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Brain Development in Fetal Ventriculomegaly

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Brain Development in Fetal Ventriculomegaly Brain development in fetal ventriculomegaly Vanesa Kyriakopoulou Imperial College London Institute of Clinical Sciences Submitted for the degree of PhD 1 Declaration of Originality I declare that the contents of this thesis are my own work and work by others is appropriately referenced and acknowledged. 2 Abstract Introduction Fetal ventriculomegaly is the most common detectable central nervous system abnormality affecting 1% of fetuses and is associated with abnormal neurodevelopment in childhood. Neurodevelopmental outcome is partially predictable by the 2D size of the ventricles in the absence of other abnormalities while the aetiology of the dilatation remains unknown. The main aim of this study was to investigate brain development in the presence of isolated ventriculomegaly during fetal and neonatal life. Methods Fetal brain MRI (1.5T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly from 22-38 gestational weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3D reconstructed datasets while cortical maturation was assessed using a detailed cortical scoring system. The metabolic profile of the fetal brain was assessed using magnetic resonance spectroscopy. During neonatal life, volumetric analysis of ventricular and supratentorial brain tissue was performed while white matter microstructure was assessed using Diffusion Tensor Imaging. The neurodevelopmental outcome of these children was evaluated at 1 and 2 years of age. Results Fetuses with isolated ventriculomegaly had significantly increased cortical volumes when compared to controls while cortical maturation of the calcarine sulcus and parieto-occipital fissure was delayed. NAA:Cho, MI:Cho and MI:Cr ratios were lower whilst Cho:Cr ratios were higher in fetuses with ventriculomegaly. Neonates with prenatally diagnosed ventriculomegaly had increased ventricular and supratentorial brain tissue volumes and reduced FA values in the splenium of the corpus callosum, sagittal striatum and corona radiata. At year 2 of age, only 37.5% of the children assessed had a normal neurodevelopment. 3 Conclusions The presence of relative cortical overgrowth, delayed cortical maturation and aberrant white matter development in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language and behavioural deficits in these children. Dedication This thesis is dedicated to my mother Eleni Kyriakopoulou, my partner Michael Powner and my supervisor Mary Rutherford for their support and guidance throughout my PhD. 4 Contents 1 Introduction ................................................................................................................................ 18 1.1 Fetal Ventriculomegaly ....................................................................................................... 18 1.1.1 Ventriculomegaly overview ...................................................................................................... 18 1.1.2 Definition and prevalence ......................................................................................................... 18 1.1.3 Causes of ventriculomegaly ...................................................................................................... 21 1.1.4 Isolated ventriculomegaly ......................................................................................................... 29 1.1.5 Outcome .................................................................................................................................... 30 1.1.6 Ventriculomegaly in childhood and adulthood ......................................................................... 39 1.1.7 Animal models of ventriculomegaly ......................................................................................... 43 1.2 Development of the brain and ventricular system .............................................................. 44 1.2.1 The ventricular system .............................................................................................................. 47 1.2.2 The role of embryonic CSF ....................................................................................................... 49 1.2.3 Cavum septum pellucidum ........................................................................................................ 51 1.2.4 Cortical development ................................................................................................................ 54 1.3 Aims and Hypothesis .......................................................................................................... 59 1.4 Magnetic Resonance Imaging ............................................................................................. 60 1.4.1 Physics of Magnetic Resonance Imaging .................................................................................. 60 1.4.2 MR safety .................................................................................................................................. 63 1.4.3 Imaging the fetus using ultrasound and MRI ............................................................................ 67 1.4.4 Fetal CNS assessment ............................................................................................................... 68 1.4.5 Imaging the neonate .................................................................................................................. 76 2 Materials and Methods ............................................................................................................... 79 2.1 Ethics................................................................................................................................... 79 2.2 Study population ................................................................................................................. 80 5 2.2.1 Normal control cohort ............................................................................................................... 80 2.2.2 Isolated ventriculomegaly cohort .............................................................................................. 80 2.3 Fetal Imaging ...................................................................................................................... 81 2.3.1 MR safety .................................................................................................................................. 82 2.3.2 Imaging ..................................................................................................................................... 83 2.4 Neonatal Imaging .............................................................................................................. 121 2.4.1 Patient preparation ................................................................................................................... 121 2.4.2 Neonatal volumetry ................................................................................................................. 123 2.4.3 Diffusion Tensor Imaging ....................................................................................................... 126 2.5 Neurodevelopmental assessments ..................................................................................... 127 2.5.1 Griffiths Mental Development Scales ..................................................................................... 128 2.5.2 Bayley Scales of Infant and Toddler Development-III ........................................................... 129 2.5.3 Ages and Stages Questionnaires.............................................................................................. 131 2.6 Statistics ............................................................................................................................ 132 2.6.1 Power calculations ................................................................................................................... 132 3 Results ...................................................................................................................................... 133 3.1 Contribution of MRI in the sonographic diagnosis of ventriculomegaly ......................... 133 3.1.1 Background ............................................................................................................................. 133 3.1.2 Aims ........................................................................................................................................ 133 3.1.3 Cohort ...................................................................................................................................... 133 3.1.4 Detection of additional abnormalities on MRI ........................................................................ 134 3.1.5 Ventricular size and risk of additional abnormalities .............................................................. 136 3.1.6 Discussion ............................................................................................................................... 138 3.2 Volumetric quantification of intracranial structures from 22-38 weeks of gestation and after birth ................................................................................................................................. 141 3.2.1 Background ............................................................................................................................. 141 6 3.2.2 Aims .......................................................................................................................................
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