Sleep in Children
LUNG BIOLOGY IN HEALTH AND DISEASE
Executive Editor Claude Lenfant Former Director, National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland
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Immunologic and Infectious Reactions in the Lung, edited by C. H. Kirkpatrick and H. Y. Reynolds The Biochemical Basis of Pulmonary Function, edited by R. G. Crystal Bioengineering Aspects of the Lung, edited by J. B. West Metabolic Functions of the Lung, edited by Y. S. Bakhle and J. R. Vane Respiratory Defense Mechanisms (in two parts), edited by J. D. Brain, D. F. Proctor, and L. M. Reid Development of the Lung, edited by W. A. Hodson Lung Water and Solute Exchange, edited by N. C. Staub Extrapulmonary Manifestations of Respiratory Disease, edited by E. D. Robin Chronic Obstructive Pulmonary Disease, edited by T. L. Petty Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris Genetic Determinants of Pulmonary Disease, edited by S. D. Litwin The Lung in the Transition Between Health and Disease, edited by P. T. Macklem and S. Permutt Evolution of Respiratory Processes: A Comparative Approach, edited by S. C. Wood and C. Lenfant Pulmonary Vascular Diseases, edited by K. M. Moser Physiology and Pharmacology of the Airways, edited by J. A. Nadel Diagnostic Techniques in Pulmonary Disease (in two parts), edited by M. A. Sackner Regulation of Breathing (in two parts), edited by T. F. Hornbein Occupational Lung Diseases: Research Approaches and Methods, edited by H. Weill and M. Turner-Warwick Immunopharmacology of the Lung, edited by H. H. Newball Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by B. L. Fanburg Sleep and Breathing, edited by N. A. Saunders and C. E. Sullivan Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L. S. Young Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by H. L. Atkins Acute Respiratory Failure, edited by W. M. Zapol and K. J. FaIke
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Gas Mixing and Distribution in the Lung, edited by L. A. Engel and M. Paiva High-Frequency Ventilation in Intensive Care and During Surgery, edited by G. Carlon and W. S. Howland Pulmonary Development: Transition from Intrauterine to Extrauterine Life, edited by G. H. Nelson Chronic Obstructive Pulmonary Disease: Second Edition, edited by T. L. Petty The Thorax (in two parts), edited by C. Roussos and P. T. Macklem The Pleura in Health and Disease, edited by J. Chre´tien, J. Bignon, and A. Hirsch Drug Therapy for Asthma: Research and Clinical Practice, edited by J. W. Jenne and S. Murphy Pulmonary Endothelium in Health and Disease, edited by U. S. Ryan The Airways: Neural Control in Health and Disease, edited by M. A. Kaliner and P. J. Barnes Pathophysiology and Treatment of Inhalation Injuries, edited by J. Loke Respiratory Function of the Upper Airway, edited by O. P. Mathew and G. Sant’Ambrogio Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A. J. McSweeny and I. Grant Biology of Lung Cancer: Diagnosis and Treatment, edited by S. T. Rosen, J. L. Mulshine, F. Cuttitta, and P. G. Abrams Pulmonary Vascular Physiology and Pathophysiology, edited by E. K. Weir and J. T. Reeves Comparative Pulmonary Physiology: Current Concepts, edited by S. C. Wood Respiratory Physiology: An Analytical Approach, edited by H. K. Chang and M. Paiva Lung Cell Biology, edited by D. Massaro Heart–Lung Interactions in Health and Disease, edited by S. M. Scharf and S. S. Cassidy Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited by M. J. Hensley and N. A. Saunders Surgical Pathology of Lung Neoplasms, edited by A. M. Marchevsky The Lung in Rheumatic Diseases, edited by G. W. Cannon and G. A. Zimmerman Diagnostic Imaging of the Lung, edited by C. E. Putman Models of Lung Disease: Microscopy and Structural Methods, edited by J. Gil Electron Microscopy of the Lung, edited by D. E. Schraufnagel Asthma: Its Pathology and Treatment, edited by M. A. Kaliner, P. J. Barnes, and C. G. A. Persson Acute Respiratory Failure: Second Edition, edited by W. M. Zapol and F. Lemaire Lung Disease in the Tropics, edited by O. P. Sharma Exercise: Pulmonary Physiology and Pathophysiology, edited by B. J. Whipp and K. Wasserman Developmental Neurobiology of Breathing, edited by G. G. Haddad and J. P. Farber
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Mediators of Pulmonary Inflammation, edited by M. A. Bray and W. H. Anderson The Airway Epithelium, edited by S. G. Farmer and D. Hay Physiological Adaptations in Vertebrates: Respiration, Circulation, and Metabolism, edited by S. C. Wood, R. E. Weber, A. R. Hargens, and R. W. Millard The Bronchial Circulation, edited by J. Butler Lung Cancer Differentiation: Implications for Diagnosis and Treatment, edited by S. D. Bernal and P. J. Hesketh Pulmonary Complications of Systemic Disease, edited by J. F. Murray Lung Vascular Injury: Molecular and Cellular Response, edited by A. Johnson and T. J. Ferro Cytokines of the Lung, edited by J. Kelley The Mast Cell in Health and Disease, edited by M. A. Kaliner and D. D. Metcalfe Pulmonary Disease in the Elderly Patient, edited by D. A. Mahler Cystic Fibrosis, edited by P. B. Davis Signal Transduction in Lung Cells, edited by J. S. Brody, D. M. Center, and V. A. Tkachuk Tuberculosis: A Comprehensive International Approach, edited by L. B. Reichman and E. S. Hershfield Pharmacology of the Respiratory Tract: Experimental and Clinical Research, edited by K. F. Chung and P. J. Barnes Prevention of Respiratory Diseases, edited by A. Hirsch, M. Goldberg, J.-P. Martin, and R. Masse Pneumocystis carinii Pneumonia: Second Edition, edited by P. D. Walzer Fluid and Solute Transport in the Airspaces of the Lungs, edited by R. M. Effros and H. K. Chang Sleep and Breathing: Second Edition, edited by N. A. Saunders and C. E. Sullivan Airway Secretion: Physiological Bases for the Control of Mucous Hypersecretion, edited by T. Takishima and S. Shimura Sarcoidosis and Other Granulomatous Disorders, edited by D. G. James Epidemiology of Lung Cancer, edited by J. M. Samet Pulmonary Embolism, edited by M. Morpurgo Sports and Exercise Medicine, edited by S. C. Wood and R. C. Roach Endotoxin and the Lungs, edited by K. L. Brigham The Mesothelial Cell and Mesothelioma, edited by M.-C. Jaurand and J. Bignon Regulation of Breathing: Second Edition, edited by J. A. Dempsey and A. I. Pack Pulmonary Fibrosis, edited by S. Hin. Phan and R. S. Thrall Long-Term Oxygen Therapy: Scientific Basis and Clinical Application, edited by W. J. O’Donohue, Jr. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure, edited by C. O. Trouth, R. M. Millis, H. F. Kiwull-Scho¨ne, and M. E. Schla¨fke A History of Breathing Physiology, edited by D. F. Proctor Surfactant Therapy for Lung Disease, edited by B. Robertson and H. W. Taeusch
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The Thorax: Second Edition, Revised and Expanded (in three parts), edited by C. Roussos Severe Asthma: Pathogenesis and Clinical Management, edited by S. J. Szefler and D. Y. M. Leung Mycobacterium avium–Complex Infection: Progress in Research and Treatment, edited by J. A. Korvick and C. A. Benson Alpha 1–Antitrypsin Deficiency: Biology . Pathogenesis . Clinical Manifestations . Therapy, edited by R. G. Crystal Adhesion Molecules and the Lung, edited by P. A. Ward and J. C. Fantone Respiratory Sensation, edited by L. Adams and A. Guz Pulmonary Rehabilitation, edited by A. P. Fishman Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease, edited by J.-P. Derenne, W. A. Whitelaw, and T. Similowski Environmental Impact on the Airways: From Injury to Repair, edited by J. Chre´tien and D. Dusser Inhalation Aerosols: Physical and Biological Basis for Therapy, edited by A. J. Hickey Tissue Oxygen Deprivation: From Molecular to Integrated Function, edited by G. G. Haddad and G. Lister The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions, edited by R. P. Schleimer, W. W. Busse, and P. M. O’Byrne Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich Lung Growth and Development, edited by J. A. McDonald Parasitic Lung Diseases, edited by A. A. F. Mahmoud Lung Macrophages and Dendritic Cells in Health and Disease, edited by M. F. Lipscomb and S. W. Russell Pulmonary and Cardiac Imaging, edited by C. Chiles and C. E. Putman Gene Therapy for Diseases of the Lung, edited by K. L. Brigham Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz Clerch and D. J. Massaro Beta2-Agonists in Asthma Treatment, edited by R. Pauwels and P. M. O’Byrne Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L. Adjei and P. K. Gupta Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M. Orenstein and R. C. Stern Asthma and Immunological Diseases in Pregnancy and Early Infancy, edited by M. Schatz, R. S. Zeiger, and H. N. Claman Dyspnea, edited by D. A. Mahler Proinflammatory and Antiinflammatory Peptides, edited by S. I. Said Self-Management of Asthma, edited by H. Kotses and A. Harver Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J. Gryglewski, and J. R. Vane Fatal Asthma, edited by A. L. Sheffer Pulmonary Edema, edited by M. A. Matthay and D. H. Ingbar
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Inflammatory Mechanisms in Asthma, edited by S. T. Holgate and W. W. Busse Physiological Basis of Ventilatory Support, edited by J. J. Marini and A. S. Slutsky Human Immunodeficiency Virus and the Lung, edited by M. J. Rosen and J. M. Beck Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S.-E. Dahle´n, and T. H. Lee Complexity in Structure and Function of the Lung, edited by M. P. Hlastala and H. T. Robertson Biology of Lung Cancer, edited by M. A. Kane and P. A. Bunn, Jr. Rhinitis: Mechanisms and Management, edited by R. M. Naclerio, S. R. Durham, and N. Mygind Lung Tumors: Fundamental Biology and Clinical Management, edited by C. Brambilla and E. Brambilla lnterleukin-5: From Molecule to Drug Target for Asthma, edited by C. J. Sanderson Pediatric Asthma, edited by S. Murphy and H. W. Kelly Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F. Wright Air Pollutants and the Respiratory Tract, edited by D. L. Swift and W. M. Foster Gastroesophageal Reflux Disease and Airway Disease, edited by M. R. Stein Exercise-Induced Asthma, edited by E. R. McFadden, Jr. LAM and Other Diseases Characterized by Smooth Muscle Proliferation, edited by J. Moss The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and P. C. Zee Anticholinergic Agents in the Upper and Lower Airways, edited by S. L. Spector Control of Breathing in Health and Disease, edited by M. D. Altose and Y. Kawakami Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J. Coalson Asthma’s Impact on Society: The Social and Economic Burden, edited by K. B. Weiss, A. S. Buist, and S. D. Sullivan New and Exploratory Therapeutic Agents for Asthma, edited by M. Yeadon and Z. Diamant Multimodality Treatment of Lung Cancer, edited by A. T. Skarin Cytokines in Pulmonary Disease: Infection and Inflammation, edited by S. Nelson and T. R. Martin Diagnostic Pulmonary Pathology, edited by P. T. Cagle Particle–Lung Interactions, edited by P. Gehr and J. Heyder Tuberculosis: A Comprehensive International Approach, Second Edition, Revised and Expanded, edited by L. B. Reichman and E. S. Hershfield Combination Therapy for Asthma and Chronic Obstructive Pulmonary Disease, edited by R. J. Martin and M. Kraft
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Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease, edited by T. D. Bradley and J. S. Floras Sleep and Breathing in Children: A Developmental Approach, edited by G. M. Loughlin, J. L. Carroll, and C. L. Marcus Pulmonary and Peripheral Gas Exchange in Health and Disease, edited by J. Roca, R. Rodriguez-Roisin, and P. D. Wagner Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter Nosocomial Pneumonia, edited by W. R. Jarvis Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P. Barker Long-Term Mechanical Ventilation, edited by N. S. Hill Environmental Asthma, edited by R. K. Bush Asthma and Respiratory Infections, edited by D. P. Skoner Airway Remodeling, edited by P. H. Howarth, J. W. Wilson, J. Bousquet, S. Rak, and R. A. Pauwels Genetic Models in Cardiorespiratory Biology, edited by G. G. Haddad and T. Xu Respiratory-Circulatory Interactions in Health and Disease, edited by S. M. Scharf, M. R. Pinsky, and S. Magder Ventilator Management Strategies for Critical Care, edited by N. S. Hill and M. M. Levy Severe Asthma: Pathogenesis and Clinical Management, Second Edition, Revised and Expanded, edited by S. J. Szefler and D. Y. M. Leung Gravity and the Lung: Lessons from Microgravity, edited by G. K. Prisk, M. Paiva, and J. B. West High Altitude: An Exploration of Human Adaptation, edited by T. F. Hornbein and R. B. Schoene Drug Delivery to the Lung, edited by H. Bisgaard, C. O’Callaghan, and G. C. Smaldone Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited by R. P. Schleimer, P. M. O’Byrne, S. J. Szefler, and R. Brattsand IgE and Anti-lgE Therapy in Asthma and Allergic Disease, edited by R. B. Fick, Jr., and P. M. Jardieu Clinical Management of Chronic Obstructive Pulmonary Disease, edited by T. Similowski, W. A. Whitelaw, and J.-P. Derenne Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A. I. Pack Biotherapeutic Approaches to Asthma, edited by J. Agosti and A. L. Sheffer Proteoglycans in Lung Disease, edited by H. G. Garg, P. J. Roughley, and C. A. Hales Gene Therapy in Lung Disease, edited by S. M. Albelda Disease Markers in Exhaled Breath, edited by N. Marczin, S. A. Kharitonov, M. H. Yacoub, and P. J. Barnes Sleep-Related Breathing Disorders: Experimental Models and Therapeutic Potential, edited by D. W. Carley and M. Radulovacki Chemokines in the Lung, edited by R. M. Strieter, S. L. Kunkel, and T. J. Standiford Respiratory Control and Disorders in the Newborn, edited by O. P. Mathew The Immunological Basis of Asthma, edited by B. N. Lambrecht, H. C. Hoogsteden, and Z. Diamant
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Oxygen Sensing: Responses and Adaptation to Hypoxia, edited by S. Lahiri, G. L. Semenza, and N. R. Prabhakar Non-Neoplastic Advanced Lung Disease, edited by J. R. Maurer Therapeutic Targets in Airway Inflammation, edited by N. T. Eissa and D. P. Huston Respiratory Infections in Allergy and Asthma, edited by S. L. Johnston and N. G. Papadopoulos Acute Respiratory Distress Syndrome, edited by M. A. Matthay Venous Thromboembolism, edited by J. E. Dalen Upper and Lower Respiratory Disease, edited by J. Corren, A. Togias, and J. Bousquet Pharmacotherapy in Chronic Obstructive Pulmonary Disease, edited by B. R. Celli Acute Exacerbations of Chronic Obstructive Pulmonary Disease, edited by N. M. Siafakas, N. R. Anthonisen, and D. Georgopoulos Lung Volume Reduction Surgery for Emphysema, edited by H. E. Fessler, J. J. Reilly, Jr., and D. J. Sugarbaker Idiopathic Pulmonary Fibrosis, edited by J. P. Lynch III Pleural Disease, edited by D. Bouro´s Oxygen/Nitrogen Radicals: Lung Injury and Disease, edited by V. Vallyathan, V. Castranova, and X. Shi Therapy for Mucus-Clearance Disorders, edited by B. K. Rubin and C. P. van der Schans Interventional Pulmonary Medicine, edited by J. F. Beamis, Jr., P. N. Mathur, and A. C. Mehta Lung Development and Regeneration, edited by D. J. Massaro, G. Massaro, and P. Chambon Long-Term Intervention in Chronic Obstructive Pulmonary Disease, edited by R. Pauwels, D. S. Postma, and S. T. Weiss Sleep Deprivation: Basic Science, Physiology, and Behavior, edited by Clete A. Kushida Sleep Deprivation: Clinical Issues, Pharmacology, and Sleep Loss Effects, edited by Clete A. Kushida Pneumocystis Pneumonia: Third Edition, Revised and Expanded, edited by P. D. Walzer and M. Cushion Asthma Prevention, edited by William W. Busse and Robert F. Lemanske, Jr. Lung Injury: Mechanisms, Pathophysiology, and Therapy, edited by Robert H. Notter, Jacob Finkelstein, and Bruce Holm Ion Channels in the Pulmonary Vasculature, edited by Jason X.-J. Yuan Chronic Obstructive Pulmonary Disease: Cellular and Molecular Mechanisms, edited by Peter J. Barnes Pediatric Nasal and Sinus Disorders, edited by Tania Sih and Peter A. R. Clement Functional Lung Imaging, edited by David Lipson and Edwin van Beek Lung Surfactant Function and Disorder, edited by Kaushik Nag
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Pharmacology and Pathophysiology of the Control of Breathing, edited by Denham S. Ward, Albert Dahan and Luc J. Teppema Molecular Imaging of the Lungs, edited by Daniel Schuster and Timothy Blackwell Air Pollutants and the Respiratory Tract: Second Edition, edited by W. Michael Foster and Daniel L. Costa Acute and Chronic Cough, edited by Anthony E. Redington and Alyn H. Morice Severe Pneumonia, edited by Michael S. Niederman Monitoring Asthma, edited by Peter G. Gibson Dyspnea: Mechanisms, Measurement, and Management, Second Edition, edited by Donald A. Mahler and Denis E. O’Donnell Childhood Asthma, edited by Stanley J. Szefler and Sfren Pedersen Sarcoidosis, edited by Robert Baughman Tropical Lung Disease, Second Edition, edited by Om Sharma Pharmacotherapy of Asthma, edited by James T. Li Practical Pulmonary and Critical Care Medicine: Respiratory Failure, edited by Zab Mosenifar and Guy W. Soo Hoo Practical Pulmonary and Critical Care Medicine: Disease Management, edited by Zab Mosenifar and Guy W. Soo Hoo Ventilator-Induced Lung Injury, edited by Didier Dreyfuss, Georges Saumon, and Rolf D. Hubmayr Bronchial Vascular Remodeling In Asthma and COPD, edited by Aili Lazaar Lung and Heart–Lung Transplantation, edited by Joseph P. Lynch III and David J. Ross Genetics of Asthma and Chronic Obstructive Pulmonary Disease, edited by Dirkje S. Postma and Scott T. Weiss Reichman and Hershfield’s Tuberculosis: A Comprehensive, International Approach, Third Edition (in two parts), edited by Mario C. Raviglione Narcolepsy and Hypersomnia, edited by Claudio Bassetti, Michel Billiard, and Emmanuel Mignot Inhalation Aerosols: Physical and Biological Basis for Therapy, Second Edition, edited by Anthony J. Hickey Clinical Management of Chronic Obstructive Pulmonary Disease, Second Edition, edited by Stephen I. Rennard, Roberto Rodrı´guez-Roisin, Ge´rard Huchon, and Nicolas Roche Sleep in Children, Second Edition: Developmental Changes in Sleep Patterns, edited by Carole L. Marcus, John L. Carroll, David F. Donnelly, and Gerald M. Loughlin Sleep and Breathing in Children, Second Edition: Developmental Changes in Breathing During Sleep, edited by Carole L. Marcus, John L. Carroll, David F. Donnelly, and Gerald M. Loughlin
The opinions expressed in these volumes do not necessarily represent the views of the National Institutes of Health.
Sleep in Children Second Edition Developmental Changes in Sleep Patterns
Edited by
Carole L. Marcus
University of Pennsylvania School of Medicine Philadelphia, Pennsylvania, USA
John L. Carroll
University of Arkansas for Medical Sciences Little Rock, Arkansas, USA
David F. Donnelly
Yale University School of Medicine New Haven, Connecticut, USA
Gerald M. Loughlin
Weill Medical College of Cornell University New York, New York, USA
Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 # 2008 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-4200-6080-5 (Hardcover) International Standard Book Number-13: 978-1-4200-6080-5 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a notfor-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Sleep in children : developmental changes in sleep patterns / edited by Carole Marcus . . . [et al.]. —2nd ed. p. ; cm. — (Lung biology in health and disease ; v. 223-) Includes bibliographical references and index. ISBN-13: 978-1-4200-6080-5 (hardcover : alk. paper) ISBN-10: 1-4200-6080-5 (hardcover : alk. paper) 1. Sleep. 2. Children—Sleep. 3. Respiratory insufficiency in children. I. Marcus, Carole L. II. Series. [DNLM: 1. Sleep—physiology. 2. Child Development—physiology. 3. Child. 4. Respiration. 5. Sleep Disorders—physiopathology. W1 LU62 v.223- 2008 / WL 108 S6115 2008] QP425.S662 2008 612.8’21083—dc22 2007035094 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 16th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com
Introduction
Sleep is the only medicine that gives me ease. Sophocles (496–406 BC), Philoctetes Philoctetes, a play written and presented by Sophocles in 409 BC, is based on the adventures, or rather misadventures, of the hero Philoctetes, who was the son of the mythological king of Thessaly. He had been deported by the Greeks on an island where he suffered physically and psychologically. It is while commenting on his fate that he stated, “Sleep is the only medicine that gives me ease.” Of course, at that time, no one knew much about the biology of sleep, but it appears that it was already recognized that (good) sleep is an effective regulator of many biological and mental functions. Today, sleep research and sleep medicine have clearly demonstrated that sleep is a determinant of good health. Impaired or disordered sleep is associated with numerous conditions, some quite serious like sleep apnea and/or hypertension, among others. We have learned that infants, children, and adolescents are, as adults, affected by sleep disorders; this is a critical problem because physiological and mental functions develop during the early years of life. The younger the age, the more the sleep required. We also have learned that adolescents of school age will be at risk of learning, health, behavioral, and mood impairments if they do not have enough sleep (8 to 9.5 hours) or if their sleep is disordered. At the same time, we have also learned through extensive research that sleep is a complex process and that sleep patterns evolve during the years of physical growth and maturation. In addition, during these years, many physiological functions develop—respiratory, circulatory, and endocrine. In 2000, the series of monographs Lung Biology in Health and Disease introduced a volume titled Sleep and Breathing in Children. The editors, Drs. Gerald M. Loughlin, John L. Carroll, and Carole L. Marcus, aimed to emphasize the importance of the interactions of sleep and breathing during the developmental journey from infancy to adolescence. The authors and editors underscored the need for further research to understand and
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Introduction
hopefully to eventually correct the disordered patterns of sleep and breathing in early life so that these disorders would not spill into, and worsen, during adult life. Since then, a considerable amount of research has been done and our knowledge on the development of sleep and breathing and the relationship— perhaps interdependency—between these two functions has markedly increased. Thus, it is with thanks and gratitude that the series of monographs Lung Biology in Health and Disease welcomes the publication of this new volume, Sleep in Children: Developmental Changes in Sleep Patterns. Although the title is partly similar to that of the Loughlin et al. volume, the scope of the two volumes is very different. This current edition is in two volumes; one focuses on developmental changes in sleep patterns and the other on developmental changes in breathing during sleep. The editors of this new monograph, Drs. Carole L. Marcus, John Carroll, David Donnelly, and Gerald Loughlin, have reached out to experts from several countries and institutions to present a complete state of our current knowledge. The readership of these volumes will undoubtedly be stimulated by the new developments presented by the authors and will appreciate that it brings us closer to helping infants and children suffering from disordered sleep and breathing. As the executive editor of this series of monographs, I am thankful for their valuable contribution. Claude Lenfant, M.D. Gaithersburg, Maryland, U.S.A.
Foreword
Human infants at birth spend more time asleep than awake, but for a long time limited attention was given to the sleep of children. Interestingly, it was while observing sleeping infants that Aserinski and Kleitman (1) noticed periods of sleep characterized by bursts of eye movements with seemingly half-opened eyes. These researchers decided to place electrodes and monitor eye movements. This experiment lead to the discovery of two types of eye movements during sleep, one fast and the other slow, with the fast eye movements occurring episodically several times during sleep. William C. Dement (2), a student in the Kleitman laboratory, continued the work started by Aserinski and placed EEG electrodes alongside the eye electrodes to investigate infant sleep, thus discovering REM sleep in humans. During such monitoring, it was noted that bursts of rapid eye movements were associated with irregular breathing and short respiratory pauses. The question arose: why? Was control of vital functions different during periods of wake and sleep? Much work has been done since these discoveries in the mid-1950s. We have a better understanding of the physiology of sleep and the mechanisms that underlie the two different sleep states. We have also integrated sleep and wake within the 24-hour cycle, which led, for example, to distinguishing hormones whose secretory patterns are circadian dependent from those that are sleep dependent, such as growth hormone. We have deciphered differences in the control of some vital functions, such as the dependence of respiratory rhythm on central chemosensitivity during slow wave sleep (the “quiet sleep” of infants). We have begun to understand the mechanism behind congenital central hypoventilation syndrome. Our progress in understanding the mechanisms underlying sleep and wakefulness and in understanding the progressive “buildup” of sleep during the nocturnal period has led to better approaches to sleep-related disorders, as well as better diagnostics and treatment options. I recall an occasion in 1972 (3) when I had to tell the mother of a 12-year-old girl who had failed to improve following adenotonsillectomy that the only treatment available for her newly diagnosed obstructive sleep apnea syndrome (OSAS) was a tracheostomy. I also recall the joy of
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Foreword
mother and daughter in the fall of 1981 when I contacted them to indicate that there was a potential new treatment, developed in Australia, called “nasal continuous positive airway pressure” (CPAP) (4). Colin Sullivan sent one of his technicians to show us how to make a mask by hand, but it was a young craniofacial otolaryngologist, Nelson Powell, who helped us pull things together. We used a homemade CPAP device made by a small firm in South San Francisco that could probably have powered a small motorcycle. Carleen, since my encounter with her in 1972, underwent every treatment advance for OSAS and finally became free of medical care after a maxillomandibular advancement. Another patient, a three-year-old boy, at first misdiagnosed with atonic seizures due to his “drop attacks,” still requires one or two short naps daily despite modafinil and sodium oxybate. Despite his narcolepsy-cataplexy syndrome, he completed his Ph.D. this year, but vigilantly watches his food intake to avoid losing the battle of inappropriate weight gain. The discovery that narcolepsy-cataplexy was related to the destruction of hypocretin/orexin neurons located in the lateral hypothalamus, as predicted by Von Economo (5) in the mid-1920s, has allowed both a better understanding of the different clinical features of the syndrome and better treatment of symptoms. Pediatric sleep medicine is an integral part of pediatrics. All children sleep, and sleep mechanisms may trigger or worsen many disorders seen in daily pediatric practice. Difficulty falling asleep, sleep terrors, sleepwalking, and enuresis are common complaints, but so are problems associated with sleep disorders such as nasal allergies, enlarged adenoids and tonsils, difficulties in school, attention deficit hyperactivity disorder, and even orthodontic treatment. When to recommend adenotonsillectomy or to avoid nocturnal headgear as an orthodontic treatment? Sleep medicine is young, and we do not necessarily have all the answers, but we have much to contribute. We can respond better to the needs of children with a better understanding of issues and problems associated with pediatric sleep medicine. Medical students rotating through pediatric departments should be exposed to the basics of sleep medicine, and all pediatricians should be exposed to it during their residency. This book has many chapters authored by experts on the subject, and it contains important information for all health professionals dealing with children. The different chapters with their many vignettes and well-constructed bibliographies will help in responding to questions from parents and their children. It will be helpful to many in their regular practice, and not simply to those interested in pediatric sleep medicine. Christian Guilleminault, M.D., D.M., Biol.D. Stanford University Palo Alto, California, U.S.A.
Foreword
vii
References 1. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 1953; 118:273,274. 2. Dement WC, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electroencephalogr Clin Neurophysiol 1957; 9:673–690. 3. Guilleminault C, Dement WC, Monod N. Mort Subite du Nourrisson, apne´e lors du sommeil: nouvelle hypothe`se. Nouv Presse Med 1973; 2:1355–1358. 4. Sullivan CE, Issa FG, Berthon-Jones M, et al. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; 1:862–865. 5. Von Economo C. Sleep as a problem of localization. J Nerv Men Dis 1930; 71: 249–259.
Preface
Depending on age, infants and children spend one- to two-thirds of their life asleep. Despite this, very little attention was paid until recently to understanding both normal sleep and sleep-related abnormalities during development. However, the last few years have seen burgeoning research and publications in this area. Important developments have occurred in the field since the publication of the first edition of this book in 2000. Thus, the book has been totally revised. The basis of the book remains rigorously conducted scientific research. The chapters have been authored by an international group of outstanding scientists. As several clinical pediatric sleep books have been published since the first edition of this book, we have shifted the focus of the book away from some of the more clinically oriented chapters toward developmental physiology. In addition, we have divided the book into two volumes to accommodate the increased amount of literature that is now available. One volume concentrates on sleep alone, and the other on breathing during sleep. It should be noted, however, that not all chapters could be so neatly categorized, and thus the two volumes are synergistic. This volume is devoted to sleep per se, and its changes with development. There are profound changes in sleep and circadian rhythm during growth and maturation. Sleep is particularly important in children because of its putative role in consolidating memory and other neurocognitive functions, and the parents of a young child can easily describe the effects of sleep deprivation. This volume covers normal changes in sleep during development, important behavioral aspects of sleep, cultural effects on sleep, and nonrespiratory sleep-related disorders. The concluding section reviews new techniques that are currently being used in sleep-related research. The success of the book depends, of course, on the quality of the individual contributors. We therefore want to thank the many authors who have contributed to the book. They are all leaders in the field and, as such, have many demands on their time. Nevertheless, as the reader will appreciate, they have devoted time and energy into writing outstanding chapters.
ix
Preface
x
We would like to dedicate this book to the children and families who have willingly participated in sleep research experiments. Without them, this book would not exist. We thank Mary Anne Cornaglia for her invaluable assistance with the book preparation. Carole L. Marcus John L. Carroll David F. Donnelly Gerald M. Loughlin
Contributors
Candice A. Alfano Children’s National Medical Center, The George Washington University School of Medicine, Washington, D.C., U.S.A. Kristin T. Avis University of Alabama Birmingham, Birmingham, Alabama, U.S.A. Jules Verne University of Picardy, Amiens, France
Ve´ronique Bach
University of Cincinnati College of Medicine, Cincinnati,
Dean W. Beebe Ohio, U.S.A.
University La Sapienza, Rome, Italy
Oliviero Bruni
Mary A. Carskadon Warren Alpert Medical School of Brown University, Providence, Rhode Island, U.S.A. Jules Verne University of Picardy, Amiens, France
Karen Chardon
Lilia Curzi-Dascalova
INSERM U 676, Paris, France
Patricia Franco Pediatric Sleep Unit, Hôpital Debrousse and INSERM U 628, University of Lyon 1, Lyon, France Lee T. Gettler
University of Notre Dame, Notre Dame, Indiana, U.S.A.
Fiorenza Giganti
University of Florence, Florence, Italy
Jose´ Groswasser University Children Hospital Reine Fabiola, Free University of Brussels, Brussels, Belgium Ronald M. Harper David Geffen School of Medicine, UCLA, Los Angeles, California, U.S.A.
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Contributors
Susan Higgins Pediatric Sleep Unit, Hôpital Debrousse and INSERM U 628, University of Lyon 1, Lyon, France Ineko Kato
Nagoya City University, Nagoya, Japan
Suresh Kotagal
Mayo Clinic, Rochester, Minnesota, U.S.A.
Rajesh Kumar David Geffen School of Medicine, UCLA, Los Angeles, California, U.S.A. Daniel S. Lewin Children’s National Medical Center, The George Washington University School of Medicine, Washington, D.C., U.S.A. Jean-Pierre Libert Jian-Sheng Lin
Jules Verne University of Picardy, Amiens, France
INSERM U 628, University of Lyon 1, Lyon, France
Gerald M. Loughlin Weill Medical College of Cornell University, New York, New York, U.S.A. Paul M. Macey David Geffen School of Medicine, UCLA, Los Angeles, California, U.S.A. Thornton B. A. Mason II The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A. James J. McKenna U.S.A.
University of Notre Dame, Notre Dame, Indiana,
Jodi A. Mindell St. Joseph’s University, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A. Enza Montemitro Allan I. Pack
Universita di Roma “La Sapienza”, Rome, Italy
University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
Aude Raoux Pediatric Sleep Unit, Hôpital Debrousse and INSERM U 628, University of Lyon 1, Lyon, France Avi Sadeh The Adler Center for Research in Child Development and Psychopathology, Department of Psychology, Tel Aviv University, Tel Aviv, Israel Piero Salzarulo
University of Florence, Florence, Italy
Contributors
xiii
Sonia Scaillet University Children Hospital Reine Fabiola, Free University of Brussels, Brussels, Belgium Mark S. Scher
Case Western Reserve University, Cleveland, Ohio, U.S.A.
Arthur S. Walters New Jersey Neuroscience Institute, Seton Hall University School of Graduate Medical Education, Edison, New Jersey, U.S.A. Marco Zucconi Sleep Disorders Centre, Department of Neurology, H San Raffaele Institute, Milan, Italy
Contents
Introduction Claude Lenfant . . . . . . . . iii Foreword Christian Guilleminault . . . . . v Preface . . . . . . . . . . . . . . . . . . . . . . . . . ix Contributors . . . . . . . . . . . . . . . . . . . . . . xi 1.
2.
Neurophysiological Basis and Behavior of Early Sleep Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lilia Curzi-Dascalova, Fiorenza Giganti, and Piero Salzarulo I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. General Principles of Sleep-Wake Control . . . . . . . . . . . . III. Sleep Development During Early Ontogenesis: Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Development of Behavioral States During Human Ontogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . V. The Development of Sleep-Wake Rhythm . . . . . . . . . . . VI. Early Sleep-Wake Regulation . . . . . . . . . . . . . . . . . . . . VII. Awakening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ontogeny of EEG Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mark S. Scher I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Caveats Concerning Neurophysiologic Interpretation of State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. General Comments on Recording Techniques and Instrumentation for Neonates and Infants . . . . . . . . . . . IV. Maturation of Electrographic Patterns in the Neonate . . V. Midline Theta/Alpha Activity ................... VI. Maturation of Noncerebral Physiologic Behaviors That Define State in the Preterm Infant . . . . . . . . . . . . VII. Assessment of State Organization in the Full-Term Infant VIII. Sleep Ontogenesis—State Maturation from Fetal Through Infancy Periods . . . . . . . . . . . . . . . . . . . . . . IX. Ontogeny of Autonomic Behaviors During Sleep . . . . . .
xv
1 1 2 6 11 22 24 24 27 39 39 40 41 42 46 47 50 54 57
xvi
Contents X. Brain Adaptation to Stress as Reflected in Sleep Reorganization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI. Computer-Assisted Analyses of EEG Sleep Organization in Neonates and Infants . . . . . . . . . . . . . . XII. Sleep Ontogenesis and Neural Plasticity . . . . . . . . . . . . XIII. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.
