Neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices in neonatal congenital heart disease: a European survey

BACKGROUND Brain injury and neurodevelopmental impairment remain a concern in children with complex congenital heart disease (CHD). A practice guideline on neuromonitoring, neuroimaging, and neurodevelopmental follow-up in CHD patients undergoing cardiopulmonary bypass surgery is lacking. The aim of this survey was to systematically evaluate the current practice in centers across Europe. METHODS An online-based structured survey was sent to pediatric cardiac surgical centers across Europe between April 2019 and June 2020. Results were summarized by descriptive statistics. RESULTS Valid responses were received by 25 European centers, of which 23 completed the questionnaire to the last page. Near-infrared spectroscopy was the most commonly used neuromonitoring modality used in 64, 80, and 72% preoperatively, intraoperatively, and postoperatively, respectively. Neuroimaging was most commonly performed by means of cranial ultrasound in 96 and 84% preoperatively and postoperatively, respectively. Magnetic resonance imaging was obtained in 72 and 44% preoperatively and postoperatively, respectively, but was predominantly reserved for clinically symptomatic patients (preoperatively 67%, postoperatively 64%). Neurodevelopmental follow-up was implemented in 40% of centers and planned in 24%. CONCLUSIONS Heterogeneity in perioperative neuromonitoring and neuroimaging practice in CHD in centers across Europe is large. The need for neurodevelopmental follow-up has been recognized. A clear practice guideline is urgently needed. IMPACT There is large heterogeneity in neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices among European centers caring for neonates with complex congenital heart disease. This study provides a systematic evaluation of the current neuromonitoring, neuroimaging, and neurodevelopmental follow-up practice in Europe. The results of this survey may serve as the basis for developing a clear practice guideline that could help to early detect and prevent neurological and neurodevelopmental sequelae in neonates with complex congenital heart disease

White matter injury in term neonates with congenital heart diseases: Topology & comparison with preterm newborns

Background: Neonates with congenital heart disease (CHD) are at high risk of punctate white matter injury (WMI) and impaired brain development. We hypothesized that WMI in CHD neonates occurs in a characteristic distribution that shares topology with preterm WMI and that lower birth gestational age (GA) is associated with larger WMI volume. Objective: (1) To quantitatively assess the volume and location of WMI in CHD neonates across three centres. (2) To compare the volume and spatial distribution of WMI between term CHD neonates and preterm neonates using lesion mapping. Methods: In 216 term born CHD neonates from three prospective cohorts (mean birth GA: 39 weeks), WMI was identified in 86 neonates (UBC: 29; UCSF: 43; UCZ: 14) on pre- and/or post-operative T1 weighted MRI. WMI was manually segmented and volumes were calculated. A standard brain template was generated. Probabilistic WMI maps (total, pre- and post-operative) were developed in this common space. Using these maps, WMI in the term CHD neonates was compared with that in preterm neonates: 58 at early-in-life (mean postmenstrual age at scan 32.2 weeks); 41 at term-equivalent age (mean postmenstrual age at scan 40.1 weeks). Results: The total WMI volumes of CHD neonates across centres did not differ (p = 0.068): UBC (median = 84.6 mm 3 , IQR = 26–174.7 mm 3 ); UCSF (median = 104 mm 3 , IQR = 44–243 mm 3 ); UCZ (median = 121 mm 3 , IQR = 68–200.8 mm 3 ). The spatial distribution of WMI in CHD neonates showed strong concordance across centres with predilection for anterior and posterior rather than central lesions. Predominance of anterior lesions was apparent on the post-operative WMI map relative to the pre-operative map. Lower GA at birth predicted an increasing volume of WMI across the full cohort (41.1 mm 3 increase of WMI per week decrease in gestational age; 95% CI 11.5–70.8; p = 0.007), when accounting for centre and heart lesion. While WMI in term CHD and preterm neonates occurs most commonly in the intermediate zone/outer subventricular zone there is a paucity of central lesions in the CHD neonates relative to preterms. Conclusions: WMI in term neonates with CHD occurs in a characteristic topology. The spatial distribution of WMI in term neonates with CHD reflects the expected maturation of pre-oligodendrocytes such that the central regions are less vulnerable than in the preterm neonates

