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BACKGROUND Patients with epilepsy who use anticonvulsants frequently show low levels of folate and vitamin B12 and high levels of homocysteine. Patients with bipolar disorder use some anticonvulsants as mood stabilisers.br/AIM: To determine whether some anticonvulsants lower folate and vitamin B12 and raise homocysteine levels.br/METHOD: Systematic literature search to determine the relation between the anticonvulsants valproic acid, carbamazepine, lamotrigine and topiramate on the one hand and blood levels of folate, vitamin B12 and homocysteine on the other hand.br/RESULTS: The vast majority of studies in adults and children showed a correlation between use of anticonvulsant carbamazepine and decrease of the folate level. Hardly any of the studies that examined the effect of valproic acid on folate levels found a correlation. There was next to no evidence of a correlation between the use of carbamazepine and a low vitamin B12 level in adults or children. In adults and children the use of valproic acid was found to correlate with a higher vitamin B12 level. Nearly all studies found an increase in homocysteine in adults and children using carbamazepine. Among the users of valproic acid, it was only children who showed a clear association with a rise in homocysteine level. The results for adults were contradictory. We were unable to make any clear statement about topiramate or lamotrigine because there have been very few publications about these anticonvulsants.br/CONCLUSION: In adults and children with epilepsy use of carbamazepine is associated with a decrease of folate, valproic acid with a rise in the vitamin B12 level, and carbamazepine with an increase in homocysteine. Valproic acid showed only in children an association with the rise of the homocysteine level. Psychiatrists may find it advisable to control the levels of folate and homocysteine in adults and children who are taking carbamazepine and to measure homocysteine level in children taking valproic acid.

Nitrous oxide, laughing gas, is used as a party drug to achieve a euphoric effect. It has been gaining popularity in recent years and is considered a relatively innocent substance. Nitrous oxide is known to cause subacute degeneration of the spinal cord by inactivation of active vitamin B12. Vitamin B12 plays an essential role in the synthesis of myelin. Hence, vitamin B12 deficiency can lead to degeneration of the dorsal and lateral columns of the spinal cord. Polyneuropathy is a less known complication. We present a 17-year-old woman and a 19-year-old man with subacute axonal polyneuropathy caused by laughing gas abuse. Abstinence of laughing gas and treatment with intramuscular and oral vitamin B12 suppletion respectively have led to improvement of their symptoms. Our cases demonstrate a less-known but treatable complication of laughing gas.

Ataxia due to a vitamin B12 deficiency can be a cause of falls in elderly patients.An 86-year-old woman presented with functional decline and gait problems. She had been falling regularly. The patient's gait was ataxic and she was unable to stand without support. Additional laboratory tests showed a volume macrocytic blood picture and a severe vitamin B12 deficiency, as well as antibodies directed against intrinsic factor and parietal cells. We diagnosed her as having falls and ataxia caused by vitamin B12 deficiency. Vitamin B12 supplementation resulted in improvement of gait.Ataxia due to vitamin B12 deficiency is a rare problem which in 20-25% of cases is not accompanied by anaemia. Prompt treatment reduces the chance of neurological sequelae.

A 28-year-old female vegetarian was referred to a specialist in internal medicine with persistent iron deficiency. Laboratory analysis revealed microcytic anaemia with low ferritin levels but normal total vitamin B12 levels. The red blood cell distribution width, however, showed a very wide variation in red blood cell sizes, indicating a coexisting vitamin B12 deficiency, which was confirmed by the low concentration of active vitamin B12. Another patient, a 69-year-old woman with a history of previous gastric surgery and renal insufficiency as a complication of diabetes mellitus, was suspected to be deficient in vitamin B12, as she had low total vitamin B12 levels and an accumulation of methylmalonic acid and homocysteine in her blood. Testing the total concentration of vitamin B12 alone has insufficient diagnostic accuracy and no accepted gold standard is available for diagnosing vitamin B12 deficiency. With the development of newer tests, such as measuring holotranscobalamin II (concentration of active vitamin B12), atypical and subclinical deficiency states can be recognized. A new approach to diagnosing vitamin B12 deficiency is presented, based upon these 2 case descriptions.

