Infantile encephalopathy due to vitamin deficiency in industrial countries.

INTRODUCTION: Severe avitaminosis causing life-threatening conditions in the infantile age group is extremely uncommon and has been reported in babies with malabsorption receiving prolonged inadequate vitamin supplements. CASE REPORTS: We report two infants who presented with neurological deterioration. Immediate work-up and treatment for infectious and inborn metabolic disorders were initiated and the diagnosis, made with a few days delay, was prolonged avitaminosis of thiamine (B1) and cobalamin (B12). B1 deficiency was suspected when further neurological deterioration was observed during administration of intravenous fluids containing glucose in an infant with high lactate levels in the cerebrospinal fluid. High transketolase activity that normalized after thiamine treatment and the findings in the MRI and MRS of the brain confirmed the suspected diagnosis. B12 deficiency was suspected in an infant of a strict vegetarian mother who presented with neurological deterioration and severe megaloblastic anemia. The diagnosis was confirmed when low serum levels of B12 and methylmalonic aciduria were detected and treatment with B12 resulted in normalization of urinary methymalonic acid. CONCLUSION: Avitaminosis, even in industrialized countries, should be considered in an atypical age group with no known risk factors. Early diagnosis and prompt treatment may accomplish a quick recovery with fewer sequelae.

Thalamo-striatal diffusion reductions precede disease onset in prion mutation carriers.

Human prion diseases present substantial scientific and public health challenges. They are unique in being sporadic, infectious and inherited, and their pathogen is distinct from all other pathogens in lacking nucleic acids. Despite progress in understanding the molecular structure of prions, their initial cerebral pathophysiology and the loci of cerebral injury are poorly understood. As part of a large prospective study, we analysed early diffusion MRI scans of 14 patients with the E200K genetic form of Creutzfeldt-Jakob Disease, 20 healthy carriers of this mutation that causes the disease and 20 controls without the mutation from the same families. Cerebral diffusion was quantified by the Apparent Diffusion Coefficient, and analysed by voxel-wise statistical parametric mapping technique. Compared to the mutation-negative controls, diffusion was significantly reduced in a thalamic-striatal network, comprising the putamen and mediodorsal, ventrolateral and pulvinar thalamic nuclei, in both the patients and the healthy mutation carriers. With disease onset, these diffusion reductions intensified, but did not spread to other areas. The caudate nucleus was reduced only after symptomatic onset. These findings indicate that cerebral diffusion reductions can be detected early in the course of Creutzfeldt-Jakob Disease, and years before symptomatic onset in mutation carriers, in a distinct subcortical network. We suggest that this network is centrally involved in the pathogenesis of Creutzfeldt-Jakob Disease, and its anatomical connections are sufficient to account for the common symptoms of this disease. Further, we suggest that the abnormalities in healthy mutation-carrying subjects may reflect the accumulation of abnormal prion protein and/or associated vacuolation at this time, temporally close to disease onset.

Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula.

