Acquired Brain Injury in the Fetus and Newborn [1 ed.] 9781907655364, 9781907655029

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Michael Shevell and Steven Miller

ACQUIRED BRAIN INJURY IN THE FETUS AND NEWBORN

Acquired Brain Injury in the Fetus and Newborn

The leukodystrophies are serious, progressive demyelination disorders, manifesting themselves in infancy or early childhood. Some progress rapidly, leading to loss of sight, hearing, speech, and ambulation, and early death. This book is the only up-to-date, comprehensive guide to the genetics and pathogenesis of these disorders, as well as their clinical features, diagnosis and therapy. Its purpose is to summarize for the reader all aspects of the inherited disorders of myelin in children and adults. After a thorough overview of the role of oligodendrocytes, astrocytes and microglia in white matter disease, chapters are then devoted to individual disorders, covering their biochemical and molecular basis, genetics, pathophysiology, clinical features, diagnosis, treatment and screening. The final chapters discuss the development of treatments for these disorders and present a clinical approach to diagnosis in children and adults. The book was conceived by Hugo Moser, whose research led to major developments in the treatment of adrenoleukodystrophy, and is dedicated to him by his colleagues.

Mac Keith Press

EDITED BY MICHAEL SHEVELL AND STEVEN MILLER

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C A

International Review of Child Neurology Series Mac Keith Press

International Review of Child Neurology Series

Acquired Brain Injury in the Fetus and Newborn Edited by Michael Shevell and Steven P. Miller

© 2012 Mac Keith Press 6 Market Road, London N7 9PW Editor: Hilary Hart Managing Director: Ann-Marie Halligan Production Manager: Udoka Ohuonu Project Management: Prepress Projects Ltd The views and opinions expressed herein are those of the authors and do not necessarily represent those of the publisher All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher First published in this edition 2012 British Library Cataloguing-in-Publication data A catalogue record for this book is available from the British Library ISBN: 978-1-907655-02-9

Typeset by Prepress Projects Ltd, Algo Business Centre, Glenearn Road, Perth, UK Printed by Latimer Trend & Company, Plymouth, Devon, UK Cover image is of a fractional anisotropy map of the developing brain at term-equivalent age, showing the major white matter pathways.

International Review of Child Neurology Series

Acquired Brain Injury in the Fetus and Newborn Edited by michael shevell

Chairman, Department of Pediatrics; Professor (with Tenure), Departments of Pediatrics and Neurology/Neurosurgery, McGill University; Pediatricianin-Chief, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada; Harvey Guyda Chair in Pediatrics and steven p. miller

Head, Division of Neurology, The Hospital for Sick Children; Bloorview Children’s Hospital Foundation Chair in Paediatric Neuroscience; Professor, Department of Pediatrics, University of Toronto, Toronto, ON; Affiliate Professor, University of British Columbia, Vancouver, BC, Canada; Adjunct Associate Professor, University of California, San Francisco, CA, USA

2012 Mac Keith Press

International Review of Child Neurology Series

Lieven Lagae Department of Paediatric Neurology University Hospitals KULeuven Leuven, Belgium

SENIOR EDITOR Charles RJC Newton University of Oxford Department of Psychiatry Oxford, UK

Makiko Osawa Department of Pediatrics Tokyo Women’s Medical University Tokyo, Japan

EMERITUS SENIOR EDITOR Peter Procopis The Children’s Hospital at Westmead Sydney, NSW, Australia

Ingrid Tein Division of Neurology Hospital for Sick Children University of Toronto Toronto, ON, Canada

FOUNDING EDITOR John Stobo Prichard

Jo Wilmshurst Department of Paediatric Neurology Red Cross Children’s Hospital School of Child and Adolescent Health University of Cape Town Cape Town, South Africa

EDITORIAL BOARD Peter Baxter Department of Paediatric Neurology Sheffield Children’s NHS Trust, Sheffield, UK Paolo Curatolo Department of Paediatric Neurology and Psychiatry Tor Vergata University Rome, Italy

iv

Contents

Authors’ appointments

vii

FOREWORD

x

PREFACE

xi

ACKNOWLEDGMENTS

xii

Section I The Fetus 1. BRAIN INJURY IN THE FETUS

1

Adre du Plessis

2. Imaging the Fetal Brain

18

Catherine Limperopoulos

Section II The Preterm Infant 3. Mechanisms of Acute and Chronic Brain Injury in the Preterm Infant

29

Stephen A. Back

4. Clinical assessment of the Preterm Infant including Near-infrared spectroscopy, amplitude-integrated Electroencephalography, and Electroencephalography53 Lena Hellström-Westas and Frank van Bel

5. Imaging the Brain of the Preterm Infant

66

Gareth Ball, Mary A. Rutherford and Serena J. Counsell

6. Protecting the Brain of the preterm infant

81

Christopher D. Smyser and Terrie E. Inder

7. Seizures in the Preterm Infant

95

Hannah C. Glass

v

Contents

8. Outcomes After Brain Injury in the Preterm Infant

99

Marilee C. Allen

Section III The Term Infant 9. Mechanisms of brain Neurodegeneration in the Term infant

121

Frances J. Northington, Raul Chavez-Valdez and Lee J. Martin

10. Clinical Approach to Term Encephalopathy

154

Anastasia Dimitropoulos, Steven P. Miller and Jerome Y. Yager

11. Imaging term infants with suspected hypoxic–ischemic encephalopathy 

165

Kenneth J. Poskitt, Vann Chau and A. James Barkovich

12. Protecting the Brain in term infants

183

Fernando F. Gonzalez and Donna M. Ferriero

13. Seizures in the term newborn infant

198

Mona C. Toet and Linda S. de Vries

14. Outcomes after Brain Injury in the Term infant

209

Beatrice Latal

Section IV  Specialized Topics 15. Neonatal Neurology in the Developing World

221

Nicola J. Robertson

16. PERINATAL STROKE

237

Kendall B. Nash and Yvonne W. Wu

17. Brain Injury in Newborn infants with Congenital Heart Disease

251

Patrick S. McQuillen, Steven P. Miller and Annette Majnemer

18. Metabolic Brain Injury in the fetus and the neonate

268

Linda De Meirleir

19. The Nutritionally Deprived Fetus and Newborn infant

277

Raghavendra Rao and Michael K. Georgieff

20. Ethical Considerations in Fetal and Neonatal Neurology

288

Lucie Wade, Michael Shevell and Eric Racine

Index306

vi

Authors’ Appointments

Marilee C. Allen

The Johns Hopkins Hospital, Baltimore, MD, USA

Stephen A. Back

Associate Professor of Pediatrics and Neurology, Oregon Health and Science University, Clyde and Elda Munson Professor of Pediatric Research, Director, Neuroscience Section, Papé Family Pediatric Research Institute, Portland, OR, USA

Gareth Ball

Centre for the Developing Brain, King’s College London, London, UK

A. James Barkovich

Departments of Radiology and Neurology, University of California, San Francisco, CA, USA

Frank van Bel

Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the Netherlands

Vann Chau

British Columbia Children’s Hospital, Department of Pediatrics – University of British Columbia, Vancouver, BC, Canada

Raul Chavez-Valdez

Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, and Department of Pediatrics, Division of Neonatology, Texas Tech University – Health Sciences Center, Odessa, TX, USA

Serena J. Counsell

Centre for the Developing Brain, King’s College London, London, UK

Linda De Meirleir

Department of Pediatric Neurology and Metabolics, Universitair Ziekenhuis Brussel, Brussels, Belgium

Anastasia Dimitropoulos

Division of Pediatric Neurology, BC Children’s Hospital and University of British Columbia, Vancouver, BC, Canada

Donna M. Ferriero

Department of Pediatrics and Neurology, University of California, San Francisco, CA, USA

Michael K. Georgieff

Department of Pediatrics, Division of Neonatology, Institute of Child Development, Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA

Hannah C. Glass

Department of Pediatrics and Neurology, University of California, San Francisco, CA, USA

Fernando F. Gonzalez

Department of Pediatrics, University of California, San Francisco, CA, USA

vii

Authors’ Appointments

Lena Hellström-Westas

Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

Terrie E. Inder

Departments of Neurology and Pediatrics and Mallinckrodt Institute of Radiology, Washington University, Saint Louis, MO, USA

Beatrice Latal

Child Development Center, University Children’s Hospital, Zurich, Switzerland

Catherine Limperopoulos Associate Professor of Pediatrics; Director, MRI Research of the Developing Brain; Director, Advanced Pediatric Brain Imaging Research Laboratory, Children’s National Medical Center, Washington, DC, USA Patrick S. McQuillen

Departments of Pediatrics and Neurology, Benioff Children’s Hospital and University of California, San Francisco School of Medicine, San Francisco, CA, USA

Annette Majnemer

Professor, Director, and Associate Dean, School of Physical and Occupational Therapy, McGill University and Montreal Children’s Hospital, Montreal, QB, Canada

Lee J. Martin

Professor of Pathology and Neuroscience, Departments of Pathology and Neuroscience, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Steven P. Miller

University of Toronto and The Hospital for Sick Children, Toronto, ON, and University of British Columbia and British Columbia Children’s Hospital, Vancouver, BC, Canada

Kendall B. Nash

Department of Neurology, Division of Child Neurology, University of California, San Francisco, CA, USA

Frances J. Northington

Professor of Pediatrics; Director, Neurosciences Intensive Care Nursery, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Adre du Plessis

Children’s National Medical Center, Center for Neuroscience Research; George Washington University School of Medicine and Health Sciences, Washington, DC, USA

Kenneth J. Poskitt

British Columbia Children’s Hospital, Departments of Radiology and Pediatrics – University of British Columbia, Vancouver, BC, Canada

Eric Racine

Neuroethics Research Unit, Institut de recherches cliniques de Montréal; Biomedical Ethics Unit, Division of Experimental Medicine, Department of Neurology/Neurosurgery, McGill University; Departments of Medicine and Social and Preventive Medicine, Bioethics Programs, University of Montreal, Montreal, QC, Canada

Raghavendra Rao

Department of Pediatrics, Division of Neonatology, and Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA

Nicola J. Robertson

Professor in Perinatal Neuroscience and Honorary Consultant Neonatologist, Institute for Women’s Health, University College London, London, UK viii

Authors’ Appointments

Mary A. Rutherford

Centre for the Developing Brain, King’s College London, London, UK

Michael Shevell

Departments of Neurology/Neurosurgery and Pediatrics, McGill University; Division of Pediatric Neurology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada

Christopher D. Smyser

Departments of Neurology and Pediatrics, Washington University, Saint Louis, MO, USA

Mona C. Toet

Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the Netherlands

Linda S. de Vries

Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the Netherlands

Lucie Wade

Neuroethics Research Unit, Institut de recherches cliniques de Montréal; Biomedical Ethics Unit and Division of Experimental Medicine, McGill University, Montreal, QC, Canada

Yvonne W. Wu

Department of Neurology, Division of Child Neurology, University of California, San Francisco, CA, USA

Jerome Y. Yager

Director of Research, Department of Pediatrics, Pediatric Neurosciences, Stollery Children’s Hospital and University of Alberta, Edmonton, AB, Canada

ix

Foreword

Over the last decade there have been considerable advances in understanding the neurologic conditions of the newborn infant, particularly those conditions that start during fetal life and eventually manifest after delivery. Although there are now considerable insights into the genetic basis of brain development and the maldevelopment leading to migrational disorders, the understanding of disorders that result from injury to the brain during the fetal and neonatal period are relatively unexplored, and are often not covered by textbooks and other books on neonatal and child neurology. Thus, Acquired Brain Injury in the Fetus and Newborn is a timely book, in which internationally recognized clinical scientists have written state-of-the-art reviews in their areas of expertise. Edited by two world authorities on neonatal neurology, it is a book that provides the scientific basis of these conditions and yet it is sufficiently pragmatic to be useful for the clinician. This approach, from the basic science to the bedside, provides the knowledge and insight to introduce readers to this rapidly expanding field.

