Neuropsychiatric manifestation of vitamin B12 deficiency: two case reports and literature review

Vitamin B₁₂Deficiency and Depression in the Elderly

Vitamin B₁₂ Deficiency Masquerading as Clozapine-Resistant Psychotic Symptoms in Schizophrenia

Multiple studies have established a higher prevalence of vitamin B12 deficiency in patients who have type 2 diabetes mellitus (T2DM). Metformin is prescribed as the 1st line oral glucose-lowering medication for individuals with T2DM. However, metformin therapy has been linked to vitamin B12 malabsorption, which can result in both biochemical and clinical manifestations of vitamin B12 deficiency. The long-term use of metformin is associated with a significant decrease in vitamin B12 levels, particularly in doses greater than 2000 mg per day over a period of 4 years. Vitamin B12 is a water-soluble vitamin. It acts as a cofactor for enzymes involved in DNA synthesis and neuroprotection at the cellular level. Hence, vitamin B12 deficiency can lead to various clinical consequences, including hematologic abnormalities such as megaloblastic anemia and hypersegmented neutrophil formation, peripheral neuropathy, and progressive axonal demyelination, hyperhomocysteinemia (HHcy). The latest "standards of medical care in diabetes-2017" issued by the American diabetes association recommends periodic assessment of B12 status and, if necessary, the use of B12 replacement therapy in diabetic patients taking metformin. In order to address the vitamin B12 deficiency associated with metformin several therapies are available including prophylactic supplements of calcium and vitamin B12, discontinuation of metformin, and replenishment of vitamin B12 stores through intramuscular or oral therapy. It is important to regularly monitor vitamin B12 levels for at least annually to prevent complications of vitamin B12 deficiency and continue with supplementation if metformin is still being used.

Vacuolar myelopathy: a case report of functional, clinical, and radiological improvement after highly active antiretroviral therapy

Background. Vitamin B12 deficiency is a significant problem, particularly in developing countries. The increasing complexity of the Vitamin B12 molecule, the deficiency condition, causes a complex cell level disorder. The clinical manifestation of vitamin B12 deficiency is anemia, but it is believed that due to the complexity of vitamin B12, there are still other molecular disorders. This study aims to establish the pathway of damage caused by vitamin B12 deficiency in the Nrf2 molecule.
 Methods. An animal experiment involving 12 male Sprague Dawley rats were randomly divided into control and 16-week treatment. There are two research groups, namely the control group and the treatment group. The control group was given a standard diet, while the treatment group was assigned a vitamin B12 deficiency diet. At the end of treatment, The levels of vitamin B12 in the liver tissue and plasma NRF2 were measured.
 Statistical Analysis. Nrf2 and vitamin B12 levels were statistically analyzed using the Student's T-test, and the correlation between vitamin B12 and Hb was analyzed using the Spearmen test. Data that cannot use by Independent T-test were tested using the Mann Whitney test.
 Results/Conclusion. There was no significant difference between the control and treatment groups on plasma Nrf2 levels (4.02 ± 0.59 pg/ml vs 3.34 ± 0.55 pg/ml; p = 0.07) and tissue vitamin B12 (0.0035 ± 0.0016 µg/ml vs 0.0030 ± 0.0006 µg/ml ; p = 0.8).
 Keywords: Nrf2 Plasma, Defisiensi, Vitamin B12

A 72-year-old man with hypothyroidism and type 2 diabetes sought care for a 3-year history of slowly progressive, ascending lower limb paresthesias and imbalance. Three months earlier, he noted subacute onset of finger numbness and substantial worsening of imbalance with infrequent falls. He also had a 1-year history of progressive visual decline that persisted despite cataract surgery. Additional symptoms included intermittent light-headedness and confusion. Laboratory evaluations showed a decreased hemoglobin value and an increased mean corpuscular volume. Macrocytic red blood cells were noted on a peripheral blood smear. Serum vitamin B12 level was less than 70 ng/L. Levels of plasma homocysteine and serum methylmalonic acid were markedly increased to 375 µmol/L and 143 nmol/L, respectively. Serum copper level was normal. Serum parietal cell antibodies were increased to 46 U, and intrinsic factor antibodies were absent. Serum gastrin was markedly increased. The clinical presentation in this patient suggested a myeloneuropathy. His vitamin B12 level was undetectable and accompanied by a macrocytic anemia and increased methylmalonic acid and homocysteine levels. Even though intrinsic factor antibodies were negative, the clinical picture was supportive of subacute combined degeneration in the setting of pernicious anemia. The patient was started on vitamin B12 replacement. At 6-month follow-up he had striking improvement in gait and vision. The light-headedness and confusion were no longer present. His examination was remarkable only for mild impairment, with tandem gait and a slightly positive Romberg sign. The lower limb reflexes were reduced. Impaired position perception at the toes persisted, but vibration perception in the lower limbs improved. Laboratory investigations showed normalization of the hemoglobin, vitamin B12, methylmalonic acid, and homocysteine levels. The serum gastrin level had improved but was still increased at 742 pg/mL. The best-characterized neurologic manifestations of vitamin B12 deficiency include myelopathy and myeloneuropathy. Autonomic neuropathy, optic neuropathy, and neuropsychiatric manifestations have also been reported. Neurologic manifestations may occur without evidence of the characteristic hematologic derangement, megaloblastic anemia. Macrocytosis or hypersegmented neutrophils on peripheral blood smear may be clues.

