Sally M. Pacholok, RN, BSN

 deficiency can place children at high risk for permanent brain injury.

) deficiency is an easily treated disorder that often goes undiagnosed in infants and children, placing them at high risk for permanent brain injury. It is well documented that B

 deficiency can cause developmental delay, hypotonia, tremor, seizures, failure to thrive, reduced IQ, and mental retardation. Children with B

 deficiency exhibit speech, language, and social delays, behavioral issues, and problems with fine and gross motor movement. Magnetic resonance imaging (MRI) scans reveal brain atrophy, which commonly reverses after B12 therapy. However, if the deficiency is diagnosed late, permanent intellectual disability typically occurs even after treatment, and cognitive and language development remain seriously retarded.

 deficiency frequently mimic those of autism spectrum disorders. Both autistic and brain-injured B

- deficient children have obsessive-compulsive behaviors and difficulty with speech, language, writing, and comprehension. B

 deficiency can also cause aloofness and withdrawal. Sadly, very few children presenting with autistic symptoms receive adequate testing for B

Infants and young children are often misdiagnosed. Irritability or gastric symptoms of B

 deficiency can be easily mistaken for colic or gastroenteritis. The apathetic or dull infant can be mistaken for an “easy” or “good” baby, and “late walkers” or “late talkers” can be considered variants of normal development. B

 deficiency can progress to failure to thrive and, if not promptly corrected, may lead to coma or death. Infants are also more vulnerable than adults to permanent brain injury because their central nervous systems are still developing.

deficiency often develop slowly over several months to years. An adult’s normal storage of vitamin B

 in the liver is approximately 2500 mcg. Newborns of mothers with normal B

 stores have body stores of only 25 mcg, which is thought to be enough to cover all of their metabolic needs in their first year of life. However, infants who are born to mothers with B

 deficiency due to any cause (ie, vegetarianism, autoimmune pernicious anemia, celiac disease,

, Crohn’s disease, gastric bypass, partial ileectomy, eating disorders, or use of proton-pump inhibitors, histamine

 blockers, metformin, or nitrous oxide [or abuse]) or who are exclusively breast-fed may have significantly less stored B

 and can develop a deficiency within the first year of life. Even infants who are formula-fed by these mothers may have suboptimal B

 in their formula may not be enough to correct their deficiency.

 deficiency typically have a much more rapid onset of symptoms. Many children are deficient even before birth, because their mothers have an unidentified B

 deficiency, and the existing deficiency is worsened when the deficient mom breast-feeds. Other children are deficient because of 1 of several genetic defects causing inborn errors of B

If it goes unrecognized in infancy, treating the disorder later at the toddler stage can result in rapid improvement, but some areas of the brain may be permanently injured, giving rise to fine motor difficulties, lower IQ, speech and language deficits, developmental delay, and behavioral problems. The extent of recovery and level of post-treatment functioning depend on the age at which the B

 deficiency began, its severity, how long it was present, and at what age treatment was instituted.

When breast-feeding mothers deficient in B

 switch their infants to formula or table foods, the infants may obtain sufficient B

 from these foods, but not enough to correct the existing deficiency. The minute amounts of B

 in the foods will protect a child from failure to thrive or death, but are suboptimal for the B

 needed for critical brain growth and development.

A 14-month-old boy was brought to an emergency department comatose on arrival. Severe B

 deficiency was diagnosed, with gross brain atrophy demonstrated by MRI. The boy regained consciousness within hours of treatment, and by day 3 of B

 injections, he was able to walk, eat, and drink, and was discharged. A brain MRI 10 weeks after treatment revealed that all structural brain abnormalities had disappeared, but the boy continued to show nerve damage. At 2 years of age he still displayed psychomotor retardation, agitation, and poor concentration. He could not speak any words.

Physicians and other health care providers may mistakenly believe that prenatal vitamins significantly reduce the risk of B

 deficiency in pregnancy, but they do not contain enough vitamin B

 to correct an existing deficiency. The FDA fortified all cereals and grains with folic acid in 1998 to help decrease birth defects, and women are prescribed high-dose folic acid during pregnancy. Folic acid masks the signs of anemia and macrocytosis. Surprisingly, women are not being screened for B

 deficiency before conception, during pregnancy, or while breast-feeding—and as a result are receiving substandard care. B

 deficiency is also linked to neural tube defects, preeclampsia, and miscarriages.

