Patterns of cardiac involvement in different muscular dystrophies assessed by magnetic resonance imaging.

BACKGROUND: In muscular dystrophies, it is not only skeletal muscles that can be affected, but also the myocardium. This cardiac involvement can represent a major cause of morbidity and mortality. PURPOSE: To investigate cardiac involvement in Duchenne (DMD), Becker (BMD), and limb girdle muscular dystrophy (LGMD) patients, and carriers of DMD/BMD by cardiac magnetic resonance (CMR) imaging and to search for differences in the pattern of cardiac involvement. MATERIAL AND METHODS: All patients with genetically or histologically proven DMD, BMD, and LGMD, or confirmed carriers of DMD/BMD who had undergone CMR at our clinic between January 2008 and November 2018 were retrospectively included and re-evaluated for regional and global left ventricular function, increased trabecularization, and late enhancement. RESULTS: A total of 26 DMD, 10 BMD, 11 LGMD, and seven DMD/BMD carriers were included. Only one carrier of DMD presented with normal CMR results; all other participants showed cardiac abnormalities. Regional wall motion abnormalities (RWMA; prevalence in LGMD patients: 55%) and late enhancement (prevalence in LGMD patients: 82%) were frequent. RWMA were accentuated basal inferolateral in DMD/BMD carriers, while in LGMD they were accentuated apical. In all groups late enhancement was located mainly subepicardial/midmyocardial with a basal inferolateral accentuation. Apart from the different RWMA distribution, no further group-specific differences were found. CONCLUSION: We found a high rate of cardiac involvement not only in DMD/BMD, but also in LGMD and DMD/BMD carriers with a different RWMA accentuation (apical in LGMD and basal inferolateral in DMD/BMD) as a single group-specific difference.

Update of evidence- and consensus-based guidelines for the treatment of juvenile idiopathic arthritis (JIA) by the German Society of Pediatric and Juvenile Rheumatic Diseases (GKJR): New perspectives on interdisciplinary care.

BACKGROUND: New therapeutic strategies for juvenile idiopathic arthritis (JIA) have evolved within the past ten years, and as a result, an update of the 2011 recommendations of the German management guidelines was initiated. METHODS: A systemic literature review was performed, overarching principles were proposed and pre-selected via an online survey followed by two multidisciplinary consensus conferences. Pharmacological and non-pharmacological treatments were discussed, statements were proposed and ultimately agreed upon by nominal group technique (NGT). RESULTS: 12 overarching therapeutic principles, as well as 9 recommendations on pharmacological and 5 on non-pharmacological treatments for JIA were agreed upon. CONCLUSION: This report summarizes the recent update of the interdisciplinary, consensus-based German guidelines on the management of JIA. The multi- and interdisciplinary participation of all caregivers was central for this patient-focused update. With these guidelines, physicians can choose an evidence-based approach, which allows better tailored treatment in this vulnerable cohort of children and adolescents.

Whole Exome Sequencing Identifies a Heterozygous Variant in the Cav1.3 Gene CACNA1D Associated with Familial Sinus Node Dysfunction and Focal Idiopathic Epilepsy.

Cav1.3 voltage-gated L-type calcium channels (LTCCs) are involved in cardiac pacemaking, hearing and hormone secretion, but are also expressed postsynaptically in neurons. So far, homozygous loss of function mutations in CACNA1D encoding the Cav1.3 α1-subunit are described in congenital sinus node dysfunction and deafness. In addition, germline mutations in CACNA1D have been linked to neurodevelopmental syndromes including epileptic seizures, autism, intellectual disability and primary hyperaldosteronism. Here, a three-generation family with a syndromal phenotype of sinus node dysfunction, idiopathic epilepsy and attention deficit hyperactivity disorder (ADHD) is investigated. Whole genome sequencing and functional heterologous expression studies were used to identify the disease-causing mechanisms in this novel syndromal disorder. We identified a heterozygous non-synonymous variant (p.Arg930His) in the CACNA1D gene that cosegregated with the combined clinical phenotype in an autosomal dominant manner. Functional heterologous expression studies showed that the CACNA1D variant induces isoform-specific alterations of Cav1.3 channel gating: a gain of ion channel function was observed in the brain-specific short CACNA1D isoform (Cav1.3S), whereas a loss of ion channel function was seen in the long (Cav1.3L) isoform. The combined gain-of-function (GOF) and loss-of-function (LOF) induced by the R930H variant are likely to be associated with the rare combined clinical and syndromal phenotypes in the family. The GOF in the Cav1.3S variant with high neuronal expression is likely to result in epilepsy, whereas the LOF in the long Cav1.3L variant results in sinus node dysfunction.