Fetal and neonatal neurology is becoming increasingly complex, with the interaction between the genetic predisposition to specific forms of brain damage and the wide variety of insults to which the developing brain is exposed. Studying injury of the fetal brain is difficult because the fetus is relatively inaccessible to investigation; as a result, it has been difficult to diagnosis many fetal conditions or predict the outcome. The advent of more sophisticated investigations, particularly imaging of the brain, has provided the tools to advance fetal neurology. This book provides chapters with excellent reviews of the imaging and physiologic tests that are available for examining the fetal and neonatal brain. The final section of the book addresses special populations and situations, which are often not included in standard books on child neurology. This comprehensive book on acquired brain injury in the fetus and neonate will not only be very useful for pediatric neurologists and neonatologists, but it should also appeal to the many disciplines interested in the fetal and neonatal brain. Charles Newton Scott Family Professor of Psychiatry University of Oxford Department of Psychiatry Oxford, UK

x

Preface

Over the last decade, the field of neonatal neurology has undergone tremendous advances. Advances in magnetic resonance imaging technology now provide an unprecedented view of the brain in health and in critical illness, from the fetal period through childhood. With the widespread uptake of hypothermia for the treatment of hypoxic–ischemic encephalopathy, neuroprotection is now a reality. Most recently, the integrative, collaborative, high-tech and protocol-driven approach to neonatal neurology has seen the emergence of neonatal neurological intensive care with collaboration among neurologists, neonatologists, neurophysiologists, neuroradiologists, psychologists, and the rehabilitation specialties. In the face of these advances, our approach to Acquired Brain Injury in the Fetus and Newborn Infant is pragmatic and focuses on specific populations encountered regularly by the clinician. Given the increasing demand for fetal neurology and the interpretation of fetal imaging studies, this book begins by addressing fetal neurology. We then follow a ‘bench to bedside’ approach to acquired brain injury in the preterm and term newborn infant. Preterm births have been increasing, and at earlier gestations, placing these infants at higher risk of brain injury. With improvements in intensive care, the risk of cerebral palsy is beginning to decline, yet this, and a high prevalence of other cognitive deficits, remains a considerable burden.

Our understanding of the relationship between critical illness and brain development is catalyzing new opportunities to further reduce the burden of neurodevelopmental impairments in the preterm newborn infant. Important advances have been made in our understanding of the underlying etiology and prognosis in the term newborn infant with encephalopathy. The application of hypothermia in this population has ushered in a new era of brain protection. Advances in the recognition and treatment of neonatal seizures offer new opportunities to further improve outcomes. Congenital heart disease, now increasingly diagnosed in utero, is increasingly recognized as a significant risk for brain injury and neurodevelopmental impairments. The final chapters of the book address advances related to special populations and concerns. We are very grateful to the authors of these chapters – internationally recognized clinician scientists – who synthesized the state-of-the-art understanding and clinical approach in their chapters. The advances made in our understanding of acquired brain injury in the fetus and the newborn infant has allowed us to move from a focus on vulnerability to resilience and recovery, and from diagnosis to therapy and, ultimately, prevention. We sincerely hope that the next decade brings us further in our care of affected newborn infants so that books such as this are no longer needed. Steven Miller and Michael Shevell Toronto and Montreal September 2012

xi

Acknowledgments

The editors are grateful to their teachers, mentors, colleagues, fellows, residents, and students, as well as their patients and their families, for fostering and enabling their clinical and research interests in neonatal neurology throughout their careers. The editors are especially grateful for their spouses and children who have ensured that the ‘life’ portion of the ‘work–life’ balance has been so amply filled.

The author of Chapter 3 is grateful to Dr Roger Hohimer for his helpful comments and suggestions and to Dr Art Riddle for advice and assistance with Figure 3.4. The authors of Chapter 10 thank Meisan Brown-Lum for her helpful comments and her support with editing the chapter. The authors of Chapter 19 thank Kristin Koppen for her help with preparing the manuscript.

xii

1 Brain Injury in the Fetus Adre du Plessis

Introduction The consequences of injury to the fetal brain are influenced by factors unique to this initial phase of the lifespan. Fetal brain development unfolds across gestation through a sequence of overlapping phases, each with a specific period of peak activity. These events occur in different cell types and different regions of the brain in a complex, highly programmed manner. The regions with the most active development under normal conditions are also those that are at greatest risk for injury under adverse conditions. Regional injury during critical phases of development may derail subsequent developmental events, in and around the region of injury, as well as remotely in future projection fields of the injured area (Limperopoulos et al 2005, Limperopoulos and du Plessis 2008). In summary, the topography, and consequently the long-term manifestations, of brain injury depend not only on the nature of the insult but also on its timing; ‘when’ is as important as ‘what’. Although the developing brain is more susceptible to injury, its immature state also underlies its sometimes remarkable ability to compensate for injury through the incompletely understood phenomenon of ‘plasticity’. Thus, the mechanisms of injury to the fetal brain, as well as the long-term structural and functional sequelae, are inextricably linked to normal developmental events in the brain. Although these developmental events will be reviewed briefly to provide context, the reader is referred to excellent published reviews for additional detail (e.g. Johnston et al 2009). Normal fetal brain development may be disrupted by primary disturbances in its genetic blueprint, or by internal and external environmental factors. Antenatal influences may also predispose the fetal brain to injury during the intrapartum period. A review of primary brain dysgenesis is beyond the scope of this chapter (Volpe 2008a), and intrapartum brain injury has been reviewed exhaustively elsewhere (du Plessis 2005, Volpe 2008b).

The focus of this chapter is therefore confined to fetal brain injury occurring prior to intrapartum events. Overview of normal fetal brain development Nervous system development in the fetus progresses through a series of events, starting several days after conception. During the embryonic period the principal phases of development are definition of the neural axis and formation of the neural tube (dorsal induction). The neural tube then comes under the influence of regional gene product gradients, which promote certain developmental processes and suppress others (Jessell 2000). After the neural tube closes at around 4 weeks after conception, three vesicles begin to form at its rostral end. These are the prosencephalon, mesencephalon, and rhombencephalon that will form the future forebrain, midbrain, and hindbrain respectively. This rostral region of the neural tube then goes through a series of folds in the sagittal plane forming the cervical, pontine, and cephalic flexures. The central canal, which, at its rostral end, will form the ventricular system of the brain, is surrounded by a layer of cells that form the primary neuroepithelium, the origin of all neuronal and glial cell lineages (Rakic et al 2007, Bystron et al 2008). The neuroepithelium becomes divided into dorsal and ventral segments. The dorsal neuroepithelium is the source of excitatory pyramidal neurons (that will form the future projection pathways), as well as the radial glial cells. The ventral neuroepithelium develops two thickened regions, the ganglionic eminences, which give rise to the future interneuronal population, which become critical for localized cortex-to-cortex circuits. The main neurotransmitter of these interneurons is gamma-aminobutyric acid (GABA), which has an initial excitatory influence, but ultimately becomes the principal inhibitory neurotransmitter in the brain. Neurons reach the developing cerebral cortex via two major paths of neuronal migration. Neurons from the dorsal ventricular zone

1

Section I: The Fetus

undergo radial migration along radial glial cells acting as guide-wires to the surface of the brain. During this migration the six-layered neocortex is formed in an inside-out manner, with later waves of migration passing through previous layers to settle on their outer-side. A critical part of this process is development and subsequent regression of the subplate zone (Kostovic and Jovanov-Milosevic 2008). The transient subplate zone acts as a ‘waiting station’ below the future cortex, where it is thought to ‘fine tune’ the itinerary of axons of thalamic neurons seeking to make appropriate connections in the developing cortex. Successful completion of these thalamocortical pathways establishes the fundamental neural scaffolding connecting the internal and external environment to the sensory cortex, and in so doing enables the development of conscious experience. During initial formation of the cerebral hemispheres an overabundance of neural structures are formed, including neurons, dendrites, dendritic spines, and synapses. This occurs under the influence of ‘spontaneous’ bursts of electrical activity that are endogenously generated, i.e. are not activated by incoming stimuli. Once development of the neural apparatus connects the peripheral sensory nerves to the cerebral cortex through connection in the thalamus, a reorganization of the cortex occurs under experience-driven influences. This phase coincides with normal regressive events occurring in the developing brain. Specifically, ‘unstable’ synapses are pruned back, unless they are stabilized by an appropriate level of activation. Such neural activation also releases local growth factors and activates gene programs that support the survival of neurons. On a ‘use-it-or-lose-it’ basis, redundant neurons are culled by active energy-dependent cell death, or apoptosis. These regressive events and the early abundance of neural structures might underlie the compensatory plasticity of the immature nervous system after injury. Myelination is a relatively late phase of development and by term gestation has proceeded only into the brainstem, cerebellum, and the posterior limb of the internal capsule. The subsequent pattern of myelination does not commence uniformly across the cerebral hemispheric white matter, but rather it proceeds in a predictable spatial and temporal sequence (Kinney et al 1988, Drobyshevsky et al 2005). At a cellular level, the consequences of an insult are heavily influenced by the maturational level of the neuronal and glial lineages at the time of the insult. As a broad statement, neurons in regions of the most active development at any one time have a physiology that promotes depolarization, making it most sensitive to incoming stimuli that then activate receptors responsible for controlled influx of enzyme-activating calcium. In order

to finely titrate this process and to keep it localized to establish the most regionally discrete connectivity, the neurotransmitter is then rapidly cleared from the synaptic cleft by reuptake channels. During insults such as hypoxia and hypoglycemia, this arrangement turns hostile as neurotransmitter release becomes uncontrolled and reuptake mechanisms fail, resulting in sustained neurotransmitter activity at the synapse with neurotoxic levels of calcium influx. From this brief outline it can be seen that during critical periods of development the fetal brain might be particularly vulnerable to injury, which, in turn, might disrupt the complex sequence of subsequent developmental events. The oligodendrocyte lineage goes through a series of maturational steps, from a progenitor phase to the mature myelin-generating form. Across this period, the oligodendrocyte lineage passes through a developmental phase (the late oligodendrocyte progenitor, or preOL) phase, during which it is highly vulnerable to hypoxia–ischemia and other insults (Back et al 2007, Segovia et al 2008); before and after this preOL phase the oligodendrocyte lineage is relatively resistant to insults. Data from animal models correspond with the peak period of white matter injury in preterm infants between 26 and 32 weeks’ gestation (Baud et al 2004, Back et al 2007). In fact, both the temporal and topographic distribution of the preOL overlaps with the timing and topography of preterm birth-related white matter injury (Buser et al 2010). During oligodendrocyte development there is a shift in glutamate receptor and transporter density, limitation of antioxidant defenses, and cytotoxic cytokine receptors (Back 2006, Volpe 2009), making the preOL particularly vulnerable to insults such as hypoxia–ischemia and infection–inflammation. A synopsis of published data suggests that hypoxia has different effects on the oligodendrocyte lineage at different stages of development. In the very early oligodendrocyte precursors, hypoxia may result in accelerated maturation (Akundi and Rivkees 2009). In the somewhat more mature preOL, chronic hypoxia causes either delayed preOL degeneration or developmental arrest in the vulnerable preOL phase, and thus it is primed for injury from subsequent insults (Segovia et al 2008). Finally, in its mature myelinating phase the oligodendrocyte has a relatively elevated threshold to injury. Similar phases of increased vulnerability occur during neuronal development. Immature neurons in rapidly developing brain regions have membranous and intracellular features that facilitate depolarization and promote influx of calcium for activation of growth-promoting enzymes. During earlier phases of development, neurons are maintained in a relatively hypopolarized state by the neurotransmitter GABA. At this early stage of

