Long-term follow-up of 64 children with classical infantile-onset Pompe disease since 2004: A French real-life observational study.

BACKGROUND: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes. METHODS: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. RESULTS: Sixty-four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty-seven (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow-up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors. CONCLUSIONS: This study reports the long-term follow-up of one of the largest cohorts of classical IOPD patients and demonstrates high long-term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.

Variability of Care in Infants with Severe Bronchiolitis: Less-Invasive Respiratory Management Leads to Similar Outcomes.

OBJECTIVE: To compare the management of children with severe bronchiolitis requiring intensive care (based on duration of ventilatory support and duration of pediatric intensive care unit [PICU] stay) in 2 countries with differing pediatric transport and PICU organizations. STUDY DESIGN: This was a prospective observational care study in 2 PICUs of tertiary care university hospitals, 1 in France and 1 in Canada. All children with bronchiolitis who required admission to the PICU between November 1, 2013, and March 31, 2014, were included. RESULTS: A total of 194 children were included. Baseline characteristics and illness severity were similar at the 2 sites. There was a significant difference between centers in the use of invasive ventilation (3% in France vs 26% in Canada; P < .0001). The number of investigations performed from admission to emergency department presentation and during the PICU stay was significantly higher in Canada for both chest radiographs and blood tests (P < .001). The use of antibiotics was significantly higher in Canada both before (60% vs 28%; P < .001) and during (72% vs 33%; P < .0001) the PICU stay. The duration of ventilatory support, median length of stay, and rate of PICU readmission were similar in the 2 centers. CONCLUSION: Important differences in the management of children with severe bronchiolitis were observed during both prehospital transport and PICU treatment. Less invasive management resulted in similar outcomes with in fewer complications.

Severe hemolysis after plasma transfusion in a neonate with necrotizing enterocolitis, Clostridium perfringens infection, and red blood cell T-polyagglutination.

BACKGROUND: Red blood cell (RBC) Thomsen-Friedenreich antigen exposure (T activation) in infants with necrotizing enterocolitis (NEC) has occasionally been associated with posttransfusional intravascular hemolysis thought to be due to anti-T antibodies in the donor plasma. STUDY DESIGN AND METHODS: We describe an infant with NEC and Clostridium perfringens infection complicated by severe hemolysis after plasma transfusion. After this case, infants with confirmed NEC were prospectively evaluated for T activation. We checked for hemolysis in patients with T activation receiving plasma-containing blood products. RESULTS: The infant had received 80 mL of fresh-frozen plasma (FFP). His RBCs displayed strong T activation, and agglutination was observed with four of six ABO-compatible FFP units. A direct antiglobulin test was negative. IgM-class anti-T antibodies were present in small amounts (titer of 8) in the transfused FFP. Anti-T antibodies from the blood donor were not hemolytic in vitro. In the prospective study, T activation was observed in three of 28 infants with NEC (11%). One infant presented moderate T activation and two infants presented very strong T activation but only moderate decreases in sialic acid expression on the RBC membrane. These three infants presented no signs of hemolysis after transfusion with unwashed blood products or FFP. CONCLUSION: Anti-T antibodies are unlikely to be the etiologic factor for the hemolytic reactions observed in infants with NEC and T activation. Massive RBC desialylation and the direct action of bacterial toxins are more probable causes. Strict avoidance of plasma-containing blood products does not seem justified in these infants.

Red blood cell Thomsen-Friedenreich antigen expression and galectin-3 plasma concentrations in Streptococcus pneumoniae-associated hemolytic uremic syndrome and hemolytic anemia.

