Fetal and Neonatal Neurology and Neurosurgery [4 ed.] 0443104077, 9780443104077

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Fetal and Neonatal Neurology and Neurosurgeiy

EDITION

EDITED BY

M. I. LEVENE • F. A. CHERVENAK

Fetal and Neonatal Neurology and Neurosurgery EDITION

Dedicated to our fathers, Dr Maurice Levene and Mr Frank Chervenak, who continue to live through their sons' commitment to helping fetal and neonatal patients throughout the world

For Elsevier Commissioning Editor: Ellen Green/Pauline Graham Development Editor: Helen Leng Project Manager: Kathryn Mason Design Direction: Erik Bigland Illustrations Manager: Merlyn Harvey Illustrator: Lois Hague

Fetal and Neonatal Neurology and Neurosurgery

EDITION

EDITED BY

MALCOLM I LEVENE

MD FRCPCH FMedSc

Professor of Paediatrics, Leeds General Infirmary Head of Academic Department of Paediatrics and Child Health University of Leeds, UK

FRANKACHERVENAK

MD FACOG MMM

Given Foundation Professor and Chairman Department of Obstetrics and Gynecology New York Weill Cornell Medical Center New York, USA

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r ^0,

EDINBURGH LONDON NEWYORK PHILADELPHIA STLOUIS SYDNEY TORONTO 2009

ELSEVIER

CHURCHILL LIVINGSTONE

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Contents

Preface to the fourth edition

viii

8.

The development of senses

111

Birgit Arabin

Preface to the first edition

ix 9.

Acknowledgments

x

Clinical assessment of the infant nervous system

128

Claudine Amiel-Tison, Julie Gosselin

List of contributors

xi

10.

Perinatal cerebral circulation

155

Edgar Hernandez-Andrade, Horst Steiner, Birgit Arabin SECTION I

11. STRUCTURAL DEVELOPMENT OF THE CNS

Cerebral blood flow and energy metabolism in the developing brain

171

Gorm Greisen

1.

The molecular basis of brain development

12. 1

Hugo Lagercrantz, Thomas Ringstedt

2.

Early embryonic development of the brain

EEG and evoked potentials in the neonatal period

192

Lena Hellstrom-Westas, Linda S de Vries

12

Gonzalo Moscoso

3.

Development of consciousness: fetal, neonatal and maternal interactions

SECTION III

21

Hugo Lagercrantz

4.

Ultrasound assessment of normal fetal brain development

ANOMALIES

13. 29

Harm-Gerd K Blaas, Sturla H Eik-Nes

5.

Magnetic resonance imaging of the fetal central nervous system Imaging the neonatal brain

222

Gonzalo Moscoso

45

14.

Eispeth Whitby

6.

Congenital structural defects of the brain

Genetics of neurodevelopmental anomalies

266

Mohnish Suri

68

Luca A Ramenghi, Petra Huppi

15.

Antenatal assessment of CNS anomalies, including neural tube defects

291

Ritsuko K Pooh, KyongHon Pooh

16.

SECTION II

17. Jan G Nijhuis

339

Nadav Schwartz, Han E Timor-Tritsch, Ana Monteagudo

FUNCTIONAL ASSESSMENT OF CNS DEVELOPMENT

7. Functional assessment of the fetal CNS

Transvaginal fetal neuroscan

103

Epidemiology and prevention of neural tube defects

366

Aubrey Milunsky

v

Contents

SECTION IV INFECTION OFTHE CNS

HEMORRHAGIC AND ISCHEMIC LESIONS

18.

Fetal brain injury and multiple pregnancies Isaac Bllckstein

375

19.

Infection, inflammation and brain injury Jimmy Espinoza, Roberto Romero, Francesca Gotsch, Juan Pedro Kusanovic, Offer Erez, Bo Hyun Yoon, Sonia Hassan

385

Neonatal intracranial hemorrhage Malcolm I Levene, Linda S de Vries

395

Cerebral ischemic lesions Linda S de Vries, Serena J Counsell, Malcolm I Levene

431

20.

21.

30.

Toxoplasmosis J Nizard, Guillaume Benoist, Yves G Ville

31.

Congenital viral infections and the central nervous system Guillaume Benoist, J Nizard, Yves G Ville

32.

Bacterial and fungal infections Thomas Snelling, David Isaacs

630

640

657

METABOLIC DISORDERS

PERINATAL ASPHYXIA

22.

Pathophysiology of asphyxia Laura Bennet, Jennifer A Westgate, Peter D Gluckman, Alistair J Gunn

33. Inborn errors of metabolism presenting with encephalopathy A Garda Cazorla

678

472

SECTION VIII

23.

24.

25.

Antenatal prediction of asphyxia K A Sorem, James F Smith, Maurice L Druzin

491

Intrapartum monitoring for asphyxia David A Miller

506

Prediction of asphyxia with fetal gas analysis Med hat Alberry, Sergio de la Fuente, Peter W Soothill

26.

The asphyxiated newborn infant Luc Cornette, Malcolm I Levene

27.

Neuroprotection of the fetal and neonatal brain Vincent Degos, Vincent Lelievre, Pierre Gressens

SEIZURE DISORDERS

528

542

34.

Seizure disorders of the neonate Janet M Rennie, Geraldine B Boylan

35.

Hypoglycemia and brain injury — when neonatal metabolic adaptation fails Jane M Hawdon

36.

Kernicterus Charles E Ahlfors

698

711

720

587 SECTION IX THE SPECIAL SENSES

28.

29.

VI

Medico-legal issues: the United Kingdom perspective Roger V Clements, Lewis Rosenbloom

595

Malpractice issues in perinatal medicine: the United States perspective Barry S Schifrin, Marc R Lebed, Jay McCauley

603

37.

Disorders of vision Alistair R Fielder, Laura A Crawley

743

38.

Hearing disorders K S Sirimanna

769

Contents

45.

SECTION X DISORDERS OFTHE NERVE AND MUSCLE

39.

Disorders of the spinal cord, cranial and peripheral nerves Malcolm I Levene

Congenital defects, vascular malformations and other lesions Hiroshi Nishikawa, Anthony D Hockley

856

SECTION XII EPIDEMIOLOGY OF NEUROLOGIC DISABILITY

40.

Neuromuscular disorders Eugenio Mercuri, Victor Dubowitz

SECTION XI

46.

The epidemiology of the cerebral palsies Eve Blair, Fiona Stanley

867

47.

The epidemiology of intellectual disabilities Kim Van Naarden Braun, Marshalyn Yeargin-Allsopp, Sally Brocksen

876

HYDROCEPHALUS AND NEUROSURGERY

41.

Fetal neurosurgical interventions Lan TVu, Russell W Jennings, Robert H Ball, Hanmin Lee

810 SECTION XIII ETHICAL DILEMMAS

42.

43.

44.

Neonatal hydrocephalus — clinical assessment and non-surgical treatment Andrew Whitelaw, Kristian Aquilina

819

Neurosurgical management of hydrocephalus Guirish A Solanki, Anthony D Hockley

834

Surgical management of neural tube defects Anthony D Hockley, Guirish A Solanki

847

48.

Issues for the obstetrician Frank A Chervenak, Laurence B McCullough

898

49.

Issues for the neonatologist Neil McIntosh, Terence Stephenson

905

Index

909

VII

Preface to the fourth edition

Continuing progress in developmental neurobiology of the brain and clinical applications of this new knowledge together with the introduction of emerging technologies have enhanced the clinician’s ability to investigate and manage disorders of the developing brain and nervous system. At the same time dilemmas, uncertainties and ethical constraints continue to emerge as a result of these oppor¬ tunities. The fourth edition of our book is intended to cover the basic science as it merges into clinical science as well as indicating best evidence for the management of clinical disorders seen in perinatal practice. In the seven years since our last edition, the field of peri¬ natal medicine continues to progress apace with major recent developments, including 3D ultrasound technology for imaging fetal activity and structure, magnetic resonance as a valuable method for imaging the fetal brain as well as providing novel insight into newborn brain development

viii

and the emerging therapy of hypothermia for neonatal brain injury. In 1988 when the first edition was published we intended to produce a book that covered the spectrum of brain devel¬ opment and its disorders from virtual conception to well into the first year of life and bring together international experts in the fields of basic science, fetal medicine, neona¬ tal and pediatric medicine and neurosurgery. Judging by the widespread use of our book we believe that we have fulfilled our aims and hope that this, the latest edition written some 20 years after the first edition, will continue to inform and educate to the benefit of our fetal and neonatal patients now and in the future. Malcolm Levene Frank Chervenak

Preface to the first edition

Neurological disability is the most feared complication of pregnancy, labor and the early months of life. The earliest recognizable neural tissue develops approximately 18 days after fertilization and development of the central nervous system proceeds to maturity some six years later. The devel¬ oping brain is an extremely vulnerable organ and is subject to a wide range of insults that may alter structure or func¬ tion. Problems affecting the immature brain may come under the care of the obstetrician, neonatologist, general pediatrician or pediatric neurologist and neurosurgeon. Investigations may encompass a wide range of other special¬ ists including radiologists, physicists, pharmacologists, microbiologists, physiologists, pathologists, biochemists and ophthalmologists. These major cross-specialty links make it difficult to consider the developing central nervous system (CNS) for what it is: a complex but continuous process rather than a series of loosely related parts. The basic aim of this book is to consider the developmen¬ tal neurology and pathology of the developing CNS from conception to the end of the first year of life. We have approached the subject as specialists representing obstetrics, pediatrics and neurosurgery but with a particular interest in the immature brain. We have attempted to break down the constraints of our respective specialty training to produce a book that crosses these divisions and brings together all the aspects of brain development and pathology during the critical stages of early development. We have been sup¬ ported in this aim by our 55 contributors who represent a

wide range of disciplines and the experience of 10 different countries within Europe, Australia and North America. The book is presented in three parts: morphological devel¬ opment, methods of investigation and management. Part 1 is a comprehensive review of embryology and developmen¬ tal anatomy of the CNS and provides the basic foundation necessary to understand much of the pathology that may occur. Part 2 incorporates methods of investigating the immature brain, both fetal and neonatal. The rapid advance in our understanding of cerebral pathology is directly related to the recent introduction of these methods. We have drawn upon the experience to discuss their role and limitations. Some of these methods are already used in routine clinical practice and others are state-of-the-art and unlikely to ever come into routine use but give important information on both structure and function. Part 3 involves the management of disorders of the developing brain and this is further sub¬ divided into sections related to particular areas of clinical interest. We hope that this book will provide all those involved in the management of the fetus and infant with the informa¬ tion necessary to understanding better the delicate mecha¬ nisms that exist within the CNS. Perhaps better understanding of these fragile tissues will, in the future, enable more effec¬ tive treatment or prevention of neurological handicap. M I L, M J B, J P Leicester, 1988

IX

Acknowledgments

As ever we are grateful to our publishers at Elsevier who have eased the labor pains and facilitated a beautiful birth of this, the fourth edition. We are particularly grateful to Ellen Green and Helen Leng.

x

A book of this size and scope depends on the support and enthusiasm of our contributors who number over 80 in over 20 different countries. We thank these international authori¬ ties for their selfless contributions.

List of contributors

Charles E Ahlfors MD Formerly Department of Neonatology California Pacific Medical Center San Francisco, USA

Guillaume Benoist MD Service de Gynecologie Obstetrique Centre Hospitalier Intercommunal de Poissy-St Germain Poissy, France

Medhat Alberry MB BCh MSc Clinical Research Fellow of Maternal and Fetal Medicine University of Bristol St Michael’s Hospital Bristol, UK

Harm-Gerd K Blaas MD PhD Consultant National Center for Fetal Medicine Department of Laboratory Medicine Children’s and Women’s Health St Olav’s Hospital Trondheim, Norway

Claudine Amiel-Tison MD Professor Emerita of Pediatrics University of Paris V Saint-Vincent de Paul Hospital Paris, France Kristian Aquilina FRCS Specialist Registrar in Neurosurgery Department of Neurosurgery Frenchay Hospital Bristol, UK Birgit Arabin MD PhD Professor Department of Perinatology Isala Clinics, Location Sophia Zwolle, The Netherlands Clara Angela Foundation Institute of Research and Development Witten, Germany

Eve Blair PhD Senior Research Fellow Centre for Child Health Research University of Western Australia Telethon Institute for Child Health Research West Perth, Australia Isaac Blickstein MD Professor of Obstetrics and Gynecology Kaplan Medical Center, Rehovot Hadassah-Hebrew University School of Medicine Jerusalem, Israel Geraldine B Boylan MSc PhD Clinical Scientist ft Lecturer in Paediatrics Dept of Paediatrics ft Child Health Clinical Investigations Unit Cork University Hospital Cork, Ireland

Robert H Ball MD Associate Professor Maternal-Fetal Medicine St Mark’s Hospital Salt Lake City, USA

Sally Brocksen PhD Assistant Professor Department of Sociology and Social Work Appalachian State University, USA

Laura Bennet PhD Associate Professor Department of Physiology University of Auckland Auckland, New Zealand

Angels Garda Cazorla MD PhD Pediatric Neurologist Neurology Unit Hospital Sant Joan de Deu Barcelona, Spain

XI

List of contributors

Frank A Chervenak MD Given Foundation Professor and Chairman Department of Obstetrics and Gynecology New York Weill Cornell Medical Center New York, USA Roger V Clements BM BCh FRCS FRCOG MBAE Consultant Obstetrician and Gynaecologist Harley Street London, UK Luc Cornette MD PhD PRCPCH Head of Neonatal Intensive Care Unit AZ St Jan AV Department of Paediatrics Brugge, Belgium Serena J Counsell Honorary Lecturer Robert Steiner MRI Unit Imaging Sciences Department Imperial College London Hammersmith Hospital London, UK Laura A Crawley BSc MBChB MRCP MRCOphth Registrar in Ophthalmology North Thames Rotation London Vincent Degos MD Inserm, U676 Universite Paris 7 Paculte de Medecine Denis Diderot IFR02 and ILR25 Paris, France Sergio de la Fuente Department of Obstetrics and Gynaecology St Michael’s Hospital Bristol, UK Linda S de Vries MD PhD Professor of Neonatal Neurology Department of Neonatology Wilhelmina Children’s Hospital UMC Utrecht, The Netherlands Maurice L Druzin MD Professor Department of Obstetrics Ft Gynecology Stanford University Medical Center Stanford, USA

XII

Victor Dubowitz BSc MD PhD FRCP DCH Professor of Paediatrics Department of Paediatrics and Dubowitz Neuromuscular Centre Hammersmith Hospital, Imperial College School of Medicine London, UK Sturla H Eik-Nes MD PhD Professor of Obstetrics National Center for Fetal Medicine Department of Laboratory Medicine Children’s and Women’s Health St Olav’s Hospital Trondheim, Norway Offer Erez MD Perinatology Research Branch NICHD, NIH, DHHS Bethesda, Maryland and Detroit, Michigan USA Jimmy Espinoza MD Perinatology Research Branch NICHD, NIH, DHHS Bethesda, Maryland and Detroit, Michigan Department of Obstetrics and Gynecology Wayne State University Detroit, USA Alistair Fielder FRCP FRCS FRCOphth Professor of Ophthalmology Department of Optometry Ft Visual Science City University London, UK Peter D Gluckman MBChB DSc FRACP Dean, Faculty of Medical and Health Sciences The Liggins Institute University of Auckland Auckland, New Zealand Julie Gosselin PhD OTR Associate Professor School of Rehabilitation Faculty of Medicine University of Montreal Montreal (Quebec), Canada Francesca Gotsch MD Perinatology Research Branch NICHD, NIH, DHHS Bethesda, Maryland and Detroit, Michigan USA

List of contributors

Gorm Greisen MD Dr Med Sci Professor of Paediatrics Department of Neonatology Rigshospitalet Copenhagen, Denmark Pierre Gressens Inserm, U676 Universite Paris 7 Faculte de Medecine Denis Diderot IFR02 and IFR25 AP HP, Hopital Robert Debre Service de Neurologie Pediatrique Paris, France Alistair J Gunn MBChB PhD FRACP Associate Professor Fetal Physiology and Neuroscience Group Department of Physiology University of Auckland Auckland, New Zealand Michael Harrison MD FACS FAAP Professor of Surgery and Pediatrics Co-Director, Fetal Treatment Program Chief, Division of Pedriatric Surgery University of California San Francisco, USA Sonia Hassan MD Perinatology Research Branch NICHD, NIH, DHHS Bethesda, Maryland and Detroit, Michigan. Department of Obstetrics and Gynecology Wayne State University, Detroit, Michigan. USA Jane M Hawdon MA MBBS MRCP FRCPCH PhD Consultant Neonatologist and Honorary Senior Lecturer Institute for Women’s Health Elizabeth Garrett Anderson and Obstetric Hospital University College London Hospitals NHS Foundation Trust London, UK Lena Hellstrom-Westas Neonatologist Neonatal Intensive Care Unit Department of Paediatrics University Hospital Lund, Sweden

Edgar Hernandez-Andrade MD PhD Clinical Research Coordinator Fetal and Perinatal Research Group Maternal-Fetal Medicine Unit Department of Obstetrics, Hospital Clinic University of Barcelona, Spain Anthony D Hockley FRCS LLM Emeritus Consultant Neurosurgeon Dept of Paediatric Neurosurgery Birmingham Children’s Hospital Birmingham, UK Petra S Hiippi Professor of Pediatrics Department of Pediatrics Division of Child Development and Growth University Children’s Hospital Geneva Switzerland David Isaacs MB BChir MD MRCP FRACP Clinical Professor, Paediatric Infectious Diseases Department of Immunology Children’s Hospital Westmead Westmead, Australia Russell W Jennings MD Director, Center for Advanced Care of Unborn Children Department of Surgery, Harvard Medical School The Fetal Treatment Center, Children’s Hospital Boston, USA Juan Pedro Kusanovic MD Perinatology Research Branch NICHD, NIH, DHHS Bethesda, Maryland and Detroit, Michigan USA Hugo Lagercrantz MD PhD Professor of Neonatology Karolinska Institute Astrid Lindgren Children’s Hospital Stockholm, Sweden Marc R Lebed Medical Dispute Professional Shell Beach, CA USA Hanmin Lee MD Pediatric Surgeon Department of Pediatric Surgery UCSF Children’s Hospital San Francisco, USA

xiii

List of contributors

Vincent Lelievre PhD Associate Professor Inserm, U676 Universite Paris 7 Faculte de Medecine Denis Diderot IFR02 and IFR25 Paris, France Malcolm I Levene MD FRCPCH Professor of Paediatrics Leeds General Infirmary Head of Academic Department of Paediatrics and Child Health University of Leeds Leeds, UK Jay McCauley Medical Dispute Professional Shell Beach, CA USA Laurence B McCullough PhD Professor of Medicine and Medical Ethics Center for Medical Ethics and Health Policy Baylor College of Medicine Houston, USA Neil McIntosh Dsc FRCP FRCPCH Professor of Child Life 8t Health Department of Child Life Et Health University of Edinburgh Edinburgh, UK Eugenio Mercuri MD PhD Lecturer in Paediatric Neurology Department of Paediatrics and Dubowitz Neuromuscular Centre Hammersmith Hospital, Imperial College School of Medicine London, UK Pediatric Neurology Unit, Catholic University, Rome, Italy David A Miller MD Associate Professor of Obstetrics Gynecology and Pediatrics Division of Maternal-Fetal Medicine Keck School of Medicine University of Southern California Children’s Hospital Medical Director CHLA-USC Institute for Maternal Fetal Health USC Perinatal Group Los Angeles, USA

XIV

Aubrey Milunsky MBBCh DSc FRCP FACMG DCH Professor of Human Genetics, Pediatrics, Pathology, and Obstetrics 8t Gynecology Director, Center for Human Genetics Boston University School of Medicine Boston, USA Ana Monteagudo MD Associate Professor of Obstetrics and Gynecology Department of Obstetrics 8t Gynecology New York University Medical Center New York, USA Gonzalo Moscoso MD PhD Invited Professor Early Human Development Faculty of Medicine University of Granada Granada, Spain Jan G Nijhuis MD PhD Head of Department of Obstetrics and Gynaecology University Hospital Maastricht The Netherlands Dr Hiroshi Nishikawa MD FRCS Consultant Plastic Surgeon Birmingham Children’s Hospital Birmingham, UK Jacky Nizard MD Senior Lecturer CHI Poissy-St-Germain Universite de Versailles Saint-Quentin-en-Yvelines Poissy, France KyongHon Pooh MD Department of Neurosurgery Kagawa National Children’s Hospital Kagawa, Japan Ritsuko K Pooh MD PhD Chief Director CRIFM Clinical Research Institute of Fetal Medicine Kagawa, Japan Luca A Ramenghi MD Consultant Neonatologist Neonatal Department Scientific Foundation IRCCS Ospedale Maggiore Policlinico Mangiagalli University of Milan Italy

List of contributors

Janet M Rennie MA, MD, FRCP, FRCPCH, DCH Consultant and Senior Lecturer in Neonatal Medicine Elizabeth Garrett Anderson Obstetric Hospital University College London Hospitals London, UK Thomas Ringstedt PhD Research Fellow Karolinska Institute Astrid Lindgren Children’s Hospital Stockholm, Sweden Roberto Romero MD Chief, Perinatology Research Branch NICHD, NIH, DHHS Bethesda, Maryland and Detroit, Michigan Center for Molecular Medicine and Genetics Wayne State University, Detroit, Michigan USA Lewis Rosenbloom FRCP FRCPCH Consultant Paediatric Neurologist 83 Waterloo Warehouse Waterloo Road Liverpool. UK Barry S Schifrin MD 6345 Balboa Boulevard Encino, USA Nadav Schwartz MD Fellow Department of Obstetrics and Gynecology New York University Medical Center New York, USA K S Sirimanna MS FRCS DLO(RCS) MSc FRCP Consultant Audiological Physician and Honorary Senior Lecturer Great Ormond Street Hospital London, UK James F Smith Jr MD FACOG Clinical Associate Professor Department of Obstetrics and Gynecology Stanford University Stanford, USA Thomas Snelling Department of Immunology Children’s Hospital Westmead Westmead, Australia

Guirish A Solanki MBBS FRCSI FRCS Consultant Paediatric Neurosurgeon Birmingham Children’s Hospital Birmingham, UK Peter Soothill MBBS BSc MD MRCOG Professor of Maternal ft Fetal Medicine Head of Obstetrics and Gynaecology University of Bristol St Michael’s Hospital Bristol, UK Kimberlee A Sorem MD Assistant Clinical Professor Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine Stanford University School of Medicine Standford, USA Fiona Stanley MD FFPHM FAFPHM MFCCH FRACP FRACOG Director, Telethon Institute for Child Health Research University of Western Australia West Perth, Australia Horst Steiner MD PhD Vice-Chairman and Head of Prenatal Medicine Department of Obstetrics and Gynecology Paracelsus Private Medical University Salzburg, Austria Terence Stephenson DM FRCP FRCPCH Professor of Child Health Dean Faculty of Medicine and Health Sciences The Medical School Queen’s Medical Centre Nottingham, UK Mohnish Suri MD MRCP Consultant Clinical Geneticist Department of Clinical Genetics Nottingham City Hospital Nottingham, UK Ilan E Timor-Tritsch MD Director, Obstetrical and Gynecological Ultrasound Department of Obstetrics and Gynecology New York University Medical Center New York, USA Kim Van Naarden Braun PhD Epidemiologist National Center on Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention Atlanta, USA xv

List of contributors

Yves G Ville MD Professeur Service de Gynecologie Obstetrique Centre Hospitalier Intercommunal de Poissy-St Germain. Poissy, France Lan T Vu MD Postdoctoral Research Fellow University of California San Francisco, USA Jennifer A Westgate MBChB, MD, MRCOG, FRANZCOG Associate Professor in Obstetrics and Gynaecology University of Auckland Faculty of Medical and Health Services Auckland, New Zealand Elspeth Whitby BSc MBChB FFDRCSI Senior Lecturer and Honorary Consultant Department of Radiology Royal Hallamshire Hospital and University of Sheffield Sheffield, UK

XVI

Andrew Whitelaw MD FRCPCH Professor of Neonatal Medicine Neonatal Intensive Care Southmead Hospital Westbury-on-Trym Bristol, UK Marshalyn Yeargin-Allsopp MD Medical Epidemiologist National Center on Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention Atlanta, USA Bo Hyun Yoon MD PhD Department of Obstetrics and Gynecology Seoul National University College of Medicine Seoul, Korea

1

SECTION I

STRUCTURAL DEVELOPMENT OF THE CNS

chapter

y^g molecular basis of

1

brain development Hugo Lagercrantz and Thomas Ringstedt

The development of the CNS proceeds through a series of milestones (Table 1.1). This includes patterning events like induction of the neuroectoderm and segmentation of the neural tube, and morphogenetic events like neurulation and cephalic folding. Cell proliferation, differentiation and migration are processes essential for the brain’s develop¬ ment. Once formed and positioned, the new neurons send out axonal projections that, guided by molecular cues, reach their distant targets (axon guidance). The brain is then finetuned by weeding out the excess projecting neurons, and by strengthening wanted and functional synapses and neural circuits. The first steps are probably strictly genetically con¬ trolled, while the build-up of functional neuronal synapses and circuits is more influenced by environmental inputs. It is interesting to note that while the human brain has about 100 billion neurons and trillions of synapses, we only have a few thousand more genes (22 000) than the nematode Caenorhabditis elegans (18 000 genes), which only has 302 neurons. So how is the vastly higher complexity of the human brain accomplished? One solution to this problem is ‘combination’. The human genome contains many, perhaps thousands, of genes that bind to and regulate the transcrip¬ tion of other genes. Several of these so-called transcription factors can be combined in a single cell like an alphabetic code. Time and space also matter. A single transcription factor can be used and re-used in different roles throughout development. Diffusible agents create gradients across the brain and the cells react to it in a dose-dependent manner. It is also possible that genes create a scaffold of, in part, repeated structures, which are then further developed or eliminated by the action of environmental influences (Edelman ft Tononi 1996). Epigenetic mechanisms seem to act as interfaces between genetic control and environment (Richards 2006).

INDUCTION AND PATTERNING OF THE FETAL HUMAN BRAIN During gastrulation, ‘the most important event during life’ (Wolpert 1997), the notochord is formed from the mesen¬ chyme between the endoderm and ectoderm. This structure forms the cranial-caudal axis of the embryo. It induces the neural plate and subsequently the neural tube. It is also responsible for the differentiation of the motor neurons. The phenomenon of neural induction was discovered as early as 1924 by Hans Spemann and Hilde Mangold. They grafted a piece of a newly formed newt embryo to another newt

embryo and obtained a two-headed embryo. The grafted tissue itself did not develop into a new head but chemically induced head development in the receiving embryo. Spemann and Mangold demonstrated this by transplanting tissue from an unpigmented to a pigmented newt. The resulting extra head was pigmented, i.e. induced in the receiving embryo. It was believed that the induction was transmitted by a chemical substance, which has been called Spemann’s orga¬ nizer (Wolpert 1997). Later research has added complexity to our understanding of neural induction. It has been proposed that the neural tissue is formed by a default pathway and that blocking signals (bone morphogenic protein (BMP) inhibitors) are needed to retain the non-neuronal ectoderm bordering the neural plate. However, this is probably an oversimplification that might be correct for an embryo at a certain stage but not over time. Neural induction is more likely achieved through interplay between antineural signals (BMPs, Wnts), their inhibitors, and proneural signals (fibroblast growth factor (FGF)) (Stern 2005) (Fig. 1.1). The embryo and neural plate are narrowed and elongated through a process where cells from the periphery migrate and intercalate at the midline, called convergent extension (Copp et al 2003a, 2003b). Neural folds are formed, elevate and eventually fuse to form the neural tube. During neural tube closure, a population of cells detach from the edges that are about to close, and migrate to different destinations in the body. These so-called neural-crest cells build up peripheral ganglia and many other tissues, including part of the skeleton (Jacobsson 1991, Wolpert 1997). The process of neural tube closure is called neurulation, and is influenced by convergent extension movements and by signals from the underlying notochord. This expresses the gene Sonic hedgehog (SHH) that is important for both morphogenesis and the subsequent differentiation of the neural tube. Par¬ ticularly the ‘ballooning’ of the forebrain and the midbrain vesicles seems to depend on SHH. If the notochord is ablated the SHH levels drop and the normal formation of brain vesicles does not take place (Britto et al 2002). If SHH is knocked out the animal will develop a cyclopic eye. Mutation of this gene in the human results in holoprosencephaly. The rostro-caudal axis of the embryo is formed with help of the Hox family of genes, a distinct branch of the homeobox containing genes (homeoboxes constitute a class of binding sites for transcription factors). Interestingly, in most investigated species, also mammals, their positions on the 1

SECTION

I

STRUCTURAL DEVELOPMENT OF THE CNS

women for the treatment of severe acne in the 1980s. Krox20 is necessary for the development of the cranial nerves in Formation of the neural tube

3-4 w

Prosencephaly

5-10 w

Neuronal proliferation

8-18 w

Synaptogenesis

20 w-

Wiring, organization, myelination

30 w-

Organizer (node)

Figure 1.1 Mechanisms of neural induction. Ectodermal cells can develop to neural cells by a default pathway, but this is inhibited by a tonic BMP activity (BMP — bone morphogenic protein). FGF (fibroblast growth factor) represses BMP and in this way promotes neuronal differentiation. Chordin and noggin are secreted from the organizer and ensure the progression of neuronal differentiation (modified after Jessell & Sanes 2006). chromosomes are collinear with their expression pattern on the body axis (Fig. 1.2). Their origin (and co-linear arrange¬ ment) goes back to the ancestor of all bilaterian animals, a marine wormlike creature that lived around 550 million years ago. In mammals the Hox genes exists in 4 sets, or clusters, that have arisen by genetic duplication during evolution (Lemons 8t McGinnis 2006). The combined expres¬ sion of several Hox genes from different clusters determines the developmental potential of the body segments. This is achieved via the so called ‘Hox code’; meaning that cells expressing many Hox genes develop posterior structures, while those expressing fewer Hox genes develop anterior structures (Krumlauf 1994). Knock-out of a Hox gene results in an anterior shift of the brain stem rhombomeres. Excess doses of retinoic acid, which affect the expression of more posterior Hox genes, disrupt the order of rhombomeres. This was discovered when vitamin A was used by pregnant 2

the hindbrain. More anterior (and evolutionary more recent) struc¬ tures of the brain do not express Hox genes. Other homeobox containing genes are involved in specifying these areas. The engrailed family of genes and Wntl are required for formation of the midbrain and cerebel¬ lum. Otxl, 0tx2, Emxl and Emx2 are expressed in the forebrain and midbrain regions. The Otx genes are nec¬ essary for forebrain (telencephalon) formation. Telencephalic development can proceed in the absence of Emx2, but results in schizencephaly. Neurons of the future brain develop with an initial rostral character (Stern 2001). A rostro-caudal gradient created by Wnt gene expression in the paraxial mesoderm influences the neurons to adopt successively more caudal characters (Nordstrom et al 2002). Dorso-ventral differentiation is ini¬ tially driven by signals from ventral and dorsal organizing centers. SHH derived from the notochord and floorplate is necessary for the creation of motorneurons. If this gene is knocked out all neurons will become sensory neurons. The floorplate expresses BMPs which influence neurons to adopt a dorsal character. The opposing gradients of SHH and BMP are translated into regional expression of transcription factors from the homeodomain and the bHLH (basic helix-loop-helix) fami¬ lies (Jessell ft Sanes 2000). Among these is the Pax gene family. The name is derived from the paired-box first identi¬ fied in the fruit fly. Mutations of Pax3 in the human result in Waardenburg syndrome and of Pax6 in Peters anomaly (aniridia).

Rostra aiudn! axis

Dorso ventral axis

\\’NT-1

Hox In Z J Hox a-.l

Figure 1.2 Some genes involved in the patterning of the rostro-caudal and dorso-ventral axis of the mammalian CNS. RP: roof plate. FP: floor plate, NO: notochord. R: rhombomeres. SC: spinal cord (from Lagercrantz et al 2001).

CHAPTER

The molecular basis of brain development

How do these early immature nerve cells know how to differentiate? The concentration of the inducing substance seems to be important. For example, high concentrations of the SHH protein induce the formation of most of the ventral cells of the neural plate, while lower levels specifically induce motor neurons. Thus, if undifferentiated cells are exposed to a high concentration of the substance they will become different types of cells than if they had been exposed to lower levels (Wolpert 1997). The anterior pore of the neural tube closes at 24 days and the posterior pore after 28 days postconceptionally. Neural tube defects have a prevalence of about 1 in 1000. More than half of the expected cases can be prevented with folic acid. This seems to stimulate cellular methylation reactions and promote neural tube closure (Blom et al 2006).

NEURONAL PROLIFERATION After formation of the neural tube and prosencephali, pro¬ liferation of new neurons takes place. New neurons originate from the ventricular zone (VZ) and the ganglionic eminences (GE) (Polleux et al 2002, Rakic ft Caviness 1995). In these areas the neural stem or progenitor cells initially undergo symmetric division to expand the progenitor pool, i.e. two daughter cells with properties identical to each other and the mother cells are formed (Fig. 1.3). Division subsequently becomes asymmetric, yielding one progenitor cell capable of proliferation, and one daughter cell destined to differenti¬ ate. Artificially enhancing the (3-catenin signaling pathway (the main Wnt signaling pathway) in the mouse brain forces the cells to undergo further cycles of symmetric divi¬

sion before asymmetric division begins. This results in an enhanced expansion of the progenitor pool and increased brain size, which therefore is forced to fold in gyri and sulci (Chenn Et Walsh 2002). Thus, mutations affecting the deci¬ sion to switch from symmetric to asymmetric division have likely been a driving force in the evolution of larger and more complex brains. The newly born cells will migrate radially (from VZ) or tangentially (from GE) to form the neocortex. The pace of neuron production is dependent on the exit rate of cells from the proliferative zones (Caviness et al 1995). The rate of proliferation can be determined by label¬ ing the dividing cells by the thymidine analogue BrdU, which, after it has incorporated in the DNA, can be detected with specific antibodies. By using this cumulative labeling, parameters such as the duration of the cell cycle or neurogenetic interval can be calculated. In the mouse there are 11 cell cycles over a 6-day period. In the human fetus about 200000 new neurons are formed every minute between the 8th and 18th week of gestation. The fact that most nerve cells are formed after the 8th and before the 18th gestational week was first established by Dobbing and Sands (1970), who analyzed DNA in aborted fetuses. This was also learnt in a tragic way: fetuses that were exposed to the first atomic bombs in Hiroshima and Nagasaki during this period of pregnancy became microcephalic, while fetuses that were younger or older at the time did not (Miller Et Blot 1972). Based on a series of very careful studies in monkeys whose DNA was pulse-labeled with 3H thymidine, Rakic postulated that there is no neurogenesis after birth in

Figure 1.3 (a) Proliferation of neurons. A stem cell from the germinative zone divides into two daughter cells. One returns to the basement layer and begins a new cycle, while the other is differentiated to a neuron and starts migration (after Caviness et al 1995). (b) Radial migration along glia (1) from the germinative zone and tangential migration from ganglia eminence (from Gressens 1998).

3

SECTION

I

STRUCTURAL DEVELOPMENT OF THE CNS

primates (Rakic 1985, Rakic ft Caviness 1995). This is contrary to the situation in other vertebrates such as fish and birds. Male canary birds generate new nerve cells in the singing center during the mating season. The number of syllables that they perform seems to be directly related to the number of neurons (Nottebohm 8t Arnold 1976). Later studies indicate that some new neurons can be formed even in the human adult. Terminally ill cancer patients were given radioactively labeled thymidine, and after their deaths the nuclei of about a few hundred hip¬ pocampal neurons were found to be labeled, implicating that they were newly formed neurons (Eriksson et al 1998). It is now accepted that neurogenesis occurs in the hippo¬ campal dentate gyrus in adult mammals. Furthermore, increased hippocampal neurogenesis correlates with learn¬ ing in rodents, but this may not be the case in primates. The long-lived belief that, despite the evidence presented by Rakic, there might be some remaining stem cells in the human neocortex capable of generating neurons, recently received a final blow. Above-ground testing of atomic bombs between the years 1955-1963 doubled the atmo¬ spheric level of 14C. This has since decreased exponentially. The levels of 14C incorporated into the DNA of neocortical nerve cells from patients born later than 1963 were inves¬ tigated. It was found that the levels equaled atmospheric levels at the patients’ births. Patients born before 1955 displayed the same low 14C levels as the atmosphere before testing began (Spalding et al 2005).

MIGRATION The neocortex is formed by postmitotic neurons that migrate from the proliferative zones (Fig. 1.3), either radially from the VZ (future projecting neurons) or tangentially from the GE (mainly GABAergic interneurons) (Polleux et al 2002, Rakic ft Caviness 1995). The first arriving cells form the pre-plate. Among these are the Cajal-Retzius cells, which enter by tangential migration from the GE. Cells born later migrate into the pre-plate and split it into an outer marginal zone or future layer I, which contains the Cajal-Retzius cells, and an inner sub-plate. Radial migrating cells migrate along a fan-like scaffold of glial cells (radial glia). Newly born neurons that arrive in the cortical plate continue along the radial glia and migrate past those that arrived earlier. The neocortex therefore has an inside-out pattern, with the latest born cells in layer II and the first-born (excepting those in the subplate and the marginal zone) in layer VI. Integrin receptors guide the migrating neurons along the radial glia. Reelin, secreted by the Cajal-Retzius cells (and later by GABAergic cells in the cortical plate), is also essential in guiding the radial migrating cells (D’Arcangelo et al 1995). If reelin is not produced, as in the reeler mouse, the pre-plate is never split. Instead, the neurons line up below it in the order that they were born. Its mechanism of action is still debated. It is often assumed that it acts by inhibiting the migrating neurons, instructing them to leave the radial glia and obtain their final positions. Thus, reelin would act as a 4

stop signal for the successive waves of cortical neurons. Remarkably, a recent report of transgenic mice with the Cajal-Retzius cells ablated, describes no major defects in cortical lamination. The authors speculate that the CajalRetzius cells also express other guidance factors for the migrating neurons that balance the effects of reelin. Removal of reelin would then result in signaling imbalance, while removal of the Cajal-Retzius cells themselves equally affects all signals, thus resulting in a null result (Yoshida et al 2006). Furthermore, the Cajal-Retzius cells are not the only source of reelin in the developing neocortex. Neuronal migration can be affected by glutamate. Nmethyl-D-aspartate (NMDA) antagonists were found to retard migration or result in the formation of heterotopias and the arrest of migrating neurons (Gressens 1998). Neurotrophic factors such as neurotrophin-4 (NT-4) and brain-derived neurotrophic factor (BDNF) can also affect neuronal migra¬ tion (Behar et al 1997, Ringstedt et al 1998). Migration occurs mainly between embryonic day 12 and the first post¬ natal days in rodents, and between the 12th and 24th week of gestation in the human fetus. Severe disturbance of migration can be seen in the Zellweger cerebro-hepato-renal syndrome, which is a peroxisomal disease. Migration disor¬ ders are also involved in schizencephaly and lissencephaly (Evrard et al 1997). The adult neocortex is subdivided into areas with distinct functions, cytoachitecture and projections. These are speci¬ fied already during the period of progenitor proliferation and neuronal migration. Like in the spinal cord, signals from patterning centers are involved (Grove 8t Fukuchi-Shimogori 2003) . FGF8 has been implicated as such a signal. Unlike in the spinal cord however, the signals from the patterning centers are not translated into clearly delineated areas of transcription factor expression. Instead transcription factors, like Emx2 and Pax6, are expressed as gradients across the developing neocortex. Transgenic overexpression of Emx2 in progenitor cells in mouse neocortex shifted primary sensory and motor areas rostro-caudally (Hamasaki et al 2004) . Thus, the absolute levels of Emx2 in the cortical progenitor cells specify the future area identity in their progeny. Later during development, the incoming projec¬ tions from thalamus likely fine-tune area identities in the neocortex.

AXONAL GUIDANCE Neurons send out axonal projections that make contact with targets that can be very distant. How do they find their way to a specific target, which might be hidden by layers of intervening tissue? Navigating the interstates from New York to San Francisco is relatively easy compared to what the neurons of the developing nervous system must do in order to reach their goals, as it was expressed in Science (Travis 1994). In 1892 the Spanish anatomist Ramon y Cajal discovered that the axons have special growth cones on their tips. These growth cones are like immune cells sniffing out chemical

CHAPTER

The molecular basis of brain development

and is often regulated by the same factors (Van Vactor

Figure 1.4 (a) The growth is attracted or repelled by axonal guidance molecules, (b) Neurons normally cross the midline, but (c) if the commissureless guidance molecule is deleted in the Drosophila they do not. (d) Deletion of the round-about guidance protein results in this pattern of axonal migration.

scents released by different tissues (Fig. 1.4). The target can release diffusible substances that promote their own inner¬ vations. These are called chemo-attractants. Given that the distance between the target and the neuron sending out its axon can be quite long, mechanisms other than simple attraction are also involved. By analogy with the traveler crossing continental USA, the axon divides its path into several steps, maneuvering between choice points along more or less established routes. The signals that guide a growing axon along its way can, based on their mode of action, be subdivided into four categories: chemo-attractive, chemo-repellent, contactattractive and contact-repellent (Mueller 1999). While the chemo-attractive and chemo-repellent signals are diffusible molecules that act over distance, the contact-attractive and contact-repellent molecules are bound to cell membranes or to the extracellular matrix. Contact-repulsive signals are important in axonal guidance, because they can outline a permissive path for the advancing axons. The complicated task of navigating long distances through the CNS is eased by following routes established by pioneer axons, which reached their targets during early development, when the brain was smaller and its structure considerably less complex. Axons that grow along these routes are bundled together in fascicles. At the various choice points they have to defasciculate in order to change route. The regulation of fasciculation is therefore an important aspect of axon guidance,

1998). Certain structures in the brain are of particular importance to navigating axons (Cook et al 1998). An example of this is the floor-plate, an area with mainly non-neuronal cells in the ventral part of the developing spinal cord. The floor plate expresses several guidance cues. Among these is Netrin, which acts as a chemo-attractant on commissural neurons in the upper part of the spinal cord. Netrin is evolutionary conserved and is also found in the fruit fly. The midline of the fly’s nervous system is, similarly to the spinal cord floor plate, an important landmark for axons. Axons are attracted towards the midline by Netrin. The midline also expresses the diffusible ligand Slit, which repulses axonal growth cones canying the Slit receptor Robo (Kidd et al 1998). These are thereby prevented from entering the midline, and stay on the ipsilateral side (Robo is an abbreviation of round-about, as found along British roads). However, neurons with axons that are destined to cross the midline to reach target areas on the contra-lateral side face a problem. Expression of Robo is an obvious hindrance to entering the midline. If they do not express Robo, they can cross the midline, but nothing prevents them from re-crossing (which also happens in mutants lacking robo). This is solved with the help of a regu¬ latory gene, Commissureless. The crossing neurons express Robo, but also Commissureless, which prevents Robo from being transported to the growth cone. Upon entering the midline, Commissureless is downregulated, Robo is trans¬ ported to the growth cone, and the axon is repelled from the midline and cannot re-cross (Keleman et al 2005). The com¬ bined influences of Netrin, Slit, their receptors and Commis¬ sureless thus guide the axons across the midline and ensure that they do not re-cross it. Like Netrin, Slit and Robo are also found in mammals (including humans). Other important families of axon guidance factors include the Semaphorins and the Ephrins. The Semaphorins have several members, both secreted and membrane-bound, divided in 7 classes. Semaphorins can signal both attraction and repulsion, and at least in some cases the same ligand can serve both functions. The Ephrins mediate contactrepulsion and contact-attraction via their receptors, the Eph tyrosine kinase receptors. These constitute the largest sub¬ group within the tyrosine kinase receptors. The Ephrins are membrane-bound like their receptors and have signaling activity of their own. Thus Ephrin-Eph interaction is bidirectional. A growth cone is likely to carry receptors for several classes of axon guidance molecules. The inputs from these are integrated into a ‘decision’ (Stoeckli ft Landmesser 1998). One way that this could be achieved is by intracellular sig¬ naling mechanisms affecting the growth cone’s (Ca2++) level. Growth cones have been demonstrated to turn either towards or away from a Netrin source depending on their intracel¬ lular (Ca2++) levels (Zheng 2000). The (Ca2++) level affects the small Rho-like GTPases RhoA, Cdc42 and Racl, which act on the cytoskeleton. Many axonal guidance molecules have 5

SECTION

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STRUCTURAL DEVELOPMENT OFTHE CNS

been shown to induce both attraction and repulsion, although this also might be influenced by the type of receptor involved (Bashaw 8t Goodman 1999). Axon guidance factors also have other functions. As an example, Slit also affects cell migration. Axonal guidance and cell migration share common mechanisms. The migrat¬ ing cell sends out a leading process that trails ahead of the cell soma and orients towards the target with help of a growth cone. Interestingly, blood vessels utilize the same molecules and receptors for guidance as axons. They can also follow nerve trajectories towards a distant target, sticking to their guide with the help of ephrins and Eph receptors.

NEUROTROPHIC FACTORS In the 1950s Rita Levi-Montalcini together with Victor Ham¬ burger studied the mechanism of neuronal survival in chicks (Fig. 1.5). Hamburger had previously shown that removal of a target organ also reduced the number of neurons innervat¬ ing the organ. Levi-Montalcini and Levi had demonstrated that the neurons initially are formed and grow normally, but subsequently degenerate. To further study the effects of the target organ, Levi-Montalcini and Hamburger trans¬ planted fragments of mouse tumors into the body wall of chick embryos. This increased innervation of internal organs in the chick embryo. By changing the experimental setup to in vitro co-cultures of chick sensory ganglia and mouse sarcoma tumors, they demonstrated that the mouse tumor produced a diffusible substance that promoted neuronal survival. Together with Stanley Cohen, Levi-Montalcini managed to isolate and purify this substance. It was named nerve growth factor (NGF). (See the fascinating autobiogra¬ phy by Rita Levi-Montalcini (Levi-Montalcini 1998)). Molecules similar to NGF have since then been discovered. NGF, brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and neurotrophin 4 (NT-4) together make up the neurotrophin family (Bibel ft Barde 2000). Other families of neurotrophic factors have subsequently been discovered, most importantly the glial-derived neurotrophic factor (GDNF) family (Airaksinen ft Saarma 2002). This consists of GDNF, neurturin (NTN), artemin (ART) and persephin (PSP). Levi-Montalcini described NGF as a survival factor for neurons innervating peripheral targets. During vertebrate development, the targets become contacted by an excess number of neurons. About half of these are later weeded out through the process of naturally occurring cell death (apop¬ tosis). During this process the neurons have to compete for nerve growth factors (neurotrophic support) from the target. Thereby survival of the best-positioned neuronal projections is ensured. Knock-out of neurotrophin genes (in mice) results in clear size-reductions of ganglia innervating periph¬ eral targets, thus reflecting the neurotrophins survivalpromoting effect. Very little cell death is observed in the brains however (Snider 1994). This is something of a paradox, since the neurotrophins have been shown to promote brain neuronal survival in vitro and in lesioned animal models.

6

Figure 1.5 A ganglion cell does not develop any dendrites without the presence of nerve growth factor (published with permission from Rita Levi-Montalcini).

The explanation is probably that the knock-out animals can only be studied up to a couple of weeks after birth (they do not survive longer), and that brain neurons develop neuro¬ trophin dependence after this period. Interestingly, neuro¬ trophin homologues are not found in invertebrates. It has therefore been suggested that the plasticity inferred by a cell-extrinsic regulation of neuronal survival (as opposed to cell-intrinsic regulation) has co-evolved with higher neuro¬ nal complexity (Bibel 8t Barde 2000). In addition to their first described role as target-derived neuronal survival factors, the neurotrophins are now known to affect neuronal differentiation, maturation, migration, axonal guidance and plasticity. In particular BDNF seems to be an important regulator of cell migration and plasticity in the brain. It is also a survival factor for Cajal-Retzius cells and a negative regulator of reelin expression (Ringstedt et al 1998). Throughout development and adulthood, BDNF and reelin frequently act on the same systems, although with opposing effects.

CHAPTER

The molecular basis of brain development

NEUROTRANSMITTERS Although the development of the CNS scaffold mainly is determined by genetic information, the detailed wiring of the neuronal circuits is more self-generated, depending on the action of neurotransmitters and neuromodulators. They can promote, amplify, block, inhibit or attenuate the micro¬ electric signals which are passed on to them and through them, and thereby give rise to the signaling patterns between myriads of neuron that provide the physical net¬ works of cerebral neurons. Catecholamines appear in the embiyos of vertebrate and invertebrate animals even before neurons are differentiated. Possibly, they then function as morphogenetic or trophic factors. Some of the neural crestderived neurons are noradrenergic during early develop¬ ment, but later become cholinergic through environmental influences. A neuroreactive agent might be abundantly expressed during certain stages of development, but later remains in only a small proportion of the CNS synapses. This agent may play a transitory role during a critical window of development or remain mainly as an evolutionary residue with only minor functions, e.g. in mammals (Lagercrantz et al 2001). It is interesting to note that if the synthesis of some of these neurotransmitters and modulators is blocked pharma¬ cologically or knocked out by transgenic techniques, the apparent effect may be minimal. This illustrates the plastic¬ ity of the brain during early development. Other neuroactive agents seem to be able to take over. Norepinephrine (noradrenaline) and acetylcholine are regarded as classic neurotransmitters and dominate in the peripheral nervous system. They appear at an early stage both evolutionary and during ontogenesis. Many of the neuropeptides were first identified in the gastrointestinal tract and probably also appear early during development. They act slowly since they have to be synthesized, packaged in the cell soma and carried to the terminals before they are released. The more developed and sophisticated mam¬ malian brain requires more fast-switching neurotransmitters acting directly on ion channels, such as excitatory amino acids. These seem to dominate in the mature brain, whilst the monoamines and neuropeptides may act more as neuromodulators. In the immature brain, synaptic transmission is weak, extremely plastic and mediated to a large extent by NMDA receptors. The AMPA (a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid) receptors are more or less silent at resting membrane potentials (Fox et al 1999). During maturation many NMDA receptors are substituted by AMPA receptors. Dark-rearing newborn animals or blocking the activity with tetrodoxin results in preservation of the NMDA receptors. Dark-rearing also preserves the immature form of the NMDA receptors (that contains the NR2B subunit), and expression of NR2A is delayed. This subunit is essential for rapid synaptic transmission. Thus, NMDA

receptors are important for the experience-dependent syn¬ aptic traffic. Another amino acid, y-aminobutyric acid (GABA), is known as an inhibitory neurotransmitter in the mature brain. However, it is excitatory in the developing brain. This is due to the high Cl" concentration in immature cells (Miles 1999). When GABA binds to and opens a chloride channel, the immature cell is excited since the high Cl concentration forces Cl" out of the cell, depolarizing the cell. When the cell matures it starts to express the potassium-chloride co¬ transporter KCC2 that lowers its Cl" concentration (Rivera et al 1999). This leads to a reversal of the effects of GABA: GABA-induced opening of Cl" channels leads to an outflow of Cl", hyperpolarizing and inhibiting the cell. In this way GABA-switches from being an excitatory amino acid in the fetus to being inhibitory after birth.

SYNAPTOGENESIS Five ‘waves’ of synaptogenesis have been identified in the primary visual cortex of the macaque monkey (Bourgeois 1997) (Fig. 1.6). Based on studies of the human occipital cortex (Zecevic 1998), a tentative timetable can be applied for humans.

Synaptogenesis in primary visual cortex of macaque

c CD

Q

Experience independent

Experience expectant and/or dependent

Experience dependent

Figure 1.6 Changes in the relative densities of synapses expressed on a log scale. The figure is based on studies of the visual cortex of the macaque monkey, but can be extrapolated to the human. During phase 1 synapses appear first in the marginal zone (MZ), subplate (SP) and intermediate zone (IZ). During phase 2 they also appear in the cortical plate (CP) (from Bourgeois 1997). 7

SECTION

I

STRUCTURAL DEVELOPMENT OF THE CNS

• Phase 1: begins around 6-8 weeks of gestation, at the same time as the onset of neuron proliferation. Synaptogenesis is limited to lower structures such as the subplate. • Phase 2: begins after 12-17 weeks and is relatively sparse. It occurs in the cortical plate. These early synapses form contacts on the neuronal dendritic shafts of the neurons. • Phase 3: is much more rapid and is assumed to start around midgestation (20-24 wk) and persists up to 8 months after birth. The rate of this synaptogenesis has been estimated to be up to one million new synapses every second in the whole brain. It occurs simultaneously with the arborization of axons and dendrites. • Phase 4: lasts until puberty and at a very high rate. There is also synapse elimination during this phase. Nearly 50% of the synapses have disappeared at about 1 year of age and even more synapses disappear until midpuberty (Huttenlocher ft de Courten 1987). • Phase 5: synaptogenesis continues up to 70 years of age, and there is a considerable loss of synapses during this phase. The first two phases are unaffected by a lack of sensory stimulation, but the third phase might be partially dependent on sensory input. This was demonstrated in young macaques which were visually stimulated or deprived. Synaptogenesis during the third phase is partially intrinsic and partially dependent on sensory stimulation. Thus, it coincides with the critical periods. Many of the sensory, motor and cognitive skills function very early after birth when the synaptoarchitectony is still being laid down. Synaptogenesis during the fourth phase is even more dependent on experi¬ ence. During this phase there is reorganization and fine tuning of neuronal circuits. When this phase has ended during puberty there seems to be a freezing of personality and the end of several basic learning capacities such as learning to speak a new language without an accent.

WIRING THE BRAIN The wiring of the precise neural circuits seems to be depen¬ dent on neuronal activity, which could be stimulated by either sensory input or endogenously driven activity. Redun¬ dant numbers of neural pathways and circuits are formed in the fetal brain. About half of the neurons disappear before birth by apoptosis - naturally occurring cell death (as men¬ tioned earlier). This was found in the 1930s by Hamburger, who observed that the number of neurons innervating the chicken wing decreases during maturation (Purves 8t Lichtman 1985). The importance of sensory stimulation was discovered in the 1960s by Hubei and Wiesel. They found that surgi¬ cally closing one eye during a critical period in kittens or young monkeys results in disruption of the corresponding ocular dominance columns (afferents to the visual cortex 8

have their terminals segregated in eye-specific ocular dominance columns), and blindness in the eye once it was re-opened after the critical period (Hubei 1995). In kittens the critical period for ocular dominance plasticity is between 4 weeks and 4 months postnatal, in monkeys somewhat earlier. A similar process also occurs before birth (Penn ft Shatz 1999). Penn and Schatz studied the lateral geniculate in prenatal ferrets. The optic nerves from the eyes grow into the geniculate and fan out through all layers. During matu¬ ration these structures become organized and layers are formed. This process is dependent on spontaneous neuronal activity in the retina. Blocking this with tetrodoxin disturbs the segregation into layers. The spontaneous activity begins at some focus of the retina and spreads from there in waves. This can be visual¬ ized in retina whole mounts from newborn ferrets by a fluorescence imaging technique. The activity seems to be generated by cholinergic amacrine cells, since it can be reversibly blocked by a nicotinic acetylcholine receptor antagonist (Feller et al 1996). Each wave lasts for several seconds, followed by a 1-min interval. Neighboring cells seem to fire in synchrony and this local retinal synchrony forms the basis for the layering of the geniculate bodies and the ocular dominance columns in the cortex. Schatz coined the expression: ‘Cells that fire together wire together while those which don’t won’t’ (Fig. 1.7). However, later studies by Crowley and Katz (Crowley 8t Katz 1999) showed that ocular dominance columns can be formed without electrophysiological stimulation, and thus are genetically determined. They admit that visual stimula¬ tion is important for the refinement of the ocular dominance columns, and thus for vision. In concurrence with this, dark¬ rearing animals delays the critical period for ocular domi¬ nance plasticity. The neurotrophin BDNF might mediate the effects of visual experience in the development of ocular dominance columns. Transgenic overexpression of BDNF in mice postnatal neocortex shortens the critical period for ocular dominance plasticity, and accelerates maturation of the visual cortex (Huang et al 1999). Contrary to wild-type mice, dark-rearing the BDNF overexpressing mice does not delay the plasticity window (Gianfranceschi et al 2003). Thus, BDNF stimulation can replace the need for visual experience. This illustrates the interplay between environ¬ mental and internal stimuli, including gene activity, in the formation of neuronal circuits. Proteins traditionally classified as immune proteins also seem to play a role in the wiring of the brain. Neurons can express major histocompatibility complex (MHC) proteins. This expression seems to be controlled by neuronal activity, particularly during development (Boulanger Et Shatz 2004). They seem to be involved in the refinement of the neural circuits and are also required for long-term potentiation (LTP), and may therefore be involved in memory and learn¬ ing. This may be of clinical interest since there is a genetic link between autism and the immune system.

CHAPTER

The molecular basis of brain development

Myelin is produced by oligodendroglia in the CNS and Schwann cells in the peripheral nervous system. Progenitors of oligodendroglia are formed in the ventricular-subventricular zone from around the 20th gestational week. These cells align the axons and their plasma membranes become myelin. In fetal life progenitor oligodendroglia dominate. These are veiy vulnerable to oxidative stress. Preterm birth before the 30th week seems to result in deficient myelination, particularly if the infant has suffered from intraven¬ tricular bleeding (Nagy et al 2003, Seghier et al 2006). Most of the sensory and motor neurons seem to be myelinatated during early infancy. However, myelination of particularly the intemeurons in the frontal and parietal lobes does not seem to occur until late adolescence. This may explain why the brain of the teenager is not yet mature with regard to executive functions and judgment. Myelination is crucial for rapid neuronal conduction between various areas, which may be involved in for example exec¬ utive functions.

ORGANIZATION OF THE BRAIN

Figure 1.7 (a) The immature brain is like a jungle (Edelman). (b) To organize the CN5 useful pathways are selected, while redundant pathways disappear due to neuronal activity. ‘Neurons which fire together wire together, while those which don’t won’t.'

MYELINATION The unmyelinated nerves which dominate during fetal life have a conduction velocity of 0.5-1 m/s. By wrapping the axons in myelin, the conduction speed can increase up to 150 m/s since the propagation becomes saltatory by way of the nodes of Ranvier (Purves 2004).

The fetal and the neonatal brain is not like a computer: It is rather a jungle, according to Edelman (Edelman ft Tononi 1996). This metaphor is more appropriate. The characteristic feature of the developing brain is the redundancy of neurons and their connections. There are neuronal pathways con¬ necting the retina with the auditory cortex and the cochlea with the visual cortex (Sur ft Leamey 2001). Thus in theory the fetus can see the thunder and hear the lightning. Some children retain these neuronal pathways responsible for syn¬ esthesia, but normally they disappear, probably since they are found useless and are inactivated. In a similar way infants have the capacity to differentiate between sounds in all languages (universal grammar). However, already after 6 months this ability disappears and the infant can only rec¬ ognize the sounds of its mother tongue (Kuhl 2004). The organization of the brain starts from about midgesta¬ tion and continues to adolescence, maybe even later. The brain scaffold is probably mainly constructed by the genes involved in the making of the brain. It was earlier believed that the brain is mainly hardwired by the genes. There seem to be a redundant production of neurons, dendrites and synapses. The brain seems to be organized by the selection of the most optimal pathways due to environmental and epigenetic mechanisms. The concept of selectionism (Fig. 1.7) has been proposed by Changeux (2002). In a similar way the concept of neuronal darwinism (Edelman ft Tononi 1996) explains how the brain is constructed with regard to the limited number of genes encoding the formation of the brain. This theory consists of three tenets: The first is the proliferation of neurons, their arborization and synaptogenesis. There is a stochastic fluctuation of cell movements, cell process extension and cell deaths. In the next step a variety of functional circuits are carved out and strengthened. In the third tenet physiology and psychology are combined. 9

a—mi j STRUCTURAL DEVELOPMENT OF THE CNS

Maps are formed in the brain by sensory impressions and new impressions reinforce the neuronal wiring of certain maps. Neurotransmitters such as acetylcholine and dopa¬ mine have been proposed to be involved in this selection mechanism. Recent studies indicate that epigenetic mechanisms may modulate the hardwiring. Maternal handling seems to affect gene expression. Rat pups which have been licked and

groomed extensively by their mothers seem to perform better in various behavioral tests as adults than more neglected pups (Fig. 1.8). This seems to be an environmental effect since the same results were obtained after rearing the pups by foster mothers (Meaney Ft Szyf 2005). The mecha¬ nism seems to be due to methylation/demethylation of the genome, thereby activating or silencing genes (Richards 2006). Thus there is an interaction between genetically con¬ trolled events and the environment.

SUMMARY

weeks

months

S l twitches

l

;

■Mttioves arpts/legs

|

i',

$

]i

| 4 merdes head

: -^breathing m/vemeiip ' |

i

i

-4 opens Jams, yawns MJuebs, shallows I | '•4 avaluing movements,sleep cycles | "4pain reactions, en expressions •4reactions to sound {< -4.habituation Mb/ifih reflex visual'fixation j4 imitates

i

Figure 1.8 Overview of the morphological and functional development of the CNS.

Brain development begins in the third conceptional week with induction of the neural plate through interplay between pro- and anti-neural signals. The neural tube is formed by neurulation. Co-linear arranged homeotic genes are respon¬ sible for compartmentalization of the rostro-caudal axis. The notochord which is formed under the neural tube expresses Sonic hedgehog proteins that induce the balloon¬ ing of the hemispheres, and differentiation of the motor neurons. Proliferation of neurons occurs between the 10th and 20th gestational weeks. The newly formed neurons migrate and start to branch and form synapses. This early phase of brain development is mainly genetically deter¬ mined. However, this immature brain is like a jungle with a lot of redundant pathways. Spontaneous neuronal activity, environmental influences and epigenetic mechanisms are involved in the wiring and organization of the brain, which start during late gestation and continue throughout child¬ hood (Fig. 1.9). Programmed cell death and elimination of synapses are important for this process, as are neurotrophic factors and neurotransmitters. Myelination seems to be the last step in brain maturation. It increases nerve conduction, which is of importance for the executive functions of the forebrain.

Tartilp ctimnlatinn

Figure 1.9 Epigenetic mechanisms affect the development of the brain. Increased maternal licking and grooming of rat pups increase serotonin (5-HT) turnover in the hippocampus. This results in an increased expression of NGF1-A (nerve growth factor) and AP-2 (adaptor protein) via cyclic AMP. This results in an increased expression of glucocorticoid receptors, which eliminate the influence of early experience on hyperphenylalanmemia (HPA) responses to stress (after Meaney & Szyf 2005). 10

CHAPTER

The molecular basis of brain development

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5:103-110. Caviness V S Jr. Takahashi T, Nowakowski R S 1995 Numbers, time and neocortical neuronogenesis: a general developmental and evolutionary model. Trends Neurosci 18:379-383. ChangeuxJ-P 2002 Reflexions on the origin of the human brain. In: Lagercrantz H, Hanson M, Evrard P. Rodeck C et al (eds) The newborn brain. Cambridge University Press, Cambridge. Chenn A. Walsh C A 2002 Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297:365-369. Cook G, Tannahill D. Keynes R 1998 Axon guidance to and from choice points. Curr Opin Neurobiol 8:64-72. Copp AJ. Greene N D, Murdoch J N 2003a Dishevelled: linking convergent extension with neural tube closure. Trends Neurosci 26: 453-455. Copp A J, Greene N D. Murdoch J N 2003b The genetic basis of mammalian neurulation. Nat Rev Genet 4:784-793. Crowley J C, Katz L C1999 Development of ocular dominance columns in the absence of retinal input. Nat Neurosci 2:1125-1130. D Arcangelo G. Miao G G. Chen S C et al 1995 A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374:719-723. Dobbing J, Sands J 1970 Timing of neuroblast multiplication in developing human brain. Nature 226:639-640. Edelman G.Tononi G1996 Selection and development: the brain as a complex system. Cambridge University Press. Cambridge. Eriksson P S. Perfilieva E. Bjork-Eriksson T etal1998 Neurogenesis in the adult human hippocampus. Nat Med 4:1313-1317. Evrard P, Marret S, Gressens P 1997 Environmental and genetic determinants of neural migration and postmigratory survival. Acta Paediatr Suppl 422:20-26. Feller M B. Wellis D P. Stellwagen D et al 1996 Requirement for cholinergic synaptic transmission in

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Jacobsson M 1991 Developmental neurobiology. Plenum. New York. JessellT M. Sanes J R 2000 Development. The decade of the developing brain. Curr Opin Neurobiol 10:599-611. Keleman K, Ribeiro C. Dickson B J 2005 Comm function in commissural axon guidance: cell-autonomous sorting of Robo in vivo. Nat Neurosci 8:156-163. Kidd T. Brose K. Mitchell K J et al 1998 Roundabout controls axon crossing of the CNS midtine and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92:205-215. Krumlauf R 1994 HOX genes in vertebrate development. Cell 78:191-201. Kuhl P K 2004 Early language acquisition: cracking the speech code. Nat Rev Neurosci 5:831-843. Lagercrantz H, Hanson M. Evrard P, Rodeck C (eds) 2001 The newborn brain. Neurotransmitters and neuromodulators. Cambridge University Press, Cambridge. Lemons D. McGinnis W 2006 Genomic evolution of HOX gene clusters. Science 313:1918-1922. Levi-Montalcini R 1998 My life and my work. Basic Books, New York. Meaney M J. Szyf M 2005 Maternal care as a model for experience-dependent chromatin plasticity? Trends Neurosci 28:456-463. Miles R 1999 Neurobiology. A homeostatic switch. Nature 397:215-216. Miller R W. Blot W J 1972 Small head size after in-utero exposure to atomic radiation. Lancet 2:784-787. Mueller B K1999 Growth cone guidance: first steps towards a deeper understanding. Annu Rev Neurosci 22:351-388. Nagy Z. Westerberg H. Skare S et al 2003 Preterm children have disturbances of white matter at 11 years of age as shown by diffusion tensor imaging. Pediatr Res 54:672-679. Nordstrom U. Jessell T M. Edlund T 2002 Progressive

251-255. Seghier M L. Lazeyras F, Hiippi P S 2006 Functional MRI of the newborn. Semin Fetal Neonatal Med 11:479-488. Snider W D 1994 Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627-638. Spalding K L. Bhardwaj R D. Buchholz B A et al 2005 Retrospective birth dating of cells in humans. Cell 122:133-143. Stern C D 2001 Initial patterning of the central nervous system: how many organizers? Nat Rev Neurosci 2:92-98. Stern C D 2005 Neural induction: old problem, new findings, yet more questions. Development 132:2007-2021. Stoeckli E T, Landmesser L T1998 Axon guidance at choice points. Curr Opin Neurobiol 8:73-79. Sur M, Leamey C A 2001 Development and plasticity of cortical areas and networks. Nat Rev Neurosci 2:251-262. Travis J 1994 Wiring the nervous system. Science 266:568-570. Van Vactor D 1998 Adhesion and signaling in axonal fasciculation. Curr Opin Neurobiol 8:80-86. Wolpert L1997 Principles of development. Oxford University Press. Oxford. Yoshida M, Assimacopoulos S. Jones K R, Grove E A 2006 Massive loss of Cajal-Retzius cells does not disrupt neocortical layer order. Development 133:537-545. Zecevic N 1998 Synaptogenesis in layer I of the human cerebral cortex in the first half of gestation. Cereb Cortex 8:245-252. Zheng J Q 2000 Turning of nerve growth cones induced by localized increases in intracellular calcium ions. Nature 403:89-93.

induction of caudal neural character by graded Wnt signaling. Nat Neurosci 5:525-532.

11

SECTION I

STRUCTURAL DEVELOPMENT OFTHE CNS

CHAPTER

Early embryonic development of the brain

2

Gonzaio Moscoso

INTRODUCTION The human brain is a unique organ that subordinates every organ system in the body. It generates the mind, a complex framework that tells us that ‘we are’ or that ‘we exist,’ and also that we are different from the surroundings. To the capacity of learning the brain adds the emotional compo¬ nent that comes into play at some point during develop¬ ment. Thus the individual can feel pleasure, pain, aggression or fear. The combination of intellectual and emotional reac¬ tions will determine behavior commonly, exteriorized as ‘actions’. Today, humans can modify the environment in such a way that no other living creature has ever been capable of since the creation of the universe. At present neuropathology, adult psychopathology and child psychiatry are actively revisiting developmental neuro¬ biology in an effort to identify the origins of neurologic and psychological disorders. There are two main reasons for this effort. The first is the concept that factors affecting brain development, which could start operating early during preg¬ nancy, may play a central role in the pathogenesis of neu¬ rologic and psychiatric illness. Based on good experimental evidence, an organic basis for schizophrenia and major depressive illness has been put forward by more than one team of researchers (Suddath et al 1990, Weinberger 1987, Weinberger et al 1982, 1987). The second reason is the development of new tools for research at molecular, cell and organ-system levels using genetically modified animal models, thereby providing the investigator with clearer vari¬ ables to study the emergence of form and function of the CNS in health and disease, from the earliest stages of devel¬ opment until well after birth. Brain development proceeds according to intrinsic and extrinsic influences. Intrinsic influences are given by the genetic code that modulates the development of form and symmetry and primes neural circuits for function. The extrinsic influences start in utero and will continue until the death of the individual. At organ level, brain development starts with the formation of the neural tube or neurulation, followed by neuronal migration and neuritic differentiation with synapse formation and controlled neural ‘pruning’ (Bourgeois et al 1989). The last two stages have become areas of great interest in recent years. More importantly, it is now well accepted that environmental influences condi¬ tion brain development. This chapter describes the development of the CNS at organ level from the start of embryonic life to the end of 12

the first trimester of pregnancy. In addition, some data on gene expression during brain development observed in some animal models will be presented, suggesting that similar patterns of gene expression may operate in humans.