A manic episode in old age presents a diagnostic challenge to the clinician due to the different symptomatology often difficult to distinguish from delirium, dementia, agitated depression and psychosis. To complicate matters further, a first episode of mania in later life is very often based on underlying physical and cerebral pathology ('secondary mania'). Many causes of 'secondary mania', including neurological, systemic or endocrine diseases, infections, intoxications, apnoea, post-thoracic surgery and vitamin B12 deficiency have been described to date, but there have been no reports on subdural haematomas in this context. However, the elderly are more prone to subdural haematomas following head trauma than younger patients. We present two case reports of older patients with a first manic episode in later life probably caused by subdural haematomas. A first episode of mania in later life always requires thorough assessment of the patient to determine physical and cerebral pathology.

Vitamin B12 deficiency occurs in 5-10% of the Dutch population. Serum vitamin B12 levels should be determined in patients with haematological or neurological disorders such as megaloblastic anaemia or neuropathy, and in patients with risk factors for vitamin B12 deficiency such as atrophic gastritis or intrinsic factor-deficiency. The aim of this article was to explicate the data from the literature on the efficacy of oral versus parenteral vitamin B12 supplementation. Two randomised, controlled trials have shown that oral supplementation of 1000-2000 microg/day of vitamin B12 is equally effective in raising serum vitamin B12 levels as a standard parenteral dosing schedule. Moreover, the effects on clinical endpoints were comparable. Several dose-finding studies have been performed, showing that the minimal effective oral dose is 647-1032 microg/day. It is recommended that patients with vitamin B12 deficiency be prescribed 1000 microg/day vitamin B12 orally, unless they have problems with swallowing or treatment compliance or have severe clinical symptoms. In that case parenteral administration is indicated.

Two infant boys of 7 and 12 months respectively who presented with symptoms of failure to thrive and developmental delay were diagnosed with vitamin B12 deficiency. This deficiency is a rare condition in infants living in developed countries. It does occur, however, in infants who are breastfed by mothers with an inadequate diet. Both of the children studied were breastfed by vegetarian mothers. Following vitamin suppletion, both children showed signs of recovery. The importance of considering vitamin deficiencies in similar infants presenting with failure to thrive is emphasized. Moreover, maternal dietary habits in breastfed children should be checked. To prevent irreversible neurological damage, early recognition of any nutritional deficiencies is important.

Vitamin B12 (cobalamin) deficiency is a common disorder with potential irreversible haematological and neurological consequences. Currently used diagnostic tests such as the evaluation of serum vitamin B12 and the Schilling test are insufficient, e.g. the positive predictive value of a low serum vitamin B12 level for actual vitamin B12 deficiency (i.e. tissue deficiency) is low. Insufficient availability of vitamin B12 will lead to the accumulation of methylmalonic acid and homocysteine in the body. Nearly all patients with vitamin B12 deficiency also have substantially increased levels of methylmalonic acid and homocysteine. New tests of serum methylmalonic acid and homocysteine are highly sensitive for vitamin B12 deficiency and may obviate the need for the somewhat cumbersome Schilling test.

A 57-year-old Dutch man presented with weight loss and fatigue 6 months after a visit to West Papua, when he had suffered from serious diarrhoea. Macrocytic anaemia and vitamin B12 deficiency were diagnosed. A gastroduodenoscopy with biopsies of the small intestine was performed revealing no macroscopic abnormalities but partial villous atrophy was found microscopically, suggesting tropical sprue or coeliac disease. Antibodies against endomysium and tissue transglutaminase were negative, ruling out coeliac disease. The patient was successfully treated with vitamin B12, folic acid and doxycycline. This case shows that tropical sprue should be considered in the differential diagnosis of chronic diarrhoea in patients with a history of travel in tropical regions. The most frequent medical problem that travelers to the tropics experience is diarrhoea with an incidence of 30%. A small proportion of these patients eventually present with chronic diarrhoea. At that moment, the relation to their previous travelling may not be immediately clear. One of the causes of this chronic diarrhoea to be considered is tropical sprue.

Elevated levels of serum cobalamin may be a sign of a serious, even life-threatening, disease. Diseases such as chronic myeloid leukaemia, promyelocytic leukaemia, polycythaemia vera and hypereosinophilic syndrome are often accompanied by markedly elevated levels of cobalamin in the blood. A rise in the serum cobalamin concentration is one of the diagnostic criteria for polycythaemia vera and hypereosinophilic syndrome. In haematological disorders, the increase in circulating cobalamin levels is predominantly caused by enhanced production of haptocorrin. Several liver diseases such as acute hepatitis, cirrhosis of the liver, hepatocellular carcinoma and metastatic liver disease can also be accompanied by an increase in circulating cobalamin. In liver diseases, the increase in cobalamin is predominantly caused by cobalamin release during hepatic cytolysis and/or through decreased clearance of circulating cobalamin by the affected liver. Liver disorders are not an indication for determining the serum cobalamin concentration. However, a coincidentally observed elevated serum cobalamin concentration is reason for further investigation.