2

Brain Injury in the Fetus

Normal function of the maternal placenta–fetal interface During the antenatal period the principal contact between the fetus and the environment is through the placenta. The placenta serves as the only nutrient and clearance system for the fetus. In addition, the placenta serves as a barrier to potentially noxious agents. The placenta also has a critical endocrine role in fetal growth and development. Placental development begins with ‘placentation’ several days after implantation of the embryo. The normal physiology of implantation includes trophoblast invasion of the endovascular layers of the spiral arteries, with disruption of the muscular media (Nanaev et al 1995), and conversion of the normally small caliber spiral arteries into distended flaccid vessels with limited vasoconstrictive capability. In so doing the uteroplacental system is converted to a low-resistance, low-pressure, and high-volume circulation. Exchange across the placenta occurs across an interface composed of the syncytiotrophoblast, a basal membrane, and the fetal endothelium. Such exchange occurs in several different ways: bulk flow down hydrostatic and osmotic gradients; diffusion down concentration gradients; transporter protein-mediated transfer (e.g. glucose, amino acids); and endo- or exocytosis (e.g. immunoglobulin G). Therefore, in addition to perfusion of the uteroplacental and fetoplacental circulations, the supply of nutrients across the placenta is also dependent upon the functional surface area, as well as the membranebound transporter activity on either side of the maternal– fetal interface. Transporter-mediated transfer is adaptively regulated via cellular homeostatic mechanisms, which change transporter function in response to substrate levels, and thereby maintain placental supply coupled with fetal demand. Transporters may be upregulated and may increase their efficiency during decreased circulatory supply, but, like other fetal compensatory mechanisms, this is a temporizing response and cannot be sustained over long periods (Constancia et al 2002, 2005). These responses may explain why the fetal:placental weight ratio (placental transfer efficiency) may be greater in growth restricted infants than in appropriate for gestational age infants.

development, GABA has an excitatory influence (as opposed to its later inhibitory action) related to the ambient chloride gradients across the immature neuronal membrane (Staley et al 1995, Dzhala et al 2005). Furthermore, a paucity of reuptake transporters allows GABA to accumulate in the extracellular space, where it then acts in a more diffuse paracrine manner by maintaining a field of hypopolarization, which in turn releases the magnesium blockade at the N-methyl-d-aspartic acid (NMDA) receptor channel, permitting greater calcium influx for maturational processes. However, during insults such as hypoxia–ischemia both the hypopolarized membranous state and high density of glutamate receptors in regions of accelerated brain development predispose to excitotoxic injury with necrotic and/or apoptotic cell death. The maturational development of astroglial cells is also relevant to the current discussion. Specifically, the typical response to brain injury seen in later stages of development and in the mature brain, i.e. reactive astrogliosis, does not occur before about 20 to 24 weeks gestational age (Kinney and Armstrong 1997). Consequently, tissue destruction occurring prior to this point in gestation triggers very little cicatricial response. As a result, the resulting lesions may have minimal gliosis and resemble malformations rather than encephaloclastic lesions. The nature and severity of environmental insults may disrupt brain development in a number of different ways. Milder insults may trigger subtle pathologic processes through epigenetic programming pathways. Progressively more severe insults may result in arrested or disrupted development, selective cellular injury and loss, and frank pancellular destruction (infarction) of the structural scaffolding required for normal brain development. These different pathways likely act in concert during and after insults. Furthermore, below the threshold of injury, insults may also increase (sensitize) or decrease (pre-conditioning) sensitivity to subsequent insults. The timing and nature of insult and injury might also influence the subsequent efficiency of compensatory processes, so-called plasticity. In the same way that early injury may disrupt subsequent brain development, so too may it affect the normal regressive processes of ‘pruning’ back and reorganization during later phases of brain development. As discussed above, earlier processes in fetal brain development produce an excess of neural structures, which are subsequently ‘pruned back’ by energy-dependent apoptosis, a process that occurs in part through competition for trophic factors. One theory of plasticity is that regional brain injury reduces competition for trophic factors and substrate, allowing surviving tissue to compete successfully.

Mechanisms of fetal brain injury Fetal Substrate Deprivation Fetal oxygen-substrate deprivation eventually leads to growth restriction, which in turn increases the risk of perinatal and long-term complications (Brodsky and Christou 2004). Fetal brain development is dependent upon the appropriate delivery of nutritional elements for structural accretion, and of energy substrate to support enzyme function. The appropriate availability of energy substrate is

3

Section I: The Fetus

particularly important during the third trimester, when energy-dependent neuronal activation is critical for establishing and consolidating neuronal circuitry.

significantly exceeds demands. If this supply decreases, a number of systemic and cerebral compensatory mechanisms are activated to optimize cerebral supply and demand and to maintain a normal cerebral metabolic rate until hypoxemia is severe (Richardson 1993). In fetal sheep with a 50% decrease in oxygen delivery to the placenta, cerebral oxygen consumption was maintained for at least 24 hours (Bocking et al 1992). In another experimental model in which maternal oxyhemoglobin saturation was maintained below 30% (by decreasing inspired oxygen concentration), cerebral oxidative metabolism was maintained for more than 4 days (Richardson 1993). In animal models of fetal hypoxemia, induced by decreasing uterine artery blood flow, the first fetal response was an increase in umbilical blood flow and an increase in oxygen extraction, followed by increased shunting of umbilical venous return from the placenta through the ductus venosus and foramen ovale. Sympathetic activation causes peripheral vasoconstriction, while intrinsic autoregulatory vasodilation in the brain reduces resistance and increases cerebral blood flow. These adaptations in the fetal circulation divert the most highly oxygenated perfusion to vital organs including the brain (‘centralization’ or the so-called ‘brain-sparing effect’). In addition, there are physiologic responses aimed at decreasing energy demand. Myocardial energy utilization is reduced through a chemoreceptor-mediated fetal bradycardia. Cerebral metabolism is decreased by active suppression of neuronal activation; this is achieved by adenosine, an adenosine triphosphate (ATP) breakdown product that inhibits synaptic activity by blocking the presynaptic A1 receptor (Blood et al 2003). Chronic compensated fetal hypoxemia may cause epigenetic changes in fetal programming and, by sublethal neuronal suppression, may disrupt activity-driven processes in brain development. Pure hypoxemia (with intact perfusion) may be tolerated

Restriction of specific nutrients essential for nervous system development The classic association between specific nutrient deficiency and disturbed neurodevelopment is that between folate deficiency and disturbances in neural tube closure. Maternal folate deficiency may result from inadequate dietary intake as well as malabsorption conditions (after gastric bypass surgery) (Haddow et al 1986). The precise cellular mechanisms by which folate supplementation prevents neural tube defects remains unknown; the current understanding is reviewed in detail elsewhere (Haddow et al 1986). Disturbances in cholesterol availability have been implicated in disruption of prosencephalic development. Specifically, the Sonic hedgehog (SHH) protein plays a central role in the development of the face, brain, and genitalia. In the brain the SHH gene product is critical for ventral induction and patterning, with formation of the cerebral hemispheres and the midline structures, most notably the corpus callosum. For the SHH protein to be activated it must bind to cholesterol. When cholesterol availability is limited, lesions such as holoprosencephaly (Fig. 1.1) and agenesis of the corpus callosum may develop. The classic example of cholesterol deficiency is 7-dehydrocholesterol reductase deficiency, the autosomal recessive Smith–Lemli–Opitz syndrome (ACOG 2000). Restricted energy substrate for normal brain development Under normal conditions the developing brain enjoys a privileged supply of oxygen and energy substrate. In fact, normal oxygen and glucose delivery to the fetal brain

(a)

(b)

Fig. 1.1 Holoprosencephaly semilobar with large dorsal cyst in a 36-week gestational age fetus: (a) MRI midline sagittal and (b) coronal T2 images.

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Brain Injury in the Fetus

for sustained periods of time, by adjustments in demand, redirected blood flow, and alternative energy pathways such as anaerobic metabolism and utilization of alternative energy sources (e.g. lactate and ketones). The efficacy of these compensatory mechanisms at preventing destructive brain injury is dependent upon multiple factors such as the ‘dose’, nature, and delivery of the insult, the maturational state and sex of the fetus, and pre-existing conditions in the fetal milieu (e.g. preceding energy restriction, infection). These and other processes confine the destructive brain injury caused by substrate restriction to a ‘very narrow window between intact survival and death’ (Bennet and Gunn 2009). When hypoxemia and hypoperfusion occur in combination (i.e. hypoxia–ischemia) these compensatory mechanisms rapidly collapse, in part because the interruption of glucose supply limits anaerobic metabolism and lactate formation, and destructive pathways are unleashed.

changes in the intervillous space of the placenta may be caused by infections, such as toxoplasmosis, cytomegalovirus, and other presumed viral infections, as well as autoimmune conditions, such as the antiphospholipid antibody syndrome. However, fibrin deposition and intervillous thrombi may also be seen in up to half of placentas from normal-outcome pregnancies. In addition, some studies have failed to identify an association between maternal or neonatal thrombophilic polymorphisms and an increased risk of FGR (Infante-Rivard et al 2002, Infante-Rivard et al 2005). The fetoplacental circulation normally receives almost half the fetal cardiac output. Signaling between fetal and maternal placental vessels couples fetal to uteroplacental blood flow (Talbert and Sebire 2004). However, this coupling may be disrupted by vasoconstrictive or occlusive placental lesions. The major fetal vessels in the chorionic plate perfuse large segments of the placenta, called cotyledons. The vascular territories of these large arteries do not overlap; the cotyledons have no collateral supply, and these vessels are neither innervated nor do they autoregulate. Fetoplacental blood flow is locally controlled entirely through fetal endocrine and placental paracrine systems (Poston 1997, Benoit et al 2008). Fetoplacental vascular pathology may cause significant elevation in fetal peripheral vascular resistance. In fact, sustained hypoperfusion of the fetoplacental circulation may actually lead to constriction of these vessels (Rockelein et al 1990). Fetoplacental thromboinflammatory lesions associated with adverse neurodevelopmental outcomes include fetal thrombotic vasculopathy and villitis of unknown etiology, which is associated with chronic inflammation and, ultimately, avascular distal villi (Redline 2004). Longstanding meconium exposure may cause vascular necrosis through apoptotic death of vascular smooth muscle cells and vasospasm. Intrinsic fetal conditions may adversely affect fetal brain development. As discussed above, the normal fetal circulation is arranged such that there is an optimal oxygen-substrate delivery to the developing brain. In certain forms of fetal cardiac malformation this arrangement may be disrupted with potential restriction of cerebral oxygensubstrate delivery. For example, the oxygen content of aortic (and hence brain) blood flow is decreased in conditions such as transposition of the great arteries. Conversely, volumetric cerebral blood flow may be compromised by conditions such as aortic and left ventricular hypoplasia, which, in severe cases, leaves the brain dependent on retrograde perfusion from the ductus arteriosus across the aortic isthmus. A study comparing fetal volumetric brain growth in fetuses with heart lesions with controls showed that despite similar brain volumes at the end of the

Mechanisms of fetal energy substrate deprivation Limitation of substrate supply to the fetal brain may originate at the maternal, uteroplacental, fetoplacental, or fetal level. Maternal starvation level deprivation is uncommon in the developed world but remains a problem in underdeveloped regions and those ravaged by natural and man-made disasters. Although substrate concentrations in the maternal circulation may restrict fetal supply, the more common scenario is limitation of uteroplacental perfusion, by lesions such as abnormalities of placentation, infarction, and hemorrhage. Impaired uteroplacental perfusion may stem from abnormalities at the level of the uterine arteries, the spiral arteries, or the uteroplacental vascular bed. Failure of spiral artery transformation and vasodilation results in impaired perfusion of the placental intervillous spaces, setting the stage for compromised fetal oxygenation. Failure of normal placentation may result in spontaneous miscarriage, isolated fetal growth restriction (FGR), and pre-eclampsia with or without growth restriction. In pre-eclampsia the muscular media not only persists but may even hypertrophy. Placental mechanisms of fetal substrate restriction constitute a major pathway for morbidity during the fetal period, with effects that extend through the neonatal period and beyond. However, the system has considerable reserve, and fetal growth is not impaired until approximately 30% of placental function is lost. Placental dysfunction, leading to FGR, may result from a spectrum of different etiologies, leading to a common end result. Broadly speaking, these placental pathologies may be considered in three categories: abnormal vascular development, inflammatory processes, and acquired degeneration, usually with thrombotic changes. Inflammatory

5

Section I: The Fetus

second trimester, there occurred a significant and progressive fall-off in brain growth among the congenital heart disease fetuses (Limperopoulos et al 2010a). This brain growth failure was most pronounced among fetuses with the greatest expected oxygen delivery to the brain, as well as with the presence of cerebral lactate on fetal magnetic resonance spectroscopy, suggesting the development of anaerobic metabolism in these most affected participants (Catherine Limperopoulos, Children’s National Medical Center, personal communication, 2010). The oxygen-carrying capacity may also become impaired in conditions that cause severe anemia, such as Rhesus incompatibility and fetal infections, especially with parvovirus (see below). Assessing perfusion of the uteroplacental and fetoplacental circulations by Doppler ultrasound measures of blood flow velocity and vascular resistance is now standard in the management of suspected FGR. When FGR is associated with placental infarction and/or hemorrhage on the maternal side of the circulation, uterine artery Doppler indices will show an increase in resistance. Similarly, in the fetoplacental circulation, a characteristic sequence of perfusion and resistance changes develop during progressive placental failure. Particularly concerning is the development of decreased or reversed diastolic flow in the umbilical arteries, which becomes apparent only when about 50% or more of placental function is lost. The so-called brain-sparing effect is misleading because, in many cases, the attempted compensatory response does not spare the brain. Fetuses with evidence of brain sparing on Doppler studies are almost always growth restricted (Arduini et al 1987).