OBJECTIVE: Between October and November 2003, several infants with encephalopathy were hospitalized in pediatric intensive care units in Israel. Two died of cardiomyopathy. Analysis of the accumulated data showed that all had been fed the same brand of soy-based formula (Remedia Super Soya 1), specifically manufactured for the Israeli market. The source was identified on November 6, 2003, when a 5.5-month-old infant was admitted to Sourasky Medical Center with upbeat nystagmus, ophthalmoplegia, and vomiting. Wernicke's encephalopathy was suspected, and treatment with supplementary thiamine was started. His condition improved within hours. Detailed history revealed that the infant was being fed the same formula, raising suspicions that it was deficient in thiamine. The formula was tested by the Israeli public health authorities, and the thiamine level was found to be undetectable (<0.5 microg/g). The product was pulled from the shelves, and the public was alerted. Thiamine deficiency in infants is very rare in developed countries. The aim of this study was to report the epidemiology of the outbreak and to describe the diagnosis, clinical course, and outcome of 9 affected infants in our care. METHODS: After the index case, an additional 8 infants were identified in our centers by medical history, physical examination, and laboratory testing. The group consisted of 6 male and 3 female infants aged 2 to 12 months. All were assessed with the erythrocyte transketolase activity assay, wherein the extent of thiamine deficiency is expressed in percentage stimulation compared with baseline (thiamine pyrophosphate effect [TPPE]). Normal values range from 0% to 15%; a value of 15% to 25% indicates thiamine deficiency, and >25% indicates severe deficiency. Blood lactate levels (normal: 0.5-2 mmol/L) were measured in 6 infants, cerebrospinal fluid lactate in 2 (normal: 0.5-2 mmol/L), and blood pyruvate in 4 (normal: 0.03-0.08 mmol/L). The diagnostic criteria for thiamine deficiency were abnormal transketolase activity and/or unexplained lactic acidosis. Treatment consisted of intramuscular thiamine 50 mg/day for 14 days combined with a switch to another infant formula. RESULTS: Early symptoms were nonspecific and included mainly vomiting (n = 8), lethargy (n = 7), irritability (n = 5), abdominal distension (n = 4), diarrhea (n = 4), respiratory symptoms (n = 4), developmental delay (n = 3), and failure to thrive (n = 2). Infection was found in all cases. Six infants were admitted with fever. One patient had clinical dysentery and group C Salmonella sepsis; the others had mild infection: acute gastroenteritis (n = 2); upper respiratory infection (n = 2); and bronchopneumonia, acute bronchitis, and viral infection (n = 1 each). Two infants were treated with antibiotics. Three infants had neurologic symptoms of ophthalmoplegia with bilateral abduction deficit with or without upbeat nystagmus. All 3 had blood lactic acidosis, and 2 had high cerebrospinal fluid lactate levels. Patient 1, our index case, was hospitalized for upbeat nystagmus and ophthalmoplegia, in addition to daily vomiting episodes since 4 months of age and weight loss of 0.5 kg. Findings on brain computed tomography were normal. Blood lactate levels were high, and TPPE was 37.8%. Brain magnetic resonance imaging (MRI) revealed no abnormalities. Patient 2, who presented at 5 months with lethargy, vomiting, grunting, and abdominal tenderness, was found to have intussusception on abdominal ultrasound and underwent 2 attempts at reduction with air enema several hours apart. However, the lethargy failed to resolve and ophthalmoplegia appeared the next day, leading to suspicions of Wernicke's encephalopathy. Laboratory tests showed severe thiamine deficiency (TPPE 31.2%). In patients 1 and 2, treatment led to complete resolution of symptoms. The third infant, a 5-month-old girl, was admitted on October 10, 2003, well before the outbreak was recognized, with vomiting, fever, and ophthalmoplegia. Her condition deteriorated to seizures, apnea, and coma. Brain MRI showed a bilateral symmetrical hyperintense signal in the basal ganglia, mamillary bodies, and periaqueductal gray matter. Suspecting a metabolic disease, vitamins were added to the intravenous solution, including thiamine 250 mg twice a day. Clinical improvement was noted 1 day later. TPPE assay performed after treatment with thiamine was started was still abnormal (17.6%). Her formula was substituted after 4 weeks, after the announcement about the thiamine deficiency. Although the MRI findings improved 5 weeks later, the infant had sequelae of ophthalmoplegia and motor abnormalities and is currently receiving physiotherapy. All 3 patients with neurologic manifestations were fed exclusively with the soy-based formula for 2 to 3.5 months, whereas the others had received solid food supplements. Longer administration of the formula (ie, chronic thiamine deficiency) was associated with failure to thrive. For example, one 12-month-old girl who received the defective formula for 8 months presented with refusal to eat, vomiting, failure to thrive (75th to <5th percentile), hypotonia, weakness, and motor delay. Extensive workup was negative for malabsorption and immunodeficiency. On admission, the patient had Salmonella gastroenteritis and sepsis and was treated with antibiotics. After thiamine deficiency was diagnosed, she received large doses of thiamine (50 mg/day) for 2 weeks. Like the other 5 infants without neurologic involvement, her clinical signs and symptoms disappeared completely within 2 to 3 weeks of treatment, and TPPE levels normalized within 1 to 7 days. There were no side effects. As part of its investigation, the Israel Ministry of Health screened 156 infants who were fed the soy-based formula for thiamine deficiency. However, by that time, most were already being fed alternative formulas and had begun oral thiamine treatment. Abnormal TPPE results (>15%) were noted in 8 infants, 3 male and 5 female, all >1 year old, who were receiving solid food supplements. Although their parents failed to notice any symptoms, irritability, lethargy, vomiting, anorexia, failure to thrive, and developmental delay were documented by the examining physicians. None had signs of neurologic involvement. Treatment consisted of oral thiamine supplements for 2 weeks. CONCLUSIONS: Clinician awareness of the possibility of thiamine deficiency even in well-nourished infants is important for early recognition and prevention of irreversible brain damage. Therapy with large doses of thiamine should be initiated at the earliest suspicion of vitamin depletion, even before laboratory evidence is available and before neurologic or cardiologic symptoms appear.