Metformin can result in vitamin B(12) deficiency, potentially leading to complications such as neuropathy. Annual monitoring of vitamin B(12) has been suggested; however, it is unknown whether current practice reflects this recommendation. To identify vitamin B(12) monitoring patterns in patients on long-term, high-dose metformin. Secondary objective was to determine the frequency of new vitamin B(12) deficiency, anemia, and neuropathy documented after initiation of high-dose metformin. Electronic medical records of veterans treated at the Veterans Affairs Maryland Healthcare System with high-dose metformin (≥2000 mg/day) as of November 1, 2010, were reviewed. Data regarding metformin treatment, vitamin B(12) measurements, and documentation of vitamin B(12) deficiency, cyanocobalamin supplementation, anemia, and neuropathy were collected. Subjects treated with metformin for less than 1 year or those with documented peripheral neuropathy, megaloblastic anemia, vitamin B(12) deficiency, or a condition associated with vitamin B(12) malabsorption prior to metformin initiation were excluded. Subjects (N = 235) had a mean metformin dose of 2050 mg/day and mean duration of treatment of 5.2 years. Sixty percent did not have vitamin B(12) measured. Of subjects receiving metformin for 10 years or more, nearly half (46%) never had vitamin B(12) measured. New documentation of vitamin B(12) deficiency or cyanocobalamin supplementation was found in 5.5% of the population, and anemia was found in 12%. Of the 14% with new neuropathy, 42% did not have vitamin B(12) measured. Vitamin B(12) was not routinely monitored in patients on high-dose metformin, even in those at highest risk (≥10 years of therapy), or in those with potential manifestations of vitamin B(12) deficiency (neuropathy). Cases of vitamin B(12) deficiency and resulting anemia or neuropathy may be undiagnosed and untreated because of lack of monitoring. Prospective studies examining the effect of increased vitamin B(12) monitoring on identification and treatment of vitamin B(12) deficiency in patients on metformin are warranted.

Nutritional vitamin B₁₂ deficiency in infants may occur because the maternal diet contains inadequate animal products. Clinical presentations of the infants who had nutritional vitamin B₁₂ deficiency were analyzed in this study. Patients with nutritional vitamin B₁₂ deficiency were enrolled in the study between 2003 and 2010. The diagnosis was based on a nutritional history of mothers and infants, clinical findings, hematological evaluation, and low level of serum vitamin B₁₂. Thirty children aged 1 - 21 months constituted the study group. Poverty was the main cause of inadequate consumption of animal products of the mothers. All infants had predominantly breastfed. The most common symptoms were developmental delay, paleness, apathy, lethargy, anorexia, and failure to thrive. Hematological findings were megaloblastic anemia (83.3 %), thrombocytopenia (30 %), and severe anemia (13.3 %). All of the mothers had low serum B₁₂ levels; eight of them had megaloblastic anemia. The unusual clinical manifestations of vitamin B₁₂ deficiency may also be seen apart from neurological and hematological findings. Nutritional vitamin B₁₂ deficiency due to maternal deficiency might be a serious health problem in infants. Therefore, screening and supplementation of pregnant and lactating women to prevent infantile vitamin B₁₂ deficiency should be considered.

Aging is associated with increased incidence and prevalence of chronic diseases, and the role of micronutrient deficiencies in the development of diseases is important. Vitamin B12 and folic acid deficiency are often associated with increased homocysteine (Hcy) levels. In our study, we aimed to detect the relationship between Hcy levels by examining vitamin B12 and folate levels in the healthy elderly Turkish population. In our study, the levels of vitamin B12, folate, and Hcy were analyzed and examined in 657 elderly and 642 non-elderly healthy adults admitted to the Internal medicine outpatient clinic. Vitamin B12 <200 pg/mL was considered to be deficient. Folic acid <5 ng/mL was considered a deficiency, and Hcy>15 µmol/L was considered a high concentration. Vitamin B12 levels were detected to be significantly decreased in the elderly group compared to the non-elderly group, while Hcy levels were marked to be increased (p<0.05). Women had lower levels of Hcy and higher levels of vitamin B12 and folate (p<0.05). There was a moderate negative correlation between Hcy and vitamin B12 levels in the elderly group (r=-0.576; p<0.0001), and a moderate negative correlation between Hcy and folate (r=-0.510; p<0.0001). In the elderly group, 21.5% had vitamin B12 deficiency and 21.6% had folate deficiency. An increase in Hcy level was detected in 54.8%. Those with Hcy levels >15 µmol/L had vitamin B12 deficiency in 38.4%, folate deficiency in 36.0%, and both vitamin B12 and folate deficiency in 15.8%. Our results indicate that it is important to measure vitamin B12, folate, and Hcy in the elderly, given the significant growth in the elderly population. We predict that vitamin B12 and folate supplementation, when necessary, may be beneficial in preventing some common diseases in the elderly and increasing the standard of life of the elderly and their relatives.