A Uniform Description of Perioperative Brain MRI Findings in Infants with Severe Congenital Heart Disease:Results of a European Collaboration

BACKGROUND AND PURPOSE: A uniform description of brain MR imaging findings in infants with severe congenital heart disease to assess risk factors, predict outcome, and compare centers is lacking. Our objective was to uniformly describe the spectrum of perioperative brain MR imaging findings in infants with congenital heart disease. MATERIALS AND METHODS: Prospective observational studies were performed at 3 European centers between 2009 and 2019. Brain MR imaging was performed preoperatively and/or postoperatively in infants with transposition of the great arteries, single-ventricle physiology, or left ventricular outflow tract obstruction undergoing cardiac surgery within the first 6 weeks of life. Brain injury was assessed on T1, T2, DWI, SWI, and MRV. A subsample of images was assessed jointly to reach a consensus. RESULTS: A total of 348 MR imaging scans (180 preoperatively, 168 postoperatively, 146 pre- and postoperatively) were obtained in 202 infants. Preoperative, new postoperative, and cumulative postoperative white matter injury was identified in 25%, 30%, and 36%; arterial ischemic stroke, in 6%, 10%, and 14%; hypoxic-ischemic watershed injury in 2%, 1%, and 1%; intraparenchymal cerebral hemorrhage, in 0%, 4%, and 5%; cerebellar hemorrhage, in 6%, 2%, and 6%; intraventricular hemorrhage, in 14%, 6%, and 13%; subdural hemorrhage, in 29%, 17%, and 29%; and cerebral sinovenous thrombosis, in 0%, 10%, and 10%, respectively. CONCLUSIONS: A broad spectrum of perioperative brain MR imaging findings was found in infants with severe congenital heart disease. We propose an MR imaging protocol including T1-, T2-, diffusion-, and susceptibility-weighted imaging, and MRV to identify ischemic, hemorrhagic, and thrombotic lesions observed in this patient group

Risk Factors for Perioperative Brain Lesions in Infants With Congenital Heart Disease: A European Collaboration

Background: Infants with congenital heart disease are at risk of brain injury and impaired neurodevelopment. The aim was to investigate risk factors for perioperative brain lesions in infants with congenital heart disease. Methods: Infants with transposition of the great arteries, single ventricle physiology, and left ventricular outflow tract and/or aortic arch obstruction undergoing cardiac surgery <6 weeks after birth from 3 European cohorts (Utrecht, Zurich, and London) were combined. Brain lesions were scored on preoperative (transposition of the great arteries N=104; single ventricle physiology N=35; and left ventricular outflow tract and/or aortic arch obstruction N=41) and postoperative (transposition of the great arteries N=88; single ventricle physiology N=28; and left ventricular outflow tract and/or aortic arch obstruction N=30) magnetic resonance imaging for risk factor analysis of arterial ischemic stroke, cerebral sinus venous thrombosis, and white matter injury. Results: Preoperatively, induced vaginal delivery (odds ratio [OR], 2.23 [95% CI, 1.06-4.70]) was associated with white matter injury and balloon atrial septostomy increased the risk of white matter injury (OR, 2.51 [95% CI, 1.23-5.20]) and arterial ischemic stroke (OR, 4.49 [95% CI, 1.20-21.49]). Postoperatively, younger postnatal age at surgery (OR, 1.18 [95% CI, 1.05-1.33]) and selective cerebral perfusion, particularly at ≤20 °C (OR, 13.46 [95% CI, 3.58-67.10]), were associated with new arterial ischemic stroke. Single ventricle physiology was associated with new white matter injury (OR, 2.88 [95% CI, 1.20-6.95]) and transposition of the great arteries with new cerebral sinus venous thrombosis (OR, 13.47 [95% CI, 2.28-95.66]). Delayed sternal closure (OR, 3.47 [95% CI, 1.08-13.06]) and lower intraoperative temperatures (OR, 1.22 [95% CI, 1.07-1.36]) also increased the risk of new cerebral sinus venous thrombosis. Conclusions: Delivery planning and surgery timing may be modifiable risk factors that allow personalized treatment to minimize the risk of perioperative brain injury in severe congenital heart disease. Further research is needed to optimize cerebral perfusion techniques for neonatal surgery and to confirm the relationship between cerebral sinus venous thrombosis and perioperative risk factors. Keywords: heart diseases; ischemic stroke; magnetic resonance imaging; pedatrics; risk factors; venous thrombosis; white matter

