Gideon Eshel

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. Wernickes 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 μg/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 Wernickes 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.

Mutations in LPIN1 Cause Recurrent Acute Myoglobinuria in Childhood

Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways. Using homozygosity mapping, we identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis. The LPIN1 gene encodes the muscle-specific phosphatidic acid phosphatase, a key enzyme in triglyceride and membrane phospholipid biosynthesis. Of six individuals who developed statin-induced myopathy, one was a carrier for Glu769Gly, a pathogenic mutation in the LPIN1 gene. Analysis of phospholipid content disclosed accumulation of phosphatidic acid and lysophospholipids in muscle tissue of the more severe genotype. Mutations in the LPIN1 gene cause recurrent rhabdomyolysis in childhood, and a carrier state may predispose for statin-induced myopathy.

Midazolam in treatment of epileptic seizures

Midazolam (Versed), the first water-soluble benzodiazepine, has had widespread acceptance as a parenteral anxiolitic agent. Its antiepileptic properties were studied in adult patients with good results. Midazolam was administered intramuscularly to 48 children, ages 4 months to 14 years, with 69 epileptic episodes of various types. In all but 5 epileptic episodes, seizures stopped 1-10 min after injection. These results suggest that midazolam administered intramuscularly may be useful in a variety of epileptic seizures during childhood, specifically when attempts to introduce an intravenous line in convulsing children are unsuccessful.

The role of the gut in the pathogenesis of death due to hyperthermia.

Pathologic data from the gastrointestinal tract in heatstroke victims, although documented, are confusing. The object of this study was to document the gastrointestinal changes observed during induced total body hyperthermia (42°C) followed by cooling. An established heatstroke model was used in a university animal laboratory. Group A underwent immersion hyperthermia for 1 hour, followed by cooling to normothermia. Group B underwent hyperthermia to cardiac arrest, followed by resuscitation plus cooling to normothermia. The postmortem findings in the gastrointestinal tract were evaluated. In group A, several hours after return to normothermia and stable vital signs, delayed secondary deterioration with massive gastrointestinal bleeding occurred. The postmortem findings revealed bleeding into the whole intestine and serosanguineous fluid in the peritoneal cavity. In group B, an adynamic gut was observed after 165 ± 21 minutes (range 125–174) of heating when mean arterial pressure (MAP) decreased to 38 ± 21 mm Hg (range 30–70). Cardiac arrest occurred at 178 ± 26 minutes (range 140–208) of immersion. Eight monkeys could be resuscitated to spontaneous circulation with return of normal gut motility, then they rearrested at 158 ± 68 minutes (range 45–228). The postmortem findings resembled those in group A. The Postmortem findings in the four monkeys in which restoration of spontaneous circulation failed, revealed only some intestinal wall edema and occasional petechial hemorrhages. It is concluded that after a hyperthermic event, tissue injury continues to develop. The pathologic findings are related to the time lapse between hyperthermia, cooling, and death. The similarity to the descriptions of septic shock, multiple organ failure, and the gut reperfusion syndrome is striking. An immunologic response as a mechanism for all these syndromes is discussed.

Risk factors affecting the immediate postoperative course in pediatric scoliosis surgery.