First follow-up of a breakable stent for implantation in infants dedicated for a life-long stay.

OBJECTIVE AND METHODS: The use of conventional metal stents in infants is severely limited by subsequent somatic growth. The use of a breakable balloon expandable stent (BS) designed for initial implant at small diameters but with properties that allow unlimited dilation in line with growth has potential advantages in this patient group. This study reports our experience with this stent between 2010 and 2014. A total of 17 BS were implanted in 14 infants (mean age 4.8 months). All but one stent was placed into the aorta to treat coarctation. RESULTS: All implantations were successful and initial gradients dropped from a mean of 25-6 mm Hg (range from 1-50 down to 0-24 mm Hg). Mean follow-up was 3.3 years (range 5 days to 7 years) with a total cumulative follow-up of 46.7 patient years. Stent redilation was performed a median of 2.5 times (range 0-5). Sixteen stents in 13 patients remain in place. Following redilation beyond 10 mm, circumferential integrity of the BS was lost in 10 patients. No further stent implantation or related surgery was necessary. A 3 mm dissection occurred in one patient after redilation. CONCLUSIONS: The BS performed well in terms of relief of stenosis and could be successfully dilated during the phase of the infants' most rapid growth. Mild intimal proliferation occurred in some patients early after implantation. In the course of the stepwise redilations and growth adjustments, both, planned longitudinal and transverse fractures occurred without allowing a collapse of the stented area.

Familial Mediterranean fever in children and adolescents: factors for colchicine dosage and predicting parameters for dose increase.

Objectives: The aim was to analyse factors influencing the individual colchicine dose in children with FMF, to evaluate the impact of dose adjustment on the clinical course and inflammation and to identify clinical parameters and biomarkers that predict dose increase in the near future. Methods: Data from 409 paediatric FMF patients (4566 visits) derived from the national auto-inflammatory diseases registry were analysed. Serum concentrations of S100 molecules were determined by ELISA. Results: The age-dependent colchicine dose is influenced by the present genotype. The body surface area is the anthropometric parameter that correlates best with the applied dosages. Colchicine introduction and dose increase lead to significant reduction of clinical symptoms and inflammation. During established colchicine therapy, an increase of one single biomarker increases the likelihood of a dose increment in the next 12 months with a factor of 1.62-1.94. A combination of biomarkers including S100 molecules increases this odds ratio up to 4.66 when analysing all patients and up to 7.27 when analysing patients with a high risk of severe disease. Conclusion: Colchicine therapy is currently guided mainly by the occurrence of clinical symptoms and serological inflammation. Other factors, such as the genotype, the body surface area and biomarkers, will help to manage colchicine therapy in a more individualized fashion. The additional analysis of S100 molecules as sensitive biomarkers will help to identify patients at risk for dose increases in the near future.

Cardiac pathologies in female carriers of Duchenne muscular dystrophy assessed by cardiovascular magnetic resonance imaging.