ORGANOGENESIS In the human, as in higher vertebrates, the development of the CNS starts with the formation of the neural plate at about the 18/19th day postfertilization (Carnegie stage 8). The neural plate develops cranial to the primitive streak along the midsagittal line (Fig. 2.1). It is shortly followed by the emergence of two neural folds which fuse at the level of the first pair of somites during days 20 and 21 (Carnegie stages 9-10) (O’Rahilly 8t Muller 1999). As a result of this fusion the embryonic disk adopts a tubular shape, when the crown-rump length is about 3.3 mm (Fig. 2.2). Closing of the neural tube proceeds in a zip-up action from day 20 to day 25 when the anterior neuropore closes (Fig. 2.3); 2 days later the caudal neuropore closes at the level of somite 31 or where the second sacral segment will differentiate. In this fashion the neural tube becomes isolated from the amniotic environment. Observed at 17 days postfertilization, by the 25th day the notochord is already fully formed. The otocyst becomes apparent on the 26th day. Observations in mutant mice lacking laminin a5 chain showed multiple developmental defects, including failed closure of the anterior neuropore (exencephaly) (Miner et al 1998). Therefore, absence of laminin, a non-collagen glyco¬ protein and normal constituent of the basal lamina, appears to play an important role during closure of the neural tube. From the initial stages of neural tube closing, a population of neural crest cells emerges at the level of the fusing neural crests and migrates, following chemical cues, along the lateral sides of the embryo’s body to specific target organs. Their role during morphogenesis and organogenesis, however, is ample and complex and beyond the scope of this chapter. In the early twenties, whilst studying early Drosophila embryos, Bridges and Morgan (1923) identified a cluster of homeotic selector genes, the HOM complex, which partici¬ pate in modulating the development and orientation of specific body segments and limbs (Dolle et al 1989; Oliver et al 1989). Today, it is known that mammals and other vertebrates have homeoboxes containing tightly linked clus¬ ters or HOM complexes, for example, Hox-1, Hox-2, Hox-3 and Hox-5 genes that are expressed in early mouse embryos.

CHAPTER

Early embryonic development of the brain

(a)

2

(b)

Figure 2.2 Human embryo at 23 days postfertilization (stage 11). (A) Posterior view. Note the tubular shape of the embryo's body. The anterior and caudal neuropores are open (circles). (B) Left lateral view. The cephalic end of the neural tube (arrow) and the cardiac loop (star) are very close to each other at this stage. This will facilitate neural crest cell migration to selected areas of the developing heart.

Figure 2.1 Human embryo at 19 days postfertilization (stage 8). There are prominent marginal lobulations at the cephalic end (circled). Some ectoderm has been removed (arrow heads) to reveal a midline triangular ridge and two flaking grooves. These formations are beneath the primitive streak. The amnion (arrows) has been partially removed to expose the embryonic disk. SEM x180.

Similarly, HOX genes that modulate the development of the CNS also are expressed in early embryonic stages (Holland 8t Hogan 1988). This is discussed in detail in Chapter 1. When examined at the appropriate time of development, the hindbrain of the chicken presents eight bulges known as rhombomeres limited by constrictions (Lumsden 8t Keynes 1989). In-situ hybridization has shown selective expression first of Krox-20 gene in rhombomere 3 followed by expres¬ sion in rhombomere 5. Downregulation occurred in the same order, and these observations indicate that segmentation

of the hindbrain occurs in an antero-posterior direction (Wilkinson et al 1989). Furthermore, histological examina¬ tion of these levels showed a neuronal organization in these segments, directly related to cranial sensory ganglia and cranial nerve roots connecting branchial and pharyngeal arches. Thus, patterning of the body axis and of the CNS seems to be dependent on a specific set of HOM genes if normal development is to be achieved. The Sonic hedgehog gene (p. 1) is also expressed during early embryogenesis and the peptides it generates will assist in the formation of the notochord and neural tube (neurulation). Later on, it will induce the differentiation of spinal motor neurons (Roelink et al 1994), midbrain dopaminergic neurons (Hynes et al 1994); Wang et al 1995) and dorsal forebrain dopaminergic neurons (Ericson et al 1995) (Fig. 2.4). Interestingly, the Sonic hedgehog gene has a protective effect on neurons when challenged with specific neuro¬ toxins, i.e. MMP (Miao et al 1997), and contributes to deter¬ mining the body axis (Tanabe ft Jessel 1996). The almost straight ‘tubular’ embryo at 22 days gradually folds into a ‘C’-shape embryo already apparent at 29 ± 1 13

SECTION

I

STRUCTURAL DEVELOPMENT OF THE CNS

(a)

Figure 2.3 Human embryo at 25 days postfertilization (stage 11). (a) Left lateral view. Note the tubular shape of the embryo's body and the attached secondary yolk sac (YS). The cardiac loop is larger than the head, (b) Frontal view of the embryo in (a). The rostral neuropore (circle) is about to close. The cardiac loop shows a transverse (H) and an ascending segment (outflow portion). S = septum transversum.

(b)

(c)

Figure 2.5 Human embryo at 29 days postfertilization (stage 13). On a frontal view (b). the teiencephalic vesicles are clearly seen (open circles). These are also seen laterally in (a) and (c).The head is now larger than the cardiac loop. M = mesencephalon. R = rhombencephalon. The dots point to three pharyngeal arches. The black arrow in (c) points to the stomach containing some fluid seen by translucency. H = heart; L = rhombic lips.

Table 2.1 Neuromeres in the human embryo Primary neuromeres

Secondary neuromeres S10

Telencephalon

Prosencephalon

Diencephalon 1 Diencephalon 2 Parencephalon rostralis

S14

Parencephalon caudalis

Mesencephalon

Synecephalon

513

Mesencephalon 1

SI 2

Mesencephalon 2

S9

Isthmic neuromere

S13

Figure 2.4 Neural development and the Sonic hedgehog gene.

Rhombomeres

Rh. A

Rhombomeres: Rh. 1 Rh. 2 Rh. 3

days postfertilization (stage 12) (Fig. 2.5) and remains so through to the end of the embryonic period (8th week of gestation) when the body axis ‘unfolds’ slightly whilst the head stays bent forwards over the chest. Following closure of the neuropores, the brain enters into a stage of rapid differential growth, and the gentle cervical flexure, already evident at stage 12, becomes more promi¬ nent at 35 days postfertilization (stage 15) when, on external examination, a midbrain flexure and the pontine flexure can be observed (Fig. 2.6a). However, a midsagittal histological section shows four bending points (Fig. 2.6b). The morpho¬ genetic mechanisms, at gene, cell and tissue levels, deter¬ mining and modulating the appearance and roles of these four ‘bearing’ points, have yet to be elucidated. The appearance of flexures in the body of the embryo is associated with segmentation of the CNS. These become

14

Rh. B

Rh. 4

Rh. C

Rh. 5

S11

Rh. 7 Rh. D

Rh. 8

S = Developmental stage. Source: From R. O'Rahilly & F. Muller 1999 with permission.

more apparent following closure of the neural tube. At 29 days postfertilization (stage 13), three brain vesicles or neuromeres can be clearly identified on close examination: the prosencephalon, the mesencephalon and the rhomboencephalon (Fig. 2.5). The optic vesicle invaginates to form the optic cup. At 32 days postfertilization (stage 13), each segment will develop subsegments expected to emerge at given stages of development (Table 2.1).

CHAPTER

Early embryonic development of the brain

2

Figure 2.6 (a) Human embryo at 35 days postfertilization (stage 15). Note the pronounced flexion of the head over the chest. The telencephalic vesicles are approaching the level of pigmented eye (lower dashed line). The mesencephalon (M) is a predominant brain segment. The pontine flexure appears as a straight angle made up by the rhombic lips (L) and the floor of the fourth ventricle. The space (curved red dotted line) thus created contains water-clear fluid. Brain blood vessels appear to emerge at the level of the temporal region to spread radially. R = rhombencephalon, (b) Paramedial sagittal section of the human embryo in (a). There are four bending points (lines). Note the attenuated epidermal and neural tissue (R) making together a thin membrane covering the pontine flexure. The heart (H) shows unfused atrioventricular cushions. Liver (arrow). M = mesencephalon; T = telencephalic vesicle.

The prosencephalon or forebrain is the most anterior neuromere which presents two small telencephalic vesicles at 29 ± 1 days postfertilization (stage 13) (Fig. 2.5). By the end of the 38th day (stage 16), the telencephalic vesicles have gone past the level of the eye when observed on a lateral view (Fig. 2.7). Towards the end of the embryonic period (8 weeks gestation), the telencephalic vesicles can be recognized as developing brain hemispheres. Their outer surface appears smooth and will remain so for the first 12 weeks of gestation (Fig. 2.8). However, at 12 weeks, their medial sagittal aspect, facing the falx cerebri, shows emerg¬ ing gyri, suggesting a faster growth on their medial aspect (Fig. 2.9). At the histological level, the differential growth of the brain segments is accompanied by significant changes in the

histological architecture of each segment and in the topol¬ ogy of the gray and white matter. Here it should be remem¬ bered that the anterior neuropore closes at the level where the rhombencephalon will develop. At this point, as the neural tube closes, neuroblasts start to differentiate from neuroepithelial cells generating first the periventricular germinal layer. From it, neurons will originate and migrate towards the pia, creating the second or mantle layer to become the gray matter. A third, outermost acellular layer of the brain will be formed by interconnecting neural fibers which later become the white matter. In the prospective brain hemispheres, the marginal layer or primordial plexiform lamina appears at 33 days (stage 15) according to O’Rahilly et al (1984). Although Marin-Padilla (1983) finds it at 42 postovulatory days (stage 18), this is followed, nev15

SECTION

I

STRUCTURAL DEVELOPMENT OF THE CNS

the perivascular spaces. Most of these islands disappear before 1 year of age. Studies of gene expression in the hippocampus of some animal models show that morphogenesis and neuronal dif¬ ferentiation depends in part on the LIM homeobox gene Lhx5 (Zhao et al 1999) encoding a transcription factor present in a region the earliest differentiated Cajal-Retzius (C-R) cells (Soriano et al 1994). These C-R cells guide neural migration during the development of the hippocampus (D’Arcangelo et al 1995; Nakahima et al 1997). In mutant mice, absence of Lhx5 is associated with a malformed hip¬ pocampus, agenesis of the choroids plexus in both the lateral and third ventricles and absent callosal axons crossing the midline. Furthermore, several homeobox genes, including Lhx2, Emx2 and Otxl, are needed during morphogenesis of the telencephalic choroid plexus (Pellegrine et al 1996; Porter et al 1997; Yoshida et al 1997). Absence of Lhx5 in mutant mouse embryos is associated with poor expression of Wnt5, Bmp4 and Bmp7, resulting in abnormal patterning of the midtelencephalic wall from which the hippocampus will differentiate (Zhao et al 1995). Moreover, there is rapidly accumulating evidence indicating that hippocampal cells maintain the capability for generating neurons from pro¬ genitor cells in the adult human brain (Roy et al 2000). Therefore, the hippocampus appears to hold a potential for neuron regeneration believed to be impossible once brain development is completed. The therapeutic potential, perhaps including memory improvement among others, is of much

Figure 2.7 Human embryo at 46 days postfertilization (stage 18). The left telencephalic vesicle (T) is beyond the eye level The mesencephalon (M) still predominates in size over the other brain segments. The pontine flexure (between the arrows) has an angle less than 90 degrees.

ertheless, by the appearance of the cortical plate at about 50 days postfertilization (stage 21). Neuronal migration is assisted by radial glias which extend from the ventricular walls to the pia mater. The glia processes are present at 12 weeks of gestation (Choi 1986) and can be demonstrated immunohistochemically using glial fibrillary acid protein (GFAP). In the ensuing months, the telencephalic vesicles will grow at spectacular speed to form the brain hemi¬ spheres. According to Mikhailets (quoted by Blinkov ft Glezer 1968), half-way through pregnancy the brain has over 400% of the volume of the embryo’s body but by the end of gestation the volume is only about 42%. The original germinal layer is a continuous and tightly packed subepen¬ dymal sheet of undifferentiated cells lining the ventricles up until about the 30th week of gestation when it starts to thin out. Gradually it breaks into cell islands by the 36th week of gestation. These can still be observed after birth around 16

relevance (Gould et al 1999). The mesencephalon or second neuromere, once prominent shortly after closure of the neural tube (Fig. 2.5), undergoes fewer changes than the other two primary neuromeres: the forebrain and the rhombencephalon. Its main contribution is in the formation of the cerebral aqueduct. It is also associ¬ ated with the brain peduncles, the origin of the tegmentum and the substantia nigra appear to be derived from the basal plate or the mesencephalon. A family of transcription factors containing the fork head (fkh) domain, a region-specific homeotic gene, has been identified in Drosophila. Deficient fkh-5, the homologue gene in mice, is responsible for dysgenesis in the caudal midbrain and hypothalamic mamillary body (Wehr et al 1997). From the early stages in embryogenesis the rhomboencephalon shows increasing complexity. At 20 days postfer¬ tilization (stage 9) it reaches its peak of prominence; making up to 51-67% of the neural plate (Muller ft O’Rahilly, 1983; O’Rahilly et al 1984). At 34 days postfertilization, the pontine flexure is a prominent feature made up by the rhombic lips at its cephalic end and by the developing floor of the fourth ventricle at its caudal end. The ‘roof of the pontine flexure is made up of attenuated neural and ectodermic layers (Fig. 2.5b). The pontine ‘chamber’ thus created at 34 days is a large space within the central neural system at this stage. It contains clear watery fluid (CSF). The pontine ‘angle’ decreases with continuing growth and becomes significantly

CHAPTER

Early embryonic development of the brain

2

Figure 2.8 Human fetus at 10 weeks gestation. The outer surface of the right brain hemisphere appears smooth. The caudal end of the mesencephalon (M) is in contact with the tentorium (arrow). The right cerebellar hemisphere has a smooth surface.

Figure 2.9 Fetal brain at 12 weeks gestation. Sagittal view of the developing left hemisphere of the brain facing the falx cerebri. Note the emerging gyri suggestive of a faster growth on this side when compared with its smooth parietal brain surface.

reduced to a few degrees by the end of the embryonic period. The rhombic lips contribute significantly to the formation of the cerebellum whose rate of growth accelerates towards the end of the embryonic period. At this point, the rhombic lips resemble the roof-top of an oriental temple (Fig. 2.10a). As the embryo approaches the end of the first trimester, the cerebellar hemispheres showing a smooth outer surface are clearly defined, and the vermis is developing as a medial raphe (Fig. 2. 10b). Cerebellar foliation will not form until the 14th week. Precursors of Purkinje cells form a thin lamina separated from the granular layer by a clear zone named lamina dissecans (Rakic ft Sidman 1970). The granu¬ lar layer forms from germinal cells of rhombic lip. Cerebellar morphogenesis is slow and will be completed after the second year of life. Proliferation, migration and differentiation are but a few cell attributes needed for normal organogenesis. Using posi17

SECTION

I

STRUCTURAL DEVELOPMENT OF THE CNS

Figure 2.10 (a) Posterior view of the CNS of a human fetus at 8 weeks gestation. Note the prominent mesencephalon and the characteristic'winged' shape of the rhombic lips. The curved arrows indicate their convergence during growth. The cerebellar vermix has not yet differentiated. The brain stem (circle) has a lily-like shape. The brain hemispheres (star) have not covered the mesencephalon, (b) A view of the posterior fossa of a human fetus at 11 weeks gestation. The rhombic lips (circles) have fused (V) in the midline. Thus the cerebellum can be recognized. The choroid plexus (C) crosses freely the fourth ventricle. M = mesencephalon; 5 = brain stem.

tional cloning techniques it has been demonstrated that the 30-zinc finger transcription factor Zfp423(OAZ) modulates the development of glial and neuronal precursors of midline structures in the brain. Mutation of Zfp423 results in mal¬ formation of the cerebellum resulting in lesions similar to those observed in Dandy-Walker malformation. Further¬ more, loss of Zfp423 is associated with absent corpus cal¬ losum and with an abnormal external germinal layer due to a diminished proliferation of granule cell precursors (Alcaraz et al 2006). The floor of the fourth ventricle in the brain stem appears as an unfolded lily (Fig. 2.10). Tanaka et al (1987) have identified a set of supra-ependymal cells and supraependymal fibers. Some of the latter appear to penetrate the ependymal layer but their role is unknown. 18

At 11 weeks gestation, the choroid plexus crosses freely the fourth ventricular space between the cerebellum and the floor of the fourth ventricle (Fig. 2.10b). During this time, the foramina of Luschka and Magendie communicate the fourth ventricle with the subarachnoidal space. Cell communication and its pattern together with timing with reference to brain organogenesis are now gradually being unraveled. Tyrosine kinases, peptide growth factors for receptor tyrosine kinase, are known to play important roles during neuron migration, axon guidance and neuron cell differentiation (Fantl et al 1993, Schlessinger Ft Ukkrick 1992). Furthermore, neural cell activity has been docu¬ mented shortly before the end of the first trimester. At this time brain cells are proliferating at a rate approaching 250000/min (Rakic 1995, Shatz 1996).

CHAPTER

Early embryonic development of the brain

2

Figure 2.10 Continued

(c)

FUTURE PROSPECTS The exact temporal and spatial distribution of differentiating cells during neurogenesis has been difficult to establish so far, and how organs are assembled in complex three dimen¬ sions has escaped plausible explanations. However, the advent of new methods such as genetic fate mapping, trans¬ genic and gene targeting techniques, together with recent advances in genetic-inducible fate mapping may help in determining when and where specific cell types are gener¬ ated; in other words the fundamentals or, at least, parts of

tri/fourth (the time factor)-dimensional patterns of organo¬ genesis at the molecular level may be unraveled (Carlen et al 2006, Joyner ft Zervas 2006). Whilst much of the rapidly accumulating new knowledge on brain development appears to be oriented to the understanding of brain pathology after birth, the application of diagnostic ultrasound at ever earlier stages of gestation is making possible the accurate imaging of the developing human brain (Blaas 1999). This together with other tests based on the isolation of fetal cells from maternal blood may assist, in the not-too-distant future, in diagnosing and perhaps treating neurologic disorders.

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chain. J Cell Biol 143:1713-1723. Muller F. O'Rahilly R 1983 The first appearance of the major divisions of the human brain at stage 9. Anat Embryol 168:419-432. Nakajima K, Mikoshiba K, Miyata T et al 1997 Disruption of hippocampal development in vivo by CR-50mAb against reelin. Proc Natl Acad Sci USA 94:8196-8201. O'Rahilly R. Muller F (eds) 1999 The embryonic human brain: an atlas of developmental stages. 2nd edn. Wiley-liss, New York. O'Rahilly R. Muller F. Hutchins G M. Moore G W 1984 Computer ranking of the sequence of appearance of 100 features of the brain and related structures in

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neural tube. Cell 81:747-756. Fantl W J. Johnson D E, William L T1993 Signalling by receptor tyrosine kinases. Annu Rev Biochem 62:453-481. Gould E. Beylin A, Tanapat P et al 1999 Learning enhances adult neurogenesis in the adult hippocampal formation. Nature Neurosci 2:260265. Holland P W. Hogan B L1988 Expression of homeo box genes during mouse development: a review. Genes Dev 2:773-782. Hynes M A, Porter J A. Chiang Cetal1995 Induction of midbrain dopaminergic neurons by sonic hedgehog. Neuron 15:35-44. Joyner A L, Zervas M 2006 Genetic inducible fate mapping in mouse: establishing genetic lineages and defining genetic neuroanatomy in the nervous system. Dev Dyn 235:2376-2385. Lumsden A. Keynes R 1989 Segmental patterns of neuronal development in the chick hindbrain. Nature 337:424-428. Marin-Padilla M 1983 Structural organization of the human cerebral cortex prior to the

Oliver G. Sidell N, Fiske W et al 1989 Complementary homeoprotein gradients in developing limb buds. Genes Dev 3:641-650. Pellegrine M. Mansouri A, Simeoni A et al 1996 Dentate gyrus formation requires Emx2. Development 122:3898-3993. Porter F D, Drago J. Xu Y et al 1997 Lhx2. a LIM Homeobox gene, is required for eye. forebrain and

twins discordant for schizophrenia. N EnglJ Med 322:789-794. Tanabe Y. Jessell T M 1996 Diversity and pattern in the developing spinal cord. Science 274:1115-1123. Tanaka 0. Otani H, Fujimoto K1987 Fourth ventricular floor in human embryos: scanning electron microscopy observations. Am J Anat 178:193-203. Wang M Z, Jin P. Bumcrot D A et al 1995 Induction of dopaminergic neuron phenotype in the midbrain by sonic hedgehog protein. Nature Med 1:1184-1188. Wehr R. Mansouri A, de MaeyerT. Gruss P 1997 Fkh5deficient mice shows dysgenesis in the caudal midbrain and hypothalamic mamillary body. Development 124:4447-4456. Weinberger D R 1987 Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660-669. Weinberger D R, Berman K G. Illowsky B P 1988

definitive erythrocyte development. Development

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1-6. Rakic P. Sidman R L1970 Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans. J Camp Neural 139:473-500. Roelink H. Porter J A, Chiang C et al 1994 Floor plate and motor neuron induction by Vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76:761-775. Roy N S. Wang S. Jian L 2000 In-vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6:271-277.

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SECTION I

STRUCTURAL DEVELOPMENT OF THE CNS

CHAPTER

Development of consciousness: fetal, neonatal and maternal interactions

3

Hugo Lagercrantz

Key Points • Human consciousness cannot be established until the anatomical thalamocortical connections have been established. This occurs around the 24th gestational week • The newborn infant full-term infant fulfills the following criteria of being conscious: he or she processes tactile, painful olfactory and auditory stimuli at a cortical level (according to investigations with near-infrared spectroscopy); he or she is awake and aware if the body and the self and shows emotions. Furthermore the newborn can recognize faces and imitate face expression, habituate and show preference for human speech as compared with noise • Thus the newborn has reached a minimal level of consciousness • The fetus is probably not conscious, due to low Po2 and sedation by endogenous neuromodulators • The preterm infant may begin to develop minimal consciousness from the 24th gestational week

A simple definition of consciousness is sensory awareness of the body, the self and the world. The fetus may be aware of the body, for example, perceiving pain. The newborn may be aware of itself but it takes some time to develop voluntary control and self-regulation. According to Piaget (1954) the child below 2 years is a reflex sensoiy-motor organism and not aware of the world. It takes an even longer time for the child to fulfill the criteria described by Bergson (1920): ‘To retain what no longer is, to anticipate what as yet is not these are the primary functions of consciousness.’ Using new brain imaging and functional techniques it is now possible to explore the neuronal correlates of consciousness in the fetus and the newborn. Although the knowledge of the developing brain has increased considerably thanks to these new tech¬ niques, surprisingly little is known about the development of the brain with regard to the emergence of consciousness.

NEURONS: THE ATOMS OF CONSCIOUSNESS Neurons are the atoms of perception, memory, thought and action; thus, the atoms of consciousness (see Koch 2004). They differ from other cells, for example, the intestine or the skin, in that they are explicit. Although nearly all cells react to the environment, only the neurons make this infor¬ mation explicit and available for conscious thinking. The neurons of the immature fetal brain are round and have very few connections with other cells, which explains why they are less explicit. Cortical pyramidal neurons in the primary visual cortex of the human sprout increasingly more and from the 26th week (Purpura 1982). The neurons branch, acquire dendritic spines and connect with each other.

THE LOCALIZATION OF CONSCIOUSNESS The exact anatomical localization of consciousness is not known, even in the adult. The thalamus is probably essential as the gateway to the neocortex (Koch 2004). Particularly, the parietal lobes seem to be important to shape mental images and gather information about the world around us and, possibly, within us (Baars et al 2003). If we consider verbal report ability as a hallmark of human consciousness (see Perner 8t Dienes 2002), the following areas seem to be involved: the anterior cingulate gyrus of the frontal lobe, left lateral frontal and posterior cortex, in areas involved with processing the meaning of words or sentences, and the right cerebellum (Posner ft Rothbart 1998). Pyramidal cells from layers 2 and 3 in the dorsal lateral prefrontal and inferoparietal cortical structures are probably essential (Dehaene ft Changeux 2004). Long-distance axons link most, if not all, the cortical and thalamic regions forming a neuronal workspace (Fig. 3.1). In this way one becomes conscious of sensory stimuli (Baars et al 2003, Changeux 2004). Koch also believes there are specific ‘consciousness neurons’. An alternative view is that there is a ‘dynamic core’ consisting of correlated activities of a large number of neurons in the cortex, thalamus and the limbic system (Edelman ft Tononi 2000).

DEVELOPMENTAL ANATOMY OF CONSCIOUSNESS A primary requisite to be conscious is to be aware of sensory impressions, i.e. the neuronal pathways mediating this infor¬ mation must exist and function. Palmar cutaneous sensory receptors appear around the 10th week of gestational age in the human. Spinal reflexes evoked by stimulation of most body areas can be observed from the 14th week. Nociceptive reactions can be recorded from the 19th week (Rees 8t Rawson 2002). The genesis of the cochlea starts around the fifth week after conception and the hair cells differentiate and grow from the 11th week until the 21st when they nearly have reached adult size. The sensory cells in the nasal cavity and the nasal septum are probably in contact with amniotic fluid from the 22nd week of gestation (Schaal et al 2004). The eyelids are closed until the 22nd week and the retina is very immature when the eyes open. Photoreceptors are relatively short and wide at birth. The fovea is also very immature. 21

SECTION

STRUCTURAL DEVELOPMENT OFTHE CNS

Figure 3.1 Consciousness has been proposed to be localized in a global workspace which receives inputs via long neurons from perceptual, attentional and evaluating systems and memory (Dehaene & Changeux 2004). A metaphor of the global workspace is a theater scene as proposed by Baars (1998). A number of events occur in the scene, behind the scene, among the auditorium, etc., but the conscious mind is focused on what is happening in the scene. The prefrontal cortex selects what is attended to and interprets it to a voluntary action. This is applicable only to a limited extent in the baby.

Early preterm

Cortical plate

Subplate

Figure 3.2 Maturation of the thalamo-cortical connections and the somatosensory evoked potentials (SEP) responses. This is essential to be able to process sensory inputs in the global workspace, i.e. being conscious. (Courtesy of S. Vanhatalo.)

To be conscious the various sensory modalities must become accessible to the cortex. All sensory impressions, except olfac¬ tory impressions, are relayed in the thalamus. Thalamic afferents to the cortex appear from about 12-16 weeks gestation, but these projections only reach the subplate, which is regarded as a ‘waiting compartment’ for afferents to the cortex (Fig. 3.2). At this stage only very long somatosensory evoked potentials (SEP) from the deep layers can be recorded 22

at the scalp (Vanhatalo ft Lauronen 2006). First, after about 24 weeks, there is an ingrowth of thalamocortical axons in the somatosensory, auditory, visual and frontal cortex (Kostovic ft Rakic 1984). Thalamocortical pathways mediating pain perception do not seem to function before the 29-30 gestational weeks according to Lee et al (2005). At about this time there also seems to be some synchrony of the EEG rhythm of the two hemispheres (Vanhatalo Et Kaila 2006).

CHAPTER

Development of consciousness: fetal, neonatal and maternal interactions

The cerebral cortex, particularly the prefrontal area, matures late in the human. The neurons do not become completely myelinated until early adulthood, allowing rapid neuronal activity and mature executive, actions (Sowell et al 2004). However, subcortical structures are probably of greater importance for consciousness during early life. The fusiform area, for face recognition, and the amygdala, for emotions, etc., seem to function already in the newborn. These areas are of great importance for the social brain and probably also for consciousness (Johnson 2005). These sub¬ cortical structures should not necessarily be regarded as subordinate to the cortex, particularly not in the infant.

3

Noradrenergic neurons from locus coeruleus may activate the whole brain during wakefulness

THE NEUROCHEMISTRY OF CONSCIOUSNESS Excitatory amino acids generate synchronous oscillatory activity, which probably is essential for the maintenance of consciousness. Gamma-aminobutyric acid (GABA) is the dominating excitatory neurotransmitter during fetal life. Around birth it becomes the main inhibitory neurotransmitter. This is due to the fact that the immature neurons are depolarized by GABA, while the mature neurons become hyperpolarized. This is caused by the expression of the K+/Q“ co-transporter KCC2, which maintains a low intracellular Cl“ concentration. Glutamate and aspartate probably take over the role of GABA as the major excitatory amino acids after birth (see Vanhatalo £t Kaila 2006). Classic neurotransmitters like norepinephrine (noradrena¬ line) and acetylcholine may also be involved in the genera¬ tion of consciousness by stimulating wakefulness and awareness. Noradrenergic neurons originating from the locus coeruleus have been proposed to be involved in arousal. The norepinephrine turnover was found to be relatively low in the rat fetus, but surged after birth (Lagercrantz 1996). If we extrapolate to the human newborn baby this increased nor¬ epinephrine turnover may explain the arousal of the newborn baby, who is usually awake in the first 2 hours after birth (Fig. 3.3). Although increased norepinephrine turnover has not been demonstrated in the human brain, we know that enormously high levels of catecholamines are released after vaginal delivery and that there are strong indications that the central and peripheral catecholamine systems are acti¬ vated simultaneously (Lagercrantz 1996). Acetylcholine also seems to be a more likely candidate as the neurotransmitter of consciousness (Changeux 2006). Cholinergic basal forebrain neurons send their axons to a much wider array of target structures, innervating the thala¬ mus, hippocampus, amygdala and cerebral cortex. The idea of acetylcholine as the transmitter of consciousness is cor¬ roborated by the finding of increased activity during awakeness. Furthermore, in dementia, diseases like Parkinson and Alzheimer, associated with depressed consciousness, there is a selective loss of cholinergic neurons. Acetylcholine

Figure 3.3 The newborn is awakened and aroused at birth possibly due to activation of the locus coeruleus.

has been found to promote cortical processing of incoming stimuli. Newborn mice lacking the (32 nicotinic acetylcholine receptor subunit showed impaired arousal response during hypoxia (Cohen et al 2005).

METHODS TO STUDY CONSCIOUSNESS IN THE FETUS AND THE INFANT Functional magnetic resonance imaging (fMRI) has been used to study how the human fetus processes sensory input (Gowland 8t Fulford 2004). However, it is difficult since the fetus must be immobilized. Another technique is magneto¬ encephalography (MEG), which has been used by some research groups (Preissl et al 2004). The principle is to record magnetic signals corresponding to the electrical activity in the brain. It is completely passive and non-invasive with superior temporal resolution. However, it does not provide any anatomical information; this has to be obtained by combining MEG with ultrasound or other techniques. The method has been used to study auditory and visual evoked responses in the fetus (Huotilainen 2006). Conventional EEG, amplitude integrated EEG, eventrelated potentials can be used to assess neonatal conscious¬ ness (see Ch. 12 and Fellman et al 2006). fMRI is considered as the leading technique to explore the function of the brain (Seghier et al 2006). However, the infant must be immobi¬ lized and usually asleep, which makes it difficult for studies of consciousness. This is not necessary when using near-infrared spectro¬ scopy (NIRS). This method is non-invasive, relatively simple and is a useful method to assess how the neonatal brain processes various sensory signals (Meek 2002). NIRS is based on measuring the hemodynamic responses over the cortical areas. Near-infrared light which is transmitted by optodes placed on the skull is reflected by oxyhemoglobin and deoxyhemoglobin and measured. Changes in hemoglobin 23

SECTION

I

STRUCTURAL DEVELOPMENT OFTHE CNS

oxygenation and blood volume and flow can be computed by algorithms and used as indexes of neural activation. Using this method it is at least possible to study how sensory input is processed in the brain, although it only indirectly indicates whether the infant is aware or conscious of the stimuli. The spatial resolution is 1-2 cm and the temporal sampling resolution 0.01 s, which is better than fMRI. One limitation is that structures situated deeper than 2-3 cm under the skull cannot be studied with NIRS. With this method positive responses to visual, auditory and olfactory stimulation have been documented (Bartocci et al 2000, Meek et al 1998). This method has also been used to study how the infant perceives human speech (DehaeneLamberts et al 2002).

COMPONENTS OF CONSCIOUSNESS A catalog of conscious experiences or components of con¬ sciousness can be listed for the fetus and the neonate:

1. SENSORY EXPERIENCES AND PAIN Tactile and painful stimuli (e.g. venepuncture) elicit specific hemodynamic responses in the somatosensory cortex (Fig. 3.4), implying conscious sensory perception already in the preterm neonates (Bartocci et al 2006, Slater et al 2006). The mean gestational age was 32 weeks (range 28-36) in the study by Bartocci et al (2006). A more pronounced response was seen in the youngest infants consistent with the finding that the pain threshold is lower in preterm infants. On the other hand there was a positive correlation between pain response and postnatal age, consistent with a postnatal decay of fetal inhibition. The latency between venepuncture and cortical activity was comparable to that of adults. Higher responses to noxious stimulation were seen in awake infants (Slater et al 2006), confirming the idea of

being conscious of the pain. The lateralization of pain pro¬ cessing, the latency and duration of these responses and their gradations across gestational age and postanatal age, and the neuroanatomical location of these responses suggest that preterm infants may be consciously processing the acute pain from venepuncture. However, it is less likely that fetuses and preterm infants below 25 weeks can be aware of pain (see Derbyshire 2006).

2. SMELL AND TASTE Early infant behavior is influenced by olfactory cues, many originating from the intrauterine environment (Schaal et al 2004, Varendi et al 2002). They seem to be more attractive to the smell of amniotic fluid than to other odors. Exposure to amniotic fluid and other maternal odors has a soothing effect in newborns. When babies were exposed to clothes with their own mother’s odors they stopped crying. Infants also seemed to prefer tastes that they were exposed to during fetal life through their mother’s diet (Schaal et al 2004). Odors were found to be processed in the orbito-frontal olfactory area by the use of NIRS (Bartocci et al 2000, 2001).

3. HEARING AND SEEING Low-frequency sounds can be recorded from about the 16th week. However, the fetus does not react to sounds in general until the 20th week, when tachycardia can be elicited by noise (Counter 2002). External sound is reduced to about half of its strength when it reaches the fetal cochlea. However, it is plausible that the maternal voice is transmitted also by direct conduction. This may explain why newborn infants seem to be able to discriminate between the mother’s and unfamiliar women’s voices (Gray 8t Philbin 2004). The fullterm infant can orient visually to auditory signals by turning the head and the eyes towards the sound. If an infant is shown, for example, an object at the same time as being presented with a sound, it will turn the eyes towards the sound, suggesting that hearing is more mature at birth. On the other hand, the preterm infant has difficulties orientat¬ ing towards an auditory stimulus. Fetal brain activity has been studied during visual stimu¬ lation. Bright light was shone at the maternal abdomen for short periods (8 s) repetitively and brain activity was moni¬ tored with fMRI. Activity could be recorded in the frontal eye fields but not in the primary visual cortex in the occipi¬ tal region (Preissl et al 2004). Visual acuity in the full-term newborn infants is only V40 visual acuity but they can recognize faces and imitate (Johnson 2005).

4. WAKEFULNESS

Figure 3.4 Recording of the responses to smell by nearinfrared spectroscopy (NIRS) from the olfactory cortex. This shows that various smells are processed at a cortical level. 24

The human fetus is mainly asleep, although it can be observed on ultrasound that it sometimes opens its eyes (see Mellor et al 2005). However, it may be awake without being conscious, like in some patients in vegetative states. The fetus is mainly asleep in REM sleep, which is characterized

CHAPTER

Development of consciousness: fetal, neonatal and maternal interactions

by rapid eye movements. Non-REM sleep increases succes¬ sively during maturation. It can be argued that one is conscious also during dream or REM sleep at least after birth. However, if we assume that awakefulness is required for being fully conscious, there are indications that the fetus is never awake and conscious. Rigatto et al (1986) recorded electrocortigram, eye and breathing movements in parallel with behavior in fetal sheep, which was monitored by video camera observations. No wakeful periods were discovered when analyzing video¬ tape recordings of more than 5000 hours during 8 years. Furthermore, a number of inhibitory substances have been found in the placenta which suppress the fetus and promote sleep. The low partial oxygen level of the fetus (Mount Everest in utero) may also contribute to suppress the fetal brain. This may, for example, increase the endogenous levels of adenosine (Irestedt et al 1989), which inhibits neuronal activity. The normal newborn infant is usually awake in the first 2 hours after birth. The eyes are wide open and the pupils are big. This awake state was probably missed a few decades before, because the babies received Crede prophylaxis. After a couple of hours they usually fall asleep. The awakening of the newborn baby may be due to activation of the locus coeruleus. A surge of catecholamines occurs particularly after vaginal delivery (Lagercrantz 8t Slotkin 1986). There is probably a parallel activation of the cerebral noradrenergic system (Lagercrantz 1996). Extremely preterm infants (




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."2 CL in c LU 145 mmol/L), as a marker of reduced extravascular volume, was correlated with the development of GMH-IVH, but no significant association could be found (Lupton et al 1990).

Coagulation defects It has been postulated by a variety of researchers that after capillary rupture has occurred, bleeding is more likely to continue in the presence of coagulation disturbances (Bev¬ erley et al 1984b, Chessels ft Wigglesworth 1972, Foley ft McNicol 1977, McDonald et al 1984a, Setzer et al 1982, Thorburn et al 1982). Few studies have examined clotting before the onset of hemorrhage and results are conflicting. Beverley et al (1984b) found no significant differences at birth in a variety of coagulation studies in infants who later developed GMH-IVH, but at 48 hours of age there were significant differences in activated partial thromboplastin time and the activity of some clotting factors between the non-hemorrhage and GMH-IVH groups, but they could not show a relationship between the timing of GMH-IVH and the severity of coagulopathy. Conversely, McDonald et al (1984a) found a significant association between coagulopa¬ thy in the first few hours of life and subsequent GMH-IVH or extension of intracranial hemorrhage. The use of heparin to maintain patency of intravascular catheters is an equivo¬ cal risk factor. A fourfold increased risk has been reported from a retrospective study (Lesko et al 1986), but a more recent randomized control study has shown no increased

403

SECTION

IV

HEMORRHAGIC AND ISCHEMIC LESIONS

risk (Chang et al 1997). Petaja et al (2001) showed the risk of IVH was increased in preterm infants with thrombophilic abnormality. A more recent study among 595 very low birth weight infants however found that the frequency of intra¬ ventricular hemorrhage or periventricular leukomalacia was not significantly influenced by any of the genetic variants tested (Hartel et al 2006). Indometacin, a potent prostaglandin synthetase inhibitor, is used widely in premature infants to close a PDA and has been suggested to be a risk factor for GMH. Corazza et al (1984) found that indometacin significantly prolonged the bleeding time within 2 hours of its administration, but they and others (Maher et al 1985) could find no convincing link between indometacin administration and the initiation or maximal size of hemorrhage. More recently indometacin has been convincingly shown to reduce the risk of GMH-IVH (see p. 407).

Other factors Flush solutions containing benzyl alcohol as a preservative have been suggested to cause GMH-IVH (Hiller et al 1986, Menon et al 1984), and withdrawal of benzyl alcohol from clinical use was associated with a considerable reduction in the number of infants with moderate or severe hemorrhage (Jardine 8t Rogers 1989). Clearly, iatrogenic causes of GMHIVH must always be suspected, as new treatments are com¬ monly introduced into neonatal medicine in an uncontrolled manner. Placing an umbilical artery catheter at the level of T6-Tu (a high position) has been suggested to cause retro¬ grade flow in the cerebral circulation, and in a retrospective study, placement of the catheter in the high position com¬ pared with the low (L3-L5) was significantly associated both with the development of GMH-IVH and its severity (Schick

in blood pressure, and consequently in blood flow through the germinal matrix, are most likely to occur in the presence of hypercapnia and hypoxia, as these factors maximally dilate the cerebral arterioles. Prostaglandins play an impor¬ tant role in the vascular tone of the germinal matrix vessels, and factors may act at this level to predispose the infant to changes in local blood flow and rupture of compromised vessels. Once rupture has occurred, coagulopathy will exac¬ erbate bleeding, which may then become more extensive and rupture into the lateral ventricles. Further impaired flow as the result of venous congestion (p. 398) occurs in the periventricular white matter, leading to venous infarction. This mechanism is summarized in Figure 20.7.

DIAGNOSIS Clinical This is discussed in detail in Chapter 9, and will be summa¬ rized briefly here. Before the introduction of scanning tech¬ niques, GMH-IVH was thought to be a devastating condition with obvious clinical signs. Volpe (1977) described two clinical manifestations: a rapidly evolving catastrophic dete¬ rioration and, less commonly, a slower saltatory course. Lazzara et al (1978) reported the main physical signs associ¬ ated with GMH-IVH diagnosed by computerized tomogra¬ phy (CT) to include a tense fontanelle and either increase or decrease in spontaneous activity. In another study,

Vessel factors

Hemodynamic factors

et al 1989). Vigorous and frequent physiotherapy has been described to be the cause of a particular type of intracranial hemor¬ rhage that may be confused with GMH-IVH in extremely premature infants (Harding et al 1998). In survivors this lesion leads to encephaloclastic porencephaly. Its origin is thought to be hemorrhagic infarction and is similar patho¬ logically to the findings seen in older infants with shaking injuries as a result of non-accidental injury caused by shear¬ ing of bridging vessels over the brain surface.

A unifying hypothesis GMH-IVH may occur when the structural integrity of the vessel wall is compromised and then ruptures following subsequent changes in intravascular pressure or blood flow. An additional hypothetical factor may be alterations in extravascular pressure. Various factors may be associated with acute changes in intravascular pressure which can be either respiratory or cardiovascular in origin. Respiratory risk factors include mechanical ventilation and pneumotho¬ rax which induce vasodilatation secondary to hypercapnia. The most important cardiovascular factors are those that cause a change in CBF and hypotensive infants may be most vulnerable once the blood pressure is restored. The changes

404

Figure 20.7 A model for the development of GMH and IVH which is dependent on both vessel and hemodynamic factors.

CHAPTER

Neonatal intracranial hemorrhage

decerebrate posturing was seen in one-half of infants who were shown to have GMH-IVH on CT scans, but clonic sei¬ zures were seen equally frequently in the group of infants without hemorrhage (Krishnamoorthy et al 1977). With the introduction of routine scanning techniques it was recognized that the majority of infants with GMH-IVH showed no overt symptoms. Burstein et al (1979) reported that the frequency of ‘silent’ hemorrhage was as high as 68°/o in a group of very low birth weight infants. Comprehensive neurologic assessment methods have shown that a variety of clinical signs correlate with the presence of GMH-IVH, including impaired visual tracking, abnormal popliteal angle, later development of roving eye movements, decrease in tone and poor motility (Dubowitz et al 1981). Others have also found infants with GMH-IVH to have increased tone in the lower limbs (particularly pop¬ liteal angle) and hypotonia of the neck (particularly flexor muscles) and upper limb girdle muscles. In addition, those with GMH-IVH had brisker tendon reflexes and clonus of the ankle (Stewart et al 1983a). Clinical assessment at full-term in prematurely born infants is useful in predicting outcome and has been shown to be a better predictor of poor outcome than neonatal ultrasound abnormalities (Dubowitz et al 1984). Of the 62 infants considered normal at 40 weeks, 91% were assessed as normal at 1 year. Abnormal movement patterns associ¬ ated with intracranial pathology are discussed in detail in Chapter 9.

Imaging

(see also Ch. 6)

CT was first used to diagnose GMH-IVH in 1976 (Pevsner et al 1976) but is inappropriate for routine clinical use. In 1979, ultrasound was shown to be a sensitive method for diagnosing GMH-IVH and has now become widely used as a convenient and safe method for detecting this condition. More recently, magnetic resonance imaging (MRI) has become widely used instead of CT scanning. The role of these three techniques in diagnosing hemorrhage is fully

20

PREVENTION OF GMH-IVH There is a large body of data investigating the role of vita¬ mins and drugs in the prevention of GMH-IVH (Table 20.2) and a few studies have shown convincing data that GMHIVH can be prevented when treatment is given either prenatally or postnatally. Figures 20.8 and 20.9 summarize this data where up-to-date systematic reviews are available.

Antenatal drug interventions ANTENATAL CORTICOSTEROIDS (Fig. 20.8) To date 21 ran¬ domized controlled trials involving over 4000 babies have evaluated the role of corticosteroids in improving perinatal outcome when given antenatally to women in premature labor. A systematic review (Roberts ft Dalziel 2007) of these trials has shown that corticosteroid administration is associ¬ ated with a significant reduction in the risk of intraventricu¬ lar hemorrhage (OR 0.54; Cl 0.43, 0.69). There is also a strong trend towards improving long-term neurologic outcome in survivors (OR 0.64; Cl 0.14, 2.98). It is not known whether the steroids reduce the incidence of GMHIVH through the reduction in risk and severity of respiratory distress syndrome, stabilization of blood pressure or whether there is a direct cerebral protective effect. Studies of post¬ natal rescue corticosteroid administration to premature babies with severe lung disease within 96 hours of birth have shown no reduction in the risk of severe IVH. ANTENATAL PHENOBARBITONE (Fig. 20.8) To date there have been 8 trials involving over 1600 babies of phenobarbitone given to mothers in preterm labor to prevent GMHIVH and these have been systematically reviewed (Crowther 8t Henderson-Smart 1999a). When all 8 studies were com¬ pared there was a significant reduction in the rate of GMHIVH of all grades of severity (RR 0.75; Cl 0.65, 0.88) and in more severe grades of IVH (RR 0.49; Cl 0.32, 0.74). There were few data on outcome of survivors, but no difference in the incidence of adverse outcome was found when the children between 18 and 36 months of age were assessed.

discussed in Chapter 6.

Electroencephalography

(see also Ch. 12)

Table 20.2 Agents evaluated in preventing GMH-IVH

Cukier et al (1972) first described a specific EEG abnormality associated with GMH-IVH. This was referred to as a positive rolandic sharp wave, and the association has been confirmed subsequently by other workers (Blume 8t Dreyfus-Brisac 1982). Unfortunately, this abnormality appears not to be sensitive for uncomplicated GMH-IVH (Clancy et al 1984, Watanabe et al 1983) nor specific (Lombroso 1982). Positive rolandic sharp waves have also been reported in periven¬ tricular leukomalacia (Lombroso 1982, Marret et al 1986) and this particular EEG pattern is common when GMH-IVH is associated with severe leukomalacia. Therefore, the EEG may not be a useful method for diagnosing GMH-IVH alone but may be of value in prognosis because of frequently associated parenchymal lesions. The role of this technique

*These have been shown on at least one randomized control study to significantly reduce the risk of hemorrhage, See the text for a detailed

is fully discussed in Chapter 12.

discussion.

Postnatal administration

Antenatal administration

*Ethamsylate

*Corticosteroids

*FactorXIII concentrate

*Phenobarbitone

*Fresh frozen plasma

*Vitamin K

*lndometacin *Pancuronium *Phenobarbitone Surfactant Tranexamic acid *Vitamin A *Vitamin E

405

SECTION

IV

HEMORRHAGIC AND ISCHEMIC LESIONS

Expt

Cont

47 / 300 23 / 403

77 / 296 32 / 375

Prenatal phenobarbital All GMH-IVH Severe (grades 3, 4) IVH Cerebral palsy

196 / 762 32 / 731 20 / 259

252 / 741 65 / 708 18 / 259

Prenatal vitamin K All GMH-IVH Severe (grades 3, 4) IVH

108 / 300 23 / 300

131 / 306 32 / 306

Prenatal TRH All GMH-IVH Severe (grades 3, 4) IVH

282 / 1819 72 / 1647

262 / 1826 64 / 1666

Intervention/outcome Prenatal corticosteroids GMH-IVH (diagnosed on U/S) Long' term neurological abnormality

RR (950/oCI)

-•-

'

0.57 (0.41, 0.78) 0.65 (0.39, 1.08)

-j

0.75 (0.65, 0.88) 0.49 (0.32, 0.74) 1.07 (0.58, 1.96)

-•-j-

0.82 (0.67, 1.00) 0.75 (0.45, 1.25)

1.08 (0.93, 1.26) 1.13 (0.82, 1.57)

i-1-1

O.l

1

10

Relative risk (95% Cl Fixed effects model)

Figure 20.8 Results of systematic reviews of prenatal drug interventions to prevent GMH-IVH or disability.

Intervention/outcome Indomethacin (Fowlie Ft Davies 2003) GMH-IVH (all grades) GMH-IVH (severe) Severe neurosensory impairment Surfactant (Soil Ft Morley 2001) Prophylactic vs control GMH-IVH (all grades) GMH-IVH (severe) Prophylactic vs rescue GMH-IVH (all grades) GMH-IVH (severe) Phenobarbitone (Whitelaw 2001) GMH-IVH (all grades) GMH-IVH (severe) Severe neurodevelopmental impairment

RR (95% Cl)

Cont

Expt

422/1258 115/1285 164/680

482/1274 177/1303 173/706

0.88 (0.80, 0.96) 0.66 (0.53, 0.82) 0.98 (0.81, 1.18)

184/497 75/483

184/489 61/478

0.97 (0.74, 1.26) 1.27 (0.88, 1.84)

386/1245 129/1245

365/1263 110/1263

0.92 (0.82, 1.03) 0.84 (0.66, 1.06)

144/370 50/370 5/47

143/370 58/135 4/54

1.04 (0.87, 1.25) 0.91 (0.66, 1.27) 1.44 (0.41, 5.04)

r 0.1

i

10

Relative risk (95% Cl fixed effects model)

Figure 20.9 Results of systematic reviews of postnatal interventions to prevent GMH-IVH.

The methodological quality of some of these reports was questioned (Crowther 8t Henderson-Smart 1999a). Some studies failed to randomize, others did not have a placebo arm, and the rates of exclusion of many of these studies were high. When these studies were excluded, the protective effect of antenatally administered phenobarbitone disap¬ peared. Therefore the benefit of antenatal phenobarbitone in preventing disability has not been proven and if only high-quality randomized controlled trials are considered, there is no evidence that antenatally administered pheno¬ barbitone has any effect. 406

ANTENATAL MAGNESIUM SULFATE There have been a number of retrospective reports of magnesium sulfate given either to terminate preterm labor or used as treatment for maternal hypertension in protecting the fetus against the subsequent development of cerebral palsy (Nelson 8t Grether 1995, Schendel et al 1996). The precise mechanism by which neuroprotection is apparently conferred is unknown, but a number of studies have investigated whether antenatal mag¬ nesium sulfate treatment reduces the incidence of GMH-IVH. In retrospective observational studies, the evidence that magnesium sulfate prevents GMH-IVH is equivocal, but a

CHAPTER

Neonatal intracranial hemorrhage

recent study of 799 babies with birthweight 32 weeks). They suggested that transforming growth factor-(3l might con¬ tribute to tissue remodeling and healing after ischemic injury. The incidence of PWMI in these pathologic studies varies between 7 and 34°/o (Armstrong 8t Norman 1974, Pape ft Wigglesworth 1979), but increases to over 80°/o by taking only those infants who required ventilation and survived beyond the first 7 days of life (Shuman ft Selednik 1980). In a more recent study, 68°/o of the 22 VLBW infants who survived at least 6 days were diagnosed as having some degree of white matter necrosis (Paneth et al 1990). The data by Back et al (2005) showed that early PWMI was related to oxidative damage that particularly targeted the oligodendrocyte lineage, whereas other neuronal and glial cell types were markedly more resistant. From this study they were able to conclude that the predilection of preterm infants for PWMI is related to selective lipid per¬ oxidation-mediated injury of cerebral white matter and tar¬ geted death of oligodendrocyte progenitors. Prenatal onset of leukomalacia was also noted by pathol¬ ogists when studying stillbirths or infants who died within the first few days of life. The incidence varied from l.l°/o (Sims 1985) to 20% in stillbirths and 16.4% of infants who died within the first 3 days of life. Of the preterm infants, 14.3% had prenatal onset PWMI which consisted of wide¬ spread necrosis (Iida 1993).

PATHOPHYSIOLOGY There is no generally accepted pathophysiologic mechanism to explain the development of PWMI and a number of dif¬ ferent theories exist (Back 2006).

The vascular theory The historical concept that PVL is caused by hypoperfusion is supported by only a few animal studies. Abramovicz (1964) obliterated the basilar artery and ligated one or both common carotid arteries in mature cats. Subsequently, he was able to show patchy infarcts close to the ventricular wall in the centrum semiovale. Other groups have used dogs as animal models. Young et al (1982) produced systemic hypotension either by with¬ drawal of blood or by injection of E. coli into the perito¬ 434

neum, and showed a significant reduction of cerebral blood flow (CBF) in the periventricular white matter while the blood flow to the cortical and deep gray matter was pre¬ served. Ment et al (1985a) induced hemorrhagic hypotension in beagle puppies and found similar results. Yoshioka et al (1992) performed bilateral carotid artery occlusion in 7 mongrel puppies and found that 6 of the 7 brains had unior multiloculated cysts in the periventricular white matter and significantly reduced myelination compared with con¬ trols. Using bilateral carotid artery occlusion in 5-day-old rats, Uehara et al (1999) were able to induce white matter changes in 91% of the animals. Matsuda et al (1999) induced systemic hemorrhagic hypotension in fetal sheep by rapid withdrawal of 35% of the fetoplacental blood volume and produced periventricular white matter lesions, consisting of coagulation necrosis and/or diffuse axonal swelling in 5 out of 6 fetuses. An interesting observation was made by Ohyu et al (1999) who performed repeated umbilical cord occlu¬ sion in near-term fetal sheep and subsequently detected multiple necrotic foci predominantly in the periventricular white matter. In a more recent elegant animal experiment, using instru¬ mented 0.65 gestation fetal sheep, where cerebral blood flow was interrupted by bilateral carotid occlusion, it was found that the duration of cerebral ischemia was a critical factor required to generate a graded spectrum of PWMI. Ischemia of shorter duration (30 or 37 minutes) only affected the frontal and parietal periventricular white matter, whereas a duration of 45 minutes of ischemia led to extensive damage also affecting cortical and subcortical gray matter and an even longer duration led to extensive cystic necrotic encephalomalacia (Riddle et al 2006). It was of interest that the extent of white matter damage depended on the pre¬ sence of susceptible populations of late oligodendrocyte progenitors. A reduction in CBF after hypocarbia due to vasoconstric¬ tion was noted in animal experiments (Saphiro et al 1980). Reuter and Disney (1986) have shown that there is a non¬ linear positive correlation between PaC02 and regional CBF in the white matter of newborn dogs. Hypocarbia (PaC02 2.67 kPa) of only 1 hour duration has been shown to reduce brain energy levels and increase cerebral cortex disruption in neonatal piglets compared with control normocarbic animals (Fritz et al 2001). In different types of animal experiments, the periventricu¬ lar white matter has appeared to be more susceptible than other areas of the brain. Ment et al (1985a) noted a regional increase in glucose utilization in the periventricular white matter and therefore assumed uncoupling between local CBF and glucose metabolism in the periventricular white matter. This uncoupling was also noted by Cavazutti and Duffy (1982), who looked at hyperemia following hypoxia. They found that the compensatory hyperemia was less pronounced in the periventricular white matter, while an extremely high rate of glycolysis was found in this area compared with other regions of the brain. Prostaglandin E2, a potent vaso-

CHAPTER

Cerebral ischemic lesions

dilator, was also carefully studied by Ment et al (1985b) in beagles subjected to hypotension. The concentration of pros¬ taglandin E2 was shown to increase to a lesser extent in the periventricular white matter than in the cortex and gray matter.

The excitotoxic theory Animal studies suggest that hypoperfusion alone could be an oversimplification in explaining the pathophysiology of PVL, and an increasing number of these studies are looking at the role of excitatory amino acids in relation to neuronal damage (see Chapters 22 and 27). Gressens et al (1999) were able to induce cystic PVL by injecting the glutaminergic analog ibotenate intracerebrally into newborn mice. By simultaneously injecting a trophic factor, vasoactive intestinal peptide (VIP), a reduction up to 87% of these excitotoxic lesions was obtained. Using the same model, this group also showed a protective effect of a glycine antagonist and NO synthase inhibitor (Marret et al 1999). Meng and Takashima (1999) also suggested that exogenous transforming growth factor-(3l could have a therapeutic effect, being involved in a delayed glial response. They studied 25 neonates with PVL using immunohistochemistry and found this growth factor to be present in 16 cases, especially in the subacute stage of PVL and only in the more mature infants (greater than 32 weeks gestation). The expression was more obvious in focal PVL. In a recent study by Medja et al (2006) thiorphan, a neutral endopeptidase inhibitor, administered into the peritoneum of newborn mice was found to reduce ibotenate induced corti¬ cal lesions up to 57% and cortical caspase-3 cleavage up to 59%. The window for therapeutic intervention was long, as the drug was still effective when administered 12 hours after the insult. The protective effect was seen in the gray, but not in the white matter. Leroux et al (2007) studied the role of tissue-plasminogen activator (t-PA) in a mouse model for white matter injury, using ibotenic acid. Intra¬ cerebral hrt-PA induced WM cystic lesions in t-PAw" mice and had an additive effect when co-injected with hig'h-dose ibotenic acid. Welin et al (2007) used melatonin in fetal sheep who were subjected to umbilical cord occlusion. The production of 8-isoprostanes following umbilical cord occlusion was attenuated and there was a reduction in the number of activated microglia cells and TUNEL-positive cells in melatonin treated fetuses, suggesting a protective effect of melatonin.

The oligodendroglial theory Following the work of Oka et al (1993) who showed that cultured oligodendroglial cells were highly vulnerable to glutamate induced cell death, Back et al (1998) extensively studied maturation dependent vulnerability of oligodendro¬ cytes (OLs) to oxidative stress. They were able to develop an in vitro system to study two distinct OL maturational stages: the preOL and the mature-OL, the preOL being the mitotically active premyelinating precursor to the mature myelin basic protein positive OL. They examined whether OLs

21

display maturation dependent survival in response to cystine deprivation, the latter being a form of oxidative stress that involves depletion of intracellular glutathione. PreOLs in contrast to OLs indeed displayed increased susceptibility to death associated with free radical mediated injury, induced by glutathione depletion or exogenous reactive oxygen species. Maturation of OLs correlated with increased resis¬ tance to oxidative stress. The increased vulnerability of the preOLs to oxidative stress correlated with a greater depen¬ dence on intracellular glutathione for survival. The toxicity of glutathione depletion was prevented by glutathione replacement. Glutathione depletion caused a marked rise in reactive oxygen species, whose toxicity could be prevented by antioxidants a-tocopherol and idebenone. Increased susceptibility of preOLs to oxidative stress may be due to delayed maturational expression of genes that suppress apoptosis. Alternatively, the death of preOLs may be regulated by a specific pathway triggered by oxidative stress that is downregulated in mature OLs. Jelinski et al (1999) used 7-day-old rats for a hypoxic-ischemic model, exposing them to 8% oxygen with temporary occlusion of the carotid arteries. Oligodendroblasts were identified using the 04 antibody. They suggest that the vulnerable glial cell type that makes a contribution to the development of PVL is the oligodendroblast, as a decrease of these cells was seen within 24 hours after the insult. Another group studied the distribution and development of ferritin-containing cells by immunohistochemistry and found that the OL was the predominant cell type. Ferritin-positive cells were present in the periventricular and subcortical white matter from 25 weeks onwards. They suggested that ferritin-posi¬ tive glia were related to the process of myelination and maturation of the OL (Ozawa et al 1994). More recent data by Back (2006) and Riddle et al (2006) further support this theory.

The inflammation theory Many recent experimental as well as human studies have provided strong evidence for a causal relationship between ascending intrauterine infection, the production of proinflammatory cytokines and white matter damage (see reviews by Dammann ft Leviton 1997a, 1998, 1999 and Rothwell et al 1997). The first animal study suggesting the importance of infection was by Gilles et al in 1976. They administered intraperitoneal E. coli endotoxin to neonatal kittens for 6 days and found telencephalic leukoencephalopathy at post-mortem. The severity of the lesions appeared to be related to the dose of the endotoxin. More recently, Yoon et al (1997a) performed hysteroscopy in rabbits at 20-21 days of gestation and inoculated either E. coli (n = 31) or saline (n = 14), treating both groups with ampicillinsulbactam. The rabbits were killed 5-6 days later. They noted histologic evidence of white matter damage in 12 of the E. coli inoculated group compared with none in the saline group (P < 0.005). A more recent study was performed in 435

SECTION

IV

HEMORRHAGIC AND ISCHEMIC LESIONS

the preterm ovine fetus (Duncan et al 2002). At 0.7 of gesta¬ tion, six catheterized fetuses received three to five intrave¬ nous injections of LPS (1 microg/Kg) over 5 days; seven fetuses served as controls. Brain tissue was examined 1011 d after the initial LPS injection. After LPS on day 1 and 2, fetuses became transiently hypoxemic and hypotensive and blood IL-6 levels were increased, but these responses were smaller or absent after subsequent LPS exposures. Neural injury was observed in all LPS-exposed fetuses, most prominently in the cerebral white matter. Injury ranged from diffuse subcortical damage to PWMI and in the brainstem the cross-sectional area of the corticospinal tract was reduced by 30%. In a similar experiment, also using 0.7 gestation ovine fetuses, profound reductions in placental blood flow and cerebral 02 delivery were seen, which could contribute to fetal brain injury. Reduced 02 delivery to white matter was similar to that in other brain regions. Mechanisms that enable fetal CBF to increase in hypoxemic condi¬ tions were apparently ineffective in the presence of LPS. Gamier et al (2006) also studied the preterm fetal sheep following intravenous application of endotoxin and found that this caused focal periventricular brain white matter injury, inflammation and an increase in S100B protein release. Levels of endotoxin measured in a clinical setting were measured by Okumura et al (1999a). They were unable to show a correlation between raised endotoxin levels and the presence of PVL and, unfortunately, were unable to perform simultaneous cytokine measurements. Many bacterial products besides endotoxin can stimulate the production of cytokines. Deguchi et al (1996) and Yoon et al (1997b) used immunohistochemical staining on brain sections having histologic evidence of PVL, and compared them with brain sections without leukomalacia. Expression of TNF-a and interleukin-6 was found significantly more often in brain sections that showed evidence of leukomala¬ cia. Interleukin-6 has been reported to play a role in guiding the developing bipotential oligodendrocyte precursor cell, 0-2A, towards the astrocyte and away from the pathway leading to a mature oligodendrocyte (Kahn 8t de Vellis 1994). Deguchi et al (1996) noted that TNF-a was mainly expressed in glial cells in the deep white matter. It is of interest that TNF-a expression was also present in the con¬ trols during the late fetal period, but later than in the leu¬ komalacia cases. These two studies provided further support for the hypothesis that proinflammatory cytokines play a role in the genesis of PVL. Even more convincing is the study by Dommergues et al (2000) who pretreated pups with interleukin l-(3, IL-6, IL-9 or TNF-a. They were able to show that the pretreated pups developed significantly larger corti¬ cal and white matter damage than controls when later exposed to the neurotoxin ibotenate. Induction of TNF-a and inducible nitric oxide synthase was, however, also detected following fetal hypoxia induced by repetitive umbilical cord occlusion (Ohyu et al 1999). Kadhim et al 436

(2006) explored potential TNF-a signaling pathways in 12 human brains with PVL and conducted in situ immunohis¬ tochemical investigations to search for possible expression of cytokine receptors in these brains. Six infants were 34 weeks or more and 4 of these had a congenital heart defect. TNF-a overexpression was associated with immune reactiv¬ ity for p75TNFalphaR2 and p55TNFalphaRl receptors in affected PVL areas. Several groups have subsequently measured cytokines in the amniotic fluid, in fetal plasma, and cord blood. TNF-a, interleukin-1 and interleukin-6 all play a role in normal pregnancy (Opsjln et al 1993), but levels have been shown to be elevated in the amniotic fluid of pregnant women with chorioamnionitis (Yoon et al 1997c). Baud et al (1999a) were able to find an association between the amniotic fluid level of interleukin-1(3 and the degree of vascular extension of chorioamnionitis. TNF-a best predicted the development of severe early neonatal infection. In this study, the cytokines were unable to predict the development of PVL, but Yoon et al (1997c) did show a significant relationship between raised interleukin-1(3 and interleukin-6 levels in the amni¬ otic fluid with white matter lesions. Gomez et al (1998) measured interleukin-6 levels in both the amniotic fluid as well as the fetal plasma in women with preterm labor and premature prolonged rupture of membranes and found interleukin-6 in fetal plasma to be significantly higher in the fetus who went on to develop severe neonatal morbidity, which also included PVL. In another study by Yoon’s group interleukin-6 concentrations greater than 400pg/mL in umbilical cord plasma were associated with a sixfold increase in white matter disease (Yoon et al 1996). Goepfert et al (2004) studied umbilical cord plasma IL-6 levels and neo¬ natal outcomes in 309 infants born between 24 weeks and 32 weeks gestation. IL-6 levels beyond the 90th percentile (> or = 516.6 pg/mL) were significantly associated with periventricular leukomalacia (PVL; odds ratio [OR] 15, 95% Cl 2-149) and necrotizing enterocolitis (NEC; OR 6, 95% Cl 1.1-33). In the multivariate analysis, an IL-6 level 107.7 pg/ mL or greater (determined by receiver operating curve anal¬ ysis) remained a significant independent risk factor for PVL (OR 30.3, 95% Cl 4.5-203.6). Hansen-Pupp et al (2005) analyzed pro-inflammatory [tumor necrosis factor-alpha (TNF-a), interferon-gamma (IFN-y), IL-1(3, IF-2, IL-6, IL-8, IL-12] and modulatory (IL-4, IL-10) cytokines from cord blood, and at 6, 24 and 72 hours postnatal age. Levels of IFN-y at 6, 24, and 72 hours were increased in infants developing white matter brain damage (WMD) compared with those without WMD. The same group found increased levels of cord IL-lra levels to be associated with neonatal morbidity and adverse outcome in preterm infants, with a better prediction for female infants (Elsman et al 2006). Ellison et al (2005) compared CSF and plasma cytokine levels and were unable to find a significant correlation between paired CSF and plasma concentrations for any cytokine. They were able to study 146 preterm infants and found that preterm infants with MRI-defined cerebral white

CHAPTER

Cerebral ischemic lesions

matter injury had higher levels of IL-6, IL-10, and TNF-a in the CSF than infants without such injury. Harding et al (2004) looked at a functional polymorphism in the IL-6 gene promoter: a C > G change at position -174, as it was shown that in vitro IL-6 production in lipopolysaccharide-stimulated neonatal monocytes is higher among those of CC genotype than among G-allele carriers. Compared with chil¬ dren with CG + GG genotype, children who were homozy¬ gous for the C allele had higher frequency of severe neonatal hemorrhagic lesions (large IVH or hemorrhagic parenchymal injury) and images consistent with WMD. CC genotype increased the risk of the development of severe hemorrhagic lesions (odds ratio [OR]: 3.5; 95% confidence interval [Cl]: 1.0-12.2; P = 0.038) and WMD (OR: 4.1; 95% Cl: 1.4-12.2; P = 0.008).

CLASSIFICATION Unfortunately there is no agreement on classification of lesions of the brain parenchyma. Following the introduction of the term ‘periventricular leukomalacia’ by Banker and Larroche in 1962, many groups of pathologists have used this term, but others have identified more widespread white matter damage, consisting of hypertrophic astrocytes, amphophilic globules, necrotic foci, and acutely damaged glia which were widespread in the cerebral white matter. This condition has been referred to as Teukoencephalopathy’ (Gilles ft Murphy 1969). Kuban et al (1999) prefer to describe echodensities and echolucencies as one condition, even in cases with a classic unilateral parenchymal hemor¬ rhage. Paneth (1999) proposed the term ‘white matter damage’. The majority of papers based on cranial ultrasound still use the term periventricular leukomalacia (PVL) and we have also used it in this context. We have been using a grading system for PVL (Table 21.1) that is now quite commonly employed by other groups (de Vries et al 1992). More recent papers using MRI use the term ‘periventricular white matter damage’ or ‘punctate white matter lesions’ and we have used these terms in this context as well.

Table 21.1 Classification of periventricular and subcortical leukomalacia based on cranial ultrasound findings (de Vries et al 1992) • Grade 1 • Grade II • Grade III

• Grade IV

Periventricular echodense area, present for 7 days or more Periventricular echodense areas evolving into localized frontoparietal cysts Periventricular echodense areas evolving into multiple cysts in the parieto-occipital white matter Echodense areas in the deep white matter, with evolution into multiple subcortical cysts

21

INCIDENCE The first reports of PVL described the ultrasound findings in a small number of cases only. However, several popula¬ tion studies have been performed, reporting an incidence of between 2.3 and 17.8% (Levene et al 1983, Perlman et al 1996, Sinha et al 1985, Spinillo et al 1998, Stevenson et al 1998, Trounce et al 1986b, Weindling et al 1985a, Zupan et al 1996). The lowest incidence of less than 1% was recently reported by Hamrick et al (2004) who also found a significant decrease in the incidence over a 15 year period. The incidence will vary with the type of patient admitted to the intensive care unit (Larroche et al 1986), the type of transducer used (5 or 7.5 MHz), the number of ultrasound examinations performed, the number of weeks during which the examinations were done and the definition used to describe PVL. Those authors who find a low incidence have restricted the term ‘PVL’ to apply to infants who developed extensive cystic lesions, while those giving a higher inci¬ dence have also included localized cystic lesions restricted to the centrum semiovale (Fawer et al 1985b). Trounce et al (1986b) reported a 9.5% incidence of cystic PVL. If pro¬ longed flares were included in the PVL category, the inci¬ dence increased to 26%. The incidence of flares (echodensities seen in two planes and lasting more than 2 weeks) was found to be 12.5%. Extensive cystic lesions, both in the trigone and in the centrum semiovale, were noted in only 2.7% of all the infants. Stevenson et al (1998) studied a very large inborn cohort with a birth weight 36 weeks gestation, who presented with an IVH, showing that SVT should always be considered in these children as 31% was diagnosed to have a SVT. This was especially common when the IVH was associated with a thalamic hemorrhage (p. 420). Twenty-six of the 29 infants had a CT or MRI and it was shown that 4/5 with a thalamic hemorrhage versus 5/21 without thalamic hemorrhage had an SVT (P = 0.03) (Fig. 21.18). In the population studied by Fitzgerald et al (2006), 50% had involvement of a single sinus, most commonly the sagittal sinus (67%), similar to the 61% noted by Deveber et al (2001). The transverse sinus was affected in 55% and the straight sinus in 33%. About half of the infants had more than one sinus occluded.

Management General management includes attention to the state of hydration and management of seizures. In recent years it has become more common to use antithrombotic therapy in neonates with SVT, but there are no evidence based guide¬ lines. Current recommendations are to use low molecular weight heparin if there is no evidence of major intracranial hemorrhage. Therapy is given for 6-12 weeks depending on the extent of recanalization after 6 weeks (Monagle et al 2004). If heparinization is not used initially, a second MR scan after 5 days is recommended to assess propagation of the initial thrombus. If there has been progression use of heparin may be indicated at that stage.