FGR. Some studies of preterm growth-restricted fetuses have suggested a preferential catch-up of head growth over the first few years (Jordan et al 2005, Westerberg et al 2010). At follow-up, many individuals have head sizes similar to appropriately grown ex-preterm infants. Padilla et al (2010) found no difference between growthrestricted and appropriately grown preterm infants in head circumference, total brain volume, or the volumes of gray or white matter (by three-dimensional magnetic resonance imaging [MRI]) at 12 months corrected age. Other studies of preterm FGR have shown decreased intracranial volumes and decreased cortical gray matter volumes after preterm birth, persisting at term, but no significant differences with appropriately grown ex-preterm infants at later ages (Tolsa et al 2004, Dubois et al 2008). Although overall brain size may not differ significantly, neuroimaging studies have detected lobar or regional decreases in the frontal lobe (Geva et al 2006a,b, Figueras et al 2008a; Hernandez-Andrade et al 2008), hippocampus (Geva et al 2006a, Lodygensky et al 2008), and insular lobes (Padilla et al 2010) in preterm growth-restricted infants. Other more subtle differences in cerebral cortical development gyrification (Dubois et al 2008, Esteban et al 2010); with decreased gray matter density (Tolsa et al 2004, Lodygensky et al 2008), have been described. Magnetic resonance spectroscopy studies have detected elevated cerebral lactate (Leth et al 1996, Kok et al 2002, Wolfberg et al 2007) (suggestive of anaerobic metabolism), and elevated inositol–choline ratios (Sanz-Cortes et al 2010), suggestive of reactive astrogliosis. Diffusionweighted imaging has shown significantly higher apparent diffusion coefficient values in the pyramidal tracts (SanzCortes et al 2010).

Abnormal development of brain structure in fetal growth restriction In animal studies, placental insufficiency has a broad range of effects on the developing brain, often with decreased gray matter volumes and impaired myelination (Mallard et al 1998). Experimental models of FGR have shown regional decreases in growth factor levels in the fetal brain (Duncan et al 2004), which in turn leads to apoptosis and activation of pro-apoptotic pathways. It has been proposed that the patterns of structural brain abnormality in human fetuses with FGR are dependent on the gestational age, although there is lack of consensus on this issue (Bassan et al 2011). In humans with FGR the range of structural brain changes is broad; findings between studies are not consistent. It is likely that many different factors influence this relationship, including gestational age at onset of FGR, gestational age at delivery, and postnatal age at the time of study. Microcephaly is a known complication of severe

Abnormal development of brain function in fetal growth restriction A number of studies have demonstrated the increased risk for adverse neurodevelopmental and behavioral outcome in survivors of FGR (Low et al 1992, Kok et al 1998, Monset-Couchard et al 2002, Tideman et al 2007). However, there are major inconsistencies in the reported prevalence and manifestations of these sequelae. Both preterm and term (Oros et al 2010) growth-restricted fetuses appear to be at risk; some studies have suggested that the clinical profile of these two groups may differ (Figueras et al 2008b), but this has not been consistent (Bassan et al 2011). Padilla et al (2010) suggested that preterm FGR was associated with worse neurodevelopmental outcome, especially in the fine motor domain. FGR in late preterm and term infants may be associated with a distinct clinical picture with impaired cognition and executive function (Fattal-Valevski et al 1999, Geva

6

Brain Injury in the Fetus

et al 2006a,b, 2008). FGR in preterm infants increases the risk for neurodevelopmental sequelae in some, but not all, studies (Lodygensky et al 2008, Padilla et al 2010). For term growth-restricted infants the risk for cerebral palsy increases four- to sixfold compared with those born between the 25th and 75th centiles (Larciprete et al 2005). Others have shown a significantly greater risk of subsequent cerebral palsy for growth-restricted infants born between 34 and 37 weeks’ gestation compared with those born before 33 weeks (Blair and Stanley 1990, 1992). Monset-Couchard et al (2002) showed an almost twofold increase in behavioral abnormalities when preterm infants born growth restricted compared with those appropriately grown. The need for later special education services was significantly greater for growth restricted than for appropriately grown preterm infants in some (Kok et al 1998), but not other (Schaap et al 1999) studies.

predilection for the middle cerebral artery distribution, especially on the left. Pregnancy is a naturally occurring hypercoagulable state, resulting from elevated circulating prothrombotic factors, decreased natural anticoagulants, and reduced fibrinolytic activity. The placenta has been implicated as a source for embolic phenomena in neonatal stroke, and thus presumably also fetal stroke (Burke et al 1997, Kraus and Acheen 1999). The most commonly implicated placental lesions include fetal thrombotic vasculopathy and fetal vasculitis (in intrauterine infection). As a major proportion of the normal fetal venous return from the placenta passes through the foramen ovale and from there into the major cerebral arteries, a thromboembolic source in the placenta has direct access to the fetal brain arteries. Such thromboembolic sources in the placenta may result from several different processes, including inflammatory processes such as infection, thrombosis, and abnormal arteriovenous connections between monochorionic twins, especially in cases of co-twin demise and twin–twin transfusion syndrome (Fig. 1.2). Monochorionic twin pregnancies have placental connections; the twin circulations remain balanced in all but 10% to 15%. Stroke risk is significantly increased in twin–twin transfusion syndrome; when there is co-twin demise (which is probably underestimated) thromboplastin material is transferred from the dead twin. An association between maternal thrombophilias and adverse pregnancy outcome was first suggested by Kupferminc and colleagues in 1999 (Kupferminc et al 1999). Proposed thrombophilia-related complications have included recurrent miscarriages, fetal demise, intrauterine growth retardation, pre-eclampsia, and fetalneonatal stroke. Thromophilias have been implicated in up to 70% of neonatal arterial strokes (Volpe 2008c), including factor V Leiden, prothrombin 20210A mutation, MTHFR mutation, protein C deficiency, protein S deficiency, antithrombin deficiency, antiphospholipid antibody syndrome, and elevated lipoprotein A (Golomb et al 2001, Mercuri et al 2001, Curry et al 2007, Suppiej et al 2008, Simchen et al 2009). Conversely, a recent study for a broad range of genetic thrombophilia polymorphisms failed to show an association with arterial stroke in newborn infants (Miller et al 2006). In many cases with an association between thrombophilia and neonatal stroke, it has been in the setting of other potentially prothrombotic conditions such as sepsis, chorioamnionitis, and pre-eclampsia. Infection is known to predispose to a hypercoagulable state, in part through endothelial injury and cytokine generation, with downregulation of thrombomodulin. In summary, the association (especially a causative association) between thrombophilia and arterial stroke in the fetus remains inconsistent at best

Fetal Cerebrovascular Injury Currently, the majority of cerebrovascular injury diagnosed in newborn infants is considered to be of perinatal origin. Although both ischemic and hemorrhagic lesions are more easily diagnosed by modern fetal imaging, distinguishing between antepartum, intrapartum, and neonatal-onset stroke may be difficult when imaging is delayed. Arterio-occlusive stroke of the immature brain has a relatively limited acute presentation, with seizures being the most obvious clinical change. If seizures are the heralding sign of stroke, these usually occur over a period of days, then recede whether or not they have been treated. Hereafter, there is commonly a latent period with a paucity of physical signs until around 4 to 6 months, when normally emergence of purposeful movements reveals motor asymmetry. Early stroke, including intrauterine stroke, without detected seizures, may have delayed motor asymmetry as the first indication of a focal brain lesion. By this chronic phase of the injury even advanced MRI may be unable to distinguish between antenatal, perinatal, or neonatal-onset stroke. Early intrauterine stroke occurring before mid-gestation may show little, if any, residual evidence of tissue destruction as reactive gliosis is usually minimal (see above). In fact, the resulting lesion may be misdiagnosed as a primary dysgenetic lesion. Current clinical fetal MRI techniques remain relatively limited in their ability to detect fetal hemorrhagic lesions. For all of the above reasons our understanding of the true incidence and pathogenesis of fetal arterial stroke remains poorly characterized (Curry et al 2007). Reported associations have included twin pregnancies (especially monochorionic with co-twin demise), fetal congenital heart disease, thrombophilias, and intrauterine infections. Strokes occurring in the perinatal period have a strong

7

Section I: The Fetus

(a)

(b)

Fig. 1.2  Ischemic brain injury in recipient in twin-to-twin transfusion syndrome (coronal and axial T2-weighted MRI scan).

(Infante-Rivard et al 2002, Rey et al 2003, Rodger et al 2008, Lynch 2009). Patterns of intracranial hemorrhage in the fetus resemble those described in the preterm newborn infant. These hemorrhages are likely due to an underlying anatomic and physiologic immaturity, with an intrinsic fragility of the vasculature (reviewed in more detail elsewhere) (Volpe 2008d). Hemorrhages in the fetus include the typical germinal matrix-intraventricular hemorrhage lesion, and its complications including periventricular hemorrhagic infarction (Fig. 1.3) and posthemorrhagic hydrocephalus (Fig. 1.4). Similarly, cases of fetal cerebellar hemorrhage have been reported that probably result from rupture of the fragile vessels in the germinal matrices of the immature cerebellum. Such hemorrhages may result in disruptions of cerebellar development (Glenn et al 2007), and may mimic primary dysgenetic lesions such as cerebellar clefts (Poretti et al 2009) and Dandy–Walker

spectrum lesions (Fig. 1.4 and 1.5) (Limperopoulos et al 2010b). Fetal intracranial hemorrhage has been associated with fetal thrombocytopenia (e.g. in parvovirus infection and alloimmune thrombocytopenia; Fig. 1.6), maternal ingestion of agents such as aspirin and cocaine, and thrombophilic conditions including factor V Leiden and MTHFR mutations (Petaja et al 2001, Aronis et al 2002, Ramenghi et al 2005). Another proposed mechanism underlying fetal intracranial hemorrhage is cerebral venous thrombosis, which tends to recanalize rapidly, leaving only features of hemorrhage and its complications.

Fig. 1.4 Fetal brain showing the distended fourth and lateral ventricles with low-signal hemorrhage layering along the dependent side of the dilated right lateral ventricle (arrow). Axial MRI single-shot fast spin-echo T2-weighted image.

Fig. 1.3  Periventricular hemorrhagic infarction (white star) in 30-week gestation fetus (coronal T2-weighted MRI).

8

Brain Injury in the Fetus

(b)

(c)

(a)

(d) Fig. 1.5  Macroscopic autopsy findings of brain shown in Figure 1.4. (a) Ventral view of the brain showing multifocal intracortical and focal subarachnoid hemorrhages. (b) Dorsal-inferior view of the brain with brainstem reveals membranous degeneration of the inferior vermis and calcification in the wall of the lateral ventricle (arrow). (c) Dorsal view of the brainstem and cerebellum showing the wispy tissue remnants of the cerebellar vermis and parts of the cerebellar hemispheres with punctate hemorrhages. (d) Coronal section at the level of the caudothalamic groove showing marked ventricular distention, thinning of the cerebral mantle, and blood products of varying ages in the floor of the lateral ventricles.