BACKGROUND: Pneumococcal hemolytic uremic syndrome (P-HUS) is a rare but severe complication of invasive pneumococcal disease (IPD) in young children. Consensual biologic diagnosis criteria are currently lacking. STUDY DESIGN AND METHODS: A prospective study was conducted on 10 children with culture-confirmed IPD. Five presented with full-blown P-HUS, three had an incomplete form with hemolytic anemia and mild or no uremia (P-HA), and two had neither HUS nor HA. Thomsen-Friedenreich (T), Th, and Tk cryptantigens and sialic acid expression were determined on red blood cells (RBCs) with peanut (PNA), Glycine soja (SBA), Bandeiraea simplicifolia II, and Maackia amurensis lectins. Plasma concentrations of the major endogenous T-antigen-binding protein, galectin-3 (Gal-3), were analyzed. RESULTS: We found that RBCs strongly reacted with PNA and SBA lectins in all P-HUS and P-HA patients. Three P-HUS and three P-HA patients showed also concomitant Tk activation. Direct antiglobulin test (DAT) was positive in three P-HUS (one with anti-C3d and two with anti-IgG) and two P-HA patients (one with anti-C3d and one with anti-IgG). RBCs derived from the two uncomplicated IPD patients reacted with PNA but not with SBA lectin. Gal-3 plasma concentrations were increased in all P-HUS patients. CONCLUSIONS: The results indicate high levels of neuraminidase activity and desialylation in both P-HUS and P-HA patients. T-antigen activation is more sensitive than DAT for P-HUS diagnosis. Combining PNA and SBA lectins is needed to improve the specificity of T-antigen activation. High concentrations of Gal-3 in P-HUS patients suggest that Gal-3 may contribute to the pathogenesis of P-HUS.

Experience with endoscopic management of high-risk gastroesophageal varices, with and without bleeding, in children with biliary atresia.

BACKGROUND & AIMS: Biliary atresia, the most common cause of childhood cirrhosis, increases the risks for portal hypertension and gastrointestinal bleeding. We report the results from a single-center study of primary and secondary prophylaxis of bleeding in children with portal hypertension and high-risk varices. METHODS: We collected data from 66 children with major endoscopic signs of portal hypertension, including grade 3 esophageal varices or grade 2 varices with red wale markings and/or gastric varices, treated consecutively from February 2001 through May 2011. Thirty-six children (mean age, 22 mo) underwent primary prophylaxis (sclerotherapy and/or banding, depending on age and weight). Thirty children (mean age, 24 mo) who presented with gastrointestinal bleeding received endoscopic treatment to prevent a relapse of bleeding (secondary prophylaxis). RESULTS: In the primary prophylaxis group, a mean number of 4.2 sessions were needed to eradicate varices; no bleeding from gastroesophageal varices was observed after eradication. Varices reappeared in 37% of children, and 97% survived for 3 years. In the secondary prophylaxis group, a mean number of 4.6 sessions was needed to eradicate varices. Varices reappeared in 45%, and 10% had breakthrough bleeding; 84% survived for 3 years. There were no or only minor complications of either form of prophylaxis. CONCLUSIONS: Endoscopic therapy as primary or secondary prophylaxis of bleeding appears to be well tolerated and greatly reduces the risk of variceal bleeding in children with biliary atresia and high-risk gastroesophageal varices. However, there is a risk that varices will recur, therefore continued endoscopic surveillance is needed.

High-volume hemofiltration in children with acute liver failure*.