Prognosis Information about long term outcome is still limited. DeVeber et al (2001) reported a mortality of 7% and neurological deficit in 37% of their infants and a recurrence risk of symptomatic thrombosis of 8%. In the study by Fitzgerald et al (2006) only one infant (2%) died, but 79% had some sort of impairment at last follow-up, with 41% having at least moderate to severe motor impairment and 33% moder-

CHAPTER

Cerebral ischemic lesions

21

Figure 21.18 MRI, transverse T25E (a) and midsagittalTI with gadolinium enhancement showing extensive sinovenous thrombosis with severe dilatation of the occluded superior sagittal sinus.

ate to severe cognitive impairment. The subsequent develop¬ ment of infantile spasms has also been reported in some surviving infants at the age of 7-11 months (Soman et al 2006).

PERINATAL ARTERIAL STROKE (PAS) Infarction of a major artery or a branch arising from it is now recognized in an increasing number of newborn infants, with an incidence of approximately 1 per 3000-4000 live births (Lynch et al 2001, Nelson Ft Lynch 2004). Lesions involving the left hemisphere are three to four times more common than those of the right hemisphere. This is suggested to be due to either hemodynamic differences between right and left carotid arteries arising as the result of a patent ductus arteriosus or preferential flow of placental emboli into the left side vessels rather than the right. Middle cerebral artery infarction occurs twice as commonly as involvement of any other artery. The anterior cerebral artery is rarely recognized to be affected, but this may reflect the silent nature of symptoms related to involvement of this

Figure 21.19 Schematic drawing, showing (A) the different branches of the middle cerebral artery, with (B) involvement of a cortical branch; (C) involvement of the main branch; (D) involvement of one or (E) more lenticulostriate branches and (F) the boundary zone between the anterior and middle cerebral artery. (Adapted from Kappelle et al 1991, with permission, Neuropediatrics 28:1997, de Vries et al. Fig. 1 © by the Lancet Ltd.)

vessel. Both de Vries et al (1997) as well as Mercuri et al (1999) used a classification according to the main artery involved. Infarcts in the territory of the middle cerebral artery were further subdivided into main branch, cortical branch and lenticulostriate branch infarctions (Fig 21.19).

Pathology Cerebral artery infarction in the neonate has been defined as a severe disorganization or even complete disruption of both gray and white matter caused by embolic, thrombotic or ischemic events (Barmada et al 1979). The term perinatal arterial stroke (PAS) is nowadays most commonly used. The five cases described by Friede in 1975 were all wedgeshaped hemorrhagic lesions involving cortical, subcortical and deep periventricular white matter. Friede (1975) could 457

SECTION

IV

HEMORRHAGIC AND ISCHEMIC LESIONS

only positively identify these lesions as infarctive histologi¬ cally. This is different from the experience that we have nowadays in infants who mostly survive and have early neuro-imaging, showing purely ischemic lesions in the majority of the cases. Larroche (1977) described the pathologic appearance of cerebral artery infarction in six cases. In those infants dying in the acute stage of the condition, the hemisphere was swollen and deeply congested. There was involvement of both white matter and cortex, with secondary hemorrhagic infarction in some cases. In those infants who survived for longer, contraction of the affected area was seen with soft¬ ening and multiple cystic degeneration, giving a honeycomb appearance on sectioning (Fig. 21.20). The extent of the atrophic process was thought to reflect the level of arterial infarction. In some cases, infarction occurred very early in fetal life, and these brains showed extensive porencephalic cyst formation. This is discussed in more detail in Chapter 13. More recently, Aso et al (1990) performed autopsies in nine cases and found that all but one of these had one or more additional lesions, such as PVL, pontosubicular necro¬ sis, and anoxic-ischemic neuronal necrosis.

Incidence The introduction of modern imaging techniques has con¬ firmed the pathologist’s impression that PAS occurs com¬ monly. Several hundreds of cases have been reported where the diagnosis was made in life (Benders et al 2007, Billard et al 1982, Chasnoff et al 1986, Clancy et al 1985, de Vries et al 1997, Filipek et al 1987, Fujimoto et al 1992, Hill et al 1983, Jan ft Camfield 1998, Koelfen et al 1995, Lee et al 2005, Levene 1987, Levy et al 1985, Mannino ft Trauner 1983, Mantovani ft Gerber 1984, Ment et al 1984, Mercuri

Figure 21.20 Infarction involving cortex and white matter in the distribution of the middle cerebral artery. The infant developed following cardiac surgery and the infarction may have been due to an embolus during this procedure. (Courtesy of Dr. P. Nikkels. Department of Paediatric Pathology. Utrecht.) 458

et al 1999, Nanni et al 1984, Perlman et al 1994, Roodhooft et al 1987, Trauner ft Mannino 1986, Voorhies et al 1984, Wulfeck et al 1991). Data concerning the incidence are scarce and reflect the population from which the data are drawn. Barmada et al (1979) reported PAS in over 5°/o of infants examined at autopsy. More recent studies have looked at newborn infants admitted to a neonatal unit with seizures and/or apneas. Lien et al (1995) found a prevalence of 0.01% (1 :10000). Estan and Hope (1997) studied a 7-year cohort and reported a prevalence of 0.025% (1 :4000), which is rather similar to the findings of Perlman et al (1994) who found a prevalence of 0.02% (1:5000). Several groups found neonatal stroke to be the second most common cause for neonatal seizures (Estan ft Hope 1997, Levy et al 1985, Lien et al 1995). In the latter study, 49% of the infants had sei¬ zures due to hypoxic-ischemic encephalopathy and 12% due to unilateral cerebral infarction. Little data is available about focal infarction in preterm infants except for the pathologic study by Paneth et al (1994), who found lesions in the thalami or basal ganglia in 17% of the post-mortem cases belonging to a cohort born in the New Jersey counties between 1984 and 1987. In a recent hospital based study we found an incidence of 7 per 1000 preterm infants with a gestational age less than 35 weeks (Benders et al 2007).

Timing of the infarction PAS can occur both before, as well as in the immediate, perinatal neonatal period. Before the era of widespread use of neuroimaging techniques, it was a common belief that a prenatal stroke was more common, but at present there is little data in the literature to support this. A distinction is nowadays made between ‘early neonatal stroke’ with symp¬ toms on day 1-3 and ‘late neonatal stroke’ with symptoms up until 28 days. As the infants are often well enough to go to the postnatal ward, subtle seizures, occurring during the first few days, may go unnoticed and the child may first present at 4-6 months of age with an asymmetrical grasp, which is now often referred to as ‘presumed perina¬ tal stroke’ (Lee et al 2005). Mercuri et al (1995), however, showed that when the threshold to perform neonatal imaging, and in particular MRI, is low in infants with neo¬ natal seizures, focal infarction will be identified in the majority of these infants. Using ultrasound or conventional MRI, the lesions only become apparent during the first week of life (Cowan et al 2005). Diffusion-weighted imaging always clearly showed the area of infarction on the initial scan. It is reported that acute diffusion-weighted changes are maximal between 1 and 5 days after the acute lesion and normalize between 1 and 2 weeks (de Vries et al 2005, Mercuri ft Cowan 1999). These findings suggest a perinatal onset, as diffusion-weighted imaging abnormalities become less obvious within 2 weeks after the onset (Cowan et al 1994) (Fig. 21.21).

Etiology Stroke in the newborn does not appear to be the same con¬ dition as seen in older children and adults. In children the

CHAPTER

Cerebral ischemic lesions

21

(b) Figure 21.21 Middle cerebral artery infarction in a full-term infant, (a) Cranial ultrasound, coronal view, day 7. showing areas of increased echogenicity in the distribution of the main branch of the left middle cerebral artery, (b) MRI.IR sequence of the same infant performed on day 5, shows a large area of low signal intensity in the same region, (c) Diffusion weighted imaging shows an increased signal in the same distribution as well as the internal capsule, (d) Repeat MRI. IR sequence at 3 months of age shows cystic evolution in the affected area. Also note the absence of the normal myelination of the posterior limb on the affected side and involvement of the basal ganglia. (Reproduced, with permission, from de Vries et al. Archives Disease of Childhood 2005.)

most common cause of stroke is hemorrhage (whether arteriovenous malformation, aneurysm or tumor), and arterial occlusion occurs less frequently (Eeg-Olofsson 8t Ringheim 1983). Hemorrhagic stroke is less common in the newborn; although venous infarction due to sinus throm¬ bosis is well recognized it is less frequently seen at autopsy than cerebral artery occlusion. The causes of neonatal stroke fall into three groups: embolization, thrombosis and ischemia (Mannino H Trauner 1983). Embolic causes are the most commonly reported

(Barmada et al 1979) and twin-to-twin transfusion as well as congenital heart disease are well recognized (Benders et al 2007). Emboli arising from a patent ductus arteriosus or the placenta (Cocker et al 1965) have also been reported. Temporal artery catheterization has been related to ipsilateral cerebral infarction (Bull et al 1980), and disseminated intravascular coagulation and sepsis have also been associ¬ ated with the development of thrombotic arterial infarction. Clancy et al (1985) reported that asphyxia and polycythemia were additional important predisposing factors, and described 459

SECTION

IV

HEMORRHAGIC AND ISCHEMIC LESIONS

one infant who had sustained severe and prolonged hyper¬ tension before the stroke. In some reports, infarction of watershed areas between cerebral artery vascular distributions are included with descriptions of single artery infarction (Mercuri Et Cowan 1999). These watershed infarctions are most probably due to severe partial intermittent asphyxia, which is discussed in detail in Chapter 26, and are probably best considered separately from single vessel infarction. Maternal cocaine abuse has also been considered to cause stroke (Chasnoff et al 1986, Dominguez et al 1991, Hoyme et al 1990, Volpe 1992). In a study of 43 women who abused crack cocaine during pregnancy, 17°/o of their infants had evidence of cortical infarction (stroke) compared with only 2% of the matched control group (Heier et al 1991). Others have emphasized the association with coagulation abnormalities (decreased levels of protein C, protein S and antithrombin III and elevated levels of homocysteine and Lp(a), protein Z) as well as certain genetic mutations and polymorphisms (such as factor V Leiden G1691 A, factor IIG20210A and methylenetetrahydrofolate reductase C677T) have been identified as possible risk factors (Debus et al 1988, Gunther et al 2000, Kurnik et al 2003, Thorarensen et al 1997, Varelas et al 1998). Association with elevated maternal cardiolipin and antiphospholipid antibodies has also been occasionally reported (Akanli et al 1998, de Klerk et al 1997, Silver et al 1992). More recently population based studies, using case matched controls have been looking at etiological factors responsible for PAS in term infants and these were noted to be diverse. A few reports found several maternal, pre- and perinatal risk factors to be independently associated with the development of PAS (Golomb et al 2001, Lee et al 2005). Infertility, pre-eclampsia, prolonged rupture of mem¬ branes and chorioamnionitis were recently identified as independent maternal risk factors (Lee et al 2005). Neonatal risk factors, such as congenital heart disease, infection, dehydration, polycythemia, prothrombotic factors and others, have also been found to be associated with PAS (Kurnik et al 2003, Nelson ft Lynch 2004). PAS was found to be more common in boys in a recent study by Golomb et al (2004). Arterial dissection should be especially considered when more than one arterial territory is affected and has been reported in a minority of the infants (Lequin et al 2004). Adverse perinatal events were present in 11 of the 24 infants studied by Mercuri et al (1999). However, none of these had a pH < 7.0 and only 5 infants had a 1 min Apgar score below 5. Other studies also did not find significant perinatal asphyxia among their cases (Jan et al 1998, Levy et al 1985, Perlman et al 1994). A more recent study by Ramaswamy et al (2004) found only six cases with neonatal stroke among 124 infants admitted with neonatal encephalopathy. The majority of the children reported are born at or near term age. It has however been our experience that 460

focal infarction also occurs in the preterm infant (Amato et al 1990, Barmada et al 1979, Benders et al 2007, de Vries et al 1988d), but is then often a chance finding on routine ultrasound imaging (Abels et al 2006, de Vries et al 1997). Using case matched controls (3 controls per case, matched for GA) we have looked at etiological factors responsible for PAS in our preterm infants and noted these to be different from those born at term. TTTS (19°/o vs 3«/o; OR 31.2 (Cl 2.9-340.0), P = 0.005), fetal heart rate abnormality (58% vs 26%; OR 5,2 (Cl 1.5-17.6), P - 0.008) and hypoglycemia (42% vs. 18%; OR 3,9 (Cl 1.2 — 12.6), P = 0.02) were identified as independent risk factors for preterm PAS. Involvement of the main branch was less common in the preterm population, who more often present with cortical infarction or infarction of one or more lenticulostriate branches of the middle cerebral artery.

Diagnosis Acute onset of seizures is the most common presenting feature. Billard et al (1982) reported the onset of seizures between 8 and 60 hours after birth in all 8 of their cases, and seizures occurred in 10 out of 11 reported by Clancy et al (1985). In the 16 infants studied by Mercuri et al (1995), 6 presented with seizures occurring within the first 24 hours and 8 between 24 and 48 hours. In the largest group of infants reported so far (Kurnik et al 2003), 156 (73%) of the 215 infants presented with focal seizures and a further 4% with generalized seizures. Hypotonia (10%) and apneas (13%) were the other most common presenting symptoms. Apneas were more common in 2 small studies. Three of the 18 infants reported by Fujimoto et al (1992) and 5 out of 16 studied by Mercuri et al (1995) presented with apneas, requiring a short period of mechanical ventila¬ tion in some. Among full-term infants presenting with sei¬ zures, cerebral infarction is recognized to be the second most common cause (Estan Et Hope 1997) with hypoxicischemic encephalopathy being the most common one. The convulsions are usually of the focal clonic variety, but multifocal tonic or subtle seizures may all be seen. Many of the infants show no major clinical neurologic abnormal¬ ity between seizures. In most studies, treatment with only phenobarbitone was sufficient, but among the 7 infants reported by Filipek et al (1987), 5 required more than one drug to control the seizures. In an infant who presents with hemiconvulsions, the diagnosis of PAS is most likely and always warrants MR imaging also when cranial ultrasound is considered normal. Presentation with clinical seizures is less common in preterm infants. Only 2 of the 17 preterm infants studied by de Vries et al (1997) did have clinical seizures. In our more recent study of 31 preterm infants, 8 presented with apneas/seizures. Routine cranial ultrasound will usually lead to the diagnosis in this age group (Benders et al 2007). Infants with middle cerebral artery infarction may show asymmetry or hypotonia on early neurologic examination,

CHAPTER

Cerebral ischemic lesions

but Mercuri et al (1999) did not find these early neurologic abnormalities to be predictive of an adverse neurologic outcome. Infants with posterior cerebral artery infarction may develop abnormal eye signs, which later can be shown to be due to homonymous hemianopia. In the infants with ‘presumed perinatal stroke’ presenta¬ tion is usually with a hand preference at an age of 2 months or above (Lee et al 2005).

Imaging Ultrasonography Diagnosis by ultrasound is possible, but this modality is not always reliable. If hemorrhagic infarction is present the focal increased echodensity is obvious, but Hill et al (1983) have reported increased echoes from non-hemorrhagic infarcted areas. Sometimes, extensive stroke may show none or rela¬ tively subtle changes on ultrasound and especially smaller superficially located cortical infarcts will be missed. A wedge-shaped increase in echogenicity tends to become more apparent by the end of the first week (Cowan et al 2005, Golomb et al 2003) (Fig. 21.21a). Hernanz-Schulman et al (1988) noted the absence of gyral definition, absence of vascular pulsations, altered parenchymal echogenicity and territorial distribution as characteristic sonographic findings. Absence of arterial pulsations were also noted by Messer et al (1991) and Perlman et al (1994). Taylor (1994) however, studied 8 infants using color Doppler sonography and noted an increase in size and number of visible vessels in the periphery of the infarct, and increased mean blood flow velocity in vessels supplying or draining the infarcted areas in 4 infants. A diminished vessel size number was found in one case. Repeat studies showed the development of multiple small irregular blood vessels in the periphery of the infarct in two cases. Although ultrasound may not always detect cerebral artery infarction in its early stages, it may be useful later when the honeycomb cystic lesions have developed. At this stage some ex vacuo dilatation of the ipsilateral ventricle can also be noted.

Computerized tomography As the lesion extends into the cortex, its full extent can be better identified using CT or MRI (Fig. 21.20b). CT is of more value than ultrasound in establishing the diagnosis, but a normal scan within 48 hours of birth does not exclude this condition and with easier access to MRI in most neo¬ natal centres, the latter technique is a better option. At least two CT scans over 1 week are necessary before the condi¬ tion can be excluded. The classic appearance is a wedgeshaped area of low attenuation with irregular margins. If bleeding occurs into the infarcted region, areas of high attenuation may be seen on CT scan examination. A mass effect may be seen due to severe edema surrounding the infarcted area. Rescanning some months later shows full¬ thickness loss of cerebral tissue in the same distribution. Thalamic atrophy can also be found later during the first

21

year and is regarded to be due to retrograde degeneration (Giroud et al 1995).

Magnetic resonance imaging The more widespread use of MRI has been especially useful in the diagnosis of focal infarction, but some hours at least must pass before conventional MR images can show abnor¬ mality after an acute stroke event (Mercuri ft Cowan 1999). At a very early stage (24-48 hours), when CT scans or even conventional MRI may fail to detect a focal infarction, dif¬ fusion-weighted imaging does identify the lesion within hours after its onset. In diffusion-weighted MRI (DWI), image contrast depends mainly on differences in the molec¬ ular motion of water rather than changes in T1 or T2. Increases in Tl or T2 appear later and probably require the presence of vasogenic edema. Cowan et al (1994) were the first to use this technique in neonatal infarction and showed that the diffusion-weighted changes were most marked on the initial scan, at a stage that the changes were not or less clearly seen on conventional MRI. Even when only conven¬ tional MR sequences are used, more anatomical detail is obtained compared with ultrasound or CT. Mercuri et al (1995) reported on 16 infants with neonatal seizures who had early MRI, of whom 10 had evidence of focal infarction. Although the lesion was also identified using ultrasound in 9, MRI provided much better anatomical definition of the extent of the lesions. Focal white matter hemorrhages were found in a further 4 cases and only 2 infants presenting with seizures did not show any abnormalities on MRI. Similar data were reported by Rollins et al (1994). A repeat scan can show thalamic atrophy (Giroud et al 1995) and asymmetry at the level of the mesencephalon, which can be seen as early as 6 weeks after the onset (Bouza et al 1994). Smith and Baumann (1991) found ipsilateral atrophy of the pons or midbrain to be strongly associated with congenital lesions. These changes are referred to as wallerian degenera¬ tion due to transaxonal neuronal degeneration. Using DWI during the first week after onset of PAS may show ‘pre-wallerian degeneration,’ seen as abnormal signal intensity descending into the corticospinal tracts. Abnormal signal intensity of the cerebral peduncles was noted to be a strong predictor of subsequent development of wallerian degenera¬ tion and hemiplegia (de Vries et al 2005, Kirton et al 2007). Using MRI in preterm infants with unilateral thalamic echo¬ genicities, de Vries et al (1997) identified areas of focal infarction, which looked very similar to lacunar infarcts in children and adults (Fig. 21.22). These lesions occur follow¬ ing occlusion or spasm of one or more of the lenticulostriate branches of the middle cerebral artery. Performing MRI enables us to perform proton spectro¬ scopy and MR angiography (MRA) during the same session. Groenendaal et al (1995) described three infants with a middle cerebral artery and one with a posterior cerebral artery infarction. Lactate resonances were present and con¬ fined to the area of infarction in the two infants who were scanned within the first two weeks of life and in one of 461

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HEMORRHAGIC AND ISCHEMIC LESIONS

them lactate was still present on a repeat scan at 3 months of age. All four showed a decrease in IV-acetyl aspartate to choline ratios in the area of infarction. MRA can sometimes show a decreased flow in the middle cerebral artery on the affected side (Fig. 21.23) which can resolve and be no longer present on a follow-up scan suggesting transient vasospasm. Koelfen et al (1993) performed MRA on 8 infants with a middle cerebral artery infarct aged 1.5-8.4 years. MRA studies still showed abnormalities corresponding to the expected vascular distribution of the parenchymal lesion. MRA was normal in one case and showed a hypoplastic middle cerebral artery main stem with or without visible flow in the secondary branches in the other 7 infants.

Radionuclide brain scanning This technique is no longer being used in diagnosing cere¬ bral artery infarction. It has in the past been shown that yemitting technetium is retained only in areas of damaged blood-brain barrier and thus will delineate the area of vas¬ cular damage (Fig. 21.24). O’Brien et al (1979) performed technetium scans on 85 asphyxiated full-term infants and found uptake in the region of the middle cerebral artery in 20°/o of cases.

Cerebral arteriography This is a highly invasive procedure in infancy and unneces¬ sary in most cases (Roodhooft et al 1987), especially now that MRA has become more widely available. Less invasive digital intravenous angiography has been used in the diag¬ nosis of neonatal occlusive vascular disease (Voorhies et al 1984). Contrast medium is injected via an umbilical venous catheter that has been advanced to lie near the right atrium. This technique, although relatively safe, is probably not necessary, as surgical treatment to remove an embolus is not feasible.

Electroencephalography EEG has also been used in the diagnosis of neonatal stroke (Billard et al 1982, Clancy et al 1985, Levy et al 1985, Mantovani 8t Gerber 1984, Mercuri et al 1999). This investigation revealed focal abnormalities in almost all patients. These

(a) 462

(b)

included persistent localized voltage reduction, focal slowing, sharp waves and focal seizure activity. Mercuri et al (1999) found an abnormal background pattern, even when only recorded on two channels, to be the best predictor of adverse neurologic outcome.

PROGNOSIS The outlook in most cases is relatively good. Spastic hemi¬ plegia is the most important sequel, particularly following infarction of the main branch of the middle cerebral artery. Two-thirds of children with hemiplegia, however, are of normal intelligence. Flomonymous hemianopia may follow posterior cerebral artery infarction. Outcome is very much dependent on the threshold to perform MRI and on the artery involved and whether the main branch is involved or only a cortical branch or one of the lenticulostriate branches, de Vries et al (1997) and Benders et al (2007) noted that involvement of the lenticulostriate branches was more common in preterm infants. Only 3 out of 16 infants with involvement of a cortical branch or one or more lenticulo¬ striate branches developed cerebral palsy in contrast to all 5 survivors with main branch involvement. Govaert et al (2000) suggested that cranial ultrasound was important in the prediction of hemiplegia. In the parasagittal view atten¬ tion should be paid to involvement of the central groove, which is usually present in those with involvement of the main branch and those with involvement of the anterior trunk of the middle cerebral artery. Published follow-up data from case reports suggest that over half of all infants surviv¬ ing neonatal stroke are entirely normal at 12-18 months of age. Trauner and Mannino (1986) found that 8 out of 10 infants with neonatal cerebral infarction were normal at 2-5 years. The two children in whom neurologic deficits were found were only mildly affected. In a later study, the same group (Wulfeck et al 1991) reported that a hemiplegia ini¬ tially noted in 11 out of 14 cases had resolved in 5 of these 11 cases by 2 years of age. A subsequent study by the same group (Trauner et al 1993) noted some degree of hemiparesis in 21 of their 29 cases, but a very favorable prognosis in terms of intellectual outcome. Seizures were a common

Figure 21.22 Cranial ultrasound, coronal views, showing (a) a giant lacunar infarction, seen as a wedge shaped echogemc area at the level of the caudate nucleus and the striate on dayl with (b) associated periventricular echogenicity in a more posterior coronal view, in a monozygous twin, following the death of the co-twin at 35 weeks,

CHAPTER

Cerebral ischemic lesions

21

(c) Figure 21.23 Middle cerebral artery infarction in a full-term infant, (a) MRI. a T2 weighted SE sequence, performed on day 7, shows increased signal intensity in the distribution of the right middle cerebral artery, (b) MR angiography, performed during the same examination. A difference in signal intensity is seen between the right and left middle cerebral artery, suggestive of decreased flow on the right side, (c) A repeat MRI at 8 years shows an area of large cavitation on the axial FLAIR sequence (left) and also loss of white matter on the coronal inversion recovery sequence.

Figure 21.24 Radionuclide technetium scan of an infant with middle cerebral artery infarction. There is retention of radionuclide tracer in the region supplied by the left middle cerebral artery on (A) coronal and (B) sagittal planes.

complication and occurred beyond the neonatal period in 52°/o of their infants. In the study of Fujimoto et al (1992) only 5 of the 28 infants (28%) developed hemiplegia and 11 of the 16 infants studied by Sran and Baumann (1988) were also making apparently normal developmental progress. In the cohort studied by Mercuri et al (1999) only 5 of the 24 infants (20%) developed a hemiplegia. A further 2 had mild asym¬ metry and 2 had mild global delay. Only those cases with involvement of the hemisphere, basal ganglia as well the internal capsule on their first scan tended to develop a hemiplegia or an asymmetry of tone. The same group of infant was assessed again at school age (Mercuri et al 2004). The number of infants with a hemiplegia had slightly 463

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IV

HEMORRHAGIC AND ISCHEMIC LESIONS

increased to 30°/o and a further 7 (30°/o) showed some neu¬ romotor abnormality such as asymmetry on the neurologic examination (n = 4) or poor scores on the neuromotor test without any sign of asymmetry (n = 3). The remaining 9 children had a normal motor outcome. Hemiplegia was found only in children who had concomitant involvement of hemisphere, internal capsule, and basal ganglia on brain MRI. Children with involvement of the internal capsule, associated either with basal ganglia or hemispheric lesions, did not show hemiplegia but still had motor difficulties. In another report that assessed visual function, sequential studies were performed on 12 babies with focal infarction (Mercuri et al 1996). A relatively high incidence of abnor¬ malities was reported on at least one of their battery of tests. Goodman and Graham (1996) noted that half of all chil¬ dren with hemiplegia have psychiatric disorders including problems with behavior, emotions or relationships severe enough to interfere with the child’s everyday life. They usually present with irritability, anxiety and hyperactivity/ inattention. Evidence of modified organization was shown by Lewine et al (1994) combining magnetoencephalography and MRI in an adult who had suffered a left-sided middle cerebral artery infarction as a neonate. More recently several impor¬ tant studies have been performed, combining transcranial

magnetic stimulation (TMS), functional MRI and DTI (Guzetta et al 2007, Seghier et al 2005, Staudt et al 2006). Patients with congenital unilateral brain lesions may reorganize their primary motor function in the contralesional hemisphere as a result of the preservation of ipsilateral corticospinal pro¬ jections, normally withdrawn within the first year after birth (Eyre 2003, Staudt et al 2002, 2004). Staudt et al (2004) showed that when a lesion abolishes the normal contralat¬ eral corticospinal control over the paretic hand, the contra¬ lesional hemisphere develops (or maintains) fast-conducting ipsilateral corticospinal pathways to the paretic hand. This reorganization with ipsilateral corticospinal tracts can mediate a useful hand function. Normal hand function however, seemed only possible with preserved crossed cor¬ ticospinal projections from the contralateral hemisphere. Guzzetta et al (2007) also recently suggested that ipsilesional reorganization is more effective in the restoration of a good motor function as opposed to the contralesional reorganization. In summary and based on the estimated incidence of perinatal cerebral vascular infarction, it might be expected that this condition is the cause of the neurologic deficit in up to 20% of children with cerebral palsy (Levene 1987). This is further supported by recent data by Wu et al (2006) who noted that 22% of 377 infants with cerebral palsy showed focal arterial infarction on head imaging.

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Arthur R 2006 Magnetic resonance imaging in preterm infants. Pediatr Radiol 36:593-607. Aso K. Scher M, Barmada M A1990 Cerebral infarcts and seizures in the neonate. J Child Neurol 5:224-228. Aziz K, Vickar D B, Sauve R S et al 1995 Province-based study of neurologic disability of children weighing 500 through 1249 grams at birth in relation to neonatal cerebral ultrasound findings. Pediatrics 95:837-844. Baarsma R. Laurini R N. Baerts W, Okken A1987 Reliability of sonography in non-haemorrhagic periventricular leukomalacia. Pediatric Radiology 17:189-191. Back 5 A 2006 Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms. Ment Retard Dev Disabil Res Rev 12(2):129—140Back S A. Gan X. Li Y, Rosenberg P A, Volpe J J 1998 Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci 18:6241-6253. Back S A. Luo N L. Mallinson R A et al 2005 Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Ann Neurol 58(1):108—120. Baerts W. Fetter W P F. HopW CJ etal1990 Cerebral lesions in preterm infants after tocolytic indomethacin. Dev Med Child Neurol 32:910—918. Baetmann M. KahnT. Lenard H-G. VoitT1996 Fetal CNS damage after exposure to maternal trauma during pregnancy. Acta Paediatr 85:1331-1338.

Banker B Q, Larroche J-C 1962 Periventricular leukomalacia of infancy: a form of neonatal anoxic encephalopathy. Arch Neurol 7:386-410. Barmada M A, Moossy J. Shuman R M 1979 Cerebral infarcts with arterial occlusion in neonates. Ann Neurol 6:495-502. Barth P G 1984 Prenatal clastic encephalopathies. Clin Neurol Neurosurg 86:65-75. Baud 0, d'AllestA-M, Lacaze-MasmonteilT etal 1998b The early diagnosis of periventricular leukomalacia in premature infants with positive Rolandic sharp waves on serial electroencephalography. J Pediatr 132:813-817. Baud 0. Emilie D. Pelletier E et al 1999a Amniotic fluid concentrations of interleukin-1 beta, interleukin6 and TNF-alpha in chorioamnionitis before 32 weeks of gestation: histological associations and neonatal outcome. Br J Obstet Gynaecol 10672-77. Baud 0. Foix-L'Helias L, Kaminski M et al 1999b Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N EnglJ Med 341:1190-1196. Baud 0. Ville Y. Zupan V et at 1998a Are neonatal brain lesions due to intrauterine infection related to mode of delivery? BrJ Obstet Gynecol 105:121-124. Bejar R, Vigliocco G. Gramajo H et al 1990 Antenatal origin of neurologic damage in newborn infants. II. Multiple gestations. Am J Obstet Gynecol 162:1230-1236. Bejar R. Wozniak P. Allard M et al 1988 Antenatal origin of neurologic damage in newborn infants. I. Preterm infants. Am J Obstet Gynecol 159:357-363.

CHAPTER

Cerebral ischemic lesions

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abnormalities in newborn infants. Clin Radiol 56:647-655. Chow P P. Morgan J G. Taylor K J W1985 Neonatal periventricular leukomalacia: a real-time

21

Dammann 0, Leviton A 1997a Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 42:1-8. Dammann 0. Leviton A 1997b Duration of transient

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Cioni G, Di Paco M C, Bertucelli B et al 1997a MRI

Med Child Neurol 39:2-5. Dammann 0. Leviton A1998 Infection remote from the

neurodevelopmental outcome in low-birth weight,

findings and sensorimotor development in infants

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Coley B D. Hogan M J 1997 Cystic periventricular leukomalacia of the corpus callosum. Pediatr Radiol 27:583-585. Connell J A. Oozeer R C, Regev R et al 1987 Continuous 4 channel EEG monitoring in the evaluation of echodense ultrasound lesions and cystic leukomalacia. Arch Dis Child 62:1019-1024. Cools F, Offringa M 1999 Meta-analysis of elective high frequency ventilation in preterm infants with

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respiratory distress syndrome. Arch Dis Child 80:

short term outcome in infants weighing 16 mmol/L and pH < 7.0) do not develop encepha¬ lopathy, while conversely encephalopathy can still occur, although at low frequency, in association with relatively 472

modest acidosis (Low 1997). These data contrast with the presence of (very) non-reassuring fetal heart rate tracings and severe metabolic acidosis in those infants who do develop neonatal encephalopathy (Westgate et al 1999).

CHARACTERISTICS OF PERINATAL ASPHYXIAL ENCEPHALOPATHY Perinatal asphyxial encephalopathy has a number of distinct characteristics that limit extrapolation from studies of the neonatal or adult brain. First, the etiology of the insult is generally global, affecting the whole fetus. Thus the fetal systemic and cardiovascular responses are critical to under¬ standing the pathogenesis of injury. Second, the insult is generally reversible, whether spontaneously or therapeuti¬ cally (e.g. delivery and resuscitation) and so can be associ¬ ated with an evolving pattern of cerebral dysfunction and delayed injury after the insult. Third, although the injury may be a single acute episode, it is commonly due to repeated insults. Fourth, many of the insults occur in the stable and warmer thermal environment of the uterus. Finally, the maturity of the brain has a considerable effect on how neurons and glia respond to asphyxia. It is now understood that the fetal response to asphyxia is not stereotypical, but rather depends upon both the nature of the insult and the condition of the fetus (Fig. 22.1). In fact, it appears that the fetus is spectacularly good at defend¬ ing itself against such insults, and injury occurs only in a very narrow window between intact survival and death. This chapter focuses on recent developments in our understand¬ ing of the factors that determine whether the brain is damaged after an asphyxial insult. We will review the sys¬ temic adaptations of the fetus to asphyxia, the underlying cellular mechanisms of cerebral damage and the factors modulating neuronal death.

SYSTEMIC AND CARDIOVASCULAR ADAPTATION TO ASPHYXIA The systemic adaptations of the fetus to whole body asphyxia are critical to outcome. Although the focus of most of the classic studies in this area was to delineate the cardiovas¬ cular and cerebrovascular responses, more recently the rela¬ tionship between particular patterns of asphyxia and neural outcome has been examined, as summarized in Table 22.1. The great majority of studies of the pathophysiology of asphyxia have been performed in the chronically instru¬ mented fetal sheep, studied in utero.

CHAPTER

Pathophysiology of asphyxia

22

Figure 22.1 Flow diagram of the determinants of cerebral injury after perinatal asphyxia.

ADAPTATIONS TO FETAL LIFE The fetus is highly adapted to intrauterine conditions, which include low partial pressures of oxygen and relatively limited supply of other substrates compared with postnatal life. The fetus cannot store oxygen and is wholly dependent on a steady supply, but the fetus normally exists with a surplus of oxygen relative to its metabolic needs. This surplus pro¬ vides a significant margin of safety when oxygen delivery is impaired. For the fetus hypoxia is perhaps the greatest challenge to its wellbeing in utero and consequently the fetus has several adaptive features, some unique to the fetus, which help it to defend itself from injury. These adaptive features include: higher blood flow to organs; left shift of the oxygen dissociation curve which increases the capacity to carry oxygen and oxygen extraction at typical oxygen tensions; the capacity to significantly reduce energy¬ consuming processes; greater anaerobic capacity in many tissues, and the capacity to redistribute blood flow towards essential organs away from the periphery. During hypoxia the fetus can maintain normal oxygen consumption until oxygen delivery is reduced by half. Additional structural features of the fetal circulation also augment these adaptive features including the systems of‘shunts,’ such as the ductus arteriosus and preferential blood flow streaming in the inferior vena cava to avoid intermixing of oxygenated blood from the placenta and deoxygenated blood in the fetal venous system. These features ensure maximal oxygen delivery to essential organs such as the brain and heart. The preferential streaming patterns may be augmented during hypoxia to help maintain oxygen delivery to these organs. These adaptations work sufficiently well in the majority of cases that even the concept of ‘birth asphyxia’ itself has been controversial. However, from recent studies where cerebral function has been monitored from birth in infants with clinical evidence of birth asphyxia, it is clear that many such children did have a precipitating episode in the imme¬ diate peripartum period, with evidence of acute evolving cerebral injury (Hellstrom Westas et al 1995, Roth et al 1997, Westgate et al 1999). Follow-up of these children has shown a significant number to have long-term cognitive or func¬ tional sequelae, demonstrating that birth asphyxia is a true syndrome (Roth et al 1997).

Table 22.1 Summary of cardiovascular and cerebrovascular adaptations to asphyxia The healthy fetus has considerable aerobic and anaerobic reserves to cope with transient or mild hypoxia The fetal defenses against hypoxia depend on the type and severity of the insult, maturation and fetal wellbeing During moderate hypoxia blood flow is redirected to key organs and flow is also redirected within the brain towards the structures important for autonomic function such as the brainstem During severe asphyxia of rapid onset the adaptations are similar but more extreme. Blood flow to the brain as a whole may not be increased, but appears to be maintained so long as blood pressure is normal or raised Progression of severe asphyxia results in failure of adaptation and progressive hypotension and hypoperfusion VARIABLE DECELERATIONS Intermittent or repeated insults as seen during labor allow partial recovery and adaptation between periods of hypoxia, but eventually hypotension begins to develop during hypoxia and becomes progressively more severe The initial changes in the fetal heart rate (FHR) during acute asphyxia are reflex mediated. Thus FHR changes during variable decelerations poorly reflect the development of fetal hypotension or acidosis In previously healthy fetuses, late recovery from severe variable decelerations is seen only in a subgroup of profoundly compromised fetuses

ETIOLOGY OF ASPHYXIA Systemic fetal asphyxia may be of fetal, placental or mater¬ nal origin. Fetal causes include decreased fetal hemoglobin (e.g. hemolysis or feto-maternal hemorrhage), cord prolapse, cord compression, cord entanglements and true knots in the cord. Placental causes include placenta previa, vasa previa and placental abruption. Maternal causes include systemic hypoxia (for example anemia or hemorrhage), and reduced utero-placental blood flow due to hypotension, vasospasm accompanying hypertension and uterine hyperactivity. 473

SECTION

V

PERINATAL ASPHYXIA

Clearly, the different etiological factors lead to different patterns of asphyxia, which may be acute, chronic or acute on the background of chronic impairment. In labor, fetal asphyxia will most commonly be brief, but frequently repeated. Perfusion of the placenta has been shown to be inversely proportional to the rise in intrauterine pressure during contractions (Janbu ft Nesheim 1987). Conversely, catastrophic events such as cord prolapse or abruption will cause a single profound immediate insult. After pla¬ cental abruption fetal blood loss with volume contraction further potentiates the direct effects of hypoxia on the fetus.

HYPOXIA The response of the fetal sheep to moderate, stable hypoxia has been extensively characterized (Giussani et al 1994). Fetal isocapnic hypoxia is typically induced by reduction of maternal inspired oxygen fraction to 10°/o. In the late gesta¬ tion fetus, this is associated with an initial transient, moder¬ ate bradycardia followed by tachycardia and a rise in blood pressure (Fig. 22.2). There is an overall increase in combined ventricular output (CVO) and increased flow to essentially all organs (Giussani et al 1994, Hanson 1997). As hypoxia becomes greater there is a rapid transition in the distribution of CVO, with further increases in blood flow to vital organs, such as the brain, heart and adrenals, at the expense of peripheral organs which show a decrease in flow (Giussani et al 1994, Jensen 1996). This phenomenon is termed ‘cen¬ tralization’ of the circulation. Cerebral oxygen consumption is little changed, even if arterial oxygen content falls as low as 1 mmol/L thanks to the compensating increases in both cerebral blood flow (CBF) and oxygen extraction (Jones et al 1977, Sheldon et al 1979). Within the brain there is a greater increase in blood flow to the brainstem compared with the cerebrum, such that oxygen delivery is fully maintained to the brainstem, but not to the cerebrum (Jensen 1996). Nitric oxide (NO) has been shown to play a role in mediating the local increase in CBF (Hanson 1997). Components of these changes in fetal heart rate (FHR) and CVO are reflexly mediated and the afferent limbs are in part mediated by muscarinic (parasympathetic) pathways and by a-adrenergic stimulation (Giussani et al 1994, Hanson 1997). The adrenergic input is derived partly from the sympathetic neural system and partly by circulating catecholamines released from the adrenal medulla. The rise in blood pressure during asphyxia is at least partly mediated by increased release of vasopressors, including the catecholamines, argi¬ nine vasopressin and angiotensin II (Giussani et al 1994, Hanson 1997). There are also large adrenocorticotropic and cortisol responses to hypoxia. Their role in the cardiovascu¬ lar response to hypoxia is unclear, but cortisol has been shown to modulate the actions of other vasopressors (Tangalakis et al 1992).

474

Prolonged hypoxia The effect of prolonged hypoxemia on cerebral metabolism in near-term fetal sheep has been studied during stepwise reductions of the maternal inspired oxygen concentration from 18°/o to 10-12% over four successive days (Richardson H Booking 1998). Until the fetal arterial oxygen saturation was reduced to less than 30% of baseline, cerebral oxidative metabolism remained stable. At the lowest inspired oxygen concentration (with 3% C02) a progressive metabolic acide¬ mia was induced. Initially, CBF increased, thus maintaining cerebral oxygen delivery as seen in acute studies. Eventu¬ ally, when the pH fell below 7.00, cerebral oxygen consump¬ tion fell to less than 50% of control values. If mild-to-moderate hypoxia is continued the fetus may be able to fully adapt, as measured by normalization of FHR, blood pressure, the incidence of fetal breathing and body movements, although redistribution of blood flow is main¬ tained (Richardson ft Booking 1998) by a sustained increase in peripheral tone (Danielson et al 2005). These fetuses can improve tissue oxygen delivery to near baseline levels by increasing hemoglobin synthesis, mediated by greater eryth¬ ropoietin release (Kitanaka et al 1989). This is consistent with the clinical situation of ‘brain sparing’ in growth retardation.

Maturational changes in responses to hypoxia The cardiovascular response to fetal hypoxia appears to be age related. In the premature fetal sheep before 100 days (0.7) gestation, isocapnic hypoxia and hemorrhagic hypo¬ tension are not associated with hypertension, bradycardia or peripheral vasoconstriction. Thus it has been suggested that peripheral vasomotor control starts to develop at 0.7 gestation, coincident with maturation of neurohormonal regulators and chemoreceptor function (Hanson 1997, Jensen 1996). However, when interpreting these results it is also important to consider the degree of hypoxia in relation to the much greater anaerobic capacity of the premature fetus. This is discussed below in the section on premature fetal asphyxia. It is likely that the degree of hypoxia attained in these studies did not reduce tissue oxygen availability below the critical threshold for this developmental stage.

ASPHYXIA Studies of asphyxia by definition involve both hypoxia and hypercapnia with metabolic acidosis. The complex relation¬ ship between severity of metabolic acidosis and outcome is summarized in Table 22.1. It is important to appreciate that in these studies of asphyxia a greater depth of hypoxia is typically attained than is possible using maternal inhalational hypoxia. Further, asphyxia can be induced relatively abruptly, limiting the time available for adaptation. Brief, total clamping of the uterine artery or umbilical cord leads to a rapid reduction of fetal oxygenation within a few minutes, and this is associated with massive hemodynamic changes and rapid metabolic deterioration (Parer 1998). In

CHAPTER

Pathophysiology of asphyxia

22

Figure 22.2 The responses in the near-term fetal sheep to moderate isocapnic hypoxia for 60 minutes, induced by altering the maternal inspired gas mixture, showing changes in fetal heart rate (FHR), mean arterial blood pressure (MAP), carotid blood flow (CaBF) and carotid vascular resistance (CaVR). Moderate hypoxia is associated with a sustained redistribution of blood flow away from peripheral organs to essential organs such as the brain (see Giussam et al 1994 for review). (Data derived from Bennet et al 1998.)

contrast, gradual partial occlusion induces a slow fetal met¬ abolic deterioration without the acute fetal cardiovascular responses of bradycardia and hypertension; this is a func¬ tion of the relative hypoxia attained (de Haan et al 1993). The responses to moderate asphyxia are similar to those described above for hypoxia, with redistribution of blood flow to essential organs (Bennet et al 1998). During pro¬

found asphyxia, corresponding with a severe reduction of uterine blood flow to 25°/o or less and a fetal arterial oxygen content of less than 1 mmol/L, the cardiovascular responses of the normal fetus are substantially different. Bradycardia is sustained and there is a generalized peripheral vasocon¬ striction involving essentially all organs (Bennet et al 1998). CBF does not increase or may even fall despite initially

475

SECTION

V

PERINATAL ASPHYXIA

increased fetal blood pressure, due to significantly increased cerebral vasoconstriction. In the near-term sheep, blood flow within the brain, is preferentially redirected during asphyxia to protect structures important for survival such as the brainstem. Speculatively this redirection may maintain autonomic function at the expense of the cerebrum (Jensen 1996). Further, the reduced oxygen content limits oxygen extraction from the blood. The combination of these two factors, restricted CBF and reduced oxygen extraction, pro¬ foundly restricts cerebral oxygen consumption (Parer 1998). Partial cord compression for 90 minutes, titrated to induce severe asphyxia in near-term fetal sheep, had effects similar to those following a correspondingly severe reduction of uterine perfusion (Ikeda et al 1998). Both methods produced similar levels of asphyxia and cerebral injury (Ikeda et al 1998). Figure 22.3 shows the cardiovascular and cerebrovascu¬ lar responses of a near-term fetus to asphyxia of rapid onset. This figure demonstrates the failure of carotid blood flow (CaBF, used as an index of CBF) to increase during asphyxia in contrast to the rise seen during hypoxia (Fig. 22.2). CaBF is instead briefly maintained around control values before falling. The failure of CBF to increase is not due to hypotension but rather is a function of a significant rise in cerebral vascular resistance as demonstrated by the increase in carotid vascular resistance (Fig. 22.3) (Bennet et al 1998, Parer 1998). During asphyxia blood pressure initially increases markedly but as asphyxia proceeds the fetus becomes hypotensive (Fig. 22.3). The sustained bra¬ dycardia and increased peripheral resistance in the late gestation fetus during asphyxia are mediated by chemoreflexes; a logarithmic rise in circulating catecholamine levels further augments the peripheral vasoconstriction (Hanson 1997). Hypotension is primarily related to asphyxial impairment of myocardial contractility, due to a direct inhibitoiy effect of profound acidosis and depletion of myocardial glycogen stores (Rosen et al 1986). Once gly¬ cogen is depleted, there is rapid loss of high energy metabolites such as ATP in mitochondria (Shelley 1961). During a shorter episode, e.g. 5 min of asphyxia, the fetus may not become hypotensive. If the insult is repeated before myocardial glycogen can be replenished, successive periods of asphyxia will be associated with increasing duration of hypotension. Another possible factor leading to impaired contractility during asphyxia is myocardial injury, which has been found after severe birth asphyxia and with congenital heart disease in limited case series (Donnelly 1987). Studies in adult animals have shown that there may be a signifi¬ cant delay in recovery of cardiac contractility after reper¬ fusion from brief ischemia in the absence of necrosis. This delayed recovery has been termed ‘myocardial stunning,’ and this may contribute to progressive myocardial dys¬ function and to delayed recovery of heart rate after repeated umbilical cord occlusions in the fetal lamb (Gunn et al 2000). 476

Progressive asphyxia During gradually induced asphyxia, even to arterial oxygen contents of less than 1 mmol/L, fetal adaptation may be closer to that seen with hypoxia. Progressive reduction of uterine perfusion over a 3-4 h period in near-term fetal sheep led to a mean pH < 7.00, serum lactate levels >14 mM, with a fetal mortality of 53°/o. Surviving animals remained normotensive and normoglycemic and CBF was more than doubled. Interestingly however, in surviving fetuses neuro¬ nal damage was limited to selective loss of the very large, metabolically active cerebellar Purkinje cells (De Haan et al 1993).

Brief repeated asphyxia In normal human labor, uterine contractions are relatively brief (typically less than one or two minutes). Total umbilical cord occlusions have been studied in fetal lambs near-term at frequencies consistent with active labor, either 1 min out of every 2.5 min or 2 min out of every 5 min, continued for many hours until fetal hypotension (7.10) (Mallard et al 1992). 485

SECTION

V

PERINATAL ASPHYXIA

PATHOPHYSIOLOGIC DETERMINANTS OF ASPHYXIAL INJURY Recent studies using well defined experimental paradigms of asphyxia in the near-term fetal sheep have explored the relationship between the distribution of neuronal damage and the type of insult. These studies suggest that the key factor precipitating and localizing injury is local cerebral hypoperfusion due to hypotension. In addition, a number of factors modify the impact of asphyxia on the brain, includ¬ ing the pattern of repetition of insults as well as fetal factors such as gestational age, pre-existing metabolic state and cerebral temperature (see Fig. 22.1 and Table 22.4).

HYPOTENSION AND THE ‘WATERSHED’ DISTRIBUTION OF NEURONAL LOSS The development of hypotension appears to be the critical factor precipitating neural injury after acute insults. This is readily understood as reduced perfusion will reduce the supply of glucose for anaerobic metabolism, compounding the reduction of oxygen delivery and content. The real life importance of hypotension is supported by both the pattern of neural damage, and the correlation of injury with arterial blood pressure across multiple paradigms.

Table 22.4 Summary of the determinants of acute asphyxial neural injury Cerebral perfusion is linearly compromised by hypotension during asphyxia. The combination of reduced perfusion with hypoxia (i.e. hypoxia-ischemia) not only further reduces the amount of oxygen delivered to the brain but also compounds this by reducing the supply of glucose for anaerobic metabolism. This commonly leads to a 'watershed' distribution of injury Increased spacing between relatively prolonged episodes of ischemia or asphyxia is associated with a relative increase in striatal injury The brain matures from caudal to rostral. Thus, in the premature brain the cortex is relatively immature, particularly in the superficial layers, and is less susceptible to hypoxic-ischemic injury than subcortical white and gray matter The dominant neuropathologic correlate of handicap in surviving premature infants is the distinctive white matter lesion, periventricular leukomalacia (PVL), which occurs before oligodendrocyte maturation, and is strongly associated with evidence of maternal infection, with a fetal systemic inflammatory response and with exposure to asphyxia (p. 19) Environmental conditions during recovery from asphyxia can critically affect outcome. Experimentally, moderate cerebral hypothermia initiated in the latent phase and continued until resolution of secondary changes can dramatically reduce neural injury

486

The close relationship between changes in CaBF and blood pressure during asphyxia is shown by Figures 22.3-22.5. In these fetuses, mean arterial blood pressure (MAP) initially rose with intense peripheral vasoconstriction. At this time CaBF was maintained. As cord occlusion was continued MAP eventually fell, probably as a function of impaired cardiac contractility and failure of peripheral redistribution. When MAP fell below baseline, carotid blood flow fell in parallel. It appeared that there was a small window during which flow was maintained as pressure was falling (Fig. 22.5), suggesting that autoregulation was intact. This is consistent with the normal relatively narrow range of fetal cerebrovasculature autoregulation (Parer 1998). In the term fetus, neural injury has been commonly reported in areas such as the parasagittal cortex, the dorsal horn of the hippocampus and the cerebellar neocortex after a range of insults including pure ischemia, prolonged single complete umbilical cord occlusion, prolonged partial asphyxia and repeated brief cord occlusion (Figs 22.9, left panel and 22.10) (de Flaan 1993, 1997b, Gunn et al 1992, 1997, Mallard et al 1992). These areas are ‘watershed’ zones within the borders between major cerebral arteries, where perfusion pressure is least, and, clinically, lesions in these areas in adults and children are typically seen after systemic hypotension (Torvik 1984). Some data suggest that limited or localized white or gray matter injury may occur even when significant hypotension is not seen (de Haan et al 1993, Ikeda et al 1998), particu¬ larly when hypoxia is very prolonged (Rees et al 1998). Clearly there may have been some relative hypoperfusion in these studies. Nevertheless, there is a strong correlation between either the depth or duration of hypotension and the amount of neuronal loss within individual studies of acute asphyxia (de Haan et al 1997b, 1997c, Gunn et al 1992, Ikeda et al 1998). This is also seen between similar paradigms causing severe fetal acidosis that have been manipulated to either cause fetal hypotension (Gunn et al 1992, Ikeda et al 1998) or not (de Haan et al 1993). In fetal lambs exposed to prolonged severe partial asphyxia, as judged by the degree of metabolic compromise, neuronal loss occurred only in those in whom one or more episodes of acute hypotension occurred (Ikeda et al 1998). In contrast, in a similar study where an equally ‘severe’ insult was induced gradually and titrated to main¬ tain normal or elevated blood pressure throughout the insult, no neuronal loss was seen outside the cerebellum (de Haan et al 1993).

PATTERN OF INJURY: REPEATED INSULTS The one apparent exception to a general tendency to a ‘watershed’ distribution after global asphyxial insults nearterm is the selective neuronal loss in striatal nuclei (putamen and caudate nucleus; Fig. 22.10, right panel) which is seen when relatively prolonged periods of asphyxia or ischemia are repeated (de Haan et al 1997c, Mallard et al 1993). Whereas 30 minutes of continuous cerebral ischemia leads

CHAPTER

Pathophysiology of asphyxia

1 to 2 min repeated cord occlusions

4x5 min cord occlusions

22

100 4

1

I

n

10 min x 3 1 h apart

n H -1-1-1-1-1-1-r

10

30

50

70

% Neuronal loss

Figure 22.10 The distribution of neuronallossassessed after3 days recovery from two different patterns of prenatal asphyxia in near-term fetal sheep. The left panel shows the effects of brief (1 or 2 min) cord occlusions repeated at frequencies consistent with established labor. Occlusions were terminated after a variable time, when the fetal blood pressure fell below 20 mmHg fortwo successive occlusions.This insult led to damage in the watershed regions of the parasagittal cortex and cerebellum (de Haan etal 1997b). The right hand panel shows the effect of five minute episodes of cord occlusion, repeated fourtimes, at intervals of 30 minutes.This paradigm is associated with selective neuronal loss in the putamen and caudate nucleus, which are nuclei of the striatum. CA1/2 and the dentate gyrus are regions of the hippocampus. Mean ± 5D. (Data derived from de Haan et al 1997c.) to predominantly parasagittal cortical neuronal loss, with only moderate striatal injury, when the insult was divided into three separate episodes of ischemia, a greater proportion of striatal injury was seen relative to cortical neuronal loss (Figs 22.9 and 22.11) (Mallard et al 1993). Intriguing'ly, sig¬ nificant striatal involvement was also seen after prolonged partial asphyxia in which distinct episodes of bradycardia and hypotension occurred (Gunn et al 1992). It is thus likely that the pathogenesis of striatal involve¬ ment in the near-term fetus is related to the precise timing of episodic asphyxia and not to more severe local hypoper¬ fusion, since the striatum is not in a watershed zone but rather within the territory of the middle cerebral artery. The vulnerability of the medium sized neurons of the striatum to this type of insult may be related to a greater release of glutamate into the striatal extracellular space after repeated insults compared with a single insult of the same cumulative duration. Consistent with this speculation, immunohistochemical techniques have shown that inhibitory striatal neurons were primarily lost (Mallard et al 1995).

10 min x 3 5 h apart

30 min single insult

Figure 22.11 The effects of different intervals between insults on the distribution of cerebral damage after ischemia in the near-term fetal sheep. Cerebral ischemia was induced by carotid occlusion for 10 minutes and repeated three times, at intervals of either 1 h or 5 h, compared with a single continuous episode of 30 minutes occlusion. The divided insults were associated with a preponderance of striatal injury, whereas a single episode of 30 minutes of carotid occlusion was associated with severe cortical neuronal loss. Increasing the interval to 5 h nearly completely abolished cortical injury, but was still associated with significant neuronal loss in the striatum. Light bars are results for striatum and dark bars are those for parasagittal cortex. (Data derived from Mallard etal 1993.)

PREMATURE BRAIN INJURY: THE EFFECT OF MATURATION Surprisingly little work has been done to resolve the effect of maturation on sensitivity to injury. This is of critical importance, for two reasons. First, in recent years improve¬ ments in obstetric and pediatric management have resulted in significantly increased survival of preterm infants from 24 weeks of gestation, with an associated increase in later handicap (Kiely ft Susser 1992). Second, many infants may sustain neural injuries well before birth, including a signifi¬ cant number of infants with cerebral palsy (Stanley 1992) (see also Chapters 18 and 46). The characteristic patterns of cerebral injury in the preterm fetus differ from those seen at term or after birth. Key features include preferential injury of subcortical structures and white matter.

Cortical resistance to injury Clinical imaging data suggest that profound asphyxia before 32 weeks gestation is associated with injury to subcortical structures, particularly the diencephalon (including the thal¬ amus), basal ganglia and brainstem (Barkovich ft Sargent 1995). In contrast, overt cortical injury is uncommon. This is consistent with the patterns observed in infants with cerebral palsy of prenatal origin who show predominantly diencephalic lesions, variably associated with periventricu¬ lar leukomalacia (PVL), cortical or subcortical lesions and ventricular dilatation (Volpe 1995). Similarly, fetal sheep at 0.6 to 0.7 gestation (96 to 102 days), maturations compara487

SECTION

V

PERINATAL ASPHYXIA

ble to the 26 to 32 week gestation human fetus, show the same pattern of damage to the periventricular white matter and subcortical gray matter, with sparing of the cortex (Bennet et al 2007b, George et al 2004). This difference is consistent with the normal caudal to rostral pattern of myelination and anatomical maturation, and the much greater anaerobic reserves and lower overall cerebral aerobic requirements of preterm fetuses compared with term (Gunn et al 2001). This is an area requiring con¬ siderably greater attention.

Pathogenesis of white matter injury In the very low birth weight infant the distinctive white matter lesion, PVL, is the major pathologic associate of later developmental handicap. Key factors that have been identi¬ fied include vascular development, the intrinsic vulnerability of the oligodendrocyte to neurotoxic factors and exposure to maternal/chorionic membrane infection. PVL characteristi¬ cally occurs in areas that represent arterial end zones or border zones (Perlman 1998). Prolonged hypoperfusion owing to hypotension, or associated with hypocapnia, potentially exposes these areas to greater ischemia, as discussed above. The immaturity of oligodendrocyte precursors is clearly critical, as the period of greatest risk for PVL is before myelination has begun, at a time when oligodendrocyte pre¬ cursors are actively proliferating and differentiating. Such actively differentiating cells have an increased metabolic demand and are sensitive to substrate limitation. It has been suggested that developing oligodendroglia are very sensitive to the excitatory neurotransmitter glutamate and to free radical toxicity because of a developmental lack of antioxi¬ dant enzymes to mediate oxidative stress (Back et al 2007). Finally, compelling evidence has recently linked prenatal inflammation or infection to later cerebral palsy (Nelson et al 1998). Exposure to maternal or placental infection is associated both with increased risk of preterm birth and also with brain lesions predictive of cerebral palsy (Dammann ft Leviton 1997). It is likely that the effect of infection is medi¬ ated by systemic inflammation since fetal plasma interleukin levels including interleukins 1, 8, 9, TNF-a and the inter¬ ferons are strongly and independently associated with PVL (Nelson et al 1998) (see also Chapter 21).

Intraventricular hemorrhage (IVH) and white matter injury The pathogenesis of these disorders is discussed in detail in Chapters 19 and 21. IVF1 with extension into the periven¬ tricular regions is also associated with adverse outcome. The white matter injury appears to be a venous infarction with hemorrhage occurring as a secondary phenomenon. Further, there is evidence of prolonged loss of cerebrovascular auto¬ regulation post-asphyxia which may leave the fetal brain vulnerable to factors causing fluctuations in blood pressure and thus CBF; this is proposed to be a key mechanism in the pathogenesis of IVH. Other factors that may contribute to rVH include the fragility of immature germinal matrix capillaries, deficient vascular support and a limited vasodi-

488

latory capacity impairing perfusion during asphyxia. In this regard, the antenatal administration of glucocorticoids has been associated with a significant reduction in the sono¬ graphic incidence of severe IVH and the associated white matter involvement (p. 405).

PRE-EXISTING METABOLIC STATUS AND CHRONIC HYPOXIA While the original studies of factors influencing the degree and distribution of brain injury, primarily by Myers (Myers 1977), focused on metabolic status, the issue remains contro¬ versial. It has been suggested, for example, that hyperglyce¬ mia is protective against hypoxia-ischemia in the infant rat (Vannucci et al 1997) but not in the piglet (LeBlanc et al 1993). The extreme differences between these neonatal species in the degree of neural maturation and activity of cerebral glucose transporters may underlie the different outcomes (Vannucci et al 1997). The most common metabolic distur¬ bance to the fetus is intrauterine growth retardation associ¬ ated with placental dysfunction. Although there is reasonable clinical information that this condition is usually associated with a greater risk of brain injury, recent studies have sug¬ gested a marked fall in the rate of encephalopathy in growth restricted babies over time (Westg'ate et al 1999). This would suggest that the apparently increased sensitivity to injury is mostly due to reduced aerobic reserves, leading to early onset of systemic compromise during labor (Westgate et al 2005). Neural maturation is markedly altered in intrauterine growth retardation with some aspects delayed and others advanced (Cook et al 1988, Stanley et al 1989). This is likely to influence the response to asphyxia but also to introduce a confounding independent effect on neural development. Severe growth retardation has been associated with altered neurotransmitter expression, reduced cerebral myelination, altered synaptogenesis and smaller brain size (Kramer et al 1990). The effect of the timing and severity of placental restriction has been examined in a range of studies in fetal sheep (Rees et al 1998). Chronic mild growth retardation due to peri-conceptual placental restriction was associated with delayed formation of neuronal connections in the hippo¬ campus, cerebellum and visual cortex, but did not alter neuronal migration or numbers. In contrast, in studies in the near mid-gestation fetus, hypoxia induced by a variety of methods was associated with a reduction in numbers of Purkinje cells in the cerebellum and delayed development of neural processes. With more severe hypoxia the cortex and hippocampus were also affected and there was reduced subcortical myelination. The cerebellum develops later in gestation than the hippocampus, and thus appears to be more susceptible to the effects of chronic hypoxia (Rees et al 1998). Intriguingly, a recent study suggested that rat pups with moderate growth restriction showed reduced white matter injury after an excitotoxic insult, whereas those with severe growth restriction had increased damage, pointing to a complex balance between protective and sensitizing effects of placental restriction (Olivier et al 2007).

CHAPTER

Pathophysiology of asphyxia

CEREBRAL TEMPERATURE There is now good evidence from a range of species and paradigms that small, clinically relevant changes in postischemic cerebral temperature can critically modulate encephalopathic processes that are initiated during hypoxiaischemic insults, and which extend into the secondary phase of neuronal loss (Gunn 2000). Conversely, prolonged mild hyperthermia during the secondary phase increases injury. The role of therapeutic hypothermia in neonatal brain pro¬ tection is discussed on page 569. While asphyxia may not be preventable, experimental data make it clear that cerebral injury is an evolving process, which can be modified by numerous external factors such as blood pressure management, infection and temperature.

22

This means that the opportunity exists to provide effective treatment for asphyxia. However, considerable research still needs to be done to refine our understanding of the mecha¬ nisms of injury and to develop appropriate therapeutic strat¬ egies for different clinical situations, including the very premature infant.

ACKNOWLEDGMENTS The authors’ work reported in this review has been supported by grants from the Health Research Council of New Zealand, the March of Dimes Birth Defects Trust, the Lottery Health Board of New Zealand and the Auckland Medical Research Foundation.

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SECTION V

CHAPTER

23

PERINATAL ASPHYXIA

Antenatal prediction of asphyxia K. A. Sorem, James F. Smith and Maurice L. Druzin

Key Points • Perinatal asphyxia is a hypoxic-ischemic insult that may occur antepartum, intrapartum or after birth • Perinatal asphyxia was thought to be associated with brain damage and cerebral palsy, yet it is unlikely to be the cause for cerebral palsy •

• • • • •

unless the severity of the asphyxial insult is nearly lethal Recent analysis of cerebral palsy and birth asphyxia indicates that only 10% of cases of cerebral palsy (1-2 per 10 000) were associated with birth asphyxia Fetal asphyxia occurs as a result of absent or insufficient placental blood flow due to acute or chronic events The terms 'perinatal asphyxia' and 'hypoxic-ischemic injury' imply a specific cause and effect which may be difficult to determine clinically Hypoxic-ischemic damage begins during the injury (impaired placental exchange) and extends into the period of resuscitation or reperfusion Although meconium may indicate that fetal stress has occurred, it does not predict fetal neurological impairment Later evidence for hypoxic-ischemic brain injury in the neonate is available from a variety of imaging modalities, including computed tomography (CT). single photon emission computed tomography (SPECT). magnetic resonance imaging (MRI). positron emission

tomography (PET) and cranial sonography • Fetal wellbeing is currently evaluated using several antepartum tests including the non-stress test, contraction stress test, ultrasonographic evaluation of the fetal biophysical state and fetal Doppler ultrasound • Significant advances in obstetrical and neonatal care have contributed to the observed decline in perinatal morbidity and mortality over the last half-century

INTRODUCTION Perinatal asphyxia is a hypoxic-ischemic insult that may occur antepartum, intrapartum or after birth. Historically, perinatal asphyxia was thought to be associated with brain damage and cerebral palsy (Little 1862), yet it is unlikely to be the cause of cerebral palsy unless the asphyxial insult is near lethal (Winkler et al 1991). Recent analysis of cerebral palsy and birth asphyxia indicates that only 10°/o of cases of cerebral palsy (1-2 per 10000) were associated with birth asphyxia (Nelson ft Ellenberg 1986). Conversely, 2% of newborns have ‘asphyxial exposure,’ and the majority of these recover without neurologic sequelae (Low 1993). While improvements in perinatal and neonatal care have resulted in an overall reduction of morbidity and mortality, long¬ term studies investigating cerebral palsy show the incidence of this significant condition to have remained largely unchanged in the last 50 years (Low 2004). Nevertheless, asphyxial brain injury remains a significant cause of peri¬

natal morbidity and mortality, and continues to contribute to the incidence of cerebral palsy (Bracci et al 2006). Iden¬ tification of the fetus at risk for asphyxia remains a clinical challenge.

DEFINITION OF PERINATAL ASPHYXIA A task force of the World Federation of Neurology Group has defined asphyxia as a condition of impaired gas exchange which, if it persists, leads to progressive hypercapnia and hypoxemia (Bax 8t Nelson 1993). Fetal asphyxia occurs as a result of absent or insufficient placental blood flow due to acute or chronic events. These include umbilical cord occlusion, altered placental gas exchange (placental abrup¬ tion, insufficiency or previa), inadequate perfusion of the maternal side of the placenta (maternal hypotension, vaso¬ spasm or abnormal contractions) and impaired maternal oxygenation (severe anemia, cardiac or pulmonary disease). Newborn asphyxia may result from cardio-respiratory com¬ plications after delivery, including respiratory distress syndrome, apnea and birth trauma. Hypoxic-ischemia is defined as tissue damage resulting from inadequate oxygen and substrate delivery. If blood flow and oxygenation are restored, the tissue damage is minimal; however, with pro¬ longed asphyxia irreversible cell loss may occur. The terms ‘perinatal asphyxia’ and ‘hypoxic-ischemic injury’ imply a specific cause and effect which may be dif¬ ficult to determine clinically. Furthermore, the terms ‘fetal distress’ and ‘birth asphyxia,’ which have been common in the medical vernacular, are non-specific and imprecise. Spe¬ cific criteria to define an acute intrapartum hypoxic event sufficient to cause cerebral palsy have been promoted and include: (1) profound umbilical artery metabolic or mixed acidemia (pH < 7.00), (2) persistence of an Apgar score of 0-3 for longer than 5 minutes, (3) neonatal neurologic sequelae, (4) multi-organ system dysfunction, e.g. cardio¬ vascular, gastrointestinal, hematologic, pulmonary or renal (ACOG 1996 and ACOG 2005). Complete assessment of the neonate at risk for neurologic sequelae includes evaluation of CNS dysfunction, including seizures, abnormal respiration, altered activity states (such as hyperalertness or somnolence), impaired reflexes (such as suck and gag), abnormal ocular responses or a bulging anterior fontanelle. Additionally, abnormal EEGs may be observed in newborns with hypoxic-ischemic encephalopa¬ thy. Clinical features of neonatal hypoxic-ischemic ence¬ phalopathy are shown in Table 23.1 (Carter et al 1993). 491

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disruption of sodium, chloride, calcium and cellular water. Cytotoxic edema evolves. Free fatty acids accumulate as membrane phospholipids break down and undergo peroxi¬ dation by oxygen free-radicals. Glutamate is generated from axon terminals, along with nitric oxide, both of which may be directly toxic to adjacent neuronal cells. Cell death may follow due to the effects of acidosis, energy failure and lipid peroxidation (Vannucci Ft Palmer 1997, Vannucci Ft Perlman 1997). Furthermore, depletion of growth factors and inflam¬ matory cells may lead to extensive cellular damage within

Although multiple organ systems may be affected by hypoxic-ischemic injury, including cardiovascular, respira¬ tory, renal, metabolic, gastrointestinal and hematologic, only CNS involvement has residual sequelae at long term follow-up (Shankaran et al 1991). One clinical classification of intrapartum fetal asphyxia described by Low is shown in Table 23.2.

PATHOPHYSIOLOGY OF PERINATAL ASPHYXIA

the CNS (Gluckman Ft Williams 1992). Following prolonged hypoxic-ischemic injury, some cells within the CNS may not recover function, resulting in regional or global infarction. In adults and experimental animals, the therapeutic window of intervention and recov¬ ery is longer than that of the fetus and newborn because the process of cellular destruction is much more rapid in the perinatal period (Vannucci Ft Palmer 1997). In the human fetus and neonate, the therapeutic window is estimated to be less than 2 hours (Vannucci Ft Perlman 1997). Infant laboratory primates subjected to hypoxic-ischemic injury demonstrate distinct patterns of CNS damage, depend¬ ing on the nature of the asphyxial insult. Brief total asphyxia damages subcortical nuclei in the thalamus and brainstem, whereas prolonged partial asphyxia damages cerebral white matter, beginning in parasagittal areas (Meyers 1975). Pasternak reported a study of 11 term human infants who sustained an acute near total intrauterine asphyxia and demonstrated a similar pattern of brain damage, depending on the magnitude and timing of the hypoxic-ischemic insult. On postnatal MRI, acute near total asphyxia appeared to damage the thalamus, brainstem and basal ganglia, presumably because of the relatively high basal metabolic rate, whereas subacute partial asphyxia led to damage primarily in the cerebral hemispheres owing to shunting of blood to the brainstem and cerebellum (Pasternak Ft Gorey 1998). After brief episodes of asphyxia, restoration of blood flow may lead to re-oxygenation and end organ survival. However, reperfusion of ischemic brain tissue after a severe insult may deliver harmful reactive oxygen metabolites causing further tissue damage. In addition to damaging the cell directly, reactive oxygen metabolites delivered by reperfusion also promote the expression of adhesion molecules on endothelial or parenchymal cells. This leads to accumula¬ tion of neutrophils that cause necrosis of cortical brain cells

Hypoxic-ischemic damage begins during the injury (impaired placental exchange) and extends into the period of resus¬ citation or reperfusion. At the biochemical level, cellular injury within the CNS initiates a cascade of molecular events which leads to accumulation of excitatory amino acids, increased intracellular calcium and increased free radical production (Delivoria-Papadapoulos Ft Mishra 1998). Oxida¬ tive metabolism is replaced by anaerobic metabolism, result¬ ing in the accumulation of nicotinamide-adenine dinucleotide (NADH), flavin-adenine dinucleotide (FADH) and lactic acid. ATP is depleted as glycolysis fails to keep up with cellular demands, and transcellular ionic pumps fail, leading to the

Table 23.1 Clinical features of neonatal hypoxicischemic encephalopathy Time after birth

Clinical features

(hours) 12-24

Hyperalertness; hyper-excitability; seizures; apnea; jitteriness; weakness

24-72

Obtundation or coma; ataxic respirations with respiratory arrest; abnormal oculomotor reflexes; impaired papillary response; intracranial hemorrhage (premature neonates) with subsequent deterioration

>72

Persistent stupor; abnormal or absent sucking, swallowing, and gag reflexes; generalized hypotonia; weakness

Source: Modified from Volpe J J 1987 Hypoxic ischemic encephalopathy: clinical aspects. In: Neurology of the newborn, 2nd edn. WB Saunders. Phila¬ delphia. PA. p. 236. with permission.