Study Design. A retrospective analysis of pediatric records of idiopathic scoliosis (IS) and neuromuscular scoliosis (NMS) etiology, in a search for complications and their risk factors immediately following surgical repair. Objective. To evaluate the influence of pre- and intraoperative parameters on the postoperative course and lay the cornerstone for a course-prediction model. Summary of Background Data. Only a few studies have addressed the immediate postoperative complications of pediatric scoliosis surgery. Methods. Our study included all children who underwent spinal fusion for scoliosis in our hospital between 1998 and 2006. The following data were collected: curve etiology, Cobb angle, number of fused vertebrae, fusion approach, and the addition of thoracoplasty. We evaluated the influence of this data on the rate of delayed extubations, length of intensive care unit (ICU) hospitalization, and the presence of major and minor immediate postoperative complications. Results. The study included 126 children (95 IS and 31 NMS). Delayed extubations were recorded in 17 children (3% of IS vs. 45% of NMS). The most common major and minor complications were pulmonary and hematological-biochemical, respectively. Overall pulmonary complications (major and minor) were recorded in 38 children. Major complications (of any category) were recorded in 19 children. Average length of ICU hospitalization was 3.8 days. The rate of complications in the NMS group was significantly higher than in the idiopathic group. Posterior fusions were associated with a significantly lower rate of pulmonary complications and shorter ICU hospitalizations, in comparison to anterior and combined fusions. Cobb angle, number of fused vertebrae, and the addition of thoracoplasty did not correlate with any postoperative parameters. Conclusion. While NMS etiology, anterior and combined fusions correlated with a worse course, the Cobb angle, number of fused vertebrae, and the addition of thoracoplasty did not. Optimization of postoperative care should be carried out accordingly. Scoliosis surgery is safe even in extreme curves and long fusions. Thoracoplasty can be added whenever indicated, in order to improve the overall outcome.

Visual evoked potentials: a diagnostic test for migraine headache in children

Visual evoked potentials (VEPs) were performed in a blind fashion in 114 children aged 3 to 17 years with different types of headaches, in order to investigate whether this could be helpful in the diagnosis of migraine versus other types of headaches in children. The study showed that the amplitude between P100 and N2 was significantly larger in children with migraine headaches (mean 19.8 nvol, SD 7.75) compared with other types of headaches (mean 13.1 nvol, SD 7.45). These results suggest that the sensitivity of VEP P100 amplitude to distinguish migraine headaches in children is 67%, the specificity of VEP is 83%, and the predictive positive value is 83%. VEP study might be helpful in workup of a child with headache, particularly a young child, when signs and symptoms may not be characteristic.

Postural stability by computerized posturography in minor head trauma

Mild head injuries are very common among young children. Often, these injuries are followed by a variety of subjective complaints termed posttraumatic syndrome. Posturography (balance test) was performed immediately after the trauma in 21 children who had sustained mild head injury. Significant difference in performance was observed in head-injured children in all subparts of the test as compared with a control group. We conclude that posturography may serve as a simple cost-effective method in qualifying the posttraumatic imbalance.

Blunt pancreatic trauma in children

PurposeTo report our experience with blunt pancreatic trauma in pediatric patients and evaluate several various management strategies.MethodsTen children admitted over the last 10 years with pancreatic blunt trauma were included in the present series.ResultsThe average time from injury to hospital admission was 2.4 days. All injuries resulted from accidents: bicycle handlebar injuries (5), being kicked by a horse (2), falls from a height (2), and injury sustained during closure of an electric gate (1). Additional systemic and abdominal injuries were recorded in 7 patients. The amylase levels at the time of patient admission were normal in 3 patients, mildly raised in 4 patients, and elevated in 3 patients. Abdominal computed tomography was performed in 10 patients, ultrasonography in 5, and endoscopic retrograde cholangiopancreatography (ERCP) in 4. Pancreatic injuries comprised 4 grade I, 3 grade II, and 3 grade III injuries. Grade I and II injuries were successfully managed by conservative treatment. The 3 children with grade III trauma and pancreatic ductal injury in the neck (1), body (1), and tail (1) of the gland were surgically treated, having an uneventful postoperative stay of 8–14 days and no complications during the 1-year follow-up period.ConclusionThe present study supports early ERCP as an essential part of the initial patient evaluation when pancreatic transection is highly suspected.

Comparison of fast versus slow rewarming following acute moderate hypothermia in rats

Background: The aim of this study was to compare the biochemical and physiological responses of fast vs. slow rewarming from moderate hypothermia in anaesthetized rats.

Incidence of recurrent intussusception following barium versus air enema

The aim of this study was to determine whether using air enema for acute intussusception is related to a higher rate of recurrence than other methods of treatment. A 10‐y (1986‐95) retrospective study was performed in a university‐affiliated paediatric division. The overall recurrence rate for 97 patients with acute intussusception was 7.8% (10% of whom were treated non‐surgically). There were no recurrences following the surgical treatment. In matched groups of patients, no risk factors were found for recurrence following air vs barium enema.