OBJECTIVES: High-volume hemofiltration has shown beneficial effects in severe sepsis and multiple organ failure, improving hemodynamics and fluid balance. Recent studies suggest that acute liver failure shares many pathophysiologic similarities with sepsis. Therefore, we assessed the systemic effects of high-volume hemofiltration in children with acute liver failure. DESIGN: Retrospective observational cohort study. PATIENTS: Twenty-two children. SETTING: Forty-two-bed multidisciplinary pediatric and neonatal ICUs in a tertiary university hospital. INTERVENTION: We evaluated high-volume hemofiltration therapy as part of standard management of 22 children admitted in our unit for acute liver failure. Fifteen patients had fulminant hepatic failure, three had acute-on-chronic liver disease, and four had primary nonfunction. High-volume hemofiltration was initiated in patients requiring emergency liver transplantation and when hepatic encephalopathy grade higher than 2 and/or hemodynamic instability requiring vasopressors occurred. High-volume hemofiltration was defined by a flow of ultrafiltrate of more than 80 mL/kg/hr. Clinical and biological variables were assessed before and 24 and 48 hours after initiation of high-volume hemofiltration therapy. MEASUREMENTS AND MAIN RESULTS: High-volume hemofiltration was initiated with a median grade III of hepatic encephalopathy. The median flow of ultrafiltrate was 119 mL/kg/hr (range, 80-384). After 24 hours of high-volume hemofiltration treatment, we observed an increase in mean arterial pressure (p = 0.0002) and a decrease in serum creatinine (p = 0.0002). In half of the patients, the encephalopathy grade decreased. After 48 hours of treatment, mean arterial pressure (p = 0.0005), grade of hepatic encephalopathy (p = 0.04), and serum creatinine (p = 0.0002) improved. Overall mortality was 45.4% (n = 10). Emergency liver transplantation was performed in eight children. Five patients spontaneously recovered liver function. CONCLUSIONS: High-volume hemofiltration therapy significantly improves hemodynamic stability and neurological status in children with acute liver failure awaiting for emergency liver transplantation.

Hepatic haemangioma-prenatal imaging findings, complications and perinatal outcome in a case series.

BACKGROUND: The clinical presentation of foetal hepatic haemangioma (HH) is highly variable, from asymptomatic to life-threatening. OBJECTIVE: The aim of this study was to describe foetal hepatic haemangioma and identify prognostic factors. MATERIALS AND METHODS: Antenatal and postnatal imaging studies, clinical and biological records of infants with antenatally diagnosed HH (2001-2009) were reviewed. RESULTS: Sixteen foetuses had one focal lesion, with a mean volume of 75 ml (5-240 ml). One had multifocal HH. Most presented as a focal well-delimited heterogeneous vascular mass. Four had associated cardiomegaly, five had cardiac failure. Eight of the nine foetuses with cardiac disorders were symptomatic at birth: cardiac failure with pulmonary hypertension (9), consumptive coagulopathy (8), compartmental syndrome (2). All received supportive medical treatment, four embolisation. Five of these died. The remaining eight had a normal cardiac status. Two became symptomatic after birth: one with a large porto-hepatic shunt and one with significant mass effect. Prenatal cardiac abnormality (univariate, P = 0.031), enlargement of more than one hepatic vein (P = 0.0351) and large volume (P = 0.0372) were associated with symptomatic disease. CONCLUSION: Hepatic haemangioma associated with prenatal cardiac disorders, large volume and more than one enlarged hepatic vein have poorer outcome and require specific perinatal multidisciplinary management.

Community management of anti-malarials in Africa and iatrogenic risk.

Distribution of anti-malarials at the community level is one of the interventions recommended to reduce mortality from febrile illnesses. Inappropriate treatment of fever with anti-malarials may result in missed diagnosis and delays in appropriate treatments including consideration of other illnesses than malaria. We report the case of an 8-year-old black girl receiving prophylaxis with sulfadoxine-pyrimethamine from the caretaker of the community during her holidays in Ivory Coast. A persistent fever suspected to be due to malaria was treated inappropriately with atovaquone-proguanil and then with sulfadoxine-pyrimethamine again. Cumulative toxicity of anti-malarials leads to irreversible hepatic damages requiring hepatic transplantation. Community caretakers must be aware of the potential side effects and the contraindications of anti-malarials. Early identification of drug-induced toxicity and immediate discontinuation of the drug are the more effective tools to limit the progression of tissue damage.

Respiratory variations in aortic blood flow predict fluid responsiveness in ventilated children.