Alterations in the level of neurotransmitters are evident in patients with major depressive disorder (MDD). Vitamin B12 mediates the synthesis of neurotransmitters, and hence, vitamin B12 deficiency could be associated with depression. To assess the levels of serum vitamin B12, homocysteine (Hcy), and haematological profiles in patients of MDD. Fifty-nine patients with MDD were recruited based on ICD-10 criteria. Severity of depression was assessed by HAM-D scale. Vitamin B12, Hcy levels, and haematological profiles were analysed. Vitamin B12 was deficient or depleted in all patients with MDD. The median level of vitamin B12 in serum was 164.2 pg./ml and significantly lower in patients with severe MDD. The mean value of Hcy was 18.34 μmol/L, which was high compared to the normal reference range. The red cell distribution width (RDW-CV) varied significantly between the three groups of MDD patients. Patients consuming non-vegetarian food had a significantly higher median value of serum vitamin B12. Vitamin B12 deficiency is found in patients with MDD and varies inversely with severity of MDD. Hcy is found to be higher in patients with MDD. The manifestation of depressive symptoms precedes the more commonly known haematological manifestations of vitamin B12 deficiency in this study.

ABSTRACTIn developed countries, vitamin B12 (cobalamin) deficiency usually occurs in children, exclusively breastfed ones whose mothers are vegetarian, causing low body stores of vitamin B12. The haematologic manifestation of vitamin B12 deficiency is pernicious anaemia. It is a megaloblastic anaemia with high mean corpuscular volume and typical morphological features, such as hyperlobulation of the nuclei of the granulocytes. In advanced cases, neutropaenia and thrombocytopaenia can occur, simulating aplastic anaemia or leukaemia. In addition to haematological symptoms, infants may experience weakness, fatigue, failure to thrive, and irritability. Other common findings include pallor, glossitis, vomiting, diarrhoea, and icterus. Neurological symptoms may affect the central nervous system and, in severe cases, rarely cause brain atrophy. Here, we report an interesting case, a 12-month old infant, who was admitted with neurological symptoms and diagnosed with vitamin B12 deficiency.

BackgroundVitamin B12 (cobalamin, cbl) deficiency in children is rare and may occurs in exclusively breast fed infants of mothers on vegetarian or vegan diet with lack of appropriate supplementation. The clinical manifestation of vitamin B12 deficiency include neurological disorders, megaloblastic anemia and failure to thrive. Routine and commonly used laboratory tests such as cell blood count (CBC) or serum vitamin B12 level are sufficient for appropriate diagnosis. Typical therapy is based on intramuscular cobalamin injections. Early diagnosis and early onset of treatment are crucial factors for long-term prognosis of patients as the duration of deficiency may be correlated with the development of long lasting changes in the nervous system.The purpose of this article is to present influence of maternal vitamin B12 deficiency as a cause of infant psychomotor retardation.Case presentationWe report the case of a 7 months old girl whose parents sought medical advice due to pathological somnolence and developmental regression of their daughter with onset approximately 2 months prior to the visit. Following several diagnostic tests it was determined that the infant’s symptoms were due to vitamin B12 deficiency which was secondary to the mother’s latent Addison-Biermer disease. Apart from neurological symptoms the infant also showed megaloblastic anemia which is typical to cobalamin deficiencies. Intramuscular vitamin B12 supplementation resulted in instant improvement of the patient’s general condition and blood morphology. Unfortunately, psychological examination indicated long-term psychomotor retardation due to delayed diagnosis of B12 deficiency.ConclusionsVitamin B12 levels should be considered during differential diagnosis of neurological symptoms in exclusively breast-fed infants especially if they co-exist with megaloblastic anemia and psychomotor retardation.