Four patients, three women aged 49, 47 and 74 years, and a man aged 64 years, presented with progressive sensory deficit, pyramidal tract symptoms and postural instability. Tests revealed megaloblastic anaemia and low vitamin B12 levels. Two of the female patients had undergone gynaecological surgery with nitrous oxide anaesthesia, and the male patient had undergone a gastric resection. Subacute combined degeneration of the spinal cord is a neurological disease based on vitamin B12 deficiency. It involves the posterior and lateral columns of the spinal cord, and sometimes the peripheral nerves, the optic nerve or the brain. An MRI scan of the cervical cord revealed abnormalities for three of the four patients. Following parenteral supplementation of vitamin B12, the symptoms and the MRI abnormalities either disappeared or significantly improved. Vitamin B12 deficiency can cause subacute combined degeneration of the cord by interfering with myelin synthesis. As vitamin B12 deficiency is caused by malabsorption in the gastrointestinal tract, oral supplementation is insufficient. It is essential to recognise this treatable disease at an early stage, and not to reject the possible diagnosis if the MRI findings are abnormal. Simple blood tests can lead to the diagnosis and to effective treatment.

Autoimmune type 1 diabetic patients show a high prevalence of thyroid peroxidase (TPO), parietal cell (PCA), anti-adrenal (AAA) and anti-endomysium antibodies (EmA-IgA), which may be accompanied with clinical disease. We studied the grade of associated organ-specific autoimmunity and the pattern of prevalence of TPO and PCA by age, gender, duration, age at onset of diabetes, and HLA DR haplotype in 783 type 1 diabetic patients, consisting of 286 children and 497 adults (M/F: 389/394), with a mean diabetes duration of 11.8 +/- 10.1 years. The relationship between islet cell (ICA), glutamic acid decarboxylase-65 (GADA) and thyro-gastric auto-antibodies was also investigated. TPO were present in 21.6%, PCA in 18.3%, AAA in 2.2% and EmA-IgA in 2.1% of the patients. The presence of TPO is determined by gender (p0.0001), age (P = 0.0008), and PCA status (p = 0.029). The presence of PCA is only influenced by age (p = 0.0027) and TPO status (p = 0.0155). Patients with ICA+or = 3 years had a higher prevalence of thyro-gastric auto-antibodies (p = 0.045) than ICA- subjects. Also, PCA were more prevalent in GADA+ than GADA- patients (p = 0.005). We observed an association between HLA DR5 and PCA (p = 0.0012). Dysthyroidism was more prevalent in TPO+ than TPO- subjects (p0.0001). PCA+ subjects had a higher prevalence of iron deficiency anaemia (p = 0.0099) and pernicious anaemia (p0.0001) than PCA- patients. In conclusion, particularly type 1 diabetic patients with persisting ICAor = 3 years or with GADA, show a high prevalence of thyro-gastric auto-antibodies. Based on antibody-positivity we observed a high prevalence of thyroid disease, iron deficiency anaemia and pernicious anaemia, which can compromise the health of the diabetic patient.

In recent years research was done to elucidate the relation between an increased homocysteine concentration and arterial as well as venous thrombosis. Several case control studies showed that an elevated homocysteine concentration is an independent risk factor for primary and secondary venous thromboembolism. It is not clear whether lowering homocysteine levels by administration of folic acid, whether or not in combination with vitamin B12 and vitamin B6, decreases the risk of vascular events. Randomized secondary prevention trials are being conducted at this moment. It is recommended to await the results of these trials before screening for and treating of individuals with hyperhomocysteinaemia.

Laboratory investigations were performed in group of 60 psychogeriatric patients on their admission into hospital, in order to elucidate the interdependence of erythropoiesis and the concentrations of albumin and several vitamins in blood or serum. The results of albumin concentration and ETK activity show that 47 out of 60 the patients (= 78%) are in a poor nutritional condition. In 13 of these 47 subjects (= 28%) deficiency with respect to vitamin B12 or folic acid is presumed from decreased serum concentrations. In 6 of the 47 patients in poor nutritional condition (= 13%) decreased reticulocyte concentrations are shown. Further evaluation of differences between the respective subgroups revealed significantly reduced ETK activity and lower reticulocyte concentrations in the group of delirium patients compared to the other patients groups and to the reference group.

