Cognitive and behavioral functioning in two neurogenetic disorders; how different are these aspects in Duchenne muscular dystrophy and Neurofibromatosis type 1?

The presence of neurocognitive and behavioral problems are common features in various neurogenetic disorders. In Duchenne muscular dystrophy (DMD), these problems have been linked to mutations along the dystrophin gene affecting different brain dystrophin isoforms. However, comparable cognitive and behavioral problems have been found in Neurofibromatosis type 1 (NF1). This study aims to assess disorder specific differences in cognition and behavior between DMD and NF1. Retrospective data of 38 male patients with DMD were aged-matched with data of 38 male patients with NF1. Patients of both groups underwent neurocognitive assessment for regular clinical care. Intellectual abilities, sequential and simultaneous processing, verbal memory and sustained attention were evaluated. In addition, parents and teachers completed behavioral questionnaires. Males with DMD exhibited low intellectual abilities and sequential processing problems, but these outcomes not significantly differed from males with NF1. Simultaneous processing, verbal memory and sustained attention outcomes were equal for both groups. Outcomes of questionnaires displayed higher rates of aggressive behavior (13.2%) in DMD, whereas in NF1 higher rates of problems with thinking (15.8%), withdrawn (10.5%) and social behavior (10.5%) were noticed. In the neurogenetic disorders DMD and NF1, on average overlapping cognitive and behavioral problems are noticed, suggesting that these are not only caused by gene mutations resulting in a lack of one specific protein.

The current practice regarding neuro-prognostication for comatose children after cardiac arrest differs between and within European PICUs: A survey.

PURPOSE: To describe current practices in European Paediatric Intensive Care Units (PICUs) regarding neuro-prognostication in comatose children after cardiac arrest (CA). METHODS: An anonymous online survey was conducted among members of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) and the European Paediatric Neurology Society (EPNS) throughout January and February 2019. The survey consisted of 49 questions divided into 4 sections: general information, cardiac arrest, neuro-prognostication and follow-up. RESULTS: The survey was sent to 1310 EPNS and 611 ESPNIC members. Of the 108 respondents, 71 (66%) (23 countries, 45 PICUs) completed the "neuro-prognostication" section. Eight PICUs (20%) had a local neuro-prognostication guideline. The 3 methods considered as most useful were neurological examination (92%), magnetic resonance imaging (MRI) (82%) and continuous electroencephalography (cEEG) (45%). In 50% a Pediatric Cerebral Performance Category (PCPC) score ≥ 4 was considered as poor neurological outcome. In 63% timing of determining neurological prognosis was based on the individual patient. Once decided that neurological prognosis was futile, 55% indicated that withdrawing life-sustaining therapy (WLST) was (one of) the options, whereas 44% continued PICU treatment (with or without restrictions). In 28 PICUs (68%) CA-survivors were scheduled for follow-up visits. CONCLUSION: Local guidelines for neuro-prognostication in comatose children after CA are uncommon. Methods to assess neurological outcome were mainly neurological examination, MRI and cEEG. Consequences of poor outcome differed between respondents. Inaccuracies in neuro-prognostication can result in premature WLST, thereby biasing outcome research and creating a self-fulfilling cycle. Further research is needed to develop scientifically based international guidelines for neuro-prognostication in comatose children after CA.

A Systematic Review of Neuromonitoring Modalities in Children Beyond Neonatal Period After Cardiac Arrest.

OBJECTIVES: Postresuscitation care in children focuses on preventing secondary neurologic injury and attempts to provide (precise) prognostication for both caregivers and the medical team. This systematic review provides an overview of neuromonitoring modalities and their potential role in neuroprognostication in postcardiac arrest children. DATA RESOURCES: Databases EMBASE, Web of Science, Cochrane, MEDLINE Ovid, Google Scholar, and PsycINFO Ovid were searched in February 2019. STUDY SELECTION: Enrollment of children after in- and out-of-hospital cardiac arrest between 1 month and 18 years and presence of a neuromonitoring method obtained within the first 2 weeks post cardiac arrest. Two reviewers independently selected appropriate studies based on the citations. DATA EXTRACTION: Data collected included study characteristics and methodologic quality, populations enrolled, neuromonitoring modalities, outcome, and limitations. Evidence tables per neuromonitoring method were constructed using a standardized data extraction form. Each included study was graded according to the Oxford Evidence-Based Medicine scoring system. DATA SYNTHESIS: Of 1,195 citations, 27 studies met the inclusion criteria. There were 16 retrospective studies, nine observational prospective studies, one observational exploratory study, and one pilot randomized controlled trial. Neuromonitoring methods included neurologic examination, routine electroencephalography and continuous electroencephalography, transcranial Doppler, MRI, head CT, plasma biomarkers, somatosensory evoked potentials, and brainstem auditory evoked potential. All evidence was graded 2B-2C. CONCLUSIONS: The appropriate application and precise interpretation of available modalities still need to be determined in relation to the individual patient. International collaboration in standardized data collection during the (acute) clinical course together with detailed long-term outcome measurements (including functional outcome, neuropsychologic assessment, and health-related quality of life) are the first steps toward more precise, patient-specific neuroprognostication after pediatric cardiac arrest.