OBJECTIVE: To investigate whether respiratory variations in aortic blood flow velocity (DeltaVpeak ao), systolic arterial pressure (DeltaPS) and pulse pressure (DeltaPP) could accurately predict fluid responsiveness in ventilated children. DESIGN AND SETTING: Prospective study in a 18-bed pediatric intensive care unit. PATIENTS: Twenty-six children [median age 28.5 (16-44) months] with preserved left ventricular (LV) function. INTERVENTION: Standardized volume expansion (VE). MEASUREMENTS AND MAIN RESULTS: Analysis of aortic blood flow by transthoracic pulsed-Doppler allowed LV stroke volume measurement and on-line DeltaVpeak ao calculation. The VE-induced increase in LV stroke volume was >15% in 18 patients (responders) and <15% in 8 (non-responders). Before VE, the DeltaVpeak ao in responders was higher than that in non-responders [19% (12.1-26.3) vs. 9% (7.3-11.8), p=0.001], whereas DeltaPP and DeltaPS did not significantly differ between groups. The prediction of fluid responsiveness was higher with DeltaVpeak ao [ROC curve area 0.85 (95% IC 0.99-1.8), p=0.001] than with DeltaPS (0.64) or DeltaPP (0.59). The best cut-off for DeltaVpeak ao was 12%, with sensitivity, specificity, and positive and negative predictive values of 81.2%, 85.7%, 93% and 66.6%, respectively. A positive linear correlation was found between baseline DeltaVpeak ao and VE-induced gain in stroke volume (rho=0.68, p=0.001). CONCLUSIONS: While respiratory variations in aortic blood flow velocity measured by pulsed Doppler before VE accurately predict the effects of VE, DeltaPS and DeltaPP are of little value in ventilated children.

Physiological effects of noninvasive positive ventilation during acute moderate hypercapnic respiratory insufficiency in children.

INTRODUCTION: A prospective physiological study was performed in 12 paediatric patients with acute moderate hypercapnic respiratory insufficiency to assess the ability of noninvasive positive pressure ventilation (NPPV) to unload the respiratory muscles and improve gas exchange. MATERIALS AND METHODS: Breathing pattern, gas exchange, and inspiratory muscle effort were measured during spontaneous breathing and NPPV. RESULTS: NPPV was associated with a significant improvement in breathing pattern, gas exchange and respiratory muscle output. Tidal volume and minute ventilation increased by 33 and 17%, and oesophageal and diaphragmatic pressure time product decreased by 49 and 56%, respectively. This improvement in alveolar ventilation translated into a reduction in mean partial pressure in carbon dioxide from 48 to 40 mmHg (P = 0.01) and in respiratory rate from 48 to 41 breaths/min (P = 0.01). No difference between a clinical setting and a physiological setting of NPPV was observed. In conclusion, this study shows that NPPV is able to unload the respiratory muscles and improve clinical outcome in young patients admitted to the paediatric intensive care unit for acute moderate hypercapnic respiratory insufficiency.

Prolonged refractory status epilepticus with early and persistent restricted hippocampal signal MRI abnormality.

We report a series of four children with a prolonged refractory status epilepticus with an early persistent and restricted hippocampal signal MRI abnormality but otherwise no proven etiology. The mean duration of status epilepticus was 53 days (range, 20-91 days) with a mean length of stay in Pediatric Intensive Care Unit (PICU) of 2 months (range, 26-115 days). Neurological outcome showed epilepsy disease in all, and mild to severe disability. In long-term follow-up, the initial MRI signal abnormality developed into a cortical atrophy in all cases. The establishment of the diagnosis, etiology, and options for treatment are discussed.

Nonketotic hyperglycemic coma in toddlers after unintentional methadone ingestion.

Methadone overdoses are increasing in parallel with the increased frequency of opiate substitution therapy in adults. Although unintentional methadone intoxication in children is rare, it is becoming more frequently recognized. We report 3 cases of unintentional methadone overdose in toddlers who initially displayed central nervous system depression associated with severe nonketotic hyperglycemia and discuss the possible pathophysiologic mechanisms of an underrecognized symptom of opiate intoxication in young children.

Noninvasive positive pressure ventilation: five years of experience in a pediatric intensive care unit.