4.
5.
Maturation of Sleep Patterns During Infancy and Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Avi Sadeh I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Consolidation of Nocturnal Sleep . . . . . . . . . . . . . . . . . III. Sleep Onset and Sleep Duration . . . . . . . . . . . . . . . . . . IV. Sleep State Organization . . . . . . . . . . . . . . . . . . . . . . . V. Factors Influencing Sleep Maturation . . . . . . . . . . . . . . VI. Maturation of Sleep and Cognitive Function in Children . . VII. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maturation of Processes Regulating Sleep in Adolescents Mary A. Carskadon I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Circadian Timing System . . . . . . . . . . . . . . . . . . III. Sleep-Wake Homeostasis (Process S) . . . . . . . . . IV. A Model Relating These Processes to the Adolescent Sleep Delay . . . . . . . . . . . . . . . . . . . V. What About Young Adults? . . . . . . . . . . . . . . . . VI. Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .
....
60 61 64 66 66 77 77 78 79 81 83 85 87 87 95
. . . . . 95 . . . . . 98 . . . . 102 . . . .
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Characteristics of Arousal Mechanisms from Sleep in Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patricia Franco, Ineko Kato, Enza Montemitro, Jose´ Groswasser, Sonia Scaillet, Susan Higgins, Aude Raoux, and Jian-Sheng Lin I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. The Hierarchy of the Arousal Process ............ III. Definitions and Scoring Methodologies . . . . . . . . . . . . IV. The Determination of Arousal Thresholds . . . . . . . . . . V. Factors Influencing Arousability . . . . . . . . . . . . . . . . . VI. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
105 106 107 108 115 115 116 117 120 120 128 128
Contents 6.
7.
8.
9.
Thermoregulation During Sleep in Infants: A Functional Interaction with Respiration . . . . . . . . . . . . . . Jean-Pierre Libert, Karen Chardon, and Ve´ronique Bach I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Neonatal Thermoregulation . . . . . . . . . . . . . . . . . . . . III. Sleep and Thermoregulation ................... IV. Sleep, Thermoregulation, and Respiration . . . . . . . . . . V. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behavioral Influences on Sleep in Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kristin T. Avis and Jodi A. Mindell I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Infants, Toddlers, and School-Aged Children ....... III. Adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cultural Influences on Infant and Childhood Sleep Biology, and the Science That Studies It: Toward a More Inclusive Paradigm II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James J. McKenna and Lee T. Gettler I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Culture and Childhood Sleep . . . . . . . . . . . . . . . . . . . III. Conventional Western Understandings of “Healthy, Normal” Infant and Childhood Sleep: Where Did They Come From? Is One Form of Sleep as Good as Any Other? . . . . . . . . . . . . . . . . . . . . . . . . . IV. Infant-Parent or Child Cosleeping: “The Political Third Rail?” Why So Controversial? . . . . . . . . . . . . . . V. Conclusions/Recommendations/Afterthoughts—Getting Mothers and Infants Together for Nighttime Sleep and Breast-feeding: Still Crazy After All These Years . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pediatric Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thornton B. A. Mason II and Allan I. Pack I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Disorders of Arousal from NREM Sleep . . . . . . . . . . . III. Parasomnias Usually Associated with REM Sleep . . . .
xvii
135 135 137 144 150 153 154
159 159 159 168 175 175
183 183 185
192 205 210 215 223 223 223 229
xviii
Contents IV. Other Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.
11.
12.
233 238
...........................
243
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. . . . . . . .
243 244 244 249 251 254 256 257
Sleep in Children with Neurologic Disease .............. Marco Zucconi and Oliviero Bruni I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Sleep in Children with Pervasive Developmental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Sleep in Other Forms of Mental Retardation . . . . . . . . IV. Nocturnal Frontal Lobe Epilepsy and Abnormal Motor Behaviors of Epileptic Origin: Differentiation from Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Neuromuscular Diseases . . . . . . . . . . . . . . . . . . . . . . VII. Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. Use of Melatonin in Children with Neurologic Disorders ........................ References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
261
Narcolepsy in Childhood Suresh Kotagal I. Introduction . . . . II. Epidemiology . . . III. Pathophysiology . IV. Clinical Features . V. Diagnosis . . . . . . VI. Management ... VII. Conclusions . . . . References . . . . .
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Sleep and Psychiatric Disorders in Children: A Complex Reciprocal Relationship . . . . . . . . . . . . . . . . . . . Daniel S. Lewin and Candice A. Alfano I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Sleep and Anxiety Disorders . . . . . . . . . . . . . . . . . . . III. Sleep and Depression . . . . . . . . . . . . . . . . . . . . . . . . IV. Sleep and ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Sleep and Developmental Disorders . . . . . . . . . . . . . . VI. Case Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
261 262 264 268 274 276 278 280 282 285 297 297 299 301 303 305 306 310 310
Contents 13.
14.
15.
16.
Restless Legs Syndrome and Periodic Limb Movements in Sleep in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arthur S. Walters I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Epidemiology of Adult and Childhood RLS ........ III. Essential Clinical Features of Adult RLS .......... IV. Nonessential Features of Adult Restless Legs Syndrome ...................... V. Essential Clinical Criteria for Childhood RLS . . . . . . . VI. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Relationship of Childhood RLS to Growing Pains . . . . VIII. Relationship of Childhood RLS to ADHD . . . . . . . . . . IX. Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . X. Treatment of Restless Legs and Periodic Limb Movements of Sleep in Children . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastroesophageal Reflux During Sleep . . . . . . . . . . . . . . . . . Gerald M. Loughlin I. Sleep, Gastroesophageal Function and Dysfunction . . . II. Sleep-Related Clinical Manifestations of GER . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assessing Neurobehavioral Outcomes in Childhood Sleep-Disordered Breathing: A Primer for Nonneuropsychologists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dean W. Beebe I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Psychometric Terms . . . . . . . . . . . . . . . . . . . . . . . . . III. Psychometric Issues in Child Assessment . . . . . . . . . . IV. The State of the Field Circa 2006 ............... V. Concluding Comments ....................... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural and Functional Magnetic Resonance Imaging as a Research Tool in Pediatric Sleep Research . . . . . . . . . . . Ronald M. Harper, Paul M. Macey, and Rajesh Kumar I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Structural Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . III. Functional Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Analytic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . V. Physiological Data Acquisition . . . . . . . . . . . . . . . . . .
xix
317 317 318 319 319 321 322 323 324 326 329 330 335 335 338 341
345 345 346 354 360 363 363 367 367 367 373 375 378
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Contents VI. Movement Control . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Imaging Resources and Shared Access . . . . . . . . . . . . VIII. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Index . . . . 385
379 379 380 380
1 Neurophysiological Basis and Behavior of Early Sleep Development
LILIA CURZI-DASCALOVA INSERM U 676, Paris, France
FIORENZA GIGANTI and PIERO SALZARULO University of Florence, Florence, Italy
I.
Introduction
Behavioral states [namely, wakefulness, slow-wave or non–rapid eye movement sleep (NREM), and paradoxical or rapid eye movement (REM) sleep] in infants are one of the most remarkable functions of the central nervous system (CNS) and good indicators of normal or abnormal development. Behavioral states are constellations of physiological and behavioral variables that become stable over time and occur repeatedly in all infants (1). Consequently, changes in these variables as state development progresses can be discussed only in reference to age-specific modulations in sleep parameter concordance. Since the landmark descriptions of cyclic modifications of respiratory, motor, and EEG behaviors in sleeping infants (2,3), it is well known that states of vigilance modulate vital functions. The concept of states has made it possible to group movements and physiological parameters into definable entities, whose gradual organization during nervous system maturation can be studied (4–6). This chapter is limited to a general discussion of the developmental aspects of the neurophysiological basis of sleep. Autonomic functions (respiration and cardiovascular control), development of the rest-activity cycle, thermoregulation, and 1
2
Curzi-Dascalova et al.
endocrine factors, which are all closely linked to states, will be discussed in other chapters. After briefly reviewing the CNS structures involved in states control and their development, we will discuss available data on wakefulness and sleep states during development from the fetal period to early childhood. Developmental studies of sleep-wake patterns are of utmost importance. They contribute to the understanding of CNS maturation and function and may provide answers to many fundamental, but still unsettled, questions regarding the functional role(s) of sleep. II.
General Principles of Sleep-Wake Control
Sleep is a coordinated process involving simultaneous or quasi-simultaneous changes in sensory, motor, autonomic, hormonal, and cerebral processes. The control mechanisms of these changes are manifested at every level of biological organization, from genes and intracellular mechanisms to networks of cell populations and the entire CNS (7). Sleep is controlled by mutually inhibitory or excitatory interactions between arousing or activating systems on the one hand and hypnogenic or deactivating systems on the other. However, none of the changes occurring with sleep are exclusively coupled with sleep (8). The main three behavioral states, i.e., wakefulness, NREM, and REM sleep, all obey these principles, although they are known to be each controlled by specific mechanisms. Sleep and waking states are produced by the activity of excitatory and inhibitory neurons located in several brainstem and forebrain centers, which are organized into ‘‘systems’’ or ‘‘networks,’’ each of which is responsible for controlling a given state. Figure 1 shows the main brain structures involved in sleep-wake regulation. In general, the occurrence of each sleep state involves two neuronal networks. One, the ‘‘executive’’ network, is responsible for sleep phenomenology (each state-characteristic phenomenon may depend on a specific network). The other, called the ‘‘permissive’’ network, triggers sleep (7–12). Neurochemical mechanisms underlie the neuronal and receptor functions involved in sleep. As with the first described cholinergic and aminergic neurons, many other neurotransmitter systems modulate the REM-NREM oscillator and may interact with aminergic and cholinergic control (13–16). The regulation of sleep is considered a dual interaction of circadian and homeostatic processes, which are explained later. Whereas the nature of the sleep homeostat remains partially unclear, a detailed model of a genetically controlled suprachiasmatic cell has been established, especially in mammalians. Genes transcribe and translate to proteins shortly after certain neurons became active. They are reliably involved in 24-hour rhythmicity and in state-dependent processes (17,18). Recent studies suggest that clock genes directly influence sleep states and are implicated in sleep disorders (18,19). Sleep interacts with immune and endocrine systems (20,21) and facilitates memory consolidation (22,23). REM and NREM sleep have been unambiguously identified in mammals and birds (8).
Neurophysiological Basis and Behavior of Early Sleep Development
3
Figure 1 Diagram of the main brain structures involved in behavioral states control. Abbreviations: NREM, non–rapid eye movement; REM, rapid eye movement; EEG, electroencephalogram. Source: From Refs. 7, 9–11.
A.
REM Sleep
Since the historical investigations of Dement, from N. Kleitman’s laboratory (24), and Jouvet (13), REM sleep, also called ‘‘paradoxical’’ sleep, is the beststudied sleep pattern. It is the first state that is developed during ontogenesis. REM sleep can be understood as the result of interactions between an executive network and a permissive network (12). Converging data suggest that reticular neurons in the pons and spinal cord play a key role in REM sleep regulation. Jouvet and coworkers devised a model in which the executive REM system includes REM-on neurons specific to each of the REM parameters (12,13). In adult humans and animals, REM sleep is associated with muscular atony, pontogeniculo-occipital (PGO) spikes, rapid eye movements, small facial movements, and cortical activation with a paradoxical wakefulness-like electroencephalogram (EEG) pattern. The characteristic signs of REM sleep are further modulated at different CNS levels (7,16). The REM-on system would work as a pacemaker if it were isolated, i.e., it is continuously active when the inhibitory
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systems are not functional. Cessation of aminergic REM-off system firing lifts the inhibition of REM-on neurons, thus ‘‘permitting’’ the REM-on executive system to function. In addition, REM sleep is characterized by sympathetic activation (irregular heart rate and increased blood pressure, respiratory rate, and pupil diameter), as well as by augmented metabolism and oxygen consumption. Its duration may depend on the size of available energy stores (25). It is considered the (nonexclusive) state of dreaming. B.
NREM Sleep
NREM sleep lacks the visible motility of rapid eye movements and twitches. In human adults, it is divided into stages 1 through 4, defined by a slowing of brain EEG waves and an increase in the arousal threshold. NREM stages 3–4 are also named slow-wave sleep (SWS). The term SWS is frequently used to indicate NREM sleep in animals. NREM is the consequence of the inhibition of one or more of the influences that produce arousal (see sec. II.D). Similar to REM sleep, NREM sleep may involve an executive system and a permissive system. Activity of the executive NREM sleep system is identified on the basis of only two criteria, namely, sleep spindles and slow high-voltage EEG activity. Sleep spindles are produced mainly by the thalamic reticular nucleus. Slow ‘‘synchronized’’ electrical activity has been found at various cortical and subcortical levels; however, the slow-wave characteristic of NREM sleep is strongly dependent on the integrity of the neocortex and results from pyramidal cell hyperpolarization. An isolated thalamic reticular nucleus continues to exhibit rhythmic oscillations, suggesting that it acts as a pacemaker subject to inhibitory influences from the permissive system (26). The inhibitory SWS system includes neurons responsive to acetylcholine (mesencephalo-pontine nuclei and basal forebrain), histamine (posterior hypothalamus), and noradrenaline (locus coeruleus). Many aspects of the SWS system are under thermoregulatory control. SWS is characterized by a high parasympathetic tone and a decrease in general metabolism and body temperature, accompanied by the augmented synthesis of brain proteins and replenishment of energetic reserves to prepare for subsequent waking and REM sleep (22). C.
Between-Sleep State Transition
Transition between NREM and REM sleep consists in more or less progressive changes in the constellation of characteristics of the preceding state to those of the ongoing state. Although sleep during transitions between NREM and REM sleep exhibits features of both main states, it is described as an independent, individualized mode of CNS functioning. The duration and the order of sleep parameter modifications during the switch from REM to NREM sleep, and vice versa, depend on the variables taken into consideration and the age (27). Transitional sleep (TS) is probably present in mammals in general and has been
Neurophysiological Basis and Behavior of Early Sleep Development
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linked to the activity seen in cerveau isole´ preparations (28). TS was first studied in the 1960s and 1970s (29). Work conducted more recently has demonstrated a variety of more or less progressive changes in neurotransmitter release during TS (30). Studies of TS have shown modifications in neuron activation at various CNS levels in animals (30,31), in autonomic nervous system control of vital functions (32), in the threshold of excitability (28), and in mental content as assessed by dream analysis (33). A recent study by Brandenberger et al. (21) demonstrates that in human adults, the autonomic and hormonal background of sleep state 2 (an NREM state) is characterized by a ‘‘quiet’’ period preparing slow-wave NREM sleep and an ‘‘active’’ period preceding REM sleep. Transition between sleep states in early human ontogenesis will be discussed in section IV.B. D.
Waking and Sleep Onset Promotion
Waking results from the conjunction of sleep inhibition with generalized neuronal activation. (34). It is mainly characterized by cortical activation (lowamplitude, fast EEG) and by behavioral arousal (movements and high postural muscles tonus). Wakefulness is supported by multiple, partially redundant neuronal systems that use different neurotransmitters, among these noradrenaline, histamine, and orexin (8,16). Investigations related to the recent identification of orexin (also known as hypochretin), a wakefulness-promoting peptide, denotes once more the role of gene expression in signaling systems that are subjected to behavioral states (18). The waking network is activated by endogenous and exogenous stimuli (Fig. 2). Sleep inhibition seems to be produced by systems specific to each of these states (7,34). Sleep-promoting neurons, mainly GABAergic, have been described in brainstem, thalamus, basal forebrain, and preoptic area. An anti-waking system is probably located in the anterior hypothalamus, an area also involved in the control of many vital functions (thermoregulation, reproduction, etc.). The antiwaking system may integrate information about the general condition of the body and the size of energy stores; sleep onset may be a preventive mechanism influenced by circadian rhythms controlled by biological clocks (7,22). Advances in biochemical techniques made during the last 20 years have led to intensive research, the results of which support the hypothesis that the awake brain produces diffusible ‘‘sleep-promoting substances’’ that induce sleep (14,18). Several such substances have been identified (see chap. 4 on hormonal control of sleep). Several models of the process involved in circadian wake-sleep regulation have been developed. Two of these models can be applied to the development of sleep characteristics during early human ontogenesis. The two-process model constructed by Achermann et al. (35) on the basis of EEG slow-wave activity emphasizes interactions between circadian (C) and homeostatic (S) processes and will be discussed below in section VI.
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Figure 2 Diagram of the sleep-waking regulation. This diagram presents five neuronal networks: waking, NREM sleep, REM sleep, anti-waking, and biological clock. The main known neuromediators are indicated by abbreviations (underlined). Note the anti-waking (sleep onset) is triggered by 5-HT, an element of the waking system. Abbreviations: NREM, non–rapid eye movement; REM, rapid eye movement; NA, noradrenalin; Ach, acetylcholine; ORX, orexin/hypocretin; 5-HT, serotonin; HA, histamine; GLU, glutamate; GABA, gamma-amino-butyric acid; GLY, glycine. Source: From Ref. 34.
Finally, many investigations suggest that wake-sleep alternation, as well as nearly all the functions of the organism, are modulated by a ‘‘clock’’ in the suprachiasmatic nuclei of the hypothalamus. In mammalians, the circadian oscillator is based on an intracellular molecular feedback loop involving time-ofday-dependent gene transcription, protein synthesis, and the suppression of transcription by the protein products of the genes that have been transcribed. At birth, circadian sleep-wake rhythms are fundamentally different as compared with those in adulthood. Maturation of circadian rhythms in humans is discussed below (see sec. V). III.
Sleep Development During Early Ontogenesis: Animal Studies
States are defined by the cyclic concordance of certain specific patterns of physiological variables, including cerebral electrical activity (EEG), motor activity, autonomic functions, and behavior. The neural structure underlying each of these variables must reach a certain degree of development before the corresponding state can appear. Behavioral states are present before birth. Data regarding prenatal morphological and neurochemical development of the main cerebral structures (Fig. 1) involved in sleep control are scant and fragmentary. The degree of brain structure maturity at a given prenatal or early postnatal age varies in different animal species. In any case, the relationship between structural
Neurophysiological Basis and Behavior of Early Sleep Development
7
maturation and function is complex and nonlinear. The relationship between brain structural maturation and sleep may be bidirectional. Many studies have implicated active, REM sleep as having an important role in some brain area development. In general, active (REM) sleep has been more extensively studied than quiet (NREM) sleep. A.
Development of Brain Structures Involved in Sleep Control
In macaque monkeys, the neurons in the cerebral cortex and all other cerebral structures except the cerebellum and hippocampus are present before E100 (E, days of gestation) of the 165-day gestational period. The neurons in the locus coeruleus, raphe nuclei, and basal forebrain nuclei are generated before E50. However, axon overproduction and elimination continue until birth, and synapse density continues to increase (in the cortex) between birth and two months of age (with a peak between two and four months). Synapse density declines during the next three years, and the total number of neurons (in the visual cortex) is 16% higher in newborn than in adult animals. In humans, the cerebral cortex neurons are produced between E40 and E125 of the 265-day gestation (36,37), and studies of the visual cortex found that synapse density peaked between 8 and 12 months after birth, reaching a level about 60% greater than that in adults (38). Cortical neurons are generated from E14 to E20 in rats (21 days of gestation) and from E30 to E57 in cats (65 days of gestation). Thus, generation of cortical neurons occurs at an earlier gestational age (GA) in primates than in rodents and cats (37). Circadian timing systems develop prenatally, and the suprachiasmatic nuclei, the site of circadian clock, are present by midgestation in primates (39). Although the development of the cholinergic and monoaminergic neurotransmitters involved in sleep control begins prenatally, it continues in a significant measure during the first postnatal months in all the species studied. A developmental decrease of REM sleep between 12 and 21 days of age in rats is accompanied by an important hypertrophy of cholinergic cells in the pedunculopontine nucleus at 15 to 16 days, followed by a decrease by 20 to 21 days (40) and development of choline acetyltransferase activity in rat laterodorsal tegmental nucleus (41). Development time curves for neurotransmitters vary from one neurotransmitter to the next and from one brain region to the next. Receptor concentrations sometimes increase at a rate that exceeds the capacity of the neurons to produce their neurotransmitters. The regions that mature earliest are usually the medulla and pons, followed by the midbrain, thalamus, and hypothalamus and then by the cerebral cortex and striatum (42). This pattern reflects the earlier neurogenesis of the caudal as opposed to the rostral part of the brain. Data have been reported on the ontogenesis in the brain of neuropeptides that may be sleep factors. Somatostatin (SRIF), known to promote REM sleep (43), is detectable in the macaque cortex at E120, i.e., after completion of neuron generation and migration. SRIF levels increase prenatally, reaching a peak around birth, and in adults are only 15–30% of those at birth. Similar increases
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between E100 and near term have been observed in baboons, but there was no subsequent decline during adulthood. Vasoactive intestinal peptide (VIP) enhances both NREM and REM sleep in rats and selectively increases REM sleep in cats. This neuropeptide, which is widely distributed in the mammalian nervous system, influences cell division, neuronal survival, and neurodifferentiation (44). VIP is detectable in the cortex of primates at E120, and its levels increase 4- to 11-fold between E120 and near term; in adults, VIP levels in the various cortical regions are only 5–9% of those found at birth (37). Cholecystokinin (CCK-8) may promote NREM sleep, especially postprandial sleep. In the human brain, high levels of CCK have been found in several cortical areas, in the hypothalamus, and in the cerebellum. In the cortex of nonhuman primates, CCK immunoreactive cells colocalize with GABA cells. In macaques, CCK is detectable at E120 and increases sharply until E165 and then decreases in adulthood. In rat cortex, CCK concentrations seem to increase gradually during ontogenesis. Delta-sleep-inducing peptide (DSIP) has been detected in fetal guinea pig hypothalamus at E38 (37). Neuropeptide Y (NPY), known to produce behavioral signs of sedation and significant EEG synchronization (45), is also one of the most abundant peptides in the cerebral cortex of mammalians. NPY levels in baboon visual cortex have been studied throughout ontogenesis and found to increase gradually between E100 and adulthood. In contrast, the number of NPY immunopositive cells decrease in macaque visual cortex between E110 and adulthood (37). Orexin/hypocretin expression studied in rat increases from postnatal day 1 to adulthood (46). Developmental changes of orexin/hypocretin and their receptors are complex, specific to each area of the rat hypothalamus (47). All these substances act as neurotransmitters or neuromodulators in the developing brain and have been studied chiefly in the cortex. The fact that they are all detectable during embryonic life suggests that they might be functional before birth. However, data on correlations between neurotransmitter, neuropeptide and protein ontogenesis, and intrauterine fetal behavior are currently lacking. A behavioral state effect on cerebral metabolic rate has been described in ovine fetus near term. The REM state is characterized by an increase in oxygen and glucose uptake, compared with that of the NREM state (48). Czikk et al. (49) found that cerebral leucine uptake significantly increases during the high-voltage electrocortical/NREM state in the same ovine fetus near term. Sleep in early life may play a crucial role in brain development (50). REM sleep deprivation in adolescent rats disrupts the maturational processes that underlie developmental synaptic plasticity (51) and the balance between inhibitory and excitatory mechanisms in the visual cortex (52). REM-deprived rats aged 7 to 14 days showed significant decreases in brain mass and stained positively for programmed cell death. It is well established that myelination starts in the spinal cord and then progresses to the brainstem and forebrain. Thus, REM sleep mechanisms located in the brainstem are the first to mature and be ready to function (53).
Neurophysiological Basis and Behavior of Early Sleep Development B.
9
Development of Behavioral States in Animals
Distinct behavioral states have been described in chronically instrumented fetuses. In guinea pig fetuses, Astic et al. (54) recorded paradoxical sleep beyond 41 days of gestation, with a peak at 50 days of gestation, i.e., at the time of the first appearance of SWS. Paradoxical (REM) sleep then decreased until birth (65 days of gestation), while SWS increased. The timing of the fetal sleep cycle was not correlated with that of the maternal sleep cycle. REM and NREM states were found in lambs between 120 and 140 days of gestation (normal length of gestation, 150 days) (48, 49, 55–58). In a study using rest-activity and heart rate evaluation, Belich et al. (59) documented the cyclic occurrence of three states in rabbit fetuses beyond 25 days of gestation. Two distinct EEG states have been described in baboon fetuses recorded from 143 to 153 days of gestation (normal length of gestation, 175 to 185 days). State 1 (quiet sleep) was distinguishable from state 2 (active sleep) based on the presence of ‘‘trace´ alternant.’’ Epoch duration was shorter in state 1 than in state 2, and a smaller percentage of time was spent in state 1 than in state 2 (60). Several studies starting in the early 1960s found that newborn animals exhibited a number of different behavioral states, which were first identified on the basis of the intensity and pattern of motor activity (61). Behavioral observation and polysomnographic recording in chronically implanted kittens and rat pups showed that three main behavioral states were recognizable during the first few days of life. These states were designated (1) wakefulness (defined by moving and eating behavior), (2) quiet sleep (short periods of quiescence), and (3) active, or paradoxical, seismic REM sleep characterized by neck muscle atony, rapid eye movements, and generalized ‘‘seismic’’ movements. In these species characterized by marked immaturity at birth, EEG findings were similar in all three states (62–64). In contrast, in guinea pigs and sheep, whose brain is relatively mature at birth, the characteristics of the three main states, including EEG patterns, were similar during the first days of life and in adulthood (63,65). Active and quiet sleep, defined on the basis of the concordance of the electrocorticogram, electrooculogram (EOG), and nuchal electromyogram (EMG), were found in preterm lambs born at 133 to 135 days of gestation. Compared with full-term lambs (147 days of gestation), the preterm lambs spent more time in active, REM sleep (66). In rats and cats, the establishment of adult-like EEG characteristics of quiet sleep occurs around the third week of life and may be facilitated by weaning (63,67). However, some earlier data suggested that brain electrical oscillations characteristic of sleep states occurred in pups with relatively immature brain (57,68,69). Finding sleep state characteristics may depend on methods of parameter detection as well as on environmental conditions during recording and behavior observation (69–71). In spite of the presence of epochs with an opposition between the main REM-NREM characteristics (muscle tonus, rapid eye movements, body movement aspects), some authors do not accept that the REM-NREM epochs (in animals) during infancy are near similar to REM and NREM sleep in adulthood. On the basis of the lesions of anterior raphe nuclei, locus coeruleus, and nucleus
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subcoeruleus, Adrien et al. (72) concluded that monoaminergic systems are not involved in sleep control at birth in cats and rats. Three hypotheses have been put forward to explain some of the data obtained by the authors and some from the literature demonstrating sleep state characteristics in earlier ontogenesis: (1) The few (10%) remaining terminals may be sufficient to trigger and maintain NREM sleep and, to some extent, REM sleep. (2) Sleep maturation in immature mammals may occur via nonmonoaminergic mechanisms. (3) Active sleep may be different from adult REM sleep, including in terms of its underlying mechanisms (72,73). A study by Frank et al., based on the effect of REM sleep-inhibiting drugs in neonatal rats (74), supports the last hypothesis. In a series of recent controversial articles, these authors have named sleep in the early postnatal period as presleep and argued that ‘‘presleep is not a homolog of REM sleep and instead represents a common precursor to REM and NREM sleep’’ (75). Numerous older and recent data from the literature demonstrate that REM sleep occupies a larger proportion of time in newborns than in adults. The rate of age-related modifications in states depends on the degree of maturation at birth (Fig. 3). During the first days of life, REM sleep contributes to most of the total
Figure 3 Percentage of behavioral states during the first month of life (chronic polygraphic studies) in rat pups and kittens (immature brain at birth) and guinea pig (mature brain at birth) between 1 and 28 days of life. Abbreviations: Discont, discontinuous; EEG, electroencephalogram; SWS, slow-wave sleep, NREM sleep, non–rapid eye movement sleep; W, wakefulness; REM, rapid eye movements sleep; FT, full-term newborn; d, age in days. Source: From Ref. 76.
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sleep time in animals with very immature brains at birth (e.g., rats) versus 15–20% in guinea pigs. The amount of REM sleep declines during the first three weeks of life (5,77,78). However, at three weeks of age, the amount of REM sleep in kittens, rat pups, and guinea pig pups remains twice that in adult animals (63). REM sleep in rats continues to decline between 23 and 40 days of age (79). In conclusion, the first steps of the differentiation of behavioral states seem dependent on the degree of brain maturation; in several species characterized by greater brain maturity at birth, concordance between REM and NREM state characteristics may be established during fetal life or during the first few days after birth. Interestingly, starting very early during animal and human ontogenesis, the control of vital functions during active sleep is very similar to that during REM sleep in adults (6). EEG characteristics and time spent in different sleep states continue to mature progressively between birth and puberty. The mechanisms involved in the regulation of the main states during early ontogenesis in animals remain controversial. IV.
Development of Behavioral States During Human Ontogenesis
A. Fetal Life
The perception of cyclic fetal movements, an experience that evokes a strong emotional response in many mothers, is one of oldest criteria for assessing fetal well-being. Historically, the gathering of knowledge on fetal behavior has been dependent on advances in techniques and ethical considerations related to the study of fetuses. Prechtl (80) has described the history of fetal states assessment in great detail. Advances in real-time ultrasonography made since 1980 have demonstrated that the human fetus exhibits behavioral states that are similar to those in neonates. Estimates of the time of the first appearance of behavioral states in utero have varied according to the parameter and state scoring method used. Using continuous observation and fetal heart rate recording, Prechtl and coworkers defined four fetal behavioral states: (1) F1, characterized by a slow regular heart beat, with startles but no eye movements; (2) 2F, with an irregular heartbeat, eye movements, and occasional gross body movements; (3) 3F, with a fast regular heart rate and eye movements but no body movements; and (4) 4F, with a fast irregular heart rate, eye movements, and continual body movements (80). The first studies by Prechtl and coworkers found evidence of behavioral state development in human fetuses between 36 and 38 weeks GA (81). However, Visser et al. (82) reported correlations between heart rate, eye movement, and gross body movement patterns in normal fetuses at 30 to 32 weeks GA. In a study involving the simultaneous use of three real-time ultrasound scanners, Okai et al. (83) documented stable periods of REM and NREM of more than three minutes’ duration between 28 and 31 weeks GA and also found a strong correlation between the occurrence of rapid eye movements and breathing movements after 27 weeks GA.
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Fetal behavior is characterized by state-specific patterns of complex motor activity (80) and by ‘‘breathing’’ movements that occur mainly during state 2F or REM sleep. Interestingly, thoracic and abdominal fetal respiratory movements usually occur out of phase during state 2F, a characteristic also found during active sleep in newborns (6,84,85). Fetal states are independent of maternal behavioral states (86). Groom et al. (87) studied 30 low-risk fetuses at 38 to 40 weeks GA and again at about 2 weeks postnatal age. Behavioral states were assigned similarly on the basis of the HR pattern and the presence or absence of eye and gross body movements. The proportions of active, quiet, and indeterminate sleep were virtually identical in fetuses and neonates. Studies involving monitoring of fetal EEG activity and heart rate variability recording in healthy fetuses during normal labor demonstrated two alternating sleep states identical to those observed in newborns (88,89). Prolonged real-time ultrasonography is now avoided. On the basis of previous fetal state classification, some more recent studies bring new arguments on the influence of different fetal behavioral states on fetal cerebral hemodynamic patterns (90,91). In conclusion, the bulk of data shows that differentiated behavioral states appear in utero early during the third trimester of gestation. Fetal states are similar to those observed in newborns of the same postconceptional age, as far as criteria possible to monitor in fetuses are considered (see sec. IV.B). B.
Early Postnatal Ontogenesis: From Premature to Full-Term Newborns
The pioneers of behavioral state studies in newborns, including Roffwarg (92), Dreyfus-Brisac (93), Monod et al. (94), Parmelee (95), Prechtl (96), Wolff and Farber (97), and Anders et al. (98), have argued from the outset that specific terms were needed to designate states in newborns because EEG and behavioral characteristics differed between adults and newborns. On the basis of the results of polysomnography studies, they agreed to distinguish two major sleep states in early infancy, namely, active sleep (state 2) and quiet sleep (state 1), to which they subsequently added indeterminate (undifferentiated) sleep. As befitted careful neurophysiologists, they defined the main state-related modifications of various parameters and used combinations of several of these parameters to define states. Thus, whereas the classification of sleep states in adults was developed solely on the basis of EEG patterns (99), polygraphic recording became the gold standard for state classification and developmental physiology studies in neonates. However, attempts at state classification based on a single parameter (movement or heart rate) have also been made (100). Successful polysomnography in newborns requires that a number of technical criteria be met (70): (1) the person in charge of the recording be trained in neonatal care; (2) the data be interpreted by a person conversant with agerelated EEG characteristics in premature and full-term newborns (70,101,102);
Neurophysiological Basis and Behavior of Early Sleep Development
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Figure 4 Example of digitized recordings in a 34-week PCA, healthy premature baby. Abbreviations: w, week; HE, PCA, postconceptional age; EEG, electroencephalogram; LEOG, left electrooculogram; REOG, right electrooculogram; Eye, eye movements recorded using a piezo transducer (sleep watch, respironics); O1C3 and O2C4, EEG recordings; CHIN, chin electromyograph; ECG, electrocardiogram; RR, cardiotachography based on instantaneous heart-rate measurement; FLW, nasobuccal airflow detected by thermistors; THO and ABD, thoracic and abdominal respiratory movements detected by strain gauges); RHM and ACTI1, right hand and left leg movements, respectively, detected by a piezo transducer and a commercial (Alice 4) actimeter; SaO2, oxygen saturation; sec, time in seconds; QS, quiet sleep, characterized by both a discontinuous EEG pattern and absence of eye movements; AS, active sleep characterized by a continuous EEG pattern and presence of rapid eye movements (observed and better detected by piezo recording); IS, indeterminate sleep (similar to that observed during transition between AS and QS in either direction), with a continuous EEG pattern but no rapid eye movements). Source: From Ref. 70.
(3) piezoelectric transducers rather than EOG be used for eye movement detection because of the very low amplitude of retino-corneal electrical potential differences in neonates (Fig. 4); (4) chin EMG recording may be unsuccessful because of the possibility of low amplitude activity at this level; (5) extremely lightweight transducers be used for leg movement detection. Use of recording methods that are not suited to newborns causes errors in sleep state identification. When the technician is experienced in neonatal polysomnography, the baby usually falls asleep before the end of electrode placement. Sleep state scoring data are dependent on a number of methodological factors, including (1) the nature of the variables chosen for state definition (Fig. 4, Table 1), (2) whether or not the characteristics of these variables are quantified
Discont.
AS
Cont.: DþY, or D, or semidiscont.
þ
State
EEG
Eye movements
Regular or irregular
þ/ (20%)
þþ (5.2%)
þþþ (20%)
þþþ (22%)
Irregular
AS
35–36
þþ (7%)
þ/ (20%)
Regular or irregular
QS
þþþ (22%)
Irregular
AS
37–38
Discont. or semidiscont.
