The Development of Extremely Premature Infants.

BACKGROUND: Until now, there has been no comprehensive long-term study in Germany on the development of extremely premature infants up to school age. METHODS: From October 2004 to September 2008, in the German federal state of Lower Saxony, 437 infants born at a gestational age less than 28 weeks were followed up at the ages of 2 and 5 years, and some at the age of 10 years. The 5-year follow-up data were collated with the peri- and neonatological parameters and compared with the 2- and 10-year follow-up data. RESULTS: The mortality of extremely premature infants was 25.1%. Among the five-year-olds studied, 14.1% showed cognitive impairment and 17.4% had cerebral palsy. 40.4% manifested abnormalities of speech or language, 33.1% had behavioral abnormalities, and 72.5% received therapeutic interventions. Infants in whom severe brain damage was diagnosed by ultrasonography shortly after birth were more likely to develop cerebral palsy (odds ratio [OR] 38.28, 99% confidence interval [12.55; 116.80]) and to have impaired cognitive development (OR 7.36 [2.52; 21.51]). The likelihood of cognitive impairment was also higher among infants whose mothers had a lower level of education (OR 3.83 [1.68; 8.77]). 73.1% (242 out of 331) of the two-year-olds were in the same category of cognitive function at the 5-year follow-up; 82.4% (65 out of 79) of the 5-year-olds were in the same category of cognitive function at the 10-year follow-up. CONCLUSION: Many of these extremely premature infants had developmental disturbances, and many required therapeutic interventions. The risk factors revealed by this study may help identify patients who are in particular need of support, enabling targeted measures to be taken at the earliest possible stage in order to improve their cognitive and motor abilities. Nationwide, standardized follow-up at the age of 5 years would be desirable.

[Quality analyses of the development of preterm infants: results of the Lower-Saxonian preterm infant follow-up project and a comparison group of term infants]. / Qualitätsanalysen zur Entwicklung Frühgeborener: Ergebnisse des Niedersächsischen Frühgeborenen-Nachuntersuchungsprojekts und eines Vergleichskollektivs reif geborener Kinder.

Based on perinatal and neonatal quality assurance programmes, a follow-up project for the high-risk group of extremely preterm infants, unparalleled in Germany, was initiated in the federal state of Lower Saxony in 2004. Here we describe the new approach of examining a comparison group of term infants, which, for the first time, allows a valid interpretation of the collection of area-wide long-term outcome data on preterm children. The prospective long-term outcome project investigates the medical care situation for children born at less than 28 weeks of gestation up to school age. Based on the information obtained about the children's development the quality of health care will be optimised. A standardised examining concept with established development tests at defined follow-up intervals (at the age of 6 months, 2, 5 and 10 years) is used. At the age of five years 75 % of the examined premature children exhibited impairments. In order to better assess remarkable results, a comparison group of term infants (n=305) selected by a matched-pairs method was examined at the age of five using an analogous concept in kindergartens in Lower Saxony. The results were compared with the first two age cohorts of the follow-up-project (n=226) and quality analyses performed. As expected, significant differences have been found in the children's motor, cognitive and linguistic development between the preterm and term infants examined. This fact draws attention to the importance of early support for the majority of extremely premature infants. Feedback on the results given to the medical staff involved allows for the implementation of best practices and quality improvements. Identifying potential for improvement in everyday health care will help to develop specific optimisation measures.

Pulmonary vein triggers play an important role in the initiation of atrial flutter: Initial results from the prospective randomized Atrial Fibrillation Ablation in Atrial Flutter (Triple A) trial.

BACKGROUND: The incidence of atrial fibrillation (AF) after ablation of a cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) is high. OBJECTIVE: The purpose of this study was to test the hypothesis that AFL and AF may be initiated by pulmonary vein triggers. This prospective randomized trial tested the efficacy of a standalone pulmonary vein isolation (PVI) in patients with AFL but without AF. METHODS: Patients with AFL but without documented AF were randomly assigned to 1 of 3 treatment groups: (1) antiarrhythmic drugs (AAD), (2) CTI ablation, or (3) circumferential PVI. The primary end-point was defined as any recurrent atrial tachyarrhythmia and the secondary end-point as recurrence of AFL. In case of tachyarrhythmia recurrence in the PVI group, a second PVI was performed to close gaps in the ablation lines. RESULTS: Of the 60 patients, 17 were randomized to AAD, 23 to CTI ablation, and 20 to PVI. During follow-up of 1.42 ± 0.83 years, 14 of 17 patients (82.4%) in the AAD group, 14 of 23 patients (60.9%) in the CTI group, and 2 of 20 patients (10%) in the PVI group reached the primary end-point (P <.001) after a mean of 1.4 PVI procedures per patient. AFL reoccurred in 9 patients (52.9.%) in the AAD group, in 2 patients (8.7%) in the CTI group, and after a single PVI in 3 patients (15%) in the PVI group (P = .003). After closure of gaps, 1 patient (5%) in the PVI group presented with recurrent AFL. CONCLUSION: Pulmonary vein triggers play an important role in AFL. PVI can prevent the recurrence of AFL, even without CTI ablation.