OBJECTIVES: To evaluate the feasibility and outcome of noninvasive positive pressure ventilation (NPPV) in daily clinical practice. DESIGN: Observational retrospective cohort study. SETTING: Pediatric intensive care unit in a university hospital. PATIENTS: : Patients treated by NPPV, regardless of the indication, during five consecutive years (2000-2004). MEASUREMENTS AND RESULTS: A total of 114 patients were included, and 83 of the 114 patients (77%) were successfully treated by NPPV without intubation (NPPV success group). The success rate of NPPV was significantly lower (22%) in the patients with acute respiratory distress syndrome (p < .05) than in the other patients. The Pediatric Risk of Mortality II (p = .003) and Pediatric Logistic Organ Dysfunction scores (p = .002) at admission were significantly higher in patients who were unsuccessfully treated with NPPV (NPPV failure group). Baseline values of Pco2, pulse oximetry, and respiratory rate did not differ between the two groups. A significant decrease in Pco2 and respiratory rate within the first 2 hrs of NPPV was observed in the NPPV success group. Multivariate analysis showed that a diagnosis of acute respiratory distress syndrome (odds ratio, 76.8; 95% confidence interval, 4.4-1342; p = .003) and a high Pediatric Logistic Organ Dysfunction score (odds ratio, 1.09; 95% confidence interval, 1.01-1.17; p = .01) were independent predictive factors for NPPV failure. A total of 11 patients (9.6%), all belonging to the NPPV failure group, died during the study. CONCLUSIONS: This study demonstrates the feasibility and efficacy of NPPV in the daily practice of a pediatric intensive care unit. This ventilatory support could be proposed as a first-line treatment in children with acute respiratory distress, except in those with a diagnosis of acute respiratory distress syndrome.

Pneumococcal meningitis in a pediatric intensive care unit: prognostic factors in a series of 49 children.

BACKGROUND: Despite advances in antibiotic therapy strategies and in pediatric intensive care, prognosis of Streptococcus pneumoniae meningitis remains very poor. However, few prognostic studies have been published, especially in pediatric populations. METHODS: We conducted a prognostic study to determine the factors associated with hospital mortality of 49 children admitted in a single pediatric intensive care unit during a 12-yr period (1990-2002). RESULTS: Hospital mortality was 49% (24 of 49 patients), and neurologic sequels were observed in 47% of survivors. Among them, 90% had permanent sensory deafness. Based on univariable analyses, seven variables were associated with the outcome: Pediatric Risk of Mortality II score (p = .000005), Glasgow Coma Score of >8 (p = .001), use of mechanical ventilation (p = .001), platelet count (p = .007), white blood cells count (p = .002), cerebrospinal fluid glucose level (p = .02), and lack of corticosteroids use (p = .02). In multivariable analysis, only three factors were independently associated with in-hospital mortality: Pediatric Risk of Mortality II score (hazard ratio, 1.13; 95% confidence interval, 1.06-1.20; p = .0002), platelets count of >200 x 10/L (hazard ratio, 0.25; 95% confidence interval, 0.08-0.81; p = .021) and white blood cell count above 5 x 10/L (hazard ratio, 0.31; 95% confidence interval, 0.11-0.87; p = .026). CONCLUSIONS: S. pneumoniae meningitis remains a devastating childhood disease in developed countries. Three variables were independently associated with the in-hospital death in our series-high Pediatric Risk of Mortality II score, low white blood cells count, and low platelet count-reflecting the main importance of severe sepsis and neurologic presentation in establishing the prognosis of these patients.

Fulminant Wilson's disease in children: appraisal of a critical diagnosis.