Table 23.2 Classification of intrapartum fetal asphyxia Asphyxia

Metabolic acidosis at delivery

Encephalopathy

Cardiovascular, respiratory, or renal complication

Mild

+

+

±

Moderate

+

++

+

Severe

+

-H-+

-H-+

Source: Modified from Low J A1997 Intrapartum fetal asphyxia: definition, diagnosis, and classification. Am J Obstet Gynecol 176:957-959, with permission.

492

CHAPTER

Antenatal prediction of asphyxia

or delayed neuronal death through apoptosis. Pathologic evidence of cellular damage includes cell shrinkage, mem¬ brane blebbing, chromatin concentration and DNA fragmen¬ tation (Tominaga et al 1993). Therefore, it appears that cell damage occurs during both the ischemic and reperfusion phase of an asphyxial insult (Fellman ft Raivio 1991). After a severe asphyxial event, neonates often enter a phase of neurologic depression characterized by suppressed EEG and abnormal activity level. Oxygen free-radicals may induce prolonged cerebral hypoperfusion, reducing cerebral metabolism, protein synthesis and electrical activity (Leffler et al 1989). Post-asphyxial seizures in the neonate lasting more than 30 minutes are associated with poor neurologic outcome and cerebral infarction (Mellits et al 1982, Williams et al 1992). Seizures that are primarily multifocal clonic type may add additional insult to the injured brain by increasing metabolic demands on cortical cells.

FETAL RESPONSE TO ASPHYXIA

(seealso ch.22)

A fetal asphyxial insult may vary from hypoxia (decreased oxygenation) to anoxia (absent oxygenation). The fetus may not tolerate complete anoxia for more than 10 minutes, and survivors of complete total cord occlusion generally show multiple cerebral lesions, primarily in the brain stem. Through physiologic compensatory mechanisms, experi¬ mental fetal sheep have been shown to be capable of surviv¬ ing an 80°/o decrease in cerebral oxygen uptake (Field et al 1991), indicating that the healthy fetus may tolerate even extreme hypoxia. Conversely, fetal sheep exposed to long term hypoxic stress by restricted umbilical cord blood flow demonstrate elevated nitric oxide activity and diminished cardiovascular defense to acute hypoxia (Gardner et al 2002). During a hypoxic event, blood flow is reduced to the pulmonary, renal and splanchnic areas with preferential perfusion of the heart, brain and adrenal glands (Peeters et al 1979). Furthermore, recent regional blood flow studies in fetal sheep using radioactive microspheres confirm that perfusion of the myocardium appears to be preferentially preserved over the cerebral cortex following episodes of hypoxic stress (Ley et al 2004). Within the brain, hypoxia leads to preferential blood flow to the brain stem, with decreased blood flow to white matter and the cerebral cortex. Blood oxygen level dependent signal intensity by magnetic resonance imaging appears to decrease more prominently in the fetal sheep cerebellum, compared to the cerebrum, during induced hypoxia, suggesting that the cerebellum may be more prone to effects of hypoxic stress (Wedegartner et al 2005). Experimental evidence suggests that fetal compensa¬ tory mechanisms may allow intact survival following hypoxia in the normal fetus, but chronic hypoxic stress may diminish adequate compensatory response. The fetal cerebral cortex, cerebellum, brainstem and myocardium appear to have differing responses and tolerance to hypoxic insult. The relevance of these experimental findings to the human fetus and its responses remains to be elucidated.

23

The fetal heart rate response to hypoxia has been inten¬ sively investigated experimentally and in the human fetus for many years. One fetal response to hypoxia, bradycardia, results from chemoreceptor stimulation of the vagus nerve. Increased sympathetic activity and peripheral vasoconstric¬ tion increase fetal blood pressure and maintain bradycardia (Hanson 1988). In addition to CNS regulation of fetal heart rate via sympathetic and parasympathetic neurons, cate¬ cholamines released from the adrenal glands directly depress the myocardium, leading to late cardiac decelerations ob¬ served on fetal heart rate monitoring. Although anaerobic glycolysis and the accumulation of pyruvate and lactate lead ultimately to metabolic acidosis, brain injury appears to be associated more strongly with fetal hypotension than with the degree of hypoxia or acidosis (De Haan et al 1997, Mallard et al 1992). Loss of fetal heart rate variability may accompany fetal hypoxia (Paul et al 1975) as well as other conditions that indicate CNS depression, such as drug expo¬ sure and structural CNS anomalies. In a 10-year study of antepartum fetal heart rate monitoring, Ayodeji and Kuhn reported that 19°/o of fetuses with ‘critical reserve patterns’ (late decelerations and loss of variability) had major struc¬ tural malformations, suggesting that some fetuses may have inappropriate responses to hypoxia based on pre-existing CNS abnormalities (Ayodeji £t Kuhn 1986). Genetics may also influence the fetal response to asphyxia, as demon¬ strated in animal models, which show that factors that mediate the response to induced hypoxia are genetically determined (Labudova et al 1999). Recently, complete cord occlusion for 20 versus 30 minutes was compared in fetal sheep (George et al 2004). In the 20-minute group, an increase in heart rate variability in the first 5 minutes after occlusion, followed by a decrease in variability for the remainder of the occlusion, was noted. The decrease in vari¬ ability gradually resolved over 4 hours, with return to base¬ line and normal EEG patterns and movements. However, in the last 10 minutes of occlusion in the 30-minute group, increased variability in the heart rate was noted associated with abnormal atrial activity. After reperfusion, abnormal EEG findings and associated abnormal fetal movements were noted and persisted, and decreased variability remained. Histologic exam at 72 hours demonstrated severe brain stem injury in the 30-minute group, but not the 20-minute group. This suggests that epileptiform activity related to neural injury may confound interpretation of heart rate variability, mimicking normal recovery in the presence of profound injury. Changes in fetal activity include decreased gross body movements and cessation of fetal breathing (Vintzileos et al 1991). Koos et al demonstrated in studies on fetal sheep that decrease in fetal breathing movements is evident after a decrease in fetal P02 of 6 mmHg (Koos et al 1987). This effect appears to be gestational age-dependent, with imma¬ ture fetuses exhibiting less hypoxic inhibition than fetuses close to term. The biochemical mechanisms of the hypoxic inhibition of fetal breathing movements may result from 493

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Neuron

changing brain stem concentrations of adenosine, which may be mediated by local levels of prostaglandin E2 (Kitterman et al 1983). Both the severity and duration of hypoxia contribute to the effect on fetal breathing move¬ ments, as well as to the decreased eye movements and gross body movements observed with hypoxemia.

MARKERS FOR PERINATAL ASPHYXIA Fetal meconium in the amniotic fluid is a relatively common finding in labor, occurring in 18°/o of deliveries. Although meconium may indicate that fetal stress has occurred, it does not predict neurologic impairment in the normal term fetus (Nelson 8t Ellenberg 1984). Prior to the widespread use of electronic fetal monitoring, the Collaborative Perinatal Study (1966) reported that 64°/o of the cases of amniotic fluid meconium were attributable to chorioamnionitis and only 0.2°/o to recognized intrapartum hypoxemic disorders (Anonymous 1966). Katz and Bowes suggest that among some fetuses with asphyxial exposure, it is the underlying asphyxia, rather than the observed meconium, that is respon¬ sible for the pulmonary pathology (Katz ft Bowes 1992). However, the phenomenon of meconium aspiration syn¬ drome in neonates born by Cesarean section in the absence of known adverse antepartum or intrapartum events indi¬ cates that meconium may also have direct effects on pul¬ monary vasculature. In vitro studies have demonstrated that macrophages may transport meconium directly from the amniotic fluid into the umbilical cord (Altschuler et al 1992), where it stimulates the release of vasoconstrictors within the placenta and fetus. Whether the vasoconstrictive effect of meconium contributes to damage within vulnerable cerebral vessels is speculative. In one study of 43 children with 494

Figure 23.1 Reperfusion injury and neuronal damage following hypoxic insult. Reactive oxygen metabolites generated by endothelial and parenchymal cells lead to celt necrosis and end organ damage. NGF, nerve growth factor; BDNF, brain derived neurotrophic factor: TGF. transforming growth factor; PAF. platelet¬ activating factor; 0N00*. peroxymtrite. (From Fellman V. Raivio K1997 Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. Pediatr Res 41:600. with permission.)

spastic quadriplegia, staining of the amniotic fluid was the only identified risk factor for cerebral palsy. Although all of the children had neuroimaging studies which identified lesions consistent with the type of severe brain damage produced by hypoxic-ischemia, not all of the newborns had abnormal umbilical artery pH or elevated base deficit (Naeye 1995) . Amnioinfusion, initially thought to protect against meconium aspiration sequelae by ‘dilution’ of meconium, has recently been shown to be ineffective in reducing injury related to the presence of meconium (Fraser et al 2005). This further suggests that although meconium may be associated with hypoxic stress, its presence in the amniotic fluid merely indicates a fetus at risk for the potentially damaging physi¬ ologic responses, and not direct toxicity from the material itself. Apgar scores, long used to quantify clinical depression in the first minutes of life (Apgar 1953), reflect several vari¬ ables including gestational age, muscular disorders, CNS abnormalities, cardiorespiratory problems and maternal medication, in addition to antepartum or intrapartum hypoxia. Whereas moderately and briefly low Apgar scores are not related to subsequent neurologic outcome, severely low, late and very late Apgar scores are much better predic¬ tors of cerebral palsy. Although a 5-minute Apgar score of 0-3 is associated with a slight increased risk of cerebral palsy in term infants, the increase is from 0.3% to 1% (ACOG 1996) . However, if such a score is associated with a 10-min Apgar of 4 or greater, there is a 99% chance of normal development. A 10-min Apgar score that does not improve (0-3) may indicate persistent hypoperfusion or hypoxia and is associated with a 16.7% risk of cerebral palsy (Freeman Et Nelson 1988). A score of 0-3 at 20 minutes after delivery is associated with a 59% mortality rate and cerebral palsy in 57% of survivors (Nelson Et Ellenberg 1981).

CHAPTER

Antenatal prediction of asphyxia

BPS 2/10. normal fluid

Oligohydramnios

23

BPS < 4

Figure 23.2 Schematic representation of the mechanisms by which the fetal response to hypoxic insult may affect the biophysical score. The fetal responses may vary with acute versus chronic hypoxia and will be affected by the duration, seventy, rate of onset and repetitive frequency of the insult. CNS, central nervous system; IUGR. intrauterine growth restriction: FBM, fetal breathing movements; FM. fetal movement; NR-NST, non-reactive non-stress test; AFV, amniotic fluid volume; BPS. biophysical profile score. (From Tsang FI H, Manning F A Biophysical profile scoring. In: Druzin M L (ed.) Antepartum fetal assessment. Blackwell Scientific, Boston, MA. p. 33, with permission.)

Evaluation of the acid-base status of the fetus and neonate has improved identification of newborns at risk for neuro¬ logic complications associated with antepartum or intrapar¬ tum asphyxia. The normal umbilical artery pH for term newborns is 7.2 (SD ± 0.08) and the mean base deficit is 8.3 mmol/L (SD ± 4.0 mmol/L) (Skyes 8t Johnson 1982), indicating that all newborns respond to the relative hypoxia of labor with a mixed metabolic and respiratory acidosis. This is not surprising, given the repetitive interruption of uteroplacental blood flow occurring with uterine contrac¬ tions. In the normal term fetus with an intact CNS these episodes of intermittent hypoxia are well tolerated. The level of fetal acidemia that is considered pathologic or associated with increased morbidity and mortality is controversial. For such neonatal outcomes as intensive care unit admission and need for assisted ventilation, there appears to be a pro¬ gressive risk beginning with near normal values for pH and base excess and positively associated with increasing patho¬ logic values (Victory et al 2004). For more serious neonatal sequelae such as permanent neurologic damage, umbilical artery pH less than 7.0 is a better predictor (Hauth 1996), and ACOG has included an umbilical artery pH of 7.00 as a cut-off for clinically relevant acidemia in its definition of perinatal asphyxia. In a study of 3506 newborns, 87 of whom had pH less than 7.00, Goldaber suggests that the level of pathologic fetal acidemia is even lower (Goldaber

et al 1991). Factors such as prematurity, fetal growth restric¬ tion, infection, hypertension, collagen vascular diseases and prolonged pregnancy may all contribute to both a decreased tolerance to labor and a diminished fetal response. Interpretation of umbilical artery blood gases requires examination of the P02, PC02 and bicarbonate, as well as the base deficit. According to Low, a base deficit of greater than 12 to 16 (occurring in 2°/o and 0.5°/o of newborns, respectively) represents the threshold for significant meta¬ bolic acidosis (Low 1997). Others have proposed the thresh¬ old of 15 mmol/L, with a compensatory calculation for severe hypercarbia tPC02 greater than 66 mmHg), indicating a mixed respiratory and metabolic acidosis (Goldaber et al 1991). Kruger et al have reported a threshold of 4.8 mmol/L for clinically significant lactate levels in fetal scalp blood, correlating with an increased risk of hypoxic-ischemic encephalopathy (Kruger et al 1999). All of these measure¬ ments, however, reflect a cumulative fetal response and do not indicate the timing or duration of the asphyxial expo¬ sure. As with Apg'ar scores, only extremely abnormal values of pH and base deficit are associated with abnormal neuro¬ logic outcome, as 80°/o of infants with umbilical cord pH less than 7.0 at birth will have normal neurologic develop¬ ment (Goodwin et al 1992). Other markers for hypoxemia and asphyxia, such as neo¬ natal lymphocyte count, nucleated red blood cells (NRBC) 495

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PERINATAL ASPHYXIA

and urinary lactate to creatinine ratios have been investi¬ gated for their utility in determining the timing of an asphyxial event. In 1941, Anderson reported that chorionic capillaries within the placentas of fetuses with intrauterine asphyxia had an increase in NRBCs (Anderson 1941). Phelan and Korst subsequently observed that an NRBC count greater than 10 per 100 white blood cells was significantly higher in infants who were neurologically impaired as a result of hypoxic-ischemia (Korst et al 1996, Phelan et al 1995). In one study of 46 neurologically impaired infants, lower NRBC counts were observed in intrapartum asphyxial events closer to the birth than those with presumed asphyxial events more remote from delivery. Infants whose identified hypoxemic events were uterine ruptures had lower numbers of NRBCs than those whose asphyxial exposures were described by abnormal fetal heart rate tracings (non-reactive EFM trac¬ ings or tachycardia) (Phelan et al 1995). In Naeye’s study of 16 neonates with hypoxic-ischemic encephalopathy, lym¬ phocyte counts of greater than 10000/mm3 were signifi¬ cantly higher than those observed in control groups consisting of infants with low Apgar scores and without cerebral palsy. Elevated lymphocyte counts in the affected neonates were also observed compared with infants with cerebral palsy from developmental delays unrelated to ante¬ partum and intrapartum events (Naeye 8t Localio 1995). Other biomarkers for neonatal brain injury have been investigated. In a report of 40 newborns with asphyxial exposure and 58 control infants, Huang et al reported a significantly elevated urinary lactate to creatinine ratio in infants with hypoxic exposure who developed encephalopa¬ thy (16.75), compared with both normal infants (0.09) and infants with asphyxial exposure who did not develop encephalopathy (0.19) (Huang et al 1999). Rapid measures for serum lactate exist (studies on cord blood following adverse perinatal events were carried out by Bracci et al (2006)). Non-protein-bound iron appears to be a reliable marker for brain injury (Buonocore et al 2003). The contri¬ bution of the inflammatory response to the development of neurologic injury is further supported by elevations of inflammatory protein mediators found in the cord blood of infants subsequently diagnosed with cerebral palsy (Kaukola et al 2004). Astroglial calcium binding protein S100, which is a marker for brain injury in adults, has been investigated in preterm and term neonates with and without brain injury, and may be a useful marker (Bracci 2006). Activin A, a protein produced by the placenta, decidua and fetal membranes, increases in response to hypoxia, and cor¬ relates with other markers and biochemical features of peri¬ natal hypoxia (Bracci 2006). Important in all of the investigations of biochemical markers is timing of injury in the human fetus, which is largely determined by history and clinical assessments. Because of the high number of false positive rates of any abnormal findings on fetal heart rate monitoring, and the impossibility of excluding antenatal causes, the exact timing of subcatastrophic asphyxial events in human studies cannot be accurately determined. This 496

limits the clinical application of assessments of NRBCs, neo¬ natal lymphocytes and other biomarkers of perinatal asphyxia. Because of advances in potential therapies for infants exposed to hypoxic-ischemic events (Palmer ft Vannucci 1993), rec¬ ognition of neonates at risk and understanding the timing of the insult remain critical clinical research goals.

NEUROIMAGING AND PERINATAL HYPOXICISCHEMIC BRAIN INJURY (see also Ch. 6) Later evidence for hypoxic-ischemic brain injury in the neonate is available from a variety of imaging modalities, including computed tomography (CT), single photon emis¬ sion computed tomography (SPECT), magnetic resonance imaging (MRI), positron emission tomography (PET) and cranial sonography. Recent advances in the application and accessibility of fetal MRI have led to increasing use of this modality in many aspects of fetal medicine, including the potential diagnosis of congenital and acquired brain lesions. Protocols have been developed that help systematize the application of fetal MRI (Prayer et al 2004), and several reports now describe normal embryonic and fetal neurode¬ velopment as assessed by fetal MRI (Grossman et al 2006, Prayer et al 2006, Rados et al 2006). One case of in utero fetal cerebral intra-parenchymal ischemia diagnosed by MRI has been reported in a severely growth restricted fetus (Sibony et al 1998). MRI has been used to assess fetal brain injury related to abnormal pregnancies presumably compli¬ cated by chronic stress (Borowska-Matwiejczuk K et al 2003), and in hypoxic and infectious insults (Girard et al 2003). In term infants with neuroimaging abnormalities follow¬ ing asphyxial events, the ischemic injury results in diffuse infarctions in the parasagittal cortex and parieto-occipital cortex. Thromboembolic multifocal infarcts, thalamic, and basal ganglia infarcts and middle cerebral artery infarcts may also be observed. In one study of 11 infants who suf¬ fered acute near-total intrauterine asphyxia, imaging studies reported a consistent pattern of injury in the subcortical brain nuclei with relative sparing of the white matter. Seven of the 11 infants with hypoxic-ischemic encephalopathy and this pattern of brain injury had good cognitive out¬ comes; however, long-term neurologic deficits included spastic quadriplegia, mild cerebral palsy, deafness, behav¬ ioral abnormalities and dystonia. Although 10 of the 11 patients did not have significant multiorgan system failure, the one infant who died in the neonatal period had evidence of hepatic abnormality (Pasternak H Gorey 1998). In another study of 20 term infants with moderate-to-severe hypoxicischemic encephalopathy, decreased tissue attenuation in the central gray matter (thalami and basal ganglia) was observed in the absence of cortical changes. This pattern of injury indicated an extremely poor prognosis, with 35°/o of infants expiring in the neonatal period and the remaining survivors all affected with neurologic abnormalities includ¬ ing spastic quadriplegia, microcephaly and seizures (Roland et al 1998).

CHAPTER

Antenatal prediction of asphyxia

In preterm infants with hypoxic-ischemic encephalopa¬ thy, brain injuries usually result from hemorrhage, either in the vascular subependymal areas, within the cerebral ven¬ tricles, or within the parenchyma. Infrequently, the peri¬ ventricular white matter region is affected bilaterally and periventricular leukomalacia (PVL) results. The specific pattern of perinatal CNS damage in the preterm infant is demonstrated primarily in the deep strata of the cerebellum, germinal tissue, periventricular white matter and basal ganglia, in contrast to mainly cortical damage in the term infant. This distinction is influenced by three gestational age-dependent factors: (1) presence or absence of germinal matrix tissue, (2) the underlying process of CNS organogen¬ esis and (3) the degree of development of neurovasculature (Towbin 1986). Neurodevelopmental prognoses among preterm infants with asphyxial exposure and abnormal neu¬ roimaging studies vary widely, with factors such as infection and developmental immaturity contributing to possible CNS damage from asphyxial exposure. Neuropathologic studies confirm the findings of neuroim¬ aging and have shown that both the gray matter and the white matter of the brain may undergo necrosis as a result of lethal hypoxic-ischemia. In one post-mortem study of 120 perinatal deaths attributed to perinatal asphyxia, CNS necrosis was observed in 16 infants, including lesions that occurred in the antepartum period as well as intrapartum (Low et al 1989). In the first half of pregnancy, ischemic CNS insults may lead to porencephalic cysts, multicystic encephalomalacia and hydrencephaly. In this study of term infants, two infants with antenatal hypoxic-ischemia had evidence of PVL. In five infants remote from term, the hypoxic-ischemic insult occurred in the 12-hour period before the onset of labor, presumably due to antepartum hemorrhage. The pattern of CNS pathology in this group showed neuronal necrosis of the cerebral cortex, and the inferior olive and dorsal nucleus of the vagus nerve of the brain stem, large germinal matrix hemorrhage and intraven¬ tricular hemorrhage. The four neonates in the intrapartum asphyxia group delivered with clinical evidence of asphyxia as well as abnormal pH and acid-base status. The observed neuropathology in the intrapartum asphyxia group included extensive neuronal necrosis of the basal ganglia and thala¬ mus, with limited necrosis in the cerebellar cortex and brain stem. In summary, establishing the temporal relationship between an asphyxial event and the associated findings on neuroimaging and neuropathology is difficult and imprecise. Term and preterm infants exhibit different patterns of brain injuiy after asphyxial events, and the pattern associated with asphyxial injury remote from delivery may occasion¬ ally be distinct. Neonates who expire of sudden cardiorespi¬ ratory failure as a result of catastrophic asphyxia may not demonstrate any neuropathologic findings because of rapid demise. Furthermore, as mentioned earlier, findings consis¬ tent with an acute intrapartum event do not rule out pre¬ existing subclinical subacute lesions that may enhance fetal

23

susceptibility to the intermittent hypoxia of normal and abnormal labors. Nevertheless, MRI remains a promising tool in understanding of perinatal brain injury, and likely will see an expanding role in this area in the future (Gressens ft Luton 2004).

ANTEPARTUM ASPHYXIA In the United States, perinatal mortality, which includes late fetal deaths (after 28 weeks) as well as early neonatal deaths (less than 6 days of life), has been declining steadily since 1965, reaching 8.7 per 1000 in 1991 and 7.3 per 1000 in 1997 (CDC 1998, US Department of Health and Human Services 1995). Antepartum deaths may be due to a variety of causes including congenital malformations, pregnancy complications and infection, as well as to chronic or acute hypoxic-ischemia. Of the 70-90% of fetal deaths that occur prior to the onset of labor, approximately one-third are due to hypoxia (Lammer et al 1989). In contrast, intrapartum fetal deaths are primarily asphyxial, in some cases due to severe hypoxia or anoxia and in some cases due to abnormal fetal response. Reducing the rate of lethal antepartum asphyxia remains a difficult clinical task, not only because of the unpredict¬ able nature of the underlying causes but also because of the relatively long period of time over which it may occur (Grant ft Elborne 1989). Identifying subcatastrophic hypoxial insults that may lead to long-term neurologic morbidity is yet more complex. One strategy to reduce antepartum fetal deaths is to identify pregnancies that are at increased risk for decreased uteroplacental blood flow, such as those com¬ plicated by hypertension, collagen vascular diseases and diabetes, and to subject these patients to a schedule of ante¬ partum evaluation or testing. Fetuses at risk for antenatal acute and chronic asphyxia, including those with intrauter¬ ine fetal growth restriction (Soothill et al 1987) and prolonged pregnancy, may also benefit from antepartum surveillance.

ANTEPARTUM FETAL TESTING Fetal wellbeing is currently evaluated using several antepar¬ tum tests including the non-stress test, contraction stress test, ultrasonographic evaluation of the fetal biophysical state and fetal Doppler. Of the tests that involve observations of fetal heart rate by cardiotocography, the non-stress test is the most widely used. The use of the non-stress test evolved from observations of fetal heart tracings in labor as well as in experimental animal models. Whereas late decel¬ erations and loss of variability on electronic fetal monitor¬ ing (EFM) have been linked with fetal acidosis (Murata et al 1982), accelerations of the fetal heart in response to fetal activity, contractions, or external stimulation, have been associated with adequate fetal oxygenation and neurologic response. To produce a normal (reactive) fetal heart rate tracing on EFM, the fetal heart must demonstrate intact 497

SECTION

V

PERINATAL ASPHYXIA

electrical conduction pathways involving myocardial, neu¬ rologic and hormonal receptors as well as intact sympathetic and parasympathetic reflexes and normal myocardial con¬ tractility (Dalton et al 1983). The normal fetal heart baseline is between 110 and 160 bpm. The healthy term fetus demonstrates an average of 34 heart rate accelerations per hour, averaging 20 to 25 bpm above baseline and lasting up to 40 seconds (Patrick et al 1984). At term, fetal heart rate accelerations are associ¬ ated with fetal movement more than 85% of the time and more than 90% of fetal body movements are accompanied by accelerations. The association of fetal heart rate acce¬ lerations and fetal movement increases with advancing gestational age, representing neurologic maturation and integration of reflex responses and autonomic tone. The most common cause for absent fetal heart rate accel¬ erations is fetal sleep, although other factors such as mater¬ nal narcotics, CNS depressants, maternal smoking or (3-blockers may reduce fetal heart rate variability as well (Keegan et al 1979, Margulis et al 1984, Phelan 1979). Epi¬ sodes of decreased fetal movement associated with dimin¬ ished fetal heart rate variability indicate a quiet fetal sleep cycle and may last from 20 to 120 minutes in the term fetus. Active sleep cycles in the fetus occur throughout most of a 24-hour day and involve increased fetal breathing, increased fetal heart rate variability, rapid eye movements and occa¬ sional body movements. Brief periods of‘wakefulness’ occur approximately 15-20% of the day and are associated with increased gross body movements and maximal fetal heart rate variability.

NON-STRESS TEST The non-stress test (NST) is usually performed in an outpa¬ tient setting, with the patient in a reclining chair or bed with left lateral tilt to avoid supine hypotension. The fetal heart rate is monitored using the Doppler ultrasound transducer,

Table 23.3 Indications for antepartum fetal testing • Asthma • Abnormal fetal heart tones • Cardiac disease • Cholestasis of pregnancy • Chronic hypertension • Collagen vascular disease • Congenital anomalies • Decreased fetal movement • Diabetes • Fetal growth restriction • Intrauterine procedure • Multiple gestation • Oligohydramnios • Placenta previa

498

• Polyhydramnios • Poor obstetric history • Prolonged pregnancy • Pre-eclampsia • Preterm labor • Preterm premature rupture of membranes • Prior stillbirth • Renal disease • Rh disease (isoimmunization) • Sickle cell disease • Substance abuse • Third trimester bleeding • Thyroid disease

and the tocodynamometer is used to detect uterine contrac¬ tions. During the test the patient reports fetal activity, although the record of these fetal movements does not affect the interpretation of the test. As with intrapartum fetal monitoring, acute fetal hypoxemia in the antepartum period may cause profound decreases in fetal movement and heart rate accelerations. Chronic hypoxia, however, may yield a more gradual decline in fetal function and response as com¬ pensatory circulatory shunting occurs. Guidelines for interpretation of fetal heart rate (FHR) monitoring have been developed by the Research Planning Workshop for the National Institute of Child Health and Human Development (1996) (Anonymous 1997). These guidelines apply to interpretation of antepartum as well as intrapartum EFM. First, any patterns of the fetal heart rate are reported as baseline, periodic or episodic. Second, the following five components of fetal heart rate patterns must be described qualitatively and quantitatively: (1) baseline rate, (2) baseline variability, (3) presence of accelerations, (4) periodic or episodic decelerations and (5) changes or trends in fetal heart rate patterns over time. An acceleration of the fetal heart rate is defined as a visually abrupt increase in the FHR above baseline. The peak is to be greater than or equal to 15 bpm over the baseline and lasting 15 seconds or more. Prior to 32 weeks gestation, accelerations are defined as 10 bpm over baseline for duration of 10 seconds or greater. The most widely applied definition of a normal or reactive non-stress test involves two accelerations meeting the above criteria in a 20-minute period. On initial testing, 85% of NSTs will be reactive and 15% will be non-reactive (Lavery 1982). The NST is most predic¬ tive when it is normal or reactive. A reactive NST has been associated with a perinatal mortality of approximately 5 per 1000 (Phelan 1981). Although the rate of perinatal demise after a non-reactive NST is considerably higher, up to 40 per 1000, this group contains a large number of false posi¬ tive tests, as high as 75-90% (Lavery 1982). The majority of fetuses with a non-reactive NST will not suffer death or morbidity following the test; however, follow-up testing is generally indicated, whether by prolonged NST, contraction stress test or biophysical profde. Vibroacoustic stimulation (VAS) has been used to stimu¬ late the fetus that may be in a quiet sleep state. The artificial larynx, which generates a sound pressure of 82 dB measured at 1 meter of air, is the most commonly used device (Gagnon et al 1989). VAS has been shown to increase the mean dura¬ tion of heart rate accelerations, the mean amplitude of accelerations and total time spent in accelerations. FHR variability and gross body movements are also increased. Using VAS in the setting of non-reactive NSTs, the incidence of non-reactivity is reduced from 14 to 9%, and the time spent in testing is reduced. In one study by Druzin et al, the incidence of non-reactive NSTs in fetuses after 26 weeks was significantly decreased with the use of VAS (Druzin et al 1989), obviating the need for further testing to follow up a non-reactive test.

CHAPTER

Antenatal prediction of asphyxia

Significant bradycardia, defined as a fetal heart rate of less than 90 bpm or a fall in the fetal baseline more than 40 bpm (ACOG 1984, Druzin et al 1981), has been observed in l-2°/o of all NSTs. Bradycardia on NST has been associ¬ ated with increased perinatal morbidity and mortality, including intrauterine fetal demise, structural malformations and fetal growth restriction (Bourgeois et al 1984, Druzin 1989). Moreover, the incidence of abnormal intrapartum FHR tracing and subsequent Cesarean delivery is higher in those-with bradycardia on antepartum heart tracing on NST compared with those who have reactive NSTs without sig¬ nificant bradycardia. Although a non-reactive NST is also associated with an abnormal intrapartum FHR tracing and increased intervention rate, the positive predictive value of the tracing with bradycardia leading to Cesarean delivery is higher (Dashow 8t Read 1984). Because perinatal mortality rates may be as high as 25% in fetuses with spontaneous significant bradycardias, delivery is generally indicated for the term fetus, but management of the preterm fetus may be more complex. Presence or absence of variability in the setting of significant bradycardia may not be helpful in distinguishing fetuses at increased risk for perinatal hypoxia. Corticosteroid administration and conservative management may follow assessment of the amniotic fluid index and tar¬ geted ultrasound for fetal anomalies, with continuous fetal monitoring for the early preterm fetus. In high-risk pregnancies, increasing the interval of testing to twice per week can reduce the false negative rate of the NST. Boehm et al (1986) reported an overall decrease in the fetal death rate from 6.1/1000 to 1.9/1000 when twice weekly testing was used. Because the fetal death rate is increased in pregnancies with diabetes, hypertension and fetal growth restriction, these pregnancies should be moni¬ tored with twice weekly NSTs. The incidence of fetal death following a normal NST in prolonged pregnancies is not significantly increased over the general tested pregnant population (2.7/1000) (Barss et al 1981); however, the riskbenefit ratio of intervention on behalf of the term mature fetus may favor induction of labor in some cases.

CONTRACTION STRESS TEST The contraction stress test (CST), also known as the oxytocin challenge test, was the first antepartum test used for fetal surveillance. When contractions produce decreased blood flow in the intervillous spaces of the placenta, varying degrees of hypoxia may lead to signs of stress in the fetus. On FHR monitoring, the fetus with diminished placental respiratory reserve may respond to the stress of contractions with late decelerations. Interpretation of the presence or absence of late decelerations and the pattern of decelerations form the basis for interpretation of the CST. Prior to the test, which is generally performed on a labor and deliveiy suite or specialized antepartum testing unit, maternal blood pressure is monitored periodically while uterine contractions and FHR are recorded using external monitors. Oxytocin is administered by intravenous infusion,

23

beginning at 0.5 mU/min. The infusion is doubled every 15 minutes until three contractions in 10 minutes are achieved. After the CST is achieved, FHR monitoring should continue until contractions cease. As an alternative to oxytocin infu¬ sion, the nipple stimulation test may be used. Using self¬ nipple massage, over 85% of patients can achieve adequate uterine contractions for evaluation (Oki et al 1987) with no difference in the incidence of positive and negative tests compared with the CST. Absolute contraindications to the CST include premature preterm rupture of the membranes, third trimester bleeding and cervical incompetence. Relative contraindications include preterm labor, polyhydramnios, prior cesarean section and multiple gestation. Interpretation of the CST follows the definitions described by Freeman (1975). A positive (abnormal) test is defined as a 10-minute segment of the FHR tracing which includes at least three contractions, each followed by late decelerations. A negative (normal) test is one with no late decelerations after three uterine contractions. A CST with negative windows and occasional late decelerations is read as suspi¬ cious, and equivocal describes the tracing with occasional late decelerations and no negative window. A CST with both negative and positive windows is interpreted as positive. A suspicious or equivocal CST should be repeated in 24 hours, and most of these tests will become negative. Bruce et al (1978) observed that 5 of 67 patients with initial CSTs read as suspicious were subsequently positive. Although a negative CST has been consistently associated with a good outcome (perinatal mortality less than 1/1000 within 1 week of the test), the relatively high false positive rate (up to 30%) limits the utility of the test (Evertson et al 1978, Freeman et al 1982). Furthermore, Druzin et al (1980) reported that a non-reactive NST with a negative contrac¬ tion stress test did not have the same predictive accuracy as the reactive NST. Overall, the rate of perinatal death follow¬ ing a positive CST is elevated at 7-15%. Although a positive CST is an indication for delivery, it is not necessarily an indication for cesarean section, as labor may proceed safely with continuous FHR monitoring. The positive CST had been associated not only with an increased incidence of fetal death, but also with an increased incidence of perinatal morbidity as detected by low 5-minute Apgar scores, fetal growth restriction, and meconium stained amniotic fluid, intrapartum fetal distress and neonatal depression. No prospective randomized trials with sufficient numbers of risk-matched gravidas have been reported for either the CST or the NST. Evaluation of the current literature shows a wide range of testing standards and thresholds yielding a yet wider range of test sensitivity, specificity and positive predictive values. Because the positive predictive value depends on the incidence of fetal compromise in a given population, the application of these tests to low-risk patients will decrease the performance of the test. For both the NST and the CST the specificity is relatively high (>90%), with sensitivities of 45-55%. Most evaluations of the CST use perinatal mortality as a primary outcome measure with few 499

SECTION

V

PERINATAL ASPHYXIA

conclusions regarding the impact of abnormal tests on peri¬ natal morbidity and neurologic outcome. Because of the low sensitivity of these tests (i.e. high number of false positives), additional fetal testing may be performed prior to interven¬ tion (delivery), especially when the fetus is known or sus¬ pected to be immature.

BIOPHYSICAL PROFILE Fetal hypoxemia has been shown to alter biophysical activi¬ ties such as fetal breathing and movement, as well as tone and heart rate patterns. Fetal biophysical profile (BPP) scoring was therefore developed using dynamic ultrasound examination to assess the wellbeing of the fetus. Ultrasound examination of the fetus is also used to detect abnormalities of amniotic fluid, fetal size, placental location and umbilical cord insertion site. Fetal biophysical responses to asphyxia include both acute and chronic responses. The acute fetal response to hypoxia includes changes in CNS regulated activities, such as breathing and movement. Chronic responses to decreased oxygenation include low levels of amniotic fluid and restricted fetal growth. The BPP method as described by Manning et al (1985) uses real time ultrasound for scored evaluation of fetal breathing movements, fetal tone, gross body movements and amniotic fluid volume. An NST may follow the ultra¬ sound examination of the fetus. The longitudinal scan plane is used to view the fetus with simultaneous evaluation of upper and lower extremities, as well as the fetal thorax. The test continues for 30 minutes or until all the parameters have been observed. Two points are scored for each of the above variables for a maximum score of 8 out of 8. If the NST is generally performed if one of more of the other four vari¬ ables is abnormal, two points are scored for a reactive NST and the total for a normal test is then scored as 10 out of 10. All of the components are assumed to be of equal sig¬ nificance, and therefore are each assigned two points. In one analysis of 342 abnormal tests, Manning demonstrated that the distribution of score variables is almost equal among possible combinations (Manning et al 1990). According to Vintzileos et al (1983), fetal biophysical activities that appear earliest in fetal development are the last to disappear with fetal hypoxia. The fetal tone center in the cortex begins to function at approximately 8 weeks. Fetal tone, therefore, would be the last parameter to be lost with deteriorating fetal condition. The fetal movement center, which functions at approximately 9 weeks, would be more sensitive than fetal tone. Fetal breathing, which devel¬ ops at approximately 20 weeks, may be lost sooner than movement and tone. Finally, fetal heart rate reactivity, which relies on development of the posterior thalamus and medulla as well as intact CNS reflexes, may not reliably appear until the late third trimester (>28 weeks). Using this hypothesis, the BPP may be used to evaluate the preterm fetus in which FHR reactivity has not been established. Like the reactive NST, a normal BPP is highly predictive of a non-asphyxiated fetus with intact CNS responses. In 500

one prospective blinded study of 216 high-risk pregnan cies, Manning found no perinatal deaths when all five variables of the test were normal (Manning et al 1980). However, unlike the NST, several aspects of fetal response are evaluated using the BPP, and the resulting proportion of normal tests is higher (97.5%). A false negative rate of the BPP is also lower than that of the NST alone (25/1000). Similar to the NST, the use of vibroacoustic stim¬ ulation of the fetus with an abnormal or equivocal BPP has been shown to improve the biophysical score without decreasing the false negative rate (Inglis et al 1993), and shortens the testing time when applied at the beginning of an exam (Pinette et al 2005). Moreover, the scoring system for the BPP (see Table 23.4) may reveal a spectrum of fetal asphyxial response. Good obstetric management man¬ dates interpretation of the individual components as well as consideration of obstetric factors, such as gestational age, underlying fetal and maternal disease, maternal drug exposure and prematurity. According to a summary of data in eight studies of BPP for fetal evaluation, involving 23 780 patients and 54 337 tests, the overall corrected peri¬ natal mortality of the BPP was calculated at 0.726/1000 (Manning 1992). To evaluate the effect of fetal assessment by BPP on the risk of perinatal morbidity, Manning evaluated the incidence of cerebral palsy in fetuses that were evaluated by BPP compared with those who were not. In a retrospective study of 84947 live births over a 5-year period, the overall inci¬ dence of cerebral palsy was 3.68/1000. The incidence of cerebral palsy in 26 290 referred high risk patients who had antenatal testing with BPP was 1.33/1000 live births com¬ pared with 4.74/1000 in 58 657 untested patients (Manning et al 1998). In another study examining the relationship between abnormal BPP and cerebral palsy, Manning reported that the fetuses with abnormal BPP were more likely to develop fetal distress in labor (88.8%), acidosis (77.7%) and neonatal seizures (88.8%). Antenatal asphyxia as predicted based on BPP appears to be associated with cerebral damage in 29.6% of cases (Manning et al 1997). A combined strategy of non-stress testing, evaluation of amniotic fluid index (AFI), biophysical profile, umbilical velocimetry and contraction stress testing may be used in the antepartum assessment of the fetus at risk for hypoxic stress. One general algorithm for fetal evaluation is repre¬ sented in Figure 23.3. The specific indication for testing, the gestational age, and other compounding maternal and fetal factors may influence the testing interval as well as the combined number of tests required to raise the suspicion of fetal jeopardy to the point of delivery. When abnormal antepartum testing indicates the need for delivery, this may be accomplished by either the vaginal or abdominal route, depending on the fetal response to the stress of labor and other obstetric indications. The ease and acceptability of NST and BPP, compared to the CST, have led to decreasing use of CST in favor of these other two tests in current prac¬ tice (Huddleston 2002).

CHAPTER

Antenatal prediction of asphyxia

23

Table 23.4 Biophysical profile scoring and interpretation Biophysical variable

Normal (score = 2)

Abnormal (score = 0)

Fetal breathing movements

At least one episode of fetal breathing

Absent fetal breathing or no episode of greater

movement of at least 30 seconds duration in 30

than 30 seconds in 30 minutes

minutes Gross body movements

Fetal tone

Reactive non-stress test

Amniotic fluid volume

At least three discrete body or limb movements

Two or fewer body or limb movements in 30

in 30 minutes

minutes

At least one episode of active extension with

Either slow extension with return to partial

return to flexion of fetal limbs or trunk, includes

flexion, or movement of the limb in full extension

opening and closing the hand

or no fetal movement

At least two episodes of fetal heart rate

Less than two episodes of acceleration of fetal

acceleration of greater than or equal to 15 bpm

heart rate greater than or equal to 15 bpm, and

and of at least 15 seconds duration associated

of at least 15 seconds in duration associated with

with fetal movement in 30 minutes

fetal movement in 30 minutes

At least one pocket of amniotic fluid that

Either no amniotic fluid pocket or a pocket less

measures 2 cm by 2 cm in two perpendicular

than 2 cm in two perpendicular planes

planes Source: From Tsang H H, Manning F A Biophysical profile scoring. In: Druzin M L (ed.) Antepartum fetal assessment. Blackwell Scientific. Boston. MA. p. 33. with permission.

Figure 23.3 Fetal antepartum testing scheme. The most commonly used antepartum test is the non-stress test (N5T). Depending on abnormalities of testing, other follow-up tests may be indicated; the contraction stress test is less commonly used in current practice. AFI, amniotic fluid index: VA5. vibroacoustic stimulation: BPP, biophysical profile: S/D; systolic to diastolic ratio. 501

SECTION

V

PERINATAL ASPHYXIA

DOPPLER VELOCIMETRY OF THE UMBILICAL VESSELS (see also Ch. 10) Because of the need for better antenatal tests to reduce unnecessary intervention in pregnancies with false positive tests, umbilical artery Doppler velocimetry has been widely investigated. The principle upon which Doppler testing of the fetus may be useful relies on an incomplete understand¬ ing of the physiology of uteroplacental blood flow. Continu¬ ous wave Doppler systems generate flow velocity waveforms that reflect the distribution and intensity of the Doppler frequency shifts over time. Provided the angle of insonation and the transmitted frequency of the ultrasound beam are constant, these frequency shifts are proportional to changes in flow velocity within the umbilical vessels. Clinically, the most commonly used fetal Doppler evalu¬ ation is reported as the ratio of the peak systolic velocity waveform to the nadir at diastole (S/D). The greater the diastolic flow, the lower the ratio. As the peripheral resis¬ tance increases, the diastolic flow falls, resulting in an ele¬ vated S/D. At various gestational ages the fetal circulation demonstrates characteristic Doppler waveforms. In the first trimester of pregnancy, the umbilical artery has high pulsatility and consequently generates a Doppler waveform with reduced diastolic flow (elevated S/D). This pattern results from elevated downstream resistance in the umbilical and placental vessels. As resistance in the placental vessels drops in the second trimester from growth of small muscular arteries in the tertiary stem villi of the placenta, diastolic flow increases and the S/D decreases. This pattern of decreasing pulsatility and increasing diastolic flow continues throughout normal gestation. By 30 weeks gestation, the S/D in the umbilical artery should be less than 3.0. Absent or reverse diastolic flow reflects an abnormally elevated level of fetal peripheral resistance that may indicate fetal jeopardy. Other methods of reporting fetal arterial Doppler wave¬ forms include the pulsatility index and the resistance index. The pulsatility index is calculated as the systolic minus the diastolic values divided by the mean of the velocity wave¬ form profile (S - D/mean). The resistance index (Pourcelot ratio) is expressed as S - D/S. These indices are useful in statistical analyses when there is absent (the S/D is infinity) or reversed end diastolic flow. Several studies have suggested that umbilical artery Doppler provides a reasonable estimation of umbilical cord blood flow. Decreases in the S/D ratio, therefore, reflect placental abnormalities in flow and resistance, rather than hypoxia or asphyxia per se. Using a sheep model, Trudinger et al (1987) embolized the umbilical placental circulation with microspheres each day for nine days and observed the resulting Doppler waveforms. The umbilical S/D ratio increased steadily with increasing vascular resistance in the placental bed. However, umbilical blood flow did not fall significantly until the placental resistance was maximal. Morrow and Ritchie (1989) used a similar model of progres¬ sive embolization and likewise observed a progressive 502

increase in the S/D ratio, followed by absent end diastolic flow, then reversed diastolic flow. In this study, increasing the blood viscosity 100% by increasing the fetal hematocrit had minimal effect on the S/D ratio, indicating that umbili¬ cal blood flow, not necessarily hypoxia, induced abnormal Doppler waveforms in the umbilical artery. Because decreased umbilical artery flow may not produce hypoxemia in the well compensated fetus, abnormal Doppler velocimetry neither reliably predicts antenatal hypoxic-ischemic condi¬ tions nor demonstrates chronic asphyxia, but may help determine the ‘at-risk’ fetus. Five central and peripheral vessels of fetuses with IUGR were serially investigated by Ferrazzi et al (2002) in an attempt to determine temporal and sequential changes and their correlation with fetal heart rate monitoring and BPP scoring. The vessels included the umbilical artery, middle cerebral artery, ductus venosus, pulmonary artery and aorta. Early changes were identified in the umbilical and middle cerebral arteries, and late changes in the pulmonary artery and aorta. However, 60% of fetuses demonstrated abnormal fetal heart rate changes prior to abnormal late changes in the pulmonary artery and aorta. Furthermore, concordance for abnormal BPP scores and Doppler assessments in fetuses with IUGR could be found in only 44% of cases in a study by Baschat et al (2006). In assessing placental function and umbilical blood flow, Doppler velocimetry has been investigated as an antenatal predictor of fetal condition. In one study by Devoe et al (1990), Doppler velocimetry was used along with NST and amniotic fluid evaluation to determine the predictive value in predicting poor perinatal outcome as determined by fetal distress in labor, low 5-minute Apgar scores, neonatal aci¬ dosis and perinatal mortality. The overall perinatal mortality using all three techniques was 2.1 per 1000. Although each method had a specificity of approximately 90%, sensitivities for the NST and Doppler velocimetry were 69% and 21%, respectively. The positive predictive value of all three tests combined in predicting abnormal outcome was 100%. In a meta-analysis of 12 randomized controlled trials of Doppler velocimetry in high risk pregnancies, Alflrevic and Nielson (1995) detected a significant decrease in perinatal deaths and cesarean deliveries for fetal distress among pregnancies in which Doppler velocimetry was used for antenatal surveillance. Although Doppler velocimetry has not been shown to be predictive of poor pregnancy outcome in low risk pregnan¬ cies (Mason et al 1993), this antenatal test performs better in pregnancies at risk for intrauterine growth restriction, including hypertension and collagen vascular diseases. An elevation of the S/D may precede the identification of fetal growth restriction, and may be more predictive of neonatal morbidity than the NST alone (Trudinger et al 1986). Because the absence of diastolic flow in pregnancies complicated by fetal growth restriction has been associated with increased perinatal mortality, these fetuses may require either intense on-going fetal surveillance or delivery. Abnormal Doppler

CHAPTER

Antenatal prediction of asphyxia

velocimetry appears to be associated with abnormal fetal conditions including aneuploidy (Martinex-Crespo et al 1996), and major structural malformations (Tannirandorn et al 1993), indicating a possible need for a combination of antenatal tests in evaluating the wellbeing of these high risk fetuses.

SUMMARY Overall, significant advances in obstetric and neonatal care, along with improvements in the antenatal prediction and prevention of fetal asphyxia, have contributed to the observed decline in perinatal morbidity and mortality over the last half-century. Ultrasound and other imaging tech¬ niques have allowed clinicians to observe fetal anatomy, biophysical status, the intrauterine environment and fetal response to stress. The etiologies of congenital and acquired fetal and neonatal brain disorders are diverse. The detection and prevention of neurologic damage, therefore, remain a

23

continual challenge. Early identification of risk factors for neurologic sequelae as well as advancements in understand¬ ing neonatal response to hypoxia has been crucial to the development of strategies to limit further injury. Identification and timely delivery of the fetus exposed to hypoxic stress may improve the neurologic outcomes in some cases. However, this strategy could lead to avoidable complications of prematurity if the diagnosis of hypoxia is in error. The ideal antenatal strategy would include reliable, easy and cost effective testing to identify fetuses at risk for neurologic impairment, prior to the time of irreversible damage. For benefit, the strategy would need to exist in a system allowing for identification and prevention of intra¬ partum asphyxial injury, and effective neonatal therapies to reduce the morbidity of injury once it has occurred. Inves¬ tigation in antenatal determinants of neurologic injury con¬ tinues, and will assist in advancing understanding of the pathophysiology, timing and prevention of congenital and acquired neurologic impairment.

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24

PERINATAL ASPHYXIA

Intrapartum monitoring for asphyxia David A. Miller

Key Points • Fetal heart rate decelerations (late, variable or prolonged) signal interruption of the pathway of oxygen transfer from the environment to the fetus • Acute intrapartum interruption of oxygen transfer does not result in neurologic injury unless the fetal response progresses at least to the stage of significant metabolic acidemia (umbilical artery pH < 70 and base deficit 3- 12 mmol/L) • Moderate variability and/or acceleration reliably predict the absence of metabolic acidemia

INTRODUCTION When electronic fetal heart rate monitoring was introduced into clinical practice, many believed it would have a signifi¬ cant impact on perinatal mortality and cerebral palsy. In the decades that followed, the limitations of the technology have become clearer and the original optimism has been replaced by more realistic expectations. Research has helped clarify the physiology and pathophysiology of fetal heart rate changes. Standardized terminology has been introduced and new methods of intrapartum monitoring are showing promise. This chapter will review the evolution of electronic fetal heart rate monitoring and the relationship between fetal heart rate patterns, fetal physiology and newborn outcome.

FETAL HEART RATE AUSCULTATION Auscultation of the fetal heart, described as early as the 17th century in Le Goust’s ‘Humani Foetus Historia’ (Philippeaux: Notice biographique et bibliographique sur Philippe Le Goust 1879), was first reported in Western medical literature by Mayor (1818) in 1818. In 1822, Le Jumeau (1822) reported his observations of the fetal heart sounds using Laennec’s stethoscope and proposed that auscultation of the fetal heart could be useful in confirming pregnancy, diagnosing mul¬ tiple pregnancy, determining fetal position and judging the state of fetal health or disease by changes in strength and frequency of the heart tones. Later, Kennedy (1833), Schwartz (1870), Winckel (1893) and others described fetal heart rate (FHR) changes associated with umbilical cord compression, head compression and ‘fetal distress.’ Kilian (1888) and Winckel (1893) proposed indications for forceps delivery based upon FHR abnormalities such as tachycardia, brady¬ cardia, ‘irregularity’ and ‘impurity of tone.’ Schwartz (1870) and Seitz (1903) speculated upon the relationship between

S06

FHR changes and fetal oxygenation. Remarkably, these observations were made using only the stethoscope (mediate auscultation), or the ear of the examiner placed directly upon the maternal abdomen (immediate auscultation). In 1917, Hillis described the modified stethoscope known today as the DeLee-Hillis fetoscope (DeLee 1922, Hillis 1917).

ELECTRONIC FETAL MONITORING In 1906, Cremer (1906) recorded the first fetal electrocardio¬ graph (ECG). Placing one electrode on the maternal abdomen above the fundus and another in the vagina, he observed small fetal electrical impulses among the higher-voltage maternal signals. Despite technological improvements, the quality of abdominal fetal ECG tracings has remained un¬ reliable, and the clinical usefulness of the technique is limited. The concept of direct application of the ECG electrode to the fetus in utero was introduced in the 1950s (Kaplan ft Toyama 1958, Smyth 1953, Sureau 1956), with results clearly superior to those obtained abdominally. During the 1960s, Hon (1966) in the United States, Caldeyro-Barcia et al (1966) in Uruguay and Hammacher (1967) in Germany pioneered the development of electronic monitoring. The first practical clinical electronic fetal monitor became avail¬ able in the United States in 1968 and throughout the 1970s fetal monitoring became increasingly incorporated into obstetric management (Williams ft Hawes 1979). The intro¬ duction of Doppler ultrasound technology permitted FHR monitoring in patients with intact membranes. By 2002, electronic FHR monitoring was used in approximately 85% of all births in the United States (Martin et al 2003).

‘FETAL DISTRESS’ AND ‘FETAL ASPHYXIA’ Historically, the objective of EFM was to identify the fetus in ‘distress’ so that measures could be taken in time to avert permanent brain damage or death. However, the assumptions underlying this objective have been called into question. At the most fundamental level, there has never been a consensus in the medical literature regarding the definition of the term ‘fetal distress’. Kirschbaum described it as ‘a condition in which fetal physiology is so altered as to make death or permanent injury a probability within a relatively short period of time’ (Kirschbaum 1969). Some have based the definition on FHR abnormalities (Haesslein ft Niswander 1980, Haverkamp et al 1979), while others have focused on abnormal fetal blood gas values or low Apgar scores. In

CHAPTER

Intrapartum monitoring for asphyxia

2005, the Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists expressed concern about the continued use of the term ‘fetal distress’, noting that the term is imprecise, non-specific and has a low positive predictive value even in high-risk populations (ACOG 2005a). Further complicating the situation, the evolution of nonstandardized FHR terminology led many to equate ‘fetal distress’ with ‘fetal asphyxia’, yet another term for which no consensus definition exists. For example, the term ‘asphyxia’ is derived from a Greek word meaning ‘a stopping of the pulse’. Webster defines it as ‘a lack of oxygen or excess carbon dioxide that is usually caused by interruption of breathing’ (Webster’s Ninth New Collegiate Dictionary 1985). The World Federation of Neurology Group defined asphyxia as a condition of impaired gas exchange, which, if it persists, leads to progressive hypoxemia and hypercapnia (Bax 8t Melson 1993). Low defined asphyxia as a combination of hypoxia, hypercapnia and metabolic acidosis (Low et al 1997). Historically, a clinical diagnosis of ‘birth asphyxia’ was assigned on the basis of a variety of observations, including meconium passage, ‘abnormal’ FHR patterns, low Apgar scores and ‘abnormal’ blood gases. In 1989, Gilstrap et al (1989) recommended that the diagnosis of ‘birth asphyxia’ be reserved for infants who are severely depressed (5' Apgar 2 SD) in a baby with a birth weight less than 2 SD, then chronic placental insufficiency is almost certain (Bobrow 8t Soothill 1999) and so should be seriously considered as the cause of any brain damage. Normal blood gases make previous chronic acidosis very unlikely. Acidosis at birth is very common and, when acute, is very rarely a cause of brain damage. This has been sup¬ ported by a large number of studies over the past twenty years: many of them have examined several antenatal causes and predisposing factors of brain damage. Therefore acidosis at birth in a baby with the other features of chronic placental insufficiency is important and may be a valuable predictor of outcome.

CHAPTER

Prediction of asphyxia with fetal gas analysis

25

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Peeters L L H. Sheldon R E. Jones M D et al 1979 Blood flow to fetal organs as a function of arterial oxygen content. Am J Obstet Gynecol 135:637-646. Perkins R P 1997 Requiem for a heavyweight: the demise of scalp blood pH sampling. J Matern Fetal Med 6:298-300. Perlman J M 1997 Intrapartum hypoxic-ischemic cerebral injury and subsequent cerebral palsy: medicolegal issues. Pediatrics 99:851-859. Perlman J M 2006a Intrapartum asphyxia and cerebral palsy: is there a link? Clin Perinatal 33(2):335—353. Perlman J M 2006b Summary Proceedings from the

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Pijnenborg R. Dixon G. Robertson W B et al 1980 Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy Placenta 1:3-19. Reid S M, Lanigan A. Reddihough D S 2006 Post-

Williams & Wilkins. Baltimore. MD. pp. 101-121. Sarnat H B, Sarnat M S 1976 Neonatal encephalopathy following fetal distress. Arch Neurol 33:696-705. Seelbach-Gobel B. Heupel M. Kuhnert M et al 1999 The prediction of fetal acidosis by means of intrapartum fetal pulse oximetry. Am J Obstet Gynecol 180:73-81. Shalaka L, Perlman J M 2004 Hypoxic-ischemic brain injury in the term infant — current concepts. Early Hum Dev 80:125-141. Shankaran S. LaptookA. Ehrenkranz R etal2005 Whole-body hypothermia for neonates with hypoxicischemic encephalopathy. N EnglJ Med 353:1574-1584. Small M I. Beall M, Platt L D et al 1989 Continuous tissue pH monitoring in the term fetus. Am J Obstet Gynecol 161:323-329. Snijders R J. Abbas A. Melby 0 et al 1993 Fetal plasma erythropoietin concentration in severe growth retardation. Am J Obstet Gynecol 168:615-619. Soothill P W1994 Diagnosis of intrauterine growth retardation and its fetal and perinatal consequences. Acta Paediatr Suppl 399:55-59. Soothill P W, Ajayi R A. Campbell S et al 1992a Relationship between fetal acidaemia at cordocentesis and subsequent neurodevelopment. Ultrasound Obstet Gynecol 2:80-83. Soothill P W, Ajayi R A, Campbell S et al 1993 Prediction of morbidity in small and normally grown fetuses by fetal heart rate variability. Biophysical profile score and umbilical artery Doppler studies. Br J Obstet Gynaecol 100:742-745. Soothill P W, Ajayi R A, Campbell S et al 1995 Fetal oxygenation at cordocentesis. maternal smoking and childhood neuro-development. Eur J Obstet Gynecol Reprod Biol 59:21-24. Soothill P W, Ajayi R A. Nicolaides K N 1992b Fetal

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Soothill P W. Nicolaides K H. Campbell S 1987a Prenatal asphyxia, hyperlacticaemia. hypoglycaemia, and erythroblastosis in growth retarded fetuses. BMJ (Clin Res Ed) 294:1051-1053. Soothill P W. Nicolaides K H. Rodeck C H 1987b Effect of anaemia on fetal acid-base status. Br J Obstet Gynaecol 94:880-883. Soothill P W. Nicolaides K H. Rodeck C H 1989 Fetal

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CHAPTER

Prediction of asphyxia with fetal gas analysis

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Perinatal medicine. Longman: Canada, Toronto, pp. 171-186. Wahr J A. Tremper K K. Samra S et al 1996 Nearinfrared spectroscopy: theory and applications. J Cardiothorac Vase Anesth 10:406-418. Westgate J, Garibaldi J M. Greene K R 1994 Umbilical cord blood gas analysis at delivery: a time for quality data. BrJ Obstet Gynaecol 101:1054-1063. Willcourt R F 1987 Fetal blood gases and pH: current

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pp. 155-174. Winkter CL, Hauth J C, Tucker J M et al 1991 Neonatal

25

Yeomans E R, Hauth J C, Gilstrap L C 3rd et al 1985 Umbilical cord pH. PC02. and bicarbonate following uncomplicated term vaginal deliveries. Am J Obstet Gynecol 151:798-800. Yoon B H. Kim S W1994 The effect of labor on the normal values of umbilical blood acid-base status. Acta Obstet Gynecol Scand 73:555-561. Young D C. Gray J H. Luther E R et al 1980 Fetal scalp blood pH sampling: Its value in an active obstetric unit. Am J Obstet Gynecol 136:276-281. Zalar R W, Quilligan E J 1979 The influence of scalp sampling on the caesarean section rate for fetal distress. Am J Obstet Gynecol 135:239-246.

complications at term as related to the degree of umbilical artery acidaemia. Am J Obstet Gynecol 164:637-641.

541

SECTION V

CHAPTER

26

PERINATAL ASPHYXIA

The asphyxiated newborn infant Luc Cornette and Malcolm I. Levene

Key Points • There is no single or generally agreed diagnosis of'birth asphyxia’. The diagnosis can be assessed retrospectively by attention to seven clinical features • Cerebral pathology resulting from a hypoxic-ischemic insult depends on gestational age of the infant when the insult occurred as well as the severity and duration of the insult • Access to expert and rapid resuscitation immediately after birth is essential for asphyxiated newborn infants • There are few proven evidence based interventions in the management of the asphyxiated newborn infant. Postnatal corticosteroid treatment and hyperventilation are potentially hazardous • There is no evidence that suppressing all seizure activity with anticonvulsant drugs improves the subsequent outcome of the baby • The best clinical predictor of adverse outcome is severity of hypoxicischemic encephalopathy (HIE); moderate and severe HIE has a 251 and 80% risk of adverse outcome respectively

INTRODUCTION In the developed world, birth asphyxia is arguably the most common cause of perinatally acquired severe brain injury in full-term infants. Annually, about 4 million neonates are affected world wide. Approximately one million will die and an equal number will develop serious sequelae (WHO 2003). It is a tragedy for a normally developed fetus to sustain cerebral injury during the last hours of prenatal life and then to survive for many more years with a major disability. For pediatricians, birth asphyxia remains a frustrating condition to treat as prevention of the condition is outside their control, and there have been few or no improvements in clinical management in the last 20 years. The antenatal and intrapartum aspects of detection and prevention are discussed in Chapters 23 and 24. Potentially effective new brain protection therapy for birth asphyxia is discussed in Chapter 27.

DEFINITION Apnea at birth is a relatively common feature, particularly in premature infants. This may cause the Apgar score to be depressed and require the infant to be resuscitated. There may be little evidence that the baby has suffered the hypoxic-ischemic pathophysiological insult inherent to the term ‘birth asphyxia’. Because of the fundamental differ¬ ences in the definition and neuropathological sequelae of asphyxia between preterm and full-term infants, this chapter 542

only discusses perinatal asphyxia with reference to the mature infant. The neuropathological insults seen in prema¬ ture infants are predominantly hemorrhagic or ischemic, and intrapartum events only rarely precipitate these conditions. They are discussed in detail in Section IV. The term asphyxia refers to impairment of placental or pulmonary gas exchange resulting in three biochemical components: hypoxemia, hypercapnia and acidosis (Low 1997a). ‘Birth asphyxia’ is widely used as a clinical diagno¬ sis, but there is little consensus as to what is meant by it. Hypoxic-ischemic insult better describes the pathophysiol¬ ogy of intrapartum asphyxia and stresses the two major components of the condition. Cerebral ischemia, i.e. blood flow below the level necessary to support normal function, is not well tolerated, and pure ischemic lesions may occur as the result of sudden hypovolemia. Hypoxia on its own is well tolerated by the immature brain, providing that minimum quantities of metabolic substrate (mainly glucose) are delivered to the brain. Regardless of the cause, cardiac failure ultimately occurs when hypoxia is prolonged, result¬ ing in hypotension, ischemia and lactic acidosis. Thus, isch¬ emia is both a cause and a result of hypoxia and compounds the complications of hypoxia by impairing the removal of metabolic and respiratory by-products (e.g. lactic acid). The cerebral lesions that develop following an episode of intense ischemia are different to those seen when hypoxia and ischemia act together, as occurs as the result of intra¬ partum asphyxia. Pure ischemic lesions in premature and full-term infants are discussed in Chapter 21. A diagnosis of an asphyxiating event should not be made without some evidence of an interruption of oxygen (02) supply or blood flow to the fetus. These events can be secondary to problems within the mother (e.g. hypotension, toxemia, uterine tetany, uterine rupture), the placenta or umbilical cord (e.g. abrup¬ tion, infection or inflammation, or umbilical cord compres¬ sion or occlusion), or the fetus or infant (e.g. central nervous system depression, anomalies, infection) (Nelson 2003). The fetus is well adapted to the rigors of labor, and these protective mechanisms are discussed in Chapter 22. A severe hypoxic-ischemic insult may overwhelm these adaptive mechanisms and cause the vital organs to be compromised. The determinants of whether the insult is severe enough to cause dysfunction are its intensity and duration. An intense insult such as cord prolapse or massive placental abruption causes the fetus to be rapidly compromised, whereas a less intense insult such as intermittent placental insufficiency associated with hypertonic uterine contractions will need a

CHAPTER

The asphyxiated newborn infant

longer duration to have a similarly severe effect on the fetus. It is often not possible to know clinically either the degree of intensity or the duration of the intrapartum insult.

PRECONDITIONING It has recently been recognized in animal studies that a period of hypoxia prior to a more severe hypoxic-ischemic insult protects the immature brain from hypoxic-ischemic injury compared with the animal that was not exposed to the preceding hypoxia (Brucklacher et al 2002). This has been referred to as ‘preconditioning’ and is probably due to increased expression of a variety of genes which contrib¬ ute to the development of hypoxia-induced tolerance (Bernaudin et al 2002).

THE ‘ASPHYXIA SYNDROME’ There is no universally accepted clinical definition of asphyxia, and all the following features are used as possible markers of the condition; indeed some recommended that the term ‘birth asphyxia’ should not be used (Bax ft Nelson 1993). There are many conditions in medicine that cannot be diagnosed accurately with a blood test or radiological procedure. In these cases, a careful clinical history, together with exclusion of alternative diagnoses, usually suffices to make the diagnosis. There is no single test to diagnose birth asphyxia, and it is necessary to adopt a similar approach to that for the diagnosis of migraine or epilepsy. This will involve considering asphyxia as a syndrome, or collection of features, with the exclusion of alternative conditions (Levene 1995). To adopt this approach, it is necessary for three aspects to be considered: 1. assessment of diagnostic criteria; 2. exclusion of alternative possible diagnoses; 3. consideration of results from contributory diagnostic tests. Each of these is considered below.

Assessment of diagnostic criteria None of the features listed below on their own are diagnos¬ tic, but the more that are present, the more likely it is that asphyxia has occurred. The presence of four out of six items should make the diagnosis of moderate probability, provid¬ ing that the exclusion criteria are met, and five or six out of six gives a good probability of the diagnosis being gener¬ ally accepted. The most common time for a baby to be acutely asphyxi¬ ated is at the end of labor, with birth releasing the fetus from a hostile intrauterine environment. In these cases, there is likely to be evidence of increasing fetal distress, poor adaptation to birth and hypoxic-ischemic encephalopathy with evidence of transient impairment in other organ systems. Less commonly, a severe asphyxial event may occur several hours or even days prior to delivery such as prolonged, but reversible, uterine hypertonus due to excess pharmacological stimulation or transient severe maternal

26

hypotension. Under these conditions, the baby may not show fetal distress immediately prior to birth, as cardiovas¬ cular recovery from the acute event has occurred (auto¬ resuscitation), and the baby may be born in relatively good condition. The baby may, nevertheless, show signs of hypoxic-ischemic encephalopathy (HIE), although the sequence may be altered (e.g. very early convulsions) by the interval between insult and delivery.

Fetal distress Fetal asphyxia during labor occurs as the result of placental compromise or, rarely, umbilical cord compression. These conditions affect the entire fetus, and methods to detect fetal distress usually monitor the effects of these insults on the cardiovascular system. Chapters 24 and 25 discuss these methods. There is no clinically reliable method for assessing central nervous system function during labor, and evidence of fetal distress does not necessarily indicate that the fetal brain has been compromised. Intrapartum electronic fetal heart rate monitoring, i.e. cardiotocography (CTG), is not good at distinguishing fetal stress (a normal reaction to the rigors of labor) from fetal distress. Consequently, abnormali¬ ties on a CTG are relatively poorly sensitive to intrapartum asphyxia (high number of false positives). While fetal heart rate patterns will not discriminate all asphyxial exposures, CTG supplemented by fetal blood gas and acid-base assess¬ ment can be a useful fetal assessment paradigm for intra¬ partum fetal asphyxia (Low et al 2001). The CTG is, however, more likely to be a relatively specific test, as a normal CTG probably indicates that the fetus is not suffering from acute intrapartum asphyxia at the time that the CTG is being registered. Continuous measurement of fetal 02 saturation during labor, i.e. fetal pulse oximetry, as an adjunct to electronic fetal monitoring, does not seem to provide addi¬ tional information, as there is no difference in condition of the newborn compared to using CTG alone (Bloom et al 2006). More recently fetal ECG monitoring has been shown to reduce the high false positive rate of standard CTG moni¬ toring. Automatic ST-waveform analysis appears to be a better predictor of fetal acidosis than standard CTG monitor¬ ing (Amer-Wahlin 2001).

Passage of meconium Meconium is passed prior to delivery in 10-20% of full-term infants. Heavy contamination of the amniotic fluid has been suggested to be a feature of fetal distress (Meis et al 1978). The passage of meconium is, however, a very weak marker of those babies likely to sustain irreversible cerebral injury as the result of intrapartum asphyxia. Nelson and Ellenberg (1984) reported that only 0.4% of infants weighing more than 2500 g who had meconium-stained liquor were later found to have cerebral palsy.