Background: Vitamin B12 deficiency in pregnant women is an important health issue which not only affects mothers but also their infants. The aim of this study is to reveal the frequency of vitamin B12 and folic acid deficiency in pregnant women and their newborn babies, to evaluate the relationship between maternal and neonatal vitamin B12 and folic acid levels, and to determine the risk factors for vitamin B12 deficiency. Materials and Methods: This prospective study included 600 pregnant women (gestational age: 38-42 weeks) who presented to obstetrics departments in Şanlıurfa Province and their newborn infants without perinatal complication (birth weight≥2500 g). The lower limit for vitamin B12 was defined as 200 pg/mL. Data regarding age, number of child, medication, comorbid disease or being vegetarian or not were recorded in all mothers. Results: Vitamin B12 deficiency was found in 73.8% of the included pregnant women, and folic acid deficiency was found in 10.3%. Again, 70.5% of newborn babies were found to have vitamin B12 deficiency and 3.7% to have folic acid deficiency. It was concluded that vitamin B12 levels in newborn babies were related to maternal levels. Conclusions: As a result, it has been shown that a significant portion of newborns in Turkey have vitamin B12 deficiency. Vitamin B12 levels were quite low in mothers who gave birth recently. The deficiency of vitamin B12, which plays a major role in brain development upon intrauterine period, is a preventable cause of neurological deficit. Thus, it is highly important to screen and treat vitamin B12 deficiency before onset of clinical symptoms. We believe that our study is beneficial in this regard.

We were interested to read the article by Wang et al. on a cross-sectional study of the effects of vitamin B12 deficiency on sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) in 52 patients with obsessive-compulsive disorder (OCD) [1] .Vitamin B12 levels were reduced in OCD patients and sleep disturbance scores were elevated in OCD patients [1] .Vitamin B12 deficiency has been associated with severe OCD symptoms and poor sleep quality [1] .The study is appealing, but some points should be discussed.The first point is that sleep quality depends not only on vitamin B12 serum levels and the severity of OCD, but on a host of intrinsic and extrinsic causal factors [2] .The intrinsic factors that determine sleep quality include personality type, personal ability to relax, the level of acute and chronic stress, the balance between sympathetic and parasympathetic tone, hormonal balance, the type and intensity of social interactions, strategies for processing daily experiences, the level of physical activity, genetic background and comorbidities (e.g.central nervous system disorders).e.g.diseases of the central nervous system (e.g.epilepsy, headaches, pituitary dysfunction, Parkinson's disease, restless legs syndrome, sleep apnoea syndrome, psychiatric illnesses), lung diseases (e.g.asthma, infections, chronic bronchitis, COPD), cardiac diseases (e.g.heart failure, malignant ventricular arrhythmias, high blood pressure), chronic or acute gastrointestinal diseases (e.g.nausea, gastritis, reflux, diarrhoea, constipation, flatulence), chronic or acute infectious diseases (e.g.dental foci, urinary infections), orthopaedic diseases (e.g.pain in the musculoskeletal system), metabolic diseases (e.g.hypoglycaemia), immunological diseases (e.g.arthritis, colitis, Crohn's disease), occult malignancies, and a number of non-specific abnormalities such as pain, fever, acidosis/alkalosis, or autonomic disturbances.External factors that affect sleep quality include noise in the bedroom (e.g.partner's snoring, pets, air conditioning, refrigerator, telephone) or outside the bedroom (e.g.animals, bells, cars, garbage collection, neighbours, airplanes, emergency vehicle horns), the brightness of the bedroom, the temperature, the humidity, the level of electrosmog in the immediate area, the air quality, vibrations, the presence or absence of insects or other animals in the bedroom, the relationship with neighbours in the apartment next door, eating habits (e.g.quantity, timing and quality of food and liquids), current medication (e.g.anti-seizure medication), hypnotics, sedatives, neuroleptics, antidepressants, illegal drugs, alcohol, coffee, cola, black tea or Red Bull [2] .It is therefore essential to rule out all these possible causes of sleep deprivation before attributing it to vitamin B12 deficiency or OCD.The second point is that vitamin B12 deficiency is more often manifested by other symptoms and signs than sleep deprivation, which were not reported in the 52 patients included.Common manifestations of vitamin B12 deficiency include macrocytic anaemia, sensory disturbances, muscle weakness, memory problems, cognitive changes, depression, anxiety, confusion, impaired comprehension and judgment, dementia, dizziness and impaired coordination [3] .Macrocytic anaemia itself manifests as headaches, visual disturbances, rapid breathing or shortness of breath, palpitations, loss of appetite, a sore or red tongue, sometimes with mouth ulcers, indigestion, diarrhoea, and feeling weak or tired [3] .In summary, this interesting study has limitations that put the results and their interpretation into perspective.Removing these limitations could strengthen the conclusions and reinforce the message of the study.All outstanding questions must be clarified before readers can uncritically accept the study's conclusions.Before sleep deprivation can be attributed to low serum levels of vitamin B12, all other causes of sleep disorders must be thoroughly ruled out.

Utility and Patterns of Vitamin B12 and Folate Testing in Patients with Isolated Thrombocytopenia