Epileptic Status in a PEDiatric cohort (ESPED) requiring intensive care treatment: A multicenter, national, two-year prospective surveillance study.

OBJECTIVE: The aim of this study was to provide seizure etiology, semiology, underlying conditions, and out-of- and in-hospital diagnostics, treatment, and outcome data on children with out-of- or in-hospital-onset status epilepticus (SE) according to the International League Against Epilepsy definition that required admission to the pediatric intensive care unit (PICU) for ≥4 hours. METHODS: This prospective national surveillance study on SE in childhood and adolescence was conducted over 2 years (07/2019-06/2021). RESULTS: This study examined 481 SE episodes in 481 children with a median age of 43 months (1 month to 17 years 11 months), of which 46.2% were female and 50.7% had a previous seizure history. The most frequent acute SE cause was a prolonged, complicated febrile seizure (20.6%). The most common initial seizure types were generalized seizures (49.9%), focal seizures (18.0%), and unknown types (12.1%); 40.5% of patients suffered from refractory SE and 5.0% from super-refractory SE. The three most common medications administered by nonmedically trained individuals were diazepam, midazolam, and antipyretics. The three most frequent anti-seizure medications (ASMs) administered by the emergency physician were midazolam, diazepam, and propofol. The three most common ASMs used in the clinical setting were midazolam, levetiracetam, and phenobarbital. New ASMs administered included lacosamide, brivaracetam, perampanel, stiripentol, and eslicarbazepine. Status epilepticus terminated in 16.0% in the preclinical setting, 19.1% in the emergency department, and 58.0% in the PICU; the outcome was unknown for 6.9%. The median PICU stay length was 2 (1-121) days. The median modified Rankin scale was 1 (0-5) on admission and 2 (0-6) at discharge. New neurological deficits after SE were observed in 6.2%. The mortality rate was 3.5%. SIGNIFICANCE: This study provides current real-world out-of- and in-hospital data on pediatric SE requiring PICU admission. New ASMs are more frequently used in this population. This knowledge may help generate a more standardized approach.

Correction to: Incidence of tuberous sclerosis and age at first diagnosis: new data and emerging trends from a national, prospective surveillance study.

.

Incidence of tuberous sclerosis and age at first diagnosis: new data and emerging trends from a national, prospective surveillance study.

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a rare multisystem disorder. In 2012 diagnostic criteria for TSC were revised. However, data on the incidence of TSC are limited. METHODS: Prospective, national surveillance study in Germany over a 2-year-period (03/2015-02/2017) using current revised criteria for TSC. Patients up to the age of 18 years with a new diagnosis of definite or possible TSC (clinical and/or genetic) were included. The aims of this study were 1) to generate up-to-date data on the incidence of definite or possible TSC, 2) to assess age at first diagnosis, and 3) to compare these data with previous epidemiologic data. RESULTS: In total, 86 patients met inclusion criteria (definite or possible TSC) with a median age at diagnosis of 6 months (range: 5 months before birth - 197 months of age). Among patients identified with features of TSC, 73.3% met criteria for definite diagnosis (median age: 7 months) and 26.7% met criteria for a possible diagnosis (median age: 3 months). 55.8% of patients were male. When excluding prenatally diagnosed patients, median age at diagnosis was 11 months with a range of 0 to 197 months. The 3 most common clinical features at diagnosis of TSC were central nervous system involvement in 73.3% patients (of these 95.2% experienced seizures), cutaneous involvement in 58.1% patients (with the most common lesion being hypomelanotic macules in 92%) and cardiac rhabdomyoma in half of the patients. Cardiac rhabdomyoma were detected by prenatal ultrasonography in 22.1% of patients. The presence of cardiac rhabdomyoma was associated with cardiac arrhythmias in 25.6% (about 13% of all diagnosed patients) in our cohort. The overall prevalence of seizure disorders was 69.8%. The annual incidence rate of TSC is estimated at a minimum of 1:17.785 live births. However correcting for underreporting, the estimated incidence rate of definite or possible TSC is approximately 1:6.760-1:13.520 live births in Germany. CONCLUSIONS: This is the first study that assessed prospectively the incidence rate of TSC in children and adolescents using the updated diagnostic criteria of 2012. This prospective surveillance study demonstrates a low age at first diagnosis (median: 6 months), likely due to antenatal detection of cardiac rhabdomyoma. Early diagnosis bears the potential for implementing effective therapies at an earlier stage.