Metabolic acidosis Anaerobic metabolism is a normal physiological response during episodes of hypoxemia with generation of lactic acid. Fetal acid-base balance can be assessed through antepartum 543

SECTION

V

PERINATAL ASPHYXIA

umbilical cord blood sampling, fetal scalp blood assessment, or umbilical cord blood sampling immediately after delivery. Fetal acidosis may be measured by blood pH or by the base deficit. Metabolic acidosis results in excess production of acid and decreased buffer base, which is referred to as the base deficit or negative base excess. The major buffers uti¬ lized by the fetus for neutralizing hydrogen ion production are plasma bicarbonate and hemoglobin. When adequate fetal oxygenation does not occur, complete oxidative metab¬ olism of carbohydrates to carbon dioxide (C02) and water is impaired and metabolism proceeds along an anaerobic pathway with production of organic acids, such as lactate, which are not readily excreted or metabolized. Accumulation of lactate can deplete the buffer system and result in decreased buffer base. The severity of the metabolic acidosis may reflect either the duration or the intensity of the asphyxial event, but metabolic acidosis does not correlate with those infants who later are shown to have sustained neurological deficit (see Ch. 25). Although fetal acidosis is widely taken to be pH < 7.20, a more reliable value indicating the possibility of neurologi¬ cal compromise is pH = 7.05 or pH = 7.0. Base deficit values have a significantly greater usefulness than umbilical cord pH values (Ross Ft Gala 2002), because base excess does not change significantly with respiratory acidosis and demonstrates a linear, rather than logarithmic, correlation to the degree of metabolic acidosis. The normal fetal base deficit entering labor is -1 to -2 mmol/L. It is generally assumed that asphyxial injury does not occur until the fetal base deficit is 15mmHg) to develop in the human neonate following asphyxia is 26 h (unpublished data). These data are not of course incompatible, but the implication that early cerebral edema has a role in the primary pathogenesis of brain injury following intrapartum hypoxic-ischemic injury is unsubstantiated. Cerebral edema severe enough to cause secondary cerebral hypoperfusion is a potential complication of asphyxia, and adequate treat¬ ment of intracranial hypertension will not per se prevent brain injury. Levene et al (1987) have analyzed the results of monitoring and treating raised intracranial pressure in full-term asphyxiated infants. In less than 10% of the babies studied could intervention to control intracranial hyper¬ tension have had any significant beneficial effect on

There is a predictable relationship between PaC02 and cere¬ bral blood flow. Increasing carbon dioxide tension induces cerebral arteriolar vasodilatation with increase in cerebral blood flow and vice versa (see Fig. 26.12). In adults, for every 0.13 kPa (1 mmHg) change in PaC02, there is approxi¬ mately a 3% change in cerebral blood flow over the physi¬ ological range for PaC02 (Bruce 1984). This proportional change diminishes for levels of PaC02, below 2.7 kPa (20 mmHg). Following perinatal asphyxia, the arteriolar response may be less sensitive to changes in PaC02, and in some, there may be a paradoxical increase in cerebral blood flow with controlled hyperventilation (Sankaran 1984). Cerebral ischemia is an important component of the patho¬ physiology of postasphyxial injury in cerebral hypoperfu¬ sion, and it is possible that severe hyperventilation may exacerbate impaired reperfusion to the compromised brain. This is strongly implicated in PVL in premature infants (see

outcome. There is no evidence that the routine monitoring of intra¬ cranial pressure and appropriate management makes any improvement in outcome.

Corticosteroids The role of steroids in the management of asphyxia is con¬ troversial, with few data available for either newborn humans or experimental animals. Studies on 5-day-old rats, whose brains at that age are at a comparable state of development to the full-term human brain, showed that treatment with dexamethasone before asphyxiation resulted in less severe cerebral effects than in untreated animals (Adlard £t De Souza 1976). The use of steroids following neonatal asphyxia was ineffective in treating or preventing cerebral edema (De Souza ft Dobbing 1973). It has been suggested that dexamethasone has its main benefit in treating vasogenic edema and is less effective in cytotoxic edema (Yamaguchi et al 1976), but in clinical practice, both types of brain swelling probably occur together. Corticosteroids have their major role in the treat¬ ment of focal cerebral edema associated with tumor or abscess, neither of which bears a close resemblance to the generalized brain swelling that occurs following perinatal 568

p. 441). There have been no clinical trials of hyperventilation in asphyxiated newborn infants. In practice, we attempt to maintain the PaC02 in asphyxiated infants who are mechan¬ ically ventilated at about 4.5 kPa (34 mmHgj. A high positive end-expiratory pressure (PEEP) level is likely to produce a higher PaC02 (Stewart et al 1981), and PEEP should be kept as low as possible in asphyxiated infants who are mechanically ventilated. Hyperventilation should be avoided.

Figure 26.12 Relationship between PaCo2 and cerebral blood flow (CBF). (Redrawn from Bruce 1984.)

CHAPTER

The asphyxiated newborn infant

Osmotic agents A variety of agents, including mannitol, glycerol and urea, have been used to shrink the swollen neonatal brain. These agents act by inducing a higher osmotic pressure across the blood-brain barrier, thereby causing intracerebral shrink¬ age. A theoretical hazard is the entry of the osmotic agent into the brain through the damaged blood-brain barrier, causing a rebound effect of brain swelling. In a neonatal animal model, mannitol significantly reduced the brain water content when given immediately after an asphyxial event (Mujsce et al 1988), but it did not reduce the severity or distribution of brain damage in treated versus untreated animals. Mannitol is the only osmotic agent where published data exist on its use in the newborn. Marchal et al (1974) in an uncontrolled study gave mannitol to 225 babies with the diagnosis of asphyxia, although the precise indications for treatment varied. Early treatment was defined as man¬ nitol infusion (1 g/Kg) before the baby was 2 h of age. There were significantly fewer deaths (P = 0.005), and the survi¬ vors had a better neurological outcome (P = 0.014) in the early treatment group compared with those treated after 2 hours. A fall in intracranial pressure and an improvement in cerebral perfusion pressure were found on each occasion when mannitol (1 g/Kg over 20 min) was infused intrave¬ nously in a group of severely asphyxiated babies (Levene 8t Evans 1985). This appears to be the only agent which is of proven value in treating intracranial hypertension in the asphyxiated newborn. Despite the reduction in ICP in many babies, our follow-up data did not suggest that this made any difference to long-term outcome.

Barbiturates As mentioned above, barbiturates increase cerebral vascular resistance, thereby reducing cerebral blood flow, and it is this action that contributes to the lowering of intracranial pressure in the swollen brain. It is unlikely that this will improve cerebral perfusion pressure.

New modalities in brain management There is considerable interest and ongoing research into neuroprotection following hypoxic-ischemic insults and this is reviewed in Chapter 27. Much of this work is speculative and a long way from clinical trials. Three treatment modali¬ ties have been assessed in human asphyxiated neonates and these will be discussed here.

Hypothermia There have been many studies in animal models evaluating the neuroprotective effect of hypothermia and these experi¬ ments have shown that cooling during hypoxia-ischemia, even with relatively mild hypothermia, results in long-term neuroprotection in immature animals. The mechanisms for the apparent neuroprotective effects of hypothermia are unclear, but multiple mechanisms have been proposed. These include: • reduction in neurotransmitter release, including glutamate;

26

• reduction in metabolic rate with reduced brain 02 consumption; • reduction in number of seizures; • attenuation of changes in some of the protein kinases; • inhibition in the production of free radicals, particularly hydroxyl possibly by inhibiting NO production; • reduction in inflammatory mediators such as IL-1 (3; • inhibition of apoptosis; • reduction in the disruption of the blood-brain barrier with inhibition of cerebral edema. Clinical studies of therapeutic hypothermia have been encouraging. Two studies of global cerebral asphyxial injury following cardiac arrest in adults have shown a significant improvement in outcome following cardiac arrest (Bernard et al 2002, Hypothermia after Cardiac Arrest Study Group 2002). In the neonate, therapeutic hypothermia has been shown to reduce brain injury evident on MR when cooled babies were compared with non-cooled but similarly asphyx¬ iated infants (Inder et al 2004). A number of randomized controlled studies have been conducted comparing mild therapeutic hypothermia (33.5°C) for 72 hours with normothermia (37°C). The two largest studies reported to date compared brain cooling using a cooling cap (Gluckman et al 2005) and total body cooling (Shankaran et al 2005) and both have shown that this form of treatment instituted within 6 hours of birth in severely asphyxiated infants reduces adverse outcome (death or mod¬ erate or severe disability). Therapeutic hypothermia con¬ ducted in specialized centers appears to be a safe technique and to date is not associated with a significant risk of com¬ plications. A third even larger European study (TOBY) has completed enrollment of 325 babies without any evidence of significant harm during the hypothermic management period or in the immediate rewarming stage. Outcome of this study will not be available until 2008. A recent meta¬ analysis (Table 26.5) of the three published studies to date shows a significant reduction in death or disability in the hypothermic group compared with the normothermic group (Edwards 8t Azzopardi 2006). The role of therapeutic hypothermia following severe birth asphyxia is as yet unproven although the preliminary results are encouraging. An executive summary of the US National Institute of Child Health and Human Development workshop (Higgins et al 2006) has concluded that although hypother¬ mia appears to be a potentially promising therapy for HIE, long-term efficacy and safety is yet to be established and its future use should be restricted to those babies where parents have been appropriately counseled about the uncer¬ tainty of long-term benefit. All babies subjected to thera¬ peutic hypothermia should be registered with national or international hypothermia registries.

Allopurinol Post hypoxic-ischemic injury is thought to be in part due to free-radical damage to both brain and heart. Allopurinol reduces free radical production by inhibition of xanthine 569

SECTION

V

PERINATAL ASPHYXIA

Table 26.5 Meta-analysis of three published studies of outcome following hypothermia vs. normothermia (with permission). Coolcap (Gluckman et al 2005, Eicher et al 2005a, 2005b), NICHD (Shankaran et al 2005). Reproduced from Edwards and Azzopardi 2006 Review: Hypothermia Comparison: Hypothermia versus normothermia Outcome: Death or disability Hypothermia

Control

RR (fixed)

Weight

RR (fixed)

n/N

n/N

95% Cl

%

95% Cl

Coolcap

59/108

73/110

■:

46.10

0.82 (0.66 to 1.02)

Eicher

14/27

21/25

—■—!

13.90

0.62 (0.41 to 0.92)

NICHD

45/102

64/106

40.00

0.73 (0.56 to 0.95)

100.00

0.76 (0.65 to 0.89)

Study or sub-category

Total (95% Cl)

237

241

Total events: 118 (hypothermia), 158 (control) Test for heterogeneity: %2 = 1.63, df = 2 (p = 0.44), I2 = 0% Test for overall effect: z = 3.48 (p = 0.0005)

oxidase and by possibly scavenging hydroxyl free radicals. In immature rat pups, post-treatment with allopurinol reduces hypoxic-ischemic brain damage (Palmer et al 1993) and improves electrocortical activity in newborn asphyxi¬ ated sheep (Shadid et al 1998). A double-blind randomized controlled trial of allopurinol in Holland enrolled 32 term infants with severe birth asphyxia to receive either intrave¬ nous allopurinol (40 mg/Kg) or placebo. Despite early indi¬ cations that it improved neonatal EEG function, further experience showed that allopurinol did not reduce mortality and morbidity which remained high despite treatment (Benders et al 2006).

Hyperbaric oxygen In China hyperbaric 02 is widely used to treat babies with HIE and is thought to reverse local hypoxia, inhibit postischemic vasoconstriction and promote the formation of collagen matrix essential for angiogenesis and restoration of cerebral blood flow (Liu et al 2006). A recent meta¬ analysis of 20 mainly Chinese trials of hyperbaric 02 used to treat HIE in term infants compared with ‘usual care’ showed that there was a reduction in mortality (OR 0.26 95°/o, Cl 0.14-0.46) and neurological sequelae (OR 0.41, 0.27-0.61) (Liu et al 2006). Unfortunately the quality of these trials was considered to be poor by Western standards and cannot be relied on for evidence of beneficial effect.

OUTCOME Prediction of outcome in asphyxiated infants is of obvious importance for the parents, as they will ask ‘will my baby be handicapped?’ An accurate and honest answer may be available from the results of good follow-up studies. Another important aspect of predicting outcome is the question of when it is appropriate to abandon resuscitative efforts or 570

i

i i 0.1 0.2

i 0.5

j I 1

i 2

i 5

i 10

withdraw intensive care in infants likely to be severely handicapped. The answers to these questions are beginning to emerge, but a critical review of the assessment methods is necessary, and this is discussed in detail below. A major problem in the evaluation of follow-up studies is the failure to distinguish whether the data refer to full-term babies only or a mixture of mature and immature infants. In addition, the problem of defining what is asphyxia influences outcome statistics. For the purpose of this review, only reports from full-term infants will be considered, and the outcome from different assessment techniques will be discussed separately. The utility of any test can be evaluated from its sensitivity, specificity and positive predictive value. Sensitivity refers to the percentage of handicapped infants detected by the test, and specificity is the percentage of normal infants detected by a normal test. Positive predictive value is the proportion of times a positive test predicts adverse outcome. To evaluate any assessment of outcome, all these variables should be considered. Wherever it has been possible to calculate these figures, they are given in the text. There is some evidence that the prognosis following intra¬ partum asphyxia has improved over recent years (Finer et al 1983). A Swedish study reported that 50°/o of infants surviving asphyxia between 1973 and 1976 had significant neurodevelopmental sequelae, in contrast to a 17% inci¬ dence of handicap in those born between 1976 and 1979 (Svenningsen et al 1982). Svenningsen et al related the improved outcome to the introduction of brain-oriented intensive care, but there has been no single therapeutic innovation that has improved the outcome for asphyxiated babies over recent years. Few data are available for the outcome of asphyxiated term babies born in developing countries. One recent study from Kathmandu in Nepal reports that the overall risk of death or major disability at 1 year of age in a group of term

CHAPTER

The asphyxiated newborn infant

babies with signs of neonatal encephalopathy was 62°/o compared with only 4% of normal controls (Ellis et al 1999). This is considerably higher than in the developed world. The relative risk of impairment in survivors of grade I neonatal encephalopathy was 5.3 (95% Cl 0.9, 30), and for grade II neonatal encephalopathy, 32.1 (95% Cl 7.9, 131).

MORTALITY The mortality rate of live-born asphyxiated infants depends on the severity of the insult and the intensity of treatment. If asphyxia is defined by depression of the Apgar score, then mortality increases inversely to gestational age and birth weight. MacDonald et al (1980) report an overall mortality of 46% in severely asphyxiated infants of all gestational ages, and the presence of intrauterine growth retardation, respiratory distress syndrome and hypothermia were all associated with a significantly higher risk of death. In another study, over half of the infants died, if born with an Apgar score of 0 at birth, or delay in establishing respiration until 20 minutes after birth (Scott 1976). In the well-known study of Nelson and Ellenberg (1981) over 40000 infants had an accurate assessment of the Apgar score. Those with a birth weight below 2500 g with severe depression of the Apgar score at 15 and 20 min had approximately a 90% chance of dying, but this was considerably less in infants weighing more than 2500 g. Casey et al (2001) demonstrated that the association between low 5 min Apgar scores and an increased risk of neonatal death remains pertinent almost 50 years after the introduction of the scoring system: for 132 228 infants born at term, the mortality rate was 244 per 1000 for infants with 5 min Apgar scores of 0-3, as compared with 0.2 per 1000 for infants with 5 min scores of 7-10 (Table 26.6). In addi¬ tion, the study demonstrates that the Apgar score predicts neonatal death more accurately than the umbilical-artery pH, as the risk of neonatal death in term infants with 5 min Apgar scores of 0-3 was eight times the risk in term infants with umbilical-artery blood pH values of 7.00 or less.

26

Delay in establishing spontaneous respiration also seems to predict the risk of death. Steiner and Nelligan (1975) have shown that infants who have not established regular breath¬ ing 30 minutes after return of the heartbeat subsequently have a very poor outcome. They suggest that resuscitation under these circumstances should not be continued for longer than this time. By contrast, a Swedish study found that 25% of babies who had not breathed spontaneously by 20 min were without significant handicap (Ergander et al 1983). Peliowski and Finer (1992) have reviewed the litera¬ ture and report the outcome of only 35 full-term babies who did not breathe spontaneously by 30 min and 24 (80%) died or were significantly handicapped.

When to abandon resuscitation 1. If an infant has no cardiac output after 10 min of effective resuscitation, then treatment should be abandoned. 2. If a baby is not breathing spontaneously by 30 min, then the value of further resuscitation should be seriously questioned. Other causes for failure to breathe spontaneously should be considered, such as opiate depression and neuromuscular disorders. The final decision to abandon resuscitation should be made by the most senior neonatologist/pediatrician available.

DISABILITY At present, there is no single measure of fetal or neonatal condition that accurately predicts later neurodevelopmental disability. It has been suggested that a diagnosis of encephalopathic perinatal asphyxia requires the evidence of neo¬ natal neurologic abnormalities and multi-system organ dysfunction, in addition to both a low 5 min Apgar score and neonatal acidosis (ACOG 1996). Babies born apparently dead, but resuscitated rapidly, may subsequently be neurologically normal (Jain et al 1991, Scott 1976, Steiner 8t Nelligan 1975). Casalaz et al (1998) described 29 babies of gestational age 36 weeks and above, born with a zero 1 min Apgar score and who were success-

Table 26.6 Risk of death according to Apgar scores at 5 minutes for preterm and term infants (from Casey et al 2001). The Apgar scores 7-10 represent the reference group Five minute Apgar score

No of live births

Neonatal deaths (rate per 1000 births)

Relative risk (95% Cl)

Preterm births (26-36 weeks of gestation) 0-3 4-6 7-10

315

92 556

72

12 751

5

59 (40-87) 13 (9-20) 1

Term births (>37 weeks) 0-3

86

244

4-6

561

9

7-10

131 581

0.2

1460 (835-2555) 53 (20-140) 1

571

SECTION

V

PERINATAL ASPHYXIA

fully resuscitated. Forty-five percent of these babies were subsequently described as normal, and a further 34% died prior to discharge from hospital. Of those who went home, only 31.5% were disabled. Disability probably depends on the duration and severity of the asphyxial insult as well as the development of cardiovascular complications. Asphyxia has been described as having an all or none effect. The majority of very severely asphyxiated babies die, and the majority of the remainder are without major neu¬ rological deficit and are often reported as being ‘normal’ at follow-up. Only a very small proportion are disabled. This effect may be illusory as there are veiy few good long-term follow-up studies to assess the children for less severe forms of disability such as clumsiness, attention deficit disorders and learning problems. Finer et al (1983) in Canada have regularly assessed a group of full-term asphyxiated infants at 27 months, 3.5 years (Robertson Et Finer 1985) and 8 years (Robertson et al 1989). They showed that there is a gradation of effect on the intelligence quotient (IQ) for different degrees of severity of the asphyxial insult. At 3.5 years, the children with mod¬ erate HIE had a median Stanford Binet IQ of 92.3 compared with 101.5 in babies with mild HIE (Robertson Et Finer 1985). At 8 years, there was a difference in IQ of 11 points between children with moderate HIE and mild HIE and 17 points between moderate HIE and a non-asphyxiated control group (Robertson et al 1989). Children who survived severe HIE had a median IQ of 48 at 8 years. Cognitive impairment as measured by the IQ therefore appears to represent a contin¬ uum of disability reflecting the severity of the initial asphyx¬ ial insult. The classic disability suffered by the survivors of severe asphyxia is cerebral palsy. This may be associated with intellectual impairment, blindness and epilepsy, but the motor deficit is invariably present with these other disabili¬ ties. Mental retardation alone is not a recognized sequel to intrapartum asphyxia. Two distinct forms of cerebral palsy occur as the result of birth asphyxia at full term: spastic quadriplegia and choreoathetosis, or a combination of these two. These two patterns of motor deficit presumably reflect the regions of the brain predominantly affected by the asphyxial process (see p. 546). The late onset of dystonia (including athetosis) with normal intelligence has been described many years follow¬ ing perinatal asphyxia (Saint Hilaire et al 1991, Scott Et Jankovic 1996). The mean age of onset in these studies was over 10 years, with progression over a further 7-10 years. In one study, the latency in neonates with a hypoxic-isch¬ emic etiology was 27.6 years (Scott Et Jankovic 1996). In another study, none of the subjects were severely disabled by the dystonia (Saint Hilaire et al 1991).

Fetal assessment

Passage of meconium Thick meconium present in the liquor at the onset of labor carries a sevenfold increased risk of perinatal death S72

(MacDonald et al 1985). Meconium staining of the liquor does not, however, predict the risk of subsequent disability. Ninety-nine percent of all babies born with meconiumstained liquor do not have cerebral palsy (Freeman Et Nelson 1988).

Acidosis Low et al (1978a) defined fetal acidosis as an umbilical arteiy buffer base of less than 34 mmol/L, and these infants had on average a lower 1- and 5-min Apgar score than a control, non-acidotic group. However, they could find no differences in neurological outcome between the acidotic and control groups at 12 months of age. During the course of normal labor, the f>a02 drops, the PaC02 rises, and the base deficit rises. In most centers, a pH of more than 7.2 is considered normal and a pH of 7.0 to 7.2 is considered mild or moderate acidemia. Severe acidemia is when the pH is below 7.0. Just as the Apgar score alone is a poor predictor of outcome, metabolic acidosis in isolation also proves to be a poor predictor of significant perinatal brain injury. Ruth and Raivio (1988) assessed umbilical arterial acidbase values on 982 live-born (mainly full-term) infants and correlated these measurements with neurodevelopmental outcome at 12 months of age. The positive predictive value for low pH (5.4 mmol/L) with refer¬ ence to abnormal outcome was only 8 and 5%, respectively. Of 314 infants who had severe umbilical artery acidosis with long-term follow-up that were identified in the world litera¬ ture, 27 (8.6%) children subsequently were found to be brain-damaged (Kirkendall Et Phelan 2001). Murray et al (2006) recently used early continuous electroencephalo¬ graphs monitoring after perinatal asphyxia in term infants. It was demonstrated that the degree of metabolic acidosis (whether measured as base deficit, lactate or pH) could not reliably predict neonatal seizures. Only the 5 min Apgar score was significantly associated with both Sarnat grade and electroencephalographs abnormalities. Therefore, aci¬ dosis at birth does not appear to predict adverse outcome and cannot be used as a measure of potential compromise to the fetal brain. In addition, whilst measurements of umbilical-artery blood gases provide an accurate assessment of the immediate neonatal condition, their usefulness is limited because the results are often not available until after decisions regarding the treatment of the infant have been made (Papile 2001). In contrast, the absence of severe aci¬ dosis does not ensure a favorable neurologic outcome. Hermansen (2003) suggested there even may exist a ben¬ eficial effect of a mild to moderate acidosis, i.e. an acidosis paradox. Firstly, hypercarbia may result in cerebral vaso¬ dilatation and increased cerebral blood flow. Secondly, aci¬ dosis has been shown to decrease cerebral metabolism and lower the oxidative needs of the brain. Finally, acidosis promotes the unloading of 02 from the fetal hemoglobin by shifting the 02 dissociation curve. These three mechanisms theoretically lead to an adequate amount of 02 delivery to the brain tissue, which potentially limits damage. These

CHAPTER

The asphyxiated newborn infant

protective effects would be lost, however, with severe acidosis.

26

convulsions is reduced in the group that are electronically monitored but that there is no reduction in the risk of cere¬ bral palsy.

Cordiotocography (CTC) The fetal condition is assessed widely by means of measur¬ ing the fetal heart rate (see Ch. 24). This can be done inter¬ mittently by means of a stethoscope or by an electronic device. Continuous electronic fetal heart rate monitoring and evaluation of changes in heart rate with contractions (cardiotocography) have become very widely used in recent years, but there are relatively few data on the long-term prediction of outcome. Despite a near 3-decade experience with intensive fetal heart rate monitoring, aimed at the early detection of intrapartum fetal distress in sufficient time to prevent fetal brain injury, the impact on subsequent neuro¬ logic outcome has been minimal (Perlman 2006). Grant (1989) has reviewed the literature on fetal monitor¬ ing and performed meta-analyses on the published data. When electronic fetal monitoring with scalp blood sampling for fetal pH is compared with intermittent auscultation, there is no significant reduction in perinatal deaths (odds ratio 0.81, 95°/o Cl 0.22-2.98). Cardiotocogram (CTG) monitoring increases the risk of Cesarean section fourfold compared with intermittent auscultation. When the effect of electronic fetal monitoring and scalp sampling was compared with intermittent auscultation on neonatal seizures, there was a significant reduction in the number of infants with convul¬ sions in those fetuses continuously monitored (odds ratio 0.49, 95% Cl 0.29-0.82). There are limited data on the correlation with CTG moni¬ toring and subsequent disability. Painter et al (1978) fol¬ lowed up 38 full-term infants with ‘ominous’ fetal heart-rate patterns. These infants showed moderate to severely variable patterns with or without late decelerations. Of the 38 infants, five were neurologically abnormal at 1 year of age, and four in the group had patterns showing severe variability. Sur¬ prisingly, few of these infants had depressed Apgar scores. A subsequent report stated that none of these children were abnormal in later childhood (Paneth 8t Stark 1983). Ingemarrson et al (1981) showed that fewer infants were born with depressed Apgar scores over three time periods follow¬ ing the introduction of CTG monitoring, but in the high-risk full-term pregnancies, there was no statistically significant reduction in neurological sequelae at 2 years, although there was a trend towards improvement. This study was under¬ taken over a period of time when many changes were intro¬ duced in both obstetric and neonatal management, and no firm conclusions on the prognostic value of abnormal CTGs can be made. In a limited follow-up study from Dublin of electronic fetal heart rate monitoring versus intermittent auscultation, there were no differences in the number of children with cerebral palsy in the two groups (Grant et al 1989). In conclusion, CTG monitoring increases the rate of oper¬ ative deliveries, but does not reduce the risk of perinatal death. There is good evidence that the number of neonatal

Apgar score Whilst the 10-point Apgar score was not intended to be a measure of perinatal asphyxia, depression of the score has traditionally been widely used as a method for determining asphyxia and predicting outcome. The score does not reflect how long the infant suffered from intrapartum asphyxia and, therefore, is, in most cases, a blunt instrument for predicting outcome. The risk of handicap following depression of the Apgar score is best estimated from the data of Nelson and Ellenberg (1981). In full-term infants, the risk only becomes signifi¬ cant if the Apgar score remains 0-3 at 20 minutes. Depres¬ sion of the Apgar score to this degree at 15 minutes is associated with less than a 10% risk of subsequent cerebral palsy in surviving infants. In another study, 93% of infants with severely depressed Apgar scores (0 at 1 min and/or 0-3 at 5 min) were normal at follow-up (Thomson et al 1977). An overview of three studies investigating the outcome of full-term babies with depressed Apgar scores of 3 or less at 5 min showed that this carried an overall risk of mortality of 16% but only a 3% risk of handicap in surviving infants (Peliowski 8t Finer 1992). Levene et al (1986) identified a group of infants at risk of handicap following intrapartum asphyxia and assessed the sensitivity of various degrees of Apgar score depression (Table 26.7). They found an Apgar score of 5 or less at 10 min to be the most sensitive predictor of outcome, and this was also highly specific.

Onset of spontaneous respiration The time to the onset of spontaneous breathing or the first breath, or, alternatively, the need for intubation has been used by many as an alternative marker of immediate neo¬ natal condition that might be more useful than the Apgar score in assessing the severity of asphyxia. Unfortunately, these markers are likely to be even less discriminatory, as they measure only one characteristic and may be influenced

Table 26.7 Sensitivity and specificity of six different grades of Apgar depression (Levene et al 1986) Depression of Apgar score

N

Sensitivity

Specificity

(%)

(V

5 by 5 min

42

13

38

5 by 10 min

35

17

67

5 by 10 min

10

13

90

5 by 20 min

15

43

95

5 by 20 min

5

17

99

15 had a positive predictive value of 92% with sensitivity and specificity of 71 and 96% respec¬ tively. Levene et al (1986) found a moderate or severe encephalopathy to have a positive predictive value for adverse outcome (handicap or death) of 96% and a specific¬ ity of 78%. Three further systems have attempted to look at very early markers of neonatal complications that fall short of neurodevelopmental outcome (Perlman 8t Risser 1996). The aim of these studies was to identify a group of babies soon after birth who were at risk of permanent injury and in whom timely intervention may improve outcome (see Ch. 28). Table 26.9 shows the sensitivity, specificity and positive predictive value of these scoring systems. Caution must be exercised in interpreting the predictive value of these tests as neurodevelopmental outcome was not assessed, but rather vari¬ ables that may or may not be good markers of the risk of adverse outcome. A recent large retrospectively designed study evaluated 365 infants with HIE and found three clinical parameters to be predictors of severe adverse outcome (death or severe disability): administration of chest compression for >1 min, onset of regular respirations >30 min after birth, and base deficit value of >16 mmol/L on any blood gas analysis within

Table 26.9 Comparison of four scoring systems for prediction of term infants at risk of poor outcome following asphyxia

Perlman & Risser (1996)

Sensitivity

Specificity

(%)

ft)

Neonatal seizures

80

98.8

80

HIE

71

73

69

Outcome variable

Scoring system

Author

pH >7.00

PPV (%)

Delivery room intubation Apgar 10 min Onset seizures 6a

Multiorgan failure

—

—

73

Miller et al (2004)

Encephalopathy scores3 day 1

Development at 30 months

72

94

84

73

96

89

day 1-3 aSee text for scoring system PPV = positive predictive value

575

SECTION

V

PERINATAL ASPHYXIA

the first 4 h from birth (Shah et al 2006). Severe outcome rates with none, one, two, or all three predictors were 46, 64, 76, and 93°/o respectively. Miller et al (2004) developed an encephalopathy score based on six items (feeding, alert¬ ness, tone, respiratory status, reflexes and seizures) with a maximum score of 6 (worst) whilst 0 represents optimality. A maximum score on day 1 with seizures predicted abnormal outcome at 30 months with a sensitivity of 72%, specificity of 94% and positive predictive value of 84%. The type of abnormal neurological signs may also predict poor outcome. Brown et al (1974) recognize two clinical categories that are particularly associated with death or handicap. In the group with persistent hypotonia, only 16% were normal, and in those in whom hypotonia evolved to extensor hypertonia, only 23% were normal. Among infants with a predominant extensor type of abnormality, 56% were normal on follow-up. Apathy in the newborn period had also been reported to occur more frequently in infants with abnormal outcome, but no children were found to be severely handicapped in this group (De Souza ft Richards 1978). Convulsions may predict outcome to some extent. Approxi¬ mately half of the asphyxiated infants with neonatal sei¬ zures have some functional handicap (see Ch. 34). It is clear that the severity of abnormal neurological behavior occurring after birth in infants who have suffered intrapartum asphyxia is an excellent predictor of subsequent outcome. The pattern of abnormal neurological signs in asphyxi¬ ated babies may correlate with the distribution of brain injury. Full-term infants with predominantly basal ganglia involvement on MR imaging have persistent and diffuse neurological abnormalities compared with those who sustain injury mainly in the white matter. These latter show a dif¬ ferent clinical pattern with an improved sucking reflex and less severe abnormalities in tone (Mercuri et al 1999). Rosenbloom (1994) has described a group of severely asphyxiated babies with later development of dyskinetic (choreoathetoid) cerebral palsy to have relatively little evi¬ dence of HIE in the neonatal period presumably because of cortical sparing. Interesting data is emerging from current hypother¬ mia trials in term asphyxiated newborns. For instance, Ambalavanan et al (2006) recently performed a secondary analysis of data from the multicenter, randomized, con¬ trolled trial of hypothermia in HIE (n = 205 newborns) (Shankaran 2005), identifying predictor variables and devel¬ oping scoring systems and classification trees to predict death/disability or death in infants with HIE. If validated, scoring systems and classification trees may help in the assessment of prognosis and may prove useful for risk iden¬ tification in future neuroprotection intervention trials.

Brain imaging Computerized tomography (CT) is reported to be a good predictor of bad neurodevelopmental outcome in asphyxi¬ ated babies when extensive areas of hypodensity are seen 576

in scans taken at 7-14 days after birth (Adsett et al 1985, Fitzhardinge et al 1981, Upper et al 1986). The sensitivity and specificity of abnormal scans (diffuse or global decrease in density) in the prediction of major handicap or subse¬ quent death are reported to be 90-91 and 60-80%, respec¬ tively (Adsett et al 1985, Upper et al 1986). In contrast, others have shown no correlation between abnormal CT scans and outcome, but these studies were performed within 7 days from birth (Finer et al 1983, Lipp-Zwahlen et al 1985b). In summary, CT appears to be a good predictor of subsequent outcome in asphyxiated full-term infants, but only if the scan is done after the first week of life. This limits the value of this technique in the acute management of the severely asphyxiated infant in whom withdrawal of care is considered. Distribution of MR signal abnormalities can be subdivided according to the severity of hypoxia-ischemia (Barkovich et al 1995). Cases of mild to moderate hypoperfusion are char¬ acterized by parasagittal lesions, involving vascular border zones between anterior, middle and posterior cerebral arter¬ ies (watershed pattern), whereas profound hypotension involves primary lateral thalami, posterior putamen, hippo¬ campi and perirolandic gyri (cortical highlighting) (Aida et al 1998, Barkovich et al 1998, Rutherford et al 1996). It is clear that the risk of an abnormal neurodevelopmental outcome increases with the severity of the injury; however the pattern of injury also conveys important prognostic information. Newborns with a predominantly watershed pattern suffer from cognitive impairments that often occur without functional motor deficits (Miller et al 2004). In contrast, a basal ganglia-thalamus predominant pattern (Miller et al 2004) as well as an abnormal signal intensity in the posterior limb of the internal capsule (PLIC) on MRI are associated with severely impaired motor and cognitive outcomes (Rutherford et al 1998). Indeed, the best predictor of bad outcome in MR scans taken in the first 10 days of life is abnormality of signal intensity within the PLIC (Rutherford et al 1998). This is best seen on IR sequences and often associated with more extensive abnormalities within the basal ganglia. An abnormal or equivocal signal intensity within the PLIC predicted abnormal outcome with a sensitivity of 90%, specificity of 100% and positive predic¬ tive value of 100%. Given the frequent co-occurrence of watershed injury (Miller et al 2004) and cerebellar injury (Le Strange et al 2004) with the basal ganglia-thalamus pre¬ dominant pattern, cognitive deficits may result from damage to areas outside the deep gray nuclei themselves. Advanced brain imaging, i.e. quantitative morphometric MR techniques, MR spectroscopy and DWI (see Ch. 6), is emerging as a powerful tool to correlate the location and severity of brain lesions with neurodevelopmental outcome. The techniques can now be applied to measure subtle brain injuries, such as white matter injuries, and determine their association with long-term cognitive deficits (Miller et al 2002a, Nagy et al 2005). for example, in a recent case series, five patients with delayed recall, in the setting of intact

CHAPTER

The asphyxiated newborn infant

semantic memory and motor function between 8 and 14 years, were found to have bilateral hippocampal atrophy using advanced MR techniques (Gadian et al 2000). Two scoring systems have been described, which rate abnormalities seen on early MR scans in term asphyxiated infants (Barkovich et al 1998, Rutherford et al 1995). In MR studies performed before the seventh day after birth, higher scores as the result of basal ganglia abnormalities were most highly predictive of adverse outcome at 12 months (Barkovich et al 1998).

Electroencephalography These techniques are discussed fully in Chapter 12. The EEG abnormalities seen in mature asphyxiated infants and asso¬ ciated with a poor prognosis include iso-electric recordings and periodic patterns (Holmes et al 1982, Sarnat Et Sarnat 1976, Selton Et Andre 1997, Wertheim et al 1994) and per¬ sistent low-voltage states (Holmes et al 1982). Holmes et al (1983) have shown that some infants with a burst suppres¬ sion pattern can be stimulated to produce continuous activ¬ ity, and in these infants, the prognosis is better. A normal EEG in asphyxiated infants is usually associated with an excellent prognosis (Rose Et Lombroso 1970, Sarnat Et Sarnat 1976, Selton Et Andre 1997, Watanabe et al 1980, Wertheim et al 1994). Peliowski and Finer (1992) have performed a meta¬ analysis on four studies where early EEG assessment could be correlated with outcome in groups of asphyxiated mature neonates. Severe EEG abnormalities included burst suppres¬ sion, low-voltage, or iso-electric EEGs, and moderate EEG abnormality included slow wave activity. The overall risk of death or handicap derived from these studies is 95% for a severely abnormal EEG, 64% for a moderately abnormal EEG, and 3.3% for a normal or mildly abnormal EEG. Further studies published since this meta-analysis have confirmed these findings (Selton Et Andre 1997, Wertheim et al 1994). Cerebral function monitoring, a single channel com¬ pressed EEG signal (also referred to as amplitude integrated EEG-aEEG) is now widely used in neonates and is discussed in detail in Chapter 12. Several studies aim to determine the natural course of aEEG patterns during the first days of life in severely asphyxiated term infants, this in relation to neurologic outcome at 24 months or later (Shalak et al 2003). Normal voltage patterns (continuous and discontinu¬ ous normal voltage) up to 48 h of life seem predictive for normal neurologic outcomes (Ter Horst et al 2004). Burst suppression or paroxysmal activity has been reported to be associated with a poor outcome (Thornberg Et Ekstrom-Jodal 1994), and these abnormalities may be present within 4 h of birth (Eken et al 1995). Spontaneous recovery of severely abnormal aEEG patterns is not uncommon; the sooner the abnormalities on aEEG disappear, the better the prognosis. Evoked response EEGs such as visual, auditory and somatosensory evoked potentials may also provide accurate prognostic information in asphyxia, and the role of these

26

techniques in the prediction of outcome following birth asphyxia is discussed in Chapter 12.

Intracranial pressure Continuous measurement of intracranial pressure by a sub¬ arachnoid catheter gives some prognostic information (Levene et al 1987). No infant with a sustained rise in intra¬ cranial pressure of 15 mmHg or more lasting for an hour or more survived without major handicap. Infants with sus¬ tained elevations in intracranial pressure above 10 mmHg generally had a worse prognosis than those without a rise to this level, but a cut-off of 10 mmHg was not as sensitive for handicap as a sustained elevation to 15 mmHg. Interestingly, low cerebral perfusion pressure did not predict outcome as well as intracranial hypertension (Levene et al 1987). This is probably because hypotension can cause a low cerebral perfusion pressure without any significant cerebral edema. The hypotension reflects cardiovascular injury with a good prognosis rather than cerebral compromise.

Doppler assessment The use of Doppler ultrasound to assess cerebral hemody¬ namics has been shown to be a useful prognostic indicator in term asphyxiated newborns (Archer et al 1986, lives et al 1998, Levene et al 1989, Liao Et Hung 1997, Low et al 1994). The measurement of PRI (Pourcelot’s resistance index; see p. 557) predicts outcome in asphyxiated full-term infants with an 86% accuracy (Archer et al 1986). A low PRI (7.0 despite obvious injury during labor or delivery. In addition, by insisting that extreme derangements in pH values are required to begin to make the correlation between labor events and subsequent neonatal injury, these criteria modify the level of proof normally required in malpractice suits. The burden of proof in these suits requires that the level of confidence in the relationship between the events and the outcome be more probable than not. It is well to compare these pronouncements with a widely respected authority of neonatal brain injury. Brain injury in the intrapartum [period] does occur, [it] effects a large absolute number of infants worldwide and represents a large source of potentially preventable neurological morbidity. Among the many adverse consequences of the explosion in obstetrical litigation has been a tendency in the medical profession to deny the importance or even existence of intrapartum brain injury (Volpe 1995). These issues have also been discussed at some length for the brain-damaged infant and for brachial plexus injury. Excessive doses of oxytocin or prostaglandins during induction or augmentation of labor resulting in excessive uterine activity with fetal distress or uterine rupture are very common allegations in malpracticed suits. A clear defrnition of excessive uterine activity is essential along with protocols to deal with it promptly when it occurs. While hyperstimula¬ tion of uterine activity can be the result of endogenous maternal oxytocin and prostaglandins, most hyperstimula¬ tion is the result of administration of oxytocin or prosta¬ glandins. To avoid the recognized liability inherent in using the term hyperstimulation, many defendants, their attorneys and experts are quick to reserve the term hyperstimulation for excessive contractions that result in a non-reassuring CTG pattern (Simpson ft Knox 2003). From the perspective of maternal-fetal safety, the only reasonable approach is to avoid prolonged periods of excessive uterine activity - irre¬ spective of its designation or the response of the fetus. Failure to appreciate deteriorating fetal status as a result of coached pushing efforts during the second stage of labor. In some cases, it is the maternal heart rate and not the fetal heart rate that is being monitored (Murray 2004, Schifrin et al 2001). In the presence of repetitive decelerations pro¬ longed maternal breath holding (greater than 6-8 seconds) 616

or more than 3 pushing efforts per contraction during pushing should be avoided: pushing is stopped temporarily, pushing with every other contraction or every third contrac¬ tion. It is crucial that normal baseline rate and variability should be identifiable between contractions. In the presence of an epidural, coached pushing does not significantly decrease the length of the second stage.

FETAL CARDIOTOCOGRAPHY (CTG) In part, because of the pivotal role it plays in malpractice cases, there have been attacks on fetal monitoring that have come both from within the profession and from without. In an article in the Stanford University Law Review, Margaret Lent, a defense lawyer, argues that the widespread use of electronic fetal monitoring (CTG) is both medically and legally unsound. Ms Lent points to selected clinical trials to demonstrate that CTG does not reduce fetal mortality, mor¬ bidity or CP rates. She argues that because CTG has a very high false-positive rate and its usage correlates strongly with a rise in cesarean section rates it offers no medical advantage over auscultation, and provides no protection in the courtroom. She further argues that auscultation, at least as safe and effective as CTG, is also more likely to protect physicians from liability. Ms Lent concludes that obstetri¬ cians have an obligation to their patients and to themselves to adopt auscultation as the new standard of care. She finds ‘no excuses left to defend the continued use of CTG’. The medical literature can be used to justify any position on monitoring, including those of Ms Lent (Alfirevic et al 2006, Graham et al 1997). While failure on the part of the health care provider to recognize clear fetal heart rate abnormalities is frequently alleged in malpractice cases, to isolate the CTG tracing under these circumstances frequently oversteps its permissive role in obstetrical care. A normal CTG pattern permits ongoing labor only as long as safe vaginal delivery is a reasonable option. If the pattern turns abnormal (rising baseline, decreasing variability along with variable/late decelera¬ tions), especially in the second stage, then the questions are several. Can the pattern be ameliorated (by reducing the oxytocin, moderating the pushing efforts)? If the pattern cannot be ameliorated what is the feasibility of safe vaginal delivery given the estimated fetal weight, previous obstetri¬ cal history, position, presentation of the fetal head and progress in labor to this point? Experience suggests that the vast majority of cases hinge far more on the reasonableness of the conduct of obstetrical care (especially the second stage) than on the interpretation of the fetal monitor. Regard¬ less, reviewers of malpractice cases consistently find that the CTG tracing has been frequently misinterpreted in allega¬ tions of negligence.

THE LEGAL CLIMATE Most changes in both the medical and the legal professions are evolutionary and it is often difficult to define any sea

CHAPTER

Malpractice issues in perinatal medicine: the United States perspective

change. The last three decades, however, have witnessed a number of remarkable and epochal changes in the medico¬ legal climate in the United States, with doubtless more to come. Many of the changes derive from periodic surges in malpractice premiums, reduced availability of insurance coverage and the exodus of major insurers from the market first in the early 1970s, again in the mid 1980s, a lesser event in the 1990s and more recently in the new millennium. In each epoch, affected providers clamored for policy changes to, inhibit litigation. In the 1970s, legislatures established joint underwriting associations to serve as insurers of last resort, special state patient compensation funds were intro¬ duced to absolve commercial insurers of responsibility for specified dollar portions of malpractice payments and public reinsurance mechanisms were established to fill gaps in the underwriting market. By the late 1970s, the malpractice crisis had abated — only to recur less than a decade later. In Washington State between 1984 and 1986, for example, malpractice premiums for obstetrics jumped approximately 100%. As a consequence, obstetricians marched on legisla¬ tures or joined many family physicians and midwives in an exodus from obstetric practice. Those remaining in practice became more reluctant to care for high-risk obstetric patients and less willing to accept indigent patients and reduced fees, irrespective of the fact that indigent patients, in fact, appear less likely to sue. In many rural areas across the United States obstetric care became virtually unobtainable. Periodi¬ cally, these circumstances galvanized legislative activity in virtually every state and led to further far-reaching reforms of existing tort and insurance law with some stabilization of premiums — at least initially. After almost a decade of essentially flat premiums, premiums are rising exponen¬ tially, which is said to be due to the increasing size of awards and insurers leaving the medical malpractice business because of diminishing returns on investment. This has been aggravated by rising health care costs ($1.6 trillion in 2002 and increasing yearly) and efforts to control physician income. The average annual increase in health care costs from 2000 to 2004 was 12-16% with predictions that, whether or not the result of negligent care, they will rise by a further 8% in 2005, with likely little containment beyond that. It is important to emphasize that premium levels are responsive to a variety of factors besides litigation dynam¬ ics, including previous losses, past and expected investment returns, business strategies and the degree of state regulation of rate changes. A January 2004 study found that nation¬ wide, average premiums for all physicians between 2000 and 2002 rose by 15% - a rate of rise almost twice as fast as per capita total health care spending. Certain specialties had even greater increases, including obstetricians/gynecologists (22%) and internists and general surgeons (33%). Neurosur¬ geons, obstetricians, orthopedists and emergency room phy¬ sicians are particularly likely to have premium rate increases. The rates for obstetricians/gynecologists vary nationally, but according to ACOG, between 2002 and 2003 about half of

29

obstetricians/gynecologists were experiencing increases of 10-49% in their insurance premiums. Premiums may influence physicians’ decisions to join and leave the labor force, their choice of a medical specialty and their decision of where to locate, creating the potential for undeserved patient populations in certain specialties or geo¬ graphic areas. Rising malpractice premiums may also encour¬ age physicians to practice ‘defensive medicine,’ performing more tests and procedures than necessary in order to reduce exposure to lawsuits. Parenthetically, however, defensive medicine (ordering a test not for the purpose of furthering patient care, but for the legal protection of the physician) is indefensible in court. Imagine the physician-defendant responding to a question about the indication for a certain test with the answer: ‘I didn’t want to get sued’. Both rising malpractice premiums and defensive medicine practices may contribute to the rising health care costs and thus to an increase in health insurance premiums. The choices for the obstetricians — short of some windfall protection scheme - are leave practice, move to a ‘more compliant’ state, give up obstetrics, obtain employment where malpractice insurance is provided, raise fees, discon¬ tinue seeing patients with restrictive payment structures or go bare, i.e. do not obtain any malpractice insurance. For many, there is no good option and their future will hinge on the least inimical choice. Beyond physicians, these rapidly rising medical malpractice premiums have again become an issue of increasing concern about the health care system for policy makers and the general public.

UNDERWRITER DATA CLAIMS PAYMENTS The insurance industry also has its problems. In 2003, in¬ surers were paying out in claims and expenses $1.38 for every medical malpractice premium dollar collected. (National Underwriter Data Services). Results have deterio¬ rated steadily from 1998, when the rate of return was -7.6. Medical malpractice insurers’ return on net worth was -7.4% in 2002, down from -4.7% in 2001. Results in 2002 were the worst in the following states: Arkansas, Nevada, Montana, Mississippi, Illinois and Missouri, with a return on net worth ranging from -33.7% in Arkansas -24.4% in Mis¬ souri. In reality, even in the good years, premiums rarely cover payouts. The system works in part because premiums are invested and with at least a modest return permit the insurance company to make a profit. This is abetted by the fact that malpractice suits, especially, take a long time to resolve - about 4 years on average. The average claim payment rose almost 8% per annum from $95000 in 1986 to $320000 in 2002 despite the fact that the frequency of claims per 100 doctors has remained more or less constant. Only about 30% of claims result in insurance payouts, but expenses for cases, especially obstet¬ rical (brain-injured baby cases), where there is no payout are considerable. Concurrently, insurance companies, along 617

SECTION

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PERINATAL ASPHYXIA

with the population at large, faced reduced income from investments to help offset underwriting losses. Another study in 2004 found that hospital professional liability and physician liability claims costs have increased at a steady 9.7°/o since 2000 and are likely to rise at the same rate in 2004. Frequency, or the number of claims, is growing at 3% a year; claim severity (the dollar amount) is increasing by 6.5°/o annually. Hospital liability claim costs for 2004 are expected to reach almost $150000 per claim, compared with $79 000 per claim in 1996. The average claim against a physician is expected to reach $178 000, compared with $120 000 in 1996.

JURY AWARDS AND SETTLEMENTS In early 2005, a Towers Perrin study found that over the 28 years since 1975, when they were first identified separately, medical malpractice cost increases have outpaced those in other tort areas, rising at an average of 11.8% a year, com¬ pared with 9.2% for all other tort costs. In 2003, medical malpractice, at almost $27 billion, cost each American an average of $91 a year. This compares with $5 a year in 1975. Recent data suggest that while jury awards are stabilizing and the frequency of claims may be decreasing, the severity of malpractice claims is increasing and the range of awards is moving upward, in keeping with inflation (Baker 2005). Median medical malpractice jury awards have held steady at about $1 million over the 3 years 2000-2002. Awards ranged from a low of $11 000, almost double the amount of the previous year, to a high of $95 million. The average award in 2002 hit $6.25 million, up from $3.91 million in 2001. However, only a small fraction of cases go to trial and very large awards are frequently reduced after the fact and after the publicity. The costs of perinatal injury are quite high, relative not only to the costs of settlement and defense but also to per¬ sonal and professional upheaval for all concerned. As Simpson and Knox have pointed out, the perspective of human and system factors reveals themes, context, and conditions common to accidental injury in other high-risk domains. According to the Jury Verdict Research, in 2000 the median jury award for neonatal neurological injury had increased to $5 million compared to $725 000 in 1994, with 76% of the jury awards valued at greater than $1 million (compared to 40% in 1994). Higher awards were more likely to occur when the hospital was the sole defendant than when both were defendants. Conventional wisdom holds several contributing factors to account for the increased incidence of malpractice claims. (1) People are more litigious; it is part of our culture and extends everywhere from lawyers themselves to city govern¬ ments. (2) Given the media coverage and watchdog groups, there has been an increasing understanding by the public of the fallibility of physicians. The Public Citizen Health Research Group, and the more recently formed groups emphasizing both medical error and the need to improve 618

care as part of tort reform, have also helped fuel the public’s demand for change. (3) Another factor is the diminishing intimacy of the patient-doctor relationship fomented in part by larger changes in the way health care is distributed (HMOs), by increasing overheads and by deteriorating reim¬ bursement schedules. (4) Then, there is the increasing avail¬ ability of medical experts to testify in malpractice cases (the breakdown of omerta). (5) Also, there is the increasing asser¬ tiveness of the courts and the increasing sophistication of the plaintiffs bar with more careful selection of meritorious suits. (6) Last, there is the need for assistance with financing medical bills. Indeed, there is a seeming increase in the fre¬ quency of lawsuits for the ‘damaged child,’ in part due to the large verdicts sometimes realized but also due to the increasing incidence of CP related to the increasing survival of low birth weight infants and the costs thereof. Several clinical practices and media attention would seem also to be impacting on the frequency and type of lawsuit. As an example, the United States Food and Drug Adminis¬ tration (FDA) issued a national advisory on the risks of vacuum extractors. This was rapidly followed by a nation¬ wide television program emphasizing some of the disastrous results with vacuums. In turn, there has been a dramatic increase both in the reporting of adverse events associated with vacuum deliveries to the FDA and in the number of lawsuits alleging negligent care in the use of vacuums. Similarly, the methods undertaken to lower the cesarean section rate in the United States have perhaps been accom¬ plished at the expense of an increased risk of ruptured uterus, shoulder dystocia and lawsuit. While all authorities would agree that any woman with one previous cesarean section and no other adverse features may be eligible for an attempt at VBAC, if she chooses to do so after being care¬ fully explained the options, some HMOs have refused to accede to the mother’s choice and have required that every patient with a previous cesarean be given a trial of labor; a horrific, medically indefensible recommendation. One insti¬ tution in California that adopted this policy was assessed almost $25 million as a result of 48 women who first suf¬ fered adverse outcome as a result of this policy.

PREVALENCE OF MEDICAL MALPRACTICE A study (generally known as the Harvard study) commis¬ sioned by New York State in 1986, and repetition released in 1990, showed that although actual malpractice is rela¬ tively rare, it is nevertheless underreported. If anything, the study group believed that there were too few lawsuits (Brennan 1991). When hospital medical records from New York State were examined, the incidence of adverse events or injuries resulting from medical ‘interventions’ or treat¬ ment was 3.7%. The percentage of adverse events due to what the physician team characterized as ‘negligence’ (not necessarily a legal definition) was 1%. However, only one in eight who suffered from an adverse event due to negli¬ gence filed a medical malpractice claim, and only 1 in 15

CHAPTER

Malpractice issues in perinatal medicine: the United States perspective

received compensation. Most adverse events resulted in only minimal and transient disability and most of the patients’ medical care expenses were paid for by health insurance. This helps to explain why only a small percentage of patients who are injured as a result of negligence fde medical mal¬ practice claims. However, a significant proportion (22%) of patients who did not file medical malpractice claims suffered moderate or greater incapacity. In the second phase of the study, researchers confirmed that some of the tort claims filed provided little or no evidence of medical malpractice or even an adverse event, suggesting that the tort system is ‘very error-prone,’ at least in its initial stages (related to the expert). This inefficiency in both the medical and the legal systems notwithstanding, the study noted that ‘if anything, there are too few lawsuits’. The inference here is that more patients with adverse outcomes related to negligence should be suing. Despite the allegations of ACOG regarding the lack of value of intrapartum care in the prevention of fetal injury or death, there are several studies of closed claims in obstet¬ rics and their relationship to negligence or their adherence to guidelines. Julian et al reviewed the files of 220 obstetric closed-claim cases to identify common factors predisposing to claims and to suggest preventative measures. Identifica¬ tion of common obstetric risks and correct management of these risks were poor in these cases. Only 54% of the risks were recognized; of these, only 32% were correctly managed. A high percentage of risks were thought to be directly related to the obstetric outcome leading to the claim (66%). The authors feel obstetric closed claims can be studied and suggestions made to aid obstetricians in pro¬ viding care. They concluded that obstetric malpractice closed claims are amenable to study; physicians and their patients would benefit from better data collection systems to identify risks in individual pregnancies, along with avail¬ able resources to aid their management of patients. They felt that suits can be avoided through modification of phy¬ sician behavior. In 1989, Rosenblatt and Hurst reviewed all closed obstet¬ ric claims in the records of a major physician-sponsored malpractice insurer from 1982 to 1989. Of the 54 files closed during the 6.5-year period covered by this study, 21 (39%) involved physician reports of bad outcomes that did not lead to a formal claim. Of the 33 formal claims, 14 (42%) were dismissed, either by the plaintiff s attorney or by the courts. Eighteen of the remaining 19 claims were settled before trial, with an average payment to the plaintiff of $185 000. The one suit that went to trial resulted in a defense verdict. A review of the case histories demonstrated that in the major¬ ity of cases when a payment was made, probable medical negligence had taken place. Non-meritorious claims were not compensated. For those cases in which a payment was made, the size of the settlement was commensurate with the seriousness of the injury, which almost always involved damage to the infant. Poor physician judgment was the most common source of error.

29

The surviving, handicapped infant continues to represent the highest payout/case. There are numerous representative reviews of closed cases (Table 29.3). An analysis of 353 closed claims involving obstetrician-gynecologists revealed that the 40 highest-paid claims (11.3%) accounted for 88.7% of the total dollars spent. The majority of these 23 (57.5%) were obstetrical, including the five highest claims and 17 of the first 20 highest-paid awards. Obstetrical negligence rep¬ resented over $5 million (76.5%) of the total expense. Of the 40 cases, 23 (60%) were resolved with a compromise settle¬ ment, 9 claims (22.5%) were resolved with indemnity payment on the basis of verdict or pretrial compromise; 7 (17.5%) had no indemnity payment because of a juiy verdict or voluntary dismissal. These seven were in the highest-paid claims group only because of expenses.

Table 29.3 Operative delivery notes OP DEL NOTE: (A) MF, OP OA, mid epis, no lac Apgar 8, 9 P and M intact EBL 400, M and B left DR in good cond. Signature Translation: Operative delivery note: Midforceps, occiput posterior (OP) to occiput anterior (OA), midline episiotomy. no lacerations Apgar scores 8, 9 at 1, 5 minutes. Placenta and membranes expressed intact. Estimated blood loss 400 mL. Mother and infant left the delivery room in good condition OPERATIVE DELIVERY NOTE (B) Procedures: Trial of forceps, midforceps rotation, episiotomy repaired Findings: Gynecoid pelvis, normal active phase, +3 station, minimal molding, direct OP. epidural anesthesia, second stage 2.5 hours, pushing inadequate, patient tired EFW 3000. Prev. baby 2800 Indications: Persistent occiput posterior, prolonged second stage, secondary arrest of descent, tired patient Informed consent: Discussed options with patient and husband, who agree and understand that if any difficulty is encountered, the forceps will be abandoned and cesarean section undertaken. The operating room has been alerted Methods: Midline episiotomy Kielland forceps. Direct application to OP without difficulty Gentle rotation: ROT to 0A. Kiellands removed, Simpson forceps applied. Gentle traction — delivered as 0A Fetal outcome: 3200-g male infant, APGAR 8, 9 (see individual features in chart) Resuscitation: Oxygen only, no evidence of trauma to skull forceps, marks reveal appropriate placement Maternal outcome: Perineum intact, episiotomy repaired, no lacerations Placenta and membranes intact Estimated blood loss: 300 cc Mother left delivery room in good condition

619

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Of the 40 cases, none were considered frivolous, 28 (70%) were judged to be meritorious, and 12 (30%) were judged to be non-meritorious. Seven of the latter settled without indemnity costs, including four that went to trial with a defense verdict and three that were dismissed, leaving five others in this group with proper treatment and indemnity costs. Expenses to defend all 12 cases of proper treatment totaled over $500000. Irrespective of the absence of strict negligence, each of these ‘non-meritorious claims’ illus¬ trated substantial deficits with the medical record or system failures — inviting the allegation of negligence and lawsuit (making the case appear meritorious). These analyses clearly reveal that bad outcomes may not be the fault of the physi¬ cian, but that physician behavior in the conduct of the case and the conduct of the medical record contribute heavily to successful allegations of malpractice. Ogburn et al reviewed 153 closed claims involving peri¬ natal injury or death filed from 1980 through 1982 with the St. Paul Fire and Marine Insurance Company. The claims included were those in which an indemnity was paid or $1000 or more was expended on the legal defense. Cases were classified according to the presence or absence of medical negligence. Most of the complications leading to claims arose during labor and delivery. Many claims resulted from the failure to evaluate or treat in a manner consistent with accepted standards of care. Many lacked documentation of the physician’s recognition of the risk factors involved. In the opinion of the reviewers, medical negligence occurred in 47% of the cases. Indemnity payment occurred with most (but not all!) of the claims judged to be associated with medical negligence. Payment to the claimant was also made in a number of cases in which the reviewer thought no mal¬ practice had occurred. The authors concluded that these results suggest that improvements are needed in prenatal and perinatal health care as well as in the legal system used to address the problem of perinatal medical negligence. In a study published in 2003, Ransom et al, tried to esti¬ mate whether guideline compliance affected medico-legal risk in obstetrics and whether malpractice claims data can provide useful information about compliance. From the claims experience of a large health system delivering approximately 12 000 infants annually, they retrospectively identified 290 delivery-related (diagnosis-related groups 370-374) malpractice claims and 262 control deliveries between 1988 and 1998. Clinical pathways for vaginal delivery and cesarean section, implemented in 1998, were used as a standard of care. They compared rates of noncompliance with the pathways in the claims and control groups. They found that non-compliance with the clinical pathways was significantly more common among claims than controls (43.2% vs. 11.7%, P < 0.001; odds ratio 5.76, 95% Cl 3.59, 9.2). In 81 (79.4%) of the claims involving non-compliance with the pathway, the main allegation in the claim related directly to the departure from the pathway. The excess malpractice risk attributable to non-compliance explained approximately one-third (104 of 290) of the claims 620

filed (attributable risk 82.6%). They concluded that malprac¬ tice data are a useful resource in understanding breakdowns in processes of care and that adherence to clinical pathways might (1) reduce clinical variation, (2) improve the quality of care, and (3) protect clinicians and institutions against malpractice litigation. A study by Greenwood et al from the National Perinatal Epidemiology Unit, Oxford, United Kingdom compared the prevalence of criteria suggesting acute intrapartum hypoxia in children with CP according to whether a lawsuit was brought alleging obstetrical negli¬ gence. The subjects were singleton children with CP born between 1984 and 1993, excluding cases with a recognized postnatal cause for CP. Only one-fifth (27/138) of all singleton CP children were the subject of a lawsuit. The greater the number of criteria suggesting intrapartum insult the more likely was a legal claim (P < 0.01), but 36% (4/11) of those satisfying all required criteria did not make a claim. Of the 27 claims, 12 were discontinued, 8 were settled and in 7 the legal process was still pending at the time of the article. Furthermore, the presence of the three essential cri¬ teria for acute intrapartum hypoxia did not increase the likelihood of a legal claim being settled. JCAHO has recently published a study of adverse perinatal outcome finding many examples of substandard care and communication in the genesis of adverse perinatal outcome (JCAHO 2004). Other studies have focused on the costs and outcomes of litigation but not on culpability. Closed claims provide valuable data, but because, on average, a medical liability case takes 3-5 years to come to closure, opportuni¬ ties for timely intervention in unsafe practices are lost. The research value is further compromised when the details of cases that reach settlement are suffocated by ‘gag clauses’ that mandate silence not only on the amount of award, but also on the allegations and the admission or even acknowl¬ edgment of wrong-doing, thereby removing an obvious incentive to make care better. Hatlie and Sheridan have suggested that gag orders are counterproductive.

MEDICAL RECORDS Unfortunately, the opinions that serve to launch medical or medico-legal proceedings are most often based on a review of medical records that are frequently silent on the intentions of the provider or their exercise of ‘medical judgment’. They may be silent, as well, on fundamental details of the obstetri¬ cal care. As a result, medical records, which represent both a medical document and a legal document, often promote or perpetuate cases and confound their defense. A cost analysis of 3205 multispecialty claims showed an average cost per claim of $22 584. Deficits in the medical record, e.g. inade¬ quate instructions, delayed entries, inadequate notes and consent-form issues, more than double the average cost. System failures nearly triple the average cost. Thus, while an erroneous decision may be defensible if the reasons leading to it are recorded in the chart, the changed record and the contradictory record are almost impossible to defend. Until

CHAPTER

Malpractice issues in perinatal medicine: the United States perspective

medical records objectively communicate the findings, the attention paid, the comprehension that was achieved and offer a reasonable plan followed by appropriate and consis¬ tent action, their appearance in court will continue to be an uphill battle for the physician and he/she will get little credit for the thought process or use to his/her advantage the testi¬ mony of‘a witness whose memory never dies’. As an aside, the reader is invited to compare the two enclosed notes regarding a midforceps procedure (Table 29,.3). In the first example, the note invites lawsuit if there is an adverse outcome. The note provides no indication for, or details about, the procedure. It is more a personal memo¬ randum than a responsible medical description relevant for decisions about care in future pregnancies for example. The second note, on the other hand, would seem to protect against lawsuit in several ways. The note (1) clearly bespeaks thoughtfulness, (2) bespeaks understanding of the medical issues and alternatives and (3) underscores the physician’s efforts to provide a forthright explanation to the patient and her husband — all powerful disincentives to lawsuit. Naked may be the best disguise! One can readily blame the plaintiffs attorney for bringing to suit an apparently frivolous case, but who is to blame (i.e. what has been learned?) for the negligent care and adverse outcome in situations where no suit is brought despite negligent care or where no award is made despite a suit and the physician’s care is vindicated? Should the plain¬ tiff s attorney be blamed for pursuing a case that his expert has told him, based on a review of the medical records only, is negligent care? Each of the articles that evaluated closed cases found appreciable amounts of agreed upon negligent care. Each emphasizes (1) the need for better data, (2) the inculpating role of physician behavior and (3) the impor¬ tance of the review of malpractice claims to identify problemprone clinical processes and suggest interventions that may improve outcome and reduce negligence. It must be readily apparent from even these limited studies that not all meritorious suits succeed and not all nonmeritorious suits (not the same as frivolous) lose. These articles leave it open to speculation why patients victimized by obvious medical negligence do not sue or why they are not compensated by the system in the face of agreed upon negligence. Clearly, patients without demonstrable evidence of negligence bring suit and sometimes they are rewarded in the system. The system does not work perfectly, but these studies from various specialties and perspectives strongly suggest that it is not a lottery. In a study of 36 malpractice cases involving cervical spine surgery, for example, the authors found a common basis for suits included failure to diagnose and treatment (56°/o), lack of informed consent (64%), new neurologic deficits (64%), and pain and suffering (72%). All of the six plaintiff verdicts (average, $4.42 million) and four of the nine settlements (average, $1.6 million) involving surgery that resulted in new postoperative quadriplegia appeared to be appropriate. However, the author could discern ‘no fault’ in cases five

29

defendants had settled. On the other hand, the author found ‘fault’ in five defense verdicts rendered to three newly quad¬ riplegic patients and two with new postoperative root inju¬ ries. These patients deserved monetary awards, but received no compensation whatsoever (Epstein 2002). Given the non-medical issues that incite or color a case, physicians squander much of the advantage they have in the system! Thus, it is with some justification that critics of malpractice litigation point out that it is unrealistic to expect that increased levels of litigation will make compensation for injuries more ‘just’ or health care better. A reductio ad absurdum argument suggests that immunity from lawsuit, perhaps the true goal behind physicians’ notion of tort reform, will, by eliminating lawsuits, achieve these goals. Some conventional tort reforms appear to be effective in reducing litigation costs and stabilizing insurance markets; they are not, however, designed to remedy the fundamental failings of the malpractice system - making care better and making the physician-patient relationship better. Fulfill¬ ment of these objectives may not require more sweeping tort reform; perhaps more sweeping ‘thought reform’ may be required or, alternatively, trying to make the system work as it was supposed to. These reforms can only come from the medical community.

LEGAL VULNERABILITY The last several decades have also witnessed the develop¬ ment of new bases for lawsuit in reproductive matters, including wrongful birth and wrongful life. In the former, the parents with an injured child may bring suit alleging that negligent treatment or advice deprived them of the opportunity to avoid conception or terminate a pregnancy. The latter, brought on behalf of the child born with birth defects, alleges that the child would not have been born but for negligent advice to, or negligent treatment of, the parents. It should be emphasized that such allegations are actionable in some states but not in others. While not strictly related to malpractice, a mother who pleaded with her hope¬ lessly premature infant’s caretakers to discontinue resuscita¬ tion was not heeded, resulting in the survival of a severely handicapped child and a provisional $42 million verdict for the plaintiff.