A 15-month-old child was diagnosed with severe B

 deficiency and presented with failure to thrive and developmental delay. A brain MRI revealed global cerebral atrophy, grossly elevated urinary methylmalonic acid, and a low B

 level. Hydroxocobalamin injections were immediately begun. At 28 months, the patient’s fine motor skills were at the 9-month level and his gross motor skills were comparable to those of an 18-monthold child. His expressive language was at a 10-month level and his receptive language was at a 12-month level. At 32 months, he had made developmental progress, but continued to have developmental delays, especially in speech and language.

Learning and behavioral disabilities and autism spectrum disorders have multiple causes, and B

 deficiency is only 1 piece of the puzzle. Yet it is often overlooked. In fact, it is easily treated and certainly preventable. Given the epidemic of these disorders and the devastating social and financial costs, it is crucial that we explore the B

 link. As a health care provider involved with children, remember the ABCs—Autism B

 Connection—because an early diagnosis can save a child and his or her family from a lifetime of disability and hardship.

Sally M. Pacholok, RN, BSN, has been researching cobalamin (vitamin B

) deficiency and practicing emergency nursing for 26 years. She is a frequent radio guest on nationally syndicated talk shows, lecturer, media personality, and co-author of 

 (2nd edition, 2011)—the winner of the Indie Excellence Award for best health book. Pacholok’s book was made into a documentary in 2012, and a screenplay has been completed to be made into a movie regarding Pacholok’s lifelong battle to improve the country’s health care system and expose substandard care. Pacholok is also an educator and public speaker for Superior Source Vitamins. Visit www.B12Awareness.org.

		von Schenck U, ender-Götze C, Koletzko B. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. 

		Molloy AM, Kirke PN, Troendle JF, et al. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. 

		Thompson MD, Cole DE, Ray JG. Vitamin B-12 and neural tube defects: the Canadian experience. 

		Centers for Disease Control and Prevention. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin—Georgia, 2001. 

. 2nd ed. Quill Driver Books—Linden Publishing; 2011.

Articles

Often misdiagnosed, vitamin B12 deficiency can place children at high risk for permanent brain injury.

Pediatric Vitamin B12 Deficiency: When Autism Isn't Autism

Recognizing vitamin B12 (cobalamin) deficiencies in patients early on is key.

) deficiency has been largely ignored for many decades by physicians and members of the health care team. So, exactly how many patients have an undiagnosed B

 deficiency in the United States today and why should pharmacists take note?

 deficiency strikes 16% of the population, or 48 million Americans.

 Others report the prevalence to be as high as 25%.

 The Framingham Offspring Study found that nearly 40% of people aged 26 to 83 years had B

 levels in the “low normal” range—a level at which many begin experiencing neurological symptoms. This is problematic because low B

 causes an array of neurologic and psychiatric manifestations. B

 deficiency has been severely underplayed in health care and largely ignored in favor of more recognized and more expensive-to-treat diagnoses. This has resulted in both substandard care and malpractice, costing millions of individuals their health and wasting billions of health care dollars.

Early Diagnosis and Treatment Are Critical

 deficiency strikes all ages, races, economic classes, and both sexes. It is arguably the most common nutritional deficiency causing injury in the United States. Early diagnosis and treatment is critical to prevent neurologic injury, disability, poor outcomes, and premature death. B

 deficiency causes demyelinating nervous system disease, dementia, psychiatric illness, anemia, vascular occlusions, fall-related trauma, suppressed immune system, and bone marrow failure.

 is a water-soluable vitamin synthesized by microorganisms and detected in trace amounts in foods of animal origin.

 It is crucial for DNA synthesis, methylation, folate metabolism, erythropoiesis, neurodevelopment, and nervous system function. B

 functions as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase. A deficiency thereby causes elevated homocysteine and methylmalonic acid. Uptake depends on gastric parietal cells excreting hydrochloric acid, intrinsic factor, and pepsin. Pancreatic enzymes and receptors in the distal ileum must be present along with the blood protein transcobalamin II to process B

 must follow a complex pathway of several steps for proper absorption and assimilation, there are numerous causes of deficiency. These include malabsorption syndromes, autoimmune disease, diet, drugs, chemotherapy, radiation, eating disorders, 

, gastrointestinal surgeries, nitrous oxide, hepatic disease, and genetic defects. Other groups at risk include vegans, vegetarians, alcoholics, and individuals with Crohn’s disease, small bowel bacterial overgrowth, celiac disease, gastric bypass, and AIDS.