Cont.: DþY, or D þþ
QS
AS
35–36
þþ (10%)
þ/ (20%)
Regular or irregular
QS
þþþ
Cont.: Y, or, DþY or D
AS
37–41
þþ (14%)
Irregular
AS
39–41
þ (3%)
þ/ (20%)
Regular or irregular
QS
Trace´ alternant
QS
Some authors (100) used variable/nonvariable heart rate as a state criterion; however, no quantified data are available. Note that about 20% of quiet sleep is spent with inhibited tonic chin EMG. Body movements decrease in amount with age. The number of pluses is a relative indication of eye or body movement density. For irregular respiration definition and amount, see Ref. 70. a No quantitative data available for younger infants. b In parentheses: percentage of 20 seconds spent with this parameter. Abbreviations: PCA, postconceptional age, calculated from the first day of the last menstrual period; Cont., continuous EEG trace; Discont., discontinuous EEG trace; D, delta EEG activity; Y, theta EEG activity. Source: From Ref. 70.
Body movements
b
Tonic chin EMGb
Respiratory rate
QS
Irregular
AS
State
a
31–34a
PCA in wk
(B) Ancillary Variables for Sleep State Scoring
QS
27–34a
PCA in wk
(A) Major Variables for Sleep State Scoring
Table 1 Summary of the Major Variables and Ancillary Variables That Have Been Used for Sleep State Scoring at Various Conceptional Ages
14 Curzi-Dascalova et al.
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or scored on the basis of their general ‘‘gestalt’’ aspect (e.g., what is regular vs. irregular breathing), (3) the minimum duration used to define the state, (4) the predefined duration of parameter discrepancies that can be kept within the ongoing state (state smoothing), (5) the criteria used to define the onset of a given state, and (6) the criteria used to define termination of a given state. Although scoring is done epoch by epoch, the stability of concordance between parameters throughout successive epochs of the major states (wakefulness and crying, active sleep, quiet sleep) is required before a recording period can be assigned to a given state. The onset of a major state is defined as the presence of the corresponding constellation of state-specific criteria for one minute (103,104), three minutes (96,100), or four minutes (4). Discrepancies among parameters lasting less than 60 seconds are included within the state (70,103,105), whereas a longer-lasting discrepancy (>60 seconds) or occurrence of a constellation specific to another state defines termination of the state. Periods with discrepancies between the main state criteria are scored as undifferentiated or indeterminate or ambiguous sleep. Transitional sleep (TS) (27,103) is the term used to designate periods of transition from one main state to another; its duration can be less than 60 seconds Table 1 summarizes the main and secondary criteria used to define active and quiet sleep in newborns. In addition to the consensual active sleep versus quiet sleep concept (98), many authors use the classification developed in the late 1960s by Prechtl and coworkers in full-term newborns. This classification, which does not use the EEG pattern as a state criterion, distinguishes five behavioral states (1,96) as follows: (1) state 1, eyes closed, regular respiration, no movements; (2) state 2, eyes closed, irregular respiration, no gross movements; (3) state 3, eyes open, no gross movements; (4) state 4, eyes open, gross movements, no crying; and (5) state 5, eyes open or closed, crying. The basic procedure for recording and scoring behavioral states is the same whether a chart polygraph or a computerized data acquisition system is used. For references on the computerized method for state parameter analysis in newborns, see the studies by Scher et al. (106) and chapter 2, ‘‘Ontogeny of EEG Sleep,’’ in this book. Periods of active and quiet sleep of more than three minutes’ duration, defined on the basis of concordance between EEG and REM criteria, exist in neurologically normal premature newborns of more than 27 (105) or 28 weeks PCA (107), although marked inter- and intraindividual differences occur. On the basis of REMs versus the presence of EEG discontinuity scoring, Vecchierini et al. (108) and Scher et al. (109) recently found sleep state cyclicity for a majority of neonates between 25 and 30 weeks GA. In premature babies, active sleep and quiet sleep are characterized by striking differences in EEG activity [continuous in active sleep vs. discontinuous in quiet sleep (Fig. 4)] and rapid eye movements (present in active sleep and absent in quiet sleep). Over time, slow-wave burst duration increases slightly and the amplitude of background EEG activity between the slow-wave bursts on discontinuous tracings steps up significantly,
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Figure 5 Duration in minutes (min) of between-sleep state transitions in 35 premature babies of 30–36 week post-conceptional age. AS and QS have been defined by the concordance between REMs and EEG criteria (See Fig. 4 for state definition). Abbreviations: AS, active sleep; QS, quiet sleep; REMs, rapid eye movements; EEG, electroencephalogram. Source: From Ref. 27.
finally producing the trace´ alternant pattern characteristic of quiet sleep near normal term (101,110). During the first postterm few weeks of life, the trace´ alternant pattern is replaced by a slow-wave high-voltage pattern (111–114). Between 30 and 36 weeks PCA, the duration of active to quiet sleep transition is significantly longer than the quiet to active transition, independent of GA (Fig. 5). The sequence of modification in parameters is invariable: REM cessation is the first change in active to quiet sleep transition, and REM appearance is the last change in quiet to active transition (27). Monod et al. (103) described a complex pattern of between-state transition in full-term newborns using chin EMG and body movement parameters in addition to EEG recording (103). Between 27 and 34 weeks PCA, indeterminate sleep contributes a mean of 30% of the total sleep time. Indeterminate sleep is defined on the basis of discordance between the two main criteria defining active and quiet sleep. Indeterminate sleep diminishes significantly at 35 to 36 weeks PCA and then remains stable until term (104). Beyond 31 to 34 weeks PCA, a significantly larger percentage of time is spent in active than in quiet sleep (104,105). Near term, 55–65% of the sleep time is spent in active sleep versus about 20% in quiet sleep (Fig. 6). The duration of sleep states can vary widely across successive sleep cycles in a given infant (70,109). In contrast to adults, premature and full-term newborns fall asleep in active sleep. The first active sleep period, following a period of wakefulness, is usually characterized by a shorter duration and a slower EEG
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Figure 6 Percentage of the total sleep time spent in active, REM sleep; quiet, NREM sleep; and IS. (Left) Daytime sleep in newborns from 27 to 41 w GA. (Right) Nighttime sleep in infants from 1 to 24 m of postnatal age. The data on NREM sleep from the study by Louis et al. (117) include the amount of St 2–4, and the data on IS are the sum of IS and St 1, according to the state scoring system developed by Retchtschaffen and Kales (99). Abbreviations: EEG, electroencephalogram; REM, rapid eye movement; NREM, non– rapid eye movement; PNA, postnatal age; IS, indeterminate sleep; AS, active sleep; St 1, state 1; St 2–4, states 2 to 4; GA, gestational age; w, week, m, month. Source: Adapted from Refs. 103, 104 (left) and from Ref. 115 for 1- to 6-month-old infants and from Refs. 116 and 117 for 9- to 24-month-old infants (right).
pattern compared with the next active sleep period, occurring after a quiet sleep period. Sleep cycles, defined as an active sleep and a quiet sleep period with the interpolated indeterminate sleep period, are shorter before 35 weeks GA, with a mean duration of 45 to 50 minutes according to the study. From 35 to 36 weeks GA to term, the sleep cycle duration is about 55 to 65 minutes (Fig. 7), which is similar to that observed during the first few months of life (104,105,116). Artificial ventilation per se does not modify sleep structure in premature babies who are neurologically normal and clinically stable (105,107,109). Sleep organization is unaffected by maintenance-dose caffeine in 33 to 34 weeks PCA in premature infants (119). Bertelle et al. (120) found that the Neonatal Individualized Developmental Care Assessment Program (NIDCAP), as described by Als et al. (121), promoted sleep duration and sleep stability in the neonate. Data and review of the literature (122) did not confirm the influence of some NIDCAP element on sleep in preterm infants. Sleep organization in premature
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Figure 7 Mean sleep cycle duration in minutes at different ages. Data from different laboratories are connected by a dark line. (Left): Daytime sleep in newborns from 27 to 41 weeks PCA or GA. (Right): Nighttime sleep in infants from 1.5 to 24 m of PNA and in children aged about 5 y. Abbreviations: PCA, postconceptional age; GA, gestational age; PNA, postnatal age; m, months; y, years. Source: Adapted from Refs. 104, 105 (left); Refs. 117, 118 (right).
babies reaching normal term (123,124) and in full-term, small-for-GA newborns (125) does not differ from that observed in full-term controls. In general, both in the literature and in our own experience, sleep state differentiation was documented earlier during ontogenesis in studies performed after the 1980s (104,107,126,127) than in those done previously (96,128). This differentiation is probably ascribable to the improvements made in neonatal care in industrialized countries during the last few decades. In conclusion, differentiated active sleep and quiet sleep are observed starting at 27 weeks PCA in neurologically normal and clinically stable premature infants, concordance between REMs and specific EEG patterns being observed beyond 25 weeks PCA. Until 34 weeks PCA, about 30% of the sleep time is spent in indeterminate sleep. Beyond 35 to 36 weeks GA, indeterminate sleep decreases significantly and sleep structure becomes very similar to that observed during the first month of postterm life. Thus, 27 weeks and 35 to 36 weeks PCA appear as turning points in the ontogenesis of human sleep (Fig. 6, Table 2). Knowledge of early state differentiation is important because (1) a number of physiological parameters are correlated to sleep states in young babies (6,85,129,130) and (2) a number of abnormalities in newborns occur primarily in one or the other of the two main sleep states (abnormal respiratory events are more common during active sleep, whereas EEG abnormalities are more readily detected during quiet sleep).
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Table 2 Main Steps in Sleep-Wake Maturation Sleep-wake cycle
Sleep structure
Ultradian rhythm during the fetal period and first days of life
Emergence of AS/QS at 27-wk gestational age AS increases, IS decreases; cycle duration increases (40–45 to 55–60 min) at 34–35 wk gestational age Emergence of sleep spindles between 1.5 and 3 mo Significant decrease in REM sleep with concomitant increase in NREM sleep: emergence of stages 1, 2 and 3, 4 between 3 and 5 mo Disappearance of REM sleep onset from 3 to 9 mo Nycthemeral organization of SWS and REM sleep between 9 and 12 mo Lengthening of the sleep cycle to adult level between 2 and 6 yr
Emergence of circadian rhythmicity during the first weeks of life (free running cycle of 25 hr)
Entrainment to 24-hr cycle after 3 mo Consolidation of nocturnal sleep from 6 mo of age Disappearance of naps between 3 and 6 yr of life
Abbreviations: AS, active sleep; QS, quiet sleep; IS, indeterminate sleep; REM, rapid eye movement; NREM, non–rapid eye movement; SWS, slow-wave sleep.
C.
The First Year of Life
After the first month of postnatal life, the global amount of sleep as well as of different sleep states show evident changes (Table 2). Studies aimed to trace the development of sleep states in the first year of life based on 24-hour polygraphic recordings (117, 131–134) showed that the global amount of sleep decreases with age, that quiet sleep increases, and that active sleep and indeterminate or ambiguous sleep decrease (Fig. 6). In particular, the global amount of sleep decreases from about 13 hours at term age to 10 hours at the end of the first year of life, quiet sleep increases from about 5 hours to about 7 hours, and active and indeterminate sleep decrease, respectively, from about 5 hours to about 1.5 hours and from about 3 hours to about 1 hour (Fig. 8). A distinct development occurs between day and night periods. The reduction of active sleep during the 24-hour period is mainly due to the decrease of the active sleep episodes during the day, whereas the global amount during the night does not change. On the contrary, the global amount of quiet sleep slightly decreases during the day, while markedly increasing during the night because of the increase of the mean duration of the phases. As far as indeterminate sleep is concerned (Fig. 6), a decreasing trend with age, with no particular distribution across 24-hour periods (131), is observed. The almost complete disappearance of
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Figure 8 Waking and sleep states amounts in the 24-hour period according to the age. Abbreviations: W, waking; QS, quiet sleep; PS, paradoxical sleep or REM, rapid eye movement sleep; Amb S, ambiguous sleep or IS, indeterminate sleep. Source: From Ref. 131.
this form of sleep at the end of the first year of life is an expression of the progressive maturation of the CNS (131). In addition, the reduction of indeterminate sleep also has an impact on the increasing organization of the sleep episode. Indeed, a study (135) analyzing the internal structure of the sleep cycle (i.e., the quiet sleep–active sleep sequence) during the first year of life showed an increase with age of the mean duration of the cycles because of the presence of slow-wave sleep within quiet sleep episodes and the near disappearance of indeterminate sleep within the cycle, whereas the proportion of active sleep did not change. The lengthening of sleep cycles during the second semester of life (Fig. 7) and the decrease in sleep ‘‘out of the cycle’’ lead to the increased proportion of total time spent in cycle (TCT) on total sleep time (TST) (135). During the first 12 months of age, the distribution of sleep states across the night changes, approaching what is observed in the adult. From 4 months of age the longer quiet sleep episodes tend to be located in the first part of the night, whereas at 12 months active sleep in the last part of the night is not yet prevalent. Indeed, the active sleep amount does not change with age in any epochs of the nocturnal period, and in the second semester of life the longest active sleep episodes are not yet located at the end of the night (131). Although features of quiet sleep develop later than that of active sleep (136), quiet sleep reaches the adult-like night distribution before active sleep.
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Across early epochs of postnatal life, some turning points in steps of sleep development can be underscored. During the second month, the trace´ alternant disappears (111,112,137) and spindles take place (138–140), the burst density of eye movements reaches a plateau level (141), and the difference of the heart rate values between quiet sleep and active sleep becomes more evident (142,143). Around the fifth month, the duration and the structure of quiet sleep episodes (144) become similar to those of the adult. The increase in duration does not involve all quiet sleep episodes, but mainly those containing slow-wave activity (145), which is present in alternating episodes of quiet sleep with a periodicity of about 100 minutes. At this epoch of life, two different periodicities exist within sleep episodes (144): one related to the sleep state cycle every 50 minutes, and the other related to the slow EEG activity that appears every 100 minutes. To summarize the main sleep modifications that occur during the first 12 months of life, at the end of the first year infant sleep acquires new modalities of functioning and new phenomena and loses some others. In particular, the sleep features are more and more similar to those of the adult, with nocturnal sleep composed of one or two episodes and few diurnal naps composed mainly of NREM sleep. As in adult sleep, SWS is more prevalent during the first part of the night and the eye movement activity within REM episodes is organized in bursts. D.
From Two to Five Years
Polygraphic studies analyzing sleep modification after two years of life are rare (117,146). In particular, 24-hour home polygraphic recordings of sleep in infants, observed longitudinally from 3 to 24 months, showed, at 2 years of life, a further reduction of REM sleep during the diurnal period, with sleep episodes essentially composed of SWS. As far as the nocturnal period is concerned, a significant increase in sleep efficiency and in the length of the REM period was reported, whereas the total sleep time and number of awakenings decreased (Fig. 9). A recent longitudinal study (147) analyzing sleep throughout actigraphy, in infants from 3 months to 3 years of life, reported a well-organized sleep by 12 months and a progressive increase with age in sleep continuity and in sleep efficiency, without a significant difference between boys and girls. In particular, the analysis of motor activity during sleep revealed a moderate stability of body motility across time. The sleep onset and sleep duration instability across time found by the authors could, instead, reflect the sensibility of sleep schedules and parental interventions. On the contrary, the discontinuity of the number of awakenings reported in this period of age probably reflects sleep maturational changes. Modifications in sleep parameters were also observed at later ages. In a recent study, Acebo and colleagues (148), investigating sleep-wake patterns from actigraphy recordings and maternal reports in healthy children aged one to five years, reported that 12-month-old infants had the earliest start of bedtime, the longest time in bed, and the longest sleep duration. In contrast, rise time, sleep end time, and nocturnal sleep (an average of 8.7 hour at night) were stable
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Figure 9 Evolution with age of the different behavioral stages as percentages of total 24-hour home recordings. Diurnal (left) and nocturnal (right) periods were defined based on the light-off and light-on times given by the parents. Note that waking and REM sleep are negatively correlated, especially during the daytime. Abbreviations: IS, indeterminate sleep; St 1, state 1 of NREM sleep; St 2, State 2 of NREM sleep; SWS, slow-wave sleep; REM, rapid eye movement; TRT, total recorder time; m, post-term age in months, NREM, non–rapid eye movement. Source: From Ref. 117.
across ages. Mother reports underestimate night wake time and night wake episodes, reporting lower values than those observed with actigraphy recordings. The same study showed that children of families with low socioeconomic status get up later, remain longer in bed, and have more night awakenings and higher night-to-night variability than children of families with high socioeconomic status. V.
The Development of Sleep-Wake Rhythm
Although the circadian pacemaker is probably functional in the fetal period (149–151), circadian rhythmicities are scarcely developed in the newborns. At birth, several physiological and behavioral variables show ultradian rhythms (152–158) that become longer during the first months of life. Many factors seem to be involved in the entrainment of circadian rhythmicity. The maternal influence has been shown to be involved in the fetal circadian rhythmicity of heart rate (159), whereas in the newborn, external factors such as light-dark alternation (160–162) and care practices (163,164) seem to influence the time of establishment of a circadian modulation of several physiological and behavioral variables.
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In neonates observed in the first months of life, short sleep and waking episodes alternate across the 24-hour period (158,165). Daytime sleep episode lengths assessed by behavioral observations vary between 20 and 40 minutes (166). The duration of sleep episodes measured by polygraphic recordings are shown in Figure 7. The uninterrupted period of waking lasts about 7 minutes, with an interindividual range between 3 and 21 minutes (166). During the first months of life, sleep polygraphic recordings across 24 hours showed numerous sleep episodes that tend to be longer during the nocturnal period (132). On the contrary, by one month of age, periods of prolonged wakefulness are preferentially located in the early evening hours (165,167,168). It is interesting to note that the development of monophasic sleep-wake rhythm in infants is paralleled by the difficulty in falling asleep in a delimited period of 24 hours. This phenomenon, which Lavie (169) has previously shown in the adult, has been recently also observed in preterm (170) and full-term infants across the first year of life (171). The occurrence at very early ages of a peak of wakefulness in the night for preterm infants and in the evening for full-term infants (corresponding to the time of lowest sleep propensity in the adult) looks like an example of the precocious mechanism that regulates the temporal distribution of sleep and waking. By three to four months of age, the entrainment of sleep-wake rhythm to the 24-hour cycle emerges (165,167,168). The duration of longest sustained sleep increases with age and is mainly located during the night (172), whereas the longest sustained waking is mainly located during the day (165). The longest sustained sleep period increases progressively from about 3.5 hours at 3 months to 6 hours at 6 months. Also, the longest sustained waking period increases from about 2 hours at 3 months to 3.5 hours at 6 months (133). Circadian rhythms of heart rate, body movements, body temperature, cortisol, and melatonin are present from the first months of life, and the amplitude of these rhythms increases by three months of age (154,156,173–175). Some of these rhythms could play an important role in the development of the sleep-wake cycle. In particular, the circadian rhythmicity of body temperature observed by Guilleminault et al. (155) from 10 weeks of postnatal age onward could be parallel to the change from a more polyphasic sleep-wake rhythm to a less polyphasic one, as proposed by Giganti and colleagues (193). Also, the melatonin secretion cycle seems to influence the sleep-wake rhythm. In six- to eight-month-old infants, higher melatonin secretion rates during the evening hours were associated with an earlier onset of nocturnal sleep episode, whereas a delayed peak was associated with a more fragmented nocturnal sleep (156). Feeding rhythms have no noticeable impact on sleep-wake rhythms (while they could contribute to reinforce the existing ones), as was demonstrated by the study of infants continuously fed from birth (176,177). On the contrary, feeding rhythm seems important for the circadian rhythmicity of cardiac rate (178).
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Early Sleep-Wake Regulation
Experiments involving manipulation of sleep in the adult, such as sleep deprivation, sleep extension, or shifting of sleep, demonstrate that NREM sleep, and more specifically the intensity of slow-wave sleep, is largely dependent on the duration of the prior wakefulness. This observation suggested the existence of a homeostatic process, designated process S, which becomes more intense as the duration of prior wakefulness increases and less intense as the duration of sleep increases. In the adults, SWS is abundant immediately after sleep onset and recurs during each cycle with decreasing intensity from one cycle to the next (179). In infants, no studies have used the paradigm that evaluates the effect of previous sleep deprivation. However, few studies did attempt to evaluate the time course of slow EEG activity across the sleep episode during the first year of life (180–182). A sketch of a decreasing trend of slow activity was found already at early ages from the second week on (180). Moreover, looking at naturally existing wake episodes of different lengths before a sleep episode, a close relation was found between the duration of waking and the intensity of EEG synchronization, i.e., slow-wave activity (183). This relation is a further argument for an early regulation of the homeostatic nature of the sleep process. The existence of sleep cycles with alternate slow waves in the second semester of life complicates the decreasing trend of SWS (180,184). These results point at also taking into account the basic structure of the sleep on which delta waves are superimposed. An open question is the existence of ‘‘signs’’ of homeostatic control before term age. In conclusion, a sketch of the homeostatic control of sleep can be inferred from the EEG slow-wave trends across the sleep episode observed from the first week of life on. However, to conclude for a true homeostatic control, we would need experiments that manipulate the sleep-wake rhythm and evaluate the effect on EEG activity trends. Also, to conclude about the working of the ‘‘two-process model’’ at early ages, we would need a combined homeostatic and circadian time course of EEG and other physiological variables such as temperature. A second process was considered important, i.e., the circadian one interacting with the process S, to regulate sleep-wake rhythm (179,185). No coexisting data have been collected for babies. Fagioli et al. (186) have proposed a tentative model (Fig. 10). VII.
Awakening
Awakening is an event of special interest for developmental studies, as suggested by both the high frequency in the first epochs of life and its subsequent decline. In addition, an excessive number or duration of awakenings (night waking) is well known in the clinical domain. Quite recently, several papers and meetings have been devoted to this topic (187).
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Figure 10 (Upper panel ): Process S and Process C time course in adults and resulting sleep-wake organisation: waking and sleep resulting respectively from the intersection of declining S process (black) curve and the threshold L (grey, lower sinusoidal curve) and from the intersection of the increasing S process curve and the threshold H (grey, upper sinusoidal curve) are represented by white and black rectangles in the upper part of the figure. (Lower panel ) Process S and C and sleep-wake organization in infants according to the hypotheses. Source: From Refs. 185, 186.
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Awakening (behavioral) should be distinguished from arousal, a term often used as a synonym. Arousal represents the short-lasting activation of the CNS, which is manifested either by the EEG fast activity or by an increase in muscle tonus and body movements; arousal events are often shown in sleep-related respiratory disturbances (187). Physiological mechanisms that precede awakening have been described. The sleep state preceding awakening is mainly REM (active) sleep in infants as well as in young adults (188–190). This result indirectly suggests that similar mechanisms could facilitate the transition from sleep to waking. Similar activation level in active (REM) sleep and waking could facilitate the ‘‘gating’’ role of REM sleep. The analysis of the time course of individual physiological and behavioral activities has shown that awakening is the result of progressive changes. The level of EEG activation increases some minutes before the full behavioral awakening from quiet sleep, but it does not change during active sleep (191). Tach and Ljiowska (192) have reported an increase of motor activity before awakening in infants aged one to six months. More systematic investigation of epochs preceding the awakenings for both quiet sleep and active sleep are needed, starting from preterm infants up to at least the end of the first year of life. A study of the development of awakenings during the 24-hour period in preterm and near-term infants showed that the number of awakenings does not change, but that their mean duration increases significantly (193). The increase is observed mainly during the day and is accounted for by those awakenings starting with crying. At later ages, the awakenings decrease across the first year of life mainly at nighttime (117,132), without any further change in the second year of life (117). The trend toward a decrease in the number of awakenings during the first year of life has been reported by several studies performed during nighttime only (115,189,194,195) (Fig. 11) and parallels the process of nighttime sleep consolidation (134). Where there is a high consistency in the literature concerning the trend with age in the occurrence of awakenings, some discrepancies are observed concerning the developmental trend of awakening duration. As previously suggested by Fagioli et al. (186), the difference in the minimal duration for states’ scoring can explain these results. In particular, according to Hoppenbrouwers et al. (115), the mean duration of awakenings slightly increases with age, whereas Louis et al. (117) and Ficca et al. (189) observed no changes. Only Navelet and coworkers (195), using the longest minimum duration to define the waking state (5 minutes), found an evident decrease with age. The periodicity of awakening is about 100 minutes for those coming from active (REM) sleep across the whole first year of life, but it is greater for those coming from quiet (NREM) sleep, reaching nearly the double (about 200 minutes) from six months onward (186).
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Figure 11 Number of night awakenings (y axis) as a function of age (x axis) reported in five studies. Source: From Ref. 186.
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2 Ontogeny of EEG Sleep MARK S. SCHER Case Western Reserve University, Cleveland, Ohio, U.S.A.
I.
Introduction
Electrographic and polygraphic recordings of newborns and infants have been performed for over half a century (1). Pioneering studies by multiple researchers worldwide offer neurophysiologic information concerning the developing central nervous system (2–9). Earlier investigations predated the creation of the modern neonatal intensive care unit (NICU). However, these seminal works described for the first time electrographic patterns and other physiologic behaviors that define rudimentary state of the preterm neonate, and state maturation with increasing postmenstrual ages (PMAs) to term. Given the higher rate of neonatal mortality, particularly in the premature infant, the clinical neurophysiologist had a more limited consultative role in the neurologic care of the sick neonate. With the creation of the modern-day tertiary care NICU, more sophisticated medical care now includes technological advances in physiologic recordings at bedside. Currently, the neonatal neurologist has a more interactive role as a neurointensive care consultant, combining clinical examination assessments with interpretations of neurophysiologic and neuroimaging studies for the dual purpose of diagnostic and prognostic input for the neonatal intensivist. 39
40
Scher
With the decline of neonatal morbidity and mortality, renewed attention has been directed toward the neurologic performance of the high-risk newborn during both the acute and convalescent periods in the days to weeks after birth. Given the immature clinical repertoire of the newborn and infant, as well as limited access to neonates in a busy intensive care setting, EEG-polygraphic studies can augment the neurologist’s ability to document functional brain maturation as well as the presence and severity of encephalopathic states. Serial EEG-sleep analyses can also have impact on the clinician’s ability to offer appropriate interventional therapies when altered functional brain maturation is detected (i.e., dysmaturity) (10). This degree of monitoring is particularly relevant for the very low-birth weight neonate who carries a substantially long-term risk for neurocognitive and neurobehavioral morbidities (11–15). Quantitative estimates of brain dysmaturity using computer analyses are being refined as research tools to develop objective measures for the detection of pervasive expressions of encephalopathy to better predict outcome (16). Neonatal survivors can then be evaluated after discharge at successively older ages to document continued brain maturation during infancy and later childhood by using serial neurophysiologic analyses. The documentation of maturation of neonatal and infant behaviors requires careful evaluation of both waking and sleep states. Combined neurophysiologic and noncerebral monitoring can more completely assess functional brain maturation throughout the neuraxis. The clinician utilizing skilled visual analyses will be able to apply knowledge of sleep ontogeny to the evaluation of different pediatric populations who are at risk for developmental delay (17), as suggested by altered behaviors during sleep or wakefulness. Computer-assisted analytical tools also augment our abilities to examine physiologic relationships between cerebral and noncerebral measures and to explore associations with neuroimaging, neurogenetic, and neurodevelopmental outcome measures (16,18,19). It has been recently suggested that the extensive but largely phenomenological visual analyses of neonatal EEG-sleep be integrated with computational analyses. This union of investigative techniques by visual and automated strategies can critically evaluate brain organization and maturation in conjunction with future translational and comparative studies related to brain ontogeny (20,21). II.
Caveats Concerning Neurophysiologic Interpretation of State
Knowledge of specific caveats can assist the neurophysiologist in applying an understanding of sleep analysis to developmental assessment from neonatal through infancy periods. Maturational changes on EEG-polygraphic studies are noted at successively older ages after birth, taking into account the weeks of maturity at birth. Recommendations by the American Academy of Pediatrics (22)
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suggest that the term postmenstrual age (PMA) replace the term postconceptional age. Such recommendations emphasize standardized terminology when defining ages and comparing outcomes of fetuses and newborns. Neurophysiologic maturity of a neonate can be estimated within two weeks for the preterm infant (i.e., <37 weeks PMA) and one week for the full-term infant, reflecting the PMA of the infant independent of birth weight. Temporal coincidence or concordance among physiologic sleep behaviors emerges with increasing maturity, similar to fetal behavioral states documented by abdominal sonography. Significant functional reorganization of state occurs at 30, 36, and 48 weeks PMA, reflecting cortical-subcortical neuronal networks that subserve sleep. Finally, serial neurophysiologic studies rather than a single recording accurately document normal ontogeny or the evolution of delayed or abnormal changes representing a brain disorder. Subsequent developmental stages also occur during infancy regarding sleep reorganization, principally after 3, 9, and 12 months of age. The clinician needs to develop a confident style of neurophysiologic pattern recognition and clinical correlation by repetitive experiences with a wide variety of EEG-polygraphic recordings. Before an accurate interpretation can be offered to the referring clinician, knowledge of the child’s PMA and the range of behavioral phenomena that are anticipated at that age are needed; this requires close communication between the electrodiagnostic technologist and the neurophysiologist. Ongoing discussion with the neonatologist may, then, result in continual re-evaluation of the neurophysiologic interpretations within the changing clinical context. III.
General Comments on Recording Techniques and Instrumentation for Neonates and Infants
Appropriate recording techniques will yield high-quality EEG-polygraphic studies. The neurophysiologist should apply a minimum of 10 EEG electrodes in addition to a full complement of noncerebral polygraphic electrodes, given that specific regional and hemispheric electrographic patterns need to be correlated with other noncerebral physiologic behaviors. Placement of electrodes by either paste or collodion must be achieved with ease and efficiency by the technologist, who must always be cognizant of the fragile state of the neonate within the busy NICU environment. While double interelectrode distances may be preferred for the infant of <36 weeks estimated gestational age (EGA) to better visualize electrograhic patterns, a more complete set of electrodes will be advantageous for monitoring the full-term newborn and older infant. While one and two channel screening devices for continuous surveillance have been suggested to recognize global state transitions (23), such bedside screening must be accompanied by full montage EEG-polygraphic studies to better delineate focal, regional, and bihemispheric physiologic behaviors that reflect both gestational maturity and clinical settings for health or disease states (16).
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Adjustments in sensitivity, paper speed, and filter settings will facilitate electrographic/polysomnographic interpretation. Sensitivity settings should begin with standard 7 mV/mm, but may need to be periodically adjusted during the recording. High-pass filter settings between 0.25 and 0.5 Hz are preferred for neonatal recordings, to avoid eliminating commonly occurring slow-frequency waveforms. Slower paper speeds (such as 15 mm/sec) will permit easier visualization of slowly reoccurring normal features, such as EEG discontinuity and asynchrony, or abnormal features, such as seizures and periodic discharges. Adjustment to a lower filter setting of 1 Hz and a paper speed of 30 mm/sec may be preferred for infants after six to eight weeks of age. State-of-the-art digital equipment facilitates these adjustments when viewed offline, following the completion of the study. Motility, cardiorespiratory, and eye movements are essential noncerebral physiologic behaviors to record for sleep analysis. Noncerebral physiologic observations are relevant for both state identification and corroboration of a clinical observation that may have prompted the request for the study. Documentation of transcutaneous PO2 and CO2 may be useful, since ventilatory status can affect brain activities. Sources of artifacts are also readily identified and eliminated with the consistent use of noncerebral channels, supplemented by the technologist’s comments. Frequent and accurate annotations by the technologist throughout the study are strongly advised. Eye opening and eye closure as well as repositioning of the patient’s head are common annotations that are essential for accurate state interpretation and identification of artifacts. Information from the medical records should be recorded by the technologist for the physician’s use regarding the child’s gestational and postmenstrual ages, as well as states of arousal, medications, and medical procedures. Skull defects, vital signs and pertinent laboratory studies should all be described since certain factors may affect neurophysiologic interpretation. IV.
Maturation of Electrographic Patterns in the Neonate
A number of principles should be applied by the neurophysiologist for an accurate visual interpretation of a neonatal EEG-sleep study utilizing a full montage of cerebral and noncerebral measures. The neurophysiologist’s ability to interpret expected age-appropriate neurophysiologic patterns is essential before recognition of encephalopathic features (24). Changes in EEG-polygraphic patterns occur for neonates at increasing PMAs up to term and into early infancy. This discussion complements previous reviews of the assessment of gestational age and neuromaturation that do not discuss EEG sleep measures in detail (25). PMA is calculated simply as the infant’s EGA at birth plus the number of weeks of postnatal life (i.e., EGA at birth plus postnatal age equals PMA in weeks) (22). The neurophysiologist should approximate the electrical maturity of the preterm infant within two weeks of other estimates of maturity, and one week
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for a term infant. Preterm neonates recorded at PMAs up to term will express similar EEG patterns for a child born at that comparable level of maturity; subtle differences may also be expressed because of functional brain adaptation to prematurity, as will be discussed in a subsequent section (i.e., physiologic dysmaturity). Two studies exemplify how neurophysiologic estimates of gestational maturity can be achieved by pattern recognition of EEG-sleep recordings for either healthy or sick preterm cohorts (26,27). Neurophysiologic estimates of maturity were offered even without accurate clinical examination criteria, fetal sonographic data, or other obstetrical information regarding gestational maturity. For both the healthy and sick preterm groups, assessments of neurophysiologic gestational maturity were as accurate as clinical and/or anatomical estimates. Neurophysiologic information can be helpful in problematic situations in which gestational maturity is not accurately assessed by other fetal surveillance methods, particularly with intrauterine growth restriction, those infants who lack accurate information with respect to correct gestational maturity, symptomatic infants who are medically too ill to assess postural tone or levels of arousal for gestational age maturity, or for infants who are too immature to exhibit postural tone, primitive reflexes, or behavioral alterations assigned by standardized scales to accurately estimate neurologic maturity (i.e., children <30 weeks PMA). Regional and hemispheric electrographic patterns for the preterm and full-term neonate will be initially discussed, emphasizing major features at successively older PMAs. Since brain regions also mature in an asymmetric manner in subtle degrees, interpretations of regional cerebral patterns will be helpful. This assumes that a full complement of cerebral and noncerebral measures is recorded. Specific aspects of temporal, spatial, and state organization of EEG-polygraphic recordings are subsequently highlighted, but this brief review should be supplemented by more detailed discussions in standard texts (2,5,7–9,28,29). A.