OBJECTIVES: Duchenne muscular dystrophy (DMD) is the most common and severe dystrophinopathy. DMD carriers rarely present with clinical symptoms, but may suffer from cardiac involvement. Because echocardiographic findings are inconsistent and cardiac magnetic resonance imaging (CMRI) data are limited, this study sought to investigate asymptomatic carriers for cardiac abnormalities using CMRI. METHODS: Fifteen genetically confirmed DMD carriers (age, 32.3 ± 10.2 years) were prospectively examined on a 1.5T MR system. Cine, T2, and late-gadolinium-enhanced (LGE) images were acquired, and were evaluated in consensus by two experienced readers. Left ventricular (LV) parameters were analysed semiautomatically, normalized to BSA. RESULTS: Normalized LV end-diastolic volume was increased in 7% (73.7 ± 16.8 ml/m(2); range, 48-116 ml/m(2)) and normalized LV end-systolic volume in 20% (31.5 ± 13.3 ml/m(2); range, 15-74 ml/m(2)). EF was reduced in 33% (58.4 ± 7.6%; range, 37-69%) and normalized LV myocardial mass in 80% (40.5 ± 6.8 g/m(2); range, 31-55 g/m(2)). In 80%, regional myocardial thinning was detected in more than one segment. In 13% and 40%, apical-lateral accentuation of LV non-compaction was present. LGE was found in 60% (midmyocardial inferolateral accentuation). CONCLUSIONS: Given the high frequency of cardiac pathologies detected by CMRI, regular cardiac risk assessment is advisable for DMD carriers. Besides clinical examination, CMRI is an excellent tool for this purpose. KEY POINTS: • Fifteen Duchenne muscular dystrophy carriers investigated using CMRI all showed cardiac pathologies. • Myocardial mass reduction, regional myocardial thinning, and late gadolinium enhancement were common. • Regular cardiac risk assessment is thus advisable in Duchenne muscular dystrophy carriers. • Besides clinical examination, CMRI is an excellent tool for this purpose.

Volumetric measurements in patients with corrected tetralogy of Fallot: comparison of short-axis versus axial cardiac MRI and echocardiography.

BACKGROUND: Patients with corrected tetralogy of Fallot (cToF) are prone to develop pulmonary regurgitation and right ventricular enlargement resulting in long-term complications, thus correct right ventricular volumetric monitoring is crucial. However, it remains controversial which cardiovascular magnetic resonance imaging (CMRI) slice orientation is most appropriate in cToF for the analysis of the right ventricular volume. PURPOSE: To investigate which slice orientation is most suited for right ventricular volumetry in cToF we compared short-axis and axial slices, and furthermore we compared right ventricular data between CMRI and echocardiography. MATERIAL AND METHODS: Thirty CMRI examinations of 27 patients with cToF were included retrospectively. Right ventricular end-diastolic (EDV) and end-systolic volume (ESV) were derived from short-axis and axial cine CMRI planes. Furthermore, pulmonary trunk forward flow in phase-contrast CMRI and right ventricular inner diastolic diameter in echocardiography (R VIDdiast) were measured. By Bland-Altman and variance analysis intra- and inter-observer agreement were assessed for cine CMRI data. By Pearson correlation CMRI cine and phase-contrast data and CMRI cine and echocardiographic data were compared. RESULTS: Intra- and inter-observer variability for right ventricular EDV were significantly lower in axial slices (P = 0.016, P = 0.010). For right ventricular ESV a trend towards a lower intra- and inter-observer variability in axial slices was found (P = 0.063, P = 0.138). Right ventricular stroke volume in short-axis (r = 0.872, P < 0.001) and in axial (r = 0.914, P < 0.001) planes correlated highly, respectively very highly with pulmonary trunk forward flow in phase-contrast CMRI. R VIDdiast correlated highly with right ventricular EDV assessed by short-axis and axial CMRI (P < 0.001, P < 0.001). CONCLUSION: Due to lower intra- and inter-observer variability, axial slices are recommended for right ventricular volumetry in cToF.

Pulse oximetry is insufficient for timely diagnosis of hepatopulmonary syndrome in children with liver cirrhosis.

