Crib Death Giulia Ottaviani

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Crib Death Giulia Ottaviani

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Giulia Ottaviani

Crib Death

Sudden Unexplained Death of Infants – The Pathologist’s Viewpoint

With 64 Figures and 1 Table

123

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Giulia Ottaviani, MD

Ricercatore confermato, Professore aggregato Institute of Pathology, University of Milan Via della Commenda, 19

20122 Milan, Italy

Tel.: +39-02-50320822; Fax: +39-02-50320823 E-mail: giulia.ottaviani@unimi.it

URL: http://users.unimi.it/~pathol/pathol_e.html

Library of Congress Control Number: 2007921195

ISBN 978-3-540-49370-9 Springer Berlin Heidelberg New York

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A voice is heard in Ramah, mourning and great weeping, Rachel weeping for her children and refusing to be comforted, because her children are no more.

(Jeremiah 31:15)

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To the memory of my beloved mother, Angela, my first inspiration, and to all parents whose lives are touched by the tragedy of a child’s illness or loss.

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This new book written by Dr. Giulia Ottaviani is beautifully organized and so well written that it is a genuine pleasure to read. It is enjoyable from both an intellectual and a scientific standpoint. I believe it to be a major contribution, not only to “pathology” as she modestly indicates in the title, but to almost every field of medicine, or to anyone with an intellectual curiosity. But for any special medical discipline it could be a virtual necessity. It should be readily available at locations where medical emergency treatment is necessary, especially in hospital emergency rooms and for ambulance medical services.

Pediatricians, obstetricians, and emergency room nurses will find it enormously valuable. It will also be indispensable in numerous other specialties, particularly cardiology, neurology, and even cardiac surgery. For some particular diseases (such as the long QT syndrome) this book will become essential reading, in part because infants, children, and adults can progress to sudden death with this disease.

Very few could have written this book from the standpoint of cardiology and neurology to explain crib death, but I believe that Dr. Ottaviani is uniquely qualified for this mission.

Thomas N. James, MD, MACP Former Chairman of Medicine and Physician in Chief at the University of Alabama Medical School in Birmingham Later, President University of Texas Medical Branch (1987–1997) Currently Distinguished Professor Emeritus University of Alabama in Birmingham

Foreword

Thomas N. James

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Infant and perinatal mortality is the most accurate index for evaluating the quality of health in most developed countries. In particular, the fetal mortality rate represents the main indicator of the effectiveness of mother–infant support.

Crib death, or sudden infant death syndrome (SIDS), strikes an apparently healthy baby every 750–1,000 live births and it is the most frequent natural cause of death in the first year of life. The unexpected death of the near-term fetus and of the newborn in the first week of life is unexplained in 60–80% of cases, even after performing a routine post-mortem examination. Data from the World Health Or- ganization indicate that fetal death has an incidence of one in every 100–200 preg- nancies in developed countries. Its frequency is therefore six to seven times greater than that of SIDS, and has not significantly decreased during recent years, mainly because of limited research activity.

The results of in-depth investigations performed at the Institute of Pathology of the University of Milan have contributed to the identification of the nature and location of the alterations, common to both SIDS and fetal death, underlying the onset of lethal nervous reflexes. They are mostly congenital anomalies of the veg- etative nervous system and/or of the cardiac conduction system, i.e. of the electric switchboard of the heart, which is also under the control of the autonomic nervous system.

Italian Law no. 31 of 2 February 2006 “Regulations for Diagnostic Post Mortem Investigation in Victims of Sudden Infant Death Syndrome (SIDS) and unexpected fetal death” represents a milestone in health politics. It is new and revolutionary and states fundamental rules to significantly reduce the toll in human life: the promo- tion of anatomoclinical, genetic and epidemiological research, and awareness and information campaigns, and the implementation of programs and projects for the psychological support of victims’ families.