EEG Discontinuity
Alternating segments of EEG activity and inactivity (i.e., quiescence) commonly occur in preterm neonates, and have been described as EEG discontinuity or trace´ discontinue (30). For the child less than 30 weeks PMA, neonatal recordings consist of predominantly discontinuous EEG patterns. Varying durations of inter-burst intervals define this quiescence and have been described by various authors (31–34). For the healthy preterm infant, an inter-burst interval should follow the “30-20 rule”: an inter-burst interval should not exceed 30 seconds in duration on multiple occasions for the child less than 30 weeks EGA. One report suggested that inter-bursts could be as long as 46 seconds (35), but preexisting prenatal conditions or drugs could have contributed to excessive discontinuity. As the child matures beyond 30 weeks PMA, the inter-burst interval should be less than 20 seconds in duration. Longer periods of EEG
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Figure 1 Segments of EEGs of two preterm infants less than 26-week 5-day-old and 26-week 1-day-old, respectively. Note the prominent bitemporal attenuation (arrowheads both panels), the rhythmic delta with superimposed delta brushes in the central regions ( panel one arrow), and the hypersynchronous burst in the second panel. Isolated occipital delta with superimposed occipital theta are also noted in the second panel (arrow).
activity replace quiescent intervals after 28 weeks PMA. For the preterm infant less than 30 weeks PMA, electrographic activities predominate in the vertex, central, and occipital regions. Bitemporal attenuation is commonly observed and reflects underdeveloped frontal and temporal regions of the brain at this degree of brain immaturity (Fig. 1). B.
Synchrony/Asynchrony
The electrophysiologic description known as asynchrony (36) refers to similarly appearing EEG waveforms in homologous head regions (e.g., left and right temporal regions) that are separated by at least 1.5 seconds in time. Healthy preterm neonates typically express varying degrees of physiologic asynchrony. At less than 30 weeks PMA, extremely low birth-weight neonates commonly exhibit “hypersynchrony,” given extreme cortical immaturity (35). Physiologic asynchrony emerges after 30 weeks PMA and persists until approximately 36 weeks PMA. Asynchrony in the child at 30 to 32 weeks, for example, may be as much as 50% of the discontinuous portion of the sleep cycle. However, after 36 weeks PMA the occurrence of asynchrony rapidly drops to near 0% by postmenstrual term age. C.
Delta Brush Patterns
An admixture of fast and slow rhythms appears in the preterm EEG record as morphologically discrete waveforms that are identified with preterm neonates
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at varying PMAs. Random or briefly rhythmic 0.3- to 1.5-Hz delta activity of 50 to 250 mV is associated with a superimposed rhythm of low to moderate amplitude faster frequencies of 10 to 20 Hz. Historically, different authors have described these complexes as spindle delta bursts, brushes, spindle-like fast waves, or ripples of prematurity. For infants less than 28 weeks PMA, delta brush patterns are seen in the central and midline locations with only occasional expression in the occipital regions. After 28 weeks PMA, brushes appear more abundantly in the occipital followed by the temporal regions. Brushes can be asynchronous or asymmetric, while at other times they may be symmetrical. By term PMA, brush patterns are occasionally noted during the non-rapid eye movement (NREM) quiet sleep or transitional sleep segments. Persistent expression or attenuation of brush rhythms in one region or hemisphere may reflect structural lesions. D.
Occipital Theta/Alpha Rhythms
Other patterns can help estimate gestational maturity. Monorhythmic alpha and theta activities are located in the occipital regions of neonates less than 28 weeks PMA, commonly referred to as the STOP (i.e., spontaneous theta activity in the occipital regions in the premature neonate) rhythm (37,38). This pattern usually persists for 6 to 10 seconds and can be asynchronous or asymmetric but can also be synchronous (Fig. 2). Such a pattern of occipital theta/alpha rhythms, together with midline/central brushes, are electrographic features that are associated with extremely premature infants (i.e., <28 weeks PMA). E.
Temporal Theta Rhythm
A third useful developmental marker that estimates brain maturity is the theta burst, consisting of rhythmic 4.5 to 6 Hz activities noted in the mid-temporal regions. Temporal theta bursts are rarely apparent in infants less than 28 weeks PMA but become maximally expressed between 28 and 32 weeks PMA (Fig. 3). Historically, this feature has been described as a “temporal sawtooth wave” (5), with amplitudes ranging from 20 to 200 mV. After 32 weeks PMA, its incidence rapidly diminishes (39). F.
Delta Wave Patterns
Rhythmic waveforms consisting of delta activity can also help estimate gestational maturity of the asymptomatic preterm neonate. Delta patterns in the central or midline locations are predominant for the infant less than 28 weeks gestation together with bitemporal attenuation, as previously described. Other delta rhythms occur in the temporal and occipital locations, particularly after 28 weeks gestation (35) (Figs. 4 and 5). Between 30 and 34 weeks PMA, temporal and occipital delta rhythms become quite prominent and rhythmic, with durations that may exceed 30 seconds to 1 minute (Figs. 2 and 3).
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Figure 2 An EEG segment of a 24-week 4-day-old female with prolonged occipital theta alpha that is asymmetrical in amplitude (arrows), characteristic of the STOP rhythm.
V.
Midline Theta/Alpha Activity
This waveform pattern (40) appears both in recordings of both preterm and fullterm infants, particularly during transitional or quiet sleep segments (Fig. 6). This commonly observed pattern is sharply contoured and usually of low to moderate amplitude (Fig. 7) in the alpha or theta ranges. While it is morphologically similar to a sleep spindle, classical spindles do not appear in the central regions until two to four months of age (41). While this pattern may appear sharply contoured, this age-appropriate electrographic rhythm does not reflect a pathological or encephalopathic state, and might be expressed despite significant lack of other age-appropriate background rhythms.
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Figure 3 Segments of EEGs of two preterm infants approximately 29 weeks PMA, depicting abundant delta in multiple head regions as well as temporal theta activity ( first panel arrow), temporo-occipital, vertex, and central brush patterns ( first and second panel arrowheads) and rhythmic occipital delta (second panel arrow). Abbreviation: PMA, postmenstrual age.
VI.
Maturation of Noncerebral Physiologic Behaviors That Define State in the Preterm Infant
State transitions in preterm infants less than 36 weeks PMA are not as easily identified as with the term infant. Sleep reorganization is expected to occur at, or around, 36 weeks PMA, which is similar to the coalescence of physiologic behaviors documented on abdominal sonography of temporally synchronous fetal behaviors of both primates and humans (42). As a rule, state organization in the preterm infant remains rudimentary and underdeveloped (43,44) at ages less than 36 weeks PMA, but can be detected as early as 26 weeks PMA (35). The following summary serves as an introduction to a discussion of specific physiologic behaviors that highlight state differentiation in the preterm infant with increasing PMAs. Rapid eye movements (REMs) represent one of the main identifying features of rudimentary active sleep in the preterm infant. Eye movement phenomena become consistently time-locked to continuous EEG activities as early as 30 to 31 weeks gestation (43). REM activities are not random and occur in a predictable interval despite brain immaturity (45,46). Using fetal sonography (47), eye movements of the fetus are noted during active sleep as early as 30 weeks. Preterm neonates at 24 weeks PMA already have a fixed and reciprocal occurrence of REMs with EEG discontinuity with an interval of approximately one hour (46). Various classes of
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Figure 4 An EEG segment of a nearly 30-week 5-day-old PMA male, depicting the onset of continuous EEG segment with a left temporal theta burst (arrow), prominent delta, and superimposed delta brushes in the temporal regions (arrowhead ). Note that the temporal delta is more rhythmic than in Figure 3. Abbreviation: PMA, postmenstrual age.
REM have been described during different states of sleep in the neonate, and the number and types of REMs evolve with brain maturation (48,49). Studies of multiple physiologic behaviors during sleep in the preterm infant as young as 24 weeks PMA demonstrated a correlation between REM and more continuous EEG and a negative correlation between REM and discontinuous EEG (46,50). Motility patterns are also an integral part of neonatal state definition, but differ between the preterm and full-term infants. Different motility patterns emerge at increasing PMAs, both for the fetus and the extrauterine-reared neonate (51,52). The median percentage incidence of fetal body movements decreased from 17% at 24 weeks PMA to 7% near term (53). Coupling of fetal cardiac and somatic activity increased in magnitude with advancing gestational age (54). Myoclonic and whole-body movements predominate for the preterm infant (55,56), while smaller, slower segmental body movements are seen in the full-term neonate (57). State-specific decreases in the number of small and large body movements have been correlated with increasing EEG discontinuity in
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Figure 5 An EEG segment of a 29-week 3-day-old male with a shifting asymmetry between the left temporal-central region (arrow) and the right temporal region (arrowhead ), characteristic of physiologic interhemispheric asynchrony. Also note the prominent temporal theta and brushes as well as diffuse delta slowing during this discontinuous portion of the EEG.
preterm infants (50,57); while increased head and facial movements are associated with only active sleep, between 30 and 36 weeks PMA. Combinations of state-segregated motor behaviors were more likely to exhibit co-occurrence within one minute intervals in infants 30 weeks PMA and older (58). The abnormal quality of general body movements in a risk group with growth restriction was contrasted with a low risk group (57). Maturational changes in cardiorespiratory behavior have also been studied in the preterm infant. Periodic breathing and respiratory pauses are physiologic events that commonly occur in preterm infants (59,60). Using spectral analyses, decreased variability of cardiorespiratory behavior during quiet sleep is seen at increasing PMAs (61). However, interpretation of EEG-polygraphic activities are more reliable markers for state prediction than only noncerebral measures, such as with cardiorespiratory behavior. This will be discussed below in the section on autonomic nervous system maturation. In a recent study of multiple sleep behaviors in the preterm infant less than 36 weeks PMA, REMs, rather than cardiorespiratory, motility, and temperature changes, predictably varied with
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Figure 6 An EEG segment for a 34-week 23-day-old female with a prominent vertex and parasagittal burst of theta/alpha activity (arrows). Note the rare delta brushes and absent temporal theta at a postconceptional age of 37 weeks.
EEG changes, suggesting that specific brain regions subserving specific behaviors physiologically coalesce with EEG activities before other neuronal systems (62). VII.
Assessment of State Organization in the Full-Term Infant
Extensive information has been published with respect to the functional significance of the relatively short ultradian sleep rhythm in the near term and term neonate (63,64). For older infants, the human sleep cycle is an ultradian period with an interval of 75 to 90 minutes. The full-term neonate expresses an ultradian cycle that is shorter, approximating 30 to 70 minutes in duration (65). Sleep
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Figure 7 An EEG segment of a 40-week 2-day-old female, depicting mixed frequency active sleep, characterized by continuous EEG, body movements, REMs (arrowhead ), and irregular respirations and heart rate. Note the onset of a spontaneous arousal coincident with a temporary flattening of the EEG background. Abbreviation: REMs, rapid eye movements.
segments that comprise the neonatal sleep cycle also differ from older individuals, based upon EEG and polysomnographic behaviors. Two active and two quiet sleep segments, as well as transitional or indeterminate sleep segments, have been described. Arousal periods, defined as reactivity, occur both within and between the sleep segments. Indeterminate or transitional sleep and the arousal phenomena are important expressions of sleep continuity in the immature brain. State definitions in the term infant traditionally require the temporal coalescence of specific physiologic behaviors. On the basis of visual analyses, comparisons between cerebral and noncerebral behaviors are temporally observed to determine the state for either adults or children (66). Visual interpretations of EEG sleep states are also easily identified for the full-term neonate (9). Active, or REM, sleep for the full-term neonate is traditionally associated with the coalescence of REMs, increased variability of cardiorespiratory rates, low muscle tone in the context of low voltage or mixed frequency continuous EEG patterns, and the abundance of body movements. Conversely, quiet or NREM sleep is associated with the absence of REMs, fewer body movements, higher muscle tone, and decreased variability in respiratory rates in the context of continuous high-voltage, slow, or discontinuous EEG patterns. The abovedescribed patterns are not expressed until after 36 weeks PMA and are no longer seen beyond 46 to 48 weeks PMA. Typically the ultradian sleep cycle begins an
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Figure 8 An EEG segment of a 41-week 1-day-old female that documents high-voltage slow quiet sleep. Regular respirations and the absence of REMs are noted. Abbreviation: REMs, rapid eye movements.
active sleep after sleep onset in over 50% of newborns. This initial active sleep segment is a mixed frequency EEG segment, which comprises 25–30% of the total sleep cycle (Fig. 7). This active sleep segment is then followed by a brief high-voltage low-frequency quiet sleep segment, which is approximately 3–5% of the sleep cycle (Fig. 8). Subsequently, a discontinuous quiet sleep period (historically described as a trace´ alternant pattern) now comprises approximately 25% of the sleep cycle of the neonate (Fig. 9). Finally, a post–quiet sleep active sleep segment known as “low-voltage irregular” comprises approximately 15% of the cycle (Fig. 10). Transitional or indeterminate sleep comprises between 10% and 15% of the sleep cycle. Circadian rhythms are endogenously generated rhythms with a period of approximately 24 hours. Evidence gathered over the last 15 years indicates that the circadian timing system develops prenatally, and the suprachiasmatic nuclei, the site of the circadian pacemaker, is present by mid-gestation in primates (67). While the child does not yet express a strong diurnal or circadian rhythmicity of sleep, wakefulness is distributed over a 24-hour period. As many as six to eight hours of waking sleep over a 24-hour period may occur in the neonate (3). A recent cross-sectional analysis of sleep and wakefulness over 24 hours in preterm and full-term newborns documented diurnal differences in the expression of EEG-sleep patterns (68). For example, higher percentages of quiet sleep were expressed during daytime hours. Other environmental conditions, such as sleep position, can alter the expression of EEG frequencies during quiet sleep,
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Figure 9 An EEG segment of a 40-week 2-day-old female, documenting a discontinuous trace´ alternant, quiet sleep segment.
consequently diminishing arousal when the infant is placed in a prone position. These two reports offer additional insights into diverse environmental influences of time of day and position on sleep organization and arousal, embedded in circadian rhythmicity. Two biorhythmic processes define the temporal organization of sleep in the neonate, a weak circadian sleep wave rhythm and a stronger ultradian REM and NREM rhythm (69), with maturation of circadian rhythmicity after two months of age (67). Both biorhythms consolidate with increasing age. Internal “biologic clocks” become better organized around environmental cues, such as light/dark cycle, temperature, noise, and social interaction (70). For the normal full-term neonate, sleep alternates with waking states in a three- to four-hour cycle, both during the night and day. This has historically been referred to as the basic rest/activity cycle (BRAC). Within the first month or two of life after birth for the full-term infant, sleep/wake state reorganization begins, particularly with a more dominant diurnal effect to environmental cues. Circadian rhythmicity of body temperature and heart rate is first noted in approximately 50% of preterm infants at 29 to 35 weeks PMA (71). Stronger ultradian rhythms over a three- to four-hour duration
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Figure 10 An EEG segment of a 40-week 2-day-old female, documenting a low-voltage irregular active sleep segment. Note prominent sucking and REMs. Abbreviation: REMs, rapid eye movements.
correspond to nutritive interactions, such as feeding (66). Increases in body movement activities as well as heart rate and decreases in rectal and skin temperatures are noted during these interactions, reflecting changes in the infant’s microenvironment and the infant/caretaker interaction. The length of the ultradian EEG sleep cycle increases with maturing postconceptional age, demonstrating a positive correlation between cycle length and increasing PMA (50). The circadian rhythm of wakefulness appears approximately at day 45, when increased melatonin concentration begins at sunset. The sleep circadian rhythm appears after day 56 (72). VIII.
Sleep Ontogenesis---State Maturation from Fetal Through Infancy Periods
Reasons for the continuity of fetal state expression from intrauterine through neonatal ages prior to 46 weeks PMA remain obscure. This physiologic continuity may reflect the need for homeostasis of the fetus during the transition from intrauterine to extrauterine environments, requiring approximately a postnatal month of brain development before infant sleep patterns begin to emerge. State development involves multiple interconnected neuronal networks, which are actively maturing during fetal life. Beginning as early as 10 weeks gestational age, the human fetus displays spontaneous movements as visualized on ultrasonography. These movements now are more clearly visualized with
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three-dimensional ultrasonography, which can more readily document eye opening and closure, rhythmic body movements, while fetal heart rate is electronically recorded. All these behaviors allow estimation of fetal state transitions (73). Rhythmic cycling of motoric activity has been described in fetuses as young as 20 to 28 weeks gestation (74), with the fetal rest-activity pattern for as long quiescent periods lasting minutes to hours during which time no respiratory movements are noted (75). Preterm infants as immature as 24 weeks PMA express cyclicity of rudimentary state, when time intervals are measured between successive epochs of EEG discontinuity and REM periods (46). Cycle times vary but usually range between 40 and 60 minutes (76). Behavioral estimations of quiet (i.e., NREM) sleep approximate 53% in the 30-week conceptional age study, increasing to 60% by near term ages. State studies of fetal baboons documented similar coalescence among cerebral and noncerebral behaviors while in the intrauterine environment similar to humans (77). Preterm neonates in an extrauterine environment express these same temporal relationships. These physiologic interrelationships, defining state, persist for four to six weeks of postnatal life, after which infant sleep patterns gradually emerge to resemble adult sleep rhythms between the first and second years of life. Temporal coalescence of cerebral and noncerebral behaviors occur approximately one month before term ages either in the intrauterine or extrauterine environment. Specific features regarding sleep organization occur after 46 to 48 weeks EGA (78,79). Lengthening of the overall sleep cycle and reorganization of sleep architectural segments are expressed; gradual reductions in REM sleep percentage are noted, while NREM sleep becomes more abundant. Rather than a sleep-onset active or REM sleep after wakefulness, NREM sleep segments first appear after waking to drowsiness. NREM sleep stages I to IV, as defined (66), do not fully develop until late infancy. High-voltage delta slow NREM sleep remains the predominant electrographic expression of this segment of the sleep cycle, similar in EEG frequency distribution to the high-voltage slow quiet sleep segment of the neonate. Reductions in arousals, body, and REMs are noted as the child matures past 46 to 48 weeks PMA. During the first three months of life, rapid maturation of electrical activities in the brain occurs, such as the disappearance of trace´ alternant, the emergence of sleep spindle activity, and the emergence of “adult-like” delta wave activity (80–83). Quantitative assessments of spectral EEG analyses show that increases in theta power by nine months of age (84,85) coincide with the emergence of the S1 and S2 segments of the NREM sleep segment, codified for adult subjects by the sleep state criteria of Rechtschaffen et al. (66). A decline of theta power after nine months was observed in nocturnal sleep studies of infants, interpreted as a change in sleep regulatory processes reflected as a dissipation of sleep propensity during infancy (86). There is also a continual decrease in total sleep time, REM sleep, and indeterminate sleep, while concomitant increases in waking time and NREM sleep, particularly stages I and II of NREM sleep.
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Sleep organization for 15 normal infants were studied in a natural home environment during six 24-hour sleeping periods over 12 to 24 months after birth (87). Sleep staging was scored according to adult criteria (66), with modifications for children by Guilleminault et al. (88). While these authors confirmed earlier reported changes in percentages of total sleep time, REM, NREM, indeterminate sleep, and wakefulness, the authors also reported age and day/ night effects on sleep ontogenesis. Modifications with age were more precocious and more pronounced in diurnal expression over a 24-hour cycle, especially regarding REM sleep. During the nocturnal part of the 24-hour cycle, there was a significant increase in sleep efficiency during the REM period after 12 months of age. The authors went on to demonstrate that the total sleep duration and the number of awakenings decreased. These authors point to the high stability in the percentage of slow wave sleep during the first two years of life. Until 12 months of age, stage II/REM sleep ratio equals 1, and sleep changes occur earlier during the diurnal part of the 24-hour cycle. Another study of night sleep in 48 healthy drug-free infants aged 1 to 54 weeks was recorded in a hospital sleep laboratory setting to analyze sleep organization (89). A greater proportion of time spent in cycles over the total sleep time, with lengthening of sleep cycles, was noted in older infants. An increase in the NREM sleep component was also noted. These two studies of sleep ontogeny suggest how developmental neurophysiologic changes occur within neuronal networks that are responsible for sleep expression. These data also highlight the emergence of a well-developed circadian rhythm after three months of age, prior to the maturation of nocturnal sleep organization. This rhythm coincides with the milestone of continuous nighttime sleeping, commonly asked by pediatricians and anticipated by parents. Those brain structures responsible for circadian cycling predate other regions that are responsible for generation of S2 sleep and the decrease in REM sleep. Nine months of age appears to represent an important developmental age for sleep maturation. During the night, significant reductions in REM sleep and increases in S2 occur after this age. Rapid acceleration in brain myelination, dendritic arborization, and synaptogenesis occur after nine months, resulting in increased neuronal interactions between brainstem and thalamocortical structures (90). A better understanding of sleep ontogeny during infancy yields insights into the use of sleep analyses to predict behavioral patterns and later neurobehavioral phenotypes during childhood. A longitudinal intervention study documented nighttime sleep-wake patterns and self-soothing from birth to one year of age (91). Specific infant and parental factors interact to influence the development of self-soothing. Such a trait can be interpreted as the infant’s ability to regulate states of arousal. This transactional model was proposed to advance our understanding of daytime regulatory behavior for vigilance and attention during childhood on the basis of earlier self-soothing abilities during sleep. These insights may foster research into interventional programs
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during infancy, which promote improved sleep initiation and maintenance during nighttime with positive benefits for children and caregivers over short and longterm time periods. IX. A.
Ontogeny of Autonomic Behaviors During Sleep Respiratory Patterns
The recognition of sleep states in newborns and infants was initially based on differences in respiratory rate. The breathing rhythm was more irregular during active and more regular during quiet sleep segments (92,93). Related changes in these respiratory patterns were first noted when sleep state differentiation was recognized (94). There are a number of features of respiratory patterns that will be briefly summarized, including central respiratory pauses, breathing regularity vs. irregularity, breathing frequency, and the percentage of paradoxical breathing as it refers to out-of-phase thoracic and abdominal breathing movements. Central respiratory pauses are of short duration and are normally seen in the newborn and can be documented during the waking state following body movements (95). However, they primarily occur during sleep. The apnea index, defined by the percentage of non-breathing time, is significantly higher during active than quiet sleep. It remains high until 38 weeks PMA and decreases significantly both during active and quiet sleep by term age (96). Preterm infants corrected to term age as well as infants small for gestational age also have a greater number of respiratory pauses than is appropriate for gestational age infants of the same PMA. After 35 weeks PMA, respiratory frequency is higher during active and quiet sleep. During both components of the sleep cycle, respiratory frequency increases with increasing gestational age to term, and continues to increase during the first two months of life. Thereafter at older ages the respiratory rate progressively decreases (97). Phase shifting or paradoxical breathing between thoracic and abdominal breathing movements is commonly seen during the first several months of life (98) and is closely related to intercostal muscle inhibition, particularly during active sleep, in part reflecting high chest wall compliance (99). By term ages, the time spent with a 180-degree out-of-phase shift between thoracic and abdominal breathing movements remains unchanged, but is significantly greater during active than quiet sleep. Polysomnographic reference curves for the first two years of life have been reported (100) on the basis of 13,373 sleep recordings carried out in a sleep laboratory for children referred for sleep-related respiratory problems. Six hundred eighty-one recordings were retrospectively selected to establish normative criteria. Total sleep time in a laboratory condition was constant, with a medium of six hours. Percentile curves were described for 27 polysomnographic parameters. Regular breathing movements representing quiet sleep, increased
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from a median of 24.6% of the total sleep time in the first month to 56% total sleep time in the second year of life. Irregular breathing movements representing active sleep, consequently decreased with age. Coordinated patterns of thoracic and abdominal breathing movements showed an increase from a median of 53.3% of the total sleep time in the first month of life to 97.9% total sleep time at the end of the first year. Paradoxical breathing movements decreased, particularly over the first year of life. Periodic breathing had a median of 0.4% of the total sleep time in the first month with a large range of 0–18.9%. After three months of age, the 50th percentile of periodic breathing was 0% of the total sleep time with only a small number of children with periodic breathing found in all groups. The total number of respiratory pauses of three or more seconds per hour of sleep decreased from a median of 16.1 in the first month to 3.8 in children older than two years. A large range between the 5th and 95th percentiles in the first month (3.4–82.3) decreased markedly during the first six months and remained low from the age of 6 to 24 months. Mean and maximal durations of these respiratory pauses remained relatively constant during the first two years of life. The total number of respiratory pauses of three or more seconds duration were subdivided into pauses following a sigh and following a central, obstructive, or mixed respiratory pause. The 50th percentile of pauses following a sigh was constant at three per hour with a mean duration of about five seconds and a maximal duration of eight seconds. Respiratory pauses decreased from a median of 8.8/hr in the first month to 5/hr in the second year with a mean duration of four seconds and a maximal duration of seven seconds. A strongly asymmetric distribution of individual measurements was found concerning obstructive and mixed respiratory pauses. These authors hope to offer polysomnographic parameters to compare with those children who are at possible risk for sudden infant death syndrome as well as other cardiac, cerebral, metabolic, infectious, and genetic syndromes. Control of the cardiovascular and respiratory systems undergoes rapid maturation during infancy. Integration between cardiovascular and respiratory systems includes neural networks responsible for arousal. Infants are more arousable in active sleep compared with quiet sleep from both sensory and respiratory stimuli. Postnatal and gestational age at birth have a marked influence on arousability. Arousability can be depressed by major risk factors for sudden infant death syndrome, such as prone sleeping, maternal smoking, prematurity, and pulmonary infections. By contrast, arousability is increased by factors that decrease the risk for sudden infant death syndrome, such as co-sleeping and breastfeeding (101). Rapid changes in the developmental plasticity of respiratory control occur during the first year of life (102). In contrast to the mature subject, stress or disease to the developing individual brings about different forms of adaptive strategies, with resultant alterations in respiratory control, which may persist
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later in life. “Critical periods” of susceptibility to stress have recently been summarized, indicating that the process of developmental plasticity encompasses structural and/or functional developmental changes in neural networks that are uniquely susceptible to environmental influences. Occurrence of noxious stimuli during this critical period may disrupt the normal maturation of the neuronal system responsible for respiratory drive, as well as other neural systems involving sleep integrity, influencing its ultimate configuration and function. Resultant respiratory-related sleep disorders then occur. Alternatively, identical exposures that precede or succeed these critical windows of development have less or minimal effects on maturational patterns. B.
Heart Rate and Heart Rate Variability
As the neonate matures from neonatal to infancy periods, changes in cardiovascular functions during sleep reflect changes in autonomic nervous system dominance of neuronal networks subserving cardiac activity during sleep state transitions. Highly correlated behaviors of different heart rate variability (HRV) components are present in the preterm neonate that is less than 29 weeks PMA (103). Correlation of high-frequency oscillations of HRV with respirations and that of low-frequency oscillations of HRV with blood pressure were demonstrated. These behaviors were similar to fetal HRV behaviors of comparable ages. Blood pressure and heart rates are lower during NREM sleep, than in wakefulness throughout maturation from neonatal to infancy periods. During REM sleep, sympathetic nerve activity increases, reaching values greater than those measured during wakefulness (104), reflecting increased sympathetic control of cardiovascular function. Because short-term oscillations of heart rate (i.e., HRV) reflect autonomic nervous system activity, these values can be useful for assessing autonomic control under various physiologic and pathologic conditions. Spectral analysis of HRV can provide quantitative estimations of the balance between sympathetic and parasympathetic control (105). Short-term HRV spectra distinguish three main power components. The higher frequency (HF) component (range, 0.15–0.40 Hz), corresponding to heart rate and blood pressure oscillations induced by respiratory activity, mediated by the vagal branch of autonomic nervous system, is considered a marker for parasympathetic activity. Lower frequency (LF) components (0.04–0.15 Hz) reflect baroreflex control of systemic blood pressure, providing a measure of sympathetic activity. Baroreflex sensitivity and spectral power in R-R interval series increase with increasing PMA, suggesting a progressive vagal maturation with PMA (106). Using time-domain and frequency-domain analyses of HRV signals, researchers have reported parasympathetic predominance during NREM sleep, while increased sympathetic activity is expressed during REM sleep (107). Sleep stage and age both significantly influence short-term HRV during sleep in both healthy infants and children (108). Greater parasympathetic control during sleep is observed for children than for infants. This difference may reflect
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autonomic nervous system maturation that takes place over the first several years of life (109). Greater insights into interactions among physiologic systems subserving sleep can be achieved by time-domain specific nonlinear modeling techniques. For example, the use of coupled-oscillation models can be used to describe sleep organization and maturation, as reflected in cardiorespiratory behaviors over the neonatal and infant sleep cycle (110). While there is a symmetrical interaction between respiration and heart rhythms at birth, the direction of interaction is mainly determined by respiratory frequency. Studies of arousal that originate from cortical and subcortical brain regions will improve our understanding of cardiorespiratory control in relation to interconnections among diverse brain circuitries in different states of sleep (111). This physiologic interaction becomes practically unidirectional by six months of life. Speculations regarding altered expressions of these physiologic dynamics with stress or disease may uncover neuronal mechanisms predicting epilepsy, sleep problems, and cognitivebehavioral disorders (112). The mechanism of altered vagal reactivity may also offer greater insight into the increased vulnerability of preterm neonates to sudden infant death syndrome (101), particularly during the initial portion of quiet sleep (113). In summary, sleep ontogenesis during infancy gradually evolves into adult sleep organization over the first two years of life with temporal coalescence of specific neuronal networks. Circadian rhythms appear after three months of age, followed by an expression of the adult ultradian sleep cycle after nine months of age. There is a lengthening of the ultradian sleep cycle after 12 months of age. Reductions in arousals, motility, REMs, and sympathetic control reflect developmental changes within multiple brain regions, which are responsible for sleep initiation and maintenance. Alterations of sleep state-specific autonomic control suggest vulnerabilities to disease states or environmental stresses. X.
Brain Adaptation to Stress as Reflected in Sleep Reorganization
Endogenous or exogenous factors can alter the ontogenesis of specific physiologic behaviors during sleep. This is exemplified by neurophysiologic studies that compare differences between preterm and full-term infants at matched PMAs concerning sleep architecture, continuity, phasic, spectral, cardiorespiratory, and temperature behaviors (50,65,114–116). Unlike the full-term infant, sleep in the preterm infant adapts to an extrauterine environment by expressing a one-third longer sleep cycle, a greater percentage of quiet sleep, fewer movements, and shorter arousals. Preterm infants also exhibit higher rectal temperatures over the ultradian cycle, with less change from NREM to REM segments. Greater cardiorespiratory irregularity is noted during quiet sleep, and lower spectral EEG energies are observed during specific sleep segments. These
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differences reflect conditions of prematurity on brain maturation, relatively independent of medical illnesses after birth; adaptation of brain function for the preterm infant in an extrauterine environment represents physiologic dysmaturity to biologic and/or environmental stresses (117–119). Such sleep differences reflect physiologic expressions of neural plasticity involving interconnected macronetworks subserving multiple neuronal pathways throughout the neuroaxis. The dysmature EEG sleep measures (i.e., delayed or accelerated behaviors for the given corrected age) may help predict neurodevelopmental performance for some neonates who exhibit clinical risk factors, such as prematurity (17), prenatal substance exposure (120), chronic lung disease (121), or general medical complications of prematurity (122). Documentation of the persistence or resolution of dysmature sleep behaviors during infancy for clinical risk groups needs to be better addressed. Genetic-epigenetic interactions of molecular pathways after stresses from diseases or environmental cues “reprogram” the activities of neuronal networks that can then result in positive or negative consequences for neurodevelopment. Both activity-dependent (endogenous) and experience-dependent (exogenous) influences comprise the process of developmental neural plasticity. Changes in environmental conditions during sleep for preterm infants can alter sleep architecture and continuity measures, which act as biomarkers for present and future brain behaviors (123). Within the topic of developmental neural plasticity, a scientific concept has been defined as the developmental origins of health and disease (124). This process may also encompass neurologic disorders expressed throughout the human lifespan. Physiologic dysmaturity of the newborn is one neurophysiologic expression of neural plasticity, which may reflect either adaptive or maladaptive responses to environmental stresses or disease states, with later expressions of neurologic disorders. XI.
Computer-Assisted Analyses of EEG Sleep Organization in Neonates and Infants
Relationships among multiple physiologic processes are less developed in the preterm infant. State transitions are more difficult to recognize, particularly over short recording intervals. Even with longer recording times, less well-developed associations among physiologic variables may not be easily observed by visual analysis. Automated systems for EEG sleep analyses can complement visual inspection (16,19,20) (Fig. 11). Computer analyses better characterize relationships among electrographic and polysomnographic components over extended recording intervals, and better detect rudimentary sleep behaviors. Studies which compare computer and visual analyses of neonatal EEG recordings through infancy have ascertained which physiologic relationships best represent state expression; spectral EEG energies and REM can define maturational trends when compared with other measures in the preterm infant (61–63,65) (Fig. 11).
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Figure 11 A 3-hour summary of physiologic behaviors constituting neonatal sleep at full term age, in the lower tracing: state 10 awake, state 21 mixed frequency active sleep, state 31 high-voltage slow quiet sleep, state 41 indeterminate sleep, state 32 trace´ alternant quiet sleep, state 22 low-voltage irregular active sleep. Spectral delta and total EEG energies in panels two and three illustrate changes in these values, depending on the segment of the neonatal sleep cycle. Note the minimum total EEG energy and maximum delta energy during trace´ alternant quiet sleep. The top panel illustrates a slower multiplehour temperature rhythm, which changes over multiple sleep cycles.