Use of intrathecal baclofen in children and adolescents: interdisciplinary consensus table 2013.

In recent years, intrathecal baclofen (ITB) has attained an important role in the treatment of severe spasticity and dystonia in children. There are principal differences between the use of ITB in children and its use in neurology and oncology in adults. Here, we present a consensus report on best practice for the treatment of severe spastic and dystonic movement disorders with ITB. Using a problem-orientated approach to integrate theories and methods, the consensus was developed by an interdisciplinary group of experienced ITB users and experts in the field of movement disorders involving 14 German centers. On the basis of the data pooled from more than 400 patients, the authors have summarized their experience and supporting evidence in tabular form to provide a concise, but still a comprehensive information base that represents our current understanding regarding ITB treatment options in children and adolescents.

A historical perspective of pacemaker infections: 40-years single-centre experience.

AIMS: The approach to infected cardiac devices has changed during recent decades. Optimal treatment is still a matter of debate, especially in pacemaker-dependent patients. Therefore, we investigated the management and outcome of patients with pacemaker infections in a single centre over four decades. METHODS AND RESULTS: We conducted a retrospective analysis of 4212 patients and extracted those with pacemaker infections admitted to Rostock Heart Center between 1973 and 2012. One hundred and thirty-one consecutive patients (median age 69.6 ± 14.9 years) were admitted for device infections. Two-stage exchange was performed in 42 patients (32.8%). In 72 patients (55%), explantation and implantation on the contralateral side was performed simultaneously. In 17 cases the device was not replaced. Mean follow-up was 63 ± 81 months. Reinfection rate was 12.2%, which declined from 24% (1980s) to 2.6% (after 2000). Complete device removal (in 57.3%) reduced the risk for reinfection by 75% (P = 0.02), as well as increasing age (0.049% per year, P = 0.001). One-stage exchange increased the risk of reinfection six-fold (P = 0.021). Cultured bacteria after initiation of antibiotic therapy predicted a four-fold increase in risk of a recurrent infection (P = 0.01). CONCLUSION: Continuous assimilation of guidelines for pacemaker infection improved the outcome over time: complete extraction of the infected device seems to be highly desirable. A one-stage exchange increased the risk of recurrent device infection and should probably be avoided, but complete extraction seems to be more important than timing.

[State-wide follow-up of extremely preterm infants: a model of cross-sectoral quality analysis]. / Landesweite Nachuntersuchung extrem unreifer Frühgeborener: Ein Modell sektorübergreifender Qualitätsanalyse.

A long-term outcome project for the special high-risk group of extremely preterm (ELBW) infants has been established in the federal state of Lower Saxony, which is unique in Germany. All departments of neonatology and all divisions of paediatric neurology are participating. Since October 2004 children who were born at <28 weeks gestation are examined using a standardised concept at defined follow-up intervals (at the age of 6 months, 2, 5 and 10 years). The aim is to achieve a cross-sectoral improvement of quality in healthcare on the basis of neurodevelopmental outcome parameters (the right therapy for the right child, at the right time). So far 739 extremely preterm infants (81% of the survivors) were examined at the age of six months, 513 ELBW infants (74% of the survivors) at the age of two years, and 99 children (59% of the survivors) at the age of five years. The comparison of the follow-up intervals has demonstrated an increase of children with minor and major impairment, which indicates the importance of the long-term scheme. At the age of five years 27% of the children exhibit normal development, 49% minor impairment and 24% major impairment. Many ELBW infants need therapy. The model of the project can be transferred to other federal states or regions and other high-risk groups.

Erythropoietin improves neurodevelopmental outcome of extremely preterm infants.