The need to submit these small victims to post-mortem examination and to accurate histological investigations is unanimously recognized. Prevention is mainly based on the recognition of lesions detectable in various organs, particularly of the autonomic nervous system regulating the vital activities (respiratory, cardiac, di- gestive and arousal) and of the pathogenic role of the major risk factors (cigarette smoking and maternal alcoholism, air pollution, sedatives, etc.)

Being a problem of high scientific complexity, the law enacts rules for the post- mortem procedures, with the necessary parents’ consent, and it establishes criteria to identify local reference centers, with recognized professional and scientific com-

Foreword

Luigi Matturri

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Foreword XII

petences, according to the diagnostic guidelines devised by the Institute of Path- ology of the University of Milan.

In the present book a systematic study is presented of the autonomic nervous system and cardiac conduction system in a large number of infants and fetuses dying suddenly and unexpectedly, as well as in age-matched control cases. The purpose of this book is to describe the nervous and cardiac histopathological findings and to describe an investigated standardized post-mortem protocol to apply to all cases of sudden unexpected infant and perinatal death.

I wish this monograph all the success it deserves. The book is aimed at patholo- gists, neonatologists, pediatricians and researchers with a university degree in medicine or biology, laboratory histotechnicians, pediatric nurses, as well as medical stu- dents and general practitioners. I am sure that the readers will be able to learn from it useful tools and hints to apply in their research and practice.

Luigi Matturri, MD Full Professor of Pathology Chairman, Institute of Pathology University of Milan

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This book is based on my PhD dissertation defended at the University of Milan on 3 February 2004.

The sudden unexpected death of a baby in the crib is surely one of the most heartbreaking tragedies for the family and for society. Everyone who reads this book has always to keep in mind that crib death is the leading form of death in otherwise healthy babies within the first year of life. Most of the people and even physicians underestimate the frequency of this problem and do not know how devastating its consequences are. The sudden unexpected death of a baby is so out of order with the sequence of life that there has been no preparation. The parents’ terrible loss is then compounded by feelings of guilt; they blame themselves for overlooking possible baby’s symptoms or signs. Poignantly and most sadly, the death occurs too often when no one is around, with the dead infant only being discovered later.

After an unexpected sudden infant death a post-mortem examination will be performed. This involves examination of the body, organs and tissues by a pathologist. In this monograph I present a systematic study of the cardiac conduction system and of the autonomic nervous system carried out in a large number of cases.

There is a point that I wish to clarify. The term SIDS (sudden infant death syndrome) is a mistake. It takes origin from its popularization by people who did not know the anatomopathological basis of this form of death. The correct term is sudden death of a baby or infant, crib death (in the United States) or cot death (in the United Kingdom). SIDS is an abhorrent term to families and physicians who care for these tragic cases. Unfortunately, it is also often quoted in my monographs, and I apologize for the use of this terminology.

I wish to transmit to readers the interesting and expanding knowledge of the pathology of crib death and to make them aware of the important role and viewpoint of the pathologist.

Giulia Ottaviani

Preface

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I am very grateful to Prof. Luigi Matturri, MD, Chairman, and to Prof. Anna Maria Lavezzi, MD, Associate Professor, of the Institute of Pathology, University of Milan, for heartily encouraging me to pursue academic research on the pathology of sudden infant and perinatal death. Their valuable support and teaching made this book possible. Sincere thanks are given to Prof. Thomas N. James, MD, MACP, University of Texas Medical Branch at Galveston, for guidance and help. I pay respectful tribute to the memory of Prof. Lino Rossi, MD, Honorary Fellow, American Heart Associa- tion Council on Clinical Cardiology, a valued and much appreciated teacher. Ap- preciation is extended to the staff histotechnicians, particularly Dr. Graziella Alfonsi for skillful assistance. Finally, I am indebted to Prof. Simone Gusmão Ramos, MD, PhD, University of São Paulo, for encouraging this research from the early years of my residency in pathology.