TORT REFORM MEASURES Most liability reform acts have four major components: (1) reforms directly addressing the size of awards - under the heading of caps on damages; (2) reforms intended to modify liability rules, to control the number of claims and size of payouts by eliminating joint and several liability for cases in which a plaintiff found to be partially at fault becomes responsible for a disproportionate share of the damages; (3) reforms limiting access to the courts, through shortening statutes of limitation — a reduction in the length of time during which lawsuit can be brought; and (4) periodic pay621

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PERINATAL ASPHYXIA

merits — the latitude to pay future economic damages over time. Some initiatives have legislated review panels to pass on the merit of a case prior to the institution of suit, while others have attempted to remove the infant who is brain damaged during birth from the medico-legal arena by the institution of no-fault insurance. Still other initiatives have attempted to increase the percentage of any award that goes to the patient by limiting the attorney’s fees. The most popular of these, caps on premiums, have had the benefit of moderating the increases in insurance payments. A pub¬ lication from the Rand Corporation has emphasized that in cases with modest claims there is indeed a reduction in indemnity payouts, but they cast doubt on the likely benefit of caps on the high-award cases where economic damages are large and ‘pain and suffering’ may be much smaller. It seems axiomatic that caps should not apply to frivolous suits where the cap should be zero. In the 1970s 22 states legislated some form of prelitiga¬ tion processes, including screening panels and mandatory binding and non-binding arbitration: only two remain active and neither has been effective. The costs of constitutional battles over due process rights for binding processes and the failed reduction of litigated cases in non-binding processes led to further soaring legal costs, rather than reductions. The only lasting ‘tort reform,’ although, as discussed later, with questionable material impact on malpractice frequency and awards, has been caps on non-economic damages, with the gold standard being that of California’s Medical Injury Com¬ pensation Reform Act of 1975 (MICRA). Tort reform, the mantra of the ACOG, the Bush adminis¬ tration, the Chamber of Commerce, the American Manufac¬ turers Association and other business organizations to deal with high medical malpractice costs, makes sense only from the political aspect (Baker 2005). Capping awards on mal¬ practice suits may offend trial lawyers, but it helps or holds harmless special interests in the insurance, drug and health care industries. It provides no assistance to patients who suffer grievous harm as a result of negligent care nor does it improve the delivery of medical care. To many, a $250000 cap (the cap placed on non-economic damages in California) is poor acknowledgment indeed for the physical and emo¬ tional damage done to people who have suffered total paral¬ ysis, permanent blindness or severe brain injury because of medical errors. Indeed, many states burdened with high premiums have already set their own caps, but generally at more reasonable levels. It would seem more useful to con¬ sider making it harder for insurance companies to gain rate increases. Guidelines forjudges and juries might be enacted to help determine what compensation is reasonable in a given cir¬ cumstance. Similar guidelines could help ensure that puni¬ tive damages, sometimes masquerading as non-economic damages, are high enough to deter bad conduct; $250000 would hardly amount to a slap on the wrist. The problem with frivolous lawsuits is best addressed by raising the hurdles for filing a malpractice suit, for example, 622

requiring an expert judgment on the merits of a case before it can proceed through the courts. As mentioned above, there seems to be no place for the expert witness to certify a case as meritorious if that same expert will not appear on the record for (public) report, deposition and trial if necessary. The notion that the crisis of escalating malpractice insur¬ ance premiums is forcing doctors out of business remains murky. Insurance companies have substantially raised pre¬ miums for malpractice coverage for doctors in high-risk specialties like obstetrics and neurosurgery in some states, leading at least some doctors to curtail their services, retire or move. But when the Government Accountability Office visited five of the hardest hit states in 2003, it found only scattered problems and was unable to document wide-scale lack of access to medical care. None of the tort reform proposals deal with the underlying need to diminish malpractice and to identify harmed patients and provide them with fair, prompt compensation, or provide tools for health care providers to properly prepare patients and deal effectively with unanticipated outcomes. Although they do resolve the desire of the health care industry and the insurance companies for fewer big court awards, they do not materially impact the frequency of suit. But they do act as a rollback of the legal rights of patients who are injured. The Center for Justice and Democracy, a consumer advo¬ cacy group, recently commented that: It may be hard to understand why ‘tort reform’ is even on the national agenda at a time when insurance industry profits are booming, tort filings are declining, only 2°/o of injured people sue for compensation, punitive damages are rarely awarded, liability insurance costs for businesses are minuscule, medical malpractice insurance and claims are both less than l°/o of all health care costs in America, and premium-gouging underwriting practices of the insurance industry have been widely exposed. (See also Baker 2005.) Despite claims by the insurance industry, there is no evidence that malpractice premiums are the result of sharp increases in the amounts of money paid out for malpractice claims. And, tellingly, industry execu¬ tives have carefully acknowledged that tort reforms will not result in substantial premium reductions — only an improve¬ ment in care can do that (Baker 2005). Caps do not limit lawsuits. More reasonably, caps are intended to increase the hurdles to a lawsuit by diminishing the economic value of a suit. In cases where there is little economic loss (irrespective of negligence), victims may not be able to find lawyers to take their cases (www. saynotocaps.org/) because malpractice cases can cost plain¬ tiff s lawyers hundreds of thousands of dollars out of pocket to prosecute, with no guarantee of recouping those expenses. As pointed out by the Rand Corporation study, caps have little impact on lawsuits where there are substantial eco¬ nomic losses, e.g. brain-damaged infant, maternal death. A

CHAPTER

Malpractice issues in perinatal medicine: the United States perspective

one-size-fits-all cap cannot encompass the unique facts in any case and, in fact, more reasonably creates a system of ‘one-size-fits-none’. It unfairly discriminates against victims with no economic losses, such as children, stay-at-home moms, the elderly, the poor and the mentally handicapped. The media unflinchingly promulgates numerous cases of tragic, ineffable medical error where such arbitrary limits (originally set in 1979) seem inadequate and, if not inade¬ quate, arbitrary. Caps will not lower doctors’ malpractice insurance premiums. (www.saynotocaps.org/reports/ Premium Deceit.pdf: The Failure of Tort ‘Reform’ to Cut Insurance Rates) Average premiums are actually 16°/o higher in states with caps. In states that have recently adopted caps, most notably Texas and Florida, insurance rates are continu¬ ing to increase. Indeed the only thing keeping rates down in California — a state often cited as a model for caps - is insurance industry regulation provided by Proposition 103. The amount of money awarded on pain and suffering is not known. In the majority of awards, those reached by settlement out of court, there is no distinction between economic and non-economic damages. In jury trials eco¬ nomic and non-economic damages are awarded separately, but there appears to be no calculation of either the amount or the propriety. Nor has there been any compilation of those extreme awards that are reduced, sometimes drasti¬ cally, by judicial review. In three cases where the jury awarded over $220 million, the total cumulative amount received was $14 million (6 cents on the dollar!). There was no publication of the reduction! When adjusted for the skyrocketing rate of health care inflation, total payouts in malpractice cases remained flat until 2001. In the 3 years since, total payouts have declined each year. Many states have enacted legal reforms that have effec¬ tively eliminated any lawsuits that could be construed as ‘frivolous’ by requiring a ‘certificate of merit’ from a physi¬ cian certified in the same medical specialty as the doctor being sued. There have also been laws enacted to prevent ‘venue shopping’ for a more favorable jury. Indeed, a Repub¬ lican state senator from Pennsylvania declared that ‘There is no such thing as a frivolous lawsuit any more’ in Penn¬ sylvania. In addition, again in Pennsylvania, one of the ‘red alert states,’ there has been a significant increase in the number of physicians over the past several years, prompting one state legislator to call such claims of a doctor exodus as ‘scare tactics’. It is far from clear that malpractice costs are driving up the costs of health care. Malpractice costs account for less than 2% of the US health care budget. The Congressional Budget Office, in a report released in January 2004, found that legislation to cap damages in medical malpractice law¬ suits would ‘do little to hold down health care spending’ or eliminate the practice of ‘defensive medicine’. There is little evidence that the threat of malpractice lawsuits contributes to the practice of defensive medicine. Rather, it has been suggested that doctors order additional tests because it is good medical practice; doctors make money from additional

29

testing; and managed care discourages unnecessary testing, or ‘bad’ defensive medicine. Faulty underwriting and misfeasance by malpractice underwriters are additional factors contributing to the rise in premiums; they cannot be relieved by tort reform. In Pennsylvania in the late 1990s, six major malpractice insur¬ ers became insolvent because of risky premium underpric¬ ing, poor investment strategies and Enron-style malfeasance, leaving doctors to pay for their mismanagement. There is no basis for the notion that insurance companies routinely settle lawsuits just to make them go away. This seems more like a strategy for self-destruction and is contradicted by the closed-claims data presented above. There can be little doubt that there is an immediate ques¬ tion of affordability that must be dealt with acutely. Indeed, several states have contributed significant amounts of public money to subsidize insurance premiums. Physicians remain the highest-paid professionals in the state, according to US Census data. Indeed, the incomes of obstetricians - the physicians most affected by higher premiums — are rising. For many, on average, doctors spend l-5°/o of their gross revenues on medical malpractice insurance. It seems obvious also that many doctors supplement their incomes with fees from attorneys for providing ‘independent medical evalua¬ tions’ in malpractice cases.

ALTERNATIVE SYSTEM REFORMS Experts have suggested a number of approaches, including special health courts with judges trained to deal with mal¬ practice issues, required mediation, mandatory reporting of errors by doctors and prompt offers of compensation. Some of these will be reviewed briefly here. Not strictly a part of tort reform, alternative dispute resolution has much to rec¬ ommend it. The strict liability (no-fault) administrative system sup¬ ports creation of a just patient safety culture and encourages reporting (and prevention) of adverse events. It has the advantages of dispensing with trial and supports open dis¬ closure to the patient (not the public) as the deliberations are administrative. In this system the provider is accountable for all avoidable medically related losses and the matter can be resolved promptly. It eliminates the requirement of proving negligence, but the patient must establish that their injury was actually caused by the treatment. As a general¬ ization, eligibility is based on avoidability rather than pro¬ viders being strictly responsible for medically related losses. There is, unfortunately, the common perception that ‘no¬ fault’ means ‘no accountability’. Examples include the Neu¬ rological Injury Compensation Association (NICA) in Florida and Virginia. Although, the system of No-Fault is modeled after that of Workers Compensation and Automobile No-Fault claims, the complexity of determining causal and avoidable injury medical injury claims is very different. And although it removes negligence as a basis for the claim, it does not 623

SECTION

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replace the regulatory system of reporting and the resultant physician fear, nor does it address the inbred philosophy of ‘do no harm,’ ‘zero tolerance’. Since premiums in any no¬ fault system are based on injury rates, this creates an incen¬ tive to conceal injuries and reduce the admission of high-risk specialists to medical staffs. It may also discriminate against patients at high risk for injury. It is uncertain how the establishment of a no-fault system will impact cost. Some test programs have demonstrated that costs of a general no-fault system would exceed those of the present tort system. Finally, the introduction and administration of a no-fault medical injury system, whether public or private, will be complicated and likely politically encumbered. Preventable events (ACEs) represents consensus on what constitutes an avoidable event. These are predetermined events that should not occur in quality health care delivery. They encourage prevention of avoidable events that can trigger eligibility for an early compensation offer. ACEs make ‘avoidability,’ and therefore eligibility for compensa¬ tion, transparent to providers and patients alike. They stan¬ dardize eligibility for compensation and provide quicker identification of eligible cases. There is, however, no com¬ prehensive ACE list currently available, and there is concern as to who is to develop the categories of avoidable events. Brain-damaged infants, for example, would not be covered. Development of the list will, of course, require an array of expert consensus (selected by whom?). The use of ACEs provides a basis to determine eligibility for alternative and conventional compensation systems. It can also be paired with a standardized compensation fee schedule.

MEDIATION Mediation represents a highly efficient option for nonadversarial resolution of health care conflicts. It is a process in which the parties to the conflict themselves, not lawyers, craft their own unique resolution to a conflict. Mediation is essentially facilitated communication and negotiation using a neutral third party. The process itself is non-binding and does not prevent the patient from moving forward to litiga¬ tion. However, if a resolution is reached, it becomes binding under contract law and may even be brought as an order of the court. Mediation is highly cost-efficient and time sparing, in that it makes response to adverse events and their resolu¬ tion more timely and boasts a greater than 90°/o resolution rate. It is widely accepted and highly successful in many ‘industries’ such as real estate and education, but has met with much resistance in the health care industry, especially in medical malpractice. It intensifies the pressure on patients to settle, thus reducing or avoiding litigation. Because con¬ fidentiality has been stripped from the mediation process in medical malpractice disputes by medical regulatory boards and reporting agencies, the successful application of the mediation process in physician-patient conflicts has there¬ fore been crippled. Although confidentiality in error report¬ ing is the foundation of most of the proposed legislation, it 624

has not been extended to the resolution of conflicts arising from alleged medical errors. The statutory obligation physi¬ cians have to report settlements of disputes involving quality of care issues creates a perverse incentive for physicians to move forward in litigation, especially when one considers the high attrition rate of malpractice claims and the likeli¬ hood of a physician prevailing in those cases that persist. It is likely that even in the face of tort reform mediation will remain an infrequently used medium for the resolution of physician-patient disputes.

ARBITRATION As with mediation, arbitration provides economical and prompt adjudication of adverse events. Like mediation, it provides prompt, private settlement and compensation, yet is also subject to reporting requirements and regulatory oversight. The processes differ, however, in a few major factors. With arbitration the decision maker is a third party, the arbitrator(s) and the process is highly formalistic and adversarial. There are two forms of arbitration, binding and non¬ binding. The latter is similar to mediation in that if either party disagrees with the arbitrator’s decision, they may move on to litigation. The former, however, is a binding decision that cannot be appealed. Binding arbitration for malpractice claims has met with considerable legal opposi¬ tion and non-binding arbitration has met with low utiliza¬ tion and increased litigation costs. Such systems intensify the pressure on patients to settle, thus reducing or avoiding litigation. They may be used with the current tort system — as well as with no-fault and ACEs. Kaiser Permanente, for example, requires enrollees to sign a ‘willingness to arbi¬ trate’ agreement. With this approach, the health plan under¬ takes to resolve disputes through arbitration rather than go through the courts. This of course is not the same as a waiver of liability.

SPECIALIZED MEDICAL MALPRACTICE COURTS There are three types of specialized courts under consider¬ ation: the Health Court, the Medical Board Administrative Adjudication System and the Tripartite Panel. Health Court: This involves the creation of an alternative court system within the federal court system. This proposal will, as touted by the consumer advocate group Common Good, presumably make judgments more reliable and provide clearer lessons for deterrence of adverse outcome. In theory, it can provide more timely access, faster resolution of claims, along with more reliable and standardized compensation. It requires appointment of special expert courts to hear medical cases or administer compensation based on avoidable events. Health courts also make the system more transparent by providing public access to settlement and adjudication find¬ ings. It will require judges who have special knowledge or

CHAPTER

Malpractice issues in perinatal medicine: the United States perspective

29

training in medicine. Although proponents believe that this form of adjudication will offer more consistent and informed decisions than the traditional trier of fact, a lay jury, many studies find that in comparison with expert’s reviews, the present jury system is quite consistent. Health courts may be paired with ACEs and a standardized compensation schedule - and may even add a trial option to an administrative system. There are precedents for these types of courts in certain tax and patent infringement and workers’ compensation laws.

used by lay juries, ‘preponderance of the evidence’. It evalu¬ ates the case on the basis of the four Ds of negligence. Unanimous decisions by the panel on negligence and causa¬ tion are admissible in court, in favor of either the patient or the provider. The decision of the panel, like in non¬ binding arbitration, does not bind either party from pursuing litigation and trial. Some systems allow recovery of costs by the losing party, but as stated previously, if it is the plaintiff, actual recovery is unlikely.

Medical Board Administrative Adjudication System: In 1988, the AMA, 31 medical specialty associations, the Phy¬ sician Insurer’s Association of America (PLAA), and the Counsel of Medical Specialty Societies created the Medical Liability Project to develop an equitable and efficient method to handle malpractice claims. They proposed a claims adju¬ dication process based on fault and suggested that the states’ medical boards act as the trier of fact in addition to their regulatory and disciplinary roles. This system would initially screen cases, offer free legal counsel for cases passing review and offer limited judicial review. In a parallel development, the AMA considers that the provision of expert testimony constitutes ‘the practice of medicine’ and that it should be subject to peer review by state medical boards. The AMA encourages the state medical associations to work with the licensing boards to develop effective disciplinary measures for fraudulent testimony. Tripartite Panel: Also in 1988, the PLAA proposed an administrative system similar to that used for workers’ com¬ pensation in the hope that patients would elect this more speedy system through the offer of incentives. The panel would consist of a judge, a physician and a lay person and function much like the few state screening panels that remain active. In cases where malpractice was found, all medical expenses would be paid under a specific method of computation, all non-economic awards would be based on a fixed schedule of benefits, and there would be a limit on attorney’s fees.

ENTERPRISE LIABILITY

PRETRIAL SCREENING PANELS This is a system that is modeled after state programs that are presently functioning, with those of Maine and Vermont the most recognized. To enlist the Panel, the patient provides written notice to the physician and with the superior court to be acted upon within 90 days. The superior court selects a Panel Chair from a pool of retired judges and/or mediators with judicial or legal experience. The Chair selects from a court issued list one attorney and one physician panelist, of the same or relevant specialty. The parties may challenge the selection for cause. There is a Prehearing Discovery, then a Pretrial Screening Hearing that follows the format of an arbitration. Depositions are admissible, but expert testimony is unusual. The panel has prior access to written briefs, complete medical records, deposition transcripts. The panel then acts as the trier of both fact and law, under the standard

Enterprise liability provides an incentive for prioritization of enterprise-wide safety. It shifts liability from the indi¬ vidual provider to a provider organization such as an inte¬ grated medical staff, IPO, large group practice, or hospital capable of influencing care across the systems. Enterprise liability essentially makes these organizations ‘strictly liable’ in both a legal and an economic sense by their responsibility for liability premiums for all staff involved in the organiza¬ tion, which could potentially impact the present punitive reporting system and allow for a freer flow of error report¬ ing. Such a system would promote institutional safety and potentially stabilize liability insurance fees. Legal provisions (Stark laws) may prohibit liability insurance coverage of non-employee physicians. It works equally well with alter¬ natives as well as the current tort system. The Department of Health and Human Services Office of Inspector General (OIG) historically has been concerned that a hospital’s subsidy of malpractice insurance premiums for potential referral sources, including hospital medical staff, may impli¬ cate the antikickback statute, because the payments may be used to influence referrals. ‘There is a particular concern where subsidies are offered in a conditional or selective manner that reflects current or anticipated referrals from the subsidized practitioners.’ Hospitals may be able to subsidize the malpractice insurance of local obstetricians without trig¬ gering antikickback sanctions, according to an advisory opinion issued by the OIG. In this opinion, OIG outlines a specific case in which it would not impose antikickback sanctions against a medical center that provides subsidies to four community-based obstetricians who hold staff privi¬ leges at the medical center but are not employees of the facility. Tort reform in many of its guises, however, has histori¬ cally not been universally ‘friendly’ to the physician. In 1988, the US Congress established a National Practitioner Data Bank authorizing the collection of data about physi¬ cians and dentists from malpractice settlements, awards and disciplinary actions; these data were to be supplied by insur¬ ers, hospitals and HMOs. Queries of the Data Bank might be made by hospitals and physicians, but there is to be no access by the public or actual or prospective litigants includ¬ ing patients and attorneys although expanded access to this information is the subject of much debate. This tracking by the Data Bank has probably decreased the willingness of 625

SECTION

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physicians to settle cases, but has probably not decreased the frequency of malpractice. The non-departmental public body (NDPB) reporting system is primarily based on the reporting of any formal written claim of malpractice that results in even one penny changing hands, regardless of admission of blame or severity of injury. Such reports carry great weight in considerations for staff privileges, provider contracts, and malpractice premium rates. Hatlie and Sheridan have argued that the NDPB should be abandoned. Even more recently, there has been increasing attention on the amount of medical error that has heretofore gone unnoticed and undocumented. The AMA has created a Patient Safety Initiative and the Federal Government is considering legislation that will likely reorient the approach to error. Indeed, since the publication of the prestigious IOM’s ‘To Err is Human,’ which claims that between 44000 and 98 000 hospitalized patients die per year as a result of medical error, and subsequent studies such as that of Chaudhry and coworkers, patient safety has become the mantra of the Joint Commission on Accreditation, which has now embellished the requirements for disclosure of error. Programs for the evaluation of root cause analyses of reported errors and the resulting error reducing actions have become, as they should, a national priority. Also potentially threatening to the physician are those tort reforms that are linked (politically) to the establishment of enhanced physician review panels, the creation of ‘three strikes and you are out’ rules, etc. In Texas, for example, along with a stringent tort reform bill passed in 2003, the Texas legislature gave the Texas State Board of Medical Examiners new authority to regulate medical practice through the passage of S.B. This bill gave the board increased funding for expert consultants and staff. These resources were used to assess the approximately 6000 complaints the board receives each year. As a result, Board enforcements have increased dramatically. Before the augmentation, cases were fded against physicians immediately, which immediately affected their records. The new system provides more due process, but is more far wide-ranging. Opponents of this feature of Texas Health litigation argue that standard of care issues should be left to local community medical societies or hospital peer review and credentialing societies. But when the boot is on the other foot and these organizations engage in sham peer review or economic credentialing, physicians complain about their unfair practices (see below). Physician groups com¬ plaining about S.B. want the presumption of innocence, the right to access details of the complaints against them, the right of discovery, the right to present witnesses and crossexamine witnesses and the right to appeal. How seductive is the illusion of a new idea — all of these features are present in current malpractice law, the beneficiary of 200 years of accumulated jurisprudence. Public Citizen’s Health Research Group ranked Texas 23 out of the 50 states. Reviews of the impact of tort reform on premiums suggest that while premiums do respond to increases in payments, they do not increase dollar for dollar (http://www.nber.org/ 626

papers/w 10709). This suggests that other factors may also be important in explaining the recent jump in malpractice premiums, such as a less competitive insurance industry or a decline in insurers’ investment income. There is little evi¬ dence that changes in malpractice premiums are linked to changes in either the total number of physicians or the number of physicians working in obstetrics/gynecology, surgery or internal medicine. There is weak evidence to suggest that the entry decisions of young physicians and the exit decisions of older physicians may be affected by mal¬ practice premiums. There is stronger evidence to suggest that rural physicians are more sensitive to a change in pre¬ miums - a 10°/o increase in premiums results in a 1% decrease in rural physicians per capita and a 2% decrease in older rural MDs (http://www.nber.org/papers/wl0709). Although there is no change in the frequency of most treat¬ ments, some data suggest that physicians may increase the use of screening procedures in response to higher premiums. Such practices however have had little effect on total Medi¬ care expenditures, suggesting that the costs associated with defensive medicine practices may be small, at least for this age group. Thus, it is far from clear that state tort reforms will avert local physician shortages or lead to greater effi¬ ciencies in care. The stabilization of premiums, the initial response to most rounds of tort reform, may not indeed be the result of the tort reform legislation. Normally, it takes years before legislative tort reform has a direct impact on malpractice premiums and several, but not all, state courts have invalidated the cap on damages, the component of the law with the greatest potential to reduce premiums. Mal¬ practice premiums are affected by a constellation of addi¬ tional factors, including the general investment climate, interest rate cycles and insurance regulations. Whether driven by legislation or not, it seems reasonable that stable malpractice insurance premiums offered by expe¬ rienced, reputable companies are important reasons for maintaining physician availability and equilibrium. There is no evidence that tort reform has resulted in better care or more realistic confrontation of error. Tort reform simply ‘tinkers with certain aspects of the system in a piece¬ meal fashion without having to grapple with fundamental reform of either the health care delivery system, the reim¬ bursement system or physician behavior’.

TORT REFORM AND FINANCES — LITIGATION AND RISK MANAGEMENT There is universal agreement that the medical needs of those with adverse outcome require more attention, whether they are related to negligence or not. There is also universal agreement that the present functioning of the medico-legal system is an anachronism — neither is it efficient or errorfree in reaching a settlement nor is the distribution of money equitable. In the United States, only about 28 cents of every premium dollar goes to injured patients after an average delay of 4.9 years to dispose of a case.

CHAPTER

Malpractice issues in perinatal medicine: the United States perspective

Is no-fault insurance better? To determine whether Florida’s implementation of a no-fault system for birthrelated neurological injuries reduced lawsuits and the total spending associated with such injuries, and whether no-fault was more efficient than customary tort procedures in distrib¬ uting compensation, Sloan et al compared claims and pay¬ ments before and after implementation of a no-fault system in 1989. They found that the number of tort claims for per¬ manent labor-delivery injury and death indeed fell by about 16-32%. Flowever, when no-fault claims were added to tort claims, the total frequency of claims rose by 11-38%. Further, of the estimated 479 children who suffered birth-related injuries annually, only 13 were compensated under no-fault. The total combined payments to patients and all lawyers did not decrease, but under no-fault, a much larger portion of the total went to patients. Thus, less than 3% of the total payments went to lawyers under no-fault versus 39% under tort — a new equilibrium. Some claimants with birth-related injuries were winners, taking home a larger percentage of their awards than their tort counterparts. Lawyers clearly lost under no-fault, but so did many children with birth-related neurologic injuries who did not qualify for coverage because of the narrow statutory definition.

SOLVING THE MALPRACTICE PROBLEM While the focus of clinical risk management intuitively rests on the analysis of adverse events, it seems clear that this is the most inefficient way of reducing or eliminating harm to the patient. In the current climate, risk management tends to deal more with avoidance of blame and litigation than with the avoidance of harm to patients. One of health care’s principal patient safety success stories is anesthesiology. In the 1980s, in the midst of a separate medical liability crisis, the rate of anesthesia-related deaths was one in 10000; 6000 people per year who had undergone anesthesia died or suffered brain damage, and anesthesiolo¬ gists’ liability insurance premiums had sharply escalated. Following a national news magazine broadcast that pilloried the field for these outcomes, the American Society of Anes¬ thesiologists (ASA) decided to seize the opportunity pre¬ sented by the crisis to improve anesthesiology safety. It started with the hiring of a systems engineer. Through close scientific examination of 359 anesthesia errors, every aspect of anesthesia care - equipment, practices, and caregivers — was analyzed. Eventually, with the commitment of leader¬ ship and resources toward the task, the many system failures revealed by the study were re-engineered, and anesthesiarelated death rates fell dramatically. The ASA uses case analysis to identify liability risk areas, monitor trends in patient injury, and design strategies for prevention. Today, the ASA Closed Claims Project - created in 1985 - contains 6448 closed insurance claims. Analyses of these claims have, for example, revealed patterns in patient injury in the use of regional anesthesia, in the place¬ ment of central venous catheters and in chronic pain man¬

29

agement. Results of these analyses are published in the professional literature to aid practitioner learning and promote changes in practices that improve safety and reduce liability exposure. Closed claims data analysis is the one way in which the current medical liability system helps to inform improve¬ ments in care delivery. However, reliance on closed claims for information related to error and injury is cumbersome at best. It may take years for an insurance or malpractice claim to close. These are years in which potentially vital information on substandard practices remains unknown. Providing patient safety researchers with access to open claims, now protected from external examination, could vastly improve efforts aimed at identifying worrisome patterns in care and designing appropriate safety interventions. In addition to anesthesiology’s early work in identifying the human factors and system failures that cause error, anesthesiology has also promoted reliance on standards and guidelines to support optimal anesthesiology care. Anesthe¬ siology has also been at the forefront in the use of patient simulation for research, training and performance assess¬ ment. With simulation, no patients are at risk of exposure to novice caregivers or unproven technologies. Anesthesiol¬ ogy is still far from perfect, but its ‘institutionalization of safety’ continues to serve the field well as it tackles the continuing threats to patient safety that are endemic to modern medicine. Medicine is different from industry in that the medical system has not adjusted to the realities of human fallibility. The circumstances of the contemporary malpractice situa¬ tion continue to compromise both the provision and the safety of health care as well as our notions of justice, of access to the law and to health care. Defensive statements over the value of obstetrical care cited above, notwithstanding, there is broad agreement that improvement in perinatal outcome is possible, that the events of labor do contribute significantly and that review¬ ing adverse outcomes and making obstetrical units more reliable in terms of communication and interpretation of tracings will enhance outcome (Knox et al 1999, Simpson H Knox 2000). Irrespective, we do not yet know the totality of injury related to the intrapartum period — irrespective of the mechanism. The estimates of the role of hypoxia vary widely, in great measure due to incompatible definitions and limited follow up. We have some estimates of the role of obvious trauma due to forceps or vacuum, but there are no reliable estimates of the toll of the other factors, nor are there universally agreed upon techniques for reliably deter¬ mining the precise timing and mechanism of injury (Towner et al 1999). This state of affairs benefits neither the patient nor, in the long run, the physician. While in some instances the fear of lawsuit has increased the amount of surveillance and may have even had a salutary effect on outcome, there is little argument that the present format for dealing with allega627

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tions of negligence provides any incentive to the profession to practice better medicine, provide better peer review, or, in the occasional instance, restrict the future practice of the physician whatever his conduct. True reform will require a systemic approach to error in medicine as elsewhere and some refinement of our ethics and an appreciation of the paradoxes of contemporary malpractice. To lower the risk of malpractice we must continue to attempt to raise the standards of care. We need this more than we need the identification of the ‘bad apples’ of our specialty. We must increase communication with the patient and remain their advocate. We must address the formal teaching of commu¬ nication skills, conflict management and team development techniques throughout medical school and residency. We must construct effective error reporting and systems analysis programs that promote error reduction, while protecting physicians from being punished by arbitrary and ineffective reporting systems. We must not squander our greatest asset — the medical record - and we must stop playing the role of victim. Often the ultimate failure is often not the indi¬ vidual provider but the latent, systemic errors, errors for which our systems are programmed, but which are function¬ ally immune from lawsuit. A lawsuit cannot make ‘the system’ a defendant. Finally, we must be willing to partici¬ pate in the process of uncovering error and make the patients our allies in these efforts.

NOTE 1 The medical malpractice business, as with the property and casualty industry as a whole, has been characterized by a ‘boom and bust’ cyclicity since the mid-1970s. History would tell us that profitability can be restored in time, perhaps with tort reform and pricing structures (Martin ft Bade 2002), or, more persuasively, by an ‘increased empha¬ sis on improving patient safety and elimination of all pre¬ ventable medical errors’ (Weinstein 2006). It seems that realizing these desiderata will require a national electronic medical record and the availability of rapid response teams in most hospitals. Most ‘privileged communications’ and ‘peer review’ are counterproductive and should be elimi¬ nated. There is benefit for patient and physician alike for full and prompt disclosure of any medical error or injury abetted, if necessary, by outside consultants. Physicians must be taught proper teamwork and communication skills, including how to give ‘bad news’ and how to learn from error. Frequent patient, nursing or medical staff complaints against providers must be critically, and constructively reviewed. The objectives of risk management and patient safety need to be aligned and proactive. Our science and research should support improved outcomes not defensive postures. Claims management should offer the patient early compensation when appropriate and pursue a vigorous defense when medical care is adequate. Experts should be identified who will render fair, unbiased reviews of medical care for either side with all of their findings being disclosed.

628

Similar experts need to devise clear, concise, evidencebased standards of care for common medical conditions’ (Weinstein 2006).

NOTE 2 For the past decade, Radiology Associates of Albuquerque has provided physician expert testimony to plaintiff and defense attorneys. Initially, the business was confined to radiology consultation only. The division has expanded; it now includes more than 35 specialties and a national client base. This article will include a history of the division’s growth and lessons learned as well as a look at the future of expert testimony in light of increasing emphasis on standards of care. Medical marketing in the present as well as in the future will also be addressed (Stevenson 1999).

NOTE 3 Using' 36 malpractice cases involving cervical spine surgery. Queries included who sued, who was sued, who won, who lost and why? Six different tort reform models also were identified and explored. RESULTS: Common bases for suits included failure to diagnose and treatment (56%), lack of informed consent (64%), new neurologic deficits (64%), and pain and suffering (72%). All of the six plaintiff verdicts (average, $4.42 million) and four of the nine settlements (average, $1.6 million) involving surgery that resulted in new postoperative quadriplegia appeared to be appropriate. However, the author could discern ‘no fault’ in cases five defendants had settled and the surgeons did not deserve to lose. On the other hand, the author found ‘fault’ in five defense verdicts rendered to three newly quadriplegic patients and two with new postoperative root injuries. These patients deserved monetary awards, but received no com¬ pensation whatsoever. There currently are two models that would work better than the system in place in most states. These include the American Medical Association National Specialty Societies Medical Liability Project with the Alter¬ native Dispute Resolution Model (SSMLP), and the Selective No Fault Models. Among the advantages shared by one or more of these models is their ability to reimburse injured patients while eliminating physician liability, to use mal¬ practice panels rather than trials and to put a cap on damages. CONCLUSIONS: To solve the medical malpractice crisis, Congress, the individual states, or both should adopt tort reform. Two tort reform models, compensating injured patients and eliminating physician liability, appear to be not only effective but also fair to all concerned parties (Epstein 2002).

NOTE 4 Caps won’t help patients by substantially lowering or stabi¬ lizing health-care costs. Malpractice-insurance premiums account for less than 2 percent of the nation’s health-care spending.

CHAPTER

Malpractice issues in perinatal medicine: the United States perspective

29

REFERENCES ACOG 2005 Practice Bulletin #70. Intrapartum fetal

Hankins G D. MacLennan A H, Speer M E et al 2006

heart rate monitoring. Obstet Gynecol

Obstetric litigation is asphyxiating our maternity

106(6):1453—1460.

services. Obstet Gynecol 107(6)1382-1385.

AlfirevicZ, Devane D, Gyte G M 2006 Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour.

JCAH0 2004 Sentinel Event Alert Issue # 30. Preventing infant death and injury during delivery. USA.

Schifrin B, Harwell R. Rubinstein T et al 2001 Maternal heart rate pattern — a confounding factor in intrapartum fetal surveillance. Prenat Neonat Med 6:75-82. Scott J R 2005 Expert witnesses: perpetuating a flawed system. Obstet Gynecol 106(5 Pt 1):902—903.

Cochrane Database Syst Rev 3:CD006066.

Knox G E, Simpson K R. Garite T J 1999 High reliability

Althaus J E. Petersen 5 M, Fox H E et al 2005 Can

perinatal units: an approach to the prevention of

electronic fetal monitoring: decreasing risk of

patient injury and medical malpractice claims.

adverse outcomes and liability exposure. J Perinat

electronic fetal monitoring identify preterm neonates with cerebral white matter injury? Obstet Gynecol 105(3)458-465. Baker T 2005 The medical malpractice myth. The University of Chicago Press, Chicago. Beckman H B. Markakis K M. Suchman A L et al 1994 The doctor-patient relationship and malpractice. Lessons from plaintiff depositions. Arch Intern Med 154(12)1365-1370. Chauhan S P, Martin J N, Henrichs C E et al 2003

J Healthc Risk Manag 19(2)24-32. LaveryJ P. Janssen J, Hutchinson L1999 Is the obstetric guideline of 30 minutes from decision to

Simpson K R. Knox G E 2000 Risk management and

Neonatal Nurs 14(3):40—52. Simpson K R. Knox G E 2003 Common areas of litigation related to care during labor and birth:

incision for Caesarean delivery clinically significant?

recommendations to promote patient safety and

J Healthc Risk Manag 19(1)11-20.

decrease risk exposure. J Perinat Neonatal Nurs

MacLennan A H 2001 A guest editorial from abroad: medicolegal opinion-time for peer review. Obstet Gynecol Surv 56(3)121-123. MacLennan A, Nelson K B. Hankins G et al 2005 Who

17(2)110-125; quiz 126-127. Stevenson J R 1999 An expert experiment — medico¬ legal expert testimony. Med Law 18(1):47—53. Studdert D M, Mello M M, Gawande A A et al 2006

Maternal and perinatal complications with uterine

will deliver our grandchildren? Implications of

Claims, errors, and compensation payments in

rupture in 142,075 patients who attempted vaginal

cerebral palsy litigation. JAMA 294(13)1688-1690.

medical malpractice litigation. N Engl J Med

birth after Cesarean delivery: A review of the literature. Am J Obstet Gynecol 189(2):408—417. Epstein N E 2002 It is easier to confuse a jury than convince a judge: the crisis in medical malpractice. Spine 27(22):2425-2430. Finkelstein D, Wu A W, Holtzman N A1997 When a physician harms a patient by a medical error: ethical, legal, and risk-management considerations. J Clin Ethics 8(41:330-335. GallagherT H, Waterman A D, Ebers A G et al 2003 Patients' and physicians’ attitudes regarding the disclosure of medical errors. JAMA 289(8): 1001-1007. Graham E M, Forouzan I. Morgan M A1997 A retrospective analysis of Erb's palsy cases and their

MacLennan A, Robinson J 2004 Cerebral palsy and clinical negligence litigation: a cohort study. BJ0G 111(11:92-93. Martin T, Bade D 2002 Professional liability insurance rates — some history & solutions. Mo Med 99(10):532—534. Meadow W 2005 Evidence-based expert testimony. Clin Perinatal 32(1)251-275, ix. Meadow W, Lantos J D 1996 Expert testimony, legal reasoning, and justice. The case for adopting a databased standard of care in allegations of medical negligence in the NICU. Clin Perinatal 23(3)583-595. MohrJ C 2000 American medical malpractice litigation in historical perspective. JAMA 283(13)1731-1737. Murray M L 2004 Maternal or fetal heart rate? Avoiding

354(19)2024-2033. Towner D, Castro M A. Eby-Wilkens E et al 1999 Effect of mode of delivery in nulliparous women on neonatal intracranial injury. N Engl J Med 341(23)1709-1714. Volpe J, Neurology of the newborn, 3rd edn, 2001, Saunders, New York. Weinstein L 2006 A multifacited approach to improve patient safety, prevent medical errors and resolve the professional liability crisis. Am J Obstet Gynecol 194(4)1160-1165; discussion 1165-1167. Woods M M D 2004 Healing Words: The Power of Apology in Medicine’: [email protected] Zimmerman R 2004 Doctors' new tool to fight lawsuits: saying 'I'm sorry.' Malpractice insurers find owning up to errors soothes patient anger. ‘The risks are

relation to birth weight and trauma at delivery.

intrapartum misidentification. J Obstet Gynecol

extraordinary'. J Okla State Med Assoc

J Matern Fetal Med 6(1):1—5.

Neonatal Nurs 33(1):93-104.

97(6)245-247.

629

SECTION VI

CHAPTER

30

INFECTION OFTHE CNS

Toxoplasmosis J. Nizard, Guillaume Benoist and Yves G. Ville

MODES OF CONTAMINATION PARASITOLOGY Toxoplasma gondii is a single-cell parasite protozoon. The oocyst form is excreted in the feces of cats, the definitive hosts in nature. Toxoplasmosis is spread by ingestion of oocysts or of cysts in their host-tissue either by ingestion of undercooked meat or by congenital vertical transmission. Ingestion of oocysts or tissue cysts will result in the spread¬ ing of organisms which will invade the intestinal mucosa and disseminate widely. Toxoplasma can infect, replicate and form cysts in all tissues. Tissue cysts persist for the host’s lifetime and are considered the most likely cause of recrudescence of disease under particular circumstances such as immunosuppression (Desmonts et al 1990, Pons et al 1995).

MATERNAL INFECTION Primary infection of the mother is usually asymptomatic, which justifies universal screening during pregnancy in some countries. When symptomatic, fever, malaise, fatigue and lymphadenopathy are the most frequent signs. However, persistent dysphagia and hepatitis can also reveal maternal toxoplasmosis.

been reported to occur in immunocompetent mothers, in whom the toxoplasmosis could be dated to have happened a few weeks prior to the beginning of pregnancy (Desmonts et al 1990, Marty et al 1991, Pons et al 1995, Velin et al 1991). These cases should lead us to advise women to wait at least 6 months before starting a new pregnancy after toxoplasmosis (Couvreur 1999). Nevertheless, there are reported cases of vertical transmission in immunocompetent mothers with a proven proper immunization long before pregnancy (Couvreur 1999, Fortier et al 1991, Gavinet et al 1997, Hennequin et al 1997, Lebas et al 2004). It is suspected that these cases are the consequence of either massive rein¬ fection, or of infection with a different strain. The vertical transmission rate of the parasite varies from 15°/o at 13 weeks of gestation, to 44% at 26 weeks and 71% at 36 weeks (Thiebaut et al 2007) (Fig. 30.1a). Desmonts (Desmonts 8t Couvreur 1974) in 1974 reports that, in all severe cases or fetal deaths, fetal infection was likely to have occurred between the 10th and the 28th week of gestation. On the contrary, in documented cases where infection devel¬ oped during the third trimester of pregnancy they described subclinical symptoms in 56% and clinical symptoms in 5% of infected neonates (Desmonts 8t Couvreur 1974) (Fig. 30.1b). It seems that the rate of chorioretinitis is independent of gestational age at infection (Thiebaut et al 2007).

CONGENITAL TOXOPLASMOSIS Congenital transmission of toxoplasmosis occurs when Toxoplasma infects the fetus, most probably after having infected the placenta. There seems to be a close correlation between Toxoplasma isolation in the placenta and congeni¬ tal toxoplasmosis (Desmonts ft Couvreur 1974). However, the placenta acts as a barrier as well as a reservoir for Toxo¬ plasma. Daffos (Daffos et al 1988) reported that in as much as 8°/o of the cases with an infected placenta, the fetuses and neonates did not show any evidence of seroconversion and remained asymptomatic by ten months after birth. These findings suggest that there must be a placentitis preceding fetal congenital infection (Desmonts 8t Couvreur 1984). This placentitis may evolve independently from the fetal infec¬ tion. In up to 27°/o of cases, fetuses were found to be infected with non-infected placentae (Daffos et al 1988). The fetus can theoretically only become infected if the mother acquires the infection during pregnancy or when the mother is immunosuppressed, mainly by long-term gluco¬ corticoids treatments, Hodgkin disease, AIDS or systemic lupus erythematosus. Materno-fetal transmission has also 630

IMMUNOLOGY IN THE MOTHER Since maternal infection by Toxoplasma gondii is rarely diagnosed clinically, the diagnosis relies almost exclusively on biological and immunological findings to document infection and subsequent seroconversion. The parasitemia seems to occur veiy early after the infection and resume shortly after. It is therefore likely that placental infection, secondary to maternal parasitemia, also occurs very early after maternal acute infection. Thus, placenta infection occurs before any treatment is started. Some cases of chronic parasitemia have however been described. It is uncertain whether chronic parasitemia is responsible for congenital toxoplasmosis, and whether it can disappear after appropriate treatment (Miller et al 1969). A large number of different immunological tests can be used. Toxoplasma infection can be detected by the appear¬ ance of specific antibodies. The real challenge is to date precisely maternal seroconversion.

CHAPTER

Toxoplasmosis

30

-Risk 95°p .5°p

Weeks of pregnancy

(c)

The Sabin-Feldman dye test is one of the first to have been used on a large epidemiological scale. It is testing the presence of specific anti-Toxoplasma antibodies in the mother using the lytic capacity of the tested serum on live Toxoplasma. Sabin-Felman test is expressed in international units (IU) per milliliter of serum and is said to be high above 300UI/mL. Indirect hemagglutination test (IHA) uses the agglutination of red blood cells expressing Toxoplasma anti¬ gens when exposed to serum containing anti -Toxoplasma IgG or IgM antibodies. Agglutination test is sensitive to IgM antibodies and can be used on a large scale in pregnant women. Conventional indirect fluorescent antibody test (IFA) detects specific antibodies using fluorescent-tagged specific Toxoplasma antigens and serum gammaglobulins. IFA is considered to be as specific as the dye test, provided it is not used in the serum of women with connective tissue disorder. IFA is considered high above a titer of 1 :1000 (Dannemann et al 1990, Thulliez et al 1986). The conven¬ tional or capture enzyme-linked immunosorbent assay (ELISA) can be used independently to detect specific antiToxoplasma IgG, IgM or IgA (Stepick-Biek et al 1990). Immunosorbent agglutination assay (ISAGA) can detect anti-Toxoplasma IgG, IgM and IgE. Other specific tests can be used to detect selectively anti -Toxoplasma IgM antibodies such as the IgM fluorescent antibody test or the IgM enzymelinked immunosorbent assay (Naot et al 1981). Finally, IgG

Figure 30.1 (a) Schematic representation of the vertical transmission of toxoplasmosis depending on the trimester of maternal seroconversion, (b) Schematic representation of the severity of the fetal affection depending on the trimester of maternal seroconversion (intracranial lesions; chorioretinitis), (c) Estimate risk of clinical signs before age 3 years according to the term of maternal seroconversion, when fetal infectious status is known (Dunn et al 1999).

avidity for Toxoplasma antigens has become an essential step in difficult circumstances. This test can separate lowaffinity IgG antibodies, which are produced at an early stage of the infection (4 months) (Jenum et al 1997, Lappalainen et al 1993). A conventional single-serum assay does not make a clear distinction between a primary and a chronic infection, it only makes the diagnosis of toxoplasmosis. Specific IgM can persist for a long time, even at high levels. Elements in favor of a recent seroconversion (primary infection) are: the rise from negative or low titers to high titers at two different serum samples for the dye test, IHA or IFA and/or the rise from negative or low titers to high titers of specific IgM tests in two different serum samples 2-3 weeks apart. It is only when this does not support clearly the scenario of seroconversion that testing for IgG affinity or using specific assay for IgA and IgE can be helpful and is required (Lappa¬ lainen et al 1993).

IN THE FETUS AND THE NEWBORN All these tests can be applied to fetuses and neonates, pro¬ vided the serum sample is available. However the diagnosis of congenital toxoplasmosis in fetuses and newborns is more often based on the finding of toxoplasmosis DNA in the amniotic fluid rather than on immunological criteria. It is 631

SECTION

VI

INFECTION OFTHE CN5

not clear whether the antibody response of the fetus/neonate is aimed at the same antigens. Low-molecular weight IgG can cross the placenta and therefore a fetus/neonate immu¬ nological answer to Toxoplasma will be detected by the presence of specific IgM, IgA or Ig'E in fetal/neonatal blood (Fortier et al 1997, Pinon et al 1996, Pratlong et al 1996).

et al 1998, Ljungstrom et al 1995, Valcavi et al 1995). It also depends upon ethnicity, influenced by cooking and eating habits (Gilbert et al 1993). The incidence of toxoplasmosis among seronegative women depends primarily upon the prevalence in the general population. It ranges from 0.03°/o to 2.6°/o among seronega¬ tive women (Allain et al 1998, Ljungstrom et al 1995).

EPIDEMIOLOGY PREVENTION Seroprevalence for Toxoplasma among pregnant women varies widely not only from country to country but also from region to region within a given country. The relevance of a universal screening program for pregnant women to detect seronegative women, and perform subsequent serial screening of seronegative women for Toxoplasma through pregnancy depends on the seroprevalence and the incidence of seroconversion during pregnancy. It is therefore impor¬ tant to know the differences in different countries for these parameters. Table 30.1 shows a non-exhaustive list of recent studies on seroprevalence and incidence of toxoplasmosis in different countries. Seroprevalence for toxoplasmosis increases with maternal age and parity (Ades 8t Nokes 1993, Allain et al 1998, Jenum

Primary prevention is derived from the different modes of contamination: ingestion of oocysts from cat feces either directly by contact with cats or indirectly by contact with objects or food contaminated by cat feces, or by ingestion of meat containing cysts. Prevention should target sero¬ negative pregnant women. This is therefore only possible in countries where serologic status is known, ideally before pregnancy. Primary prevention of maternal toxoplasmosis, as well as that of immunodeficient patients, is based on education. The following recommendations should be given: meat should be cooked well done. Hands must be washed after handling raw meat and must not touch the eyes or mouth. Fruits and

Table 30.1 Seroprevalence and incidence of toxoplasmosis in different countries from recent studies Country Sweden

Seroprevalence and incidence if available Seroprevalence from 12 to 26% with a declining gradient from south to north. The estimated incidence of maternal toxoplasmosis ranges from 0.2% to 2.6% of susceptible pregnancies (Ljungstrom et al 1995).

Italy

Area of Parma: seroprevalence of 48.7% with an observed incidence of 0.27 to 0.69% (Valcavi et al 1995). Area of Naples: seroprevalence of 39% of pregnant women and 1.2% probably recently infected before the pregnancy (Buffolano et al 1996)

Norway UK

Seroprevalence of 10.9% among pregnant women with a decline from south to north (Jenum et al 1998) Eastern England: seroprevalence of 7.7% among pregnant women with 0.4% recent seroconversions. The estimated incidence of seroconversion ranges from 0.03-0.16% of pregnancies (Allain et al 1998). South Yorkshire: seroprevalence in a general population aged 20-40 years of age from 22.2% in 1969-1973 to 7.8% in 1988-1990 (Ades & Nokes 1993) West London: seroprevalence from 7.6 to 71.4%, with an average of 18.8%, these variations depend on the country of birth and ethnic group (Gilbert et al 1993)

Switzerland

Seroprevalence of 46.7% of pregnant women with an estimated incidence of 2.4% (Zuber & Jacquier 1995)

France

Paris: seroprevalence of 71% among French pregnant women and 52.4% among immigrant pregnant women with an estimated incidence of 1.6% seroconversion in susceptible pregnant women similar in French and non-French subpopulation (Jeannel et al 1988). Thirty years ago the incidence was estimated to be 6.3% among seronegative immigrant women in Paris and 1%0 in the general population (Desmonts & Couvreur 1974)

Bangladesh

Seroprevalence of 38.5% of pregnant women with wide variations according to socioeconomic status (Ashrafunnessa et al 1998)

Denmark

Seroprevalence of 27.8% with an estimated incidence of 0.2% of seroconversion among seronegative women (Lebech et al 1999)

Germany Belgium

Seroprevalence of 41.6% of pregnant women, the incidence of toxoplasmosis was 0.52% (Roos et al 1993) Brussels: seroprevalence of 53%, with an incidence of 1.4% to starting a program of counseling seronegative mothers. It was reduced to 0.53% after (Foulon et al 1984)

Greece

632

Seroprevalence estimated at 52.3% of pregnant women (Decavalas et al 1990)

CHAPTER

Toxoplasmosis

vegetables must be washed before consumption and hands must be washed after handling them. Women should avoid contact with cats and cat litter boxes and finally avoid gardening or wear gloves when gardening (Foulon et al 1988, McCabe ft Remington 1988). Prevention of congenital toxoplasmosis is based on the identification of women at risk (i.e. seronegative women), treatment of women with seroconversion during pregnancy to reduce the risk of vertical transmission of the parasite, and termination of severely affected fetuses according to parents’ wish after extensive counseling if the legislation of the country allows (Foulon et al 1988, McCabe Ft Remington 1988). Freezing meat seems to be efficient if it can be done for long enough (>24 hours) and at a temperature below -20°C. If these conditions cannot be met, freezing should not be proposed as a method of prevention of toxoplasmosis (McCabe Ft Remington 1988). With these measures of primary prevention of maternal seroconversion, Foulon et al (1988) found a decrease of seroconversion during pregnancy among initially seronega¬ tive women from 1.43% (20 of 1403) over 1979 to 1982 when women had no particular recommendations concern¬ ing prevention to 0.95% (15 of 1571) over 1983 to 1986 following preventive measures. This reduction in the sero¬ conversion rate of 34% was not statistically significant. When the same authors continued their study and included seronegative women who were given recommendations during pregnancy up to 1990, they found a reduction rate of seroconversion of 63%, going from 1.43% (20 of 1403) to 0.53% (19 of 3605). This reduction was found to be statistically significant and thus suggests that primary pre¬ vention can reduce the number of seroconversions during pregnancy. Another way of prevention is acting on the parasite before it can directly or indirectly contaminate humans. This has been tried by vaccination of sheep against Toxoplasma gondii (Buxton 1998, Buxton et al 1993, Washing et al 1994). Vaccination seems to be effective in sheep and could reduce the prevalence in humans in countries like France or Austria in the not too distant future.

CONGENITAL TOXOPLASMOSIS The aim of diagnosing maternal toxoplasmosis is the pre¬ vention of materno-fetal transmission. The aim of diagnosis of fetal toxoplasmosis is to evaluate the severity of the disease in order to either treat the mother to reduce the severity of the disease in the fetus or terminate the preg¬ nancy where applicable.

IN THE FETUS The diagnosis of congenital toxoplasmosis may be attempted in utero when the mother develops primary toxoplasmosis either during the months preceding pregnancy (arbitrarily 6 months) or during pregnancy. To affect the fetus, the para¬ site first infects the placenta. The rate of transmission from

30

the mother to the fetus is known and depends on gestational age (Fig. 30. la,b). Overall, the rate of maternal-fetal trans¬ mission seems to be influenced by the delay between mater¬ nal seroconversion and initiation of treatment. There seems to be a benefit in vertical transmission when the treatment is initiated within 3 weeks compared to after 8 weeks after maternal seroconversion (Thiebaut et al 2007). The probabil¬ ity of transmission increases with gestation, whereas the severity of fetal infection decreases with gestation. There¬ fore, there are fewer cases of very early congenital toxo¬ plasmosis, but they tend to be more severe. On the other hand, there are more congenital infections acquired at the end of the pregnancy but they tend to be less symptomatic. Thus, the largest number of severe cases occurs during the second trimester of pregnancy (Mombro et al 1995). It is important to consider that chorioretinitis rate is stable through gestational age (Thiebaut et al 2007). It is the rate of intracranial lesions that diminishes with gestational age at seroconversion. The diagnosis of congenital toxoplasmosis in the fetus can be made using a combination of ultrasound examination and detection of the Toxoplasma in the amniotic fluid directly or by using polymerase-chain-reaction (PCR). Fetal blood sampling is feasible after 20 weeks of gestation. Fetal blood sampling after 20 weeks of gestation for Toxoplasma isolation or measuring specific Toxoplasma IgM and IgA and non-specific biological markers are no longer used for diag¬ nostic purposes. The detection of Toxoplasma is done by intraperitoneal inoculation of the tested sample to the mouse. The drawback of this method is the 4 to 6 weeks delay to prove the isolation of the parasite. Before the development of PCR amplification of the parasite’s DNA from amniotic fluid, the use of fetal blood sampling and ultrasound exami¬ nation detected 83 to 92% of infected fetuses (Daffos et al 1988, Pratlong et al 1994). PCR on amniotic fluid seems to have better results than the conventional method alone, with a sensitivity of 97.4% (95% Cl 86.1-99.9) compared with 89.5% (95% Cl 75.297.0%) and the same 100% specificity (95% Cl 98.8-100) (Hohlfeld et al 1994). This technique, as the former ones, is dependent upon the experience of the laboratory and there¬ fore pleads for processing all samples in a reference labora¬ tory which will be able to control for technical pitfalls and provide with the most reliable interpretation of the tests. For non-specific blood test, the main parameters are ele¬ vated eosinophils, thrombocytopenia, elevated gamma-GT and elevated LDFI (Pratlong et al 1996). Asymptomatic infected fetuses would only show at most some degree of growth retardation as a marker of placental infection which can also typically show increased placental width which may also contain areas of calcifications or necrosis (Fig. 30.2A). When PCR on amniotic fluid is positive for Toxo¬ plasma DNA, the diagnosis of an affected fetus is usually made by a combination of the following signs (Pratlong et al 1994): evidence of liver or other systemic failure with hepatomegaly (Fig. 30.2B) and ascites (Fig. 30.2F); 633

? INFECTION OFTHE CNS

Figure 30.2 Pathological ultrasound findings during congenital toxoplasmosis. Arrows represent: in (A) a placentitis; in (B) hepatic calcifications: in (C) cerebral calcifications; in (D) destructive bilateral ventriculomegaly; in (E) another type of destructive ventriculomegaly; in (F) hyperechoic bowel with ascites.

634

CHAPTER

Toxoplasmosis

hyperechogenic bowel (Fig. 30.2F) and/or intrauterine growth retardation that can be severe with normal Doppler, which should raise suspicion towards an infection. The neu¬ rological signs are both the most evocative and severe. Microcephaly is a major but late sign of severe affection. Unilateral or bilateral dilatation of the lateral ventricles of the brain with or without hydrocephaly are the most classic features (Fig. 30.2D,E), whereas intracranial calcifications or patchy hyperechogenic areas featuring areas of necrosis within the white matter are the most specific features for toxoplasmosis (Fig. 30.2C). Toxoplasmosis could be respon¬ sible for foci of necrotic encephalitis even if the ultrasound examination is normal, but these studies are now old (Desmonts et al 1985). Most importantly, one should be aware that transplacental infection is dependent upon the ability of the placenta to prevent the passage of the parasite which can therefore be delayed as can also be the development of the fetal lesions. It is therefore mandatory to follow up the infected fetuses by serial targeted ultrasound examination every fortnight in a referral center. Indeed, subtle changes such as eye lesions (Lakhanpal et al 1983, Rothova et al 1993) could only be picked up by trained sonographers and would mandate appropriate counseling and other investigations such as intrauterine MRI in order to refine the prognosis. When PCR for Toxoplasma DNA is positive, ultrasound examination should be carried out every month. When maternal serocon¬ version occurs during the first trimester of pregnancy and subsequent ultrasound follow-up is normal, prognosis seems good with 78°/o subclinical toxoplasmosis and 19% chorio¬ retinitis without major vision loss (Berrebi et al 2006). In this series, one child in 38 developed severe congenital toxoplasmosis. All mothers were treated.

IN THE NEONATE When congenital toxoplasmosis is diagnosed in utero, clini¬ cal disease represents that approximately 25% of the cases will be asymptomatic (Daffos et al 1988, Desmonts et al 1985, Hohlfeld et al 1989, Pratlong et al 1996). This rate may be dependent upon treatment of the mother during pregnancy. Up to recently, it was assumed that the percentage of infected neonates from mothers who seroconverted during the pregnancy was likely to be lower if the treatment was adequate, than if is inadequate or absent (Desmonts ft Couvreur 1984, Mombro et al 1995). The Syrocot Study Group published a meta-analysis on individ¬ ual patients’ data showing that there seems to be no evi¬ dence that prenatal treatment significantly reduces the risk of clinical manifestations. These findings were consistent irrespective of the treatment sequence used (Thiebaut et al 2007). Infected neonates are not always symptomatic at birth. Clinical symptoms can sometimes appear several years after birth and in some cases be severe (Wilson et al 1980). The consequences of congenital toxoplasmosis are:

30

Neurological: the most commonly described abnormalities, although rare, are mental retardation, microcephalus, hydrocephalus and its complications, motor disabilities, with sometimes hemiplegia and epilepsy (McAuley et al 1994). Roizen (Roizen et al 1995) described cases with seizures and motor abnormalities that resolve under treatment. He also described discontinuation of anticonvulsant therapy after adequate treatment of the neonate. These same children, that were treated for a year and followed up for 10 years, had cognitive functions mildly impaired when compared to noninfected children, but above the cognitive function of infected children with only a short course or no treatment. Radiologically, intracranial calcifications are very common signs that can be seen with or without symptoms. Patel showed that these calcifications were not stable and that their evolution depended upon treatment given to the child (Patel et al 1996). Children with at least one year of treatment after birth tend to have less intracranial calcifications, as opposed to children with short or no treatment who had calcifications that remained stable or even progressed further. Ophthalmological: chorioretinitis is the most frequent complication of congenital toxoplasmosis. Toxoplasma invades the retina of the fetus, where it may change into the cyst form. Chorioretinitis and its most adverse consequences, severe visual loss and blindness, are thought to happen when cysts rupture and release parasites that multiply in the surrounding cells. Lesions are not always present at birth and most of them will appear during the first year of life. The occurrence of chorioretinitis is independent of the timing of maternal seroconversion and maternal-fetal transmission (Thiebaut et al 2007). Lesions may appear only after several years, justifying long-term treatment and follow-up even when the child is asymptomatic at birth (Guerina et al 1994, Koppe et al 1986, Peyron et al 1996, Wilson et al 1980). The probability of recurrence of acute episodes of chorioretinitis is around 50% (Rothova et al 1993). Others: intrauterine death or spontaneous abortion, severe disseminated parasitemia that can result in death or serious handicap. It is estimated that the probability of intrauterine fetal demise or termination of pregnancy is 2% in a population of infected pregnancies (Thiebaut et al 2007). Neonatal complications also include hypoxia and hypoglycemia that can also cause neurological disabilities.

TREATMENT In utero treatment includes the prevention of transmission of Toxoplasma from the mother to the fetus when the mother presents with acute infection and the reduction of the sever¬ ity of the symptoms in the fetus and in the neonate. 635

SECTION

VI

INFECTION OFTHE CNS

Postnatal treatment aims at reducing the number of acute phases of infection and at decreasing the severity of the symptoms. Treatment is ineffective on the cyst form within tissues. The aim of the treatment is to stop the replication of the parasite during the invasive phase of the infection. Treatment does not seem to reduce the inflammation in chorioretinitis, which is more dependent upon the initial severity of the lesion (Rothova et al 1993). However, it is unclear whether early treatment of congenital toxoplasmosis can decrease the incidence of lesions in neonates (Couvreur et al 1984, Thiebaut et al 2007). Ideally, treatment should be used during the acute phase of disease in mothers. However, when maternal seroconversion is diagnosed, the acute phase is resumed, thus limiting the efficacy of any treatment. Treatment usually combines different drugs. Some can cross the placenta and reach the fetus, some only get to the maternal circulation. • Pyrimethamine is a folic acid antagonist. It can therefore depress the bone marrow and give most often only a macrocytic anemia, neutropenia or thrombopenia. It should therefore be associated to folinic acid that only the human cells can use. Folinic acid does not reduce the efficacy of pyrimethamine against Toxoplasma. • Sulfonamide, associated to pyrimethamine and folinic acid, is the treatment of reference of an active infection. • Spiramycin is the most commonly used macrolide to prevent placental passage of Toxoplasma in mothers who seroconverted. It is probably not effective in fetuses already infected and does not prevent for example neurotoxoplasmosis in immunosuppressed patients (Leport et al 1986). • Corticosteroids are used in chorioretinitis to limit the inflammatory process. • Clindamycin is commonly used instead of spiramycin in cases with proven allergy (Lakhanpal et al 1983). • Trimethoprim associated with sulfamethoxazole (cotrimoxazole). • Azithromycin and clarithromycin, both recent macrolides, are effective against Toxoplasma gondii and increase the effectiveness such as associations like pyrimethamine-sulfonamide at least in vitro (Alder et al 1994, Araujo et al 1988, Cantin 8t Chamberland 1993, Derouin 1995, Derouin et al 1992). Moreover, azithromycin was found effective on the cyst form in vitro (Huskinson-Mark et al 1991).

PREVENTION OF FETAL INFECTION IN ACUTE MATERNAL INFECTION JUST BEFORE OR DURING THE FIRST OR SECOND TRIMESTER OF PREGNANCY (Fig.30.3) If the vertical transmission occurs during the first or second trimester, the risk of severe fetal affection is important. 636

Transmission is however rare. It is therefore important to make the diagnosis of fetal infection. It is best done by PCR amplification of the Toxoplasma genome in amniotic fluid after amniocentesis.

If the fetus is not infected (i.e. PCR negative or before amniocentesis) Spiramycin is the drug most widely used. It seems to reduce the frequency of placentitis thus hopefully reducing the number of infected fetuses. Studies support that there were less infected fetuses with treatment, in each trimester of the pregnancy (Desmonts ft Couvreur 1974). In this study, using prevention by spiramycin, only 24% of the fetuses from infected mothers were infected and a total of 11% of fetuses had a clinical disease. Spiramycin is said not to be curative for the fetus. The prevention of fetal toxoplasmosis by spi¬ ramycin, or other drugs, is not well established for all. Wallon (Wallon et al 1999), reviewing several studies, con¬ cludes that there are ‘no good comparative data measuring the potential harms and benefits of antiparasitic drugs used for presumed antenatal Toxoplasma infection’. This state¬ ment was confirmed by Foulon (Foulon et al 1999) in a large multicenter study who found that the maternal-fetal trans¬ mission depended more upon gestational age at which the infection occurred than upon any treatment given to the mother. This is probably because placentitis occurs very early after maternal infection, hence before any treatment is given. Once more, by meta-analysis the Syrocot Study Group showed that only treatment given less than three weeks from maternal seroconversion seems to reduce the risk of vertical transmission.

If the fetus is infected (i.e. PCR positive on amniotic fluid), there are two possibilities If monthly ultrasound examination is normal, the risk of severe congenital toxoplasmosis after birth is estimated to be less than 5% (Berrebi et al 2006). These patients are commonly switched from spiramycin to pyrimethaminesulfonamide. If ultrasound examination is abnormal, parents opt for either treatment by pyrimethamine-sulfonamide or termina¬ tion of pregnancy following extensive counseling when applicable. It is nevertheless important to explain that up to now, there is no evidence that any treatment reduces the incidence of clinical manifestations in infancy (Thiebaut et al 2007). Termination of pregnancy is a possibility in severely affected cases, when legally and ethically possible. It is mainly done when fetal infection occurs during the first or second trimester of pregnancy, in 30 to 50% of the cases of infected fetuses (Daffos et al 1988, Hohlfeld et al 1989). Looking at recent and well documented studies, 60% of children born with congenital toxoplasmosis had no clinical or laboratory abnormality, and within the remaining 40% only 4% had symptoms at follow-up (Berrebi et al 1994). It is therefore very difficult to asses the risk of handi¬ cap in an infected fetus and to justify a termination of pregnancy.

CHAPTER

Toxoplasmosis

Spiramycine AND Search for fetal signs of infection

30

|

PCRon AF US —

Figure 30.3 Management of maternal seroconversion during the first or second trimesters.

PREVENTION OF FETAL INFECTION WHEN THE MOTHER DEVELOPS ACUTE INFECTION JUST BEFORE OR DURING THE THIRD TRIMESTER OF PREGNANCY (Fig. 30.4) The incidence of vertical transmission is very high here. The probability of severe neurological affection is rare but the risk of chorioretinitis is constant both in utero and after birth. The diagnosis of fetal infection is also made by com¬ bining PCR on amniotic fluid and ultrasound findings, but there is a risk of false negative results. We can either treat these fetuses as if they were infected or perform amniocen¬ tesis and serial ultrasound examination after starting spira¬ mycin treatment. This will be continued up to delivery and placenta and cord blood will be examined for infection.

AT BIRTH The attitude depends on the infectious status of the fetus and the results of the neonatal examination.

If the diagnosis of fetal infection was negative, investigations that should be performed after birth include: • • • •

Parasitology of the placenta and the fetal blood. Neurological and ophthalmological examination. Ultrasound examination of the central nervous system. Neonatal immunological status.

It is important to be cautious with false negative results on amniotic fluid in the third trimester of pregnancy. An infected neonate, whether symptomatic or asymptomatic, 637

SECTION

VI

INFECTION OFTHE CNS

Maternal seroconversion during the S"* trimester

I Search for fetal signs of infection PCR on AF US

But risk of false negative

Spiramycin And Examination at birth Or systematic: Sulphonamide Pyrimethamine Folinic acid US examination

Sulphonamide Pyrimethamine Folinic acid US examination

will be treated by alternate treatment of pyrimethaminesulfonamide-folinic acid for 3-4 weeks, followed by 4 to 6 weeks of spiramycin and so on for at least a year. Pyrimethamine-sulfonamide-folinic acid can also be used alone for a year. New lesions of chorioretinitis seem to develop less often during the first year of life in children receiving several courses of treatment (Couvreur et al 1984). The long term follow-up study of the Chicago Collaborative Treat¬ ment Trial (McAuley et al 1994), up to 10 years, suggested that after one year of treatment up to 70% of infants with severe central nervous system and ophthalmologic involve¬ ment at birth developed normally. Delay in diagnosis and therapy is indicative of a poor prognosis. It is noteworthy that only one infant was diagnosed with congenital toxo¬ plasmosis in utero and all others after birth. Treatment is also known to decrease the occurrence and the development of intracranial calcifications. The association of pyrimethamine-sulfonamide during pregnancy when the fetus is infected decreases the fetal immunological reaction to infection in the first year of life more than spiramycin alone (Fortier et al 1997). The associa¬ tion of pyrimethamine, sulfonamide and corticosteroids seems to be more efficient than the association of clinda¬ mycin-corticosteroids, cotrimoxazole-eorticosteroids or no treatment in chorioretinitis (Rothova et al 1993). The treat¬ ment should be followed for at least one year and the follow-up continued until adolescence.

If the diagnosis of fetal infection was positive: US = ultrasound PCR= polymerase chain reaction AF = amniotic fluid TOP = termination of Dreanancv

Figure 30.4 Management of maternal seroconversion during the third trimester.

The most important thing here is not the diagnosis but the prognosis. Neonatal examination is usually easy: • neurological and ophthalmological examination • ultrasound examination of the central nervous system The treatment started in utero should be continued and there will be a long-term follow-up.

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639

INFECTION OFTHE CNS

Congenital viral infections and the central nervous system Guillaume Benoist, J. Nizard, Yves G. Ville

INTRODUCTION Prenatal ultrasound examination is both a screening and a diagnostic tool for the assessment of fetal congenital infec¬ tions. Neonatal prognosis of fetal infections is often depen¬ dent upon abnormalities visualized during fetal life, because these infectious agents may have devastating long term effects. MRI is a complementary tool for the evaluation of clastic processes secondary to CNS infection that needs to be further studied in order to establish its role in this field of prenatal diagnosis management. Congenital infections differ from those in adults and children by the fact that their target is a developing organ. The features of brain involvement will depend on the timing of fetal infection. In early pregnancy, the infection will result in abnormal development while later infections will cause clastic lesions. Knowledge of the development process combined with precise dating of maternal infection will help identify brain imaging abnormalities and understand the mechanism and severity of the disease in order to provide prognostic assessment and appropriate counseling. This chapter aims to review the most important infectious agents affecting the fetal central nervous system (CNS) and to describe the main features of prenatal diagnosis.

CYTOMEGALOVIRUS (CMV) Virology, pathogenesis, epidemiology The cytomegalovirus (CMV) or herpesvirus 5 is a member of the Herpetoviridae family. Its size is the largest in this family. Its genome is composed of a double stranded DNA. It is highly species-specific and humans are its only reser¬ voir. Like other members of the herpesvirus group, CMV remains latent in the organism after acute infection. Reac¬ tivation can occur during latent infection. The transmission of the virus occurs by direct or indirect person to person contact, via body secretions or by blood products or organ transplants. Indeed, the CMV is shed for a long time after the primary infection. However, CMV infection is not very contagious and requires intimate contact. The main cells’ targets are the endothelial cells and the polymorph nuclear leukocytes (PMLs). The dissemination of the virus is then hematogenous with a viremic phase which can be diagnosed by laboratory testing. After wide¬ spread dissemination the CMV replicates mainly in the liver and the spleen. 640

Seroprevalence ranges from 50 to 85% in the United States and in Western Europe. This rate increases with age and in lower socioeconomic backgrounds. Incidence of CMV primary infection in pregnancy also varies with socioeconomic conditions and ranges from around 2% per year in developed countries to 6% in devel¬ oping countries (Stagno et al 1982).

Maternal infection Most primary infections in immunocompetent hosts are subclinical. Nigro et al (2003) reported fever in 42.1% of primary infection and in 17.1% of recurrent infection (P > 0.01), fatigue in 31.4% and 11.4% (P < 0.001), myalgia in 21.5% and 6.7% (P < 0.001), flu-like syndrome defined as the simultaneous occurrence of fever and at least one of these signs in 24.5% and in 9.5% (P < 0.001), lymphocytosis = 40% (39.2% and 5.7%, P < 0.001), increased plasma levels of aminotransferases >40IU/L in 35.3% and in 3.9%, (P < 0.001). The diagnosis of primary infection can be easily con¬ firmed by serologic testings. Seroconversion is the de novo appearance of virus-specific Ig'G antibodies in a pregnant woman who was seronegative before the onset of preg¬ nancy. It enables the diagnosis of primary infection. Never¬ theless, this event is rare as, in most developed countries, non-systematic follow-up of the serologic status is recom¬ mended during pregnancy. Serological testing is usually performed when contamination is suspected following maternal clinical symptoms, or when fetal abnormalities are suspected on ultrasound examination. IgM antibody response begins in the first days after maternal contamination reaching a peak in the first month after maternal contamination. High to medium levels of IgM antibodies can therefore be detected during the first 1 to 3 months after the onset of infection after which the titers start declining. However, IgM can remain positive for more than a year (Revello ft Gerna 2002). When dating maternal infection is difficult, evaluation of IgG avidity is useful. Soon after primary infection, antibodies show a low avidity for the antigen, but this increases progressively thereafter. An avidity index (Al) > 70% is considered to reflect a primary infection >3 months, and Al < 30% is highly sug¬ gestive of a recent primary infection (80 UI/L), thrombocytope¬ nia, conjugated hyperbilirubinemia, hemolysis, increased cerebrospinal fluid proteins (Boppana et al 1992). Long term follow-up of these children enabled the establishment of the occurrence of at least one sequela of 90% in this subgroup (psychomotor delay, sensorineural hearing loss, ocular abnor¬ malities). Death consecutive to congenital CMV infection was estimated to be around 6%. In this group, the best predictor for adverse neurodevelopmental outcome is the presence of intracranial computed tomographic (CT) abnormalities within the first month of life (Boppana et al 1997). These abnormali¬ ties were also associated with sensorineural hearing loss (SNHL) at birth or with deterioration of audiometric status during the first months of life. Ninety percent of infected newborns are asymptomatic although infected as shown by the presence of the virus in their urine or their saliva during the first weeks of life. These infants are known to have a better long-term prognosis than symptomatic ones; 10 to 15% will develop sequelae, more often during the first 2 years of life. These sequelae include SNHL in 7%, chorioretinitis in 2%, intellectual deficit in 4% and microcephaly in 2% (Fowler et al 1997, Kumar et al

31

1973, Melish 8t Hanshaw 1973, Noyola et al 2000, Saigal et al 1982). SNHL is the most frequent deficit related to congenital CMV infection in asymptomatic neonates. Fowler et al (1997) have reported that 50% of CMV-related audio¬ metric deficits were bilateral, 50% worsened during the first years of life and for 18% of them the audiologic deficit was diagnosed on average only at 27 months. CMV congenital infection could be the cause of one third of all SNHL in childhood.

