Fetal stroke and cerebrovascular disease: advances in understanding from lenticulostriate and venous imaging, alloimmune thrombocytopaenia and monochorionic twins

Fetal stroke is an important cause of cerebral palsy but is difficult to diagnose unless imaging is undertaken in pregnancies at risk because of known maternal or fetal disorders. Fetal ultrasound or magnetic resonance imaging may show haemorrhage or ischaemic lesions including multicystic encephalomalacia and focal porencephaly. Serial imaging has shown the development of malformations including schizencephaly and polymicrogyra after ischaemic and haemorrhagic stroke. Recognised causes of haemorrhagic fetal stroke include alloimmune and autoimmune thrombocytopaenia, maternal and fetal clotting disorders and trauma but these are relatively rare. It is likely that a significant proportion of periventricular and intraventricular haemorrhages are of venous origin. Recent evidence highlights the importance of arterial endothelial dysfunction, rather than thrombocytopaenia, in the intraparenchymal haemorrhage of alloimmune thrombocytopaenia. In the context of placental anastomoses, monochorionic diamniotic twins are at risk of twin twin transfusion syndrome (TTTS), or partial forms including Twin Oligohydramnios Polyhydramnios Sequence (TOPS), differences in estimated weight (selective Intrauterine growth Retardation; sIUGR), or in fetal haemoglobin (Twin Anaemia Polycythaemia Sequence; TAPS). There is a very wide range of ischaemic and haemorrhagic injury in a focal as well as a global distribution. Acute twin twin transfusion may account for intraventricular haemorrhage in recipients and periventricular leukomalacia in donors but there are additional risk factors for focal embolism and cerebrovascular disease. The recipient has circulatory overload, with effects on systemic and pulmonary circulations which probably lead to systemic and pulmonary hypertension and even right ventricular outflow tract obstruction as well as the polycythaemia which is a risk factor for thrombosis and vasculopathy. The donor is hypovolaemic and has a reticulocytosis in response to the anaemia while maternal hypertension and diabetes may influence stroke risk. Understanding of the mechanisms, including the role of vasculopathy, in well studied conditions such as alloimmune thrombocytopaenia and monochorionic diamniotic twinning may lead to reduction of the burden of antenatally sustained cerebral palsy.</p

Pressure passivity of cerebral mitochondrial metabolism is associated with poor outcome following perinatal hypoxic ischemic brain injury

Hypoxic ischemic encephalopathy (HIE) leads to significant morbidity and mortality. Impaired autoregulation after hypoxia-ischaemia has been suggested to contribute further to injury. Thalamic lactate/N-Acetylasperate (Lac/NAA) peak area ratio of > 0.3 on proton (H) magnetic resonance spectroscopy (MRS) is associated with poor neurodevelopment outcome following HIE. Cytochrome-c-oxidase (CCO) plays a central role in mitochondrial oxidative metabolism and ATP synthesis. Using a novel broadband NIRS system, we investigated the impact of pressure passivity of cerebral metabolism (CCO), oxygenation (haemoglobin difference (HbD)) and cerebral blood volume (total haemoglobin (HbT)) in 23 term infants following HIE during therapeutic hypothermia (HT). Sixty-minute epochs of data from each infant were studied using wavelet analysis at a mean age of 48 h. Wavelet semblance (a measure of phase difference) was calculated to compare reactivity between mean arterial blood pressure (MABP) with oxCCO, HbD and HbT. OxCCO-MABP semblance correlated with thalamic Lac/NAA (r = 0.48, p = 0.02). OxCCO-MABP semblance also differed between groups of infants with mild to moderate and severe injury measured using brain MRI score (p = 0.04), thalamic Lac/NAA (p = 0.04) and neurodevelopmental outcome at one year (p = 0.04). Pressure passive changes in cerebral metabolism were associated with injury severity indicated by thalamic Lac/NAA, MRI scores and neurodevelopmental assessment at one year of age

Paediatric UK demyelinating disease longitudinal study (PUDDLS)

BACKGROUND: There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years) to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS. METHODS/DESIGN: The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS) is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA), allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS) is an epidemiological surveillance study that already received ethical approvals, and started on the 1st September 2009. There is no direct patient involvement, and UCID-SS aims to determine the UK and Ireland incidence of CNS inflammatory demyelinating disorders in children under 16 years. DISCUSSION: A paediatric population should reflect the vanguard of MS epidemiological changes and may reflect trends yet to be observed in adult MS cohorts. The restricted window between clinical expression of disease and exposure to environmental factors in children offers a unique research opportunity. Studying a paediatric population from the first demyelinating event will allow us to investigate the changing epidemiology of MS, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS

Post-mortem examination of human fetuses:a comparison of whole-body high-field MRI at 9.4 T with conventional MRI and invasive autopsy

SummaryBackgroundConventional whole-body MRI at 1·5 T does not provide adequate image quality of small fetuses, thus reducing its potential for use as an alternative to invasive autopsy. High-field whole-body MRI at 9·4 T provides good images of small animals. We therefore compared the diagnostic usefulness of high-field MRI with conventional MRI for post-mortem examination of human fetuses.MethodsWe did whole-body MRI at 9·4 T and 1·5 T on 18 fetuses of less than 22 weeks' gestation, using three-dimensional T2-weighted fast-spin echo sequences, before doing invasive autopsy. Images obtained with MRI for each system were compared with the findings of invasive autopsy in a blinded manner. Tissue contrast of 14 different regions was compared on 1·5 T and 9·4 T images that were provided by paediatric radiologists separately and in a random order, and image quality was scored on a four-point scale. The primary endpoint was diagnostic accuracy.FindingsSpatial resolution, tissue contrast, and image quality of all organ systems were much better with high-field MRI than with conventional MRI. All structural abnormalities that were detected with invasive autopsy and internal examination of visceral organs were also detected with high-field MRI, whereas conventional MRI was not diagnostically useful in 14 (78%) cases.InterpretationWhole-body high-field MRI is a feasible option for post-mortem examination of human fetuses, and can provide good tissue characterisation even in small fetuses (5 g). The use of MRI at 9·4 T might be helpful in the development of a minimally invasive perinatal autopsy system.FundingDepartment of Health Policy Research Programme, British Heart Foundation, National Institute of Health Research, Higher Education Funding Council for England, Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, Great Ormond Street Hospital, University College London (UCL) Institute of Child Health, UCL Hospital, and UCL