Maternal Toxins A multitude of substances may have toxic effects in the developing nervous system, with both teratogenic and destructive consequences. Only select examples are discussed here, and are confined to drugs of abuse (alcohol and cocaine) and the effect of phenylalanine on the fetus in asymptomatic maternal phenylketonuria. Understanding the mechanisms of fetal brain injury associated with

maternal drug abuse is complicated by confounding psychosocial factors and frequent multisubstance abuse. Alcohol remains the most commonly implicated teratogenic toxin. Fetal alcohol exposure may result in a spectrum of outcomes, related in large part to the timing and dose of alcohol exposure. The classic fetal alcohol syndrome has well-known facial and somatic features (Clarren and Smith 1978, Erb and Andresen 1978), and almost universal microcephaly and mental impairment. In addition to the full-blown fetal alcohol syndrome, lower fetal exposure may be associated with less obvious somatic features but with some level of cognitive impairment. The precise mechanisms by which alcohol induces its effects on the developing brain are not well established, and probably include a variety of mechanisms related to the maturational stage at exposure, as well as the confounding socioeconomic, nutritional, and multitoxin exposures. Putative mechanisms have included the following: a decrease in uterine blood flow, possibly due to vasoconstriction of the uterine arteries leading to fetal hypoxemia; fetal hypoglycemia; fetal zinc deficiency; an effect on NMDA receptors with pro-apoptotic effects; and impaired vitamin A synthesis. Fetal alcohol exposure has been implicated in disruption of all the major phases of brain development. The most common lesions described

Fig. 1.6  Massive cerebral hemorrhage in 32-week gestational age fetus with alloimmune thrombocytopenia (axial T2-weighted MRI).

9

Section I: The Fetus

have been neural tube defects, and disturbances in neural proliferation and migration, with cell–cell adhesion disturbances being implicated. Examples of neuropathologic lesions include schizencephaly and polymicrogyria, as well as disturbances in midline prosencephalic development, including agenesis of the corpus callosum and septum pellucidum. Cocaine is another maternal intoxicant with potentially devastating impacts on the fetal brain. Fetal cocaine exposure has been associated with a spectrum of structural and functional neurologic sequelae. Cocaine readily crosses the placenta and fetal blood–brain barrier. Once in the fetal brain, cocaine blocks presynaptic catecholamine reuptake, leading to sustained catecholaminergic activity in the developing brain. Under normal conditions, the immature nervous system is in autonomic imbalance with delayed parasympathetic maturation favoring relatively unopposed sympathetic tone, a scenario further amplified by the action of cocaine. Disturbances in cognition, affect, attention, visual– motor and visual–spatial function, and behavioral regulation have been described after fetal cocaine exposure, even in the absence of obvious structural lesions. Several mechanisms have been proposed for these effects, including neurochemical, cerebrovascular, and non-specific ‘stress’ effects. During fetal life endogenous catecholamines form part of a regulating signal system that influences many of the major processes of brain development, including neurogenesis, neuronal differentiation, neural migration, and cortical organization (Gressens et al 1992, Garg et al 1993, Lipton et al 1999, Lidow and Song 2001). The unregulated neurotransmitter increase during cocaine exposure may disrupt development at any or all of these developmental pathways, as seen in the spectrum of developmental brain lesions associated with fetal cocaine exposure ranging from microcephaly, neuronal migration defects, disorders of prosencephalic development (including agenesis of corpus callosum and septo-optic dysplasia), and neuronal migration abnormalities (Dominguez et al 1991, Handler et al 1991, Gieron-Korthals et al 1994, Addis et al 2001, He and Lidow 2004, Salisbury et al 2009). Cocaine and its metabolites may also cause vasoconstriction in the maternal, placental, umbilical (especially umbilical vein), and fetal (Zhang and Dyer 1991, Schreiber 1995, Patel et al 1999, Robinson et al 2000) circulation disrupting fetal oxygen-substrate supply. Although this mechanism of cocaine-mediated brain injury has been challenged, hypoxic–ischemic/reperfusion injury and hemorrhagic destructive brain lesions are well described in these infants (Fig. 1.7). Another proposed pathogenetic mechanism of developmental cocaine toxicity relates to the features it shares with the general fetal

Fig. 1.7  Major cerebral ischemic and hemorrhagic injury in a newborn infant after major fetal cocaine exposure. Of note, negative diagnostic testing for congenital infections. Axial T1-weighted MRI.

stress response (Lester and Padbury 2009). The early part of the fetal response to cocaine, specifically the elevation of catecholamines, is common to the fetal stress response. Therefore, it is possible that the more downstream events known to occur after fetal stress also play a role in survivors of fetal cocaine exposure. Specifically, the secondary effects of catecholamine on the hypothalamic– pituitary–adrenal axis include an elevation in circulating glucocorticoids, which in turn have potent effects on fetal and placental genetic programming, with potential health effects into adult life and across generations (Lester and Padbury 2009). Maternal phenylketonuria may have major toxic effects on the fetal brain, with more than 75% of offspring having an intellectual disability. During normal development phenylalanine hydroxylase expression begins as early as the sixth week of gestation; however, early function of the immature enzyme may be incapable of handling a phenylalanine level that is elevated but asymptomatic in the mother. Elevated phenylalanine levels in the fetal circulation may have dose-dependent teratogenic effects on the fetal brain (Levy and Ghavami 1996, Levy et al 1996), including microcephaly, hypomyelinated white matter, and callosal dysgenesis. Although a precise mechanism(s) for these fetal effects remains unclear, possible pathways include disruption of essential nutrient transport by the placenta or phenylalanine’s direct oligodendrocyte toxicity resulting in hypomyelination. Fetal infections The developmental neuropathology of fetal infection may be categorized broadly into two, often overlapping, forms. Specifically, fetal encephalitis may cause disruption of

10

Brain Injury in the Fetus

normal pathways for brain development and/or destructive brain lesions, often with prominent inflammatory features. It is likely that multiple mechanisms may operate with direct viral injury, vascular and inflammatory injury, and possibly viral disruption of genetic mechanisms. It may be difficult to establish congenital infection early in gestation as neither humoral inflammatory nor reactive astroglial responses in the fetus becomes evident until midgestation. Although many clinical and imaging features are common to the fetal encephalitides, certain features are more suggestive of certain agents (Bale 2009). For example, microcephaly is common to congenital encephalitis due to cytomegalovirus (CMV), rubella, herpes simplex (HSV) type II, and varicella zoster (VZV) infections, whereas congenital toxoplasmosis may be associated with hydrocephalic macrocephaly. Congenital infections are commonly associated with ocular findings, with chorioretinitis occurring in approximately 75% of infants with congenital toxoplasmosis, but infrequently in congenital CMV (20%) (Bale 2009). Sensorineural hearing loss is common in congenital rubella and CMV (Fowler et al 1997, Grosse et al 2008), and less common in congenital toxoplasmosis. Neuroimaging findings common to fetal encephalitis include periventricular hyperechoic and/or cystic lesions with atrophic ventriculomegaly and intracranial calcifications. The distribution of calcifications tends to be periventricular in congenital CMV, more scattered in fetal toxoplasmosis, and basal ganglia–thalamic in fetal HSV encephalitis (Hutto et al 1987). While cerebral cortical malformations such as schizencephaly, pachygyria/ lissencephaly, and hydranencephaly may develop after fetal HSV, CMV, and VZV encephalitis (Wright et al 1997, Bonthius et al 2007, Bale 2009), polymicrogyria is highly suggestive of CMV, particularly when associated with cerebellar hypoplasia (Bonthius et al 2007, Volpe 2008e). In this chapter we focus on the neurologic sequelae of fetal CMV and parvovirus infections because they illustrate certain themes and are more common than other forms of fetal viral infections with neurologic complications. Most cases of HSV encephalitis are acquired in the perinatal and neonatal periods, with only about 10% of HSV-II infections acquired in utero (Kimberlin 2004a,b). Congenital rubella syndrome, a potentially catastrophic transplacental infection associated with necrotizing encephalopathy with marked inflammation, has become rare in developed countries since the advent of widespread vaccination. Congenital CMV infection remains the most common viral infection affecting the fetus, with approximately 1% of neonates in the USA infected at birth; of these 10% (or 4000 individuals) per year will be symptomatic at birth, with a significant mortality (Istas et al 1995). Humans

are the only reservoir and transfer is through salivary or genital secretions and breast milk. Fortunately, fetal transfer rates are low, occurring in only 2% of individuals. Most fetal CMV infections occur after primary maternal infections, but may also occur after maternal reinfection or reactivation. The best predictor of adverse outcome in fetal CMV is neuroimaging evidence for brain involvement. The CMV is tropic to rapidly proliferating cells and to endothelial cells. The tropism toward rapidly proliferating cells likely underlies the microcephaly, often progressive. Cerebellar hypoplasia is present in around 50% of individuals with symptomatic CMV, which is likely to be related to the protracted development of the cerebellum with its primary and secondary germinal matrices for cell proliferation. Inflammatory changes are prominent and diffuse in CMV encephalitis, and involve the periventricular white matter, germinal matrices, and cerebral cortex. The white matter pathology may mimic periventricular leukomalacia (PVL) with its predilection for hypomyelination and periventricular cysts, particularly in a parietal distribution (Fig. 1.8a). However, unlike PVL, CMV encephalopathy commonly also involves the anterior temporal white matter (Fig. 1.8b). Another feature that distinguishes CMV from other forms of fetal encephalitis is the often striking involvement of gray matter, ranging from neuronal migration defects, particularly when the infection occurs earlier in gestation. In fact, in individuals with white matter abnormalities but normal cortical gray matter, the likely onset of CMV encephalitis is in the third trimester (Barkovich and Girard 2003). The cortical gray matter lesions include heterotopias, schizencephalies, pachygyria–lissencephaly (suggesting infection at between 16 and 18 weeks), and polymicrogyria (suggesting infection at between 18 and 24 weeks). The predilection of CMV for endothelial cells underlies the mineralizing vasculopathy (‘candelabra sign’, Fig. 1.9) of the basal ganglia–thalamus vessels evident in one-third of individuals with congenital CMV encephalitis. The prominent inflammatory changes may underlie the atrophic ventriculomegaly, porencephaly, hypomyelination, and cystic changes of the periventricular and subcortical white matter in congenital CMV encephalitis. Parvovirus B19 infection has a spectrum of potentially catastrophic effects during pregnancy, including neurodevelopmental disability in one-third of survivors (Nagel et al 2007). ‘Fifth disease’ is the most common form of parvovirus infection in childhood, and is transmitted by respiratory droplets and blood products. Transmission of the virus from mother to fetus is vertical. Parvovirus is tropic for erythroid lineage cells and may cause severe fetal anemia and thrombocytopenia, resulting in anemic hypoxia and hemorrhage, as well as

11

Section I: The Fetus

(a)

(b)

Fig. 1.8  (a) T1-weighted MRI axial views in a 3-month-old infant with cytomegalovirus encephalitis showing diffuse white matter injury resembling preterm birth-related white matter disorder. (b) Anterior temporal white matter cysts.

non-immune hydrops and fetal death, especially when transmitted between 17 and 24 weeks’ gestation. Fetal brain involvement ranges from perivascular calcifications in the cerebral cortex, subcortical gray matter, and germinal matrix layers to ventriculomegaly (Katz et al 1996), polymicrogyria, cerebellar hemorrhage, and hypoplasia of the cerebellar hemispheres and vermis (Glenn et al 2007, Nagel et al 2007, Pistorius et al 2008). In animal models, fetal parvovirus infection is associated with destruction of the external granular layer and cerebellar hypoplasia.

Broadly speaking, the neuropathology in these conditions may reflect disruption of cellular energetics, disturbed development of the cell membrane, and abnormal signaling between cells. The fetal brain lesions may manifest in several ways. First, the metabolic defect may cause ‘acquired’ disruption of brain development or destructive lesions, often in combination. In certain conditions (e.g. sulfite oxidase deficiency, nonketotic hyperglycinemia, pyruvate dehydrogenase deficiency) this combination of developmental disruption and encephaloclastic changes may be prominent (Dobyns 1989, Schiaffino et al 2004). A broad range of nervous system malformations (Nissenkorn et al 2001, Prasad et al 2007, Prasad et al 2009) has been described in infants with inborn metabolic errors. Certain developmental lesions are more common in certain metabolic conditions. This reflects a stage-dependent interaction between the ‘product’ of the metabolic defect and the concurrent events in brain development. Malformations of the developing nervous system from the early stages of neurulation, through prosencephalic and callosal development, to the late stages of cerebral cortical development have been described in children with inborn errors of metabolism. All phases of brain development during the fetal period (rapid neuronal proliferation, differentiation and neuronal migration, and the synaptically mediated development of normal circuitry) are, to some extent, energy dependent. It is therefore not surprising that inborn disturbances in energy metabolism, such as pyruvate dehydrogenase deficiency (Shevell et al 1994, Nissenkorn et al 2001) and mitochondrial respiratory chain defects (Shevell et al 1994, Rotig and Munnich 2003, von Kleist-Retzow et al

Fetal errors of metabolism Inborn errors of metabolism in the fetus are usually due to enzyme or co-factor deficiencies. These conditions may exert injurious effects on the developing brain through accumulation of neurotoxic by-products or/and a deficiency in substances essential for normal brain development (Nissenkorn et al 2001).