Up to 30% of older adults have atrophic gastritis with hypochlorhydria inhibiting the release dietary protein-bound B

 Similarly, chronic use of drugs that decrease gastric acid, such as proton pump inhibitors, H

 Medications such as metformin, colchicine, potassium, cholestyramine, neomycin, chloramphenicol, and para-aminosalicylic acid also interfere with B

 deficiency can cause vascular disease, including stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis, because this deficiency causes hyperhomocystinemia. B

 is the cofactor for the conversion of homocysteine into methionine. Excess homocysteine causes blood vessels to lose their elasticity, making it harder for them to dilate and damaging their inner lining. That damage, in turn, allows cholesterol, collagen, and calcium to build up, causing plaque formation.

The short- and long-term ramifications are enormous. Untreated B

 deficiency causes balance problems, paresthesias, weakness, dizziness, postural hypotension, and visual disturbances. These symptoms dramatically increase the risk of falls, which, in turn, lead to trauma (ie, fractures, subdural hematomas), hospital stays, loss of independence, nursing home placement, and premature death.

 deficiency epidemic is frustrating because well-educated health care providers overlook such an easily diagnosed and inexpensively treated condition. Not only does B

 deficiency cause severe neurologic disease, but it also causes chronic anemia, which contrary to popular belief is frequently not macrocytic.

 Often, prescription drugs such as epoetin alfa (Procrit and Epogen) are prescribed. Untreated B

 deficiency can cause hypercellular and dysplastic bone marrow, which can be mistaken for signs of acute leukemia.

In the emergency department (ED), we routinely diagnose B

 deficiency in patients presenting with generalized weakness, anemia, shortness of breath, neuropathy, difficulty ambulating, mental status changes, mental illness, and fall-related trauma. Diagnosing B

 deficiency in the ED indicates that these patients’ primary care physicians and other specialists failed to include B

 deficiency in the differential diagnosis of their complaints or perhaps blamed their conditions on “normal aging.”

Many people of all ages suffering from severe anxiety, depression, and a host of other psychiatric disorders are prescribed dangerous and costly psychotropic drugs, narcotics, or benzodiazepines when the underlying problem actually may be B

Similarly, children diagnosed on the autism spectrum and prescribed psychiatric medications may have behavioral and neurologic manifestations because of low B

. Developmental delay and mental retardation caused by B

 deficient because of their mother’s undiagnosed B deficiency during pregnancy and breast-feeding.

Every pharmacist needs to be aware of the neurologic consequence of B

 deficiency and how it can masquerade as mental illness, multiple sclerosis, Parkinson’s, dementia/Alzheimer’s, seizure disorders, autism, and other neurological disorders.

 deficiency, injectable hydroxocobalamin is the most dependable medication, especially if neurologic symptoms are present. Hydroxocobalamin should replace cyanocobalamin injections because of improved retention, greater availability to cells, and no need for decyanation. Largely unknown, hydroxocobalamin does not cost more than cyanocobalamin, and it is readily available in the United States (distributed by Watson Pharmaceuticals, Inc). Hydroxocobalamin is the form used in infants and children with inborn errors of B

 metabolism and is the preferred form for use in smokers and patients with hepatic and renal disorders.

 tablets (2000 mcg or greater) are the next best alternative and are an effective approach for some patients. Compressed tablets and capsules contain many binders and fillers, making proper absorption difficult.

The Centers for Medicare & Medicaid Services is taking several actions to improve the quality of care in hospitals and reduce the number of “never events”—preventable medical errors that result in serious consequences for the patient. Undiagnosed and untreated B

 deficiency is an unrecognized preventable medical error that needs to be addressed and eliminated. Pharmacists are vital members of the health care team and are needed to spread B

 awareness to both patients and physicians.

Sally Pacholok has been researching cobalamin (vitamin B

) deficiency and practicing emergency nursing for 26 years. She is a frequent radio guest on nationally syndicated talk shows, lecturer, media personality, and co-author of

(2nd edition, 2011)—the winner of the Indie Excellence Award for best health book.

 has been translated into Dutch and Slovenian, and is now being published in India as well. Pacholok’s book was made into a documentary in 2012, and a screenplay has been completed to be made into a movie regarding Pacholok’s lifelong battle to improve the country’s health care system and expose substandard care. Pacholok is working with other countries to improve early diagnosis and treatment worldwide. She aspires to get September designated as B

 Awareness Month. Pacholok is also an educator and public speaker for Superior Source Vitamins. Visit www.B12Awareness.org.

		Dharmarajan TS, Norkus EP. Approaches to vitamin B

 deficiency: early treatment may prevent devastating complications. 