Low serum vitamin B12 levels and vitamin B12 deficiencies are frequently found in the elderly. The full syndrome of a vitamin B12 deficiency is rather simple to diagnose. The large applicability of the vitamin B12 assay also gives rise to many probably incomplete features. Low/low-normal vitamin B12 levels in screening procedures raise uncertainty whether this finding represents deficiency and should be followed by supplementation. In this paper the occurrence of low serum levels of vitamin B12 are discussed. To assess the clinical relevance of low/low-normal outcomes supplementary diagnostic procedures will be needed. Within this scope we illustrate the d.o.s.-test and the MMA-assay. Especially the latter will probably provide more answers to the treatment question. Systematic research is needed to clarify this issue. Meanwhile supplementation of all low and low-normal outcomes of the B12-assay seems the best answer.

Vitamin B12 deficiency is an uncommon disorder in a prosperous western country. In two children a nutritional vitamin B12 deficiency was observed. The first was a 2-year-old girl with neurodevelopmental regression and macrocytic anaemia, a result of a combination of a maternal vitamin B12 deficiency and inadequate feeding after birth. The second patient was a 14-year-old adipose girl with severe polyneuropathy and mild macrocytic anaemia as a result of a nutritional vitamin B12 deficiency. In her case the deficiency resulted from a bizarre feeding pattern. She turned out to be the victim of child abuse. It is concluded that even in a prosperous western country like the Netherlands vitamin B12 deficiency in children can develop as a result of an inadequate feeding pattern. It can lead not only to macrocytic anaemia but also to severe neurological abnormalities.

The clinical course is described of a 69-year-old patient with a malabsorption syndrome since her stay in Indonesia. Besides chronic diarrhoea and weight loss she suffered from malnutrition and had partial villous atrophy. Coeliac disease was considered in the differential diagnosis but considering the endemic appearance of postinfectious tropical sprue (PTS) in Indonesia and the extreme vitamin B12 deficiency our patient experienced, PTS appeared more likely. A good response to the therapy prescribed for PTS confirmed the diagnosis.

In order to determine the relevance of low vitamin B12 concentration in elderly persons (greater than 65 years), serum vitamin B12 levels were measured in 292 consecutive patients upon their admission to a geriatric ward. Eighty (27%) of them were anaemic (haemoglobin less than or equal to 7.14 mmol/l). The vitamin B12 concentration was not statistically different between males and females, nor between the anaemic and non-anaemic groups. Twenty-two patients (7.5%) had a low vitamin B12 level; of these, 10 had a haemoglobin concentration higher than 7.14 mmol/l and a mean corpuscular volume lower than 98 fl. In addition, serum vitamin B12 levels were also measured in 178 consecutive anaemic patients hospitalized in the same ward. Seventeen (9.5%) of them had a vitamin B12 deficiency although in 11 the MCV was lower than 98 fl. Hypersegmented polymorphonuclear leukocytes were rarely observed in the peripheral blood smear. Pernicious anaemia could only be diagnosed in 1 patient. Serum vitamin B12 estimation may be necessary to detect vitamin B12 deficiency but a low level requires additional diagnostic investigation.

This case report concerns a patient with a vitamin B12 deficiency and a normal Schilling test, who had macrocytosis of many years' duration and finally polyneuropathy. All known causes of a vitamin B12 deficiency were excluded. When the Schilling test was performed with egg consumption, excretion of vitamin B12 was clearly diminished. It appears highly likely that this vitamin B12 deficiency developed as a result of malabsorption of protein-bound vitamin B12.

This article, which is the second in a series of two articles, discusses available scientific information on the nutritional status of infants and preschool children on alternative diets with regard to calcium, iron, vitamin B12 and D. Some favourable aspects of alternative food habits in such children are also mentioned. Most studies report low intakes of vitamin D and in vegan and macrobiotic children also of calcium and vitamin B12, but it cannot be excluded that some alternative sources of these nutrient may have been missed. Deficiencies have been described for vitamin D and B12 but the evidence is often unconvincing. For example, exposure to sunlight has not been measured in most of the studies on rickets. From the literature available, it would appear that there is a need for longitudinal research on the growth and development of alternatively fed infants and preschool children and for information on the nutrient composition of alternative foods.