Acknowledgments

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I Introduction and Aims . . . . 1

I.1 Sudden Infant Death Syndrome . . . . 2

I.1.1 Definition and History of SIDS . . . . 2

I.1.2 Epidemiology and Risk Factors . . . . 5

I.1.3 Etiopathogenesis of SIDS . . . . 8

I.1.3.1 Reflexogenic SIDS . . . . 9

I.1.3.2 SIDS due to Metabolic Impairment . . . . 10

I.1.4 “Near Miss” and “ALTE” Episodes . . . . 10

I.1.5 SIDS Prevention . . . . 11

I.2 Sudden Intrauterine Unexplained Death . . . . 12

I.3 Cardiac Conduction System . . . . 13

I.3.1 Sinoatrial Node . . . . 13

I.3.1.1 Histology . . . . 15

I.3.1.2 Vascular Supply . . . . 16

I.3.1.3 Collagen Framework . . . . 16

I.3.1.4 Innervation . . . . 17

I.3.2 Internodal and Interatrial Pathways . . . . 17

I.3.3 Atrioventricular Node . . . . 18

I.3.3.1 Histology . . . . 18

I.3.3.3 Lymphatic Drainage . . . . 20

I.3.4 Morphological Concept of the Atrioventricular Junction . . . . 20

I.3.4.1 Central Fibrous Body . . . . 20

I.3.4.2 Tendon of Todaro . . . . 21

I.3.5 Bundle of His . . . . 21

I.3.5.1 Histology . . . . 22

I.3.6 Bifurcating Bundle of His or Bifurcation . . . . 23

I.3.7 Right Bundle Branch . . . . 23

I.3.7.1 Histology . . . . 24

Contents

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Contents XVIII

I.3.8 Left Bundle Branch . . . . 25

I.3.8.1 Histology . . . . 25

I.3.9 Fetal and Postnatal Development of the Conduction System . . . . 25

I.3.9.1 The Sinoatrial Node: Fetal and Postnatal Development . . . . 26

I.3.9.2 Internodal Pathways: Fetal and Postnatal Development . . . . 27

I.3.9.3 Atrioventricular Node Development . . . . 27

I.3.9.4 Bundle of His and Bundle Branches Development . . . . 28

I.3.9.5 AVN and Bundle of His Postnatal Molding . . . . 28

I.3.10 Accessory Cardiac Conduction Pathways . . . . 30

I.3.10.1 Kent Fibers . . . . 31

I.3.10.2 James and Mahaim Fibers . . . . 32

I.4 Central, Peripheral and Autonomic Nervous Systems . . . . 32

I.4.1 Brainstem . . . . 32

I.4.1.1 Arcuate Nucleus . . . . 32

I.4.1.2 Parabrachial/Kölliker-Fuse Complex . . . . 33

I.4.1.3 Dorsal Motor Vagal Nucleus . . . . 33

I.4.1.4 Ambiguous Nucleus . . . . 33

I.4.1.5 Solitary Tract Nucleus . . . . 33

I.4.1.6 Locus Coeruleus . . . . 34

I.4.1.7 Hypoglossal Nucleus . . . . 34

I.4.2 Spinal Cord . . . . 34

I.4.3 Extrinsic Cardiac Innervation . . . . 34

I.4.3.1 Right Side of the Heart . . . . 34

I.4.3.2 Left Side of the Heart . . . . 35

I.4.4 Intrinsic Cardiac Innervation . . . . 35

I.4.5 Nervous Structures Regulating Cardiac Activity . . . . 36

I.4.5.1 Juxtacardiac and Mediastinal Ganglia and Paraganglia . . . . 37

II Materials and Methods . . . . 39

II.1 Clinical and Pathological Information . . . . 39

II.2 Post-Mortem Regulation on SIDS and Unexpected Fetal Death . . 44

II.3 Necropsy Procedure . . . . 44

II.4 Cardiac Sampling and Study of the Conduction System . . . . 48