. 2nd ed. Chicago, IL: Quill Driver Books—Linden Publishing; 2011.

 in Modern Nutrition in Health and Disease

. 8th ed. Baltimore, MD: Williams & Wilkins; 1994.

		Zittoun J, Zittoun R. Modern clinical testing strategies in cobalamin and folate deficiency. 

		Antony AC. Megaloblastic anemias. In: Hoffman R, et al. 

Hematology: Basic Principles and Practice.

 3rd ed. Philadelphia, PA: Churchill Livingstone; 2000.

		Andrès E, Federici L, Affenberger S, et al. B

 deficiency: a look beyond pernicious anemia. 

		Healton EB, et al. Neurological aspects of cobalamin deficiency. 

		Johnsen R, Bernersen B, Straume B, Førde OH, Bostad L, Burhol PG. Prevalences of endoscopic and histological findings in subjects with and without dyspepsia. 

		Suter PM, Golner BB, Goldin BR, Morrow FD, Russell RM. Reversal of protein-bound vitamin B

 malabsorption with antibiotics in atrophic gastritis. 

		Hurwitz A, Brady DA, Schaal SE, Samloff IM, Dedon J, Ruhl CE. Gastric acidity in older adults. 

		Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. 

 levels during prolonged treatment with proton pump inhibitors. 

		Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B

		Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor. 

		den Elzen WF, Groeneveld Y, de Ruijter W, et al. Long-term use of proton pump inhibitors (PPIs) and vitamin B

		Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on vitamin B

		de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. 

		Liu KW, Dai LK, Jean W. Metformin-related vitamin B

		Buvat DR. Use of metformin is a cause of vitamin B

		Refsum H, Nurk E, Smith AD, et al. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. 

		Schulz RJ. Homocysteine as a biomarker for cognitive dysfunction in the elderly. 

		Lichtenstein AH, Appel LJ, Brands, et al. American Heart Association Nutrition Committee. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. 

		Malinow MR. Plasma homocyst(e)ine and arterial occlusive diseases: a mini-review. 

		Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. 

		Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B

 from diet and supplements in relation to risk of coronary heart disease among women. 

		Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease.

		Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. 

		Catalano G, Catalano MC, O’Dell KJ, Humphrey DA, Fritz EB. The utility of laboratory screening in medically ill patients with psychiatric symptoms. 

		Silver H. Vitamin B12 levels are low in hospitalized psychiatric patients. 

		Hermesh H, Weizman A, Shahar A, Munitz H. Vitamin B

 and folic acid serum levels in obsessive compulsive disorder. 

		Hector M, Burton J. What are the psychiatric manifestations of vitamin B

		Catalano G, Catalano MC, Roenberg EI, Embi PJ, Embi CS. Catatonia: another neuropsychiatric presentation of vitamin B12 deficiency? 

		Buchman N, Mendelsson E, Lerner V, Kotler M. Delirium associated with vitamin B

		Turner MR, Talbot K. Functional vitamin B

		Castella EB, Valente M, Medeiros de Navarro J, et al. Vitamin B

 deficiency in infancy as a cause of developmental regression. 

		Honzik T, Adamovicova M, Smolka V, et al. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiency—what have we learned? 

		Muhammad R, Fernhoff P, et al. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin—Georgia, 2001. 

		Graham SM, Arvela OM, Wise GA. Long-term neurologic consequences of nutritional vitamin B

		Pearson HA, Vinson R, Smith RT. Pernicious anemia with neurologic involvement in childhood. 

 deficiency presenting with an acute reversible extrapyramidal syndrome. 

 deficiency neurological syndromes: correlation of clinical, MRI and cognitive evoked potential. 

		Matrana MR, Gauthier C, Lafaye KM. Paralysis and pernicious anemia in a young woman. 

		Isajiw G. To peg or not to peg: a case of a hospice referral for vitamin B

		Paul I, Reichard RR. Subacute combined degeneration mimicking traumatic spinal cord injury. 

		Svenson J. Case report: neurologic disease and vitamin B

		Kumar S. Recurrent seizures: an unusual manifestation of vitamin B

		Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. 

		Andrès E. Comment: treatment of vitamin B

 deficiency anemia: oral versus parenteral therapy. 

		Lane LA, Rojas-Fernandez C. Treatment of vitamin B

-deficiency anemia: oral versus parenteral therapy. 

		Hertz H, Kristensen HPØ, Hoff-JØrgensen E. Studies on vitamin B

 retention comparison of retention following intramuscular injection of cyanocobalamin and hydroxocobalamin. 

. 1964;1:5-15. doi: 10.1111/j.1600-0609.1964.tb00001.x.