OBJECTIVE: To prospectively investigate the prevalence of hepatopulmonary syndrome (HPS), the importance of pulse oximetry in diagnosing HPS, and the longitudinal course after liver transplantation in children with cirrhosis referred for liver transplantation. STUDY DESIGN: Fifty-six patients aged 1-17 years (mean age, 4.6 ± 5.0 years) with liver cirrhosis were screened for HPS by hyperemic capillary blood gas (CBG) analysis and contrast-enhanced transthoracic echocardiography. Eleven patients were excluded owing to conditions that can produce cardiopulmonary dysfunction, including 5 with cystic fibrosis, 1 with pulmonary arterial hypertension, and 5 with an intracardial shunt. HPS was classified in accordance with the European Respiratory Society Task Force criteria on pulmonary-hepatic disorders. Patient groups were compared for biochemical and clinical characteristics. RESULTS: Eighteen children (40%) with cirrhosis were intrapulmonary vasodilatation (IPVD)-positive and had a pulse oximetry oxygen saturation level >98%. Two of these patients (11%) exhibited moderate HPS with an elevated alveolar arterial oxygen gradient >15 mm Hg and PaO2 <70 mm Hg; they died before undergoing liver transplantation. The sensitivity and specificity of CBG analysis for detecting elevated alveolar arterial oxygen gradient in children with IPVD was 94% and 53%, respectively. HPS was associated with late hepatoportoenterostomy (P < .04). Liver transplantation led to resolution of HPS in all patients. CONCLUSION: IPVD is frequent in children with liver cirrhosis (40%). Pulse oximetry is insufficient for timely HPS diagnosis. Pathological CBG analysis data indicate IPVD in the majority of cases, but are imprecise in children aged <2 years. Contrast-enhanced transthoracic echocardiography and CBG analysis are recommended for evaluation of HPS in children with cirrhosis, regardless of liver synthesis capacity and clinical chemistry data.

Quantification of congenital aortic valve stenosis in pediatric patients: comparison between cardiac magnetic resonance imaging and transthoracic echocardiography.

Previous studies showed the reliability of cardiac magnetic resonance imaging (cMRI) in the quantification of aortic valve stenosis in adults. The aim of this retrospective study was to assess the ability of cMRI in the quantification of congenital aortic valve stenosis (CAS) in children. Nineteen patients (mean age 14.0 ± 3.2 years, 15 boys and 4 girls) with CAS were imaged by cMRI and transthoracic echocardiography (TTE). cMRI was performed on a 1.5-Tesla MR scanner (Magnetom Avanto; Siemens Healthcare, Erlangen, Germany) using cine steady-state free precession sequences for the assessment of the aortic valve area (AVA) by MR planimetry and left-ventricular function. Phase-contrast measurement was used in cMRI to assess peak flow velocity above the aortic valve. A positive correlation was found between maximum systolic pressure gradient (MPG) as assessed by cMRI and TTE (28.9 ± 21.2 vs. 41.3 ± 22.7 mmHg, r = 0.84, p = 0.001) with a mean underestimation of 12.4 mmHg by cMRI. Only a weak correlation could be observed between AVA by cMRI and MPG at the aortic valve by TTE (r = -0.50, p = 0.029) and cMRI (r = -0.27, p = 0.40). Furthermore, a positive correlation between myocardial mass (cMRI) and MPG (TTE, r = 0.57, p = 0.01), but not between myocardial mass (cMRI) and AVA (cMRI, r = 0.07, p = 0.77), was found. The assessment of MPG by cMRI in patients with CAS is feasible with a trend toward underestimatation compared with TTE. Moreover, MPG seems to be a more accurate parameter than AVA regarding the prediction of myocardial hypertrophy.

Contrast-enhanced time-resolved 4D MRA of congenital heart and vessel anomalies: image quality and diagnostic value compared with 3D MRA.