Fig. 1.9  CMV encephalitis with arrow showing mineralizing vasculopathy (‘candelabra sign’). Angled parasagittal ultrasound.

12

Brain Injury in the Fetus

2003, Sarnat and Marin-Garcia 2005), are associated with a spectrum of developmental brain anomalies. In these cases intrauterine somatic and cerebral growth restriction is common. White matter lesions, often cystic, ranging from germinal matrix and other periventricular cysts to extensive cystic encephalopathy with calcifications have been described, together with ventriculomegaly and callosal dysgenesis (Samson et al 1994). Gray matter lesions have included cerebral cortical malformations such as polymicrogyria and heterotopias in these disorders of energy metabolism, as have a variety of cerebellar lesions, including cerebellar (von Kleist-Retzow et al 2003) and pontocerebellar hypoplasia (Lincke et al 1996), and ‘Dandy–Walker malformation’. Callosal dysgenesis may be seen in a wide variety of inborn metabolic disorders including pyruvate dehydrogenase deficiency, nonketotic hyperglycinemia, as well as mitochondrial and peroxisomal disorders. White matter lesions may occur as areas of cystic destruction and/or hypomyelination due to cytotoxic death of oligodendrocyte precursors with subsequent failure of myelination. Certain inborn metabolic conditions exert their effect on brain development by disrupting normal cell-to-cell signaling. One example is the Smith–Lemli–Opitz syndrome, a multisystem dysmorphic condition resulting from 7-dehydrocholesterol reductase deficiency (Porter 2003, 2008), and hence very low cholesterol levels. The SHH gene plays a central role in development of the brain, cranium, face, and other organs (Opitz et al 1987, Penchaszadeh 1987, Porter 2008). The effect of SHH is mediated by a cholesterol-dependent gene product that is critical for cell–cell membrane signaling (Ingham 2001). Insufficient cholesterol results in failed SHH signaling and results in the lesions described in SLOS, such as

craniofacial (e.g. cyclopia and cebocephaly) and forebrain development (failure of cerebral prosencephalic ‘cleavage’ or holoprosencephaly) (Porter 2003). Congenital disorders of glycosylation (CDG) result in multisystem malformation syndromes including the brain and face (Krasnewich and Gahl 1997, Baric et al 1998). The most common subtype, CDG type 1a, is associated with cerebellar hypoplasia, hypotonia, fetal hypokinesia, and intellectual disability (Krasnewich and Gahl 1997, Baric et al 1998), as well as inverted nipples, aberrant fat distribution, and disturbed coagulation and endocrine function (Baric et al 1998). An associated cardiomyopathy may result in non-immune hydrops fetalis (Hertz-Pannier et al 2006, van de Kamp et al 2007, Malhotra et al 2009). Peroxisomal disorders in the Zellweger syndrome spectrum are associated with the whole spectrum of neuronal migration anomalies including lissencephaly, pachygyria, polymicrogyria, and heterotopias, as well as callosal hypoplasia and cerebellar anomalies (Fig. 1.10) (Volpe and Adams 1972, Barkovich and Peck 1997). Nonketotic hyperglycinemia is associated with callosal dysgenesis, dysmyelination, and cortical anomalies (Press et al 1989, Paupe et al 2002). Conclusions The fledgling clinical field of fetal neurology has advanced dramatically in recent years. Factors playing a major role in these developments have been the advances in fetal imaging and the accelerated understanding of neurogenetic mechanisms underlying normal and abnormal fetal brain development. Advances in these areas have provided invaluable insights into the phenotype–genotype associations in fetal neurology. Likewise, as highlighted in this chapter, a broad

(a)

(b)

Fig. 1.10  Cytomegalovirus encephalitis in a 36-week gestation infant showing striking white matter abnormality and cortical malformation, with prominent polymicrogyria particularly in the fronto-parietal and Sylvian regions: axial (a) and coronal (b) T2-weighted MRI.

13

Section I: The Fetus

spectrum of environmental influences may affect brain development. The ability of advanced in vivo fetal brain imaging to detect and measure the effect of these ‘insults’

on the developing brain will, in future, be critical for the design of clinical trials aimed at preventing irreversible derangements in brain development.

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2 Imaging the Fetal Brain Catherine Limperopoulos

Introduction Fetal magnetic resonance imaging (MRI) is becoming a powerful tool with which to assess the developing fetal brain. The advent of accelerated single-shot MRI techniques is opening a new window into the timing, rate, and limits of variability of normal brain development in vivo. Better understanding of the dynamic and highly elaborate developmental processes that underlie normal brain maturation in vivo is providing important insights into the onset and progression of acquired fetal brain injury. This chapter will briefly review techniques of fetal ultrasound and MRI. Advantages and disadvantages of each modality are summarized, followed by an overview of the MRI features associated with normal fetal brain development, and a review of the role of MRI for acquired brain injury in the fetus. Finally, this chapter will explore the advancing role of fetal MRI and its application to the compromised fetus.

Fetal MRI was first introduced in the early 1980s using T1-weighted inversion recovery and proton density sequences at low field magnet strength. These initial imaging acquisitions were long (i.e. several minutes in duration) and were highly susceptible to motion, necessitating fetal and/or maternal sedation. The advent of ultrafast T2-weighted sequences (described below), together with improved MRI hardware, enabled the acquisition of MRI sequences in less than 20 seconds, eliminating the need for sedation (Huisman et al 2002). Fetal MRI offers three-dimensional resolution, multiplanar imaging capabilities, large field of view, and robust image quality. Additionally, fetal MRI overcomes challenges of fetal ultrasonography resulting from reduced amniotic fluid volume, the position of the fetus, and acoustic shadowing (Glenn and Barkovich 2006). Compared with ultrasound, ultrafast MRI has been repeatedly shown to have greater sensitivity in up to 50% of cases for detecting fetal brain lesions/injury including nodular heterotopias, periventricular leukomalacia, multicystic encephalomalacia, and germinal matrix and intraventricular hemorrhages (Levine et al 1997, 1999, Simon et al 2000, Wagenvoort et al 2000, de Laveaucoupet et al 2001, Whitby et al 2004, Glenn and Barkovich 2006, Girard et al 2009, Peruzzi et al 2010). The remainder of this chapter will focus on the role of MRI for studying acquired injury in the fetus.

Imaging the fetal brain: ultrasound versus magnetic resonance imaging Fetal ultrasonography has been the primary imaging modality for prenatal diagnosis of fetal brain anomalies. The principal advantages of ultrasound include its low cost, portability (can be performed at the bedside), and widespread use. Fetal ultrasound imaging quality has improved dramatically as a result of high frequency three-dimensional transducers, as well as transvaginal sonography. Despite these advances, sonographic evaluation of the fetal brain continues to be limited by decreased resolution of the side of the brain near the transducer, acoustic shadowing resulting from ossification which obscures visualization of posterior fossa structures, and limited visualization of the developing cortex and subtle parenchymal abnormalities (Levine 2001, 2002, Pugash et al 2008). Moreover, multiplanar views may be difficult to obtain with ultrasound because of fetal position or advanced gestational age.

Imaging the fetal brain: the role of conventional magnetic resonance imaging Fetal MRI is performed on a 1.5-T scanner, generally from about 18 to 20 weeks’ gestation onward. Prior to 20 weeks, MRI resolution is poor overall because of the normally enlarged ventricles, thin cerebral mantle, and thick germinal matrix (Girard et al 2009). Ultrafast MRI techniques, known as single-shot fast spin-echo (SSFSE) or half-Fourier acquired single-shot turbo spin-echo (HASTE), have enhanced the study of the developing

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Imaging the Fetal Brain

brain in vivo. Using these ultrafast techniques, a single T2-weighted image can be acquired in less than 1 second, and thus dramatically reduces the exposure to fetal motion (Glenn 2009). Routine clinical studies include the acquisition of multiple stacks of slices acquired in different plans to enable complementary views of the developing brain anatomy. Typically, SSFSE T2-weighted images form the basis of an MRI study and are used to assess the morphology and signal intensity of the fetal brain. Additionally, gradient-echo echo-planar T1-weighted images or fast multiplanar gradient recalled-echo T1 techniques are used to detect hyperintense lesions such as hemorrhage, lipoma, subependymal nodules, or calcifications. T1-weighted imaging also offers information about the myelination process (Girard et al 2006a, Glenn 2009). T2* sequences are used to detect blood breakdown products and have been recently explored in the fetus. Diffusion-weighted imaging is performed using single-shot, echo-planar diffusion imaging, which can be acquired in less than 15 to 20 seconds and assists in identifying destructive brain lesions. Advanced MRI techniques, such as three-dimensional volumetric MRI, diffusion tensor imaging (DTI), and magnetic resonance spectroscopy, have also recently been successfully applied to the living fetus, though their development is still in the early stages. It is anticipated that these advanced imaging tools will shortly provide valuable diagnostic and prognostic information. These techniques are described later.

plate (Fig. 2.1). Briefly, the ventricular zone (or germinal matrix) corresponds to the innermost layer of the fetal cerebral hemisphere. Early in gestation the ventricular zone is very broad and has the appearance of a smooth band of high T1–low T2 signal lining the lateral ventricles. The ventricular zone regresses with increasing gestational age, and by 27 to 29 weeks gestational age, a single layer of ependymal cells will replace the ventricular zone and line the wall of the ventricles (Kinoshita et al 2001, Bystron et al 2008). The periventricular zone is located just superficial to the ventricular zone and is a thin area of increased T2 signal and decreased T1 signal. The subventricular zone contains the germinal matrix and the intermediate zone, which encompasses the fetal white matter located superficially to the periventricular zone. The subventricular zone appears as a relatively homogeneous strip of slightly low T2 and high T1 signal. The subplate comprises neurons, profuse hydrophilic extracellular matrix, and evanescent synapses (Bystron et al 2008). Although the role of the subplate remains poorly understood, it is presumed to be a waiting compartment for the development of thalamocortical connections and other cortical afferent pathways (Sur and Rubenstein 2005, Huang et al 2009, Kostovic and Judas 2010, Tau and Peterson 2010). The subplate is thickest toward the end of the second trimester, and progressively disappears at around 32 to 36 weeks gestational age as axons leave the subplate and migrate to their destined targets in the cortex. Its appearance on MRI is characterized by a low T1–high T2 signal. Finally, the cortical plate has a similar intensity to the germinal matrix high T1–low T2.

Normal fetal brain development on conventional magnetic resonance imaging Although a comprehensive review of normal fetal brain development is beyond the scope of this chapter, a brief overview is warranted. Prior knowledge of normal brain anatomy and the corresponding changes of the magnetic resonance signal in relation to increasing gestational age are essential. The appearance of the supratentorial (Garel 2004a, Parazzini et al 2008, Tilea et al 2009) and infratentorial (Garel 2004a, Schneider et al 2007, 2009, Tilea et al 2009) structures of the fetal brain using conventional MRI have been well established with corresponding normative reference values. The cortical mantle has a multilayered appearance on MRI until about 28 weeks’ gestation (Girard and Raybaud 1992, Girard et al 1995, Chong et al 1996, Brisse et al 1997, Kostovic et al 2002, Garel et al 2003, Garel 2004a, Prayer et al 2006a). This multiple layer appearance represents the different layers of the developing fetal brain (Kostovic et al 2002, Rados et al 2006), which include the ventricular zone, periventricular zone, subventricular and intermediate zone, subplate zone, and cortical

Fig. 2.1  Coronal T2-weighted single-shot fast spin-echo MRI of a 25-week gestational age fetus, illustrating the multilayered appearance of the developing brain. The germinal matrix is the deepest layer and is of low signal intensity (white arrowhead). Adjacent to the germinal matrix is the periventricular zone (white dotted arrow) with corresponding high signal intensity. Adjacent to the periventricular zone is the subventricular zone (double white arrows), which is of low signal intensity, and just superficial to this layer is the high signal intensity subplate zone (single white solid arrow) and the cortical plate (black arrow), represented with low signal intensity.