Recommendations for cardiovascular magnetic resonance in adults with congenital heart disease from the respective working groups of the European Society of Cardiology

This paper aims to provide information and explanations regarding the clinically relevant options, strengths, and limitations of cardiovascular magnetic resonance (CMR) in relation to adults with congenital heart disease (CHD). Cardiovascular magnetic resonance can provide assessments of anatomical connections, biventricular function, myocardial viability, measurements of flow, angiography, and more, without ionizing radiation. It should be regarded as a necessary facility in a centre specializing in the care of adults with CHD. Also, those using CMR to investigate acquired heart disease should be able to recognize and evaluate previously unsuspected CHD such as septal defects, anomalously connected pulmonary veins, or double-chambered right ventricle. To realize its full potential and to avoid pitfalls, however, CMR of CHD requires training and experience. Appropriate pathophysiological understanding is needed to evaluate cardiovascular function after surgery for tetralogy of Fallot, transposition of the great arteries, and after Fontan operations. For these and other complex CHD, CMR should be undertaken by specialists committed to long-term collaboration with the clinicians and surgeons managing the patients. We provide a table of CMR acquisition protocols in relation to CHD categories as a guide towards appropriate use of this uniquely versatile imaging modality

Development of Ac2-26 Mesoporous Microparticle System as a Potential Therapeutic Agent for Inflammatory Bowel Diseases

Milena Fronza Broering,1,2 Pedro Leonidas Oseliero Filho,3,4 Pâmela Pacassa Borges,1 Luis Carlos Cides da Silva,3 Marcos Camargo Knirsch,5 Luana Filippi Xavier,1 Pablo Scharf,1 Silvana Sandri,1 Marco Antonio Stephano,5 Fernando Anselmo de Oliveira,6 Ibrahim M Sayed,2 Lionel Fernel Gamarra,6 Soumita Das,2 Márcia CA Fantini,3 Sandra HP Farsky1 1Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil; 2Department of Biomedical and Nutritional Sciences, University of Massachusetts, Lowell, MA, USA; 3Department of Applied Physics, Physics Institute, University of Sao Paulo, São Paulo, Brazil; 4Materials Innovation Factory, University of Liverpool, Liverpool, MSY, UK; 5Department of Biochemical and Pharmaceutical Technology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil; 6Instituto do Cérebro, Instituto Israelita de Ensino e Pesquisa, Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein, São Paulo, SP, BrazilCorrespondence: Sandra HP Farsky, Email [email protected]: Inflammatory bowel diseases (IBDs) disrupt the intestinal epithelium, leading to severe chronic inflammation. Current therapies cause adverse effects and are expensive, invasive, and ineffective for most patients. Annexin A1 (AnxA1) is a pivotal endogenous anti-inflammatory and tissue repair protein in IBD. Nanostructured compounds loading AnxA1 or its active N-terminal mimetic peptides improve IBD symptomatology.Methods: To further explore their potential as a therapeutic candidate, the AnxA1 N-terminal mimetic peptide Ac2-26 was incorporated into SBA-15 ordered mesoporous silica and covered with EL30D-55 to deliver it by oral treatment into the inflamed gut.Results: The systems SBA-Ac2-26 developed measurements revealed self-assembled rod-shaped particles, likely on the external surface of SBA-15, and 88% of peptide incorporation. SBA-15 carried the peptide Ac2-26 into cultured Raw 264.7 macrophages and Caco-2 epithelial cells. Moreover, oral administration of Eudragit-SBA-15-Ac2-26 (200 μg; once a day; for 4 days) reduced colitis clinical symptoms, inflammation, and improved epithelium recovery in mice under dextran-sodium sulfate-induced colitis.Discussion: The absorption of SBA-15 in gut epithelial cells is typically low; however, the permeable inflamed barrier can enable microparticles to cross, being phagocyted by macrophages. These findings suggest that Ac2-26 is successfully delivered and binds to its receptors in both epithelial and immune cells, aligning with the clinical results.Conclusion: Our findings demonstrate a simple and cost-effective approach to delivering Ac2-26 orally into the inflamed gut, highlighting its potential as non-invasive IBD therapy. Keywords: annexin A1, SBA-15, oral route, tissue recovery, inflammatio