Prenatal diagnosis Without screening programs in pregnancy the most frequent circumstance of diagnosis of congenital CMV infection is the fortuitous discovery of abnormal ultrasound findings related to CMV congenital infection. This may explain that severe abnormalities are described more often than subtle finding's. In primary infections around 50% of the infected fetuses can be diagnosed by ultrasound examination. This is more likely to reflect the proportion of papers published on this particular aspect than the performance of ultrasound as a screening test (Ville 1998). It is also important to remember that the correlation between abnormal sonographic findings and evidence of maternal infection is made several weeks apart (Revello H Gerna 2002). In the literature, ultrasound features of fetal CMV infec¬ tion are twofold: gross abnormalities leading to the diagno¬ sis of fetal CMV infection (mainly ventriculomegaly or hydrocephalus, microcephaly, posterior fossa cysts, cerebel¬ lar hypoplasia, severe intrauterine growth restriction or even hydrops fetalis), and subtle findings discovered after thor¬ ough serial ultrasound examination of fetuses at high risk when vertical transmission of the virus has been shown (mainly extracerebral findings or more subtle cerebral abnormalities). CNS abnormalities can be categorized in both classes of ultrasound findings. The most characteristic lesions are bilateral periventricu¬ lar hyperechogenicities (Ghidini et al 1989, Graham et al 1982). These lesions are calcifications and are visualized as hyperechogenic foci, which, despite their high reflectivity, do not cast any acoustic shadow (Fakhiy H Khoury 1991, Koga et al 1990). They are the result of a necrotizing inflam¬ mation of the periventricular area at the level of the lateral ventricles with subsequent calcification. These calcifications are seen whatever the timing of the infection. However, the lack of specificity does not enable these lesions to be related to the CMV infection. Tassin et al (1991) reported ring-like areas of the periven¬ tricular fluency appearing earlier than calcifications. They could be the earliest stage of brain infection, due to the cellular necrosis consecutive to the cytopathogenic effect of the virus. This effect could ensure edema and local blood effusion. These effusions could be further cleared by the reticuloendothelial system and the calcifications would be the scars of this process (Tassin et al 1991). 641

SECTION

VI

INFECTION OFTHE CNS

Other locations of the calcifications can also be observed in the fetal brain. Localization of branching linear echogenic areas in the thalami has been described during fetal life and at birth (Estroff et al 1992, Teele et al 1988). These calcifications correspond to the arteries in the basal ganglia and in the thalamus and justify the nickname ‘lenticulostrial vasculopathy’. These lesions are due to thickening of the vessels. This abnormality has been observed up to 31 weeks (Estroff et al 1992) (Fig. 31.1). Calcifications have also been observed inside the paren¬ chyma more often at the convexity of the circumvolutions.

These mineralized necrotized cortical areas are named polymicrogyria. Differential diagnoses of cerebral calcifications include other infections, intracranial teratomas, tuberous sclerosis, Sturge-Weber syndrome and sagittal or transverse sinus thrombosis. Furthermore, linear areas of the basal ganglia and the thalami have also been described in association with trisomy 13 and 21. The fetal ventriculitis related to CMV infection is visual¬ ized as periventricular cysts. These cysts could be due to ischemia of the subependyma with further necrosis and calcifications (Shaw ft Alvord 1974). These cysts are named

Figure 31.1 (a) Coronal section. Subependymal germinolysis cysts, (b) Parasagittal section. Linear echogenic areas in the thalami lenticulostnatal vasculopathy. (c) Axial section. Ventriculomegaly. periventricular hyperechogenicities, microencephaly (enlargement of the pericerebral space), (d) Coronal section. Delayed closure of the Sylvian fissure, microencephaly (enlargement of the pericerebral space). 642

CHAPTER

Congenital viral infections and the central nervous system

subependymal germinolysis cysts (Shaw ft Alvord 1974). They are typically located around the frontal horns of the lateral ventricles (Fig. 31.1). Inside the ventricular areas intraventricular synechiae or adhesions can also be observed. Ischemic process has also been implicated in the genesis of these lesions. Other abnormalities related to ischemic phenomenon have also been observed: porencephaly, hydranencephaly and polymicrogyria (Friede ft Mikolasek 1978, Marques Dias et al 1984, Tassin et al 1991). Barkovich and Lindan (1994) have summarized the mech¬ anisms that could explain the development of cerebral lesions due to CMV infection. The lesions of the fetal brain could originate from placentitis causing perfusion insuffi¬ ciency resulting in ischemia with the consequences described above. They could also be the result of the special affinity of the virus for the immature cells of the germinal matrix (Barkovich ft Lindan 1994) that could lead to the loss of brain tissue and abnormalities of the cerebral cortex. An early infection between 16 and 18 weeks of gestation, occurring at the onset of the neuronal migration, can lead to lissencephaly. Ultrasound features can include micro¬ cephaly, ventriculomegaly and absence of normal closure of the sylvian fissure (Barkovich ft Lindan 1994, Hayward et al 1991, Twickler et al 1993) (Fig. 31.1). Cerebellar hypoplasia could also be associated with early infection (Barkovich ft Lindan 1994, Steinlin et al 1996). The transverse diameter can be easily measured by ultra¬ sound but examination of the vermis and its measurement are easier by MRI. Precise evaluation of the vermis by pre¬ natal imaging techniques needs further investigations as it is currently difficult to differentiate vermian hypoplasia and partial agenesis of the vermis. Ventriculomegaly can also be an isolated prenatal finding (Dommergues et al 1996). The severity of the dilatation ranges from mild to severe and up to hydrocephalus (Achiron et al 1994, Sekhsaria et al 1992). Nevertheless, asymmetry between the two occipital horns of the lateral ventricles has also been described without any clinical implications (Achiron et al 1994). The possible etiologies of ventriculomegaly include obstruction of the fourth ventricle or aqueductal stenosis due to ependymitis, or intraventricular hemorrhage but also destructive ventriculomegaly or brain atrophy. Other exceptional abnormalities have been reported in CMV congenital infections including hemimegalencephaly (Jay et al 1997) and schizencephaly (Iannetti et al 1998, Sener 1998). Irrespective of the type of injury of the fetal brain during congenital CMV infection, none is specific of this infectious agent. Suspicion of CMV infection is often based on the association of evocative signs such as microcephaly and periventricular calcifications, particularly if they are associ¬ ated with extra-cerebral lesions. The development of fetal MRI has become an asset in the assessment of infected fetuses (Barkovich 8t Lindan 1994, Malinger et al 2003, Soussotte et al 2000). MRI using both

31

T1 and T2 sequences could help define the onset of fetal infection. Sulcation has been precisely described by MRI (Garel et al 2001). Lissencephaly may reflect injury before 16 or 18 weeks whereas polymicrog'yria is likely to follow injury of the brain at 18 to 24 weeks and finally cases with normal g'yral patterns would have probably been injured during the third trimester showing diffuse heterogeneity in the white matter (Barkovich ft Lindan 1994). The wide spectrum of the extracerebral ultrasound find¬ ings illustrates the affinity of CMV for endothelial cells, which explains the large number of organs involved. Hyperechogenic bowel grade 2 has to be considered often as a transient finding. However, in a series comprising 175 fetuses with hyperechogenic bowel, only one case was related to CMV infection (Al-Kouatly et al 2001). It is recognized to be the expression of viral enterocolitis and is rarely expressed as meconium ileus or peritonitis (Dechelotte et al 1992). Oligohydramnios is more often reported than polyhy¬ dramnios and considering the affinity of CMV for the kidney, it can be seen as the expression of a fetal nephropathy. The fetal heart can also be affected showing cardiomegaly with a thick myocardium which may contain punctate calcifications. As a functional consequence, Drose et al (1991) have also described tachyarrhythmia. This is a rare finding that could participate in the development of fetal hydrops. Generalized edema and ascites may also suggest anemiarelated hydrops due to the combined effect of liver failure and infection of the bone-marrow. This spectacular presen¬ tation has also proven to eventually be transient with both ultrasound and biological normalization at follow-up (WattMorse H Hill 1995). Ultrasound findings are summarized in Table 31.1. Despite evocative ultrasound findings associated with laboratory diagnosis of maternal infection, confirmation of fetal infection is necessaiy. It can be done by the recovery of the virus or the viral DNA in the fetal compartment. CMV can be detected in the amniotic fluid by conventional viral isolation, rapid culture or molecular assays. Virus isolation has a high specificity but has a lower sensitivity than poly¬ merase chain reaction (PCR). In recent years, PCR has been established as a reliable technique in reference laboratories. The efficacy of these methods has been evaluated in several studies (Enders et al 2001, Guerra et al 2000, Lazzarotto et al 2000, Liesnard et al 2000, Revello 8t Gerna 2002). False-negative results could be explained in most cases by inappropriate timing of amniocentesis. Following serocon¬ version or reactivation, the process leading to CMV excre¬ tion in the fetal urine will take an average of 6-8 weeks and this interval should be recognized in order to avoid false negative prenatal diagnosis (Revello ft Gerna 2002). Amnio¬ centesis should also be performed once fetal urination is well established and therefore not before 22 weeks. When the conditions of sampling are ideal (Revello et al 1999a), the sensitivity of prenatal diagnosis by PCR in amniotic fluid has been reported to be close to 100%. False positive PCR 643

SECTION

VI

INFECTION OFTHE CNS

Table 31.1 Fetal abnormalities diagnosed in utero by ultrasound examination as reported in 7 series in the literature from 2000 (Guerra et al 2000, Liesnard et al 2000, Azam et al 2001, Enders et al 2001, Gouarin et al 2002, Lipitz et al 2002, Picone et al 2004) NUMBER OF CASES OF CONGENITAL CMV INFECTION *

277

Overall ultrasound findings

116 (42%)

IUGR**

45 (16%)

Hydrops

8 (3%) 20 (7%)

Ascites Pericardial effusion

4 (1%)

Pleural effusion

1 (80% of cases), compared with early-onset sepsis when strains I, II and III are equally common. Thus, early onset GBS meningitis typically involves a high-risk baby who acquires maternal GBS at the time of delivery, develops high-level septicemia and hence meningitis. In contrast, late-onset meningitis usually occurs in an appar¬ ently healthy full-term baby whose nasopharynx is colo¬ nized (at birth or subsequently) with serotype III GBS and who lacks antibody to the capsule.

Staphylococci Other organisms that are common causes of neonatal septi¬ cemia virtually never cause meningitis. Coagulase-negative

CHAPTER

Bacterial and fungalinfections

staphylococci are one of the commonest causes of late-onset septicemia in industrialized countries, but meningitis virtu¬ ally only occurs if there is a CSF shunt. Staphylococcus aureus is another common cause of septicemia, but a rare cause of meningitis unless there has been surgery, a shunt, or seeding from bacterial endocarditis. A polysaccharide capsule is one characteristic of the organisms causing men¬ ingitis that is lacking in staphylococci.

Listeria Listeria monocytogenes, like GBS, can cause early and lateonset forms of bacterial meningitis. The early form may be acquired transplacentally (granulomatosis infantiseptica) or by inhalation of infected amniotic fluid, whereas the lateonset form follows nasopharyngeal colonization and later invasion of the blood and meninges, usually at 2-6 weeks of age.

PATHOLOGY Toxic products of the bacterial cell wall, peptidoglycans and teichoic acid from gram-positive and lipopolysaccharide (endotoxin) from gram-negative organisms, cause substan¬ tial damage to the endothelial cells of the cerebral capillar¬ ies, which form the so-called ‘blood-brain barrier’. Disruption of the tight junctions between the endothelial cells increases the permeability and allows entry of bacteria and white cells and leakage of protein (see Fig. 32.1). The host immune response causes damage to the central nervous system. High levels of tumor necrosis factor (TNF-a) and interleukin-1 and 6 (IL-1|3 and IL-6) in the CSF have

32

been correlated with prolonged fever, fits, spasticity and death. These cytokines from mononuclear cells may damage endothelial cells and lead to raised intracranial pressure and cerebral edema. Oxygen free radicals have also been found to be released in association with meningitis-causing strains of E. coli in healthy full-term neonates. These could harm surrounding tissue and potentiate the inflammatory process. Arachidonic acid metabolites from platelets are also proba¬ bly important in pathogenesis. Levels of prostaglandin E2, a potent vaso-active substance, rise in the CSF in experimen¬ tal meningitis, and this contributes to cerebral edema; both the increased levels and cerebral edema can be blocked by indometacin. Complement may be important in opsonizing organisms, but can also lyse host cells if bacterial cell-wall products are incorporated into them. Soluble CD 14 from intrathecal leucocytes is massively released into the CSF and may play an important role in the pathogenesis of meningitis. Intracranial pressure (ICP) is always elevated in bacterial meningitis. The possible mechanisms include cerebral edema, vasodilatation of cerebral veins and capillaries, vascular leak, loss of auto-regulation of cerebral blood flow and impaired circulation of CSF. Reduced cerebral blood flow produces regional hypoxemia, increased metabolism of ara¬ chidonic acid, and anaerobic glycolysis with increased pro¬ duction of lactate. There is also decreased carrier-mediated transport of glucose into CSF, and this is probably the main cause of the characteristic low CSF glucose (hypoglycorrhachia) seen in bacterial meningitis. Consumption of glucose by bacteria or white cells is unlikely to be a major cause of low CSF glucose, since the CSF sugar can be low, even zero, for weeks after acute bacterial meningitis, without causing any symptoms. The outcome in neonatal meningitis is generally worse than that in older children. The relatively poor neonatal immune response, permitting rapid bacterial multiplication, is one possible reason. Severe ventriculitis, a hallmark of neonatal meningitis, is rarely seen outside the newborn period. Fever is relatively uncommon in neonatal meningi¬ tis, and this may contribute to the poor outcome, since CSF bacterial multiplication in experimental pneumococcal men¬ ingitis is far more rapid at normal body temperatures than when animals are febrile.

Summary of pathology

Figure 32.1 Pathophysiology of bacterial meningitis.

• Ventriculitis is common in neonatal bacterial meningitis, particularly gram-negative meningitis, and there may be collections of pus in the ventricles and subarachnoid space. • Subdural effusions are rarely of a sufficient size to cause raised intracranial pressure. • Hydrocephalus may develop secondary to purulent exudate obstructing the arachnoid granulations over the surface of the brain, or as a result of exudate in the ventricles obstructing the foramina of Magendie and Luschka or the aqueduct. 661

INFECTION OFTHE CNS

• Intraventricular hemorrhage may occur and contribute to hydrocephalus. • Vasculitis is common and may lead to venous thrombosis; there may be infarcts and focal necrosis. • Neuronal damage is often widespread in severe cases and leads to necrotic liquefaction or cerebral atrophy.

CLINICAL FEATURES The classic clinical features of bacterial meningitis are fre¬ quently absent and there may be no apparent distinction between the newborn with sepsis with or without meningitis. A body temperature greater than 38°C or less than 36.7°C is an indication for further investigation and consideration of lumbar puncture. However, in one series of 223 proven cases of neonatal bacterial meningitis, only nine cases had a temperature greater than 38°C (de Louvois 8t Lambert 1991). The neonate may even appear well yet still be found to have meningitis. A bulging fontanelle strongly suggests meningitis but may be absent with dehydration. Group B streptococcal sepsis can present with respiratory distress within a few hours of birth that may be confused with hyaline membrane disease, and will progress rapidly to meningitis if untreated. The majority of gram-negative men¬ ingitis associated with obstetric complications occurs in the first 2 weeks. The more premature and the younger the baby, the less specific the symptoms and signs. Palazzi et al (2006) summarized the clinical signs in 255 neonates with bacterial meningitis in six centers (see frequencies in Table 32.3).

LUMBAR PUNCTURE Indications Because of the difficulty in making a clinical diagnosis of meningitis, it is vital that if sepsis is suspected, either a lumbar puncture (LP) is performed or, if the LP is delayed because of the baby’s unstable condition, blood cultures are taken and antibiotics started that will adequately cover the organisms likely to cause bacterial meningitis. The wide

range of possible pathogens makes empiric antimicrobial therapy without a lumbar puncture far more difficult. Up to 40% of cases of neonatal meningitis are associated with negative blood cultures (Garges et al 2006, Visser 8t Hall 1980), so if antibiotics are started for suspected early-onset sepsis without performing a lumbar puncture, the LP should be done later, particularly if blood cultures are positive. However, occasionally meningitis may be present with normal CSF microscopy, while an intraventricular hemor¬ rhage may complicate the later interpretation of the CSF white-cell count. In a study of 728 LPs performed in the first week of life on babies with early-onset respiratory dis¬ tress, bacteria were isolated from the CSF of nine, but only one had a clinical course consistent with meningitis. The indications for lumbar puncture are controversial. They range from inclusion of LP as part of a routine septic work-up in asymptomatic neonates based on maternal risk factors, to restricting LP to those who have signs and symp¬ toms of severe sepsis. A study of 9641 VLBW neonates found that 5% of LPs performed after 72 hours were positive, 34% of which were associated with negative blood cultures (Stoll et al 2004). Visser and Hall (1980) reported that of 21 neonates with late onset bacteremia, 5 also had concur¬ rent meningitis. In one study, 43 cases of meningitis were reviewed retrospectively by application of selective criteria for performing LP only if CNS symptoms or signs were present, and the diagnosis of bacterial meningitis would have been delayed or missed in 37% of them. Of admission lumbar punctures for respiratory distress, only one of over 1700 infants had an organism identified in the CSF that was not isolated in the blood. In Australia, a survey of neonatologists revealed that none performed an LP routinely for a preterm neonate with respiratory distress and 83-85% if the blood culture was positive (Joshi 8t Barr 1998). Neonates can decompensate rapidly with handling during lumbar puncture, due to hypoxia and hypercapnia. The LP should be delayed if there is significant respiratory distress or labile blood pressure. Pre-oxygenation can help prevent

Source: Frequencies from Klein et al 1995, Palazzi et al 2006.

662

CHAPTER

Bacterial and fungal infections

desaturation. Local anesthesia decreases the amount of struggling but not physiological changes. The risk of coning of the medulla oblongata into the foramen magnum is low, even with raised intracranial pressure. Topical local anes¬ thetic mixtures reduce pain and are safe in term neonates but cause raised methemoglobin in preterm infants, although this has not been shown to have any clinical consequences. Performing the LP with the neonate in the sitting position has been shown to reduce the degree of hypoxia. The rate of coning in neonates has been reported as 1% (four out of 423 neonates) (de Louvois et al 1991). Lumbar puncture should be performed with a stiletted needle in preference to a hypodermic needle. This is to prevent the risk of an epidermoid tumor in the spinal canal from a fragment of skin that may not present for many years after neonatal LP. There has been some suggestion that the stylet should be reinserted before the needle is removed to reduce CSF leak. The success rate in 181 neonates using different types of needle has been shown to be the same, and the traumatic taps did not result in pleocytosis on repeat LP. A formula for the depth of insertion of the lumbar puncture needle has been calculated in centimeters as 0.03 x height of child (cm). A sterile technique should be used to prevent introduction of infection and contamination of the specimen. Contamination is particularly important when a shunt is being tapped, as the organisms causing shunt infections are often skin flora. However, iodine containing disinfectants should not be used, because of the risk of transient hypothyroidism. Chlorhexidine is a suitable dis¬ infectant. The opening pressure should be measured. The normal pressure in neonates is 0-5.7 mmHg (7.6 cm water) with the head de-flexed, and the baby horizontal and quiet. The larger the specimen of CSF, the more chance of isola¬ tion of organisms that are present in small numbers such as mycobacteria and fungi. CSF should also be sent for protein and glucose assay with simultaneous blood glucose assay. The measurement of CSF lactate is not routinely useful in meningitis, though it may be of use in the investigation of the neonate with seizures or suspected metabolic abnormal¬ ity. Further tests may be of use such as latex agglutination test for group B streptococcus, which is commercially avail¬ able. However, it is possible to have a false-negative result when excess antigen is present (prozone effect) and false positives from skin contamination. Urinary antigen testing

32

is not generally useful because of high false-positive and false-negative rates. Newer methods of ultrasound-enhanced particle agglutination show improved detection rates. The sensitivity of latex agglutination for infants with group B streptococcal meningitis varies from 73-100°/o for CSF and 75-84% for urine. If syphilis is suspected, a non-treponemal test such as VDRL should be performed on the CSF. The CSF should be examined by microscopy and a differential cell count. A Gram stain should be performed even if there are no white cells, because meningitis can occur in the absence of pleo¬ cytosis. The spun CSF should be cultured on blood agar and chocolate agar routinely. If there is a shunt, this should be brought to the attention of the microbiology laboratory so that the CSF can be cultured in enrichment broth. A viral culture should also be performed when indicated clinically and, if appropriate, specific viral polymerase chain reaction (PCR) for herpes simplex virus (HSV) and enterovirus. Inflammatory markers can be useful in diagnosing infec¬ tion. C-reactive protein (CRP) can be measured in the CSF and blood. The result of a meta-analysis suggests that only a negative CRP test is highly informative in the diagnosis of bacterial meningitis. Interleukin-1 receptor antagonist (IL-lra) and interleukin-6 (IL-6) levels have been found to rise in serum 2 days before clinical manifestation of infec¬ tion in neonates. However, an LP is effectively a biopsy, giving a rapid diagnosis of the condition and the likely cause, whereas no acute phase reactant will have 100% specificity, nor will it distinguish septicemia from meningitis.

INTERPRETATION OF CSF FINDINGS CSF white-cell count In general, CSF white-cell count and protein levels are higher and CSF glucose levels lower in normal neonates than in older children and adults (see Table 32.4). These differences are even more marked in preterm infants. In normal preterm infants, the mean CSF white-cell count is up to 27 pL, about one-half neutrophils, with a range of 0-112. In normal-term infants, the mean white-cell count is lower (5-10 pL) in most studies, but again the range is up to 130 (Ahmed et al 1996). There is no difference in CSF findings between term and preterm infants at high risk of infection but without meningitis. The mean CSF white-cell counts were 8 and 9 pL and the ranges 0-32 and 0-29 for

Table 32.4 Normal CSF combined values from selected studies Number of

White cells

infants

(x106/L)

Protein (g/L)

Glucose (mg/L)

Mean (range)

Mean (range)

Mean (range)

Preterm

188

12 (0-112)

1.09 (0.31-2.69)

7.1 (2.4-10.6)

Term

409

8.8 (0-130)

0.72 (0.17-1.74)

5.0 (2.6-24.8)

Source: From Klein et al 1995 and Isaacs & Moxon 1999.

663

SECTION

VI

INFECTION OFTHE CNS

term and preterm babies, respectively. Sixteen babies with septicemia without meningitis had a mean CSF white count of 20 pL (range: 0-112). Traumatic taps are common, but interpretation of the ratio of white to red cells is not reliable. A repeat lumbar puncture after a traumatic tap may also be misleading as the blood can cause an inflammatory response or red cells can lyse giving a falsely low RBC count. Of 21 babies with proven group B streptococcal meningi¬ tis and of 98 babies with gram-negative enteric meningitis, 29% and 4%, respectively, had CSF white counts 3SD below the mean, two had hearing loss and one had vision loss. The mortality rate for Candida albicans infection is higher than for Candida parapsilosis. Neonates acquire Candida albicans through vertical trans¬ mission most commonly, but Candida parapsilosis and Candida lusitaniae are most often nosocomially acquired infections. The incidence of Candida parapsilosis infection is increasing, and it has now been reported as the main cause of candidemia in a NICU in the USA. Contrast-enhanced CT scanning can be useful in the diagnosis of neonatal cerebral candidiasis (see Fig. 32.2). Apart from Candida species, there are other fungal infec¬ tions, including Trichosporon bcigelii, reported as causing invasive neonatal infections and shunt infections. This organism can be successfully treated with amphotericin. Other rare case reports of neonatal CNS infections include the fungi Cryptococcus ncoformans, Torulopsis glabrata, Aspergillus sydowi and A. fumigatus.

SUMMARY OF FUNGAL MENINGITIS • Use amphotericin B (±5-flucytosine). • Fluconazole is an acceptable alternative to amphotericin B for Candida albicans or Candida parapsilosis. • Fluconazole can be given orally if i.v. access is a problem late in course. • Treat for at least 4 weeks.

Age (days) Mean (range)

Slovakia

8

6:2

27 (15-29)

Lee et al 1998

Canada

8

_

_

Arisoy et al

USA

9

2:7

Candida

Fluttova et al

fungaemia

1998

Premature

32

CSFWCC

CSF

Blood

Died

6

8

4

175 (1-529)

5

6

3

184 (0-1120)

9

3

2

Mean (range)

+ve culture

candiasis CSF Candida

12 (5-26)

1994

673

SECTION

VI

INFECTION OFTHE CNS

Infantile botulism

(see also p 788)

Infantile botulism is caused by ingestion of spores followed by gut colonization. In a case-control study from the USA of 68 infants with laboratory-confirmed infantile botulism, the main risk factor for infants under 2 months of age was living in a rural area or on a farm. Eleven of the 68 cases had consumed honey. Clostridium botulinum spores are ubiquitous in the soil. Breast-feeding may generate the optimal conditions for ger¬ mination of the spores. The organism colonizes the gut and produces a powerful exotoxin. The toxin is absorbed into the bloodstream via the gut and carried hematogenously to cholinergic nerve synapses, particularly neuromuscular junctions. Here, it binds irreversibly to receptors on the presynaptic nerve terminal, blocking acetylcholine release. This explains the atropinic manifestations of the disease such as pupillary dilatation and constipation, as well as the muscular hypotonia and cranial-nerve palsies. The disease is characterized by a descending paralysis of the cranial nerves followed by paralysis of the nerves to the axial and truncal muscles. The presentation can also be acute with a sepsis-like illness and respiratory arrest. Recovery invariably occurs after some days or weeks due to sprouting of new nerve terminals. The diagnosis is confirmed by intra-peritoneal injection of purified stool from the patient into two mice, one of which is also given the antitoxin. Death of the mouse without the antitoxin and survival of the other confirms the diagnosis. Otherwise, there are commercial assays for type A neurotoxin. Isolation of Clostridium botulinum from the stool and the characteristic electromyogram (EMG) also support the clinical diagnosis. The management of infantile botulism is to protect the airway and support respiration, if necessary, until spontaneous recovery occurs. Tracheostomy prolongs hospitalization. Nasogastric feeds are usually well tolerated and obviate the need for parenteral nutrition. There is no indication for anti¬ microbial therapy (except for aspiration or hypostatic pneu¬ monia). Penicillin does not speed recovery from infantile botulism, and gentamicin may exacerbate the condition due to its effect on neuromuscular transmission. Botulinum immune globulin is available but not in routine use. Equine botulinum immune globulin is more readily available and speeds recovery. The prognosis nowadays is excellent, although relapses can occur. A proposed association between infantile botulism and sudden infant death syndrome is totally unproven. Other species of Clostridium including C. barati have also been recognized as causing infantile botulism.

SUMMARY OF INFANTILE BOTULISM • Classic triad of clinical features: • bulbar palsies (slow/absent pupil response); • alert; • absent fever. • Also commonly presents with constipation, ptosis and poor feeding. 674

NEONATAL TETANUS Neonatal tetanus still causes significant mortality in devel¬ oping countries despite the World Health Organization’s goal of global elimination of the disease by the year 2000. The disease is caused by the neurotoxin produced by Clos¬ tridium tetani, a ubiquitous spore forming bacterium found in high concentrations in soil and animal excrements. The anaerobic conditions of the necrotic cord allow the spores to germinate. The cord becomes contaminated by nonhygienic practices of cutting the cord or traditional prac¬ tices. In Turkey from 1991 to 1997, 55 babies with neonatal tetanus had all been delivered by untrained birth attendants in rural areas. The cord had been cut with a razor blade (55%), scissors (27%), or knife (18%). In KwaZulu-Natal, cow dung has been used to staunch the blood flow from the severed cord, and in Pakistan, neonatal tetanus has been associated with the practice of bundling, where the infant is wrapped for prolonged periods in a sheepskin cover after dried cow dung is applied. The incidence in developing countries may not be accu¬ rately known, for example, when the infant dies before reaching medical help, and the diagnosis has to be made from care-givers’ interviews. In Bangladesh, the sensitivity and specificity of particular combinations of signs are >80% for neonatal tetanus. In 1997, there were an estimated 277 400 deaths world-wide due to neonatal tetanus, but 20 years ago, there were an estimated 800000 deaths annually. In the USA, there has only been one case from 1989 to 1997. Several studies have shown a male predominance: 78% (161/207) and 76% (42/55). The mean age of onset of symptoms is 5-6 days (range 121 days) with the fatal cases presenting significantly earlier in reviews of cases from 1976 to 1994 and 1991 to 1997. The most common symptoms are spasticity (76%), lack of sucking (71%), trismus (60%), fever (49%), omphalitis (44%), irritabil¬ ity (24%), risus sardonicus (22%) and opisthotonus (15%). Treatment includes intravenous human tetanus immuno¬ globulin. The dose required for neonates is not well estab¬ lished. Four thousand international units (IU) are probably appropriate for neonates. The infusion should be started slowly and increased as tolerated (e.g. from 0.1 mL/min for 30 min increased to 0.2 mL/min). If this is not available intramuscular tetanus immune globulin (TIG) should be given. A dose of 500 IU has been effective in neonates, part of the dose traditionally being injected around the umbili¬ cus, though this is not of proven value. If neither is avail¬ able, equine tetanus antitoxin (TAT) can be given after a test dose because 10-20% develops serum sickness. Ten thousand international units has been found to be an ade¬ quate dose. Alternatively intravenous gammaglobulin can be given, though the dose has not been evaluated. The umbilicus should be debrided if there is necrotic tissue, but wide excision of the umbilical stump is not recommended. Metronidazole (30 mg/Kg/day given at sixhourly intervals) is effective at reducing the number of

CHAPTER

Bacterial and fungal infections

vegetative forms of C. tetani and is the antibiotic of choice. Penicillin G (100000 U/Kg/day) given at 4-6-h intervals is an alternative treatment. The antibiotics should be contin¬ ued for 10-14 days. High-dose diazepam (40 mg/Kg/day), phenobarbitone and chlorpromazine have been found to lower the mortality significantly compared to less sedation. The mortality remains high, even when intensive care is available. The mortality rate was 47% in the older study and 40% in the more recent study without any equipment for mechanical ventilation. In Nigeria, a mortality rate of 59% was reported, and in South Africa, where ventilation in a pediatric intensive care setting was available, the mortality rate was 22%. The mean age at death is 9 days and 5 days from admission. In those ventilated, the mean duration of ventilation was 23 days (range 17-60 days) and ICU stay 35 days (range 13-87 days). The World Health Organization’s major strategy for pre¬ vention of neonatal tetanus is the administration of at least two properly spaced doses of tetanus toxoid to women of child-bearing age in high-risk areas to passively protect their newborns at birth. Part of the failure to reach the goal of elimination of neonatal tetanus has been subpotent vaccine, as well as a failure to immunize. Other strategies have been the provision of ‘safe-birth kits’ with a sterile razor blade (or half blade so that it is not taken for use for other purposes!); teaching birth attendants hand washing (OR 0.64 P - 0.005); and application of topical antibiotics and disinfectants to the cord.

SUMMARY OF NEONATAL TETANUS • WHO aims to eliminate neonatal tetanus, but cases still occur, even in industrialized countries.

CONGENITAL NEUROSYPHILIS A dramatic increase in syphilis, which occurred in the late 1980s and early 1990s in the USA, has subsequently declined. In the UK, there were nine presumptive cases of congenital syphilis reported between 1994 and 1997. Acute syphilitic leptomeningitis usually appears between 3 and 6 months of age. Infants present with symptoms and signs of acute bacte¬ rial meningitis, including a stiff neck, progressive vomiting, a positive Kernig sign, bulging of the fontanelles, separation of the sutures and hydrocephalus. The CSF shows a monocy¬ tosis, with up to 200 cells/mm3, a modest increase in protein (0.5-2 g/L) and a normal glucose level. The CSF VDRL is positive. This form of CNS syphilis responds to penicillin. Late manifestations of involvement of the central nervous system usually occur after 1-2 years of age. Chronic menin¬ govascular syphilis may have a protracted course with pro¬ gressive communicating hydrocephalus due to obstruction in the basilar cisterns. It may also cause VHth cranial nerve palsies (occasionally III, IV or VI), optic atrophy and gradual intellectual deterioration. Vascular lesions of the brain have been described, with endarteritis causing convulsions and an acute hemiplegia.

32

For the diagnosis of neurosyphilis, a raised neonatal CSF protein (>1.8 g/L) and raised CSF white-cell count (>25 x 106 WBC/L) in the presence of maternal evidence of inade¬ quately treated syphilis is sufficient for treatment of the infant for neurosyphilis. The CSF white-cell count and protein can be normal in neurosyphilis. The only serological test that should be performed on the CSF is the non-treponemal Venereal Disease Research Laboratory (VDRL) slide test. The other non-treponemal tests such as rapid plasma reagin (RPR) or the automated reagin test (ART) should not be used on the neonatal CSF. The treponemal test such as fluorescent treponemal antibody absorption (FTA-ABS) test or the microhemagglutination test for T. pallidum (MHA-TP or TPHA) measure Ig'G and Ig'M. IgG can be detected coin¬ cidentally in the neonatal CSF after the mother has been successfully treated before pregnancy. IgM detection by immunoblot from CSF of neonates has been found to be positive in two out of six cases of neurosyphilis (defined by Rabbit Infectivity Testing (RIT)). T. pallidum DNA PCR was positive in five out of the six cases. A negative CSF VDRL does not exclude neurosyphilis, and the CSF VDRL can be falsely positive by transplacental acquisition of antibody from a mother with high titer. Specific Ig'M to T. pallidum has been found in infants with congenital syphilis and is being evaluated as an alternative diagnostic tool. However, in developing countries where congenital syphilis is most common, the IgM is often not available. The American Pediatric Association recommends that a lumbar puncture and CSF VDRL, cell count, and protein be performed on the infants of mothers with positive syphilis treponemal tests who have not had appropriate treatment documented or if the treated mother has not had an ade¬ quate decrease in non-treponemal antibody titer over 1 month. However, the need for lumbar puncture in asymp¬ tomatic infants is debatable, e.g. 329 infants from two Washington hospitals in 1990-1993 met the APA criteria for LP, but the CSF was normal, and CSF protein and glucose were not significantly different from normal controls. The treatment for neurosyphilis is penicillin G 200000 to 300000 U/Kg/day (50000 U/Kg eveiy 4-6 h) for 10-14 days, possibly followed by benzathine penicillin, 50000 U/Kg/ dose in three weekly doses. CSF concentrations of penicillin reach treponemicidal concentrations when given as aqueous penicillin G at 100000 U/Kg/day and were not significantly increased when the dose was raised to 200000 U/Kg/day. They were significantly higher than using procaine penicil¬ lin 50000 U/Kg/day, which did not reach treponemicidal levels in CSF in a third of infants.

SUMMARY OF NEUROSYPHILIS • Consider LP if maternal VDRL is positive and inadequate documentation of maternal treatment. • LP mandatoiy if neonate has signs of syphilis. • CSF dark ground microscopy, WCC and protein. • CSF VRDL [±T. pallidum PCR, IgM if available). 675

SECTION

VI

INFECTION OFTHE CNS

REFERENCES Adhikari M, Coovadia Y M, Singh D 1995 A 4-year study of neonatal meningitis: clinical and microbiological findings. J Trap Pediatr 41:81-85. Ahmed A, Hickey S M. Ehrett S et al 1996 Cerebrospinal

de LouvoisJ, Lambert H P (eds) 1991 Infections of the central nervous system. In: Neonatal meningitis. B.C. Decker, Philadelphia, PA. Ch. 13, pp. 161-174. de Oliveira R S. Pinho V F, Madureira J F. Machado H R

Kenyatta National Hospital. East Afr Med J 80:456-462. Lee B E, Cheung P Y, Robinson J L et al 1998 Comparative study of mortality and morbidity in

fluid values in the term neonate. Pediatr Infect Dis J

2006 Brain abscess in a neonate: an unusual

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THE SPECIAL SENSES

Figure 37.10 Acuity card procedure. The infant is clearly looking towards the grating (the near-side panel has been turned sideways for the photograph).

Figure 37.11 Acuity card procedure. In certain circumstances, the stimulus cards may be used without the surrounding apparatus.

much longer than originally thought, maturity not being reached until between 15 and 45 months after birth (Hen¬ drickson ft Yuodelis 1984), corresponding closer to PL than VEP results. One exception is the VEP study of de VriesKhoe and Spekreijse (1982), which correlates with both anatomical and PL data. In 1992 Sokol et al reported a smaller discrepancy if phase-alternating gratings were used to estimate both VEP and PL, compared to the usual method which employs phase-alternating gratings to estimate the VEP and stationary gratings to estimate PL. Prager et al (1999) compared the test-retest variability of the 3 main testing modalities of visual function in infants: card pro¬ cedure (ACP), sweep VEPs and pattern VEPs. They found the test-retest results of all 3 methods to be reliable for group testing; however there was poorer agreement in testing an individual infant. They concluded that each test, while valid, is probably evaluating a different aspect of vision a point emphasized by Madan et al (2005). In summary, PL-based test results correlate quite closely with the sweep VEP.

The VEP: PL-based test discrepancy

The PL:Snellen acuity discrepancy

Using standard pattern reversal and flash techniques, VEP acuity estimates tend to be higher than those obtained by PL. The basis of this discrepancy has not been fully resolved, but it is interesting to note that foveal development takes

The clinician, already confused by the discrepancy between behavioral (ACP) and evoked potential acuity estimates, is now confronted with another discrepancy: that between PL and Snellen estimates. Acuities obtained by PL are not

756

CHAPTER

Disorders of vision

always directly comparable to those obtained by Snellen or other recognition targets. Thus, PL grating acuities may be significantly better than Snellen acuities in certain clinical conditions, particularly amblyopia (Mayer et al 1984). This difference is not fully understood (Fielder et al 1992) but may be due partly to methodological differences in measur¬ ing PL and Snellen acuities (Moseley et al 1988). While it does not negate the value of PL it does reduce its value as a method of determining the precise magnitude of amblyo¬ pia. Despite these problems it should not be forgotten that the ACP is the only quantitative test of vision which can be used simply and rapidly in the clinical situation and gives far more information than existing qualitative tests. Its value in recording visual development and assessing the infant who appears not to see well is not in question (Fielder et al 1992).

Pupil grating response The subtle pupillary constriction to sinusoidal gratings of varying frequency can be used to measure visual acuity and correlates well with levels obtained by behavioral methods by 4-6 weeks after birth (Cocker et al 1994). The use of pupillometry is currently confined to clinical research.

Visual development of preterm infants It is now pertinent to consider the effect of preterm birth on the visual system (Fielder et al 1988, 1993, van Hof-van Duin H Mohn 1986). What is the effect of removal from the protective milieu of the uterus and early exposure to the harsh neonatal environment? Does additional time in the extrauterine environment accelerate visual maturation? Central retinal photoreceptor cells although formed by 24 weeks gestation have only rudimentary outer segments (Johnson et al 1985, Provis et al 1985). Rod photoreceptors are still developing at 40 weeks (Hollenberg et al 1972). The preterm infant brain blood supply also differs significantly from that of the term infant (Madan et al 2005). With this background it is pertinent to consider whether visual devel¬ opment is hastened, retarded or unaffected by premature exteriorization (Fielder Et Moseley 2000). This is not the place to consider retinopathy of prematu¬ rity, but it should be borne in mind that most neonates with a birth weight below 1000 g will have developed at least minor stages of this condition. The ERG can be recorded from around 32 weeks PMA (Mactier et al 2000) and Kennedy et al (1997) did not detect any effect with light reduction by goggling. At full-term, the vision of the preterm infant is lower than that of his or her full-term counterpart (Morante et al 1982), and remains so until about 30 weeks, if postnatal age is used as the parameter (van Hof-van Duin Et Mohn 1984a, van Hofvan Duin et al 1983). However, when corrected for the degree of prematurity, preterm and full-term infants develop simi¬ larly as assessed by behavioral techniques (Brown ft Yama¬ moto 1986, Dobson et al 1980, Kos-Pietro et al 1997, Morante et al 1982, Roy et al 1995, van Hof-van Duin Et Mohn 1984a, van Hof-van Duin et al 1983, Weinacht et al 1999). In con¬

37

trast to the above, some VEP studies show mild hastening of acuity development (Norcia et al 1987, Sokol Et Jones 1978), although, more recently (Mirabella et al 2006), all showed that preterm birth had no effect on VEP development. All these results show that, very broadly speaking, premature birth neither hastens nor retards visual development in infancy, i.e. the visual maturation is controlled predomi¬ nantly by innate rather than environmental processes. Neurologically abnormal preterm infants may show a delay in visual acuity maturation (Dubowitz et al 1983, Groenendaal et al 1989, Norcia et al 1987, Placzek et al 1985). Controversy still exists as to whether the flash VEP (within days to 3 weeks of birth) is a reliable prognostic tool in predicting neurological outcome in preterm infants. Shep¬ herd et al (1999), Pike and Marlow (2000) and Kato et al (2000) and Kato and Watanabe (2006) showed that the flash VEP in preterm neonates has some predictive value for both survival and cerebral palsy. This contrasts with Beverley et al (1990) and Ekert et al (1997) who did not find any prog¬ nostic value of the flash VEP in predicting neurological outcome. Harvey et al (1997a) reported that grating acuity is affected by IVH, but this is not related to its grade or presence of PVL, and visual field development is reduced only before 17 months. For children with bronchopulmonaiy dysplasia, uncomplicated by neurological problems, their grating and field development is normal, but recogni¬ tion acuity may be affected (Harvey 1997b). The predictive value of a single measure in early infancy is limited as the slope of visual development (whatever function is assessed) may differ and multiple assessments are essential so that this slope can be calculated (O’Connor et al 2007).

ABNORMALITIES OF VISION — GENERAL One of the most difficult clinical problems is the assessment of the infant or child who might be harboring a visual deficit. A carefully taken history can be more informative than the subsequent clinical examination. Concern volun¬ tarily expressed by a parent must always be taken seriously as this is rarely unfounded and usually more reliable than most qualitative tests of vision. Seeming lack of concern must, however, be treated with caution as it does not neces¬ sarily indicate that all is well. This attitude can be adopted for a number of reasons. First, a low expectancy is generally held for vision in very early infancy. Second, anxiety may be hidden until the parent’s fear that their baby has defective vision is either allayed or confirmed by medical staff, fol¬ lowing which they may pour out a detailed account accu¬ rately describing reduced vision dating back to very early infancy. Third, information may be withheld for fear of biasing the professional towards an unfavorable verdict. The visual pathway abnormalities to be considered in this section are divided into those affecting the anterior (eye to optic chiasm) and posterior (optic tracts to visual cortex) portions. Only neuro-ophthalmic conditions are considered, and problems such as cataract and retinopathy of prematu¬ rity are omitted. 757

SECTION

IX

THE SPECIAL SENSES

While the above two paragraphs represent the current situation, the situation is changing rapidly. Thus, we are now aware of certain patterns of acuity development (Fielder et al 1992) which are shown in a stylized form in Figs 37.12-37.14. This information has introduced a degree of complexity hitherto unsuspected, but it does offer the clini¬ cian insight into fundamental mechanisms and provides valuable information for patient care and for counseling.

Age Figure 37.14 Regression. This may occur in a large range of progressive ophthalmic or neuro-ophthalmic disorders.

DISORDERS OFTHE ANTERIOR VISUAL PATHWAY

Age Figure 37.12 Normal visual development is shown by line (i). Early delayed visual development may be followed by rapid (ii) or slow (iii) improvement. These patterns are seen in delayed visual maturation types 1 and 4 (see later). Following normal or delayed development, acuity may plateau or become asymptotic (iv). The level at which this occurs depends on the seventy of the visual pathway abnormality, but is seen in infantile nystagmus.

Lesions of the anterior visual pathway (i.e. eye to the optic chiasm) sufficient to reduce vision bilaterally in early life lead to nystagmus and afferent pupillary defects. The latter can be difficult to test clinically in infants and children.

Electroretinography in infancy For several conditions ophthalmoscopic signs are either minimal or absent. In this situation an ERG is essential to distinguish retinal pathology from that elsewhere in the visual pathway (Weleber Et Palmer 1991). Clinicians must have a low threshold for arranging this test. As a general rule it should be performed on all infants and children with unexplained low vision, nystagmus, myopia or optic atrophy, i.e. where there is a possibility of retinal disease. As mentioned, an ERG can be obtained without sedation, using lid, fiber, gold foil or, even, contact lens electrodes. Stimulus rates of 2 Hz (generating both rod and cone responses) and 30 Hz (generating only a cone response) (see Fig. 37.6). Performed this way it is probably advisable to consider the ERG obtained as qualitative rather than quan¬ titative, but in most clinical instances this is adequate.

Retinal disorders

Age Figure 37.13 Parallel visual development. This is seen after surgery for congenital cataract surgery or severe retinopathy of prematurity. Late catch-up does not always occur. 758

Many retinal disorders produce a severe visual defect. Some of these are ophthalmoscopically obvious such as retinopa¬ thy of prematurity or chorioretinal scarring. Other condi¬ tions such as achromatopsia (see p. 750) and the tapetoretinal degenerations (including Leber congenital amaurosis) fre¬ quently do not have significant ophthalmoscopically visible signs, at least in early infancy, so an ERG is essential to make a diagnosis.

CHAPTER

Disorders of vision

The cherry-red spot This classic, but rarely seen sign, results from storage of abnormal substances in the retinal ganglion cells. As these cells are abundant around the macula but are absent from the very centre, the fovea is red and its surround white. This subtle sign, which fades with time, is seen in a number of conditions, including Tay-Sachs, Sandhoff, Niemann-Pick and Farber diseases, metachromatic leukodystrophy and the mucolipidoses.

Optic nerve disorders Optic atrophy Optic atrophy is a sign and not a diagnosis, which can be difficult to identify if mild. The appearance of the optic disc alone does not indicate the amount of visual function. Optic atrophy (particularly if associated with retinal arteriolar attenuation) may be the only visible sign of serious retinal disease, for instance in Leber congenital amaurosis or the Laurence-Moon-Biedl (Biedl-Bardet) syndrome. Only by an ERG can retinal involvement be confirmed or eliminated. Optic nerve damage secondary to retinal disease is termed consecutive or ascending atrophy. Damage to the optic radiation and visual cortex can cause trans-synaptic degeneration and a descending type of optic atrophy, but this response is confined to visual pathway insults before and during early infancy. Hereditary optic atrophy. Behr optic atrophy is an auto¬ somal recessive condition in which optic atrophy is associ¬ ated with mild mental retardation, hypertonia and ataxia. Onset may be within the first year of life. Whether isolated recessive optic atrophy is a true entity is uncertain. Other hereditary optic atrophies such as Leber optic neu¬ ropathy, dominant optic atrophy and the DIDMOAD syn¬ drome all present after the first year of life and are not considered here. Retinal disease. Tapetoretinal degenerations such as Leber’s congenital amaurosis, and Laurence-Moon-Biedl (Biedl-Bardet) and Zellweger syndromes, may all cause optic atrophy. Intrauterine disease. Optic atrophy may occur following intrauterine infections, asphyxia and cerebral malformations (described elsewhere). Perinatal damage. It is well established that optic atrophy can result from neonatal events, but even following very premature birth is infrequent. The mechanism(s) by which this occurs is poorly understood. Birth trauma very rarely leads to unilateral nerve damage. Birth asphyxia is some¬ times associated with optic atrophy which may be transsynaptic, resulting from damage to the postgeniculate pathway (Hellstrom et al 1997). This is a feature of the immature visual system alone and may result from perinatal brain asphyxia or malformation, e.g. holoprosencephaly, porencephaly and hydranencephaly. It is generally thought that damage between 24 and 28 weeks is associated with small optic disc (optic nerve hypoplasia) while damage after this time but before 34 weeks may cause optic discs with

37

large cups (pseudoglaucomatous) (Dutton ft Jacobson 2001). Optic atrophy may follow damage to both the visual cortex and subcortex, although with cortical damage the discs are frequently normal. Subcortical damage is frequently associ¬ ated with optic nerve hypoplasia (Brodsky et al 2002). It is likely that the timing of the insult influences optic nerve morphology (Brodsky 2003, Jacobson et al 2003), although a recent study (McLoone et al 2006) could not detect such an relationship. Inflammatory. Severe meningoencephalitis in infancy may cause optic atrophy. Compression. Hydrocephalus, by stretching or compres¬ sion, can lead to optic atrophy. Tumors may compress the chiasm or nerve (e.g. craniopharyngioma) or involve the anterior visual pathway (glioma). Metabolic. This includes the lipid storage diseases (e.g. Tay-Sachs disease), Leigh subacute necrotizing encepha¬ lopathy and osteopetrosis.

Optic nerve hypoplasia This is a congenital anomaly of the optic nerve (Brodsky 1991, 2005) whose incidence may be increasing (Robinson ft Jan 1987). Typically, the optic disc is small, surrounded by a peripapillary pigmented ring (Lig. 37.15), the retinal vessels are slightly tortuous and the nerve fiber layer is thinned (Lrisen 8t Holmegaard 1978, Skarf ft Hoyt 1984). As none of these signs are pathognomonic, mild optic nerve hypoplasia (ONH) may be difficult to diagnose - the disc may be of normal size and examination of the nerve fiber layer is not feasible in infancy. To add to this difficulty the double-ring sign is quite common in the ‘normal’ premature infant.

Figure 37.15 Optic-nerve hypoplasia. 759

SECTION

IX

THE SPECIAL SENSES

The pathogenesis of optic nerve hypoplasia is not known but it may represent a non-specific manifestation of damage to the developing visual system (Frisen Ft Holmegaard 1978). Not surprisingly, therefore, a degree of optic atrophy often coexists (Brodsky et al 2002). Thus, optic nerve hypoplasia (ONH) may be associated, particularly if bilateral, with a large variety of ocular or systemic abnormalities (Margalith et al 1984, Skarf Ft Hoyt 1984). Optic nerve hypoplasia is more common in areas with higher unemployment and teenage pregnancy rates (Patel et al 2006) and also can be associated with preterm birth, fetal alcohol syndrome, mater¬ nal diabetes and endocrine abnormalities (Garcia et al 2006). Structural CNS abnormalities associated with ONH include absence of the septum pellucidum, hydranencephaly, poren¬ cephaly, holoprosencephaly, cerebral atrophy and cystic subcortical leukomalacia, and may therefore be occasionally detected on routine examination of neurologically abnormal neonates (Fielder et al 1986b). Optic nerve hypoplasia has been described in infants exposed to cocaine in utero (Good et al 1992). Neuroendocrine dysfunction occurs in 20-30°/o of cases of optic nerve hypoplasia, with or without a structural neuro¬ logical anomaly. As this often does not become apparent until about 2-5 years of age, continued surveillance is neces¬ sary. Growth, thyroid and gonadotropin hormones may all be affected, and diabetes insipidus has been reported (Costin Ft Murphree 1985, Margalith et al 1984, 1985, Skarf Ft Hoyt 1984). Transient neonatal cholestatic jaundice and hypogly¬ cemia are reported associations (Stanhope et al 1984), but it is not known whether these are the patients liable to develop other neuroendocrine problems later. Absence of a septum pellucidum is not in itself associated with intellectual, behav¬ ioral or neurological deficits (Williams et al 1993). Finally it is important to note that sudden death during a febrile illness has been reported in children with ONH and corticotropin deficiency (Brodsky et al 1997). Because of this possibility it is recommended that all children with ONH should have a detailed neuroendocrine workup. CT or ultrasound scanning may determine the extent of, and anticipate, possible future neurodevelopmental prob¬ lems. Also, MRI spectroscopy may predict neuroendocrine problems (Brodsky Ft Glasier 1993). It is important for clini¬ cians to recognize that while neurological and neuroendo¬ crine abnormalities are more frequent in bilateral they do occur in unilateral ONH (Garcia et al 2006).

Other congenital abnormalities of the optic disc Abnormalities such as coloboma, the morning glory syn¬ drome and pits are not considered here.

DISORDERS OF THE POSTERIOR VISUAL PATHWAY Disorders of the posterior visual pathway, in contrast to those of the anterior visual pathway, do not affect the pupil responses and nystagmus is not a feature. As a caveat to 760

the last comment, many posterior visual pathway disorders are the consequence of widespread neurological damage. Thus, a few jerks of nystagmus may be present, but this is not the sustained oscillation in the straight ahead position which is due to the visual deficit per se.

Delayed visual maturation Parents and clinicians have known for years that the sight of a blind infant may later improve. First described by Beauvieux in 1926, the term ‘delayed visual maturation’ (DVM) was introduced by Illingworth (1961). This is proba¬ bly the most common cause of a severe bilateral visual defect in early infancy and, at its simplest, DVM is an iso¬ lated defect with subsequent complete and permanent visual improvement. Unfortunately, as Beauvieux (1947) recog¬ nized, not all infants with DVM do so well. Although a degree of visual improvement by definition occurs in all, some with associated ocular and/or neurological problems behave differently clinically and suffer a permanent visual defect, the extent being dependent upon the underlying pathology. Expanding upon Beauvieux’s observations, DVM has been classified by Uemera et al (1981), Fielder et al (1985) and by Fielder and Mayer (1991): Type 1. DVM as an isolated anomaly: A. Normal perinatal period. B. With perinatal problems. Type 2. DVM associated with obvious and persistent neurodevelopmental problems. Type 3. DVM associated with nystagmus and albinism. Type 4. DVM with severe congenital, bilateral structural ocular abnormalities. The spectrum is becoming increasingly broad. As RussellEggitt et al stated (1998), DVM is not a single condition but a feature common to neurological abnormalities affecting several areas of the brain. In practice many reserve the term to DVM as an isolated anomaly. DVM as an isolated anomaly — types 1A and IB. In this type of DVM the infant presents with severely reduced or absent vision. There are no abnormal signs on examination, other than those attributable to the visual defect (e.g. ocular divergence). Nystagmus is never present. The ERG is always normal, and the flash VEP may range from absent to normal. The time of visual improvement ranges from about 10 to 18 weeks for type 1A, although for type IB this may not occur for up to 24 weeks. Characteristically this change is rapid, often occurring over only a few days or a week or so, and the subsequent visual acuity development is normal (Fig. 37.16). Although DVM is considered the sole abnormality in this group, a significant number are either born prematurely or suffer perinatal problems (type IB), on occasion resulting in permanent, usually mild, neurological sequelae including squint (Tresidder et al 1990). DVM associated with obvious and persistent neurodevel¬ opmental problems - type 2. That blind infants with severe

CHAPTER

37

Visual acuity (cycles/degree)

Disorders of vision

neurodevelopmental problems may later improve visually is well known. However, in contrast to the first type of DVM the improvement is often slow, occurring over weeks and months rather than days (Fig. 37.17). The eventual level of vision achieved is obviously governed by the amount of visual pathway damage but does not reach normal levels. Nystagmus, consequent upon associated neurological damage, may be present in this group, but this is rarely sustained. Again the ERG is always normal and the VEP variably affected, and may be normal during the period of amaurosis (Lambert et al 1989). DVM associated with infantile nystagmus and albinism — type 3. For over a century it has been known that infants with albinism may be blind in early infancy and then sub¬ sequently improve. This also occurs in congenital/infantile nystagmus. It is interesting to note that during the period of blindness nystagmus is not a feature, and this oscillation commences around the time of (or slightly before) the devel¬ opment of vision (see earlier that nystagmus rarely com¬ mences at birth). Vision improves in this group between 13 and 21 weeks (Tresidder et al 1990) (Fig. 37.18), and the pattern of change is quite different from that seen in type 4 DVM, which is slow and extremely limited. Delayed visual maturation with severe congenital, bilat¬ eral structural ocular abnormalities (excluding albinism) — type 4. Clinicians have known for years that some infants who are blind due to severe ocular abnormalities may exhibit a degree of improvement (Fielder Ft Mayer 1991) (Fig. 37.19). Type 4 DVM is seen in optic nerve hypoplasia, Leber’s con-

Figure 3717 Delayed visual maturation type 2. No infant achieved normal acuity. (Reprinted, with permission, from Tresidder et al 1990.)

Visual acuity (cycles/degree)

Figure 3716 Delayed visual maturation type 1A. Visual acuities recorded by the ACP. (Reprinted, with permission, from Tresidder et al 1990.)

Figure 3718 Delayed visual maturation type 3. Although normal acuity (ACP data) was achieved during infancy, if the measurements had continued, plateauing would have become apparent in early childhood as children with nystagmus have subnormal acuity (see Fig. 33.10). (Reprinted, with permission, from Tresidder et al 1990.) 761

SECTION

IX

THE SPECIAL SENSES

£

100

0.5 mV). The EMG may show some fibrillation potentials at rest, and isolated motor units of normal size and configuration on volition, but will not show the classic changes of reinnervation (i.e. large isolated motor units). Spinal muscular atrophy is autosomal recessive, and the severity in affected siblings is usually similar, but occasion¬ ally there may be marked discordance in severity. Infants with Werdnig-Hoffmann disease generally do not show central nervous system involvement, but non¬ specific changes such as cerebral atrophy or other ischemic changes have been observed in some of these children, mainly associated with prematurity or birth asphyxia (Rudnick-Schoneborn et al 1996).

Management The median age of survival in infants with SMA 1 is reported to be around 9 months. In the last few years there has been increasing evidence that infants with SMA type 1 may benefit from non-invasive ventilation (Bach et al 2000, 2002, Bush et al 2005). Although there are no systematic double blind studies to establish the long term effect of these procedures on survival, these have become part of the routine in many centers and there is evidence that the com¬ bined use of non-invasive ventilation and of other tools that reduce the accumulation of secretions, such as the insufflator-exsufflator machine can increase the chance of survival during acute respiratory infections and the overall manage¬ ment of these children.

CHAPTER

Neuromuscular disorders

40

(a) Figure 40.8 (a) A 4-week-old boy with severe spinal muscular atrophy. There was insidious onset of weakness with poor limb movement and internal rotation of the arms. Fetal movements were normal, and movements seemed normal at birth. Note the typical frog posture, together with the jug-handle posture of the arms and internal rotation at the shoulders, and the alert facies. There is also a narrow chest with poor intercostal movement and a distended abdomen, reflecting the well-preserved diaphragmatic function. With inspiration there is further expansion of the abdomen and costal retraction. Tongue fasciculation was present. Motor nerve conduction (peroneal nerve) showed a markedly reduced motor action potential at 0.05 mV (normal >0.5 mV). Electromyography of the quadriceps showed fasciculation potentials at rest but no activity on volition, (b) Needle muscle biopsy (quadriceps) at 4 weeks of age showed variability in fiber size (H and E) (c) The larger fibers were all type 1, suggestive of some reinnervation (ATPase 9.5).

805

SECTION

X

DISORDERS OFTHE NERVE AND MUSCLE

It has recently also been suggested that other measures such as gastrostomy at the onset of swallowing problems or even before their onset may also help not only to prolong survival but also to improve management and quality of life, reducing the risk of choking episodes and aspiration pneumonia.

Molecular genetics The gene for the autosomal recessive, proximal symmetrical spinal muscular atrophies was localized to chromosome 5q 11-q 13 in 1990 (Melki et al 1990a, 1990b), but it took another 5 years before the molecular defect, was identified by Lefevbre et al (1995) because of the duplication of this part of chromosome 5. The hitherto unknown gene was designated survival motor neuron gene (SMN] and in over 95% of classic cases there was a deletion of exon 7 in the active telomeric copy of the SMN gene, now designated SMNl. This has provided a very useful and rapid diagnostic tool, and also opened the possibility for prenatal diagnosis of chorionic villus biopsy.

The differential diagnosis is with other forms, such as the carbohydrate-deficient glycoconjugate syndromes which show cerebellar and brainstem hypoplasia and peripheral nerve involvement. The carbohydrate-deficient glycoconju¬ gate syndromes include a group of genetic disorders char¬ acterized by a deficiency of the carbohydrate moiety of glycoconjugates (Jaeken et al 1991, 1997). Type 1 is the most common and has been related to a deficit in phosphomannomutase. Infants present with dysmorphic features, hypotonia and hyporeflexia, abnormal eye movements and poor feeding. Other signs, such as skeletal abnormalities, hepatomegaly, proteinuria and cardiomyopathy, are also frequent. The involvement of the peripheral nerves is shown by abnormal motor and sensory nerve conduction velocity. Brain MRI shows brainstem and cerebellar hypoplasia (Akaboshi et al 1995, Jaeken 1991, 1997).

NON-NEUROMUSCULAR DISORDERS

Diaphragmatic SMA

PRADER-WILLI SYNDROME

Diaphragmatic spinal muscular atrophy, also known as spinal muscular atrophy with respiratory distress (SMARD), is another disorder with onset in infancy characterized by spinal muscular atrophy and diaphragmatic weakness, with early life-threatening respiratory failure. The prevalence of SMARD is unknown, but it has been estimated that dia¬ phragmatic paralysis could comprise about 1% of patients with early-onset SMA (Rudnik-Schoneborn et al 1996). In contrast to the typical spinal muscular atrophy (SMA) with proximal limb involvement, the distal muscles are pre¬ dominantly involved in SMARD. Another striking clinical difference is that in SMARD respiratory distress results from severe diaphragmatic paralysis with an elevation of both hemidiaphragms on chest X-ray, while in typical SMA the diaphragm is spared and the respiratory pattern is mainly diaphragmatic and the intercostal muscles are more severely affected, showing costal recession with inspiration. SMARD is a clinically and genetically heterogeneous con¬ dition. SMARD 1 results from mutations in the gene encod¬ ing the immunoglobulin-binding protein 2 (IGHMBP2) on chromosome 11 q 13.

Prader-Willi syndrome usually presents in the newborn period with profound hypotonia associated with sucking and swallowing difficulty, without any associated respiratory problems, in contrast to conditions such as myotonic dys¬ trophy or myotubular myopathy, which have both. With time the hypotonia resolves, and all these children become ambulant, but then problems with hyperphagia and obesity usually start. It is a relatively common disorder with an estimated inci¬ dence of about 1 in 10000 births. It occurs in all races. It was originally described by Prader et al (1956), in five patients with adiposity, short stature, mental subnormality and undescended testes in the males. There is a characteristic facies, with a high forehead, narrow bifrontal diameter, upslanting almond-shaped palpebral fissures, and triangular mouth with a thin upper lip. Squint is present in approxi¬ mately two-thirds, and there are small hands and feet, which may be more apparent in later childhood. The facies may be more distinctively abnormal when the infant is crying, as these infants tend to screw up the face in a particular way (Fig. 40.9). The striking feature about these infants, in comparison with those with neuromuscular disorders, is that the severity of the hypotonia is disproportionate to the intermittently good antigravity movements which may be observed.

Pontocerebellar hypoplasia type 1 In the condition called pontocerebellar hypoplasia type 1, spinal muscular atrophy is associated with hypoplasia of the cerebellar vermis and, often also of the cerebellar hemi¬ spheres, associated with a thin brainstem and pons (Barth 1993). Infants affected by this form show a combination of clinical signs related to both spinal and central nervous system involvement. The clinical course is progressive, and respiratory and feeding difficulties, already present at birth or in early infancy, become more severe.

Molecular genetics This form is not allelic to SMA (Dubowitz et al 1995) and the gene responsible for this form has not yet been identified.

806

There is no neuromuscular involvement; the EMG, nerve conduction velocity and muscle biopsy are normal. Diagno¬ sis is primarily clinical. Routine chromosome analysis is usually normal in these patients, but with high-resolution techniques a deletion may be demonstrated on the long arm of chromosome 15 (15ql2) (Fear et al 1985, Ledbetter et al 1982). A further important observation was that the deletion appears to be of paternal origin (Butler Ft Palmer 1983). Recent advances with molecular genetic techniques have shown that those cases without an overt deletion usually

CHAPTER

Neuromuscular disorders

40

jm

Figure 40.9 Male infant with Prader-Willi syndrome, (a) The baby was clearly hypotonic on day 4. (b) The facies show dysmorphic features at rest, (c) There is excessive wrinkling of the forehead when crying.

807

SECTION

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DISORDERS OFTHE NERVE AND MUSCLE

have maternal disomy, with two copies of the maternal chromosome and a corresponding absence of the paternal contribution. This is an example of genetic imprinting.

CONCLUSION Hopefully this comprehensive description will alert the clinician to the wide range of neuromuscular and

non-neuromuscular disorders that may present in the neo¬ natal period with hypotonia and associated problems. A good clinical assessment of the baby and of the mother remains the first important step towards a provisional clini¬ cal diagnosis, and giving guidance as to the appropriate investigations to establish a definitive diagnosis. Inappropri¬ ate and unnecessary investigations often delay the diagnosis in these cases.

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Neuromuscular disorders

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Robertson W C, Chun R W M. Kornguth S E 1980 Familial infantile myasthenia. Arch Neurol 37:117-119. Rudnick-Schoneborn. Forkert R, Hahnen E et al 1996 Clinical spectrum and diagnostic criteria of infantile

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Child Neurol 22:371-373. Strehl E, Vanasse M 1985 EMG and needle muscle biopsy studies in arthrogryposis multiplex congenita. Neuropediatrics 16:225-227. Swinyard C A1982 Concepts of multiple congenital

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Teyssier G. Damon G. Bertheas M F et al 1982

1995 A gene for autosomal recessive nemaline myopathy assigned to chromosome 2q by linkage analysis. Neuromusc Disord 5:441-443. Wallgreen-Petterson C, Laing N G 1996 Nemaline myopathy. Neuromusc Disord 6:389-391. Wallgreen-Pettersson C, Thomas N S T1994 A report

Disord 4:71-74. Wallgren-Petterson C 1998 Genetics of the nemaline myopathies and the myotubular myopathies. Neuromusc Disord 8:401-404. Wallgren-Petterson C. Laign N G 2006 138th ENMC Workshop: nemaline myopathy, 20-22 May 2005,

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40

Tsujihata M, Shimomura C.YoshimuraT et at 1983

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809

SECTION XI

CHAPTER

41

HYDROCEPHALUS AND NEUROSURGERY

Fetal neurosurgical interventions Lan T. Vu, Russell W. Jennings, Robert H. Ball and Hanmin Lee

Key Points • Fetal surgery can now be considered if: prenatal diagnostic methods can accurately identify fetuses that would most benefit, the pathophysiology and natural history of the disease are well understood, the natural history can be altered by intervention and the risk to the mother is small • The successful treatment of neonatal hydrocephalus with postnatal CSF shunting generated considerable enthusiasm to attempt prenatal treatment of fetal hydrocephalus, but results to date have not been encouraging • Approximately 25% of MMCs can be prevented by adequate dietary folic acid intake during pregnancy; a significant number will still develop despite adequate replacement • With widespread maternal serum alpha-fetoprotein screening and the use of high-resolution ultrasonography, over 80% of the cases of fetal MMC are now detectable in the mid-second trimester of pregnancy • Despite early detection, management options have been limited to either termination or continuation of the pregnancy with neonatal therapy • Open fetal surgery for myelomeningocele has emerged as a viable solution to prevent neurological dysfunction in the newborn • Fetal surgery remains an innovative treatment strategy and is not currently the standard of care for any neurological anomalies • The principal obstacle still encountered in fetal surgery is maternal morbidity and fetal morbidity and mortality from preterm labor • Ultimately, the decision to widely apply in utero surgical techniques for neurological anomalies as well as for other organ system anomalies will depend on the long-term effectiveness of the treatment protocols and their ethical acceptability in terms of safety for the mother and quality of life for the affected infant

INTRODUCTION Fetal neurosurgical intervention is the natural sequela of advances in sonography and invasive diagnostic procedures that have dramatically changed the understanding and management of many congenital neurological anomalies. Prenatal sonographic detection and serial examinations have made it possible not only to define their natural history, but also to determine the features that most affect clinical outcome. Sonography can now identify a growing number of disorders at a stage of development early enough to plan management strategies to improve prognosis. Fetal surgery can now be considered if: (1) prenatal diagnostic methods can accurately identify fetuses that would most benefit; (2) the pathophysiology and natural history of the disease are well understood; (3) the natural history can be altered by intervention; and (4) the risk to the mother is small (Harrison 1993). From the fetus’ perspective, the risk

810

of the procedure is weighed against the benefit of correct¬ ing a fatal or debilitating defect. The risks and benefits for a mother are more difficult to assess. She must incur the risk of surgery and preterm labor while not deriving any direct health benefits. If the uterus is opened, the mother may require a cesarean section for all subsequent births to prevent the possibility of uterine rupture. It still remains unknown whether in utero intervention for hydrocephalus and myelomeningocele potentially offers better outcomes than management by medical and surgical therapy after term delivery.

TREATMENT OF FETAL HYDROCEPHALUS ANIMAL STUDIES The successful treatment of neonatal hydrocephalus with postnatal CSF shunting generated considerable enthusiasm in attempting prenatal treatment of fetal hydrocephalus. Experimentally, Michejda and Hodg'en (1981) created a fetal rhesus monkey model of fetal hydrocephalus by administering the teratogen triamcinolone acetonide to pregnant females during the first several weeks of gesta¬ tion resulting in hydrocephalus and neural tube defects in 90°/o of fetuses. They followed the neural tube defects and development of hydrocephalus using ultrasonography, alpha-fetoprotein levels and fetoscopy. Untreated hydroce¬ phalic monkeys developed severe, progressive ventricular enlargement, marked growth retardation, poor coordina¬ tion and frequent seizures; most died within 2 weeks of delivery. The monkeys that received antenatal CSF shunts at the beginning of the third trimester not only survived, but also demonstrated markedly superior postnatal devel¬ opment of motor skills and grew at near-normal rates (Michejda 8t Hodgen 1981). Glick and Harrison, working with fetal lambs and monkeys, created animal models of hydrocephalus uncomplicated by concomitant neurological abnormalities by injecting kaolin into the cisterna magna during the third trimester (Glick et al 1984). They reported that shunting, 21-25 days later, improved gross ventriculomegaly and overall survival.