II.4.1 Cardiac Sampling . . . . 48

II.4.2 Removal of the Cardiac Conduction System Blocks . . . . 48

II.4.3 Treatment of the Cardiac Conduction Blocks . . . . 53

II.5 Brainstem Sampling . . . . 57

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Contents XIX

II.5.1 Complete Examination of the Brainstem . . . . 58

II.5.2 Simplified Examination of the Brainstem . . . . 59

II.5.3 Treatment of the Brainstem Blocks . . . . 59

II.5.4 Morphometric Analysis . . . . 61

II.6 Study of the Carotid Bifurcation, Ganglia and Paraganglia . . . . 61

II.6.1 Carotid Bifurcation . . . . 61

II.6.2 Mediastinal Ganglionic and Paraganglionated Plexuses . . . . 62

II.6.3 Cervical Sympathetic Ganglia . . . . 62

II.7 Lung: Evaluation of the Stage of Development . . . . 63

II.8 Immunohistochemistry and Other Techniques . . . . 63

II.8.1 Apoptosis . . . . 63

II.8.2 Proliferating Cell Nuclear Antigen (PCNA) . . . . 63

II.8.3 c-Fos . . . . 64

II.8.4 Fluorescence In Situ Hybridization (FISH) . . . . 64

II.8.5 α-Actin Immunohistochemistry . . . . 65

II.9 Cases Analyzed . . . . 65

II.9.1 SIDS Cases . . . . 65

II.9.2 “Gray Zone” SIDS Cases . . . . 66

II.9.3 SIUD Cases . . . . 66

II.9.4 Explained Death Cases . . . . 66

II.10 Statistical Analysis . . . . 67

III Results . . . . 69

III.1 Epidemiological Results . . . . 69

III.1.1 Age . . . . 69

III.1.2 Sex . . . . 69

III.1.3 Season . . . . 70

III.1.4 Time . . . . 70

III.1.5 Death Scene: Place of Death . . . . 70

III.1.6 Death Scene: Position in the Crib . . . . 70

III.1.7 Feeding . . . . 71

III.1.8 Cigarette Smoke Exposure . . . . 73

III.2 Cardiac Conduction Findings . . . . 73

III.2.1 Resorptive Degeneration . . . . 73

III.2.2 Atrioventricular Node and Bundle of His Dispersion/Septation . . 73

III.2.3 Persistent Fetal Dispersion . . . . 75

III.2.4 Accessory Pathways . . . . 75

III.2.5 Cartilaginous Metahyperplasia/Hypermetaplasia . . . . 75

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Contents XX

III.2.6 Hemorrhage of the Cardiac Conduction System . . . . 75

III.2.7 Intramural Right Bundle Branch . . . . 75

III.2.8 Left-Sided Bundle of His . . . . 78

III.2.9 Intramural Left Bundle Branch . . . . 78

III.2.10 Septation of the Bifurcation . . . . 78

III.2.11 Hypoplasia of the Cardiac Conduction System . . . . 78

III.2.12 Atrioventricular Node/Bundle of His Dualism . . . . 78

III.2.13 Zahn Node . . . . 78

III.2.14 Fibromuscular Hyperplasia of the Conduction System Arteries . . 78

III.2.15 Apoptosis Expression in the Conducting Tissue . . . . 80

III.2.16 PCNA Expression in the Conducting Tissue . . . . 81

III.2.17 ECG Findings . . . . 81

III.2.18 Coronary Artery Findings . . . . 84

III.2.18.1 Infants . . . . 84

III.2.18.2 Fetuses . . . . 84

III.2.19 “Gray Zone” or Borderline Cases . . . . 85

III.2.19.1 Cardiac Purkinje Cell Tumor . . . . 85

III.2.19.2 Myocardial Infarction and Mahaim Fibers . . . . 87