Incidence, disease onset and short-term outcome in urea cycle disorders -cross-border surveillance in Germany, Austria and Switzerland.

BACKGROUND: Urea cycle disorders (UCDs) are a group of rare inherited metabolic disorders. Affected individuals often present with hyperammonemic encephalopathy (HE) and have an increased risk of severe neurologic disease and early death. The study aims to provide epidemiologic data and to describe the disease manifestation and short-term outcome. METHOD: Cross-border surveillance of newly diagnosed patients with UCDs - below 16 years of age - was performed from July 2012 to June 2015 in Germany and Austria and from January 2012 to December 2015 in Switzerland. Inquiries were sent monthly to all Pediatric Departments in Germany and Switzerland, and quarterly to the Austrian Metabolic Group. In addition, data were collected via a second source (metabolic laboratories) in all three countries. RESULTS: Between July 2012 and June 2015, fifty patients (Germany: 39, Austria: 7, Switzerland: 4) with newly diagnosed UCDs were reported and later confirmed resulting in an estimated cumulative incidence of 1 in 51,946 live births. At diagnosis, thirty-nine patients were symptomatic and 11 asymptomatic [10 identified by newborn screening (NBS), 1 by high-risk-family screening (HRF)]. The majority of symptomatic patients (30 of 39 patients) developed HE with (n = 25) or without coma (n = 5), 28 of them with neonatal onset. Despite emergency treatment 15 of 30 patients with HE already died during the newborn period. Noteworthy, 10 of 11 patients diagnosed by NBS or HRF remained asymptomatic. Comparison with the European registry and network for intoxication type metabolic diseases (E-IMD) demonstrated that cross-national surveillance identified a higher number of clinically severe UCD patients characterized by earlier onset of symptoms, higher peak ammonium concentrations in plasma and higher mortality. CONCLUSION: Cross-border surveillance is a powerful tool to identify patients with UCDs demonstrating that (1) the cumulative incidence of UCDs is lower than originally suggested, (2) the mortality rate is still high in patients with neonatal onset of symptoms, and (3) onset type and peak plasma ammonium concentration predict mortality.

[ESPED-Survey: TSC-disease in children and adolescents: preliminary results from a German epidemiological survey]. / ESPED-Erhebung: TSC-Erkrankung bei Kindern und Jugendlichen: eine einjährige Interim-Analyse.

BACKGROUND: Tuberous sclerosis complex (TSC) disease is a rare genetic, multi-organ disorder characterized by the occurrence of multiple hamartoma. METHODS: In cooperation with ESPED, Germany, a prospective, epidemiological study was performed to assess the incidence of newly diagnosed TSC disease in patients ≤18 years in Germany. Moreover, the following parameters were assessed: 1. Age distribution at initial diagnosis; 2. Percentage of patients with in utero diagnosis of TSC; 3. Detailed description of pathological clinical findings; 4. Results from genetic testing. RESULTS: In this one-year interim analysis, 84 electronic questionnaires were received, 17 of which did not contain complete sets of data and were not included in data analysis. Twenty-three of 67 questionnaires did not report TSC patients and 3 reports contained redundant data sets and were excluded. In total, 41 reports were included into data analysis (female: 23; male: 18); median age at first diagnosis was 6 months (range: 0-151 months). The three most common symptoms were: central nervous affection: 31/41 patients ((75.6 %); 29/31 with seizures); rhabdomyoma: in 20/41 (48.8 %); cutaneous affection: hypomelanotic maculae ("white spots"): 20/41 (48.8 %). The three following organ manifestations were seen most often in a comprehensive diagnostic work-up: rhabdomyoma: 23/41 ((56.1 %); cortical dysplasia: 22/41 (53.7 %); "white spots"): 20/41 (48.8 %). In 11/41 patients, cardiac rhabdomyoma were detected by ultrasonography prenatally. In 6 patients, a TSC-2 mutation was found while in 4 patients a TSC-1 mutation was noted; in 1 patient, genetic testing was negative. CONCLUSIONS: Based on our preliminary findings, the annual incidence rate for TSC disease is estimated at approximately 1:12,300 live births, but this is a very rough approximation.

Incidence and clinical presentation of invasive neonatal group B streptococcal infections in Germany.