OBJECTIVES: To evaluate time-resolved interleaved stochastic trajectories (TWIST) contrast-enhanced 4D magnetic resonance angiography (MRA) and compare it with 3D FLASH MRA in patients with congenital heart and vessel anomalies. METHODS: Twenty-six patients with congenital heart and vessel anomalies underwent contrast-enhanced MRA with both 3D FLASH and 4D TWIST MRA. Images were subjectively evaluated regarding total image quality, artefacts, diagnostic value and added diagnostic value of 4D dynamic imaging. Quantitative comparison included signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and vessel sharpness measurements. RESULTS: Three-dimensional FLASH MRA was judged to be significantly better in terms of image quality (4.0 ± 0.6 vs 3.4 ± 0.6, P < 0.05) and artefacts (3.8 ± 0.4 vs 3.3 ± 0.5, P < 0.05); no difference in diagnostic value was found (4.2 ± 0.4 vs 4.0 ± 0.4); important additional functional information was found in 21/26 patients. SNR and CNR were higher in the pulmonary trunk in 4D TWIST, but slightly higher in the systemic arteries in 3D FLASH. No difference in vessel sharpness delineation was found. CONCLUSIONS: Although image quality was inferior compared with 3D FLASH MRA, 4D TWIST MRA yields robust images and added diagnostic value through dynamic acquisition was found. Thus, 4D TWIST MRA is an attractive alternative to 3D FLASH MRA. KEY POINTS: • New magnetic resonance angiography (MRA) techniques are increasingly introduced for congenital cardiovascular problems. • Time-resolved angiography with interleaved stochastic trajectories (TWIST) is an example. • Four-dimensional TWIST MRA provided inferior image quality compared to 3D FLASH MRA but without significant difference in vessel sharpness. • Four-dimensional TWIST MRA gave added diagnostic value.

Neurogenic stunned myocardium after embolization in two children with vein of Galen aneurysmal malformation.

INTRODUCTION: This study reports the first cases of neurogenic stunned myocardium in two children with vein of Galen aneurysmal malformation after interventional treatment. PATIENTS: Two newborns with vein of Galen aneurysmal malformation and high output cardiac failure developed a severe reversible left ventricular dysfunction shortly after embolization, concurrently with acute hydrocephalus. RESULTS: There was a resolution of the cardiac symptoms of left ventricular dysfunction within a few days under treatment with milrinone and dobutamine. CONCLUSIONS: Reversible left ventricular dysfunction is observed in adult patients mainly after subarachnoid hemorrhage and is called neurogenic stunned myocardium (NSM). Other forms of brain injuries have also been identified accounting for this condition in adults. In pediatric population especially with specific cerebral diseases, NSM may be underdiagnosed.

Working Towards a Treat-to-Target Protocol in Juvenile Proliferative Lupus Nephritis - A Survey of Pediatric Rheumatologists and Nephrologists in Germany and Austria.

Background: To describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN. Methods: Survey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Pediatric Nephrology (GPN) on diagnostics and (concomitant) therapy of LN. Results: Fifty-eight physicians completed the survey. Overall, there was a considerable heterogeneity regarding the suggested diagnostics and management of juvenile proliferative LN. Increased urinary protein excretion, either assessed by 24 h urine collection or spot urine (protein-creatinine ratio), and reduced estimated glomerular filtration rate were specified as important parameters for indication of kidney biopsy to diagnose proliferative LN and monitoring of therapy. Corticosteroids were generally proposed for induction and maintenance therapy, most often in conjunction with either mycophenolate mofetil (MMF) or cyclophosphamide (CP) as steroid-sparing immunosuppressants. MMF was clearly preferred over CP for induction therapy of LN class III, whereas CP and MMF were equally proposed for LN class IV. MMF was most often recommended for maintenance therapy in conjunction with oral corticosteroids and continued for at least 3 years and 1 year, respectively, after remission. Hydroxychloroquine was widely accepted as a concomitant measure followed by renin-angiotensin system inhibitors in cases of arterial hypertension and/or proteinuria. Conclusion: The majority of pediatric rheumatologists and nephrologists in Germany and Austria propose the use of corticosteroids, most often in combination with either MMF or CP, for treatment of proliferative LN in children. The considerable heterogeneity of responses supports the need for a treat-to-target protocol for juvenile proliferative LN between pediatric rheumatologists and nephrologists.

Translational research network and patient registry for auto-inflammatory diseases.