Intramuscular botulinum toxin prior to comprehensive rehabilitation has no added value for improving motor impairments, gait kinematics and goal attainment in walking children with spastic cerebral palsy.

OBJECTIVE: Botulinum toxin (BoNT-A) is widely used in combined treatment for spastic cerebral palsy, but its added value preceding comprehensive rehabilitation for motor impairments, gait, and goal attainment has not been studied. DESIGN: A comparative multi-centre trial, in which two groups underwent comprehensive rehabilitation (i.e. high-intensive functional physiotherapy, and indicated casting/orthoses). One group received intramuscular BoNT-A prior to rehabilitation, and the other group did not receive BoNT-A. SUBJECTS/PATIENTS: Children with spastic cerebral palsy, Gross Motor Function Classification System (GMFCS) levels I-III, age range 4-12 years, indicated for BoNT-A treatment regarding mobility problems. METHODS: Sixty-five children participated (37 boys), mean age 7.3 years (standard deviation (SD) 2.3, range 4-12 years), equally distributed across GMFCS levels. Forty-one children received BoNT-A+ comprehensive rehabilitation and 24 received comprehensive rehabilitation only. Functional leg muscle strength, passive range of motion, angle of catch, cerebral palsy-related pain, walking speed, kinematic gait parameters, goal attainment, and proxy-reported general functioning were assessed at baseline, primary end-point (12 weeks) and 24-week follow-up. Statistical analyses were performed with linear mixed models. RESULTS: At the primary end-point there were no statistically significant differences in treatment effects between the groups, except for the angle-of-catch of the rectus femoris, which was in favour of comprehensive rehabilitation without BoNT-A (12° difference, 95% confidence interval (95% CI) 2:23, p = 0.025). Results at follow-up were similar. CONCLUSION: At the group level, treating with BoNT-A prior to comprehensive rehabilitation did not add to the clinical effectiveness of rehabilitation. Thus, BoNT-A prescription and use should be critically reconsidered in this cerebral palsy age- and GMFCS-subgroup.

The COSMAM TRIAL a prospective cohort study of quality of life and cosmetic outcome in patients undergoing breast conserving surgery.

BACKGROUND: Cosmetic result in breast cancer surgery is gaining increased interest. Currently, some 30-40% of the patients treated with breast conserving surgery (BCS) are dissatisfied with their final cosmetic result. In order to prevent disturbing breast deformity oncoplastic surgical techniques have been introduced. The extent of different levels of oncoplastic surgery incorporated in breast conserving surgery and its value with regard to cosmetic outcome, patient satisfaction and quality of life remains to be defined. The aim of this prospective cohort study is to investigate quality of life and satisfaction with cosmetic result in patients with breast cancer, undergoing standard lumpectomy versus level I or II oncoplastic breast conserving surgery. METHODS: Female breast cancer patients scheduled for BCS, from 18 years of age, referred to our outpatient clinic from July 2015 are asked to participate in this study. General, oncologic and treatment information will be collected. Patient satisfaction will be scored preceding surgery, and at 1 month and 1 year follow up. Photographs of the breast will be used to score cosmetic result both by the patient, an independent expert panel and BCCT.Core software. Quality of life will be measured by using the BREAST-Q BCT, EORTC-QLQ and EQ-5D-5 L questionnaires. DISCUSSION: The purpose of this prospective study is to determine the clinical value of different levels of oncoplastic techniques in breast conserving surgery, with regard to quality of life and cosmetic result. Analysis will be carried out by objective measurements of the final cosmetic result in comparison with standard breast conserving surgery. The results of this study will be used to development of a clinical decision model to guide the use oncoplastic surgery in future BCS. TRIAL REGISTRATION: Central Commission of Human Research (CCMO), The Netherlands: NL54888.015.15. Medical Ethical Commission (METC), Maxima Medical Centre, Veldhoven, The Netherlands: 15.107. Dutch Trial Register: NTR5665 , retrospectively registered, 02-25-2016.

Value of botulinum toxin injections preceding a comprehensive rehabilitation period for children with spastic cerebral palsy: A cost-effectiveness study.