Conversely, other noncerebral measures such as cardiorespiratory, motility, and temperature changes may predict unique maturational trends of sleep state organization specific to these interconnected neural networks throughout the neuroaxis. Computer algorithms can detect diurnal or nocturnal rhythmicities more accurately than by visual inspection (16,19). Comparatively less attention has been directed to automated analyses of neonatal EEG sleep studies compared with older persons (125). Since an earlier review of this topic (19), further advancements in the development of both computerized devices and mathematical programming have been achieved (16). To successfully develop an automated state detector for neonates, technical
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innovations must recognize the unique neurophysiologic expressions of state transitions of the newborn that are not expressed by the older patient. A short list of these unique electrographic/polysomnographic behaviors include a shorter sleep cycle, prominent EEG delta rhythms in different regional locations, intraand inter-hemispheric electrographic asynchrony, discrete neonatal waveform patterns (i.e., delta brush and theta burst patterns), a high percentage of periodic breathing, a greater number and heterogeneity of REMs, and unique motor patterns that reflect fetal postural reflexes, which precede the expression of more sophisticated developmental movement patterns. Previous neonatal sleep studies initially applied automated techniques to assess functional brain maturation, using analyses that were based on assumptions of linearity, without consideration of time-dependent changes (32,34,84,126–131). The preferred methodological approach has been Fast Fourier transform analyses, studied initially with full-term neonates (132–136), followed by more recent reports in preterm infants (137–146). Similar calculations, based primarily on assumptions of linearity, were also described for specific neonatal and infant risk groups for sudden infant death syndrome (147), apnea (141,148), hyperbilirubinemia (149), white matter necrosis (150), and asphyxia (151). Single channel monitoring devices have been discussed as surveillance devices for decades (152). Over the last decade, there has been a wave of studies “rediscovering” this technique for monitoring healthy and sick neonates (151). With more sophisticated acquisition devices, suggestions for seizure detection, estimating degrees of encephalopathic changes, and tracking global maturational trends in spectral values have been reported (153). Global maturational trends using these devices lack regional or even hemispheric specificity, relying only on frequency-dependent spectral measures (23). Such devices, nonetheless, can be useful for bedside screening, if designed for greater flexibility to allow the neurophysiologist to analyze raw digitally acquired physiologic signals by selected linear or nonlinear analytical methods, using either time-dependent or frequency-dependent measures. Patterns derived from these screening devices then must be compared with more comprehensive EEG-polygraphic studies that utilize more complete montages, including noncerebral physiologic signals (16). Few reports have combined cerebral and noncerebral measures to more comprehensively study newborn sleep state organization and maturation (154,155). Comparing data from two-channel EEG recordings, an association between autonomic and central nervous system behaviors were noted during quiet sleep in 36-week PMA neonates (156). Automated analysis methods of neonatal EEG-sleep using a full complement of cerebral and noncerebral measures can more comprehensively detect and quantify linear and nonlinear sleep behavior relationships. Simultaneous assessments of multiple cerebral and noncerebral measures better define neonatal state (65). Spectral analyses of EEG (10,61,116,157), cardiorespiratory behavior (115,116,118), arousal behavior (65,158), and REMs (10,65,159), establish that there are important physiologic
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differences during sleep between healthy preterm and full-term cohorts. Nonlinear computations for feature extraction of EEG signals (160), arousals (158), and state/outcome prediction (161) have also been suggested as a part of the overall strategy to develop an automated neonatal state detector. Differences in the functional brain organization between neonatal cohorts have been incorporated into a statistical model that offers a mathematical paradigm to define physiologic brain dysmaturity of preterm neonates at corrected full-term ages. This dysmaturity index has been originally derived from seven selected physiologic measures (10,62,117,158,162) that best represent differences in functional brain organization and maturation between healthy preterm and full-term cohorts by comparative analysis. This statistical model characterizes specific physiologic behaviors of the preterm infant as either delayed or accelerated in relation to full-term controls. Automated methodologies which can better define altered expressions of state behaviors with advancing age offer an opportunity to characterize the process of developmental neural plasticity within the fetal and neonatal brain, stressed by environmental or disease conditions (16). Computer analyses of EEG-sleep during infancy also have helped demonstrate the physiologic ontogenesis of the neuronal macro-networks (163–168). EEG frequency determination with maturation, based on power spectral analyses, documents alterations in all frequency bandwidths, particularly at the higher frequency ranges for human EEG (i.e., the alpha and beta ranges). These changes are surrogate markers of cognitive and behavioral development, especially in the frontal lobe (167,169). Deviations in the ontogenesis of spectral signals help differentiate specific high-risk populations of children (170–172). Relatively little attention has been devoted to either extremely low or very high frequency spectral bandwidths (i.e., <0.5 or > 40–1000 Hz) which have been studied primarily in adult populations (20). Spectral analyses have also been performed involving sleep studies for noncerebral physiologic parameters, particularly cardiorespiratory measures, as discussed under the section for cardiorespiratory maturation. Changes in the balance between sympathetic and parasympathetic influences during sleep can be assessed by the spectral analysis of HRV (108). Few studies extend these evaluations up through infancy. Most studies dealing with maturation of cardiorespiratory behavior do not include ages beyond six months. XII.
Sleep Ontogenesis and Neural Plasticity
Advances in developmental neuroscience over the last 15 years have expanded our knowledge base regarding the sequential steps in brain maturation. Third trimester and early postnatal developmental stages of brain maturation encompass extensive remodeling or resculpting of interconnected neural networks. During the last trimester of pregnancy and into the first year of life, dendritic
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arborization, synaptogenesis, myelinization, and neurotransmitter development rapidly evolve in the immature brain (173). The developmental processes of experience and activity-dependent development signify how signaling at the molecular level influences both individual cell types and interconnected neural networks, which subserve complex brain functions. Use or disuse of specific neuronal populations or networks will lead to either adaptive or maladaptive pruning and remodeling of the brain’s neuronal circuitry during critical periods of development. Apoptosis or programmed cell death also contributes to modifying brain structure or function both during prenatal and postnatal periods (174,175). Adverse conditions of prematurity (i.e., during both prenatal and postnatal time periods) from medical illnesses and environmental stresses collectively alter these processes of synaptogenesis and apoptosis, changing neuronal circuitry relative to the stage of maturation. Given that remodeling of neuronal connectivity is ultimately required for the expression of complex neurobehaviors of sleep, cognition, emotion, and social skills at older ages (176), aberrant remodeling may alternatively contribute to neurocognitive and neurobehavioral deficits. Automated neurophysiologic methodologies can assess brain organization and maturation in the newborn, offering a surrogate biomarker of activitydependent development in the fetal and neonatal brain with adverse developmental consequences at older ages. Sophisticated analysis tools can convert the spatio-temporal aspects of EEG-sleep activity into three-dimensional images (177) similar to those used in neuroimaging protocols with magnetic resonance imaging. Computational phenotypes from computerized neurophysiologic studies can then be more fully integrated with quantitative neuroimaging datasets, neuropsychologic testing results, and genetic polymorphisms associated with disease risk to improve rapid and accurate diagnosis and prognosis of pediatric brain disorders. Computational algorithms applied to selected physiologic measures of neonatal sleep provide functional insights into the process by which neuronal networks change and adapt over longer periods of time during extrauterine life under adverse medical and socioeconomic conditions, and in the context of genetic endowment. Applications and methods of nonlinear dynamics to experiments in neurobiology will help better characterize the biologic process of neural plasticity (20,112,178). Computational analyses of complex physiologic behaviors reflect changes in neuronal circuitry throughout the neuroaxis and enhance our understanding of the encoding and transmission of information by neuronal networks that subserve human performance ranging from sleep to cognition. The application of these processing techniques in both neonatal intensive care and pediatric sleep laboratory settings will permit better assessment of EEG-sleep state organization and maturation through computational neuroscience. The developmental origins of neurologic health and disease can be better studied using these computational phenotypes. These biomarkers can also be applied to neurorehabilitative interventions to assess therapeutic efficacy.
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Summary
EEG sleep studies remain the only bedside neurodiagnostic procedure that provides a continuous record of cerebral function over long periods of time. Other advanced methods of neuroanatomical assessments, such as volumetric and functional magnetic resonance images, document snapshots of cerebral anatomy and function. Neurophysiologic studies provide a time- and frequencydependent functional perspective into brain ontogeny, which complement structural analyses. Studies of sleep ontogenesis in neonates and infants, using both visual and computational analysis strategies, can document expected patterns of brain maturation, to better anticipate deviations from these biologically programmed processes under stressful and/or pathological conditions. References 1. Samson-Dollfus D. L’e´lectroencephalogramme du pre´mature´ jusqu’a`l’aˆge de trois mois et du nouveau ne´ a` terme. Foulon R, ed. Paris: These Med, 1955. 2. Anders T, Emde R, Parmelee AH. A Manual of Standardized Terminology, Techniques, and Criteria for Scoring of State of Sleep and Wakefulness in Newborn Infants. Los Angeles, CA: UCLA Brain Information, 1971. 3. Parmelee A, Stern R. Development of states in infants. In: Clemente D, Purpura D, Mayer E, eds. Sleep and the Maturing Nervous System. New York: Academic Press, 1972:199–228. 4. Ellingson R. Studies of the electrical activity of the developing human brain. In: Himwich W, ed. The Developing Brain-Progress in Brain Research. Amsterdam: Elsevier, 1964:26–53. 5. Dreyfus-Brisac C. Neonatal electroencephalography. In: Scarpelli E, Cosmie E, eds. Reviews in Perinatal Medicine. New York: Raven Press, 1979:397–430. 6. Prechtl HF. The behavioural states of the newborn infant (a review). Brain Res 1974; 76(2):185–212. 7. Lombroso C. Neonatal electroencephalography. In: Niedermeyer E, Lopez-Desilva F, eds. Electroencephalography, Basic Principles, and Clinical Applications in Related Fields. Baltimore and Munich: Urban and Schwarzenberg, 1989:599–637. 8. Hrachovy R, Mizrahi E, Kellaway P. Electroencephalography of the newborn. In: Daly D, Pedley T, eds. Current Practice of Clinical Electroencephalography. 2nd eds. New York: Raven Press, 1990:201–242. 9. Stockard-Pope JE, Werner SS, Bickford RG. Atlas of Neonatal Electroencephalography. 2nd ed. New York: Raven Press, 1992. 10. Scher MS, Jones BL, Steppe DA, et al. Functional brain maturation in neonates as measured by EEG-sleep analyses. Clin Neurophysiol 2003; 114(5):875–882. 11. Hack M, Taylor HG, Drotar D, et al. Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age. Pediatrics 2005; 116(2):333–341. 12. Allin M, Rooney M, Cuddy M, et al. Personality in young adults who are born preterm. Pediatrics 2006; 117(2):309–316.
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89. Ficca G, Fagioli I, Salzarulo P. Sleep organization in the first year of life: developmental trends in the quiet sleep-paradoxical sleep cycle. J Sleep Res 2000; 9(1):1–4. 90. van der Knaap MS, Valk J. MR imaging of the various stages of normal myelination during the first year of life. Neuroradiology 1990; 31(6):459–470. 91. Nikolopoulou M, St James-Roberts I. Preventing sleeping problems in infants who are at risk of developing them. Arch Dis Child 2003; 88(2):108–111. 92. Aserinsky E, Kleitman N. A motility cycle in sleeping infants as manifested by ocular and gross bodily activity. J Appl Physiol 1955; 8(1):11–18. 93. Monod N, Pajot N. [The sleep of the full-term newborn and premature infant. I. Analysis of the polygraphic study (rapid eye movements, respiration, and E.E.G.) in the full-term newborn]. Biol Neonat 1965; 8(5):281–307. 94. Curzi-Dascalova L. Physiological correlates of sleep development in premature and full-term neonates. Neurophysiol Clin 1992; 22(2):151–166. 95. Mathew OP, Thoppil CK, Belan M. Motor activity and apnea in preterm infants. Is there a causal relationship? Am Rev Respir Dis 1991; 144(4):842–844. 96. Curzi-Dascalova L, Christova-Gueorguieva E. Respiratory pauses in normal prematurely born infants:a comparison with full-term newborns. Biol Neonate 1983; 44(6):325–332. 97. Curzi-Dascalova L, Lebrun F, Korn G. Respiratory frequency according to sleep states and age in normal premature infants: a comparison with full term infants. Pediatr Res 1983; 17(2):152–156. 98. Curzi-Dascalova L. Thoracico-abdominal respiratory correlations in infants: constancy and variability in different sleep states. Early Hum Dev 1978; 2(1): 25–38. 99. Curzi-Dascalova L. Phase relationships between thoracic and abdominal respiratory movement during sleep in 31–38 weeks CA normal infants. Comparison with full-term (39–41 weeks) newborns. Neuropediatrics 1982; 13(suppl):15–20. 100. Schlu¨ter B, Buschatz D, Trowitzsch E. Polysomnographic reference curves for the first and second year of life. Somnologie 2001; 5:3–16. 101. Tuladhar R, Harding R, Michael AT, et al. Comparison of postnatal development of heart rate responses to trigeminal stimulation in sleeping preterm and term infants. J Sleep Res 2005; 14(1):29–36. 102. Reeves SR, Gozal D. Developmental plasticity of respiratory control following intermittent hypoxia. Respir Physiol Neurobiol 2005; 149(1–3):301–311. 103. Rassi D, Mishin A, Zhuravlev YE, et al. Time domain correlation analysis of heart rate variability in preterm neonates. Early Hum Dev 2005; 81(4):341–350. 104. Somers VK, Dyken ME, Mark AL, et al. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993; 328(5):303–307. 105. Baharav A, Kotagal S, Gibbons V, et al. Fluctuations in autonomic nervous activity during sleep displayed by power spectrum analysis of heart rate variability. Neurology 1995; 45(6):1183–1187. 106. Andriessen P, Oetomo SB, Peters C, et al. Baroreceptor reflex sensitivity in human neonates: the effect of postmenstrual age. J Physiol 2005; 568(pt 1): 333–341. 107. Gaultier C. Cardiorespiratory adaptation during sleep in infants and children. Pediatr Pulmonol 1995; 19(2):105–117.
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143. Vanhatalo S, Tallgren P, Andersson S, et al. DC-EEG discloses prominent, very slow activity patterns during sleep in preterm infants. Clin Neurophysiol 2002; 113(11): 1822–1825. 144. Okumura A, Kubota T, Toyota N, et al. Amplitude spectral analysis of maturational changes of delta waves in preterm infants. Brain Dev 2003; 25(6):406–410. 145. Victor S, Appleton RE, Beirne M, et al. Spectral analysis of electroencephalography in premature newborn infants: normal ranges. Pediatr Res 2005; 57(3): 336–341. 146. West CR, Harding JE, Williams CE, et al. Quantitative electroencephalographic patterns in normal preterm infants over the first week after birth. Early Hum Dev 2006; 82(1):43–51. 147. Schechtman VL, Harper RK, Harper RM. Aberrant temporal patterning of slowwave sleep in siblings of SIDS victims. Electroencephalogr Clin Neurophysiol 1995; 94(2):95–102. 148. Holthausen K, Breidbach O, Scheidt B, et al. Clinical relevance of age-dependent EEG signatures in the detection of neonates at high risk for apnea. Neurosci Lett 1999; 268(3):123–126. 149. Gurses D, Kilic I, Sahiner T. Effects of hyperbilirubinemia on cerebrocortical electrical activity in newborns. Pediatr Res 2002; 52(1):125–130. 150. Inder TE, Buckland L, Williams CE, et al. Lowered electroencephalographic spectral edge frequency predicts the presence of cerebral white matter injury in premature infants. Pediatrics 2003; 111(1):27–33. 151. Hellstrom-Westas L. Comparison between tape-recorded and amplitude-integrated EEG monitoring in sick newborn infants. Acta Paediatr 1992; 81(10):812–819. 152. Rosen MG. Effects of asphyxia on the fetal brain. Obstet Gynecol 1967; 29(5): 687–693. 153. Hellstro¨m-Westas L, De Vries L, Rosen I. An atlas of amplitude-integrated EEGs in the newborn. New York: Parthenon Publishing, 2003. 154. Pan XL, Ogawa T. Microstructure of longitudinal 24-hour electroencephalograms in healthy preterm infants. Pediatr Int 1999; 41(1):18–27. 155. Regalado MG, Schechtman VL, Khoo MC, et al. Spectral analysis of heart rate variability and respiration during sleep in cocaine-exposed neonates. Clin Physiol 2001; 21(4):428–436. 156. Pfurtscheller K, Muller-Putz GR, Urlesberger B, et al. Synchronous occurrence of EEG bursts and heart rate acceleration in preterm infants. Brain Dev 2005; 27(8): 558–563. 157. Scher MS. Normal electrographic-polysomnographic patterns in preterm and fullterm infants. Semin Pediatr Neurol 1996; 3(1):2–12. 158. Scher MS, Kelso RS, Turnbull JP, et al. Automated arousal detection in neonates. Sleep 2003; 26(suppl):A143. 159. Scher MS, Dokianakis SG, Sun M, et al. Computer classification of sleep in preterm and full-term neonates at similar postconceptional term ages. Sleep 1996; 19(1): 18–25. 160. Turnbull JP, Loparo KA, Johnson MW, et al. Automated detection of trace alternant during sleep in healthy full-term neonates using discrete wavelet transform. Clin Neurophysiol 2001; 112(10):1893–1900. 161. Turnbull JP, Johnson MW, Loparo KA, et al. Nonlinear dynamical system analyses of neonatal sleep state. Sleep 2003; 26(suppl):A404.
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3 Maturation of Sleep Patterns During Infancy and Childhood
AVI SADEH The Adler Center for Research in Child Development and Psychopathology, Department of Psychology, Tel Aviv University, Tel Aviv, Israel
I.
Introduction
The evolution of normal sleep patterns in children starts with a rapid maturational process during the first year of life and continues with slower and more gradual changes in later ages. The major maturational process—the consolidation of sleep during the night—is a very striking process that has direct impact on the evolving relationships between children and their immediate environment and particularly with their parents. Difficulties in this process are associated with night-waking and settling problems, which are the most common sleep problems in early childhood. The maturation of sleep is closely linked to other major health issues such as physical health or illness. Sleep is very vulnerable and could be adversely affected by almost any health problem that disrupts well-being or cause discomfort or pain. Furthermore, sleep problems or insufficient sleep could compromise the health status of the child causing or exacerbating health problems. Similarly, the links between sleep and psychological well-being are bidirectional. Psychological stress or anxiety can dramatically influence sleep and sleep problems, or insufficient sleep can compromise the emotional status or psychological functioning of the child. 77
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This chapter contains a brief description of the maturation of sleep-wake patterns in normal infants and children and a discussion of the factors influencing, and influenced by, the evolving sleep patterns of the child. II.
Consolidation of Nocturnal Sleep
During the first days of their lives, full-term newborns spend an average daily amount of about 16 hours in sleep. Their sleep is distributed around the clock, day and night, across a number of sleep episodes (five to six on average) with relatively short intervals of wakefulness between them (1–4). A newborn’s sleep is not evenly distributed across the day and night, and studies have shown that there is a preference for sleep at nighttime hours even in the early days of life (2,5). This uneven distribution of sleep could be due to biological factors or the fact that the conditions at the hospital nurseries are more conducive for sleep during the nighttime hours (i.e., less noise, fewer procedures, and darker rooms). During the first year of life, a rapid maturational process leads to a clear preference to sleep during the night (3). The consolidation of a prolonged nighttime sleep episode, also referred to as ‘‘sleeping through the night,’’ is achieved by most infants during this period (3,6–10). However, studies have shown that night wakings as a common phenomenon persists in early childhood and many infants who are reportedly ‘‘sleeping through the night’’ are in fact self-soothers who do wake up during the night but resume their sleep without parental involvement (7,9–13). Furthermore, night wakings are considered as a very common problem in infancy, and it is estimatedthat 20–30% of the infants and toddlers suffer from night-waking problems (14–16). Multiple biological and psychosocial factors determine the concentration and consolidation of sleep during the night. Circadian brain mechanisms develop prenatally, and the suprachiasmatic nuclei, which is considered to be the master circadian clock area, is present by midgestation (17). Synchronization of the sleep-wake system with the light-dark cycle has been demonstrated in early ages (18,19). It has been suggested that the synchronization of the sleep-wake cycle with the light-dark cycle is mediated by the secretion of the pineal hormone melatonin, which rises in the dark hours and drops in response to light exposure. It has been shown that maturation of the melatonin secretion occurs during the first six months of life (20), a period that corresponds to the accelerated process of sleep consolidation during the night. Furthermore, the infant’s melatonin secretion is influenced by circadian rhythms of tryptophan in the mother’s breast milk; thus, perhaps, biologically synchronizing the mother-infant circadian rhythms (21). A significant association between melatonin secretion patterns and sleep-wake patterns has been demonstrated in six- to eight-month-old infants, suggesting that the two systems are indeed interrelated (22). In this study, sleep onset was associated with measures of melatonin secretion levels during the evening hours and sleep fragmentation was associated with inappropriate peak time of melatonin secretion.
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In addition to light exposure, a variety of environmental factors play a role in encouraging the preference for sleep during the night. The most established factor is probably related to parental behaviors that exert significant influence on sleep consolidation in infancy: excessive parental involvement is associated with more fragmented sleep in infants (7,23–25). Most interventions and treatments for night wakings are based on reducing parental bedtime involvement and encouraging the child to develop self-soothing skills (15,26,27). Another way to describe the maturation of the sleep-wake system is to address the changes in daytime napping. As sleep consolidates during the night and sleep needs decrease, daytime sleep gradually disappears. Studies on naps in children indicate that the percentage of children who nap, the number of napping episodes, and the time spent in naps decreases with age (16,28,29). More specifically, Weissbluth (28) reported that most infants were napping two (83.7%) or three (16.3%) times per day at six months of age. By three years of age all the children were napping only once a day. Napping almost completely disappeared at seven years of age. No gender differences were found in the napping habits of children. Acebo et al. reported similar results (29) in children between one and five years of age. This study demonstrated that nocturnal sleep remains quite stable during these years, while daytime napping almost disappears. Difficulties in the process of nighttime sleep consolidation are not restricted to early childhood (see chap. 7). Studies have shown that sleep fragmentation continues throughout childhood, although surveys based on parental reports usually find that these problems improve with age. For instance, in a study of 2889 Italian infants and children, Ottaviano et al. found that the prevalence of night-waking problems decreases from a range above 34% during the first two years of life to 13.4% in fourto six-year-olds (30). However, studies suggest that night-waking problems are persistent and may turn into a chronic sleep problem, if not treated (31–33). Studies on the prevalence of night-waking problems in older children yielded somewhat confusing results. Surveys based on subjective or parental reports suggest that night wakings are less frequent in older children in comparison to early childhood (32,34–36). However, studies conducted with objective sleep recordings (i.e., EEG or actigraphy) suggest that night wakings are frequent in older children (37–39). For instance, in an EEG study, it was found that children between 6 and 11 years of age had an average of one to three brief night wakings (39). In a naturalistic actigraphic study of sleep in normal schoolage children, an average of more than two night wakings was found, and 18% of these children could be characterized as ‘‘poor sleepers’’ on the basis of their fragmented sleep patterns (38). Fragmented sleep was found in 41% of kindergarten-age children, using similar methodology (37). III.
Sleep Onset and Sleep Duration
Sleep duration is another aspect of sleep that undergoes significant change during development. From an average of 16 hours of sleep per day as a newborn
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to an average of 7 to 8 hours as a young adult, the ratio between sleep and wake hours is virtually reversed. In the first five to six years, the decrease in daily sleep time is mainly due to the reduction in daytime sleep or naps (29). In the following years the continuing decrease in sleep time is mostly related to the decrease in nocturnal sleep (38,40). As could be seen in Figure 2, the age-group means do not reflect the entire picture. The individual differences in sleep duration or sleep needs are striking and preclude simple answers to questions such as how much sleep is appropriate for a child at a certain age. It has been shown that in newborns, during their first 48 hours in the nursery, sleep duration ranged between 10 hours and 22 hours per day (2). This dramatic individual variability decreases with age, but still individual variability in naturalistic sleep patterns is striking (Figs. 1 and 2). The issues of sleep onset time and sleep onset difficulties are among the factors determining sleep duration. There are conflicting reports with regard to what maturation does to sleep latency during early and middle childhood. One study reported a trend of a gradual increase with age in the time taken to fall asleep (41). Another study reported a steady significant decrease in sleep latency from early infancy to six years of age (30). When sleep latency over 30 minutes long was considered as the criterion, the percentages of children meeting this criterion dropped from 13.7% during the first few months of age to 2.2% within the age range of four to six years. It has been estimated that 10–15% of children of one to eight years of age have difficulties going to bed or falling asleep (32,42–44). Similar and higher rates of these difficulties have been reported in adolescents (45,46). For most children, child-care, school, or parental requirements and demands determine morning rise time. In contrast, sleep onset time is much more
Figure 1 Night wakings across development: average number of actigraphy-based night wakings (per night) in normal children. Source: Based on data derived from Refs. 37, 38, and 120.
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Figure 2 Sleep duration across development: Average duration of nocturnal sleep (per night) in normal children. Source: Based on data derived from Refs. 37, 38, and 120.
negotiable and is determined by the child’s physiological needs and by multiple psychosocial factors of the child and his or her family. Therefore, the maturational trend of reduced sleep duration is primarily determined by delays in sleep onset. There are different potential causes for these delays in sleep onset, including biobehavioral factors associated with sleep-phase shift and a variety of psychosocial factors. From a psychosocial perspective, it is clear that at around two to three years of age the child becomes increasingly aware of, and involved in, the social life of the family. Sleep rituals are extended, and settling problems become more prevalent. Between three to five years, nighttime fears and nightmares also increase in prevalence and may complicate going to bed, which is associated with darkness and separation from the parents and family social life (47–49). The pervasive belief is that children’s fears subside when they reach school age (the ‘‘latency period’’). However, Kahn et al. reported nighttime fears in as much as 15% of their large sample of preadolescents (50). These fears were associated with difficulties in initiating sleep (i.e., increased sleep latency). In this age group, bedtime struggles are often associated with the evolving tendency of the child to delay sleep and with parental difficulties in limit setting. IV.
Sleep State Organization
Early sleep state organization suggests that rapid eye movement (REM) sleep plays a unique role in early brain development (51). This is suggested by the high REM pressure that exists in the early months of life as evident by the unique characteristics of infant sleep are the facts that: (1) young infants either fall
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asleep directly with the onset of REM sleep or with a very short REM latency compared with older children and (2) infants spend a high proportion of their sleep time in REM sleep. These two unique features are the ones that undergo the most prominent maturational processes. Roffwarg et al. (52) published the earliest systematic scientific inquiry of the ontogenesis of sleep structure. Since then, a limited number of polysomnographic studies have contributed to our knowledge on normal maturation of sleep organization in children (39,53–62). Kahn et al. indicated (53) that the methods used by different laboratories differ in many aspects and, therefore, the results do not always overlap. Nevertheless, consistent maturational processes have been identified and are reported in the following sections. A.
REM-NREM Sleep Distribution
During their earlier months of life, infants spend around 50% of their sleep time in REM sleep (almost 8 hr/day). By the time they are one-year-old they spend only around 30% of their sleep time in REM sleep, and this proportion only slightly decreases during the next few years to the adult proportion of 20–25%. Indeed, the major component of the outstanding decrease in sleep duration from 16 hours in the newborn period to 7 to 8 hours in adults is the reduction in REM sleep. As stated earlier, newborns experience an immediate onset of REM sleep when they fall asleep, but this tendency changes quickly during the first few months as quiet sleep becomes more dominant during the early phases of sleep. There is scientific support to the hypothesis that REM sleep is so predominant in infancy because it facilitates information processing and brain maturation of the human infant who is born with a small brain in comparison with its mature brain size (51). It is important to note that during the early childhood period (age, 2–5 years) most children nap during the day and their state distribution might be affected by their napping sleep structure (52,54–57). For instance, it has been suggested that the lower amount of non– rapid eye movement (NREM) sleep in infants in comparison with older children results from the fact that they spend much more time in REM sleep during their naps. Quan et al. studied EEG sleep of children aged between 6 and 11 years and reported a progressive decline in REM time (in minutes) but not in REM percent (61). No significant age-related differences in REM percent were reported in a recent study of children aged between three and seven years (59). Dahl et al. have reported a significant association between REM sleep parameters and reproductive hormones in school-age children during their pubertal development (58). Higher levels of reproductive hormones were associated with shorter REM latency, lower REM activity, and lower REM density. In a recent large-scale study on normative EEG sleep of three- to seven-year-old children, an age-related decrease in sleep latency, an increase in REM latency, and a decrease in wake time were found (59).
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In addition to the maturational changes in REM-NREM sleep, the distribution of the NREM sleep stages also undergoes significant developmental process. The differentiation of slow-wave sleep (SWS) stages 3 to 4 becomes possible during the second half of the first year of life (53). During the school years, stage 4 NREM sleep appears to decrease from 18% in 6- to 7-year-olds to 14% in 11-year-olds. This reduction is accompanied by an increase in NREM stage 2 (39). Acebo et al. have reported similar findings. (62). Bes et al. (63) have compared the distribution of SWS across the night in infants (between 20 weeks and 1 year), children (1–6 years), and adults (20–36 years). They found that SWS reached its peak in all age groups during the first NREM sleep episode. Following the first NREM episode, SWS percent decreased across the night in children and adults, but not in infants. B.
REM-NREM Cycle
The REM-NREM state cycle also undergoes maturational changes. Since different studies use different criteria, the reports are somewhat discrepant although the trends are similar (53). In newborns and very young infants, the cycle lasts approximately 40 to 60 minutes. In one study, it has been reported that by two years of age the cycle increases to 75 minutes and continues to increase to an average of 84 minutes in five-year-olds. Another study reported an increase of the cycle from 40 minutes at two years of age to 60 minutes at five years of age (54). The length of the REM-NREM cycle continues to gradually increase until it reaches the 90 to 120 minute adult-like cycle (59). Another important aspect that should be noted is that in early infancy, the EEG distinction between REM and NREM sleep is not as sharp as in older children and adults. This is demonstrated by the relatively large proportion of sleep scored as ‘‘indeterminate’’ or ‘‘transitional’’ in infancy. Bes et al. have shown that when REM recurrence times are considered in the assessment of the sleep cycle there is a clear peak of recurrence time in infants, children, and adults (63). This peak recurrence time increases from about 50 minutes in infants to almost 100 minutes in adults. However, when SWS recurrence is considered there is no clear peak in infants or children, and only in adults, there is a peak recurrence time of about 100 minutes. This pattern appears to result from the fact that infants and children often skip SWS in their NREM sleep episodes. V.
Factors Influencing Sleep Maturation
Sleep is very sensitive to any disruption in the medical or the psychological wellbeing of the child. It is often difficult to identify or distinguish between medical and psychosocial factors influencing sleep. It is beyond the scope of this chapter to review the extensive literature on this topic and only a brief summary is included.
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Medical Factors
Sleep is very sensitive to the medical and physiological status of the child. Any common upper respiratory tract infection or congestion of the upper airways could lead directly to severe disruptions of sleep. Other, more serious and chronic common medical problems of infancy and childhood have been associated with poor sleep. For instance, in early childhood, allergy to cow milk (64,65), esophageal reflux (66–68), colic (69,70), atopic dermatitis (71–74), headaches (74–77), and asthma are among the common conditions that may exert negative effects on sleep. B.
Psychosocial Factors
The early environment of the child appears to have a significant influence on the child’s developing sleep-wake patterns. During infancy and early childhood, parental personality and psychopathology (particularly maternal), interaction style, and bedtime practices have been associated with infants’ and toddlers’ sleep patterns and sleep disruptions (23,78). A review of behavioral influences on children’s sleep is presented in chapter 7. A comprehensive review of parental and cultural influences on children’s sleep is presented in chapter 8. Children’s sleep is also very vulnerable to psychosocial stressors (see Ref. 79, for comprehensive review). For instance, recent studies show that sleep of school-age children is adversely affected by marital conflict and family stress (38,80). Sleep is closely linked to the child’s emotional status and psychopathology (78,81–84). The cause-and-effect relationship between these phenomena is quite complex, since sleep characteristics can modulate the emotional regulation of the child and vice versa (84). From a developmental perspective it is interesting to note that normal maturational stages or milestones in early childhood may have significant impact on sleep. For instance, it has been argued that the normal separation anxiety that develops toward the end of the first year may increase night wakings because of the association between sleep and separation (85,86). Furthermore, the onset of crawling has been associated with more fragmented sleep in infants (87,88). C.
Gender Differences in Sleep Maturation
The issue of gender differences in children’s sleep and sleep maturation is still a very confusing research topic because of many conflicting and inconsistent reports in the literature. It is beyond the scope of this chapter to extensively review this topic, and only a few examples based on objective measures of sleep will be presented here. An actigraphic sleep-wake study of more than 200 newborns during their first 48 hours of life did not reveal any significant gender differences (2). A study of 9- to 24-month-old infants using the same methodology revealed significant
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gender differences with boys presenting higher proportion of active sleep than girls (13). An earlier EEG study of children, 6 to 12 years of age, reported a different gender difference: boys aged 10 years and older had higher percentage of stage 3 sleep and a higher delta ratio compared with girls (39). Carskadon et al. have reported higher absolute amounts and percentages of SWS in boys than in girls (89). On the basis of a longitudinal EEG study of children during their pubertal development, Dahl et al. found significant gender differences (58). Girls spent less time in REM sleep, had lower REM activity and lower REM density. The authors also reported a significant age-by-sex interaction for bedtime and sleep onset time. Interestingly, Acebo et al. (62) also reported age-by-sex interactions for SWS measures that suggest that there may be distinct maturational trajectories for boys and girls. In a naturalistic actigraphic study of school-age children (38), significant gender differences were found on measures of true sleep time (excluding all wakefulness after sleep onset time) and percent of quiet sleep (motionless sleep). Similar findings were reported in a study of Japanese school-age children (90). However, another study using the same methodology (actigraphy) found no such gender differences (91). It is difficult to depict a clear gender-related picture from the pattern of results described above. It appears that gender differences vary with age and thus appear or disappear in various studies. It is also possible that some findings on gender differences are related to psychosocial factors associated with the methods of the study. For instance, it is possible that girls and boys respond differently to questionnaires, resulting in gender differences in questionnairebased studies. Another possibility is that gender differences in actigraphic studies result from differences in motor activity rather than sleep itself (92). It is also possible that boys and girls have differential emotional reactions to sleeping in a ‘‘strange’’ environment, such as a sleep laboratory, which may lead to gender differences on sleep measures. A close inspection of the differential ‘‘first-night effect’’ seen in boys and girls in the data reported by Carskadon et al. (89) lend some support to this hypothesis. VI.
