocal fold palsy. Journal of Laryngology & Otology, 125(12), 1309-1311. doi:10.1017/s0022215111001824

Healton, E. B., Savage, D. G., Brust, J. C., Garrett, T. J., & Lindenbaum, J. (1991). Neurologic aspects of cobalamin deficiency. (0025-7974 (Print)).

Heil, S. G., de Jonge, R., de Rotte, M. C., van Wijnen, M., Heiner-Fokkema, R. M., Kobold, A. C., et al. (2012). Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study. Ann Clin Biochem, 49(Pt 2), 184-189. doi:10.1258/acb.2011.011039

Hooper, M., Hudson, P., Porter, F., & McCaddon, A. (2014). Patient journeys: diagnosis and treatment of pernicious anaemia. (0966-0461 (Print)).

Hunt, A., Harrington, D., & Robinson, S. (2014). Vitamin B12 deficiency, Clinical review. 349. doi:10.1136/bmj.g5226

Iqtidar, N., & Chaudary, M. N. (2012). Misdiagnosed vitamin B12 deficiency a challenge to be confronted by use of modern screening markers. J PAk Med Association.

Kalita, J., Agarwal, R., Chandra, S., & Misra, U. K. (2013). A study of neurobehavioral, clinical psychometric, and P3 changes in vitamin B12 deficiency neurological syndrome. Nutritional neuroscience, 16(1), 39-46. doi:10.1179/1476830512y.0000000028

Lindenbaum, J., Healton, E. B., Savage, D. G., Brust, J. C. M., Garrett, T. J., Podell, E. R., et al. (1988). Neuropsychiatric Disorders Caused by Cobalamin Deficiency in the Absence of Anemia or Macrocytosis. New England Journal of Medicine, 318(26), 1720-1728. doi:doi:10.1056/NEJM198806303182604

Miller, J. W., Garrod, M. G., Allen, L. H., Haan, M. N., & Green, R. (2009). Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate. Am J Clin Nutr, 90(6), 1586-1592. doi:10.3945/ajcn.2009.27514

Mitchell, E. S., Conus, N., & Kaput, J. (2014). B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. LID – S0149-7634(14)00204-8 [pii] LID – 10.1016/j.neubiorev.2014.08.006 [doi]. (1873-7528 (Electronic)).

Pacholok, S. M. S., Jeffrey. (2014 edition 2). Could It Be B12?: An Epidemic of Misdiagnoses (2 ed.).

Permoda-Osip, A., Dorszewska, J., Skibinska, M., Chlopocka-Wozniak, M., & Rybakowski, J. K. (2013). Hyperhomocysteinemia in bipolar depression: Clinical and biochemical correlates. Neuropsychobiology, 68(4), 193-196. doi:10.1159/000355292

Pront, R., Margalioth, E. J., Green, R., Eldar-Geva, T., Maimoni, Z., Zimran, A., et al. (2009). Prevalence of low serum cobalamin in infertile couples. Andrologia, 41(1), 46-50. doi:10.1111/j.1439-0272.2008.00895.x

Solomon, L. R. (2016). Functional vitamin B12 deficiency in advanced malignancy: implications for the management of neuropathy and neuropathic pain. Support Care Cancer. doi:10.1007/s00520-016-3175-5

Stabler, S. P. (2013). Vitamin B12 Deficiency. New England Journal of Medicine, 368(2), 149-160. doi:doi:10.1056/NEJMcp1113996

Stuerenburg, H., Mueller-Thomsen, T., & Methner, A. (2004). Vitamin B 12 plasma concentrations in Alzheimer disease. Neuro Endocrinol Lett, 25(Suppl 3), 176 – 177.

Torsvik, I., Ueland, P. M., Markestad, T., & Bjørke-Monsen, A.-L. (2013). Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study. The American Journal of Clinical Nutrition, 98(5), 1233-1240. doi:10.3945/ajcn.113.061549

van Dyck, C. H., Lyness, J. M., Rohrbaugh, R. M., & Siegal, A. P. (2009). Cognitive and psychiatric effects of vitamin B₁₂ replacement in dementia with low serum B₁₂ levels: A nursing home study. International Psychogeriatrics, 21(1), 138-147. doi:10.1017/s1041610208007904

Visser, P. (2013). On line Survey 1500 patients diagnosed with vitamin B12-deficiency. from Stichting B12 tekort

Zhang, Y., Hodgson, N. W., Trivedi, M. S., Abdolmaleky, H. M., Fournier, M., Cuenod, M., et al. (2016). Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLoS ONE, 11(1), e0146797. doi:10.1371/journal.pone.0146797

© 2016 Clara Plattel, B12 Institute Nederland, Rotterdam


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