OBJECTIVE: Erythropoietin has been reported to possess neuroprotective properties in animal studies. No previous studies have investigated the neurodevelopmental outcome of extremely low birth weight (ELBW) infants treated with recombinant human erythropoietin (rEpo) and evaluated it at school age. METHODS: Of 200 ELBW infants treated from 1993 to 1998, 171 (86%) survived, and 148 (87%) were followed up to the age of 10 to 13 years. The neurodevelopmental and school outcome of the ELBW infants receiving rEpo treatment for stimulation of erythropoiesis in the first weeks of life (n = 89) was compared to that of untreated children (n = 57). To test for a neuroprotective effect of erythropoietin therapy, analyses of variance (ANOVAs) were conducted with erythropoietin treatment and intraventricular hemorrhage (IVH) as independent variables and Hamburg-Wechsler Intelligence Test for Children-III (HAWIK-III) intelligence quotient (IQ) scores as dependent variables. RESULTS: The rEpo group scored significantly better than untreated children in the overall developmental assessment (55% vs 39% normally developed, p < 0.05) as well as in the psychological examination (mean composite HAWIK-III IQ score, 90.8 vs 81.3, p < 0.005). The results of ANOVAs show that these differences were ascribable to children with IVH. Whereas those children with IVH treated with rEpo scored significantly better than untreated children (52% vs 6% normally developed, composite HAWIK-III IQ score, 90.3 vs 67.0), treated and untreated children without IVH did not differ in their outcome. The treatment and control groups were comparable in perinatal parameters relevant to prognosis. INTERPRETATION: The results of our observational study confirm the hypothesis of a neuroprotective effect of rEpo in ELBW infants with IVH. This offers a promising preventative therapeutic option for the treatment of these high-risk infants.

Long-term follow-up in patients with congenital myasthenic syndrome due to CHAT mutations.

BACKGROUND: Congenital myasthenic syndromes (CMSs) are a group of clinically and genetically heterogeneous inherited disorders of the neuromuscular junction. Mutations in the acetylcholine transferase (CHAT) gene cause a pre-synaptic CMS, typically associated with episodic apnoea and worsening of myasthenic symptoms during crises caused by infections, fever or stress. Between crises symptoms may be mild and variable. Acetylcholinesterase - inhibitor therapy is reported to improve clinical symptoms and reduce crises. PATIENTS AND METHODS: We present data on the long-term follow-up of 11 patients with a congenital myasthenic syndrome due to nine different CHAT mutations; ten of the patients have not been previously reported. RESULTS AND CONCLUSIONS: Manifestation varied from the neonatal period to the age of two years, follow-up time from nine months to 12 years. This cohort of CHAT patients studied here enabled us to describe two distinct phenotypes: The neonatal-onset group suffers from apnoeic crises, respirator dependency and bulbar weakness. Apnoea should be carefully distinguished from seizures; a CMS should be taken into account early to start appropriate therapy. Infantile-onset patients show mild permanent weakness, but experience apnoeic crises and worsening which resolve with Acetylcholinesterase - inhibitor treatment. However, after several years of treatment proximal muscle strength may decrease and lead to wheelchair dependency despite the continuation of Acetylcholinesterase - inhibitor therapy.

Outcome of extremely low birth weight survivors at school age: the influence of perinatal parameters on neurodevelopment.

Extremely low birth weight (ELBW) is associated with impaired neurodevelopmental outcome in infancy. Information on the long-term cognitive and neurological consequences of ELBW is scarce. We aimed to identify the perinatal and neonatal factors of ELBW infants associated with adverse cognitive and neurological outcome at school age. A regional cohort of 135 ELBW infants born between 1993 and 1998 was prospectively evaluated at 3, 6, 12, and 18 months postmenstrual age and at yearly intervals up to age 10 years. The comprehensive follow-up programme for high-risk infants included neurological examinations and psychometric evaluations. According to the overall results of these tests, children were classified as either being normal or having minor or major impairment. At a mean age of 8.4 (SD: 1.6) years, 43% of children had survived without any impairment. Minor impairment was diagnosed in 39% and major impairment in 18% of assessed children. The proportion of disabled school children rose with decreasing gestational age. The following neonatal complications were significant risk factors for developing major or minor impairment at school age: an increase in head circumference < 6 mm per week (OR 4.0, 95% CI: 1.1-14.8), parenteral nutrition > or = 6 weeks (OR 2.5, 95% CI: 1.1-6.0), and mechanical ventilation > 14 days (OR 2.3, 95% CI: 1.0-5.1). High-grade intraventricular haemorrhage (IVH) and/or PVL (OR 13.3, 95% CI: 4.0-44.9), neonatal seizures (OR 5.2, 95% CI: 1.2-22.4) and bowel perforation, and/or necrotizing enterocolitis (OR 4.4, 95% CI: 1.1-17.0) were significant risk factors for developing major impairment. In spite of the relatively large proportion of normal children, ELBW remains an important risk factor for neurodevelopmental impairment at school age. Thus, measures to prevent complications such as necrotizing enterocolitis, cerebral haemorrhage, and undernutrition remain important goals for neonatal intensive care.