Maturation of Sleep and Cognitive Function in Children
Beyond the complex relationships between sleep and emotional regulation and psychopathology in children, sleep is also closely associated with cognitive functioning, learning, and attention. The sleep-wake system is a biobehavioral system that lends itself to a scientific investigation from the earliest stages of life and the principles of its organization, which are well documented, may shed light on other brain systems that their maturation is behaviorally manifested only in
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later phases of development. Therefore, it appears that it is particularly important to understand the relationships between the developing sleep-wake systems and the maturation of other neurobehavioral systems. Insufficient sleep and sleep disruptions have been associated with compromised neurobehavioral functioning in numerous studies in adults (93). It is surprising how limited the research is on this topic in children, where the dramatic maturation of sleep overlaps the maturation of brain systems responsible for information processing, response inhibition and modulation, attention, and regulation of motivational systems (94–97). A number of studies have associated infant sleep-wake patterns with neurobehavioral development (98–103). For instance, Scher et al. demonstrated that EEG sleep measures of newborns can predict mental and motor maturation as measured by Bayley mental scores at 12 and 24 months of age (100). Lower Bayley mental scores were associated with higher spectral EEG correlations, lower spectral EEG energies in the beta frequency ranges, fewer arousals per minute, lower REMs per minute, and shorter sleep latencies from wake state to active sleep. In an actigraphic study of 10-month-old infants, increased sleep fragmentation and higher motor activity during sleep were associated with lower mental development score on the Bayley Scales (99). In a recent study of eightmonth-old infants, increased snoring-arousal index was associated with lower Mental Development Index of the Bayley Scales (104). Taken together, these studies suggest that early organization of the sleep-wake system is associated with neurobehavioral organization and maturation. Additional support comes from other studies in infants that have demonstrated a concomitant relationship between inadequate sleep and short attention span or attention problems in infants (105,106). In older children, severe sleep disruptions have been associated with attention and cognitive problems (81,83,94,96,97). Sleep disruptions have often been implicated in attention deficit hyperactivity disorder (ADHD) and it has been repeatedly suggested that ADHD-like symptoms could result from insufficient or disordered sleep and the resultant decrease in arousal level (81,83,107). Recent studies have shown that inattention and other ADHD-like symptoms are among the common correlates of sleep-related problems, such as sleep apnea and snoring (94,108–111), and periodic leg movements (81,112). It has been demonstrated that children suffering from sleep-disordered breathing improve their academic achievements following surgical intervention of tonsillectomy and adenoidectomy (113). Insufficient sleep is another cause for compromised neurobehavioral functioning. In normal children, early school-start time and shortened sleep duration correlated with subjective complaints of sleepiness and attention problems at school (114,115). Experimental studies on sleep restriction have also indicated that insufficient sleep as a consequence of sleep restriction leads to compromised
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neurobehavioral functioning as manifested on neurobehavioral tests (116,117) and teachers’ ratings (118). In sum, a growing body of research demonstrates the close ties between the evolving sleep-wake system and the neurobehavioral maturation of the child. These findings are compelling enough to argue that insufficient or disturbed sleep patterns adversely affect the maturing brain and the concurrent (and probably the future) neurobehavioral functioning of the child. These findings reemphasize the critical role of sleep in child development. VII.
Summary and Conclusions
The maturation of sleep-wake patterns during child development consists of a complex dynamic of change and balance. While sleep time dramatically decreases with age, the relationships between various components of sleep also change to meet the changing needs of the maturing brain. These maturational processes appear to be influenced by multiple biological and psychosocial factors. Because the maturation of the sleep-wake system is an ongoing process and, at certain periods, a very rapid and dramatic phenomenon, the knowledge of normal sleep development is essential for any evaluation and understanding of clinical phenomena. The maturation of the sleep-wake system exerts significant influences on the psychosocial and neurobehavioral functioning of the child. Thus, the early identification and treatment of childhood sleep disorders or inappropriate sleep patterns is essential for the child’s development and well-being. Finally, although the focus of this chapter was not on methodological issues, it is important to note that the representation of many of the maturational and clinical sleep phenomena depends on the instruments used to measure sleep (119). Research on sleep-related phenomena often provides different picture depending on the assessment tools. Evaluation of the appropriateness of the sleep assessment method should be an integral part of research and clinical practice in this field. References 1. Hoppenbrouwers T. Sleep in infants. In: Guilleminault C, ed. Sleep and Its Disorders in Children. New York: Raven Press, 1987. 2. Sadeh A, Dark I, Vohr BR. Newborns’ sleep-wake patterns: the role of maternal, delivery, and infant factors. Early Hum Dev 1996; 44(2):113–126. 3. Coons S, Guilleminault C. Development of sleep-wake patterns and non-rapid eye movement sleep stages during the first six months of life in normal infants. Pediatrics 1982; 69(6):793–798. 4. de Weerd AW, van den Bossche RAS. The development of sleep during the first months of life. Sleep Med Rev 2003; 7(2):179–191.
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4 Maturation of Processes Regulating Sleep in Adolescents
MARY A. CARSKADON Warren Alpert Medical School of Brown University, Providence, Rhode Island, U.S.A.
I.
Introduction
Chapter 3 has provided a good introduction to the notion that sleep shows dramatic progressions as a function of development. Indeed, as young people pass into and through adolescence, sleep behaviors as well as underlying regulatory processes continue to manifest significant reworking. For example, in a report of the longitudinal progression of children’s sleep durations reported by mothers of Swiss children across the first decade and one-half of life (1), a decline in hours of sleep extends into the 16th year. This paper also showed an interesting cohort effect in which sleep time was significantly reduced across cohorts that began the study in 1974, 1979, and 1986; however, this cohort effect was greater for young children than for adolescents. Nevertheless, the issue of temporal cohort (likely combined with cultural impact) may account for differences between the Swiss data and a newer U.S.-based data set, in which reported sleep times are significantly lower than reported in the Swiss data. The National Sleep Foundation 2006 Sleep in America Poll surveyed approximately 1600 adolescents and caregivers (2). Table 1 lists the nocturnal sleep data reported in this poll of U.S. children (ca. November, 2005) aged 11 to 17 years. 95
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Table 1 Self-Reported Sleep Patterns of US Children: 2006 National Sleep Foundation Poll School nights School grade 6 7 8 9 10 11 12
Weekend nights
N
Hrs of sleep
Bedtime (PM)
Wake time (AM)
Hrs of sleep
Bedtime
Wake time (AM)
228 238 244 233 239 221 199
8.4 8.1 8.1 7.6 7.3 7.0 6.9
9:24 9:52 9:53 10:15 10:32 10:51 11:02
6:42 6:35 6:36 6:28 6:23 6:23 6:31
9.2 8.9 9.0 8.8 8.9 8.8 8.4
10:31 11:05 11:20 11:53 12:03 12:25 12:45
8:53 9:12 9:21 9:54 9:52 10:06 9:51
PM PM PM PM AM AM AM
Abbreviation: N, number of children. Source: From Ref. 2.
Comparing the hours of reported sleep on school nights with the maternal reports of Swiss adolescents, the mean nocturnal sleep of the U.S. adolescents falls near the 2nd to 10th percentiles. This contrast highlights potential cultural differences as well as those that may accrue to contemporary social conditions. The international literature emphasizes the overarching trend for sleep to diminish and bedtime (and often rise time) to delay across adolescence. Findings of survey studies from Asia (3–6), South America (7), North America (2,8–11), Europe (1,12–14), Australia, New Zealand (15,16), and South Africa (17) converge to make this point quite clear. Additional research emerging from one Brazilian group also draws attention to technological changes: adolescents living in homes without electricity show a delay in sleep; however, those in nearby electrified homes delay sleep to a greater degree and sleep less (18). Another example of the influence of technology on adolescent sleep patterns comes from the National Sleep Foundation poll data (2), showing that older adolescents reported having in their bedrooms more electronic devices (e.g., television, computer, cellular phone, instant messaging, Internet access, game stations, music players) than younger adolescents. Furthermore, the presence of four or more such devices in the bedroom was associated with a 30-minute reduction in reported sleep amount on school nights. A similar finding emerged recently from a Belgian study showing that adolescents who report using electronic media as an aid to fall asleep slept less and were significantly more tired than other adolescents (19). While patterns of change in adolescent sleep behavior are undeniably influenced by societal factors that include technology and school schedules, maturation of underlying physiological and bioregulatory processes are important
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as well. For example, one of the earliest markers for the onset of puberty is the sleep-dependent pulsatile release of luteinizing hormone, which subsequently results in sleep-related release of sex steroids (20). Further, nighttime levels of melatonin are thought by some to associate with pubertal onset. High nocturnal levels of melatonin appear to inhibit the pulsatile generation of gonadotropinreleasing hormone (21), and when circulating nighttime melatonin levels fall due to increased volume of distribution as children grow in stature, the release of this inhibition permits a reactivation of the hypothalamic pituitary adrenal (HPS) axis and the onset of puberty (20). Finally, while melatonin may have a role in the pubertal cascade, it is also important to recognize that neurotransmitter systems are also involved, and sex steroids likely have significant broad effects on the central nervous system function (20). One can also envision that this spectrum of changes affects a host of processes in addition to sleep-wake timing, including those such as learning, memory, attention, emotion regulation, behavior regulation, impulse control, and so forth. These changes also interact with sleep-wake timing in complex ways that are not addressed in this chapter but are summarized by Dahl and Lewin (22). The primary goal of this chapter is to describe maturational changes in two bioregulatory systems affecting sleep. Borbe´ly (23,24) have articulated a model that provides an organizing structure for understanding and examining biological systems underlying the timing of sleep and wakefulness, called the two-process model. In this model, a rhythmic daily oscillatory process (Process C) operates independent of a sleep-dependent homeostatic or drive-related process (Process S). Figure 1 provides a simple schematic illustration of the major features of the model. Although the two processes can be considered to act independent of one another, their effects interact to facilitate waking alertness in the daytime and consolidated sleep at night. Indeed, recent neuroanatomic
Figure 1 A schematic illustration of the major components of the two-process model of Borbe´ly and Achermann (65). Abbreviation: S, sleep, W, wake. Source: Redrawn from Ref. 75.
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investigations have begun to identify pathways that connect central nervous system regions involved in circadian timing (suprachiasmatic nucleus of the hypothalamus; SCN) and the so-called sleep switch in the ventrolateral preoptic (VLPO) nucleus of the hypothalamus (25). II.
Circadian Timing System
As indicated above, the circadian timing system functions independent of prior waking and sleep (26). The internal mechanism or pacemaker that organizes daily biological processes in mammals has been localized to a small paired nucleus in the hypothalamus, the SCN (27). This neuronal system has both intrinsic rhythmic properties and the capacity to synchronize (entrain) to rhythmic environmental stimuli. The principal entraining stimulus is the cycle of daylight and darkness. One common metaphor for the circadian timing system is that of an oscillator whose oscillatory period is entrained by an external time-giver, termed a zeitgeber. Therefore, when one measures physiological variables round the clock in organisms living in natural conditions, the expressed period of the system is 24 hours because the internal pacemaker is entrained to the natural 24-hour day length. When an organism is removed from natural conditions and placed in an environment with constant conditions, the internal oscillator is said to run free (free run) at its intrinsic period because of the absence of external control. Most organisms have a non-24-hour intrinsic period. In adult humans, the average intrinsic period is thought to be slightly longer than 24 hours (28). Measures of intrinsic period have been derived from humans living under forced desynchrony (FD) conditions because it is difficult to study humans under constant conditions (i.e., confined to constant darkness for many days and nights) as one would study a hamster. When organisms live under normal environmental conditions, the non24-hour nature of the intrinsic circadian period and other intrinsic features of the circadian timing system influence the way internal rhythms become synchronized to the environmental factors setting the 24-hour day. Light has a major influence as a synchronizer of the human circadian timing system (29–38), and it is becoming increasingly clear that the human circadian timing system is sensitive to relatively low light levels, including those commonly encountered indoors (39–44). The process by which the internal oscillatory period is synchronized to the external day is called entrainment. This process is phase dependent and can be mapped onto a function called the phase response curve (PRC). The shape of the PRC function is generally similar, but can vary from species to species and also from individual to individual (45). The nature of the response is genetically regulated on the basis of molecular components of the neural clock mechanism. Descriptions of human PRCs to light indicate that the human system in general functions in a systematic and predictable manner: evening light (before the minimum of the core body temperature rhythm, called Tmin) produces phase delays and morning light (after Tmin) produces phase advances (35).
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Classic circadian rhythm theory provides a framework for predicting other features of the system on the basis of individual and environmental characteristics, much of it deriving from oscillator theory. Among these predictor and predicted features are phase (the instantaneous state of an oscillator within a period), amplitude (the absolute value of the full peak-to-trough excursion of a rhythm), and phase angle (the temporal difference between phases of two rhythms or between a rhythm and a recurrent environmental signal). At this time, there is no reason to presume that these general principles differ during adolescence, though certain features of the system may change systematically as a function of adolescent maturation. Several phase markers are commonly used to describe the circadian timing system in humans. These include the onset, offset, or midpoint of the melatonin secretory rhythm,a the peak or trough of the core body temperature rhythm, and the onset, offset, or midpoint of activity, inactivity, or sleep. The timing of melatonin secretion is one of the most reliable of such measures (46) and is easily accessible in young humans through radioimmunoassay of melatonin from serial saliva samples. Thus, one can assess the phase of the circadian system using the phase of melatonin secretion. With this framework in mind, let us examine the influence of the circadian timing system on the sleep-wake process. The circadian timing mechanism affects the infrastructure of sleep, as well as the timing of sleep and wakefulness. Studies that involve temporal isolation or multiple sleep opportunities across a day (e.g., 90-minute or 180-minute day) show that the timing of sleep onset (47–52), the length of sleep (49,52), and the timing of REM sleep (53–55) vary as a function of circadian phase. More recent studies under FD conditions that provide multiple opportunities to examine human sleep at different circadian phases while controlling the wake-dependent process confirm and extend these findings (26,56–58). A.
Developmental Changes in Circadian Regulation
One of the earliest indications that changes in the intrinsic circadian timing system accompany puberty stemmed from a self-report assessment of pubertal development and circadian phase preferenceb in sixth graders (59). These data a
Pineal melatonin secretion is controlled by the circadian timing mechanism (and feeds back on this system) to rise during the brain’s nighttime and cease during the daytime of the brain. Melatonin secretion can be suppressed by light, and such suppression is thought to be one indicator of the extent to which light affects the timing system. We use melatonin levels to mark internal time as the ‘‘hands’’ of the intrinsic circadian clock. b Kleitman provided the first clear articulation of the construct of morningness/eveningness in his classic review of sleep and wakefulness (110). He proposed that this dimension was identifiable in individuals on the basis on differences in the peak of body temperature and performance efficiency: those who were ‘‘morning’’ types would peak earlier in the day than the ‘‘evening’’ types. Methods have also been devised to assess phase preference with questionnaires. The first reliable method for establishing M/E type was published in English in 1976 (100). Other measures have since been devised, including one by our group to assess morningness and eveningness in children (42).
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showed that sixth-grade girls who rated themselves as more physically mature also rated themselves as more ‘‘evening’’ type in their phase preference. Subsequent studies used physiological markers of circadian phase and physicianrated pubertal stage. One such study confirmed the circadian phase delay tendency in a laboratory study in which the Tanner stage (a measure of secondary sexual characteristics) was assessed by physician evaluations and the circadian phase was measured by salivary melatonin levels. Again, the pubertal stage correlated with the circadian phase marker such that more mature children showed a later phase of melatonin secretion offset (60). Others have made similar observations, which together provide convergent evidence that the circadian phase undergoes a delay in association with puberty under field conditions, as well as when controlling for psychosocial influences on sleep-wake patterns. This association is strong evidence that Process C is changing during adolescence. An unresolved issue, however, regards the nature of the mechanism underlying this adolescent phase delay. One mechanism predicted by circadian rhythms models is that a circadian phase delay may be related to a longer period of the circadian clock, that is, a longer internal day length (61). Under normal, day-to-day circumstances, environmental features that have a 24-hour period, particularly the light-dark cycle, entrain the internal clock to 24 hours. The phase angle with which the internal clock time aligns with the external day, however, is determined in part by the intrinsic circadian period: the phase angle of entrainment is delayed in parallel with the extent to which the internal day length exceeds 24 hours. For example, Wright et al. (62) showed that a 6-minute increase in period length is associated with a 24-minute delay in the phase angle of sleep. Thus, if the intrinsic period lengthens in association with pubertal development, it could provide an impetus that drives the phase delay. The method for measuring the intrinsic period in humans is a bit arduous, involving prolonged laboratory stays under carefully controlled conditions that schedule a day length either significantly longer or shorter than 24 hours. Our group has studied adolescents using an FD protocol to collect phase markers across 12 cycles on a 28-hour day. An initial analysis of the intrinsic period in adolescents showed that it was longer than that reported by others in young adults (63). We have also examined the intrinsic period of only those adolescents who were in their pre (Tanner stage 1) or late (Tanner stage 5) puberty when they completed the FD protocol. As Figure 2 depicts, these data do not provide firm evidence of a pubertal change in period in this rather small cross-sectional sample. On the other hand, when the distribution of intrinsic period of the complete adolescent sample is compared with samples of adults in whom the period was also derived from melatonin phase markers in FD (28,64), the data show that the circadian clock period in the combined adolescent sample is significantly longer than in the adult sample (65) (Fig. 3). Another important feature of the circadian timing system is the phasedependent sensitivity to light, which is intrinsic to the clock-resetting process (66).
Figure 2 Intrinsic period measured with a 28-hour forced desynchrony approach in one group of children at Tanner stage 1 and another at Tanner stage 5. The square symbol represents boys and the filled circle, girls.
Figure 3 A comparison of the intrinsic period from our group’s combined adolescent sample open bars with data reported by the others for adults from three studies (28,58,64) darkened bars. The average intrinsic period for 26 adults (age, 19–41 years) was 24.14 hours (24 hour 8 minutes 0.14 hour) versus 24.26 hours (24 hour 16 minutes 0.18 hour) in 35 adolescents (age, 9–15 years), a statistically significant difference (t = 3.11, p = .003) when outliers (2SD) were removed from both samples.
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One marker of the effects of light on the circadian timing system is the suppression of melatonin levels when exposed to light (67). Our group has hypothesized that the sensitivity of the circadian system to light may change during pubertal development in a manner that accentuates the tendency for a phase delay (68). In brief, we suggested that a heightened sensitivity to evening light or a decreased sensitivity to morning light across pubertal development could result in the pubertal delay of sleep timing. We assessed this hypothesis in 66 participants who received four levels of light on consecutive nights, either in the late evening or early morning. Greater suppression occurred in response to the lowest level of light (15 lux) administered in the morning for pre- and early-pubertal participants than for late- or postpubertal participants; no differences in response to late-night light were found (68). Again, the findings are suggestive but inconclusive, in part because of the cross-sectional design. Furthermore, the recent identification of a novel opsin (69) localized to specific retinal ganglion cells that carry light information directly to the SCN (70,71) questions whether methods using broadspectrum light provide an adequate test of the hypothesis. Indeed, studies with human subjects show that the circadian system is most reactive to short (i.e., blue) wavelengths, approximately 460 nm (72,73). Thus, our previous study may have missed a developmental difference because an ineffective stimulus was used. We can conclude from the findings summarized above that the circadian timing system in many adolescents undergoes a phase delay. The mechanism of this phase delay is unknown, though it may be related to an increase in the intrinsic period length or a change in phase-dependent light sensitivity. Further research, particularly longitudinal studies, would help clarify how the circadian timing system affects the sleep-wake patterns of adolescents. As described below, the full story is likely to include features of the sleep-wake homeostatic system. III.
Sleep-Wake Homeostasis (Process S)
In brief, the sleep-wake-dependent process is modeled as Process S, which accumulates while awake and dissipates during sleep (Fig. 1) (23). This process is most simply stated as: sleep favors wake and wake favors sleep. All other things being equal, therefore, the longer one is awake, the greater is the pressure to sleep; conversely, the closer one is to having slept, the less pressure there is to sleep. Process S accounts for the increased need for sleep after staying awake all night and the difficulty of staying awake, in general, when faced with a chronic pattern of insufficient sleep. Although the neurobiological underpinnings of this system have not been fully delineated, the operational outputs of this sleep-wake regulatory system—such as quantitative measures of the EEG—have been well described (for an overview, see Ref. 74), and extensive modeling has successfully predicted outcomes (75) in response to experimental manipulations. Electrophysiological markers of Process S include (1) stage 4 NREM sleep, also known as slow-wave sleep, or SWS (76), and (2) EEG power density in the low frequency range (0.75–4.5 Hz), also known as slow-wave activity, or
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SWA (77). The time course of Process S exhibits an exponential decay during sleep and is best described by a saturating exponential rise during waking. Sleep occurring after a brief episode of waking (as in a daytime nap) shows relatively little stage 4 and low levels of SWA (78,79) as compared with these features during sleep that follows a normal or extended day length (77,80). Thus, SWA levels during NREM sleep are determined by the duration of prior wakefulness. In addition, the speed of falling asleep (sleep latency) has been demonstrated to be a marker for the sleep pressure aspect of Process S (81). For example, reduced sleep over several nights induces a progressive reduction of sleep latency (82). A.
Developmental Changes in Process S and the Homeostatic Process
A developmental alteration of SWS during adolescence has been known for a number of years. Feinberg (83) as well as the Williams group using cross-sectional samples, showed that SWS declines across the adolescent years (84,85). Karacan et al. (86) showed an adolescent decline in SWS in a longitudinal study where sleep was on the participants’ ‘‘usual’’ schedules, a finding confirmed by Carskadon (87) in a longitudinal study that held the sleep schedule constant, and most recently reconfirmed by the Feinberg group (88). In the Carskadon report (87), SWS declined by approximately 40% from Tanner stage 1 (age, 10–12 years) to Tanner stage 5 (age, 14–16 years). [Tanner staging uses secondary sexual characteristics to gauge pubertal development (89). Tanner stage 1 is prepubertal, stage 2 early pubertal, stage 3 midpubertal, stage 4 late pubertal, and stage 5 mature.] Several groups have presented data examining spectral EEG variables, including SWA, across adolescent development (90–92). Gaudreau et al. (91), for example, reported a nocturnal decline of SWA between children and adolescents. One report (93) presented findings across a longitudinal sample of early adolescents showing a decline of nocturnal SWA in adolescents, although the authors interpret these data as evidence against pubertal involvement in the developmental decline of SWA. Because the change occurred at a younger chronological age in girls than boys, however, the phenomenon may be associated more with pubertal status than chronological age, since girls typically enter puberty at a younger chronological age than boys. The fundamental question remains, however, whether the decline of SWA reflects altered sleep-wake regulation. Our group has begun to examine pubertal changes in the sleep EEG within the context of the sleep-wake homeostasis model. To summarize briefly, we have shown significant reduction in EEG power density during NREM sleep at frequencies <2 Hz and 4 to 6 Hz for mature (Tanner stage 5) versus prepubertal (Tanner stage 1) participants in a cross-sectional design (92). [Fig. 4 illustrates in one participant the changes in sleep (especially SWS) and SWA between recordings made approximately two years apart encompassing maturation from Tanner stage 1 to Tanner stage 5.] These data also showed an exponential overnight decay of SWA in both developmental groups, with equal time
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Figure 4 An illustration of sleep hypnograms (gray) and EEG spectral power (black) in the slow frequencies (SWA, 0.75–4.0 Hz) in one girl studied on the same protocol two times. On the first occasion, she was aged 12.3 years and Tanner stage 1; on the second occasion, she was aged 14.5 years and Tanner stage 5. The decline of stage 4 sleep and SWA activity in the lower plots versus the upper plots are clear. Abbreviations: EEG, electroencephalogram; SWA, slow-wave activity. Source: From Ref. 92.
constants for the fitted decay function (Fig. 5). This finding indicates that the regulatory process involved in the dissipation of Process S across sleep under controlled sleeping conditions does not change across pubertal development. One interpretation of this finding is that it lends support to the notion that the ‘‘need’’ for sleep does not diminish across adolescence (87). The substantial decline of SWS and low-frequency EEG power across adolescence may rather reflect changes in the underlying brain structure (e.g., declining cortical synaptic density) as hypothesized by Feinberg (94,95). On the other hand, small crosssectional data sets may not be adequate to test the notion that the rate of sleep recovery changes across adolescent development. The accumulation of Process S may also differ in its expression across adolescent development on the basis of preliminary evidence from cross-sectional samples. A test of this hypothesis requires assessment of the homeostatic markers under conditions that involve an alteration of the usual daily sleep-wake schedule, such as napping or extended wakefulness. Our group has performed spectral EEG analyses in the sleep episode, following an extended waking interval of 36 hours. These analyses showed the expected increase in low-frequency EEG power during NREM sleep for pre- and early-pubertal and late-pubertal groups (96).
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Figure 5 The overnight decline in SWA in prepubertal (closed circles) versus postpubertal (open circles) adolescents. Functions fitted to the two data sets confirmed that the decay of Process S across the night is the same in both groups. Abbreviation: SWA, slowwave activity. Source: From Ref. 92.
Prepubertal children, however, manifested a less pronounced (30%) average increase of low-frequency power comparing recovery with baseline versus the mature adolescents (70%), indicating that the younger child’s brain may more quickly reach maximal capacity for low-frequency activity during sleep. Subsequent analysis of these data included application of features of the homeostatic model and showed a significant difference in the rise-time constant of Process S between groups, with a faster rise time in the less mature group (8.9 hours) than in the mature group (12.1 hours) (96). This finding indicates that the wakeresponsive component of Process S builds up more quickly during the waking day in prepubertal than postpubertal adolescents. Our group has also examined the accumulation of Process S using the multiple sleep latency test (MSLT) in adolescents during 36 hours of sleep deprivation (97). These data showed that sleep latencies during initial hours of extended wakefulness, that is, 14.5 to 16.5 hours after morning awakening, were longer in more mature participants than in prepubertal children. Combined with the SWA analyses, we interpret these findings to indicate that the accumulation of Process S across the day occurs at a slower rate in more mature adolescents. As with the data showing no maturational differences in the overnight decay of Process S, however, longitudinal assessments are needed. IV.
A Model Relating These Processes to the Adolescent Sleep Delay
Our working model of the adolescent sleep delay involves developmental changes of the sleep-wake and circadian systems and acknowledges as well the impact of behavior and lifestyle changes that characterize adolescent development. We
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propose that young children, even if mimicking adolescent sleep behavior (i.e., attempting to stay awake late at night), are physiologically unable to experience much of a sleep delay. Further, we propose that this preventive mode of late childhood development stems from the immaturity of both of the intrinsic regulatory processes described above. A combination of ‘‘preventive’’ phenomena in late childhood is replaced by ‘‘permission’’ and ‘‘pressure’’ to delay during adolescence. Shorter internal circadian period, greater sensitivity to phase advancing light, and a more rapid build-up of Process S, all may prevent delaying sleep during childhood. On the other hand, maturation of the intrinsic regulatory processes may facilitate an adolescent phase delay in several ways. We hypothesize that the intrinsic circadian period lengthens during adolescent development, providing an actual driving force to the delay through the interaction of a slow oscillator (long period) with the entraining oscillator (24-hour period), which leads to a phase delay of entrained rhythms (61). On the Process S side of the ledger, we propose that the developmental process opens a ‘‘gate’’ permitting phase delays by enabling extended wakefulness (later bedtime). Once later bedtimes begin to occur—either because of behavioral changes or through the Process S gate opening—the circadian process is engaged through exposure to light on the phase-delaying portion of the PRC. We hypothesize that the delaying property of the PRC becomes more sensitive during adolescent development, an as yet untested hypothesis. These maturational changes are fed, in part, by the behavioral patterns of adolescents, which in contemporary Western countries involve greater accessibility to activities later and later in the evening. Whether enhanced by television, computers, cellular communications, or the Internet, or whether fueled by homework, employment, or social events, lifestyle interacts with these bioregulatory processes to delay the hours for sleeping. Unfortunately for many teens, another fact of adolescent life is an early start to the school day. As a result, many adolescents not only sleep too late, but also too little. V.
What About Young Adults?
One question that frequently arises is whether/when the sleep phase delay of adolescence resolves or reverses. Roenneberg et al. (98) measured ‘‘chronotype’’ in about 25,000 Europeans (primarily Swiss and German), using the midpoint of the sleep episode (bedtime to rise time) on ‘‘free’’ days (that is, when behavior is not scheduled by work or school, e.g., weekends) as their phase marker. They proposed that the reversal of a linear delay of chronotype that takes place across the second decade is a ‘‘marker for the end of adolescence.’’ Part of the case that Roenneberg et al. make for their strong statement of the biological nature of this ‘‘turn’’ from adolescence to adulthood is that the timing of this developmental pattern differs between sexes. Thus, the adolescent delay begins at a younger age for girls than boys, and the start of the adult
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advance also occurs at an earlier age in young women than men. This sex-age association may indicate that hormonal differences influence circadian timing. Again, these are cross-sectional data, however, and thus fall prey to making developmental assumptions without actually measuring within individuals (99). One of the most important concepts of circadian biology is that behavior can feed back on the clock in important ways, either through gating light exposure and thus affecting the light PRC or through affecting nonphotic phaseresetting responses, for example, by influencing activity (100). Sociocultural changes occurring early in the third decade might, therefore, be most influential in producing the young adult reversal in phase. On the other hand, Roenneberg et al. (98) noted a similar pattern of age-related change in chronotype in a sample drawn from isolated and socially distinct areas of the Tyrol. If, indeed, the sleep-delaying pattern of adolescence is driven by intrinsic biological changes, then a strong candidate for the reversion to earlier timing across adulthood is a shortening of the intrinsic period. As reviewed above, period is correlated with phase, in that animals expressing long internal period manifest delayed entrainment to zeitgebers versus animals expressing short internal period (61). Duffy et al. (101) have shown that intrinsic period correlates with morningness/eveningness in human adults, which could account for these differences in phase preference/chronotype. In a study of 17 young men in whom the circadian period was assessed using FD, these authors reported a significant negative correlation of morningness/eveningness with period: those with a shorter circadian period were more morning-type than those with a longer circadian period. Furthermore, our data comparing the intrinsic period of adolescents with those of young adults show longer period in the younger group (Fig. 3). VI.
Implications
In the United States in particular, as well as in several other industrialized societies, the changing adolescent sleep-wake system exists in the context of an unforgiving educational structure demanding earlier school attendance in older rather than younger children. This combination of factors leads to inadequate and ill-timed sleep in a large number, if not a majority of young people. Our group has found, for example, that the estimated amount of school-night sleep in youngsters in grade 6 averages 500 minutes, in grade 8 is 473 (102), and in grade 10 is 452, and in grade 12 is 420 minutes on the basis of objective monitoring in the field. Laboratory data indicate that the sleep ‘‘need’’ in these youngsters is closer to nine hours per night (87,103). As we learn more about the effects of chronic insufficient sleep, concerns grow about the potential for negative impacts on adolescents. For example, rates of automobile crashes attributed to falling asleep while driving are markedly higher for the youngest drivers. Indeed, a retrospective analysis of over 4000 such occurrences showed that the drivers’ ages in just over 50% of crashes were 16 to 25 years (104). Growing evidence also indicates that adequate sleep plays an
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important role in memory consolidation and learning processes (105–108), though research specific to adolescents is scarce. The preponderance of evidence from a variety of studies examining the association of sleep patterns with academic performance indicates that too little and poorly timed sleep has a negative impact on achievement in children, adolescents, and young adults (109). Furthermore, tardiness, absenteeism, and high school graduation rates in adolescent students have been linked to sleep schedules and early school starting times (110). Mood regulation also suffers with inadequate sleep. The recent National Sleep Foundation poll results, for example, show greater rates of depressed mood in adolescents who report sleeping fewer than eight hours at night (2). Behavior disruption has also been noted as a concomitant of disturbed sleep in children with sleep disorders (111–114); less is known about this association in adolescents. Substance use, including caffeine, alcohol, and tobacco, is also greater in teens who sleep less (115,116). Recent data in adults show that sleep is not simply for the mind, but affects metabolic processes as well (117). Indeed, adolescent obesity has been linked with poor sleep patterns (118). As sleep patterns are examined along with other lifestyle or medical outcomes, we can anticipate more negative associations to become apparent. The robust tendency for the timing of sleep to delay during adolescent development is undeniably associated with the changed psychosocial environment of the developing teen and is also affected by developmental changes in fundamental regulatory processes. For many teens, this sleep-delaying pattern cascades into a chronic pattern of insufficient school-day sleep, forced arousals at a biologically inappropriate time, and resulting negative impacts on performance, behavior, mood, and other processes. Countermeasures that are implemented on a personal, family, community, or societal level need to acknowledge all the factors contributing to the issue. A primary step in this direction is to acknowledge a positive priority for sleep and a need for a better understanding of the sleep-wake regulatory process through education and research. References 1. Iglowstein I, Jenni OG, Molinari L, et al. Sleep duration from infancy to adolescence: reference values and generational trends. Pediatrics 2003; 111(2):302–307. 2. National Sleep Foundation. 2006 Sleep In America Poll Summary Findings. Available at: http://www.sleepfoundation.org/site/c.huIXKjM0IxF/b.2419037/k.1466/ 2006_Sleep_in_America_Poll.htm. Accessed February 14, 2007. 3. Arakawa M, Taira K, Tanaka H, et al. A survey of junior high school students’ sleep habit and lifestyle in Okinawa. Psychiatry Clin Neurosci 2001; 55(3):211–212. 4. Gau SF, Soong WT. The transition of sleep-wake patterns in early adolescence. Sleep 2003; 26(4):449–454. 5. Park YM, Matsumoto K, Seo YJ, et al. Changes of sleep or waking habits by age and sex in Japanese. Percept Mot Skills 2002; 94(3 pt 2):1199–1213. 6. Yang CK, Kim JK, Patel SR, et al. Age-related changes in sleep/wake patterns among Korean teenagers. Pediatrics 2005; 115(1 suppl):250–256.
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5 Characteristics of Arousal Mechanisms from Sleep in Infants and Children
PATRICIA FRANCO, AUDE RAOUX, and SUSAN HIGGINS Pediatric Sleep Unit, Hoˆpital Debrousse and INSERM U 628, University of Lyon 1, Lyon, France
INEKO KATO Nagoya City University, Nagoya, Japan
ENZA MONTEMITRO Universita di Roma ‘‘La Sapienza’’, Rome, Italy
JOSE´ GROSWASSER and SONIA SCAILLET University Children Hospital Reine Fabiola, Free University of Brussels, Brussels, Belgium
JIAN-SHENG LIN INSERM U 628, University of Lyon 1, Lyon, France
I.
Introduction
If sleep is of great importance for the well being of humans, the propensity to arouse from sleep is an integrative part of the sleep structure. Compared with the large amount of studies on sleep characteristics, little attention has been paid to the mechanisms controlling arousals. These mechanisms allow sleep to continue in the face of stimuli that normally elicit responses during wakefulness, but also permit awakening to the most urgent information. Such adaptive mechanisms imply that malfunction may have clinical importance. Inadequate arousal control in infants and children is associated with a variety of sleep-related problems. An excessive propensity to arouse from sleep favors the development of repeated sleep disruptions and insomnia, with impairment of daytime alertness and performance (1–3). Lack of adequate arousal response to a noxious nocturnal stimulus reduces the infant’s chances to autoresuscitate, and survive, increasing the risk for the sudden infant death syndrome (SIDS) (4–10). Indeed, future SIDS
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victims arouse less frequently, mainly during the last part of the night, when most deaths from SIDS occur (11). This chapter reviews the mechanisms underlying the arousal process, the definition of an arousal, the techniques for the recording, the different methods used to evaluate the arousability, and the confounding factors that modify the determination of arousal thresholds. The levels of arousal thresholds depend on experimental conditions (type and time of arousal challenge). The infant’s arousability is decreased by maternal factors, such as exposure to cigarette smoke or illegal drugs. The levels of arousal thresholds also depend on age and sleep conditions. Some factors can also occur together and influence arousability. II.