HUMAN STUDIES Birnholz and Frigoletto (1981) described the first human trial of in utero treatment of hydrocephalus in a fetus with progressive hydrocephalus diagnosed at 24 weeks. Six serial, atraumatic, cephalocenteses were performed between weeks 25 and 32 under ultrasound guidance (Fig. 41.1a-d). After

CHAPTER

Fetal neurosurgical interventions

41

in a human fetus in 1982 (Fig. 41.2a-c). The fetus carried a diagnosis of X-linked aqueductal stenosis, and the treatment plan was conceived and performed by a multispecialty team of perinatologists, radiologists, a neurosurgeon, a bioengi¬ neer and a geneticist. After the procedure, there was a decrease in the ventricular size, lateral ventricle width to hemisphere width ratio and biparietal diameter, with a con¬ comitant increase in cortical mantle thickness. The infant was delivered at 32 weeks of gestation, and a standard ventriculo-peritoneal shunt was placed postnatally. Several other groups reported similar decreases in ventricular size after shunt placement (Depp et al 1983, Duncan et al 1982, Frigoletto et al 1982). The following guidelines for fetal hydrocephalus patient selection were recommended by Frigoletto et al 1981 (Birnholz ft Frigoletto 1981).

Figure 41.1 (a) Sonogram of fetal head priorto cephalocentesis. (b) Sonogram of fetal head after cephalocentesis with arrow pointing to overlapping cranial sutures, (c) Sonogram of fetal head with arrow pointing to tip of 18-gauge needle in dilated ventricle, (d) Sonogram of fetal head after cephalocentesis. with arrows outlining stream of blood. the 28th week, cranial puncture became increasingly diffi¬ cult because of advanced ossification. Delivered at 35 weeks of gestation, the infant received a postnatal ventricularperitoneal shunt; however, at 16 months of age, the infant remained severely developmental^ retarded. It was later discovered that the infant had Becker muscular dystrophy and unrecognized intracranial abnormalities (Cromblehome 1994). Nevertheless, it was felt that intermittent serial ceph¬ alocentesis would not be able to deliver consistent ventricu¬ lar decompression (Lorber Ft Grainger 1983, Milhorat 1978). This led to the development of experimental ventriculoamniotic shunt systems. Clewell et al (1982) described the first ventriculo-amniotic shunt placement for hydrocephalus

1. The hydrocephalus should be detected sufficiently early that delivery and postnatal shunting are not realistic options. 2. The hydrocephalus should appear as a simple obstructive variety without associated major dysmorphic brain development. 3. The hydrocephalus should not be associated with other major malformations that are incompatible with survival or that indicate an irremediable malformation syndrome. 4. Each pregnancy should be evaluated for chromosomal abnormalities and associated neural tube defects during initial work-up. 5. The ventricular dilatation should be progressive. 6. Pretreatment evaluation should include a multidisciplinary team’s consultation with physicians in perinatology, neonatology, ultrasonography, neurosurgery and genetics. The consensus in the early 1980s was that the ideal patient for intervention was one with progressive ventriculomegaly that was isolated from any concomitant congenital anoma¬ lies. Subsequently, the international Fetal Surgery Registry was established in 1982 with the dual goal of (1) providing updated information on cumulative results to all inquiring institutions and (2) accumulating data to assess treatment efficacy and safety (Clewell et al 1982, Manning et al 1986). In 1986, the results of 44 procedures for obstructive hydro¬ cephalus reported to the registry over the preceding 3 years were published (Table 41.1) (Manning et al 1986). These cases were drawn from a large number of centers but had no consistent selection criteria for intervention. In this series of patients, the survival after in utero shunt placement was 83°/o. However, the overall mortality was 19°/o, over half of which were procedure-related (10.25%) (Fig. 41.3a-c). Even more troubling was that 53% of survivors were left with moderate to serious neurological handicaps and only 12% developed normally (Manning et al 1986). Although these shunt systems had sparked considerable enthusiasm, it became clear that the results were poor (Cromblehome 1994).

811

SECTION

XI

HYDROCEPHALUS AND NEUROSURGERY

Figure 41.2 (a) Cranial sonogram demonstrating ventricuioamniotic shunt protruding from fetal skull. (b) Ventricuioamniotic shunt protruding from skull of newborn infant, (c) Radiograph demonstrating ventricuioamniotic shunt entering fetal skull (arrow).

812

CHAPTER

Fetal neurosurgical interventions

41

Table 41.1 Fetal obstructive hydrocephalus: distribution by primary diagnosis and survival in 41 treated cases Primary diagnosis (postnatal)

No of

Percentage of total

No of

Percentage

No of

Percentage survival

cases

cases diagnosis

deaths

mortality by

survivors

by diagnosis

32

76.9

4

13.3

28

87.5

Associated anomalies

5

12.7

2

40

Holoprosencephaly

1

2.6

0

Dandy-Walker syndrome

1

2.6

0

Parencephalic cyst

1

2.6

Arnold-Chiari syndrome

1

2.6

Aqueductal stenosis

Total

41

100

3

60

0

1

100

0

1

100

0

0

1

100

0

0

1

100

17

17

34

83

Source: Adapted from Manning et al (1986).

Figure 41.3 (a) Coronal section of brain demonstrating a large subarachnoid hemorrhage (H) resulting from cephalocentesis. (Modified from Isaacson 1984). (b) Section of brain demonstrating intraventricular hemorrhage (H) resulting from cephalocentesis. (c) Subdural hematoma (H) resulting from cephalocentesis.

813

SECTION

HYDROCEPHALUS AND NEUROSURGERY

This was primarily because many of these patients had CNS and non-CNS anomalies that went undetected. In fact, the associated comorbidities, rather than the degree of ventriculomegaly, overwhelmingly determined prognosis. Further¬ more, the shunts failed to deliver consistent ventricular decompression due to clogging and migration (Manning et al 1986). As a result of this 1986 report and the inadequacies in diagnosis and shunting technique, the Fetal Medicine and Surgery Society recommended that intrauterine treatment of obstructive hydrocephalus be considered of unproven effi¬ cacy and an experimental procedure to be attempted only at highly specialized centers (Adzick 8t Harrison 1994, Manning 1986). The introduction of open fetal surgery for the treatment of hydrocephalus had initially renewed public interest in the possibility of fetal treatment for hydrocephalus in the late 1900s. From 1999 to 2003, Bruner and colleagues placed ventriculoamniotic shunts through a hysterotomy during the second trimester of pregnancy on four cases of isolated aqueductal stenosis. Even though the cases were technically successful, there was no improved neurological function in any of the infants, whose neonatal course was also compli¬ cated by prematurity and infection (Bruner et al 2006). Despite advances in fetal imaging studies, appropriate case selection still remains the main limitation to fetal shunting and, currently, this intervention has failed to improve peri¬ natal outcomes.

Table 41.2 Chiari classification of hindbrain hernias Chiari class

Pathologic changes

Chiari 1

Caudal movement of the cerebellar tonsils Impaction of the tonsils through the foramen magnum (usually >3 mm) Tip of the tonsils is rarely below C-2 Commonly associated with syringohydromyelia

Chiari II

Caudal movement of the cerebellar vermis through the foramen magnum Commonly, the lower brainstem and 4th ventricle migrate caudally as well Seen almost exclusively in association with MMC

Chiari III

Displacement of the cerebellum and brainstem into a high cervical pouch Patients generally have a guarded prognosis with regard to eventual level of function

Source: Adapted from Guin (1999).

TREATMENT OF MYELOMENINGOCELE AND THE CHIARI II MALFORMATION (seealso P 224) Myelomeningocele (MMC), the most severe form of spina bifida, is defined as a herniation of the meninges, spinal cord, and nerve roots through a cleft in the spinal column (Harrison et al 1980, Longaker et al 1991, Reigel 1982). All children born with MMC develop an associated Chiari II malformation that is characterized by a low-lying tentorium, small posterior fossa and abnormal cerebellum with down¬ ward displacement of the vermis through the foramen magnum (Coltran et al 1999, Guin 1999) (see Table 41.2).

ANIMAL STUDIES Although it is accepted that the congenital defect of MMC contributes significantly to neurological dysfunction, growing experimental evidence suggests major damage to the exposed spinal cord as a result of environmental factors occurring during gestation. Drewek et al (1997) showed that after 34 weeks of gestation, the amniotic fluid became toxic to cultured rat spinal cord tissue. Studies of surgically induced neural tube defects in fetal animals have demon¬ strated that prenatal repair of the lesion may preserve neu¬ rological function (Heffez et al 1990). Mueli et al (1995a, 1995b) created a spina bifida-type defect at 75 days of ges¬ tation in fetal lambs. Four weeks later, the developing MMC lesions were repaired in utero. Unrepaired lambs were char¬ acterized by complete sensorimotor paraplegia and urinary 814

Figure 41.4 Development of the Chiari II malformation in the unrepaired myeLomeningocele-type lesion.

and stool incontinence. Evaluation of the sagittal brain sec¬ tions revealed that lambs undergoing the creation of a myelomeningocele-type lesion developed distinct signs of the Chiari II malformation (Fig. 41.4). Repaired lambs, however, demonstrated near-normal neurological function with only mild paraparesis and no signs of incontinence. Additionally, all animals that had undergone repair of the lesion either by coverage with Alloderm or by primary neu¬ rosurgical repair did not show any signs of a Chiari II mal¬ formation (Fig. 41.5a-c). The posterior fossa was of normal size, and the medulla and vermis of the cerebellum were located well above the foramen magnum.

CHAPTER

Fetal neurosurgical interventions

41

Similarly, Michejda (1984) created a spina bifida-like lesion in eight Macaca mulatto fetuses by performing intra¬ uterine lumbar laminectomies and displacing the spinal cords from the central canals. In five monkeys, this condi¬ tion was repaired in utero. At delivery, the five repaired animals developed normally, while those with open lesions were paraplegic with lower extremity somatosensory loss and incontinence. Heffez et al (1990) reproduced similar results in a rat model. In addition, Julia et al (2006) showed that, even though there was no difference in the gross motor function, the somatosensory-evoked potentials of the hind limbs were absent in the group of rabbits who did not have in utero repair of their defects. Therefore, from these animal studies, it is hypothesized that the neurological defects seen in children with MMC result from both congenital myelo¬ dysplasia and progressive intrauterine spinal cord injury (Hoffman et al 1987). The mechanism of injury, physical and/or chemical trauma, to exposed neural elements is unknown. The milieu of amniotic fluid can be caustic to exposed spinal cord. One study showed that meconium exposure increases spinal cord necrosis in fetal rats. In the control group, after laminec¬ tomy, amniotic fluid was restored with saline solution, while a solution of human meconium diluted in saline (10%) was used in the experimental group. All liveborn pups had severe paralysis of hind limbs and tail. However, histologic exami¬ nation of spinal cords at site of surgical exposure showed increased necrosis and delay in repair processes in those that were exposed to meconium (Correia-Pinto et al 2002).

PATHOGENESIS

(c) Figure 41.5 Absence of Chiari II malformation. Arrows indicate level of foramen magnum, (a) Control lamb without creation of a surgical myelomeningocele-type lesion. (b) Lamb with standard neurosurgical repair, (c) Lamb with synthetic Alloderm used as coverage.

The development of the fetal brain and calvaria are inter¬ linked and exquisitely dependent on fluid pressures. In the normally developing fetal CNS, the CSF develops in the lateral and third ventricles and passes through the aqueduct into the fourth ventricle. From here, the fluid flows through the lateral recesses into the posterior fossa to bathe the developing fetal cerebellum. This gentle fluid distention enlarges the size of the fetal posterior fossa as the fluid works its way around the tentorium, separating the cerebel¬ lum from the cranial fossa. Upon reaching the vein of Galen, the fluid is reabsorbed. Of note, the CSF also flows around the developing spinal cord. However, within the central spinal canal, the CSF is essentially stagnant. The fluid access to the spinal canal is via the obex located on the anterior surface of the fourth ventricle. Early views suggested that the Chiari II malformation was a result of a tethered spinal cord pulling the posterior fossa structures downward (Fig. 41.6). In the 1960s, Gardner pro¬ posed the hydrodynamic hypothesis in which alteration in CSF dynamics at the craniospinal junction arises from a failure of the primitive rhombic roof to be permeable during fetal development (Caban 8t Bentson 1982). Accordingly, obstruction of the foramen of Magendie results in hydro¬ cephalus and caudal displacement of the tentorium and hindbrain (Carmel 1982). 815

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An alternative hypothesis is that fluid drainage from the posterior fossa creates a low-pressure situation so that the posterior cranial fossa is not induced to increase its capacity (Fig. 41.7). This leakage of low-pressure fluid can occur through an open MMC. In such a case, CSF in the fourth ventricle flows into the obex, down the central canal and out into the amniotic fluid. This creates a low-pressure circuit with concomitant lower posterior fossa distention pressures. Because of this low-resistance circuit, there is little fluid accumulation in the posterior fossa. As the fetal cerebellum develops, it is forced to fill a smaller volume, resulting in a higher resistance to flow around the cerebel¬ lum in order to get the outside of the cerebellum into the posterior fossa.

Due to the unique anatomy of the fetal brain, even when the cerebellum essentially obstructs fluid flow around and into the posterior fossa, the fluid still flows out through the obex and down the central canal into the amniotic fluid. It is only later in the development of the brain that fluid egress is inhibited to create the hydrocephalus that results from increased fluid build-up within the ventricles. In this theory, hydrocephalus is a consequence of hindbrain herniation, rather than the cause. Based on this relatively simple hydrodynamic theory of fetal brain development, correction of the MMC lesion may prevent some or all elements of impending Chiari II malformation.

CURRENT PREVENTION AND TREATMENT Although approximately 25% of MMCs can be prevented by adequate dietary folic acid intake during pregnancy (see Ch. 14), a significant number will still develop despite adequate replacement. With widespread maternal serum a-fetoprotein screening and the use of high-resolution ultrasonography, over 80% of the cases of fetal MMC are now detectable in the mid-second trimester of pregnancy. Nevertheless, despite early detection, management options have been limited to either termination or continuation of the pregnancy with neonatal therapy. In light of this, the concept of in utero surgery to correct the defect of MMC before the open spinal cord can be damaged remains extremely attractive.

PROSPECTS FOR FETAL SURGERY Early results from endoscopic in utero repair of myelome¬ ningocele, where operating ports were inserted directly into the uterine wall after maternal laparotomy, showed a high incidence of mortality and no improvement of neurological function. The 50% mortality in four fetuses that underwent endoscopic coverage of the defect with a maternal split¬ thickness skin graft halted further use of this technique.

Figure 41.7 Development of the Chiari II malformation. Normal development of the brain and the skull, in particular the posterior fossa, is thought to be dependent upon gentle distention of the embryonic ventricles. Decrease of pressure due to loss of spinal fluid through a myelomeningocele lesion induces the development of an abnormally small posterior fossa. This malformation causes the herniation of brainstem and cerebellum through the foramen magnum and tentorium. As the cerebellum herniates through the foramen magnum, the normal circulation of CSF is obstructed. Hydrocephalus subsequently develops. 816

CHAPTER

Fetal neurosurgical interventions

Furthermore, endoscopic patching was only a temporary solution since the graft degraded and the infants needed definitive postnatal repair (Bruner et al 1999a). Farmer et al (2003) also reported limited success with the fetoscopic approach (FETENDO), which did not require maternal lapa¬ rotomy. One case was converted to open fetal repair, and two other repairs were noted to be leaking CSF at birth and required definitive neonatal closure. Open fetal surgery for myelomeningocele has emerged as a-viable solution to prevent neurological dysfunction in the newborn. Adzick et al (1998) reported the first clinical case of fetal surgery for MMC in a 23-week infant who later demonstrated improved distal neurological function. Subse¬ quently, Tulipan and Bruner have shown that, despite a significant risk of preterm labor and preterm delivery, patients treated with in utero repair had a significantly decreased need for ventriculo-peritoneal (VP) shunting and hindbrain herniation compared to cohort controls (Tulipan ft Bruner 1998, Tulipan et al 1998). They initially published a single-institution, observational study comparing 29 patients with isolated fetal MMC repaired between 24 and 30 weeks to 23 historical controls (Bruner et al 1999b). Cases were matched for diagnosis, level of lesion, practice para¬ meters and calendar time, and all infants were followed up for a minimum of 6 months after delivery. They noted that older median age at shunt placement (50 vs. 5 days) as well as a 35% reduction in the need for VP shunting after in utero repair. The results might be explained by a 60% reduc¬ tion in the incidence of hindbrain herniation among study infants. However, the patients were at a significantly higher risk of oligohydramnios and preterm labor compared to controls. Concurrently, Adzick et al reported on a series of ten patients undergoing MMC closure between 22 and 25 weeks (Sutton et al 1999). No controls were utilized. Using serial MRI scans at 19-24 weeks (prior to fetal surgery) and 3 and 6 weeks after fetal surgery, they demonstrated serial improvement in hindbrain herniation. Recently, Tulipan et al (2003) published an observational study comparing 104 patients with isolated fetal MMC repaired between 24 and 30 weeks at two institutions to 189 historical controls (Tulipan et al 2003). There was an overall absolute 30% reduction in the need for VP shunting after in utero repair; this difference, when stratified by level of lesion, was only statistically significant for lesions below L2. In addition, the benefit of in utero repair was seen only in fetuses younger than 25 weeks of gestation. Even though case series have demonstrated improvement in surrogate markers of neurological function, e.g. need for VP shunting and radiographic reduction of hindbrain her¬ niation, improvement in long-term function, such as lower extremity gross motor function, neurocognitive develop¬ ment and urinary continence has yet to be proven. Tubbs et al (2003) showed no difference in lower extremity func¬ tion between the group of 37 consecutive patients who had fetal surgery for myelomeningocele and the group of 40 controls who had traditional postnatal repair. The neurode-

41

Figure 41.8 Open fetal repair of myelomeningocele, (a) Fetus at 22 weeks of gestation with myelomeningocele sac at level 51. Only the defect is exposed through the hysterotomy. (b) The same defect after primary closure.

velopmental outcomes at two years of age were assessed in 30 patients who had fetal closure of myelomeningocele and compared to the published reports in patients who had postnatal closure. Even though the incidence of shunting was lower, the overall cognitive and developmental scores were similar in both groups (Johnson et al 2006). In addi¬ tion, both Holmes et al (2001) and Holzbeierlein et al (2000) showed no difference in the short-term urodynamic profiles. They hypothesized that in utero repair had the potential to reverse the detrimental effects on somatic neurons, but the damage on the sensory neurons that control urinary func¬ tion was irreversible. The role of fetal surgery for myelomeningocele is cur¬ rently under investigation in a prospective randomized clinical trial involving three centers in United States. Eligible cases include fetal myelomeningocele at level Tl through Si with hindbrain herniation. Open fetal surgery occurs between 19 and 26 weeks of gestation and involves a single layer closure (Fig. 41.8a, b). The results of this study will 817

SECTION

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HYDROCEPHALUS AND NEUROSURGERY

hopefully answer the question of whether the possible neu¬ rological benefit to the infant justifies the risk of fetal surgery to mother and fetus.

HORIZONS IN FETAL NEUROSURGERY Fetal surgery remains an innovative treatment strategy and is not currently the standard of care for any neurological anomalies. The principal obstacle still encountered in fetal

surgery is maternal morbidity and fetal morbidity and mor¬ tality from preterm labor. Ultimately, however, the decision to apply in utero surgical techniques widely for neurological anomalies as well as for other organ system anomalies will depend on the long-term effectiveness of the treatment protocols and their ethical acceptability in terms of safety for the mother and quality of life for the affected infant (Wilberg ft Baghai 1983).

REFERENCES Adzick N S, Harrison M R 1994 Fetal surgical therapy. Lancet 343:897-902. Adzick N S, Sutton L N. Crombleholme T M et al 1998 Successful fetal surgery for spina bifida [letter]. Lancet 352(9141):1675-1676. Birnholz J C, Frigoletto F D 1981 Antenatal treatment of hydrocephalus. N Engl J Med 303:1021-1023. Bruner J P. Davis G.Tulipan N 2006 Intrauterine shunt for obstructive hydrocephalus — still not ready. Fetal Diagn Ther 21:532-539. Bruner J P, Tulipan N. Pachal R L et al 1999a Fetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 282:1819-1825. Bruner J P, Tulipan N, Reed G et al 2004 Intrauterine

Presented at the 32nd Annual Meeting of the Congress of Neurological Surgeons. Toronto. Canada. October 3-8. Farmer D L, von Koch C S. Peacock W J et al 2003 In utero repair of myelomeningocele. Arch Surg 138:872-878. Frigoletto F D. Birnholz J C. Greene M F 1982 Antenatal treatment of hydrocephalus by ventriculoamniotic shunting. N EnglJ Med 248:2496-2497. Glick P L. Harrison M R. Halks-Miller M et al 1984 Correction of congenital hydrocephalus in utero. II. Efficacy of in utero shunting. J Pediatr Surg 19:870-881. Guin P R 1999 Arnold-Chiari malformation. A closer look. World Arnold-Chiari Association..

repair of spina bifida: preoperative predictors of

Harrison M 1993 Fetal surgery. West J Med 159:341-349.

shunt-dependent hydrocephalus. Am J Obstet

Harrison M R. Jester J A, Ross N A1980 Correction of

Gynecol 190:1305-1312. Bruner J P. Tulipan N. Richards W 0 et al 1999b In utero repair of myelomeningocele: a comparison of endoscopy and hysterotomy. Fetal Diagn Ther 15:83-88. Caban L. Bentson J 1982 Considerations in the diagnosis and treatment of syringomyelia and the Chiari malformation. J Neurosurg 57:24-31. Carmel P 1982 The Arnold-Chiari malformation. Pediatric neurosurgery of the developing nervous system. Grune & Stratton. New York. NY, pp. 61-77. Clewell W H, Johnson M L, Meier P R et al 1982 A surgical approach to the treatment of hydrocephalus. N Engl J Med 306:1320-1325. Coltran R S. Kumars V. Collins T1999 Robbins pathologic

Manning F A1986 International fetal surgery registry: 1985 update. Clin Obstet Gynecol 29:551-557. Manning F A, Harrison M R. Rodeck C et al 1986 Catheter shunts for fetal hydronephrosis and hydrocephalus. Report of the International Fetal Surgery Registry. N EnglJ Med 315:336-340. Michejda M 1984 Intrauterine treatment of spina bifida: primate model. Z Kinderchir 39:259-261. Michejda M, Hodgen G D 1981 In utero diagnosis and treatment of non-human primate fetal skeletal anomalies. I. Hydrocephalus. JAMA 246:1093-1097. MilhoratT H 1978 Pediatric neurosurgery. FA Davis. Philadelphia, PA, p. 112-121. Mueli M. Meuli-Simmen C. Hutchins G M et al 1995b In utero surgery rescues neurological function at birth in sheep with spina bifida. Nat Med 1:342-347. Mueli M. Mueli-Simmen C, Yingling C D et al 1995a

congenital diaphragmatic hernia in utero. The model:

Creation of myelomeningocele in utero: A model of

intrathoracic balloon produces fetal pulmonary

functional damage from spinal cord exposure in fetal

hypoplasia. Surgery 88:174-182. Heffez D S. Aryanpur J, Hutchins G M et al 1990 The paralysis associated with myelomeningocele: clinical

sheep. J Pediatr Surg 30:1028-1032. Reigel D H 1982 Spina bifida in pediatric neurosurgery, surgery of the developing nervous system. Section of

and experimental data implicating a preventable

Pediatric Neurosurgery of the American Association

spinal cord injury. Neurosurgery 26:987-992.

of Neurological Surgeons. Grune & Stratton. New

Hoffman H J, Neill J. Crone K R et al 1987 Hydrosyringomyelia and its management in childhood. Neurosurgery 21:347-351. Holmes N M. Nguyen H T, Harrison M R et al 2001 Fetal intervention for myelomeningocele: Effect on postnatal bladder function. J Urol 166:2383-2386. Holzbeierlein J. Pope J C, Adams M C et al 2000 The

York. NY. Ch. 2. pp. 23-47. Sutton L N. Adzick N S. Bilaniuk L T et al 1999 Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 282:1826-1831. Tubbs R S. Chambers M R, Smyth M D et al 2003 Late

urodynamic profile of myelodysplasia in childhood

gestational intrauterine myelomeningocele repair

basis of disease. 6th edn. WB Saunders,

with spinal closure during gestation. J Urol

does not improve lower extremity function. Pediatr

Philadelphia. PA, pp. 1301-1302.

164:1336-1339.

Correia-Pinto J. ReisJ L, Hutchins G M etal2002J Pediatr Surg 37:488-492. Cromblehome T M 1994 Invasive fetal therapy: Current status and future directions. Semin Perinatal 18:385-397. Depp R. Sabbagha R E. Brown J T et al 1983 Fetal

Johnson M P, Gerdes M, Rintoul N et al 2006 Maternalfetal surgery for myelomeningocele:

utero: a report of three cases. Pediatr Neurosurg

Neurodevelopmental outcomes at 2 years of age. Am

28:177-180.

J Obstet Gynecol 194:1145-1154. Julia V. Sancho M A. Albert A et al 2006 Prental covering of the spinal cord decreases neurologic sequelae in a

surgery for hydrocephalus: successful in utero

myelomeningocele model. J Pediatr Surg

ventriculoamniotic shunt for Dandy-Walker

41:1125-1129.

syndrome. Obstet Gynecol 61:710-714. Drewek M J, Bruner J P. Whetfell W 0 et al 1997 Pediatr Neuro Surg 27:190-193. Duncan C C. Berkowitz R L, Hobbins J C1982 Fetal hydrocephalus: An approach to management.

818

Neurosurg 38:128-132. Tulipan N. Bruner J P 1998 Myelomeningocele repair in

Longaker M T, Golbus M S. Filly R A et al 1991 Maternal outcome after open fetal surgery. A review of the first 17 human cases. JAMA 265:737-741. Lorber J. Grainger R G 1983 Cerebral cavities following ventricular puncture in infants. Clin Radiol 14:98-109.

Tulipan N, Hernanz-Shulman M, Bruner J P 1998 Reduced hindbrain hernation after intrauterine myelomeningocele repair: a report of 4 cases. Pediatr Neurosurg 29.274-278. Tulipan N, Sutton L N, Bruner J P et al 2003 The effect of intrauterine myelomeningocele repair on the incidence of shunt-dependent hydrocephalus. Pediatr Neurosurg 38:27-33. Wilberg J E, Baghai P 1983 Fetal neurosurgery. Neurosurgery 13:596-600.

SECTION XI

CHAPTER

42

HYDROCEPHALUS AND NEUROSURGERY

Neonatal hydrocephalus — clinical assessment and non-surgical treatment Andrew Whitelaw and Kristian Aquilina

Key Points • Use recognized diagnostic criteria, e.g. 4 mm over 97th centile for ventricular width • Differentiate cerebral atrophy or leukomalacia from CSF-driven ventricular enlargement • Note the presence, location and extent of any parenchymal cerebral lesions • Do a neurologic examination and assess the rate of head enlargement and ICP effects • If there is symptomatic raised pressure or rapid enlargement averaging 2 mm/day, the pressure should be normalized (to 15mmHg); compared to 42% when more than one suture was affected (Renier et al 1982). The incidence of raised intracranial pres¬ sure is higher in syndromic cases. (3) Associated abnormalities. Premature fusion of the skull usually involves the cranial base, and this may modify the growth of the facial skeleton producing certain deformities and syndromes, of which Apert and Crouzon are the best known examples.

CRANIOSYNOSTOSIS SYNDROMES A syndrome can be defined as congenital malformations occurring in two or more embryologically unrelated areas. A few important syndromes, which are part of the FGFRrelated craniosynostosis spectrum, are described below.

APERT SYNDROME Apert syndrome has a prevalence of 15.5 per million or 1 per 160000 live births (Bergsma 1973). A baby with Apert syndrome will have bicoronal synostosis and a widely patent midline defect, corresponding to the open sagittal suture, which allows some anterior growth (Fig. 45.Id). Other cranial sutures such as the lambdoids may be involved (Cohen ft

Figure 45.1 The three dimensional CT scans on the left correspond to the clinical appearance of the craniosynostosis depicted on the right, (a) shows the scaphocephalic skull shape of a baby with sagittal craniosynostosis. The CT scan demonstrates fusion of the sagittal suture, (b) is a case of metopic craniosynostosis. The skull base is triangular in form and the forehead is typically keel-shaped (trigonocephaly) with a midline ridge. There is relative hypotelorism of the orbits, (c) illustrates right-sided unilateral coronal synostosis (anterior plagioeephaly). The nasal root is deviated towards the side of the flattened forehead and the ear on this affected side is pulled forwards. The orbital shape is different due to skull base distortion and in this case there is a degree of orbital dystopia, (d) is a baby with Apert syndrome. The CT scan shows bicoronal craniosynostosis as well as the wide open enlarged sagittal suture, typically seen in neonates with Apert syndrome. The skull shape is brachycephalic. the canthi are downward slanting, and there is midface hypoplasia. The open mouth is a sign of airway compromise.

858

CHAPTER

Congenital defects, vascular malformations and other lesions

45

SECTION

XI

HYDROCEPHALUS AND NEUROSURGERY

Kreiborg 1993). There is constriction of the cranial base and approximately 5 to 10% has hydrocephalus with diminished venous outflow. An associated Chiari malformation is a frequent finding on MRI. Bony and soft tissue abnormalities are also present such as complex bilateral syndactyly of the hands and feet. There is a high incidence of cleft palate and all have characteristic downward-sloping' canthi with varying degrees of midface hypoplasia. Sometimes the midface constriction is so severe that the airways are sig¬ nificantly impaired. Deafness occurs in 30% of cases and developmental delay is common (Renier et al 1996).

CROUZON SYNDROME Crouzon syndrome is associated with craniosynostosis of the coronal, but also sagittal, metopic and lambdoid sutures, which can be involved singly or multiply. Crouzon syn¬ drome occurs in 1 in 25000 live births and follows an autosomal dominant mode of transmission, although 3060% of cases are sporadic (Al-Qattan ft Phillips 1997). Hydrocephalus affects 10% of neonates. The orbits are hypo¬ plastic so that in severe cases extreme proptosis can occur endangering the eyes due to exposure. As in Apert, Crouzon babies have mid face hypoplasia and can have severe airway compromise. Conductive hearing deficits are also common.

PFEIFFER SYNDROME Pfeiffer syndrome has heterogeneous characteristics and consists of craniosynostosis, orbital dystopia (uneven posi¬ tion of the eye sockets), variable midface hypoplasia and broad, medially deviated thumbs. Syndactyly can also occur along with brachydactyly, elbow ankylosis and visceral abnormalities. Inheritance is autosomal dominant and Cohen (1986) described 3 types. Type 1 usually presents with bicoronal synostosis with severe to mild midface hypoplasia. The prognosis is good and intelligence can be normal. Type 2 Pfeiffer syndrome has cloverleaf skull deformity (‘Kleeblattschadel’), and the midface deficiency is severe. Hydrocephalus is present and the life span is usually limited. Type 3 is the rarest. These cases present with turricephalic (tower-shaped) skulls, extreme proptosis, hydrocephalus, choanal atresia and laryngotracheal abnormalities. Their prognosis is poor.

MANAGEMENT OF CRANIOSYNOSTOSIS: SYNDROMIC AND NON-SYNDROMIC Management of craniosynostosis should be under a multi¬ disciplinary team in a center regularly dealing with cranio¬ facial conditions (Posnick ft Ruiz 2000). Diagnosis is made on clinical grounds, with skull X-rays and CT scans confirm¬ ing the nature of the synostosis. MRI is helpful in recogniz¬ ing the type of hydrocephalus if present and the presence of a Chiari malformation. The indications for surgery in craniosynostosis are to relieve raised intracranial pressure, improve functions (ocular, nasal, phonetic, dental), cosmetic and psychological. 860

The aim is to correct established deformity, prevent compli¬ cations and redirect growth towards normality (Hockley et al 1988). In simple craniosynostosis when only one suture is affected and the deformity mild then expectant treatment may be appropriate. The decision on what constitutes an unacceptable deformity is not easy, and one must take into consideration the feelings of the parents, society and the natural history of that particular craniosynostosis. When surgery is advocated the next issue is timing. Under normal conditions the infant’s skull enlarges in response to the growing brain, which reaches 50% of adult size by the age of 6 months and 80% by the age of 2 years. The tradi¬ tional method of excising the prematurely fused suture (‘linear craniectomy’), using the brain growth or ‘drive’ to relieve pressure and correct deformity, can be regarded as ‘passive surgery’. With modern ‘active’ surgical techniques, based on the pioneering work of Dr. Paul Tessier in the 1960s (Tessier 1967), corrective repositioning of bony struc¬ tures is possible. For most cases of simple craniosynostosis surgery at the age of 1 year is considered a good compromise between brain drive and the easier surgical handling of maturing neonatal bone. The exception is scaphocephaly where earlier calvarial remodeling at three months of age has been shown to produce superior esthetic results. The use of the limited linear craniectomy of the sagittal suture before the age of 6 months has been found to be unpredictable (Panchal et al 1999). Minimally invasive techniques involving endoscopic strip craniectomy with postoperative moulding helmet therapy are under evaluation. Established surgical methods for syndromic synostosis involve exposure of the skull and orbits using craniofacial approaches. The aim of surgery is to increase intracranial volume as well as improve the esthetic appearance of the calvarium, forehead and upper orbits (Fig. 45.2). The timing of intervention depends upon the threat of raised intracranial pressure and exposure of the eyes, which occur in severe syndromic cases such as Apert and Crouzon syndromes. Sometimes an emergency tarsorrhaphy may be necessary to achieve corneal protection. Ventricular shunts or posterior calvarial decompression (Sgouros et al 1996), within the first few months of life, may be necessary to relieve the raised intracranial pressure from associated hydrocephalus or the craniosynostosis. A Chiari malforma¬ tion is a frequent finding in multi-sutural and syndromic craniosynostosis. It has been reported in 70% of patients with Crouzon syndrome, 50% with Pfeiffer syndrome and 100% with Kleeblattschadel deformity (Cinalli et al 2005). The definitive procedure for most craniosynostosis involves a fronto-orbital advancement, which can be done primarily or at a second stage following a posterior skull decompression or shunt. In severe Apert and Crouzon cases it may also be necessary to address airway problems and sleep apnea due to midface hypoplasia. Early tracheostomy may be necessary.

CHAPTER

Congenital defects, vascular malformations and other lesions

45

devices. This increases the intracranial, orbital and airway passage volumes in one stage (Mathijssen et al 2006). It is possible now to carry this out before one year of age but these babies will need long-term observation for raised ICP, ocular and airway difficulties. Inevitably they all have inher¬ ent midface hypoplasia and will require further surgery to address this in early adulthood.

CRANIOFACIAL DYSPLASIA WITH CLEFTING HYPERTELORISM Hypertelorism is the increase of the apparent distance between the orbits. This is not a syndrome but is a clinical sign of several pathologies affecting the craniofacial skele¬ ton and soft tissues, including those that fall into this cate¬ gory of craniofacial dysplasia with clefting.

CRANIOFACIAL CLEFTS Craniofacial clefts are rare but form an important group of deformities. Tessier has classified these clefts on a clinical and observational basis (Tessier 1976). They are numbered from 0 to 14 and follow predictable paths through the soft tissues of the lips, nose, cheeks, eyelids, as well as the underlying craniofacial skeleton. The clefts are orbitocentric in that the clefts numbered from 0 to 7 lie below the orbit. Cleft 8 runs lateral to the orbit, while clefts 9 to 14 are above the orbit. These clefts generally run in a north-south direc¬ tion and those above and below the orbit can occur in combination.

FRONTONASAL DYSPLASIA

Figure 45.2 Fronto-orbital advancement and cranial remodeling as carried out for coronal and metopic synostosis is schematically shown in (a) and (b).The deformed frontal bone B is swapped with the more normal contoured bone flap A, whilst the orbital bar C is reshaped and moved forward. This allows improved forehead shape and an increase in intracranial volume. Absorbable plates are used for fixation.

Frontonasal dysplasia is a midline facial clefting that encom¬ passes several anomalies, with clinical features including orbital hypertelorism, a broadened nasal root, a grooved or deficient nasal tip, a widow’s peak and occult cranium bifidum. Frontonasal dysplasia is also associated with agen¬ esis of the corpus callosum and basal encephaloceles. Devel¬ opmental delay can be present but is not pathognomonic. The degree of clefting and hypertelorism is variable. The management of frontonasal dysplasia is multidisciplinary and should be carried out in a craniofacial center in order to correct the hypertelorism, and the deformities of the nose and lips caused by the midline cleft.

GROUP 4. CRANIOFACIAL DYSPLASIA OF OTHER ORIGIN This group consists of defects which do not fit well with the sequential embryology of the brain or the timing of facial fusion processes.

VASCULAR ANOMALIES The use of a technique called ‘monoblock distraction’ advancement is currently becoming established to treat raised ICP, ocular exposure and midface hypoplasia at the same time. The frontal bone, the orbits and the bones of the mid face are advanced, using internal or external distraction

Vascular anomalies may be either high flow or low flow and are classified as either hemangiomas or vascular malforma¬ tions (Mulliken 8t Glowaki 1982). They can occur anywhere on the body and the majority can be diagnosed by history and examination alone. The management of major vascular 861

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HYDROCEPHALUS AND NEUROSURGERY

anomalies should be multidisciplinary as they can affect any part of the body and treatment can involve several medical disciplines.

HEMANGIOMA Seventy percent of hemangiomas (formerly called straw¬ berry nevi) arise on the head and neck, but they can also involve bone, liver or the viscera. These are high flow vas¬ cular tumors and usually present shortly after birth. They rapidly expand over a period of months. They are usually solitary but it is not unusual for several to be present. Mul¬ tiple hemangiomas were thought to cause the consumptive coagulopathy of the Kasabach-Merrit syndrome. However this is now known to be caused by Kaposiform hemangio¬ endothelioma and tufted angiomas, which are very rare vascular tumors (Enjrolas ft Wassef et al 1997). Diffuse hemangiomas of the face can be associated with DandyWalker malformations, which are characterized by agenesis or hypoplasia of the cerebellar vermis and cystic dilatation of the fourth ventricle with enlargement of the posterior fossa. Approximately 70-80% of these patients develop hydrocephalus postnatally (Reese et al 1993). Hemangiomas, which ulcerate and bleed, can be managed with non-adherent dressings and topical antibiotic steroid preparations (Terra-Cortril®). Hemangiomas affecting the face cause distressing esthetic deformity but they should be treated conservatively during the growth phase. The excep¬ tions to this are hemangiomas which obscure vision which, if untreated can cause amblyopia; hemangiomas affecting the airways; and multiple hemangiomas causing high output cardiac failure. Steroid, injected directly into an isolated hemangioma or given orally at a dose of up to 4 mg/Kg/d, is the first-line treatment. Other agents have been used to treat hemangiomas such as interferon alpha-2a (Spiller et al 1992) and vincristine. Its anti-angiog'enic affects have been demonstrated to be very effective in steroid resistant hem¬ angiomas (Enjrolas et al 2004). After this growth phase, which can last for a period of 12 months or more, they all involute. Most regress totally and most have disappeared by the age of 10 years with little or no scarring. However larger hemangiomas, or those which have ulcerated, can leave permanent fibrofatty skin rem¬ nants, which require surgical treatment. Extensive, sub¬ cutaneous hemangiomas can also lead to differential bony growth and facial asymmetry requiring specialized plastic and maxillofacial treatment in later childhood (Enjrolas ft Mulliken 1997).

VASCULAR MALFORMATIONS: EXTRACRANIAL Vascular malformations, unlike hemangiomas, are present at birth and do not have a proliferative or regressive phase. They will grow in proportion with the baby and are classi¬ fied according to the dominant vessel type they contain. Capillary malformations (port-wine stains) are cutaneous malformations and if located in the distribution of the trigeminal nerve, Sturge-Weber syndrome should be con¬ 862

sidered (Comi 2003). The associated abnormal blood vessels in the brain (leptomeningeal angioma) can lead on to devel¬ opmental delays, epilepsy and eye problems (glaucoma). The management of capillary vascular malformations is not indicated in the neonate and in later childhood lasers and plastic surgical techniques with tissue expansion can be employed. Venous malformations are slow flow lesions consisting of abnormal ectatic collections of veins. These can affect large or small areas and encroach upon several tissue planes. There are few indications for treatment in the neonatal period, except if affecting the airway or feeding. Lymphatic malformations (formerly called cystic hygro¬ mas) can be either macrocystic or microcystic in structure. Both types, if extensive and large enough, can cause sig¬ nificant airway problems for the neonate. Macrocystic lesions tend not to affect the oropharyngeal airways but cause mass effects from the surface. They can be treated with sclerotherapy in later childhood. Extensive lesions affecting tongue, oral cavity and the neck are among the most difficult vascular malformations to treat. Usually not amenable to sclerotherapy, they can pose serious airway and feeding problems for the neonate necessitating tracheostomy and feeding tubes. Microcysts in the cheek, tongue and neck can cause macroglossia leading to facial and jaw deformity and permanent open bite or occlusal problems. Multistage surgery involving debulking and correction of facial ptosis as well as orthognathic inter¬ vention will be necessary. An arterio-venous malformation (AV fistula) of the scalp is a rare lesion, characterized by abnormal arterial and venous connections with grossly dilated and expansile masses of vessels that can predispose to dramatic complica¬ tions. The so-called ‘cirsoid aneurysm’ is a rare but florid type of this lesion seen in neonates. These lesions may be a threat to life due to high-output cardiac failure, dissemi¬ nated intravascular coagulation and septicemia secondary to infection. Such lesions are also at risk from local com¬ plications such as recurrent hemorrhage, ulceration and infection. There are a large number of treatment methods for arterio-venous malformations of the scalp which include embolization, selective ligation of feeding vessels and surgi¬ cal excision (Taylor et al 1990).

VASCULAR MALFORMATIONS: INTRACRANIAL Intracranial aneurysms and intracranial arterio-venous mal¬ formations do occur in childhood, but rarely in the neonatal period. Intracranial aneurysms in children usually present with spontaneous intracranial hemorrhage, producing irritability and seizures. In the young infant other features are a bulging fontanelle, retinal hemorrhages, low hemoglobin level and blood stained CSF obtained at lumbar puncture that has been performed to exclude meningitis. These features may suggest non-accidental injury, but the pattern of the intra¬ cranial hemorrhage on CT scan is more suggestive of a

CHAPTER

Congenital defects, vascular malformations and other lesions

spontaneous rather than traumatic origin (McLellan et al 1986). The general principles of diagnosis and treatment for aneurysms in childhood are basically the same as for adults. After the causative aneurysm has been demonstrated by angiography (either by MR angiography or arterial catheter¬ ization), and the child is in a stable state, treatment to exclude the aneurysm from the circulation is undertaken. Such treatment may be by craniotomy with clipping of the aneurysm, or increasingly now by interventional radiology methods, using detachable metal coils or balloons. Aneurysms in young children are frequently large and occur in the posterior circulation three times more com¬ monly than in adults, even more so during the first two years of life. It should be remembered that children with coarctation of the aorta, polycystic kidney disease and Ehlers-Danlos syndrome are at increased risk of developing intracerebral aneurysms and should undergo screening studies. So-called ‘infectious’ or ‘mycotic’ aneurysms can arise within two days from septic emboli in children (Khoo 8t Levy 1999). Intracranial arterio-venous malformations are twice as common as aneurysms as a cause of spontaneous intracra¬ nial hemorrhage in childhood (Humphreys 1982). Only 4°/o of childhood arterio-venous malformations occur in infancy (Shapiro 1985), and virtually none of these occur in the neonatal period. Intracranial arterio-venous malformations may present with congestive cardiac failure or spontaneous intracranial hemorrhage that may be intraventricular, intra¬ cerebral or subdural (Wakai et al 1990). Raised intracranial pressure from hydrocephalus may be the presentation, when the arterio-venous malformation is within the ventricular system or there is a secondary dilation of the vein of Galen obstructing the aqueduct. Epilepsy, presumably from gliosis of the brain due to ischemia adjacent to the arterio-venous malformation, can occur as a presenting symptom in 2067% of adult patients, but in contrast less than 15% of children present with a chronic seizure disturbance. Spon¬ taneous intracranial hemorrhage is the means by which 80% of children declare their malformations. While modern radiology techniques have revolutionized the ability to diagnose and treat vascular malformations of the central nervous system, surgical excision remains the most common treatment for localized intracranial arterio-venous malformations. Endovascular embolization may be helpful as a prelude to surgical excision. The advent of stereotactic radiotherapy (‘radiosurgery’) has been successful for smaller lesions, either in strategic locations such as the thalamus or motor cortex, or for small residual lesions after operative removal of their hematoma and major malformation components. Venous angiomas are the most common of all the vascular malformations of the brain, yet are the least likely to cause symptoms. The current view is held that a venous angioma represents an anomalous but competent venous drainage pattern.

45

Cavernous malformations account for 8-16% of all cere¬ bral vascular malformations and occur most frequently in the cerebral hemispheres. The appearance on CT and MRI scanning is of a well circumscribed mass, with the surround¬ ing brain frequently stained by old hemorrhage (hemosid¬ erin). The cavernous malformation (or ‘cavernoma’) typically comes to attention because of hemorrhage, seizures or pro¬ gressive neurological deficit. With the exception of those lesions in the brainstem, most episodes of bleeding are minor and may be undetected. The majority of cavernous malformations do not demonstrate abnormal vasculature, and MRI scanning is now the investigation of choice. Once there has been a clinical hemorrhage, and it is technically possible, surgical excision is the treatment of choice. If sei¬ zures are well controlled medically excision may be kept in reserve. Perhaps the most challenging cavernoma is the brainstem lesion which has bled. While there are significant neurological risks from surgery, the presence of a surround¬ ing hematoma can facilitate surgery and neurological recovery when the bleed has caused profound deficit.

VEIN OF GALEN AND DURAL MALFORMATIONS IN CHILDHOOD A rare group of vascular lesions in infancy and childhood are the vein of Galen and dural malformations, which have a high vascular flow and characteristic clinical presentation. Vein of Galen malformations are thought to result from fistulous connections that develop near the embryonic choroid plexus. The consequent high-flow arterio-venous shunt between branches of the anterior, middle, posterior cerebral and superior cerebellar arteries and the vein of Galen, leads to progressive aneurysmal dilation of the vein, whose wall becomes thick and tough. Vein of Galen malformations can be classified clinically (Gold 1964), or angiographically. These lesions tend to be age dependent and can be placed in three categories 1. Neonates present with severe congestive heart failure. 2. Infants with hydrocephalus and/or seizures. 3. Older children or adults with subarachnoid hemorrhage, or hydrocephalus. Angiographically, there are two types of malformation. In one type there is a primary vein of Galen malformation in which large arteries feed directly into the aneurysmal sac. In the other type a secondary vein of Galen aneurysmal dilation, in which an adjacent arterio-venous malformation in the cerebral or cerebellar hemispheres, brainstem or ten¬ torium drains via the Galenic vein, which becomes dilated. Until the advent of interventional radiology, the morbid¬ ity and mortality for this lesion when symptomatic were unacceptably high. The mortality related to the intractable neonatal heart failure and intra-operative hemorrhage. In addition there was a high incidence of severe neurodevelopmental deficits in the survivors after surgery. Occa¬ sionally spontaneous obliteration with calcification has been reported (Chapman & Hockley 1989). 863

SECTION

XI

HYDROCEPHALUS AND NEUROSURGERY

With increasing experience from multidisciplinary teams involving interventional radiologists and neurosurgeons, results are improving in specialized centers. With early aggressive trans-arterial or trans-venous embolization employing iV-butyl cyanoacrylate (Berenstein ft Lasjaunias 1992) it is possible to reverse neonatal cardiac failure. In children who can be stabilized and who do not have severe cerebral damage, there is a therapeutic ‘window of opportunity’ that, if missed, will lead to progressive loss of brain tissue with inevitable neuro-developmental deficits. It is now known that ventricular shunting for the frequent associated hydrocephalus is to be avoided, because there are major complications and a poor neurological outcome. A shunting procedure does not solve the complex hemody¬ namic problems that exist in these babies (Zerah et al 1992). Dural malformations in childhood are very rare and less frequent than vein of Galen aneurysms. They generally have a more benign course than intra-parenchymal AVMs, pre¬ senting with hemorrhage in only 10% of cases. These high flow shunts usually involve a major dural sinus at the base, but usually involve more posteriorly placed sinuses, in par¬ ticular the transverse and sagittal sinuses and torcula. Clinically these lesions present by causing increased intra¬ cranial pressure from hydrocephalus, seizures, spontaneous subarachnoid hemorrhage and in neonates high output cardiac failure. The arterial supply of these lesions consists of dural vessels from the external carotid, vertebral and internal carotid arteries. Venous drainage occurs through either vir¬ tually normal sinuses or abnormal sinuses that may be duplicated or stenosed. Treatment in these rare lesions has mainly concerned neonates with cardiac failure, and these have been treated by embolization methods similar to those used with vein of Galen malformations. Both trans-venous and trans-arterial therapies are effective and surgical resection of the involved sinus is not usually required.

OTHER NEUROSURGICAL LESIONS IN THE NEONATAL PERIOD INTRACRANIAL INFECTION The major aspects of neonatal central nervous system infec¬ tions have been covered in Chapters 30-32. There are aspects of neonatal meningitis or intracranial suppuration where neurosurgical intervention is required.

CONSEQUENCES OF NEONATAL MENINGITIS There are really two complications of neonatal meningitis that may require neurosurgical assistance, namely hydro¬ cephalus and subdural effusions. A degree of usually temporary hydrocephalus occurs at some stage in 30% of cases of neonatal meningitis (Karan 1986). When suspected clinically by a tense anterior fontanelle, increased head circumference or a poor neurological 864

condition, further investigation is indicated with ultrasound, CT or MRI imaging. Diagnostic and therapeutic ventricular punctures can assist both the management of the infection and the temporary hydrocephalus. When repeated ventricu¬ lar CSF samples are needed or intraventricular therapy, surgical implantation of a ventriculostomy reservoir or an external ventricular drain can be extremely helpful. At a later stage even if the meningitis has been success¬ fully treated, a progressive hydrocephalus, usually of the communicating type, may result from the leptomeningeal fibrosis. Endoscopic third ventriculostomy has been uni¬ formly unsuccessful, so that treatment is by insertion of a ventricular shunt (Buxton et al 1998). So-called ‘post¬ meningitic’ hydrocephalus occurs particularly with certain forms of meningitis, including listeria, pneumococcal and tuberculosis. The prognosis in terms of neuro-developmental sequelae relates to the extent of brain damage (cerebral infarction) rather than to the occurrence of hydrocephalus. The management of hydrocephalus in this group of children can be complicated by the development of multiloculated ventricles, requiring additional surgical procedures. Subdural effusions are seen on imaging in the convales¬ cent phase of neonatal pyogenic meningitis in up to 50% of cases. Usually such effusions are asymptomatic, but occasionally in about 5% of cases (Milhorat 1978) can cause symptoms. These comprise persistent fever, irritability, sei¬ zures or signs of raised intracranial pressure. A subdural needle aspiration, with the needle inserted through the lateral corner of the anterior fontanelle (on each side) will provide a sample for microbiological investigations as well as relieving intracranial pressure. Most symptomatic subdu¬ ral effusions will resolve with or without repeated subdural taps. However, occasionally a sizeable subdural effusion may re-accumulate. If this happens and the subdural fluid is sterile, a subdural shunt into the peritoneal cavity may be required (Till 1968).

INTRACRANIAL SUPPURATION There are two types of intracranial purulent collection, a subdural empyema and intracerebral abscess, whose man¬ agement requires surgical drainage along the same princi¬ ples as for adult intracranial infection. In neonates the presence of an anterior fontanelle may allow drainage of a subdural empyema in its early stage when the fluid is thin. When the pus is too thick to be drained in this way it can only be evacuated adequately by burr holes or craniotomy. Intracerebral or brain abscesses (p. 670) in neonates are the result of bacteremia occurring during or shortly after birth. They are predominantly due to gram-negative organ¬ isms and the abscess may reach a large size, associated with thin walls and extensive surrounding cerebral edema. Any neonate who displays features that are atypical for menin¬ gitis should undergo cranial imaging. While ultrasound will exclude any large parenchymal abscess, a CT or preferably MRI scan will give more detailed information. Most abscesses

CHAPTER

Congenital defects, vascular malformations and other lesions

are frontal in location and not usually multiple (Renier et al 1988). The principles of treatment are the same as for cerebral abscess whatever the patient’s age, namely accurate micro¬ biological diagnosis from the pus, relief of raised intracra¬ nial pressure by aspiration of pus from the abscess, control of the sepsis by appropriate antibiotics in high intravenous dosage, and suppression of fits with anticonvulsant drugs (Hockley 8t George 1982). . In the neonate, the abscess may be aspirated by needle aspirations through the anterior fontanelle, through a diastased suture or through a burr hole. Aspirations should be repeated until the abscess cavity has collapsed, and surgical excision of the acute abscess can usually be avoided.

INTRACRANIAL TUMORS Intracranial tumors very rarely present at birth or produce symptoms within the first few months of life. According to the literature, they account for 0.5-1.9% of all childhood brain tumors (Jooma ft Kendall 1982, Sato et al 1964), an incidence of 0.34 per million live births. Unlike older chil¬ dren, 70% of neonatal brain tumors are supratentorial and only 30% infratentorial. Presentation is with symptoms of raised intracranial pressure. Macrocephaly may be severe enough to cause disproportion and dystocia. Babies may be

45

stillborn or premature, with teratoma as the most frequent tumor type. Neonatal brain tumors are frequently very large and vas¬ cular, with surgical excision a major challenge to the neu¬ rosurgeon and anesthetist. The use of chemotherapy may enable safer and more complete excision as seen in the case of malignant choroid plexus tumors (Greenberg 1999), and such a strategy might apply to other tumor types.

SPINAL TUMORS Spinal tumors are exceptionally rare in the neonatal period, but should be suspected in an infant with paraplegia who does not have features of spinal dysraphism or other abnor¬ malities. The majorities are neuroblastomas (Punt et al 1980) but other tumor types occur. After appropriate imaging, surgical decompression is indicated to prevent neurological deterioration and obtain tissue for histological diagnosis. In the case of neuroblastoma, without progressive neurological deterioration, treatment is initially with chemotherapy, sur¬ gical excision being reserved for any residuum. The outcome is dependent upon the nature of the tumor and the neuro¬ logical condition at presentation. For infants with neuro¬ blastoma, the prospects of survival are excellent. Late spinal deformity may require corrective surgery.

REFERENCES Alden T D, Lin K Y, Jane J A1999 Mechanisms of premature closure of cranial sutures. Child's Nerv Syst 15:670-675. Al-Qattan M M, Phillips J H 1997 Clinical features of Crouzon's syndrome patients with positive family history of Crouzon's syndrome. J Craniofac Surg 8(1):11—13. Anderson H 1977 Craniosynostosis. In Vinken P J. Bruyn GW (eds) Handbook of clinical neurology. Congenital malformations of the brain and skull. Elsevier. Amsterdam, vol 30, part 1, pp. 19-233. Becker D B, Petersen J D, Kane A A et al 2005 Speech,

and mutations of fibroblast growth factor receptor 3:

management of craniosynostosis. BrJ Neurosurg

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2:307-314.

Chapman S, Hockley A D 1989 Calcification of an aneurysm of the vein of Galen. Ped Radiol 19:541-542. Cinalli G. Spennato P. Sainte-Rose C et al 2005 Chiari malformations in craniosynostosis. Childs Nerv Syst 21(101:889-901. Cohen M M 1986 Craniosynostosis diagnosis, evaluation, and management. Raven, New York. Cohen M M. Kreiborg S 1993 An updated pediatric

cognitive and behavioural outcomes in nonsyndromic

perspective on Apert syndrome. Am J Dis Child

craniosynostosis. Plast Reconstr Surg

147(91:989-993.

116(21:400-407. Berenstein A. Lasjaunias P1992 Surgical neuroangiography volume 4: Endovascular treatment of cerebral intravascular lesions. Springer. Berlin. Bergsma 1973 Birth defects. Atlas and compendium. Williams and Williams. Baltimore. Besnick S, Schnendel S 1995 Crouzon's disease correlates with low fibroblast growth factor receptor activity in stenosed cranial sutures. J Craniofacial Surg 6:245-248. Besnick S. Schnendel S 1998 Apert's syndrome correlates with low fibroblast growth factor receptor activity in stenosed cranial sutures. J Craniofacial Surg 9:92-95. Buxton N, Macarthur D, Malluci C et al 1998 Neuroendoscopic third ventriculostomy in patients less than one year old. Pediatr Neurosurg 29:73-76. Cassileth L B, Bartlett S P, Glat P M et at 2001 Clinical characteristics of patients with unicoronaf synostosis

Hockley A D. Wake M J. Goldin J H 1988 Surgical

a preliminary report. Plast Reconstr Surg

Comi A M 2003 Pathophysiology of Sturge-Weber syndrome. J Child Neurol 18(81:509-616. Enjrolas 0, Breviere G M, Roger G et al 2004 Vincristine treatment for the function- and lifethreatening infantile hemangioma. Arch Pediatr 11(21:99-107. Enjrolas 0, Mulliken J B 1997 Vascular tumours and vascular malformations (new issues). Adv Dermatol 13:375-423. Enjrolas 0. Wassef M, Mazoyez E et al 1997 Infants with Kasabach-Merritt syndrome do not have 'true' hemangiomas. J Pediatr 130(41:631-640. Gold A P. Ransohoff J R. Carter S 1964 Vein of Galen malformation. Acta Neuro Scand 40 (suppl 111:5. Greenberg M 1999 Chemotherapy of choroid plexus carcinoma. Child's Nerv Syst 15:571-577. Hockley A D. George R 1982 Brain abscess. In: Current therapy (the nervous system). WB Saunders, Philadelphia.

Humphreys R P 1982 Arteriovenous malformations of the brain and spinal cord. Pediatric neurosurgery: surgery of the developing nervous system. Grune and Stratton. New York. Jooma R, Kendall B E 1982 Intracranial tumours in the first year of life. Neuroradiology 23:267-274. Karan S 1986 Purulent meningitis in the newborn. Child's Nerv Syst 2:26-31. Khoo LT. Levy M L1999 Intracerebral aneurysms. In: Albright A L. Pollack I F. Adelson P D (eds) Principles and practice of pediatric neurosurgery. Thieme, New York. Lahiri A. Nishikawa H 2005 A nonadherent dressing for aplasia cutis congenita. J Plast Reconstr Surg 59(7)781-782. Lajeunie E. Le Merrer M, Marchac M et al 1998 Syndromal and nonsyndromal trigonocephaly: analysis of a series of 237 patients. Am J Med Genet 13.75(21:211-215. McLellan N H. Prasad R, Punt J 1986 Spontaneous subhyaloid and retinal haemorrhages in an infant. Arch Dis Childhood 61:1130-1132. Mathijssen I. Arnaud E. Marchac D et al 2006 Respiratory outcome of midface advancement with distraction: a comparison between Le Fort III and frontofacial monoblock. J Craniofac Surg 17(51:880-882. MilhoratT 1978 Pediatric neurosurgery. Davis. Philadelphia. PA. Mohr G. Hoffman H J. Munro I R et al 1978 Surgical management of unilateral and bilateral

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coronal craniosynostosis. Neurosurgery 2:83-92. Mulliken J B, Glowaki J 1982 Haemangiomas and

Renier D. El Ghouzi V. Bonaventure et al 2000

de Crouzon, syndrome d'Apert: Oxycephalies,

nonsyndromic coronal synostosis: clinical spectrum,

scaphocephalies, turricephalies. Ann Chir Plast

vascular malformations in infants and children: a

prevalence, and surgical outcome. J Neurosurg

classification based on endothelial characteristics.

92:631-636.

Plast Reconstr Surg 69:412. Opperman L A, Sweeney T M. Redman J et al 1993 Tissue interactions with underlying dura mater inhibit osseous obliteration of developing cranial sutures. Dev Dynam 198:312-322. Panchal J. Marsh J L. Park T S et al 1999 Sagittal craniosynostosis outcome assessment for two methods and timings of intervention. Plast Reconstr Surg 103(61:1574-1584. PosnickJ C. Ruiz R L 2000 The craniofacial dysostosis syndromes: current surgical thinking and future directions. Cleft Palate Craniofac J 37(51:433. PuntJ, Pritchard J, PincottJ et al 1980 Neuroblastoma: a review of 21 cases presenting with spinal cord compression. Cancer 45:3095-3102. Reese V, Frieden I J, Paller AS et al 1993 Association of facial hemanigiomas with Dandy-Walker and other

Tessier P 1967 Osteotomies totales de la face. Syndrome

Fibroblast growth factor receptor 3 mutation in

Renier D, Flandin C, Hirsch E et al 1988 Brain abscesses in neonates. A study of 20 cases. J Neurosurg 69:877-882. Renier D. Saint-Rose C, Marchac D et al 1982 Intracranial pressure in craniosynostosis. J Neurosurg 57(31:370-377. Sato 0, Tumura A, Sano K1964 Brain tumours of early infants. Child's Brain 1:121-125. Sgouros S, Goldin J H, Hockley A D, Wake M J C1996 Posterior skull surgery in craniosynostosis. Child's Nerv Syst 12:727-733. Shapiro K1985 Subarachnoid haemorrhages in children. In: Fein J M, Flamm E S (eds) Cerebrovascular surgery. Springer. New York. Simmons D R. Peyton WT1947 Premature closure of the cranial sutures. J Pediatr 31:528-547. Spiller J C, Sharma V, Woods G M et al 1992 Diffuse

12:173-186. Tessier P 1976 Anatomical classification of facial, cranio-facial and latero-facial clefts ,J Maxillofacial Surg 4(21:69-92. Till K1968 Subdural haematoma and effusion in infancy. BMJ ii:400—402. Van Der Meulen J C. Mazolla R. Strieker M et al 1990 Classification of craniofacial malformations. In: Strieker M, Van Der Meulen J C. Raphael B et al (eds) Craniofacial malformations. Churchill Livingstone, Edinburgh. Virchow R 1851 Uber den Cathismus. namentlich in Franken. und uber pathologische. Schadeljormen Verk Phys-Med Ges Wurzberg 2:230-270. Wakai S, Andon Y, Nagai M et al 1990 Choroid plexus arteriovenous malformation in a full-term neonate. Case report. J Neurosurg 72:127-129. Wilkie A 0, Slaney S F. Oldridge M et al 1995 Apert syndrome results from localized mutations of FGFR2

posterior fossa malformations. J Pediatr

neonatal hemangiomatosis treated successfully

and is allelic with Crouzon syndrome. Nat Genet

122(31:379-384.

with interferon alfa-2a. J Am Acad Dermatol

9(21:165-172.

Renier D. Arnaud E. Cinalli et al 1996 Prognosis for mental function Apert syndrome. J Neurosurg 85:66.

866

27:102-104. Taylor J L, Hockley A D, Downing R 1990 Vascular anomalies of the scalp. Child's Nerv Syst 6:356-359.

Zerah M, Garcia-Monaco. Rodesch G et al 1992 Hydrodynamics in vein of Galen malformation in 43 cases. Child's Nerv Syst 8:111-117.

EPIDEMIOLOGY OF NEUROLOGIC DISABILITY

The epidemiology of the cerebral palsies Eve Blair and Fiona Stanley

Key Points •

Cerebral palsy is defined as motor impairment resulting from a non¬

•

It is a clinical description, not a diagnosis

•

Since it cannot be applied until the motor impairment becomes

progressive brain lesion or anomaly acquired early in life

apparent, only neonatal survivors are at risk •

Despite considerable efforts, inter-center agreement of sub-classification remains elusive

• The effect on function ranges from imperceptible to total incapacitation •

Motor impairment may be accompanied by other impairments, which

•

Its causes are heterogeneous and may be multifactorial

•

Risk factors include preterm birth, restricted intra-uterine growth,

may additionally limit functional attainment

multiple gestation, male gender, several antenatal factors, sentinel intrapartum events, poor condition at birth or neonatally and post neonatal cerebral infection or trauma • With the exception of post neonatal events, the relationships between risk factors and causes are often poorly understood and no risk factor is an accurate predictor •

Birth prevalence has changed little in the latter half of the twentieth century, but an increasing proportion are born very prematurely, concurrent with the increasing survival of premature infants associated with the increasing sophistication of neonatal intensive care

DEFINITION: A REAL CHALLENGE FOR EPIDEMIOLOGISTS Cerebral palsy is an umbrella term (Mutch et al 1992) cover¬ ing a group of clinical descriptions that have four criteria common to the many proposed definitions (Bax et al 2005, Stanley et al 2000): (1) a disorder of movement or posture, (2) resulting from some developmental or acquired abnor¬ mality in the brain (3) that is acquired early in life and (4) static by the time the motor disorder is recognized. It is an unusual medical definition that provides a real challenge for epidemiologists. There is no diagnostic test for cerebral palsy. Although the cerebral pathology can now be visualized in some cases, these images cannot tell us whether the four defining criteria will be met. Instead cerebral palsy can be identified only by following clinical description over time. If the clinical symptoms disappear or the condition proves to be progressive, it is the description of cerebral palsy that is withdrawn, rather than amending the natural history of cerebral palsy, hence, to assess whether the crite¬ ria are met the person must be followed over time. However, the four criteria above are not sufficiently spe¬ cific to ensure that the classification of cerebral palsy is sufficiently reliable to allow valid comparisons between

different observers (Blair 8t Love 2005). The criteria do not specify: (a) how severe the movement disorder must be, (b) how to ensure that the cerebral abnormality is static, (c) the age by which the cerebral abnormality must be acquired or (d) the age before which cerebral palsy cannot be reliably recognized. In practice the four criteria are interpreted vari¬ ously, and the limits of (a) to (d) defined differently by dif¬ ferent individuals. In addition, a number of conditions that do meet the four criteria may not necessarily be included, depending on the purpose of classifying and local conditions and customs (Badawi et al 1998). Therefore, given that the cerebral palsies are heterogeneous with respect to etiology, pathology and to clinical description, we suggest that a label of cerebral palsy is not useful for communicating the cause, severity or prognosis of a child’s condition. Since the term also appears to have limited reliability, it is reasonable to ask whether ‘cerebral palsy’ is a term worth retaining. The term ‘cerebral palsy’ refers to a group of disorders with clinical similarities, which is useful for service provid¬ ers. With decreasing perinatal mortality, the prevalence of cerebral palsy has been used as a measure of pregnancy outcome to evaluate obstetric and neonatal care. This is of dubious validity for term infants for whom the quality of medical care has been reported as either not (Niswander 1985) or only weakly (Blair 1994, Gaffney et al 1994, Rich¬ mond et al 1994) associated with the likelihood of cerebral palsy. It may be a more reasonable measure of the care of infants born extremely preterm, though the evidence for separating motor from other central nervous system impair¬ ments is weak (Stanley et al 2000). There are better grounds for using it together with other adverse pregnancy outcomes to assess the general health of a population and for using the incidence of post-neonatally acquired cerebral palsy as a measure of preventable social risks (Stanley et al 2000), similar to the use of perinatal and post neonatal deaths respectively. A major reason for retaining the term is not medical. It identifies a group at risk of severe disability and handicap in a non-pejorative manner which is now familiar to policy¬ makers and to the public. Additionally, in this era of infor¬ mation technology the term is short and unique. A keyword of cerebral palsy or even of palsy will give references almost exclusively related to non-progressive motor impairments of central origin recognized in childhood or infancy. It conveys considerable information and yet it is flexible. However, the term can be most useful if it conveys the same information to everyone. This could be achieved by 867

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XII

EPIDEMIOLOGY OF NEUROLOGIC DISABILITY

increasing the specificity of the four generally accepted criteria for cerebral palsy by: (1) defining the lower limit of severity using a recognized and validated measure; e.g. defining the degree of functional impairment required (now usually assessed with the Gross Motor Function Classification System (GMFCS) (Palisano et al 1997) or whether neurological signs alone are sufficient; (2) specifying the upper age limit of acquired brain injury; e.g. this has varied between birth and 13 years. If post neonatally acquired cases are included, this limit usually lies between 2 and 10 years; (3) specifying the inclusion status of known syndromes (see Badawi et al 1998); (4) defining the age at which the possibility of progression or resolution can be rejected and cerebral palsy (CP) status confirmed; in current registers this varies between 2 and 8 years, the majority choosing 5 years of age; and (5) defining the minimum age of inclusion and the criteria to be met should the child die before the age of confirmation. Several registers accept a description of cerebral palsy from a reliable source at any age; for others this criterion is set between 1 and 3 years of age. A higher minimum age will make the prediction of cerebral palsy more secure, but risks excluding the most severe cases, since severity of impairment correlates with mortality, which drops exponentially over time (Blair et al 2001). Compared with including cases at first description of CP, delaying the minimum age to 2 years would exclude 7% of Western Australian cases who would not achieve independent ambulation, and they would be the most severely impaired in this category. Agreement on these further criteria may not be necessary, but they should be specified when describing CP samples. Maximum flexibility is achieved with the most inclusive criteria, together with clinical descriptions and age of acqui¬ sition and/or death where applicable, so that appropriate comparisons may be made with collections which have dif¬ ferent inclusion criteria. The only impairment necessary to meet the criteria for CP is a disorder of movement or posture, but CP is frequently associated with cognitive and learning disabilities, seizure and behavioral disorders and sensory defects which can very significantly affect functional prognosis. The likelihood and severity of associated impairments increase with increasing severity of motor impairment (see Table 46.1).

DIFFERENTIAL DESCRIPTIONS: IMPORTANT FOR BOTH EPIDEMIOLOGISTS AND SERVICE PROVIDERS Sub-classification of cerebral palsy may logically be based on clinical description, etiology or pathology. Etiology is an 868

Table 46.1 Percentage of persons with CP born in Western Australia 1975-1999 with severe associated impairments, by severity of motor impairment Severity of motor impairment

N

Minimal

Mild

Moderate

Severe

227

522

439

472

0/

v

;v

70

83.7

74.5

62.2

18.9

50-69

10.0

14.6

16.2

9.0

/o

ASSOCIATED IMPAIRMENT Current epilepsy IQ/DQ

35-49

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7.5

12.8

19.9

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