III.2.20 Not SIDS/Sudden Explained Death . . . . 88

III.2.20.1 Cardiac Fibroma . . . . 88

III.2.20.2 Hypertrophic Cardiomyopathy . . . . 90

III.3 Central and Autonomic Nervous System Findings . . . . 90

III.3.1 Hypoplasia and Agenesis of the Arcuate Nucleus . . . . 90

III.3.2 Combined Pulmonary and Arcuate Nucleus Hypoplasia . . . . 93

III.3.3 Parabrachial/Kölliker-Fuse Complex Findings . . . . 93

III.3.3.1 Morphological Analysis of the Parabrachial/Kölliker-Fuse Complex . . . . 94

III.3.3.2 Lateral Parabrachial Nucleus . . . . 94

III.3.3.3 Medial Parabrachial Nucleus . . . . 94

III.3.3.4 Kölliker-Fuse Nucleus . . . . 95

III.3.3.5 Morphometric Analysis of the Parabrachial/Kölliker-Fuse Complex . . . . 95

III.3.4 Brainstem Neurons Responding to Hypoxia (c-fos-Positive) . . . . 96

III.3.5 Combined Cardiac Conduction and Brainstem Study . . . . 96

III.3.6 Gray-Zone/Borderline SIDS . . . . 96

III.4 Peripheral Autonomic Nervous System Findings . . . . 97

III.4.1 Paraganglionic Hyperplasia . . . . 97

III.4.2 Stellate Ganglion Alterations . . . . 98

IV Discussion . . . . 99

IV.1 Cardiac Conduction Pathology . . . . 99

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Contents XXI

IV.1.1 Resorptive Degeneration . . . 100

IV.1.2 Atrioventricular Node and Bundle of His Dispersion/Septation 101 IV.1.3 Persistent Fetal Dispersion . . . 102

IV.1.4 Accessory Pathways . . . 102

IV.1.4.1 Mahaim Fibers . . . 102

IV.1.4.2 Kent Fibers . . . 103

IV.1.4.3 James Fibers . . . 103

IV.1.5 Cartilaginous Metahyperplasia . . . 104

IV.1.6 Hemorrhage of the Cardiac Conduction System . . . 104

IV.1.7 Intramural Right Bundle Branch . . . 105

IV.1.8 Left-Sided Bundle of His . . . 105

IV.1.9 Intramural Left Bundle Branch . . . 105

IV.1.10 Septation of the Bifurcation . . . 105

IV.1.11 Hypoplasia of the Cardiac Conduction System . . . 105

IV.1.12 Atrioventricular Node/Bundle of His Dualism . . . 106

IV.1.13 Zahn Node . . . 106

IV.1.14 Fibromuscolar Hyperplasia of the Conduction System Arteries 106 IV.1.15 Apoptosis Expression in the Conducting Tissue . . . 107

IV.1.16 PCNA Expression in the Conducting Tissue . . . 108

IV.1.17 ECG Findings . . . 109

IV.1.18 Coronary Artery Findings . . . 109

IV.1.18.1 Infants . . . 109

IV.1.18.2 Fetuses . . . 110

IV.1.19 “Gray Zone” or Borderline Cases . . . 111

IV.1.20 Other Cardiac Findings . . . 111

IV.2 Neuropathology . . . 112

IV.2.1 Hypoplasia and Agenesis of the Arcuate Nucleus . . . 112

IV.2.2 Combined Pulmonary and Arcuate Nucleus Hypoplasia . . . 112

IV.2.3 Parabrachial/Kölliker-Fuse Complex Findings . . . 113

IV.2.4 Brainstem Neurons Responding to Hypoxia (c-Fos-Positive) . . . . 114

IV.2.5 Gray Zone/Borderline SIDS . . . 115

IV.2.6 Paraganglia Hyperplasia . . . 115

IV.2.7 Long QT Syndrome . . . 116

V Concluding Remarks . . . 119

VI Summary . . . 123

References . . . 127

Subject Index . . . 141