The Hierarchy of the Arousal Process
The arousal response is not a discrete state, but a continuous process. Arousals reflect the activation of various structures, from subcortical to cortical areas (8,12,13). It has been suggested that there is a hierarchy of arousal phenomena generated from subcortical as well as cortical sites. Following CO2 exposure, infants showed a specific sequence of stereotyped behaviors before awakenings from a sigh (i.e., an augmented breath) coupled with a startle, followed by thrashing movements and full arousal (8). Activation of brain stem arousal reflexes alone can cause recovery from hypercapnic episodes without the need for cortical arousal. The startle response observed in these infants was viewed as a subcortically mediated defensive response, as it was frequently effective in providing access to fresh air without necessarily involving a full behavioral arousal. Considering the evidence that repeated sleep disruption retards infant growth and development, it is biologically appropriated that arousal occurs as a stepwise escalation of responses, preserving the integrity of rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. Using a nonrespiratory (tactile) stimulus to elicit arousal, the same progression of central nervous system activation from a spinal to cortical levels was found in active sleep (AS) and quiet sleep (QS) (14). Tactile stimulus elicited an arousal sequence that commenced with a spinal withdrawal reflex, was followed by brain stem responses (respiratory and startle responses), and ended in a cortical arousal. The entire pathway, or part of it, in the order of spinal to cortical responses, could be elicited in AS and QS. It could be inferred that the spinal response threshold is lower than the brain stem responses, and similarly that the brain stem threshold is likely lower than the cortical response threshold. The spinal or the brain stem responses were largely unaffected by the presence or absence of a cortical arousal from sleep. These findings are consistent with previous research that found that arousing stimuli, i.e., acoustic stimulation or obstructive sleep apnea, were associated with autonomic brain stem responses, such as increases in heart rate and in blood pressure, without causing EEG arousals (15,16). During spontaneous microarousals in adults, increases in heart rate appeared before cortical arousals. Rises in heart rate increased with arousal intensity, suggesting a
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continuous spectrum in the arousal mechanism, starting at the brain stem level and progressing to cortical areas (17). In response to various stimuli, an increase in heart rate and blood pressure was also found in infants (18). These findings were postulated to result from the involvement of active brain stem centers regulating arousals. For a complete awakening, there is a need for an increase in cortical activation. From the analysis of the EEG background before spontaneous awakenings in AS and QS in 9- to 14-week-old infants, the EEG activation level increased before awakening only in QS. The EEG background activity did not change in the minutes preceding awakening out of AS, suggesting that high levels of EEG activity are necessary for the occurrence of a spontaneous awakening (19). III.
Definitions and Scoring Methodologies
The literature offers a wide range of terminologies for the scoring of arousal (Table 1) (20–27,30). Terms such as arousals or awakenings are often used to describe changes from sleeping to waking states. Brief or transient arousals are different from behavioral awakenings. Awakenings or arousals range from subtle polygraphic changes such as physiologic activation, subawakenings, and stimulus awareness to (eventually) full awakening. The child may appear asleep but manifest abrupt changes in cardiac, respiratory, muscular, galvanic skin, or EEG responses. Some of these manifestations represent autonomic responses, whereas changes in the EEG microstructures, with the intrusion of K complexes, characterize arousals without awakenings (28). Such changes are scored as polygraphic or electric arousals. According to the American Sleep Disorders Association (ASDA) report, transient polygraphic arousals are defined by the occurrence over at least three seconds of an abrupt shift in EEG frequency associated, only in REM sleep, with an increase in electromyography (EMG) submental amplitude (26). The reliability of ASDA criteria has been evaluated in adult patients with respiratory disorders (29). The overall agreement was moderate (k ¼ 0.47), but was best for events during slow-wave sleep (k ¼ 0.60), moderate for REM (k ¼ 0.52), and poor for light sleep (k ¼ 0.28). The authors concluded that agreement would be better in clinical practice because the reviewers had access to only a 40-second epoch EEG recording rather than the complete record, and did not have access to the respiratory variables. In addition, it is possible that agreement would have been improved by making the criteria more specific, perhaps by extending an EMG criterion to all sleep. As there is no similar set of guidelines for children, many investigators are using the ASDA guidelines when evaluating children’s sleep arousal. However, a number of investigators have scored arousals in children using a shorter duration criterion of one second in an attempt to detect sleep disruption in children with more sensitivity (22,30,31). Wong et al. (32) evaluated interscorer reliability in the assessment of arousals lasting one, two, and three seconds in children. They
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Table 1 Definitions of Arousal Proposed in the Literature Types of arousal
Duration
Reference Subject
Behavioral
Sustained
20
Behavioral
Sustained
21
Polygraphic
Brief
26
Polygraphic
Brief
20
Polygraphic
Brief
22
Polygraphic
Brief
30
Polygraphic
Brief
23
Polygraphic
Brief
24
Polygraphic
Brief
25
Polygraphic
Brief
27
Definition
To indicate arousal from sleep, Children, adolescents, subjects were instructed to press a hand-held button three and adults times and say ‘‘I’m awake’’ Children Eye opening, sustained body movement, or crying Adults Abrupt changes in EEG frequency for at least 3 sec plus an increase in submental EMG amplitude only during REM sleep Children, EEG desynchronization and/or adolescents, elevated EMG activity and adults Children Changes in any two signals for at least 1 sec: EEG, chin or arm EMG, heart rate, pulse waveform, breathing Infants, ASDA’s definition, but with a children minimum duration of 1 sec Infants Presence of tonic muscle tone concomitant with low-voltage, mixed-frequency EEG Infants Abrupt changes in EEG frequency with increase amplitude in breathing volume and muscular tonus for at least 3 sec Infants At least 3 of the 4 criteria for subcortical arousal: changes in breathing, behavioral, heart rate, and submental EMG Infants Subcortical activation: changes (0–6 mo) in any two signals for at least 3 sec: gross movement, heart rate, breathing (NREM sleep), EMG (REM sleep). Cortical arousal: same criteria plus EEG changes (>1 Hz)
Abbreviations: EEG, electroencephalogram; EMG, electromyography; REM, rapid eye movement; NREM, non-rapid eye movement; ASDA, American Sleep Disorders Association. Sources: From Refs. 20–27, 30.
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showed that in children, as in adults (33), three second arousals were highly reproducible (ICC ¼ 0.90), whereas arousals less than three seconds had poor interscorer reliability (ICC ¼ 0.35 and 0.42, respectively, for 1 and 2 seconds criteria). On the basis of this study, it seems reasonable to use the three-second ASDA criterion for scoring cortical arousals in children, as shorter arousals are difficult to score accurately. Crowell et al. have applied the ASDA criteria in 35- to 64-week-old infants and found that ASDA arousals could also be scored reliably in this age group (34). However infants, during the first year of life have a maturational process of EEG activity and sleep structure (35). In the newborn and the young infant, the well-known spontaneous variability in respiratory, body movements, and heart rate significantly complicate the evaluation of arousals. In 1998, an International Pediatric Work Group was set up by sleep experts with an aim to define a method for the scoring of arousals in infants. This group has recently published a consensus on the method for the scoring of arousals in healthy term infants aged from one to six months, on the basis of the analysis of polysomnographic recordings (27). Arousals were subdivided into subcortical activation or cortical arousal. A subcortical activation was scored if no change in EEG was seen, while at least two of the following changes occurred: a gross body movement detected by movement sensors or seen as an artifact movement in the somatic channels, changes in heart rate (of at least 10% of baseline values), changes in breathing pattern (frequency and/or amplitude) in QS, or increase in chin EMG tonus in AS. A cortical arousal was scored using the above criteria, with the addition of the occurrence of an abrupt change in EEG background frequency of at least 1 Hz, for a minimum of three seconds. Still, the above method for the scoring of arousals leaves several technical and physiological questions unresolved, such as the magnitude of the EEG and heart rate changes according to the age of the infant, the differentiation of cortical arousals from subcortical activations in the presence of movement artifacts on EEG channels, the significance of isolated cortical changes occurring during sleep, and the differentiation between phasic events of AS and subcortical activation or cortical arousal during AS. In addition to the technical problems, there are pathophysiological limitations to the ASDA definitions. There is no correlation between ASDA arousal index and behavioral, psychiatric, or neurocognitive outcomes in children. Subjective sleepiness was observed in 28–43% of children with sleep-disordered breathing (36,37). However, studies have not shown a significant relationship between the arousal index and daytime sleepiness using either subjective scores [modified Epworth Sleepiness Scale (36) or Pediatric Sleep QuestionnaireSleepiness Subscale (37)] or objective measure by multiple sleep latency test (MSLT) (37). In 103 children aged 5 to 12 years, the EEG arousal index was not statistically different between subjects with sleepiness (13.9 7.7/hr) compared with those without sleepiness (11.6 6.1/hr) (37). However, using a research version of the MSLT that used 30-minute nap opportunities, Gozal et al. found a correlation between the arousal index and the MSLT (38).
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Similar limitations have been found in adult studies (39,40). Most studies in adults have failed to find a correlation between the ASDA arousal index and sleepiness or neurocognitive outcomes (39). To best assess the complications of sleep fragmentation, other alternative techniques have been advocated, such as EEG spectral analysis (41), respiratory cycle-related EEG changes (42), cyclic alternating pattern (28), or the sleep pressure score (43). Methods of evaluation of autonomic nervous tonus may also be useful [pulse transit time (44), peripheral arterial tonometry (45) or evaluation of beat-to-beat blood pressure changes (Portapress) (46)]. IV.
The Determination of Arousal Thresholds
Spontaneous arousability can be differentiated from arousal responses to environmental stimuli. The propensity to arouse from sleep can be evaluated by exposing the sleeper to awakening challenges. These stimuli can be exogenous or endogenous. An arousal threshold is determined by measuring the intensity of the stimulus needed to induce an arousal. The time spent between the start of the stimulus and the arousal reaction can also be evaluated. The study of the arousal threshold requires that the subject investigated spends a long enough period asleep to exhibit all classic sleep stages and to permit continuous polygraphic recordings of EEG, ECG, airflow, and thoracic and abdominal movements, in order to monitor EEG as well as non-EEG changes. Stimuli used in the evaluation of arousability should be noninvasive, easily quantifiable, and induce specific as well as reproducible responses. It is not clear from the literature how a threshold should be determined. It can be scored following a single reaction to an increasing, or decreasing, series of stimulations. It can also require several intensities of the stimuli administered both above and under the level of reaction so as to define supra- and infraliminal intensities of the challenge (25). No consensus exists on the type of challenge that best fits the determination of the thresholds. Noise, gases, light, nociceptive, mechanical, chemical, and temperature stimuli have all been used. Individual characteristics as well as experimental conditions greatly modify the subjects’ arousal responses. Some of these potential experimental confounders are discussed in the following section. V.
Factors Influencing Arousability
A.
Experimental Conditions
Type of Arousal Challenge External Stimuli
Auditory Stimulation. No standard method exists for the administration of auditory stimuli. Auditory arousal challenges have been performed with unfamiliar stimuli, such as white noise (24) or 1-kHz pure tones (47), or with familiar noises (e.g., telephone ring, train sounds) (48). Various strategies have
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been used to administer auditory stimulations. The signal generators may be located in the midline of the crib (47) or near the ears of the infant (20,24). The initial signals have been either constant stimuli with fixed tones (49) or tones of increasing intensity (24,20). The lapses between stimulations also varied from milliseconds (47) to a minute (24). Apart from the methodological differences, this method has been well studied. The reproducibility of the method has been demonstrated. There is a significant night-to-night correlation in the auditory threshold during NREM and REM sleep in the adult population (50). Light Stimulations. These appear to be a weak arousal stimulus in infants (47,51). Only 47% of infants had behavioral arousals with photostimulation during QS (51). Controlled Pulsatile Air Jets. These evoke trigeminal stimulation by applying a jet of air to the nostrils with varying intensities (25). Vibrotactile Stimuli. These excite muscle receptors and/or Pacinian corpuscules by mechanical stimulations at different frequencies and intensities on the arm (4). Head-Up Tilt Test. Infants were tilted 608 head-up, and arousal responses were observed (52). The postural change induced a fall in blood pressure, stimulating the arterial baroreceptors. Arousal Stimuli Related to Respiration. Respiratory arousal is defined as arousal from sleep associated with progressive increases in stimuli related to respiration (hypoxia, hypercapnia, and respiratory effort) (6). Hypoxic and Hypercapnic Challenges. Hypoxemia is considered to be a poor arousal stimulus in adults (53) as well as in infants (54) and children (55). Arousal to hypoxia (15% O2) was observed in 32% of normal infants (4– 14 weeks) during QS (56). The majority of normal infants younger than seven months failed to arouse from QS in response to hypoxia, despite the apparent presence of a hypoxic ventilatory response (56). Approximately one-fourth of children (9 2 years) aroused in response to hypoxia (SaO2 of 75%), whereas all subjects aroused in response to hypercapnia (55). Hypercapnia is a much more potent arousal stimulus than hypoxia (56,57). The arousal response to hypoxic and hypercapnic challenges is influenced by the duration of the exposure, the depth of hypoxia, the method of delivery of the gas mixture, the sleep stage, and age (55–58). Normal infants (59), adults (57), children (60), and adolescents (61) arouse to hypercapnia, although the arousal thresholds differ: an end-tidal PCO2 of 52 mmHg in infants (59), 59 mmHg in prepubertal children (55), 46 mmHg in adolescents (61), and 49 mmHg in adults (57). In real-life conditions, however, hypoxemia is likely to be associated with a mild and transient increase in endtidal PCO2. During hypoxic challenges, marked interindividual and interspecies variations in arousal thresholds are seen (55,62). Arousal from Airway Occlusion. Arousal from upper airway narrowing or occlusion appears to involve more stimuli than arterial blood gas changes alone, as arousal can occur at the termination of apneas or hypopneas that are too brief for substantial asphyxial blood gas changes to develop (6).
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Internal Arousal Stimulations
A spontaneous arousal can occur during an arousal challenge. It may then be difficult to evaluate whether the infant woke up spontaneously or responded to the challenge. Various endogenous stimuli induce adaptive responses in the form of arousals. These factors include prolonged apneas (6), acid esophageal reflux (63,64), leg movements (65), pain (66), changes in body temperature (67), and changes in blood pressure (68). Laryngeal Chemostimulation. Gastroesophageal reflux is reported to be a strong arousal stimulus (63,64,69). The acidity of the content contributes to the arousal (69). However, chemical stimulation of the larynx with water also induces arousals, particularly during QS (70). The awakening effects of laryngeal stimulation are impaired by respiratory syncytial virus infections in young lambs (71), especially during REM sleep. Apnea. During the terminal portion of an obstructive apnea, while the patient remains asleep, the muscle activity of both the upper airway and respiratory muscles progressively increase, yet the airway remains closed. The tendency of the upper airway muscles to restore patency is, thus, apparently balanced by increased suction pressure, and the airway remains obstructed. Airway opening is typically preceded by a preferential increase in upper airway muscle activity (compared with the diaphragm). The large increase in upper airway tone is usually preceded by, or coincident with, evidence of arousal (72). This finding has resulted in the proposal that apnea is terminated by the arousal response to respiratory stimuli (4,73). The frequency of arousal responses to obstructive apnea differs between children and adults. In adults, obstructive apnea termination in NREM sleep is associated with cortical arousal in approximately 70% of obstructive events (73,74), whereas in children and infants arousals frequently do not occur. McNamara et al. (30) studied infants (<21 weeks) and children (1–14 years) with the obstructive sleep apnea syndrome (OSAS). In the children, obstructive apnea termination was associated with cortical arousal in 51% of NREM events and only 35% of REM events. In the infants, obstructive apnea termination was associated with cortical arousal in 18% and 12% of events during quiet (NREM) sleep and active (REM) sleep. Arousals after central apnea were less likely to occur, with 16% of central apneas associated with arousal from NREM sleep in children and 5% in infants. The lack of cortical arousal in children in response to apnea may be secondary to the higher arousal threshold in infants and children compared with adults. This may be a protective mechanism to preserve sleep structure in children. However, approximately 20% of obstructive events in adults resolve without cortical EEG arousals. There are several possible explanations for apnea termination without arousal: the method to detect cortical arousal may not be sensitive enough (this may be altered by the choice of montage or the use of sophisticated spectral analysis of EEG frequency); or cortical arousal may not be necessary for apnea termination, which can result from subcortical processes. In favor of the first explanation, O’Malley et al. found that the addition of a frontal lead (Fz) in
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adults improved the detection of cortical arousal following obstructive events from 71% to 97% (74). On the other hand, Wulbrand et al. studied the effect of obstructive events in preterm infants and showed that a deep inspiration preceded by a short expiration terminated apneas and bradycardia, inducing a ‘‘cardiorespiratory arousal’’ without a change in sleep stage (75). This suggests that subcortical arousals are in most cases sufficient to cause the termination of obstructive events. Virtually all obstructive events in adults terminate with detectable autonomic changes, such as increased heart rate, skin vasoconstriction, and elevations in blood pressure (76). In children, several studies have shown that the vast majority of obstructive apneas terminate with movement, even in the absence of EEG arousals (22,44). Katz et al. (44) studied the pulse transit time, an indicator of autonomic function, in children. They demonstrated that 91% of obstructive apneas were associated with pulse transit time arousals, although only 55% of the events were associated with ASDA arousals (44). Moreover, Pepin et al. reported that respiratory events in which there was a small airflow reduction and no desaturation, the additional information provided by pulse transit time measurement in terms of increased respiratory effort and demonstration of a microarousal allowed for the recognition of more respiratory events (77). Studies have shown that children with OSAS also have a specific arousal deficit in response to respiratory stimuli when compared with age-matched controls. Patients with OSAS aroused at a higher PCO2 during hypercapnic and hypoxic hypercapnic challenges than controls (55). The children with the highest apnea index had the highest arousal threshold to CO2 (55). Children with OSAS also have a blunted arousal response to inspiratory resistive loading (78). Children with OSAS have normal arousal responses to acoustic stimuli (79), suggesting specific arousal deficits to respiratory stimuli. It is not known whether this blunted arousal mechanism is primary or secondary. However, one study in infants showed an increase in the arousal response to apnea following continuous positive airway pressure therapy, suggesting that the blunted arousal threshold may be secondary (80). Harrington et al. studied infants with apparent life threatening events (ALTEs) and found that infants with ALTEs and OSAS had abnormal cardiovascular autonomic control and decreased arousability in AS in response to head-up tilt (81). No differences were found between control infants and ALTE infants without obstructive apnea. In this condition, it is not known whether OSAS plays a causal or consequential role. There may be a common cause for both the obstructive apnea and the autonomic cardiovascular abnormalities responsible for the ALTE. Time of Night
Arousal thresholds decline across the night as a function of accumulated sleep time (82,83). This decline is independent of sleep stage in infants, children, and adults (20,83). In infants born at term, arousal thresholds to pulsatile air jets applied to the nostrils increased progressively with the duration of QS (84).
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Spontaneous arousals and awakenings occur more frequently in infants during AS than QS (23,85). The frequency of movements and arousals are greater in AS than in QS, although the difference is smaller in neonates than after one month of life (86). In infants and children, lower arousal thresholds are seen during active (REM) sleep in response to diverse stimuli, such as pharyngeal (69), auditory (82,83), vibrotactile (4), pulsatile air jet to the nostrils (25), airway occlusion (6,87), head-up tilt challenges (52), or hypoxic and hypercapnic challenges (55,88). In QS, infants frequently failed to arouse in response to hypoxia (15% O2) (55% at 2–5 weeks, 38% at 2–3 months, and 44% at 5–6 months), whereas in AS they almost invariably aroused (18%, 0%, and 0%, respectively) (88). Furthermore, the arousal latency to hypoxia is longer during QS than AS. The oxygen saturation at which infants arouse is not different between sleep states, suggesting that desaturations are more rapid during AS. In children (9 2 years), arousal to hypoxia occurred less during slow-wave sleep than in stage 2 NREM and REM sleep (55). The time to hypercapnic arousal was longer during slow-wave sleep than stage 2 NREM. There was no significant difference in the level of PCO2 at which arousal occurred among the different stages for controls, as most subjects reached a steady state before arousal. (55). Frequency of Stimuli and Habituation
The rapid repetition of stimuli can favor the development of habituation and modify the sleeper’s arousal threshold. In 22 infants, it was shown that rapid habituation of arousal responses occurred with repeated tactile stimulation to the feet during daytime nap studies (14). The habituation occurred more quickly for cortical than for subcortical responses, especially during REM sleep. B.
Infant and Children Characteristics
Age
During the first six months of life, the frequency of movements and of time spent in movement decreases with age (23,85,86). Although these parameters decreased sharply from birth to one month of age in QS, the decrease was more progressive in AS (86). From birth to nine months of age, the maturation of subcortical activation and cortical arousals were studied (90). Maturation of the arousal events differed according to sleep state and type of arousal. With age, subcortical activations decreased in active (REM) sleep and quiet (NREM) sleep, although cortical arousals increased in active (REM) sleep and decreased in quiet (NREM) sleep (90). Arousal thresholds also depend on the age of the infant. Arousal thresholds decrease from birth to the age of three months in response to auditory stimulation during QS (91). Only 12.5% of infants older than nine weeks and 70% of infants less than nine weeks were aroused in response to hypoxia in QS (92). These data
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suggest that as normal infants mature, their ability to arouse in response to hypoxia diminishes by two to three months of age. There is a significant increase in arousal thresholds to vibrotactile stimuli in REM sleep at three months of age (4). According to McGraw (93), between the period of reflex dominance (subcortical control) and the eventual ‘‘voluntary, deliberate behavior’’ (cortical control) that will be acquired, the infant’s style of response undergoes a period of ‘‘disorganized’’ activity. This important transitional period from, principally, subcortical to cortical controls occurs between two and five months of age, typically the age of greater SIDS risk (94). The loss of reflexive behaviors could be a risk factor if the voluntary responses are not already acquired. On the other hand, Horne et al. studied the subcortical responses to nasal air jet stimulation and found that arousal thresholds were lower in AS at two to three months compared with those at two to four weeks of age, and higher in QS at five to six months than at two to four weeks of age (95). In response to hypoxia, the same authors found that in QS the probability of infants failing to arouse to hypoxia was greater at two to three months and five to six months of age compared with two to four weeks. No difference was found in AS. The discrepancies between the studies confirm that the results depend on the methodology of arousal stimulation, sleep stages, and types of arousals. The duration of gestation can modify the infant’s arousability. Compared with healthy term infants (37–42 weeks’ gestation), preterm infants born at 31 to 35 weeks’ gestation have a delay in the maturation of sleep-state-related difference in arousability between AS and QS; this difference only appeared at two to three months of age as compared with two to three weeks for term infants (96). Moreover, preterm infants (26–32 weeks’ gestation) with a history of apnea and bradycardia of prematurity showed decreased responses in both QS and AS at term, and in QS at two to three months post term (97). From 5 to 20 years of age, the frequency of awakening increases with age, whereas the stimulus intensity required to affect these awakenings decreases (20). Children have a higher arousal threshold than adults; the younger the child, the higher the arousal threshold. In response to a 120 dB acoustic stimulus, young children (5–7 years) awoke in 43% of trials, preadolescents (8–12 years) in 54% of trials, adolescents (13–16 years) in 72% of trials, and adults in 100% of trials. Although the frequency of spontaneous arousal changes with age, normative data for ASDA arousal indices range from 9 5/hr to 11 4/hr in normal children aged two to nine years (98). However, some authors have found slightly lower values of approximately 5/hr (99,100). The reason for this difference is unclear, since all these studies used the same criteria for defining arousals and the same population age. Sleep Deprivation
In adult subjects, sleep deprivation significantly increases the pressure to sleep. The arousal threshold is increased during the second part of the night, in both
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REM and NREM sleep (83). Following short-term sleep deprivation in infants, a decrease in spontaneous movements and an increase in the arousal threshold were found after auditory challenge in AS (101), but no detectable alteration was found after photic and auditory stimuli in QS (47). Infection
It is conceivable that sleep deprivation from any cause, including upper respiratory infections, can result in diminished arousal responsiveness. Sleep deprivation can result from nursing conditions (handling, feeding) as well as from sleep fragmentation due to respiratory infections or fever. Sleep deprivation and infection by respiratory syncytial virus decreases the arousal responses to chemical stimulation of the larynx in young lambs (70). On the day of discharge from hospital after either a respiratory or urinary tract infection, infants showed decreased arousability to nasal air jet stimuli in QS compared with when they were completely well 10 to 15 days after discharge (102). Some medications, such as antitussive drugs, can also diminish the frequency of spontaneous movements and decrease arousability (103). C.
Environmental Factors
The temporal association between SIDS and sleep suggests that the arousability from sleep provides a protective mechanism for survival when the infant is confronted with a life-threatening challenge during sleep. It has been shown that infants who became victims of SIDS not only aroused less from sleep than control infants but also had different arousal characteristics. Compared with control infants, SIDS victims had significantly more subcortical activations during the first part of the night between 9:00 PM and midnight, and fewer cortical arousals during the latter part of the night, suggesting an incomplete arousal process (104). As failure to arouse from sleep has been postulated as a mechanism to explain the final pathway of SIDS, the effects on arousability of the environmental risk and protective factors for SIDS have been studied extensively. All major risk factors for SIDS decrease spontaneous and induced arousals from sleep. In contrast, protective factors for SIDS favor arousal from sleep. Maternal Factors
Some studies reported significantly higher arousal thresholds in newborns and infants prenatally exposed to nicotine and cigarette smoke. These findings were reported for newborns and infants of mothers who smoked during gestation. When exposed to auditory (105,106), hypoxic (107), or nasal air jet (108) arousal challenges, these newborns and infants had significantly higher arousal thresholds than subjects born to nonsmoking mothers. The newborn’s arousability is also
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depressed following maternal exposure to illegal drugs. Infants of substanceabusing mothers required a significantly longer exposure to hypercapnia before arousal than did age-matched control infants (109). A study reported that disturbances in spontaneous arousals occurred in neonates of mothers who consumed alcohol during the first trimester of pregnancy (110). No data are yet available on the effects of alcohol consumption on the arousal threshold. Infant Sleep Conditions Body Position During Sleep
Body position during sleep significantly modifies the arousal response in infants. Newborn and three-month-old infants sleeping prone showed less spontaneous arousals (25,111) and higher arousal thresholds (24,52,112) than when lying supine. The sleep-promoting effect of the prone sleep position is independent of the infant’s usual sleep position and remains unexplained. Prone sleep position decreased the frequency of cortical arousals but did not change the frequency of subcortical activations, as previously found in SIDS victims (113). These results suggest that specific pathways are involved in the impairment of the arousal process in SIDS victims, and support the idea that structural or maturational dysfunction, rather than functional changes, are implicated within the infants’ arousal system in future SIDS victims. Body and Room Temperature
Newborns exposed to cold showed a decrease in sleep continuity and an increased frequency of AS and body movements (114). Compared with what was observed during thermoneutrality, infants sleeping in a warm environment had higher arousal thresholds to auditory stimuli, particularly by the end of the night (82). Bedding Conditions
Face Covered by a Bed Sheet. Infants sleeping with their face covered by a bed sheet had higher auditory arousal thresholds and greater rectal and pericephalic temperatures (115). These increased arousal thresholds have been related to an elevation in temperature within the infant’s microenvironment. Bedsharing. Bedsharing favors repeated arousals (116). Infants from nonsmoking mothers have been studied during successive bedsharing and solitary sleeping nights, or vice versa. Bedsharing facilitated awakenings and transient arousals during slow-wave sleep compared with solitary nights (116). Swaddling. Swaddling decreases spontaneous arousals in QS and increases the duration of AS, thereby consolidating sleep (117). Less intense auditory stimuli were needed to induce arousals in swaddled infants than in infants who were free to move during AS (118). The observed effects of swaddling on arousal could be attributed to the greater autonomic changes seen after auditory stimulation in the swaddled conditions (119).
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Pacifier Use
The auditory arousal threshold was significantly lower in infants sleeping with a pacifier than in those sleeping without it (120). This finding could be related to the disruptive effect of losing a pacifier during sleep because most infants lost their pacifier after 30 minutes of continuous sleep. In this study, all the infants, whether pacifier users or not, were challenged without a pacifier. Breastfeeding
Compared with formula-fed infants, breast-fed infants spent more time awake during the night and received more frequent nighttime parental visits (121). During AS, two to three month old breast-fed infants were significantly more arousable in response to both auditory stimulation (120) and to nasal air jet stimulation (122) than formula fed infants. VI.
Conclusion
Infants’ sleep/wake behavior contributes to our understanding of diverse clinical conditions, such as insomnia, parasomnias, obstructive sleep apnea, and sudden infant death. Arousal mechanisms continue to be under investigation. There is a need for a consensus within the scientific community on definitions, techniques, and scoring methods for the evaluation of arousability from sleep. Special attention should be devoted to the identification of early changes in the arousal process, such as respiratory or autonomic responses. A better knowledge of arousal mechanisms, technique limitations, and confounding factors are needed for a more reliable interpretation of sleep/wake studies in infants and children. References 1. Davies RJO, Bennett LS, Stradling JR. What is an arousal and how should it be quantified? Sleep Med Rev 1997; 1:87–95. 2. Bonnet MH, Arand DL. Hyperarousal and insomnia. Sleep Med Rev 1997; 1:97–108. 3. Wesensten NJ, Balkin TJ, Belenky G. Does sleep fragmentation impact recuperation? A review and reanalysis. J Sleep Res 1999; 8:237–245. 4. Newman NM, Trindler JA, Phillips KA, et al. Arousal deficit: mechanisms of the sudden infant death syndrome? Aust Paediatr J 1989; 25:196–201. 5. Philipson EA, Sullivan CE. Arousal: the forgotten response to respiratory stimuli. Am Rev Resp Dis 1978; 118:807–809. 6. Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. Sleep 1997; 20:654–675. 7. Harding R, Jakubowska AE, McCrabb GJ. Arousal and cardiorespiratory responses to airflow obstruction in sleeping lambs: effect of sleep state, age, and repeated obstruction. Sleep 1997; 20:693–701.
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69. Ramet J, Egreteau L, Curzi-Dascalova L, et al. Cardiac, respiratory, and arousal responses to an esophageal acid infusion test in near-term infants during active sleep. J Pediatr 1992; 15:135–140. 70. Jeffery HE, Megevand A, Page M. Why the prone position is a risk factor for Sudden Infant Death Syndrome. Pediatrics 1999; 104(2):263–269. 71. Lindgren C, Lin J, Graham BS, et al. Respiratory syncytial virus infection enhances the response to laryngeal chemostimulation and inhibits arousal from sleep in young lambs. Acta Paediatr 1996; 85:789–797. 72. Remmers JE, DeGroot WJ, Saurerland EK, et al. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 44:931–938. 73. Rees K, Spence DP, Earis JE, et al. Arousal responses from apneic events during non-rapid eye-movement sleep. Am J Respir Crit Care Med 1995; 152:1016–1021. 74. Malley EB, Norman RG, Farkas D, et al. The addition of frontal EEG leads improves detection of cortical arousal following obstructive respiratory events. Sleep 2003; 26:435–439. 75. Wulbrand H, Von Zezschwitz G, Bentele KHP. Submental and diaphragmatic muscle activity during and at resolution of mixed and obstructive apneas and cardiorespiratory arousal in preterm infants. Pediatr Res 1995; 38:298–305. 76. Guilleminault C, Poyares D. Arousal and upper airway resistance. Sleep Med 2002; 3:S15–S20. 77. Pepin JL, Delavie N, Pin I, et al. Pulse transit time improves detection of sleep respiratory events and microarousals in children. Chest 2005; 127:722–730. 78. Marcus CL, Moreira GA, Bamford O, et al. Response to inspiratory resistive loading during sleep in normal children and children with obstructive apnea. J Appl Physiol 1999; 87:1448–1454. 79. Moreira GA, Tufik S, Nery LE, et al. Acoustic arousal responses in children with obstructive sleep apnea. Pediatr Pulmonol 2005; 40:300–305. 80. McNamara F, Sullivan CE. Effects of nasal CAPP therapy on respiratory and spontaneous arousals in infants with OSA. J Appl Physiol 1999; 87:889–896. 81. Harrington C, Kirjavainen T, Teng A, et al. Altered autonomic function and reduced arousability in apparent life-threatening event infants with obstructive apnea. Am J Respir Care Med 2002; 165:1048–1054. 82. Franco P, Scaillet S, Chabanski S, et al. Ambient temperature is associated with changes in infants’ arousability from sleep. Sleep 2001; 24(3):325–329. 83. Rosenthal L, Bishop C, Helmus T, et al. Auditory awakenings thresholds in sleepy and alert individuals. Sleep 1996; 19:290–295. 84. Read PA, Horne RSC, Cranage SM, et al. Dynamic changes in arousal threshold during sleep in the human infant. Pediatr Res 1998; 43:697–703. 85. Navelet Y, Payan C, Guilhaume A, et al. Nocturnal sleep organization in infants ‘‘at risk’’ for sudden infant death syndrome. Pediatr Res 1984; 18:654–657. 86. Vecchierini-Blineau MF, Nogues B, Louvet S, et al. Maturation de la motilite´ ge´ne´ralise´e, spontane´e au cours du sommeil, de la naissance a` terme a` l’aˆge de 6 mois. Neurophysiol Clin 1994; 24:141–154. 87. Thach BT, Schefft GL, Pickens DK, et al. Influence of the upper airway negative pressure reflex on response to airway occlusion in sleeping infants. J Appl Physiol 1989; 69:749. 88. Parslow PM, Hardling R, Adamson TM, et al. Of sleep state and postnatal age on arousal responses induced by mild hypoxia in infants. Sleep 2004; 27:105–109.