Pentalogy of Cantrell: two patients and a review to determine prognostic factors for optimal approach

Two patients with incomplete pentalogy of Cantrell are described. The first was a girl with a large omphalocele with evisceration of the heart, liver and intestines with an intact sternum. Echocardiography showed profound intracardiac defects. The girl died 33 h after birth. The second patient was a female fetus with ectopia cordis (EC) without intracardiac anomalies; a large omphalocele with evisceration of the heart, stomach, spleen and liver; a hypoplastic sternum and rib cage; and a scoliosis. The pregnancy was terminated. A review of patients described in the literature is presented with the intention of finding prognostic factors for an optimal approach to patients with the pentalogy of Cantrell. In conclusion the prognosis seems to be poorer in patients with the complete form of pentalogy of Cantrell, EC, and patients with associated anomalies. Intracardial defects do not seem to be a prognostic factor

Water-Soluble Fullerene (C60) Derivatives as Nonviral Gene-Delivery Vectors

A new class of water-soluble C60 transfecting agents has been prepared using Hirsch-Bingel chemistry and assessed for their ability to act as gene-delivery vectors in vitro. In an effort to elucidate the relationship between the hydrophobicity of the fullerene core, the hydrophilicity of the water-solubilizing groups, and the overall charge state of the C60 vectors in gene delivery and expression, several different C60 derivatives were synthesized to yield either positively charged, negatively charged, or neutral chemical functionalities under physiological conditions. These fullerene derivatives were then tested for their ability to transfect cells grown in culture with DNA carrying the green fluorescent protein (GFP) reporter gene. Statistically significant expression of GFP was observed for all forms of the C60 derivatives when used as DNA vectors and compared to the ability of naked DNA alone to transfect cells. However, efficient in vitro transfection was only achieved with the two positively charged C60 derivatives, namely, an octa-amino derivatized C60 and a dodeca-amino derivatized C60 vector. All C60 vectors showed an increase in toxicity in a dose-dependent manner. Increased levels of cellular toxicity were observed for positively charged C60 vectors relative to the negatively charged and neutral vectors. Structural analyses using dynamic light scattering and optical microscopy offered further insights into possible correlations between the various derivatized C60 compounds, the C60 vector/DNA complexes, their physical attributes (aggregation, charge) and their transfection efficiencies. Recently, similar Gd@C60-based compounds have demonstrated potential as advanced contrast agents for magnetic resonance imaging (MRI). Thus, the successful demonstration of intracellular DNA uptake, intracellular transport, and gene expression from DNA using C60 vectors suggests the possibility of developing analogous Gd@C60-based vectors to serve simultaneously as both therapeutic and diagnostic agents