Neurodevelopmental outcome in extremely low birth weight infants: what is the minimum age for reliable developmental prognosis?

AIM: We present a longitudinal study on the neurodevelopmental outcome in preterm infants with extremely low birth weight <1000 g (ELBW) to answer the question at which age a developmental prognosis can be given. METHODS: A group of 129 ELBW, median birth weight: 794 g (SD 123 g), gestational age: 27.0 weeks (SD 2.0 weeks), born between 1993 and 1998, were followed up to the age between 6 and 10 years (mean 8.5 years [SD 1.7 years]) and evaluated by neurodevelopmental and psychometric tests. The status of children without cerebral palsy was ranked into categories of major, minor and no developmental impairments. RESULTS: At the time of the last follow-up examination 17% of the children showed a major impairment including 9% cerebral palsy, 42% a minor impairment and 41% were normally developed. The longitudinal analysis of cases without cerebral palsy reveals that an assessment 'at term' can only give the correct developmental prognosis in 49% of the cases. At the corrected age of 12 months the prognosis is correct in 59% of the cases, whereas at the corrected age of 3 years 70% proves to be right. Diagnosis of cerebral palsy could be confirmed at the corrected age of 2 years with sufficient reliability. CONCLUSION: The neurodevelopmental evaluation of former preterm infants with a birth weight <1000 g demands a follow-up period of at least 6 years in order to make reliable statements. We are doubtful that follow-up testing completed prior to this age can yield reliable results.

Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase.

Congenital myasthenic syndromes are caused by different genetic defects affecting proteins expressed at the neuromuscular junction. Recently, the first molecular genetic defect resulting in a presynaptic congenital myasthenic syndrome has been reported: Recessive loss-of-function mutations in CHAT, the gene encoding choline acetyltransferase, were described in five congenital myasthenic syndrome families. In this study, we investigated three patients from two independent Turkish kinships. Clinically, all patients presented with moderate myasthenic symptoms including ptosis and muscle weakness with increased fatigability. Multiple episodes of sudden apnea were reported for all patients. One child suffering from a second, unrelated disorder, i.e. hepatocellular carcinoma, showed a severe myasthenic phenotype, requiring permanent ventilation. Genetically, we identified a novel missense mutation (I336T) in the CHAT gene homozygously in all three patients. Haplotype analysis revealed that the mutant allele cosegregates with the clinical phenotype in both families (maximum combined two-point LOD-score of 2.46 for D10S1793). In summary, we confirm that CHAT mutations are responsible for a clinically distinct form of congenital myasthenic syndrome, characterized by episodic apnea. Infections and stress may lead to a life-threatening failure of neuromuscular transmission in congenital myasthenic syndrome with episodic apnea. The observation of the same mutation (I336T) in two independent Turkish kinships may suggest a common origin, i.e. founder.

A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene.

Multi-minicore disease is an autosomal recessive congenital myopathy characterized by the presence of multiple, short-length core lesions (minicores) in both muscle fiber types. These lesions being nonspecific and the clinical phenotype being heterogeneous, multi-minicore disease boundaries remain unclear. To identify its genetic basis, we performed a genome-wide screening in a consanguineous Algerian family in which three children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. We mapped the disease to chromosome 19q13 in this family and, subsequently, in three additional families showing a similar phenotype, with a maximum LOD score of 5.19 for D19S570. This locus was excluded in 16 other multi-minicore disease families with predominantly axial weakness, scoliosis, and respiratory insufficiency ("classical" phenotype). In the Algerian family, we identified a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. New muscle biopsies from the three patients at adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. This subgroup of families linked to 19q13 represents the first variant of central core disease with genetically proven recessive inheritance and transient presentation as multi-minicore disease.