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 (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 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.

Thiamine (vitamin B ₁) was the first B vitamin to have been identified. It serves as a cofactor for several enzymes involved in energy metabolism. The thiamine-dependent enzymes are important for the biosynthesis of neurotransmitters and for the production of reducing substances used in oxidant stress defenses, as well as for the synthesis of pentoses used as nucleic acid precursors. Thiamine plays a central role in cerebral metabolism. Its deficiency results in dry beriberi, a peripheral neuropathy, wet beriberi, a cardiomyopathy with edema and lactic acidosis, and Wernicke—Korsakoff syndrome, whose manifestations consist of nystagmus, ophthalmoplegia, and ataxia evolving into confusion, retrograde amnesia, cognitive impairment, and confabulation. Patients on a strict thiamine-deficient diet display a state of severe depletion within 18 days. The most common cause of thiamine deficiency in affluent countries is either alcoholism or malnutrition in nonalcoholic patients. Treatment by thiamine supplementation is beneficial for diagnostic and therapeutic purposes.

The relationship between somatic growth and neurocognitive outcome was studied in a cohort of 136 children with intrauterine growth retardation. The children were followed up from birth to 9 to 10 years of age by annual measurements of growth parameters, neurodevelopmental evaluations, and IQ. The rate of catch-up for height between 1 and 2 years of age was significantly higher than the catch-up for weight (P < .001). The cognitive outcome at 9 to 10 years correlated with head circumference at all ages. The neurodevelopmental outcome at 9 to 10 years correlated with weight at all ages. Correlation with head circumference was more significant with IQ, while with weight it was stronger with the neurodevelopmental score. Height at 1 year was a significant predictor for IQ and neurodevelopmental outcome at 9 to 10 years. These findings are of distinct importance for prediction of subsequent neurodevelopmental outcome in children with intrauterine growth retardation.

Spinal muscular atrophy (SMA) is one of the most common genetic diseases and was, until recently, a leading genetic cause of infant mortality. Three disease-modifying treatments have dramatically changed the disease trajectories and outcome for severely affected infants (SMA type 1), especially when initiated in the presymptomatic phase. One of these treatments is the adeno-associated viral vector 9 (AAV9) based gene therapy onasemnogene abeparvovec (Zolgensma®), which is delivered systemically and has been approved by the European Medicine Agency for SMA patients with up to three copies of the SMN2 gene or with the clinical presentation of SMA type 1. While this broad indication provides flexibility in patient selection, it also raises concerns about the risk-benefit ratio for patients with limited or no evidence supporting treatment. In 2020, we convened a European neuromuscular expert working group to support the rational use of onasemnogene abeparvovec, employing a modified Delphi methodology. After three years, we have assembled a similar yet larger group of European experts who assessed the emerging evidence of onasemnogene abeparvovec's role in treating older and heavier SMA patients, integrating insights from recent clinical trials and real-world evidence. This effort resulted in 12 consensus statements, with strong consensus achieved on 9 and consensus on the remaining 3, reflecting the evolving role of onasemnogene abeparvovec in treating SMA.

Objective: To report the follow-up findings of 7 children with severe epilepsy as a result of thiamine deficiency in infancy caused by a defective soy-based formula. Methods: The medical records of 7 children aged 5-6 years with thiamine deficiency in infancy who developed epilepsy were reviewed and their clinical data, EEG tracings, and neuroimaging results were recorded. The clinical course and present outcome of these children, now 5 years after exposure to thiamine deficiency, are described. Results: All infants displayed seizures upon presentation, either tonic, myoclonic, or focal. Six infants had an EEG recording at this stage and all showed slow background. Five of them had no epileptic activity and only 1 displayed focal activity. Following a seizure-free period of 1-9 months, the seizures recurred, and all 7 children displayed either myoclonic or complex partial seizures. Multifocal or generalized spike wave complexes were recorded on the EEGs of all 7 patients, and the tracings of 3 children evolved into hypsarrhythmia. The seizures were refractory to most antiepileptic drugs, and 4 children remain with uncontrolled seizures. All children have mental retardation and motor disabilities as well as symptoms of brainstem dysfunction. Conclusions: Our findings indicate that severe infantile thiamine deficiency may result in epilepsy.