OBJECTIVES: To characterize fulminant Wilson's disease in children, outline clinical and biochemical differences to fulminant hepatic failure of other etiologies, and compare sensitivity and specificity in diagnosing fulminant Wilson's disease of alkaline phosphatase to total bilirubin ratio and aspartate aminotransferase to alanine aminotransferase ratio. DESIGN: Retrospective case study. SETTING: Twenty-two-bed multidisciplinary pediatric intensive care unit in a tertiary university hospital, national referral center for pediatric liver transplantation. PATIENTS: Between March 1986 and December 1999, seven children, aged between nine and 16 yrs, were admitted in our unit for fulminant Wilson's disease. During the same period of time, aged-matched analysis identified 12 other children with fulminant hepatic failure of other etiologies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: On admission, pediatric risk of mortality score, coagulation variables, and hepatic encephalopathy grade were similar in both groups. Children with fulminant Wilson's disease (n = 7) were characterized by lowered hemoglobin and serum transaminases, elevated serum bilirubin, and the occurrence of Kayser-Fleischer rings. Although some admission variables were significantly different between both groups, the elevated variability did not allow us to define acceptable cutoff values. Receiver operating characteristics curve for alkaline phosphatase to total bilirubin ratio showed a good discriminative power (Az = 0.87) in differentiating fulminant Wilson's disease from fulminant hepatic failure of other causes, and a ratio <1 showed a 86% sensitivity and 50% specificity (odds ratio, 6; 95% confidence interval, 66-0.5; p =.173) for fulminant Wilson's disease diagnosis. CONCLUSIONS: Although requiring prospective study to confirm, Kayser-Fleischer rings and serum alkaline phosphatase to total bilirubin ratio may assist in the early diagnosis of fulminant Wilson's disease.

[Infantile and maternal choriocarcinoma]. / Choriocarcinome infantile et maternel.

Infantile or congenital choriocarcinoma is a very uncommon complication of gestational choriocarcinoma. We report such a case with fatal outcome in a 3-week-old newborn, admitted for a hemorrhagic syndrome. Lungs, liver and brain masses were discovered and suggested an angiomatous process. The diagnosis was made later on gingival biopsy with necropsic confirmation. The mother's B-HCG level was elevated. She had asymptomatic pulmonary nodules and a uterine mass. This case report highlights characteristic but non specific clinical findings leading to the diagnosis. Chemotherapy must be undertaken as soon as possible to be effective. It is also necessary to assay maternal serum B-HCG when infantile choriocarcinoma is disclosed.

Improved clinical and economic outcomes in severe bronchiolitis with pre-emptive nCPAP ventilatory strategy.

PURPOSE: Severe bronchiolitis is the leading cause of admission to the pediatric intensive care unit (PICU). Nasal continuous positive airway pressure (nCPAP) has become the primary respiratory support, replacing invasive mechanical ventilation (MV). Our objective was to evaluate the economic and clinical consequences following implementation of this respiratory strategy in our unit. METHODS: This was a retrospective cohort analysis of 525 infants with bronchiolitis requiring respiratory support and successively treated during two distinct periods with invasive MV between 1996 and 2000, P1 (n = 193) and nCPAP between 2006 and 2010, P2 (n = 332). Costs were estimated using the hospital cost billing reports. RESULTS: Patients' baseline characteristics were similar between the two periods. P2 is associated with a significant decrease in the length of ventilation (LOV) (4.1 ± 3.5 versus 6.9 ± 4.6 days, p < 0.001), PICU length of stay (LOS) (6.2 ± 4.6 versus 9.7 ± 5.5 days, p < 0.001) and hospital LOS. nCPAP was independently associated with a shorter duration of ventilatory support than MV (hazard ratio 1.8, 95% CI 1.5-2.2, p < 0.001). nCPAP was also associated with a significant decrease in ventilation-associated complications, and less invasive management. The mean cost of acute viral bronchiolitis-related PICU hospitalizations was significantly decreased, from 17,451 to 11,205 € (p < 0.001). Implementation of nCPAP led to a reduction of the total annual cost of acute viral bronchiolitis hospitalizations of 715,000 €. CONCLUSION: nCPAP in severe bronchiolitis is associated with a significant improvement in patient management as shown by the reduction in invasive care, LOV, PICU LOS, hospital LOS, and economic burden.

Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a rare and severe parainfectious central nervous system disease in which previously healthy children develop rapidly progressive coma following viral illness. While most ANE are sporadic, familial autosomal dominant ANE due to mutations in the RANBP2 gene has been recently reported (ANE1 or infection-induced acute encephalopathy-3 (IIAE3)). To date, only few IIAE3 families with ADANE episodes have been described. OBJECTIVE: To report a new family with ADANE, describe clinical and radiological features and discuss differential diagnosis including Leigh syndrome or multiple sclerosis. OBSERVATION: The family included 3 symptomatic individuals and one 59 year-old asymptomatic obligate carrier. Patients presented acute episodes of encephalopathy few days after common viral infection. Ages of onset ranged from 6 months to 5 years. Episodes not only occurred in childhood but also recurred in adulthood. Initial neurological signs included coma, focal neurological deficits and seizures. MRI showed typical necrotizing lesions primarily in the thalamus and brainstem, and in the temporal lobes and insula. CSF cell count and cultures were normal during episodes. RANBP2 gene screening identified pathogenic heterozygous c.1754C>T mutation (p.Thr585Met). Episodes led to cognitive or physical handicap in 2 patients and were fatal in one child. CONCLUSION: IIAE3 or ADANE due to RANBP2 mutations has a large clinical heterogeneity. Our family illustrates the associated phenotypes from asymptomatic carrier to severe episodes of encephalopathy. Based on MRI features, the genetic IIAE3 diagnosis is important since prophylaxis and symptomatic management of infections may be beneficial, possibly in association with steroid or gammaglobulins.

Acute liver failure in neonates, infants and children.

Acute liver failure (ALF) is a rare but devastating syndrome. ALF in children differs from that observed in adults in both the etiologic spectrum and the clinical picture. Specific therapy to promote liver recovery is often not available and the underlying cause of the liver failure is often not determined. Management requires a multidisciplinary approach and should focus on preventing or treating complications and arranging for early referral to a transplant center. Although liver transplantation has increased the chance of survival, children who have ALF still face an increased risk of death, both while on the waiting list and after emergency liver transplantation. This article will review the current knowledge of the epidemiology, pathobiology and treatment of ALF in neonates, infants and children, and discuss some recent controversies.

Optimal level of nasal continuous positive airway pressure in severe viral bronchiolitis.

PURPOSE: To determine the optimal level of nasal continuous positive airway pressure (nCPAP) in infants with severe hypercapnic viral bronchiolitis as assessed by the maximal unloading of the respiratory muscles and improvement of breathing pattern and gas exchange. METHODS: A prospective physiological study in a tertiary paediatric intensive care unit (PICU). Breathing pattern, gas exchange, intrinsic end expiratory pressure (PEEPi) and respiratory muscle effort were measured in ten infants with severe hypercapnic viral bronchiolitis during spontaneous breathing (SB) and three increasing levels of nCPAP. RESULTS: During SB, median PEEPi was 6 cmH(2)O (range 3.9-9.2 cmH(2)O), median respiratory rate was 78 breaths/min (range 41-96), median inspiratory time/total duty cycle (T (i)/T (tot)) was 0.45 (range 0.40-0.48) and transcutaneous carbon dioxide pressure (P (tc)CO(2)) was 61.5 mmHg (range 50-78). In all the infants, an nCPAP level of 7 cmH(2)O was associated with the greatest reduction in respiratory effort with a mean reduction in oesophageal and diaphragmatic pressure swings of 48 and 46%, respectively, and of the oesophageal and diaphragmatic pressure time product of 49 and 56%, respectively. During nCPAP, median respiratory rate decreased to 56 breaths/min (range 39-108, p < 0.05), median T (i)/T (tot) decreased to 0.40 (range 0.34-0.44, p < 0.50) and P (tc)CO(2) decreased to 49 mmHg (range 35-65, p < 0.05). Only one infant with associated bacterial pneumonia required intubation and all the infants were discharged alive from the PICU after a median stay of 5.5 (range 3-27 days). CONCLUSION: In infants with hypercapnic respiratory failure due to acute viral bronchiolitis, an nCPAP level of 7 cmH(2)O is associated with the greatest unloading of the respiratory muscles and improvement of breathing pattern, as well as a favourable short-term clinical outcome.