OBJECTIVE: Auto-inflammatory diseases (AIDs) are characterized by recurrent self-limiting systemic inflammation. In a multicentre effort, we set out to register genetic, epidemiological and clinical features as well as prognostic factors of these diseases by prospective longitudinal and long-term documentation, in order to define novel AIDs and to better understand treatment responses and outcome. METHODS: In 2009, a federally funded clinical and research consortium (AID-Net) was established, including an online registry for AIDs (http://www.aid-register.uk-essen.de). Inclusion criteria are disease-associated mutations for hereditary periodic fever syndromes [FMF, hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), TNF receptor 1-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS)], or, alternatively, clinically confirmed AID, systemic-onset JIA (SoJIA) and periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome with unknown genetic background. Patients were recruited to the registry and patient material was deposited in biomaterial banks (DNA/serum). In addition, basic research projects were initiated that focus on molecular mechanisms of AID. RESULTS: During the first 9 months, 117 patients (65 males, 52 females; age 1-21 years) have been recorded and classified as FMF (n=84), HIDS (n=1), TRAPS (n=3) and CAPS (n=1); clinically confirmed AID (n=5); SoJIA (n=22); and PFAPA (n=1). One hundred and fifty blood samples of 18 patients were included in biomaterial banks. CONCLUSION: Recruitment and follow-up of patients with AID will enable us to comprehensively address the correlation between clinical and epidemiological data, genetics and biomarkers. The translational approach may help to identify genetic or inflammatory markers relevant for the course and outcome of diseases.

TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19.

Among children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are typically mild. Here, we describe the case of a 3.5-year-old girl with an unusually severe presentation of coronavirus disease (COVID-19). The child had an autoinflammatory disorder of unknown etiology, which had been treated using prednisolone and methotrexate, and her parents were half cousins of Turkish descent. After 5 days of nonspecific viral infection symptoms, tonic-clonic seizures occurred followed by acute cardiac insufficiency, multi-organ insufficiency, and ultimate death. Trio exome sequencing identified a homozygous splice-variant in the gene TBK1, and a homozygous missense variant in the gene TNFRSF13B. Heterozygous deleterious variants in the TBK1 gene have been associated with severe COVID-19, and the variant in the TNFRSF13B gene has been associated with common variable immunodeficiency (CVID). We suggest that the identified variants, the autoinflammatory disorder and its treatment, or a combination of these factors probably predisposed to lethal COVID-19 in the present case.

Experiences with IL-1 blockade in systemic juvenile idiopathic arthritis - data from the German AID-registry.

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with dysregulation of the innate immune system driven by cytokines. A major role is ascribed to interleukin-1ß (IL-1ß), supporting the autoinflammatory character of the disease and offering an effective blocking mechanism for treatment. Here we present clinical practice data from the German AID-registry for patients treated with IL-1 inhibition (IL-1i). METHODS: In 2009 a clinical and research consortium (AID-Net) was established, including an online AID-registry. Patients with documented sJIA diagnosis were identified. Data for this retrospective IL-1i study were recorded by 17 centers. Response to treatment was evaluated according to Wallace criteria and additionally by an own classifying clinical response system. RESULTS: In 6 years, 202 patients with confirmed sJIA were recorded in the AID-registry. Out of these, 111 children received therapy with Anakinra (ANA) (n = 84, 39 f) and/or Canakinumab (CANA) (n = 27, 15 f) at a median age of 8.7 y (range 0.6-19.1). During the first 12 months 75/111 (ANA 55, CANA 20) patients were evaluated according to Wallace criteria (achievement of inactive disease 28/55 and 17/20, remission over 6 months under medication 13/55 and 7/20 cases). Over the whole period of time, clinical response was preserved in the majority of patients (ANA 54/80, CANA 20/27). Arthritis mostly persisted in polyarticular (PA) courses. During treatment with IL-1i concomitant medication could be tapered in about 15%. IL-1i was discontinued in 59/111 patients. 45 (15) adverse events (AE)s in ANA (CANA) treated patients (19.7 (26.6) AE/100 ANA (CANA) exposure years, 95%CI: 14.4-26.4 (14.9-43.9)) were reported. CONCLUSION: In a large cohort of sJIA patients from Germany, we can confirm an overall favorable clinical response to both available IL-1 blocking agents. IL-1i was well tolerated with acceptable safety and effectiveness in a real-life clinical setting.

Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism.

BACKGROUND: Newborns with inborn errors of metabolism often present with hyperammonaemic coma, requiring prompt diagnosis and specific medical therapy, nutritional support and efficient toxin removal. Little information regarding the efficacy and safety of continuous venovenous haemodialysis (CVVHD) as an option for extracorporal ammonia detoxification in children is available. METHODS: Twenty-one patients with hyperammonaemia [19 neonates (mean age 4.1 +/- 2.4 days) and two children 1 and 7 years of age, respectively] were admitted to our hospital for dialysis between 1996 and 2008. Seventeen children (15 neonates), received CVVHD. Four neonates received continuous peritoneal dialysis (CPD). All started medical treatment with sodium benzoate, l-arginine hydrochloride and carnitine as well as protein-restricted parenteral diets with high caloric intake before dialysis. RESULTS: Plasma ammonia levels (range 464-7267 microg/dl before dialysis and 27-3317 microg/dl after dialysis) were significantly reduced by 50% within 4.7 +/- 2.5 h with CVVHD compared with 13.5 +/- 6.2 h with CPD (P < 0.0001). Plasma ammonia levels <200 microg/dl critical range were achieved within 22.4 +/- 18.1 h in CVVHD patients compared with 35.0 +/- 24.1 h with CPD. Depending on the weight and blood pressure stability of the patients, mean blood flow velocities of 9.8 +/- 3.4 ml/kg/min and mean dialysate flow rates of 3925 +/- 2398 ml/min/1.73 m(2) were employed. Blood and dialysate flows significantly correlated with ammonia clearance and decay of ammonia in vivo. Because of the severe underlying disease, 18% of CVVHD patients died compared with 50% undergoing CPD. In total, 82% of CVVHD patients survived the first 6 months after dialysis. Among these, 43% were without sequelae, 43% developed moderate mental retardation, and two (14%) developed severe mental retardation. CONCLUSION: CVVHD effectively and quickly eliminates plasma ammonia. To optimize long-term mental outcome, rapid identification and appropriate treatment of the underlying disease as well as starting dialysis early are of enormous therapeutic value.

Cardiac biomarkers for the detection of cardiotoxicity in childhood cancer-a meta-analysis.

AIMS: Childhood cancer therapy is associated with a significant risk of therapy-related cardiotoxicity. This meta-analysis aims to evaluate cardiac biomarkers for the detection of cancer therapy-related left ventricular (LV) dysfunction in childhood cancer patients. METHODS AND RESULTS: PubMed, Cochrane Library, Wiley Library, and Web of Science were screened for studies investigating brain natriuretic peptide (BNP)/N-terminal proBNP (NT-proBNP) or cardiac troponin in childhood cancer patients. The odds ratios (OR) for elevation of cardiac biomarkers and association with LV dysfunction were calculated using a random-effects model. Data from 27 studies with 1651 subjects were included. BNP/NT-proBNP levels were higher post-treatment compared with controls or pre-treatment values [standardized mean difference = 1.0; 95% confidence interval (CI) = 0.6-1.4; n = 320; P < 0.001]. LV dysfunction was present in 11.76% of included patients, and risk for LV dysfunction was increased in patients with elevated BNP/NT-proBNP (OR = 7.1; 95% CI = 2.0-25.5; n = 350; P = 0.003). The sensitivity of BNP/NT-proBNP for the detection of LV dysfunction was 33.3%, and the specificity was 91.5%. Sensitivity increased when selecting for studies that assessed patients < 5 years after anthracycline exposure and for studies including high cumulative anthracycline doses. Anthracycline chemotherapy was associated with an increased frequency of elevated troponin (OR = 3.7; 95% CI = 2.1-6.5; n = 348; P < 0.001). The available evidence on the association between elevated troponin and LV dysfunction was insufficient for an adequate analysis. In five included studies, the frequency of LV dysfunction was not increased in patients with elevated troponin (OR = 2.5; 95% CI = 0.5-13.2; n = 179; P = 0.53). CONCLUSIONS: BNP/NT-proBNP is associated with cardiotoxicity in paediatric cancer patients receiving anthracycline therapy, but owing to low sensitivity, BNP/NT-proBNP has to be evaluated in the context of further parameters including clinical assessment and echocardiography. Future studies are needed to determine whether troponin serves as a marker for cardiotoxicity in children. Standardized recommendations for the application of cardiac biomarkers in children undergoing cardiotoxic cancer therapy may benefit management and clinical outcome.

Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology.

The acute and long-lasting side effects of modern multimodal tumour therapy significantly impair quality of life and survival of patients afflicted with malignancies. The key components of this therapy include radiotherapy, conventional chemotherapy, immunotherapy and targeted therapies. In addition to established tumour therapy strategies, up to 30 new therapies are approved each year with only incompletely characterised side effects. This consensus paper discusses the risk factors that contribute to the development of a potentially adverse reaction to tumour therapy and, in addition, defines specific side effect profiles for different treatment groups. The focus is on novel therapeutics and recommendations for the surveillance and treatment of specific patient groups.

Incidence of TNFRSF1A mutations in German children: epidemiological, clinical and genetic characteristics.

OBJECTIVE: TNF receptor 1-associated periodic syndrome (TRAPS) is a rare disease belonging to the heterogeneous group of hereditary periodic fever (HPF) syndromes. By their monogenic origins, the HPF syndromes are clearly differentiated from other periodic inflammatory episodes occurring in autoimmune, neoplastic and infectious diseases. We aim to determine the incidence of TRAPS and the spectrum of mutations in the TNFRSF1A gene, and to give a brief survey of clinical signs. METHODS: A prospective surveillance of children with TRAPS was conducted in Germany during a time period of 3 years (2003-06). Monthly inquiries were sent to 370 children's hospitals by the German Pediatric Surveillance Unit (Clinic-ESPED, n1) and to 23 laboratories (Laboratory-ESPED, n2). Inclusion criteria were TNFRSF1A mutation-positive patients < or =16 years of age, more than three self-limiting episodes of fever >38.5 degrees C, and increased inflammation markers. Clinical, epidemiological and genetic data were evaluated via questionnaires. RESULTS: Of the 23 cases included, 19 were identical in 20 clinical and 22 laboratory reports. The incidence of TRAPS in German children was estimated to be approximately 5.6 per 10(7) person-years. In 20 TRAPS patients of the Clinic-ESPED, median age of onset and duration of fever periods were 6 (range 1-16) years and 6.3 (range 2-24) days, respectively. Main symptoms were arthralgia, abdominal pain, lymphadenopathy, headache and skin involvement. The R92Q substitution was found in 19 (83%) of 23 cases. CONCLUSION: The incidence of TRAPS is low and corresponds to 6-10 newly diagnosed patients < or =16 years per year in Germany.

Diagnostic Work-Up of Pulmonary Hypertension - Think About Shunt Flow! A Case Report.

BACKGROUND The diagnostic work-up and treatment of pulmonary hypertension can be complex. Pulmonary arterial hypertension (PAH), pulmonary hypertension second to lung or heart diseases and thromboembolic pulmonary hypertension, and other rare causes of pulmonary hypertension such as congenital heart diseases must be considered in the differential diagnostic work-up. CASE REPORT We report on a patient who has been treated for PAH over many years. At the age of 65, progressive symptoms required a complete re-evaluation. Here, a complex shunt vitium with a partial anomalous pulmonary venous return (PAPVR) and a sinus venosus defect (SVD) was diagnosed. CONCLUSIONS PAPVR is a rare congenital heart disease that is often associated with an SVD. It is usually diagnosed during childhood but may also be detected in adult patients who develop pulmonary hypertension and dyspnea as primary symptoms. The initial predominant left-to-right shunting associated with this disease may be undetected for years, with a slow development of right heart failure with right heart volume overload and pulmonary hypertension. Early detection is important, with a subsequent surgical intervention.