19

Section I: The Fetus

Normal brain development is characterized by expansion and folding of the cerebral cortex. The emergence of sulci follows a consistent spatial and temporal program. Primary sulci are the first to appear followed by the formation of secondary and tertiary sulci. Overall, a sulcus first appears as an initial smooth, shallow, and wide indentation on the brain surface that progressively deepens and narrows, ultimately forming the secondary and tertiary sulci (Glenn 2009). Importantly, sulcation is considered to be one of the most accurate ways of dating a fetus by pathologists. The appearance of sulci on two-dimensional fetal MRI has been well described, and the sulcation landmarks appear on magnetic resonance images in the order predicted on neuropathology. However, the timing has been reported to lag behind that observed on fetal autopsy specimens by an average of 2 weeks (range 0–8 weeks) compared with MRI visualization (Chi et al 1977, Levine and Barnes 1999, Garel 2004b). A comparison of the appearance of major sulci by gestational age on autopsy versus MRI is summarized in Table 2.1. More recently, advanced MRI techniques are beginning to quantify cerebral cortical development in vivo and are offering exciting insights into normal and aberrant fetal cortical development (described later). The cerebellar hemispheres appear multilayered as early as 21 weeks (evident by a central area of low T2 and high T1 signal), and the cerebellar vermis is completely formed by 20 weeks of gestation (Adamsbaum et al 2005,

Limperopoulos et al 2006). The primary fissure is seen on midline sagittal images by 25 to 26 weeks gestational age, but can be seen as early as 21 weeks. The dorsal pons and dorsal medulla have a high T1 and low T2 signal, which is evident as early as 23 weeks gestational age. A comprehensive understanding of normal brain development on MRI is important in order to appreciate the MRI features of acquired brain injury, which will vary accordingly. Fetal brain injury in the fetus on conventional magnetic resonance imaging Of all fetal organ systems, study of the fetal brain has undoubtedly benefited most from the superior image quality and anatomical detail offered by MRI. The high resolution afforded by fetal MRI can identify critical yet subtle changes in central nervous system landmarks, especially early in gestation. Acquired brain injury represents the third most frequent indication (up to 20%) for fetal MRI (Girard et al 2001, 2009, Girard and Huisman 2005) comprising a major thrust for antenatal diagnosis. Cerebral insults can result from a number of fetal– maternal conditions. Risk factors and underlying pathogenetic mechanisms of fetal brain injury are described in detail in Chapter 1. Cerebral insults that ensue early in gestation are frequently associated with embryo/fetal demise or developmental malformations (Gilles and Gomez 2005). The selective vulnerability of the developing gray versus white matter also depends on the

Table 2.1 Comparison of major sulci appearance by gestational age (weeks) by fetal MRI versus autopsy

Sulci

Detected by autopsy (25–50% of cases)a

Detected by fetal MRI (75% of cases)b

Sylvian

14

16–17

Callosal

14

22–23

Parieto-occipital

16

22–23

Calcarine

16

24–25

Cingulate

18

26–27

Central

20

26–27

Superior temporal

23

27

Precentral

24

26–27

Postcentral

25

28–29

Superior frontal

25

29

Inferior frontal

28

29

Inferior temporal

28

32

Insular

34

32–33

Adapted from Glenn (2009). aChi et al (1977). bLevine and Barnes (1999), Garel (2004b).

20

Imaging the Fetal Brain

(a)

(b)

(c)

Fig. 2.2  Intraventricular hemorrhage with mild unilateral ventriculomegaly, which is dark on T2-weighted (a) and bright on T1-weighted (b) fetal (gestational age of 31 weeks) MRI, and corresponding bright signal intensity on the diffusion-weighted image (c).

gestational age at which the injury occurred. White matter injury is more prevalent than gray matter injury in the fetus. When present, gray matter injury most commonly occurs in the upper brainstem and thalami, followed by lesions in the convexity border zone resulting in sclerotic microgyria (Girard et al 2009). The MRI presentation of acquired brain injury in the fetus varies depending on whether the injury is acute or chronic. Acute brain injury may manifest as hemorrhage (intra- or extra-axial), edema, thrombosis, focal ischemia, or loss of lamination of the brain parenchyma until the end of the second trimester (Girard et al 2006a, 2009, Prayer et al 2006b). The chronic response to acquired fetal brain injury is more commonly detected by prenatal MRI than is the acute response, and may be characterized by a host of abnormalities including ventricular enlargement and/ or ventricular distortions (e.g. irregular margin, abnormal shape); abnormal gyration; parenchymal abnormalities (e.g. small hemisphere); calcifications; laminar necrosis; cerebral and cerebellar disruptions; intracranial spaceoccupying lesions; or cerebral atrophy (Girard et al 2006a, 2009, Prayer et al 2006b). A combination of an acute and chronic response is also commonly seen in response to fetal brain injury (Girard et al 2009). Moreover, lesions that ensued at different gestational ages may coexist and likely reflect ongoing responses after injury (Girard et al 2006a). The MRI features of these acquired lesions are presented below.

seen as a hemorrhagic parenchymal lesion (Fig. 2.3). In addition to intraventricular hemorrhage, intracranial hemorrhages in the form of sudural, subarachnoid, and supratentorial parenchymal hemorrhages can be present. Hemorrhagic injury usually appears as an area of dark signal on T2 and bright signal on T1. The signal intensity can vary depending on the stage of hemorrhage. Moreover, small hemorrhages in the subependyma may be difficult to differentiate because of the similar signal intensity of blood and the normal intensity of the germinal matrix (Girard et al 2006a, 2009, Prayer et al 2006b). T2* weighted gradient echo and echoplanar sequences can be used to confirm the presence of blood, as hemorrhage appears more hypointense than the germinal matrix using these sequences (Glenn and Barkovich 2006, Girard et al 2009). Posterior fossa hemorrhages also appear bright on T1 and dark on T2, and MRI is helpful in localizing the topography of injury. Fetal MRI can be used to identify the location of the hemorrhage (i.e. intra- vs. extra-axial hemorrhage) and can assess the integrity of the cerebellar

Hemorrhage Hemorrhagic injury in the fetus may occur in the setting of fetal hypoxia or infection (e.g. chorioamnionitis) secondary to anticoagulant activity and cytokine-mediated endothelial cell damage (Dammann and Leviton 1998). Hemorrhagic injury can be confined to the germinal matrix or may be intraventricular (Fig. 2.2). Intraventricular hemorrhage can be complicated by ventricular dilation or hydrocephalus. Associated venous infarction may be

Fig. 2.3  Multiple small periventricular cysts adjacent to the right frontal horn with abnormal white matter signal consistent with right periventricular hemorrhagic infarction on axial T2-weighted single-shot fast spin-echo MRI (imaged fetus of gestational age 33 weeks).

21

Section I: The Fetus

hemispheres, vermis, and brainstem (Gorincour et al 2006).

similar signal intensity (Gicquel et al 2000). Noteworthy, fetal strokes that occur early in gestation (before 20 weeks) may present with limited to no corresponding tissue injury on MRI and may be subsequently misdiagnosed as a primary dysgenetic lesion on follow-up imaging.

Cerebral Edema Acute edema is difficult to visualize on fetal MRI. White matter injury in the fetus is often characterized by acute edema, which may be transient or lead to focal necrosis, in which the topographic predilection is in the parietooccipital and frontal regions (Girard et al 2009). However, this is not frequently visible on MRI. The absence of the intermediate layer of the white matter can be the sole finding on MRI in young fetuses. Briefly, risk factors for focal necrosis include placental vascular anastomoses, funisitis, and purulent amniotic fluid (Grafe and Kinney 2002, Gilles and Gomez 2005). Infection and inflammation are established mediators of white matter damage (Dammann and Leviton 1998, Chew et al 2006, Sen and Levison 2006). The application of diffusion-weighted acquisitions can facilitate the detection of edema, which appears as a bright signal on diffusion-weighted MRI and a dark signal on the corresponding apparent diffusion coefficient (ADC) images. Loss of lamination of the brain parenchymal may also be evident on MRI (Girard et al 2009).

Ventriculomegaly Ventriculomegaly can be divided into two categories: atrophic ventriculomegaly and hydrocephalic ventriculomegaly (described below). Ventricular dilation is frequently the result of prior hemorrhage. Enlarged ventricle size (usually unilateral) is a common (chronic) response after fetal brain injury (Fig. 2.5), whereas bilateral ventriculomegaly is typically present in the setting of cerebral malformations. Brain atrophy may be documented in cases of enlargement of the ventricles and/or the outer cerebrospinal fluid spaces (de Laveaucoupet et al 2005), which may result from a number of different primary pathologies (de Laveaucoupet et al 2001, 2005, Barkovich and Girard 2003, Brunelle 2003, Prayer et al 2006b). Abnormal ventricular shape/margin or irregular germinal matrix (Barkovich and Girard 2003, Girard et al 2006a) is often present in the chronic phase of injury. A common MRI finding is a thickened irregular ventricle present after 30 weeks gestational age (Girard et al 2009). Interestingly, this MRI finding has been shown to correspond with ependymal abrasion post mortem, resulting from brain atrophy, subventricular gliosis, and fetal ependymal inflammation (Sarnat 1995). Hydrocephalic ventriculomegaly may result from an acquired injury such as posthemorrhagic hydrocephalus, after infection, or compression of the aqueduct by a spaceoccupying lesion. Hydrocephalus results in enlarged ventricles secondary to disruption/distension of cerebrospinal fluid circulation (Fig. 2.6).

Cerebral Infarction and Thrombosis Arterial infarction may be associated with a number of conditions including vascular occlusive disease, infection, trauma or arteriovenous malformations, hypercoagulability and twin-to-twin transfusion syndrome (Girard et al 2009). The MRI features of cerebral infarction often illustrate a loss of gray and white matter parenchyma within the vascular territory distribution (Fig. 2.4), as well as ventricular dilation. Venous thrombosis is less common and may be associated with prothrombotic events and be present as a parenchymal hemorrhage with a corresponding low T2 and high T1 signal. Acquiring T1 images with fat suppression may assist in ruling out a lipoma, which may show a

Fig. 2.4 Axial T2-weighted single-shot fast spin-echo MRI at 26 gestational weeks demonstrates bilateral middle cerebral infarction.

Fig. 2.5 Axial T2-weighted single-shot fast spin-echo MRI at 26 gestational weeks shows mild isolated unilateral ventriculomegaly.

22

Imaging the Fetal Brain

chronic phase of injury. Destructive processes may lead to porencephalic cysts, which may or may not lead into the ventricular system and subarachnoid spaces (Girard et al 2009). At its extreme, hydranencephaly (of ischemic origin) may be present with limited to no cerebral tissue remaining, and the cranial cavity is filled almost entirely with cerebrospinal fluid. Calcifications Calcifications are usually seen within the cortex, germinal matrix, periventricular areas, and basal ganglia and white matter. They appear as a bright signal on T1 and a low signal on T2, and are most frequently seen in individuals with in utero infections.

Fig. 2.6  Coronal T2-weighted single-shot fast spin-echo MRI showing severe hydrocephalus secondary to aqueductal stenosis in a 29-week gestational age fetus.

White Matter Injury/Gliosis Although fetal white matter injury is not commonly identified with conventional MRI acquisitions, DTI and proton magnetic resonance imaging (described below) have the potential to identify gliosis in vivo. For example, increased creatine on spectroscopic imaging may be a marker for astrocytes (Girard et al 2006b). The application of diffusion-weighted acquisitions may also facilitate the identification of edema, which appears as a high signal on diffusion-weighted MRI and low signal on the corresponding ADC image. Acutely, white matter injury can be associated with edema with a corresponding low T1-weighted signal, particularly in the frontal and parietal regions. The absence of the intermediate layer of the white matter can be the only MRI finding in young fetuses. Nodules may also present as a high signal on T1 and a low signal on T2-weighted MRI, and have been reported in the parieto-occipital and frontal regions in individuals with twin-to-twin transfusion syndrome (Larroche et al 1994). Edema in the white matter may be transient or lead to necrosis. In the chronic stage, loss of brain volume is usually evident, which manifests as enlarged lateral ventricles and subarachnoid spaces, with or without abnormal signal on MRI (Girard et al 2009).