OBJECTIVE: Streptococcus agalactiae (group B Streptococcus) is an important cause of morbidity and mortality in newborn infants. So far, there have been no published data on the incidence, morbidity, and mortality of invasive neonatal group B Streptococcus infections in Germany. METHODS: A prospective active surveillance study involving all of the pediatric hospitals, which reported their cases to the German Pediatric Surveillance Unit, and all of the microbiological laboratories serving pediatric hospitals, which reported their cases to the Laboratory Sentinel Group at Robert Koch Institute Berlin, was conducted between 2001 and 2003. Capture-recapture analysis was used to evaluate the completeness of reported neonatal invasive group B Streptococcus infections. RESULTS: We collected and analyzed data from 347 and 360 infants with invasive group B Streptococcus infection during the first 3 months of life, as reported by pediatricians to the German Pediatric Surveillance Unit and microbiologists to the Robert Koch Institute Berlin, respectively. Using capture-recapture analysis, we calculated an incidence of 0.47 per 1000 live births. Nearly 60% of the infants suffered from early-onset disease, and 16% of these presented with meningitis. In contrast, 61.8% of infants with late-onset disease presented with meningitis. Prematurity was present in 22.4% of early-onset disease and 39.7% of late-onset disease cases, respectively. A high proportion of infants suffered from sequelae because of group B Streptococcus infection at the time of discharge from the hospital. Most common sequelae were hydrocephalus and cerebral seizure. Case fatality rate was 4.3%. CONCLUSIONS: This study, which is the first to provide information on the current national incidence and morbidity of invasive group B Streptococcus infection in Germany, demonstrates remarkable country-specific variation in comparison with other European countries, which gather data in a similar fashion. Therefore, the importance of country-specific prevention guidelines has to be stressed.

A decreasing rate of neural tube defects following the recommendations for periconceptional folic acid supplementation.

BACKGROUND/AIM: Neural tube defects (NTDs) are the most common birth defects, resulting in severe mortality and morbidity. In 1995, the supplementation of folic acid periconceptionally was officially recommended in Germany. The impact of the recommendations on the rate of NTDs was assessed. METHODS: An active surveillance system was established in the northern Rhine area. From 1996, all departments of obstetrics were asked to report cases of NTDs in all abortions, live births and stillbirths. Compliance with the recommendations was evaluated in a sample of mothers who delivered at the Department of Obstetrics of Düsseldorf University in 2001. RESULTS: From 1996-2003, 520 NTDs were reported. Compared to the rate of NTDs in 1996 (10.5/10,000), the average incidence in the years 1997 to 2003 dropped (6.8/10,000). The intake of folic acid, as recommended, was low among the general population (21.1%). CONCLUSION: Active surveillance data on the rate of NTDs are compatible with the maximum decrease of about 20% to be expected from data on the implementation of the recommendations. A much greater decrease in NTDs should be the challenge for the future.

Incidence and short-term outcome of children with symptomatic presentation of organic acid and fatty acid oxidation disorders in Germany.

OBJECTIVE: To determine the incidence of symptomatic children with inherited organic acid disorders (OADs) and fatty acid oxidation disorders (FAODs) in Germany. METHODS: An active surveillance of symptomatic children with inherited OADs and FAODs was conducted during a time period of 24 months (1999-2000) in Germany. Monthly inquiries were sent to all Departments of Pediatrics by the German Pediatric Surveillance Unit (ESPED) and quarterly to all specialized metabolic laboratories. Newly diagnosed patients were added to the database, recording clinical and biochemical information via a standardized questionnaire. RESULTS: Prospective surveillance enrolling 844 575 children identified a total of 57 symptomatic children with newly diagnosed OADs or FAODs in states with conventional neonatal screening, resulting in an estimated cumulative incidence of 1:14 800. The most frequent diagnosis among these children was medium-chain acyl-CoA dehydrogenase deficiency (n = 20). The majority of symptomatic children revealed clinical symptoms during the first year of life (n = 36), frequently presenting with acute metabolic crises (n = 31). Eight children died during these crises. Notably, 47 of the symptomatic children suffered from diseases potentially detectable by expanded neonatal screening programs. This subgroup included 29 children presenting with metabolic crises and 7 of the 8 deaths. CONCLUSIONS: Despite increased clinical awareness of OADs and FAODs, the mortality and morbidity for these children remains high, if they are diagnosed after manifestation of clinical disease. An introduction of nationwide neonatal screening programs would change the focus for organic acid analysis from patients presenting with acute metabolic crises to more chronic clinical presentations, especially the cerebral organic acid disorders.