Outbreak of Life-Threatening Thiamine Deficiency in Infants in Israel Caused by a Defective Soy-Based Formula

Abstract

Objective. Between October and No- vember 2003, several infants with encephalopathy were hospitalized in pediatric intensive care units in Israel. Two died of cardiomyopathy. Analysis of the accumu- lated data showed that all had been fed the same brand of soy-based formula (Remedia Super Soya 1), specifi- cally 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. Wer- nicke'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 sus- picions 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 ( 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 (nor- mal: 0.03-0.08 mmol/L). The diagnostic criteria for thia- mine deficiency were abnormal transketolase activity and/or unexplained lactic acidosis. Treatment consisted of intramuscular thiamine 50 mg/day for 14 days com- bined with a switch to another infant formula. Results. Early symptoms were nonspecific and in- cluded mainly vomiting (n 8), lethargy (n 7), irrita- bility (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 pa- tient had clinical dysentery and group C Salmonella sep- sis; the others had mild infection: acute gastroenteritis (n 2); upper respiratory infection (n 2); and broncho- pneumonia, 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 in- dex 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 lac- tate levels were high, and TPPE was 37.8%. Brain mag- netic resonance imaging (MRI) revealed no abnormali- ties. 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 re- solve and ophthalmoplegia appeared the next day, lead- ing to suspicions of Wernicke's encephalopathy. Labora- tory 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 oph- thalmoplegia. Her condition deteriorated to seizures, ap- nea, and coma. Brain MRI showed a bilateral symmetri- cal hyperintense signal in the basal ganglia, mamillary bodies, and periaqueductal gray matter. Suspecting a metabolic disease, vitamins were added to the intrave- nous 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