Disruptions Disruptions are often difficult to distinguish from primary dysgenetic lesions. Extrinsic factors that can disrupt normal brain development may include infection, hemorrhage, and hypoxic–ischemic events (Reardon and Donnai 2007, Poretti et al 2008a, Limperopoulos et al 2010a) that result in cortical malformations. For example, polymicrogyria can be identified on fetal MRI characterized by abnormal infoldings (excessive number of small gyri) of the cortex (Fig. 2.7) (Glenn et al 2005). Environmental insults associated with the subsequent development of polymicrogyria include intrauterine infection (e.g. cytomegalovirus), toxoplasmosis, syphilis, and intrauterine ischemia (e.g. twin–twin transfusion). Schizencephaly can also be seen on fetal MRI, which may be characterized by a unilateral or bilateral cleft of the cerebral hemispheres and communication between the ventricle and pericerebral subarachnoid spaces (Fig. 2.8). The walls of the cleft may be separated (open-lip schizencephaly) or closely adjacent (closed-lip schizencephaly) and the cortex surrounding this cleft is polymicrogyric (Guerrini 2005). The etiology of schizencephaly is likely a confluence of genetic and acquired causes, including a local failure of

Fetal Abscess Fetal abscess is relatively uncommon but may be observed in the setting of toxoplasmosis and cytomegalovirus (Kim et al 2007). The corresponding MRI feature is a high signal on T1 and low signal on T2 MRI. Noteworthy, a diagnosis of abscess is commonly made retrospectively with the presentation of calcifications on MRI, which may be isolated or multiple. Cystic Cavitation Cystic cavitation in the fetal cerebral or cerebellar parenchymal may be the result of focal ischemic or hemorrhagic injury, or leukomalacia, and is often observed in the

Fig. 2.7  Coronal T2-weighted single-shot fast spin-echo MRI showing mild bilateral ventriculomegaly and diffuse polymicrogyria characterized by irregular shallow sulci in a 28-week gestational age fetus.

23

Section I: The Fetus

and brain metabolite alternations, will likely require advanced MRI techniques, which are summarized below. Advanced magnetic resonance imaging techniques in the ex utero infant Innovative applications of quantitative MRI techniques have revolutionized the in vivo study of brain development in the ex utero infant. Specifically, volumetric threedimensional (3D) MRI has advanced our understanding of normal and abnormal cerebral cortical development and the developmental changes in specific brain tissue subtype (Huppi et al 1998, Dubois et al 2008). Similarly, DTI studies have shed new light on the impact of early injury on subsequent brain microstructural organization. These seminal studies have provided new insights into the potential mechanisms that underlie disturbed brain injury in the high-risk infant, and the immature nervous system’s adaptive response after early fetal brain injury. It is important to emphasize that although the presence of impaired structural brain development, connectivity, and metabolism is often not detectable by conventional MRI, it has been shown that these findings are associated with adverse neurodevelopmental outcomes (Rademaker et al 2006, Shah et al 2006, Bassi et al 2008, Counsell et al 2008, Kesler et al 2008, Thompson et al 2008, Soria-Pastor et al 2009). Notably, impaired brain growth and development may also be associated with remote, regional secondary growth disturbances not evident on conventional MRI (Limperopoulos et al 2005, Limperopoulos et al 2010b). These quantitative brain MRI changes in ex utero preterm infants have led to a vigorous pursuit of the same capabilities in the fetus, which are summarized below.

Fig. 2.8 Axial T2-weighted single-shot fast spin-echo MRI illustrating right open-lip schizencephaly in a 35-week gestational age fetus.

induction of neuronal migration or focal ischemic necrosis with destruction of the radial glial fibers during early gestation (Barkovich and Kjos 1992, Guerrini 2005). Prenatal cerebellar disruptions include unilateral or bilateral tissue loss or volume reduction, global cerebellar hypoplasia, unilateral cerebellar hypoplasia (Fig. 2.9), cerebellar agenesis, and unilateral cerebellar clefts (Poretti et al 2008b, 2009, Limperopoulos et al 2010b). The etiology of these findings includes genetic as well as acquired disruptive causes. Cerebellar hemorrhage may mimic a primary cerebellar dysgenetic lesion (i.e. Dandy–Walker malformation) (Limperopoulos et al 2010c). Therefore, it is important to consider the possibility of a cerebellar disruption resulting from hemorrhagic or posthemorrhagic injury and associated hypoxic–ischemic changes in individuals who seemingly meet criteria for a diagnosis of Dandy–Walker. In summary, although larger fetal brain lesions can be identified by conventional T1/T2-weighted fetal MRI, more subtle disturbances, e.g. impaired volumetric growth of brain tissue types, microarchitectural disorganization,

Acquired fetal brain injury and advanced in vivo fetal magnetic resonance imaging techniques Three-dimensional Volumetric Magnetic Resonance Imaging The recent successful application of quantitative MRI techniques to the living fetus is offering exciting opportunities to advance our understanding of the timing and progression of insults that disrupt normal brain development at a level that is below current ‘lesion detection’ on conventional MRI. Motion correction algorithms and 3D reconstruction techniques developed specifically for fetal MRI (Rousseau et al 2006, Jiang et al 2007, Kim et al 2010) are facilitating the measurement of global and regional brain growth and providing previously unavailable in vivo fetal brain growth trajectories (Habas et al 2010, Clouchoux et al 2011, Rajagopalan et al 2011). Similarly, studies are providing the first description of gyral development in the human fetal brain during the

Fig. 2.9  Coronal T2-weighted single-shot fast spin-echo MRI showing right unilateral cerebellar hypoplasia after in utero cerebellar hemorrhage in a 32-week gestational age fetus.

24

Imaging the Fetal Brain

critical period of rapid cortical development in the second and third trimester (Clouchoux et al 2011, Habas et al 2011). These data provide a strong impetus for the use of quantitative techniques to study the impact of acquired injury on the developing fetal brain. Investigators are beginning to apply these advanced techniques to the compromised fetus. A recent study (Limperopoulos et al 2010a) showed in vivo evidence of progressive impairment of brain growth measured by 3D volumetric MRI in fetuses with congenital heart disease compared with healthy control fetuses (Fig. 2.10). Surprisingly, the majority of fetuses with congenital heart disease in this study have a structurally normal brain on conventional MRI, demonstrating that advanced MRI techniques can detect injury that is not apparent using conventional imaging. Similarly, another study reported decreased brain volume in growth-restricted fetuses (Duncan et al 2005), demonstrating that the brain sparing that is evident using sonographic measurement of fetal head circumference masks a reduction in brain volume identified by advanced MRI volumetry. These preliminary data suggest that 3D volumetric MRI can reliably identify impaired fetal brain growth even in the absence of structural injury evident on conventional MRI, or available biometric measurements.

a neuroaxonal marker reflecting the development of dendrites and synapses and oligodendrocyte proliferation and differentiation; (2) creatine (Cr), responsible for cellular energy metabolism; (3) choline (Cho) involved in membrane synthesis, degradation, and myelination; and (4) lactate, a marker of anaerobic metabolism (Girard et al 2006b, Limperopoulos and Clouchoux 2009). To date, fetal 1H-MRS studies have described the developmental appearance and succession of these metabolites over the second and third trimester of pregnancy, offering critical metabolic normative data from which to examine altered metabolic profiles in the compromised fetus. Available fetal 1H-MRS data in high-risk pregnancies are primarily derived from case reports and series. Lactate (Robinson et al 2004, Azpurua et al 2008) and decreased NAA/choline (Azpurua et al 2008) have been demonstrated in growth-restricted fetuses. Increased inositol:choline ratios have also been reported in small for gestational age fetuses corroborating ex utero neonatal studies of hypoxic–ischemic encephalopathy, in which acute increases in inosotol/creatine are associated with an abnormal developmental outcome at 1 year of age (Robertson et al 2001). In one of the largest fetal 1H-MRS studies to date (Limperopoulos et al 2010a). NAA:choline ratios in fetuses with congenital heart disease were significantly and progressively lower with increasing gestational age in the third trimester than in healthy controls (Fig. 2.11). Lactate was present in 20% of fetuses with congenital heart disease, while no control fetuses had detectable cerebral lactate. Interestingly, fetuses with cerebral lactate had the lowest gestational age and total brain volume-adjusted

Proton Magnetic Resonance Spectroscopy Proton magnetic resonance spectroscopy (1H-MRS) is an exciting noninvasive technique for measuring metabolic substrates and monitoring cerebral metabolism in the fetal brain. The most commonly studied metabolites in the living fetus include (1) N-acetyl aspartate (NAA),

350

1.0 Controls

0.8

250

NAA:Cho

TBV (mL)

300

200 150

0.6 0.4 CHD 0.2

100

0.0

50 26

28 30 32 34 Gestational age (weeks)

36

38

26

28 30 32 34 Gestational age (weeks)

36

38

Fig. 2.11  Significantly slower rate of increase in NAA:choline ratio in fetuses with congenital heart disease (diamonds) compared with normal fetuses (black circles) with increasing gestational age (adapted from Limperopoulos et al 2010c).

Fig. 2.10  Progressive and significant decrease in third-trimester total brain volume (TBV) in fetuses with congenital heart disease (diamonds) compared with controls (black circles) over the same gestational age period (adapted from Limperopoulos et al 2010c).

25

Section I: The Fetus

NAA:choline ratio. Follow-up studies are needed to assess the long-term significance of these acute metabolic derangements in the high-risk fetus.

clinical application of fetal DTI remains limited to date because of challenges related to fetal motion. Only two reports have described in vivo white matter microstructure development in normal fetuses. Regional in utero white matter tract measurements were described to have a hierarchical dispersal. Specifically, the splenium demonstrated the highest fractional anisotropy followed by the genu of the corpus callosum and the internal capsule (Kasprian et al 2008, Mitter et al 2011). The application of DTI in the high-risk pregnancy awaits further study.

Diffusion-weighted Imaging Diffusion-weighted imaging has been used primarily to identify focal areas of reduced or increased diffusion after acute ischemic injury (described earlier in Righini et al 2003, Schneider et al 2007, 2009). In small for gestational age versus appropriate for gestational age fetuses, significant higher ADC values have been reported in the pyramidal tract, suggesting delayed brain development and decreased microstructural organization (Sanz-Cortes et al 2010). Similarly, higher diffusivity has been described in fetuses with congenital heart disease in the periatrial white matter and thalamus regions (Berman et al 2011), suggesting an important role for this imaging modality in the compromised fetus.

Summary Fetal MRI is becoming a vital neuroimaging tool for understanding normal in vivo developmental processes. Conventional fetal MRI has enabled us to detect acquired brain injury in the living fetus earlier in gestation and with greater accuracy, which has resulted in timely diagnosis and improved counseling. Recent advances in quantitative MRI techniques are setting the stage for promising clinical biomarkers with which to evaluate the brain in a noninvasive, integrated manner. Collectively, these techniques are opening unique windows on the timing of insults that derail normal brain development at a threshold that extends beyond the detection of lesions using conventional MRI. This in turn is providing the clinician with novel clinical tools with which to detect and monitor the high-risk fetus and facilitate and evaluate future clinical trials of prenatal intervention.

Diffusion Tensor Imaging DTI assesses the impact of early injury on subsequent white matter microstructural architecture (Basser et al 1994) by evaluating axonal/fiber formation and connectivity in the developing brain (Huppi et al 1998, Berman et al 2005, Partridge et al 2005, Bui et al 2006, Anjari et al 2007, Dubois et al 2008, Huang 2010). The visualization and quantification of white matter fiber direction is accomplished by measuring fractional anisotropy. The

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Section I: The Fetus

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3 Mechanisms of Acute and Chronic Brain Injury in the Preterm Infant Stephen A. Back

Magnitude of the problem and spectrum of brain injury in preterm survivors Although major advances in the care of preterm infants have resulted in striking improvements in the survival of very low birthweight (VLBW) infants (