OBJECTIVE: Despite the widespread use of botulinum toxin in ambulatory children with spastic cerebral palsy, its value prior to intensive physiotherapy with adjunctive casting/orthoses remains unclear. DESIGN: A pragmatically designed, multi-centre trial, comparing the effectiveness of botulinum toxin + intensive physiotherapy with intensive physiotherapy alone, including economic evaluation. SUBJECTS/PATIENTS: Children with spastic cerebral palsy, age range 4-12 years, cerebral palsy-severity Gross Motor Function Classification System levels I-III, received either botulinum toxin type A + intensive physiotherapy or intensive physiotherapy alone and, if necessary, ankle-foot orthoses and/or casting. METHODS: Primary outcomes were gross motor func-tion, physical activity levels, and health-related quality-of-life, assessed at baseline, 12 (primary end-point) and 24 weeks (follow-up). Economic outcomes included healthcare and patient costs. Intention-to-treat analyses were performed with linear mixed models. RESULTS: There were 65 participants (37 males), with a mean age of 7.3 years (standard deviation 2.3 years), equally distributed across Gross Motor Function Classification System levels. Forty-one children received botulinum toxin type A plus intensive physio-therapy and 24 received intensive physiotherapy treatment only. At primary end-point, one statistically significant difference was found in favour of intensive physiotherapy alone: objectively measured percentage of sedentary behaviour (-3.42, 95% confidence interval 0.20-6.64, p=0.038). Treatment costs were significantly higher for botulinum toxin type A plus intensive physiotherapy (8,963 vs 6,182 euro, p=0.001). No statistically significant differences were found between groups at follow-up. CONCLUSION: The addition of botulinum toxin type A to intensive physiotherapy did not improve the effectiveness of rehabilitation for ambulatory children with spastic cerebral palsy and was also not cost-effective. Thus botulinum toxin is not recommended for use in improving gross motor function, activity levels or health-related quality-of-life in this cerebral palsy age- and severity-subgroup.

Talc seromadesis in patients with chronic seroma formation after breast surgery.

BACKGROUND: Seroma formation, after breast surgery is a commonly seen complication with an incidence ranging from 10 to 85 %. In general, though seroma usually disappears within several weeks, some patients are troubled with chronic seroma. Seroma predisposes to infection leading to wound related complications and may also delay adjuvant chemoradiation, leading to less effective breast cancer treatment. CASE DESCRIPTION: A 52-years-old Dutch woman presenting with a pT3N1M0 infiltrating lobular breast carcinoma received neo-adjuvant chemotherapy, following modified radical mastectomy with sentinel node procedure. She suffered from chronic seroma formation, delaying adjuvant radiation therapy. We successfully performed talc seromadesis to eliminate seroma formation. During six-month follow-up, no seroma was detected. DISCUSSION AND EVALUATION: Talc seromadesis after breast surgery is a rarely described in literature. In order to develop this technique further research aimed to evaluate its effectiveness on safety and possible later breast reconstruction must be carried out. CONCLUSION: Talc seromadesis may be a safe, cost effective and minimally invasive solution to treat chronic seroma after breast surgery.

High frequency of variant alleles of the mannose-binding lectin 2 (MBL2) gene are associated with patients infected by hepatitis B virus.

Patients with hepatitis B virus (HBV) infection may develop severe chronic liver disease. Carriers of HBV have an increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Worldwide an estimated 350 million people are infected with HBV, and 15-40% will develop serious sequelae in their lifetime. In our study we investigated the association of single nucleotide polymorphisms (SNPs) in the first exon and promoter region of the mannose-binding lectin gene 2 (MBL2) situated on chromosome 10, with susceptibility to HBV infection. One-hundred and two patients infected with HBV were included in this study, and 232 uninfected individuals were used as healthy controls. Genotyping of the first exon (alleles A/O) was performed using a melting temperature assay. Genotyping of the promoter region (-550 H/L; -221 Y/X) was performed using the Taqman PCR technique. In the HBV-infected group we found a significantly increased frequency of haplotypes associated with low serum MBL. Our findings may indicate that MBL has a protective role against HBV infection in the studied population.

Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial.

CONTEXT: Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. OBJECTIVE: To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. DESIGN, SETTING, AND PARTICIPANTS: Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. INTERVENTION: Simvastatin or placebo treatment once daily for 12 weeks. MAIN OUTCOME MEASURES: Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. RESULTS: No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (beta = 0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (beta = -0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (beta = 0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (beta = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (beta = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment. CONCLUSION: In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration isrctn.org Identifier: ISRCTN14965707.