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89. Sullivan CE, Issa FG. Obstructive sleep apnea. In: Kryger MH, ed. Clinics in Chest Medecine: Sleep Disorders. Philadelphia: WB Saunders, 1985:633–650. 90. Montemitro E, Franco P, Scaillet S, et al. Maturation of spontaneous arousals in healthy infants. Sleep in Press. 91. Kahn A, Picard E, Blum D. Auditory arousal thresholds of normal and near-miss SIDS infants. Dev Med Child Neurol 1986; 28:299–302. 92. Davidson Ward SL, Bautista DB, Sargent CW, et al. Arousal responses to sensory stimuli in infants at increased risk for sudden infant death syndrome. Am Rev Respir Dis 1990; 141:A809 (abstr). 93. McGraw MB. The neuromuscular maturation of the human infant. New York: Hafner (Columbia), 1976:33–36. 94. Lipsitt LP. Crib death: a biobehavioral phenomenon? Curr Dir Psychol Sci 2003; 12:164–170. 95. Parslow PM, Harding R, Cranage SM, et al. Arousal responses to somatosensory and mild hypoxic stimuli are depressed during quiet sleep in healthy term infants. Sleep 2003; 26:739–744. 96. Horne RSC, Sly DJ, Cranage SM, et al. Effects of prematurity on arousal from sleep in the newborn infant. Pediatr Res 2000; 47:468–474. 97. Horne RSC, Andrew S, Mitchell K, et al. Apnoea of prematurity and arousal from sleep. Early Hum Dev 2001; 61:119–133. 98. Traeger N, Schultz B, Pollock AN, et al. Polysomnographic values in children 2–9 years old: additional data and review of the literature. Pediatr Pulmonol 2005; 40:22–30. 99. Uliel S, Tauman R, Greenfeld , et al. Normal polysomnographic respiratory values in children and adolescents. Chest 2004; 125:872–878. 100. Goh DY, Galster P, Marcus CL. Sleep architecture and respiratory disturbances in children with obstructive sleep apnea. Am J Respir Crit Care Med 2000; 162: 682–686. 101. Franco P, Seret N, Van Hees JN, et al. Decreased arousals in healthy infants following short term sleep deprivation. Pediatrics 2004; 114:e192–e197. 102. Horne RSC, Osborne A, Vitkovic J, et al. Arousal from sleep is impaired following an infection. Early Hum Dev 2002; 66:89–100. 103. Kahn A, Hasaerts D, Blum D. Phenothiazine-induced sleep apneas in normal infants. Pediatrics 1985; 75:844–847. 104. Kato I, Franco P, Groswasser J, et al. Incomplete arousal processes in infants who were victims of sudden death. Am J Respir Crit Care Med 2003; 168:1298–1303. 105. Franco P, Groswasser J, Hassid S, et al. Prenatal exposure to cigarettes is associated with decreased arousal propensity in infants. J Pediatr 1999; 135:34–38. 106. Chang AB, Wilson SJ, Masters IB, et al. Altered arousal response in infants exposed to cigarette smoke. Arch Dis Child 2003; 88:30–33. 107. Lewis KW, Bosque EM. Deficient hypoxia awakening response in infants of smoking mothers: possible relationship to sudden infant death syndrome. J Pediatr 1995; 127:691–699. 108. Horne RSC, Ferens D, Watts A-M, et al. Effects of maternal tobacco smoking, sleeping position, and sleep state on arousal in healthy term infants. Arch Dis Child Fetal Neonatal Ed. 2002 Sep; 87:F100–5. 109. Davidson Ward SL, Bautista DB, Woo MS, et al. Responses to hypoxia and hypercapnia in infants of substance-abusing mothers. J Pediatr 1992; 121:704–709.
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6 Thermoregulation During Sleep in Infants: A Functional Interaction with Respiration
JEAN-PIERRE LIBERT, KAREN CHARDON, and VE´RONIQUE BACH Jules Verne University of Picardy, Amiens, France
I.
Introduction
Neonates can only maintain an almost constant, normal body temperature within a limited range of air temperatures. The optimal condition for extrauterine survival corresponds to thermoneutrality, when homeothermy is preserved with minimal energy expenditure in thermoregulatory processes. In fact, thermoneutrality corresponds to a zone of ambient temperatures in which body temperature is mainly regulated by changing skin blood flow; there is no need to use extra energy for heat production when the body is exposed to cold or loose body heat in warm environments. For neonates, the thermoneutral range (with a lower limit of 32–358C) is set higher than for a nude adult (288C). However, the relative and absolute contributions of the various parameters determining thermoneutrality are difficult to assess, since they depend on the neonate’s thermoregulatory ability and on its heat exchanges with the environment. Low-birth-weight and premature neonates are particularly at risk of body cooling, since the efficiency of their thermoregulatory processes is inadequate; their body mass is low, whereas the body’s heat exchanges with the environment are relatively large. Under delivery room conditions (and if the infant is not 135
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protected), the rectal temperature can fall rapidly (by as much as 2–4.58C) (1) as a result. The high value of the skin surface area to body volume ratio increases heat losses to the environment: the greater this ratio, the greater the body heat losses. For neonates, this ratio is disadvantageous when compared with older children. Furthermore, when expressed per unit surface area, a neonate’s metabolic heat production capacity is considerably lower than that of older infants. Moreover, low-birth-weight infants of low gestational age have little subcutaneous fat (2), which reduces the amount of insulation and increases body heat loss. A neonate’s body surface is also characterized by strong curvature, which increases body cooling. Since small-diameter cylinders loose heat more rapidly than large-diameter cylinders, a neonate’s limbs (with their large skin surface area and slim, cylindrical shape) are particularly efficient in terms of body heat transfer. Thus, a rise in skin temperature at the fingers, toes, hands, or feet is very effective in promoting heat loss. Highly permeable skin also enhances evaporative skin cooling. For very preterm infants, the development of the epidermal water diffusion barrier is incomplete: the keratin, which renders the skin impermeable, is present in smaller quantities in preterm neonates than in term neonates (3). The risk of mortality increases when neonates are nursed at environmental temperatures outside the thermoneutral range. Hey (4) pointed out that the mortality of low-birth-weight neonates can be reduced by more than a quarter when nursing care takes body heat loss into account, with maintenance of the rectal temperature above 368C. The causes of heat- and cold-related mortality are not well established. In cold exposure, cardiovascular problems appear, fat and carbohydrate reserves are depleted, lactic acidosis increases, and body mass gain slows. Hyperthermia is also implicated in many pathophysiological phenomena, such as hemorrhagic shock, encephalopathy, and apneic attacks. Thermal stress has also been identified as a possible contributory cause of sudden infant death syndrome (5). A high thermal load (typically induced by clothing) and a number of environmental factors have been linked to this fatal event. The actual mechanism of death could be related to a breakdown in the functional interaction between thermoregulatory and sleep mechanisms, featuring that thermoregulatory capabilities differ according to sleep stages. During wakefulness, body homeothermia can be maintained, since homeostatic mechanisms are capable of counteracting body temperature changes and reestablishing a functional equilibrium. In contrast, homeostatic regulation during sleep appears to be a discontinuous process during which a functional dichotomy arises, as illustrated by the strong interactions between maintenance of both thermoregulation and sleep. For example, active sleep of neonates appears to be a very efficient sleep stage as far as thermoregulation is concerned, whereas sleeping in a cool environment can lead to reduction of quiet sleep relative duration, up to specific quiet sleep deprivation. Experimental evidence shows that this interaction occurs at the preoptic hypothalamic region, the activity of
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which also modifies cardiorespiratory control. It can be assumed that exogenous heat stress could thus induce a “functional crisis” which may trigger apnea during a vulnerable sleep state. The present article describes body temperature control in the neonate and reviews the evidence for a functional interaction between sleep, thermoregulation, and respiratory control—an interaction that may be at the origin of the above-mentioned “functional crisis.” An attempt is made to examine the role of brain structures in general (and the hypothalamus in particular) in this “crisis.” II.
Neonatal Thermoregulation
A.
The Thermoregulatory System
The Central Controller
There is no doubt that the fundamental property of homeothermy is feedback control. Changes in body heat content are measured by transducers (thermosensors), which generate neural information (Fig. 1). Skin and internal thermosensors, which activate a central controller via nervous inputs, mediate the thermoregulatory processes. The same mechanisms are involved in thermal
Figure 1 A simplified model of the thermoregulatory system.
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responses in both adults and infants; however, there are differences in terms of the maturation of the central nervous system (CNS), the availability of substrates for calorigenic mechanisms, and the state of development of heat-producing and heat-evacuating organs. The main coordinating central controller is situated in the brain’s hypothalamic structures and operates as a thermal information integration center. If the brain stem is sectioned below this level, some thermal responses may still be obtained, but coordinated control is absent. Shivering may occur in response to cold in an acute decerebrate preparation but is independent of the drop in body temperature. As a result, the shivering is exaggerated and often results in pyrexia. The thermal response to a hot environment is also delayed. There is evidence that the posterior region of the hypothalamus (close to the corpora mammillaria) is concerned with protection against cold, whereas the anterior region (near the supraoptic or paraventricular nuclei) may control the heat dissipation processes. The two centers are connected by tracts, so that the activity of one tends to inhibit that of the other. Thus, local warming of the preoptic area and the anterior hypothalamus elicits heat dissipation responses, inhibits heat production, and increases the respiratory rate. At thermoneutrality, the two activities balance each other. The hypothalamus is also sensitive to changes in its own temperature. The control of homeothermia results from interaction between temperature changes in the hypothalamus itself and those in other body regions. There are also thermosensitive centers in the cerebral cortex, the medulla, and the spinal cord. Indeed, the spinal cord is extremely thermosensitive; in animals, an increase in spinal temperature induces panting, whereas cooling the region elicits shivering. However, the detailed effects of the various thermal impulses arriving at the central integrator from various body regions have not been fully established. The most useful physical model for explaining the operation of the thermoregulatory system involves a central thermostatic controller, which operates with a reference signal (i.e., a set-point temperature) below or above which a thermal response is triggered. The set-point temperature can be said to correspond to the rectal, tympanic, or esophageal temperatures at which there is no thermal response to heat or cold exposure: body heat losses occur in parallel with heat production, net body heat storage is nil, and thermal equilibrium is maintained. The central controller acts as a comparator by analyzing an error signal proportional to the deviation of the integrated thermal inputs from the set point. Hence, depending on whether the afferent signals are higher or lower than the set-point value, a central drive is sent out to the thermal effectors, stimulating heat losses or heat production, as appropriate. The slope value of the thermal response relative to the thermal stimulus corresponds to the gain of the effector response. The set point is not constant but can change as a function of sleep stage, heat/cold adaptation, body dehydration, illness, medication status, and age. Thus, low-birth-weight premature neonates are quite capable of regulating heat
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production at a lower set point than adults. The rapid adaptation to cool stress observed in the first three days of life can be explained by a downward shift in this threshold. Similarly, the internal temperature threshold at which sweating starts is higher in neonates than in adults, and falls in the first 10 days of postnatal life. This threshold is also increased because of intrauterine growth retardation. The set-point shift may result from an increase in the number of peripheral thermosensors (since the body surface area to body mass ratio increases) or a change in the thermal input signal processing in central nervous structures. Some authors report that the concentration of sodium and calcium in the plasma and the cerebrospinal fluid can also modify the set-point threshold (6). Among premature neonates , the concentration of these ions is indeed highly variable and could explain the high variability in the thermal responses and in the level of ambient temperatures defining the thermoneutral zone observed in these infants. The factors responsible for the set-point shift remain unknown. The functioning of the central controller has only been approximately described. Effector responses are usually presented according to two temperatures (namely, mean skin and internal temperatures), even though thermosensitive structures are distributed throughout the entire body. This can lead to oversimplification and should not be accepted without a degree of objective criticism. Moreover, the set-point concept (adapted from control theory) does not probably match reality, despite its ubiquitous use (7). Some attempts have been made to eliminate the need for a reference signal (8,9), but the set-point theory is still accepted by most of today’s physiologists. There is no doubt that much time will pass before a general agreement can be reached on how the basic thermoregulatory mechanisms function. The Controlling System
Internal and peripheral skin thermosensors convey information to the central controller. Cold and warm signals are transmitted via A-delta and unmyelinated nerve fibers, respectively. Most afferent thermal information crosses through the spinothalamic tracts in the anterior spinal cord and joins the medial lemniscus. The thalamic nuclei participate in the transmission of thermal information to the cortex and the anterior hypothalamus. Afferent thermal signals going into the thalamus are also conveyed by nerve fibers from the trigeminal region, which explains why thermoreceptive regions, such as the face, play a particularly important role in thermoregulation: local cooling of this region increases metabolic heat production in premature and full-term infants (10). There is evidence that thermal inputs are also conveyed (via the spinal pathway) to the reticular formation and are projected to the hypothalamus via the raphe nuclei and the ventral noradrenergic system through the subcoeruleus area. The skin’s thermosensors are in direct contact with the environment and could serve an anticipatory purpose. A great deal of electrophysiological
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evidence (11,12) shows that cutaneous thermosensors exhibit a static discharge at constant temperature and a dynamic response in the event of skin temperature change, with either a positive coefficient (for warm sensors) or a negative coefficient (for cold sensors). Dynamic responses are more intense than static discharges. Thermosensors are also located in the CNS, muscles, the abdominal cavity, and the respiratory tract. Thermal stimulation of the upper respiratory pathways appears to be an important stimulus for thermoregulation. At birth, internal thermosensors are present and respond to blood temperature changes. There is controversy about the role of internal and peripheral thermosensors; several authors report that thermoregulation in man depends solely on the skin temperature, whereas others claim that only the internal temperature is involved (13,14). Most researchers adopt an intermediate position, according to which internal thermosensors are about 4 to 10 times as important as the skin sensors (15). In contrast to the situation in adults, the role of internal temperature in infants is thought to be of secondary importance. The Thermoregulatory Effectors
The central controller maintains homeothermia by means of effectors, which are controlled by the somatomotor system (behavioral thermoregulation and shivering) or the autonomic nervous system (non-shivering thermogenesis, vasomotricity, and sweating). Cutaneous Vasomotricity
Vasomotricity is mainly related to the modulation of the sympathetic vasoconstriction outflow (controlled by thermoregulatory structures in the hypothalamus). Changes in the peripheral vascular tone are observed in the infant immediately after birth and correspond to its initial mechanism of defense against cold or warm exposures. However, preterm neonates are only capable of vasoconstriction in the calf, hand, and foot regions. The blood temperature in medium-sized arteries falls to between 208C and 308C and often reaches even lower levels in the peripheral arterioles. The skin temperature falls as a consequence— reducing radiation, convection, and conduction on the exterior. However, this process only compensates for body core cooling within a limited range. Thus, for neonates between 33 and 36 weeks of gestational age, vasoconstriction is mainly found in the feet, whereas concomitant vasodilatation occurs in the trunk; the heat loss over this large portion of the body’s surface area rises and increases the risk of hypothermia. This difference in regional responsiveness could be explained by the fact that noradrenergic, sympathetic nerves control blood flow in distal regions, whereas the trunk has specific nerves inducing active vasodilatation. In warm environments, neonates show peripheral vasodilatation when the rectal temperature exceeds 36.78C to 37.38C. This vasomotor response appears irrespective of body mass and gestational age.
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Peripheral vasodilatation decreases vascular resistance and the mean arterial blood flow, which can be compensated for by tachycardia and hyperventilation in order to meet the need for oxygen in vital organs such as the brain and the heart. Walther et al. (16) reported that cardiac output, skin, and limb blood flow increased by 5.4%, 4.4%, and 55%, respectively. These compensatory responses are mediated by barosensitive mechanisms, together with local regulatory processes related to myogenic influences, vasomotor factors and the different organs’ metabolic needs. Shivering Thermogenesis
For more intense cold exposure, metabolic heat production can be increased by shivering thermogenesis involving involuntary muscle movements. In adults, shivering is the most important heat production process. In contrast, it is seldom observed in neonates and is suppressed as long as heat is supplied by other thermogenic organs. This particular skeletal reflex pattern is controlled by the somatomotor system, including the posterior hypothalamus, which projects to the reticular formation of the midbrain and the pons. The efferent supraspinal pathways convey information to the muscle motor neurons via the anterior horns of the spinal cord. Some studies have suggested that shivering could be inhibited by the warm thermosensors located in the spinal cord and the hypothalamic structures, since the latter organs could be rewarmed by heat produced by the brown adipose tissue (BAT). Shivering appears progressively as the neonate ages, when the amount of heat produced by BAT becomes insufficient. Non-shivering Thermogenesis
All neonates are able to increase non-shivering heat production after birth. The response is largest at the time of birth and vanishes within a few weeks. The rapid, initial increase in metabolic rate helps the neonate adapt to the extrauterine environment and is related more to age than body mass. However, this increase (mainly due to changes in brain, liver and kidney activities, cardiorespiratory work, increasing muscular tone, and the establishment of feeding activity) is not necessarily capable of preventing a fall in body temperature until the second or the third day of life. This poor thermogenic response may reflect a limitation of the operation of the central nervous system and/or a transient failure of effector organs, which could be related to the hypoxia sometimes observed just after birth. The thermal response to cold exposure (mainly controlled by the hypothalamic ventromedial nucleus) strengthens over the first days of life and oxygen consumption can reach 15 mL/(minkg) (i.e., double the minimal heat production) for extreme cold stress. However, increased heat production cannot be maintained, since the energy stores become depleted. The ability to perform nonshivering thermogenesis is lost after the first six months of life. Part of the metabolic heat production is due to the oxidation of triglycerides in the BAT, the lipolytic action of which is controlled by the sympathetic nervous system. The transmitter (noradrenalin) released at the nerve endings acts
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on cell membrane adrenergic b receptors and prompts liberation of free fatty acids from lipid droplets and stimulation of their oxidation. Non-shivering thermogenesis is thus accompanied by rises in plasma-free fatty acid, glycerol, glucose and lactose levels, and the lactate/pyruvate ratio. BAT is mainly located in the interscapular region between the ribs and near the kidneys; its role is well established in animals, but evidence of its importance in neonates is not conclusive, since it is a rather limited source of heat at birth. The tissue represents between 2% and 6% of body mass; were it to be fully oxidized during cold exposure, the amount of heat produced could only maintain an appropriate contribution to homeothermia for 1.5 to 3 days—other thermogenic organs must therefore operate. Several studies have shown that white adipose tissue can also produce heat (17,18). Neonatal white adipose tissue differs from that of adults in that it contains a greater number of mitochondria and is more metabolically active. Equally, the role of the liver in chemical thermogenesis cannot be neglected, and indeed cold exposure increases hepatic heat production. The liver’s main sources for thermogenic cellular metabolism are free fatty acids and glucose, which are mostly derived from glycogenolysis (following hepatic glucose production) and glucose precursors (via increased gluconeogenesis). The Sweating Response
The sweating activity depends on an infant’s gestational maturity, since the sweat glands are only functional after 32 weeks of gestational age (19). The internal temperature threshold at which sweating occurs is higher in premature infants (37.808C 0.078C) than in full-term infants (37.458C þ 0.068C). The threshold drops over the first 10 days of life, although the reduced sweating response in low gestational age neonates is more due to physiological immaturity than to a higher set point for the central thermostat (20). The sweat glands may only fully develop when they are centrally innervated (by cholinergic sympathetic fibers). This observation is supported by the fact that infants with cerebral developmental defects do not sweat. The number of available sweat glands appears to stabilize after the first two years of life. Furthermore, newborns do not sweat before birth, suggesting that the in utero threshold temperature for sweating is higher than it is after birth, or that certain overriding, suppressive processes operate. This difference could be due to the fact that the skin of the fetus is soaked in an aqueous fluid, inducing a hidromeiosis phenomenon that blocks sweat excretion (due to swelling of the sweat ducts), as shown by Kerslake (21) in adult subjects. Even though the regional sweat gland density is higher in neonates than in adults, the peak response of each gland in full-term infants is only about one-third that observed in adults after intradermal injection of acetylcholine (19). The forehead is the first to sweat and is chronologically followed by the upper arm, hand, thigh, foot, and abdomen. The sweat response of neonates born more than three weeks before term is limited to the head. Thus, it may be that there are separate set points for each sweating area, since the sweating reaction is not elicited at the same time over the different regions of the body. However, an
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effect of local skin temperature (potentially modifying the release of acetylcholine at the sweat gland level) cannot be ruled out. The sweat response increases progressively with postnatal age; this reflects a change in the level of sympathetic stimulation as well as a modification in the sweat gland’s responsiveness to thermal stimulation. Increased body water loss during sweating can induce dehydration when the fluid is not replaced. In low-birth-weight neonates, body dehydration is associated with hypovolemia, hypernatremia, and increased urine osmolality. In addition to body fluid imbalance, cardiovascular changes can occur in preterm neonates. Behavioral Thermoregulation
Changes in body heat exchanges can be obtained by postural movements, which modify the effective skin surface area exposed to the environment. Using a manikin shaped like a 1500-g neonate, Wheldon (22) determined the values of the radiant heat transfer coefficients to be 3.10, 3.70, and 4.90 W/(m28C) in the fetal, relaxed, and spread-eagle positions, respectively, whereas the corresponding convective heat transfer coefficients were 4.00, 3.90, and 4.91 W/(m28C). Hence, in a fixed thermal environment, the radiative and convective heat exchanges can vary by between 23% and 58%, according to the body position. Neonates make considerable use of postural reactions, and so the role of behavioral regulation in the maintenance of body temperature cannot be neglected. In a cold environment, neonates, and premature infants adopt a curled-up position, thus reducing the body heat losses to the environment. Neonates also increase their physical activity according to the intensity of the cold stress, whereas they tend to be calm in warm environments. However, body movements involved in the maintenance of homeothermia also reflect thermal discomfort, emphasizing that the neonate feels the cold stress and performs motor and postural adjustments accordingly. These unconscious reflexes could save extra energy expenditure during cold stress, but are probably limited by the reduced muscular activity of very small premature infants; body movements are more vigorous in older infants. B.
The Temperature That Is Actually Regulated
For many years, the concept of a set-point temperature was the accepted model for thermoregulation, with the body’s internal temperature often being considered as the regulated variable. However, this internal temperature does not correspond to the temperature of the body as a whole or indeed the body’s mean temperature. Several organs and the skin surface areas with variable temperatures are regulated, but these regional temperatures differ and change. Thermosensitivity has been found almost everywhere in the body. Temperature-sensitive elements are heterogeneously distributed throughout the body, with the predominant areas being the spinal cord and the hypothalamus. The central controller has thus to take into account dispersed, local measurements. All body regions participate in thermoregulation, but the respective
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influences of each of the various thermal signals have not yet been established. Hence, the temperature variable seems to be flexible and the adaptive integrative signal regulated according to a distributed parameter control strategy. Rawson and Quick (23) found that heating the ventral and lateral abdominal cavity of sheep induces panting and a fall in hypothalamic temperature, with other body temperatures remaining constant or decreasing. In dogs, hypothalamic heating lowered the internal temperature (24). Hales and Jessen (25) reported that heating the spinal cord of conscious oxen elicited thermal responses to heat, with a fall in rectal and tympanic temperatures. In all these instances, a body region (hypothalamus, spinal cord, or abdominal cavity) was heated and, as a result, other body regions showed a fall in temperature. Similar findings are also available for peripheral stimulation. Heath and Hammel (26) found a negative correlation between core and ambient temperatures. In rats exposed to a cold environment (128C), the hypothalamic temperature increased, but the mesencephalic temperature did not (27). Under these conditions, it could be assumed that the regulated variable is not a single temperature but that it results from spatial integration of local temperatures. This is a multiple-input system in which the effector responses depend on various combinations of temperatures, including a summation of positive and negative feedback information in the central controller. Thus, the temperatures recorded all over the body contribute to a measurement of the overall thermal state, which then stimulates effector responses, as required. If a thermal stimulus is applied to a single region, the regulated variable will vary in parallel with the stimulus, and the signal will elicit a thermal response, tending to bring the regulated variable back to a typical value for the given species. This does not imply that all local temperatures will return to their thermoneutral values but only that the centrally regulated variable will be almost equal to its starting value. This differentiation is true only in the case of the moderate thermal stress commonly encountered in neonatal care, and is not valid in extreme thermal stimulations, where all body temperatures change in parallel with the stimulus. Hence, a concept based on adaptive spatial integration of the temperatures of various body parts seems to be the most adequately supported by the basic technical concept and by experimental results. To elucidate this control strategy with a multiplicity of variables and a number of feedback control loops, further work is needed to assess the relationship between local thermal stimulation of various body sites and the effector responses. III.
Sleep and Thermoregulation
The fact that there is a close relationship between environmental temperature changes and sleep disturbances (and also that thermal responses differ according to sleep stage) testifies to the interdependence between sleep processes and those subserving thermoregulation.
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On the basis of behavioral and electrical signs, neonatal sleep can be divided into three stages: active, intermediate, and quiet sleep. During quiet sleep (QS), the electroencephalogram (EEG) is discontinuous, with bursts of highvoltage activity and the superimposition of rapid, low-voltage waves. Just like slow-wave sleep (SWS) in adults, eye movements are absent and the heart and respiratory rates are very stable. Respiration is characterized by a long inspiratory time. In contrast, eye and body movements occur frequently during active sleep (AS), while respiratory and heart rates are highly variable. Low-voltage, rapid-burst activity is observed on the EEG. On the basis of these observations, neonatal AS and adult rapid eye movement (REM) sleep are often considered to be homologous sleep states. However, AS in neonates only partly corresponds to REM sleep: there is no muscle atonia during AS, and the total duration of AS (50–80% of total sleep time) and the duration of episodes are longer than what is seen for REM sleep. Furthermore, AS occurs prior to QS in newborns; in contrast, QS precedes REM in adults. During fetal and childhood development, electrical changes occur in parallel with maturational changes in brain structures. Experimental studies performed in animals suggest that both REM sleep and SWS could develop from AS (28), although this hypothesis remains subject to debate (29). In neonates, intermediate sleep (IS) is scored by the simultaneous presence of AS and QS criteria. Cold exposure disturbs neonatal sleep continuity and structure (Fig. 2). In a cool environment, sleep duration is reduced as a result of an increased wakefulness after sleep onset (30,31). Concomitantly, QS-AS switches occur more frequently and the total AS duration increases. Azaz et al. (32) reported that during the first week of life, the mean duration of QS episodes decreased, whereas that of AS increased. This pattern was not observed for one- to threemonth-old neonates, who often woke up soon after the beginning of a cold exposure. Since AS is characterized by a large increase in metabolic heat production under cool conditions, this switching from QS to AS is relevant from a
Figure 2 Total sleep time (min) and sleep stage relative durations during thermoneutral and cool (28C below thermoneutrality) conditions measured on preterm neonates; **, p < 0.01; ***, p < 0.001. Abbreviations: AS, active sleep; QS, quiet sleep. Source: From Refs. 35 and 53.
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thermoregulatory viewpoint. This is reinforced by the fact that the neonates exhibiting the greatest increase in metabolic heat production during QS do not switch into AS (33). Therefore, when faced with a cool challenge, the neonate’s thermoregulatory function overcomes the need for energy conservation: this latter factor would tend to increase QS duration. Indeed, the duration of QS is reduced and its episodes become shorter and less frequent (33). Sleep stage distribution could be influenced by peripheral temperature inputs to sleep mechanisms, independently of central thermoregulatory states. In cold exposure, a fall in mean skin temperature and/or facial skin temperature can promote the transition to AS or wakefulness (since thermal responses are fully efficient during the waking state). Direct evidence that this really does happen is not presently available. Nevertheless, decreasing the air temperature from 24–278C to 18–218C over 20 minutes during QS induced preferential switching into AS in full-term newborns (32,33). When this cooling occurred during an AS episode, half of the neonates did not enter QS. Of the few studies to have analyzed the effects of warm conditions on sleeping neonates, none has shown sleep modifications (34) other than a decrease in body movement (35). Franco et al. (36) reported an increased arousal threshold when newborns slept in warm conditions. A.
Thermoregulatory Responses as a Function of Sleep Stage
Another aspect of the close relationship between body temperature regulation and sleep relates to differences in the thermoregulatory response as a function of the sleep stage. Parmeggiani and Rabini (37) pointed out that body temperature regulation in the cat is impaired during REM sleep but is fully operative during non-REM (NREM) sleep. This impairment is indicated by the suppression of shivering and panting only during REM sleep. Moreover, during REM sleep, ear skin thermoregulatory vasomotion in cats (38) and rabbits (39) is inconsistent with homeostatic requirements, since vasoconstriction and vasodilatation occur at high and low ambient temperatures, respectively. Hence, the sleep cycle represents a transition from a homeothermic state (during NREM sleep) to a poikilothermic state (during REM sleep). As a result, sleeping in a nonthermoneutral environment leads to a conflict between sleep pressure and maintenance of body homeothermia and can trigger sleep alterations (and especially REM sleep deprivation) to prevent hypo- or hyperthermia (40). In contrast to cats, rabbits, and rats, thermoregulation in adults is not completely abolished during REM sleep but is merely impaired in both cold (41) and hot environments (42). In the cold, there is an increase in oxygen consumption and a lack of changes in the vasomotor tone during REM sleep, whereas the sweating rate persists when exposed to heat. In all the sleep stages, the sweating response is proportional to esophageal temperature changes. Compared with sleep stages 1 to 2 and SWS, the lower reactivity of the thermoregulatory system during REM sleep could be explained by a decrease in the gain of the sweating response, as
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Figure 3 Individual relationships between oxygen consumption [mL/(minkg), upper part of the figure] or mean sweating rate [mg/(mincm2), lower part of the figure) and esophageal temperature (8C) during active sleep episodes in 12 different neonates (see different symbols). Source: Modified from Ref. 35.
evidenced by the slope value for the relationship between the sweating rate and the change in esophageal temperature (43). In contrast, the thermoregulatory response measured during AS in neonates is at least as efficient as that measured during QS (in the range of environmental temperatures usually studied, in any case). Indeed, during AS episodes, a linear relationship (Fig. 3) has been observed between oxygen consumption (in a cool environment) or sweating rate (in a warm environment) on the one hand and body temperature on the other, demonstrating the persistence of closed loop regulation during this sleep stage. The thermal response during AS is sometimes greater than that recorded during QS, the latter being characterized by low energy utilization (32,44,45). During cool exposure, body activity increases during AS (35), suggesting that the muscles are not subject to central inhibitory influences. Thus, AS is a well-protected sleep stage (review in 46). This may be important with regard to the duration of AS and its role in the maturation of the
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neuronal network, since the maintenance of thermoregulatory responses protects the neonate from long periods of poikilothermy (45). The organism is not endangered for the duration of the AS episode, even though the body’s thermal inertia (which is directly related to body mass) is low. B.
Sleep and Thermoregulatory: A Functional Interaction
In contrast to SWS, REM sleep inhibits thermoregulatory responses in animals and depresses them in human adults. This dichotomy in the functional organization of the two sleep stages is related to the presence of CNS neurons whose firing rate changes in response to changes in internal and peripheral skin temperatures and also during the transition between the different wake-sleep stages. These regions include the midbrain reticular formation (including the locus coeruleus and the raphe nuclei), the midline thalamic nuclei, the cerebral cortex, the diagonal band of Broca, and the posterior hypothalamus. These structures are also involved in arousal control and may participate in the generation of an appropriate response to a dangerous situation. There is strong evidence that hypothalamic structures play a key role in the control of thermoregulation, since there is a fall in the hypothalamic thermosensitive neuron responsiveness to directly applied thermal stimuli during REM sleep (47). In the kangaroo rat, cooling the anterior hypothalamus-preoptic area increases waking time, whereas warming favors both NREM and REM sleep (48). Compared with other subcortical regions, the lateral anterior and posterior dorsal hypothalamic regions and the tuberal division of the lateral hypothalamic area contain a larger number of neuron units showing a change in the firing rate during REM sleep. This suspension of homeostatic regulation is particularly evident for functions that mainly depend on control processes located primarily in the hypothalamus. According to the model described by Parmeggiani (40), the sleep stage transition corresponds to a change in the hierarchical, functional control of the central nervous structures involved in thermoregulation: the diencephalic structures (including the hypothalamus) exert dominant influences on NREM sleep but not on REM sleep. During the latter, autonomic responses are only controlled by the rhombencephalon. There is a decrease in hypothalamic-preoptic drive to the subordinate effector mechanisms. In REM sleep, the central control on brain stem and spinal cord is failing, thus impairing the stability of homeostatic regulation. Inactivation of the hypothalamic thermoregulatory structures releases a tonic, inhibitory mechanism which is located in the upper brain stem and which suppresses the extra-hypothalamic thermoregulatory processes. This implies that the thermoregulatory model includes different integrators at different levels of the CNS, as suggested in Figure 1. In this neural organization, each level is inhibited or facilitated by the levels above and below it. Thermal responses can be accounted for by the neural organization and the autonomy of brain stem and spinal operative levels. A thermal response mediated by extra-hypothalamic
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brain stem and spinal mechanisms could be elicited in REM sleep but only in the case of heavy thermal loads (49). This modification could also exist for other physiological functions, like respiration and circulation. Thus, in the cat, the lateral periaqueductal region continues to integrate cardiac and respiratory defense reactions in the absence of the hypothalamus (50). As reported by Parmeggiani and Rabini (37), tachypnea can persist during the first episode of REM sleep in cats exposed to a heavy thermal heat load but is absent in subsequent episodes. The authors interpret their results as a direct influence of severe hyperthermia on the chemoreceptive region of the medulla. This assumption could explain the fact that the sweating response observed in human REM sleep is under the control of extra-hypothalamic structures. Thus, activation of warm-responsive neurons of the hypothalamic-preoptic area is not necessary, since activation of subordinate brain stem and spinal process is possible (51). Strikingly, during continuous warm exposure in adults (52) or 75-hour-long cool thermal exposure in neonates (53), the sleep pattern does not improve, although adaptive thermal responses do appear via an increase in the sensitivity of the central controller and/or the reactivity of the peripheral effectors, the sweat glands, and the BAT. These responses suggest that the functional interaction between the central structures controlling sleep and those controlling thermal responses can be dissociated under some circumstances. The model described above cannot be easily applied to the neonates whose homeothermic mechanisms are fully efficient in AS and QS—at least in the range of environmental temperatures usually studied. The difference may be related not only to the operation of the CNS (which differs between the different species considered) but also to the various thermoregulatory effectors (which differ as a function of individual maturity and from one species to another). Strong modifications of the neonatal thermoregulatory system occur during ontogenesis. Since the infant remains in AS during a substantial portion of his/ her sleep time, the thermoregulatory system should be suited to the high surfaceto-volume ratio and to the body’s low thermal inertia, which can induce the sort of strong core temperature variations that one would expect in poikilothermic species. To provide adequate thermal responses to temperature changes, highly integrated control of autonomic thermoregulation is necessary. The maintenance of homeothermia requires a number of adjustments mediated by increased thermogenic activity via a specific mechanism (non-shivering thermogenesis) and threshold changes for eliciting thermal effector responses. Thermal stress at birth can induce a transient but rapid downward shift of the threshold temperatures and/or an increase in the gain of the temperature-response relationship for all thermoregulatory responses, thus increasing the efficiency of cold or warm defense mechanisms. This short-term threshold temperature displacement may disappear with increasing age, explaining why some autonomic thermal responses are fully efficient in the premature neonate and persist at a lower level in adults.
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Sleep, Thermoregulation, and Respiration Experimental Evidence
There is growing evidence that thermoregulation and sleep stages exert powerful influences on respiratory patterning. At birth, body cooling appears to reset the thresholds for ventilatory control and arousal state organization via the activation of the thyroid function (54). In sleeping cats, Parmeggiani and Sabattini (55) reported that the respiratory activity of the diaphragm and intercostal muscles differs for QS, wakefulness, and REM sleep. In particular, during REM sleep, the efferent neural drive to intercostal muscles is lost. Also the tone of the upper airway and abdominal muscles falls, predisposing the person to respiratory obstruction. Warming preterm neonates increases the incidence of periodic breathing and the susceptibility to apneic attacks during REM sleep (56,57). Hyperventilation occurs before other thermal responses (such as peripheral vasodilatation and sweating) (58) and can increase ventilation by almost 50% (54). In term newborns exposed to heat, Franco et al. (59) found an increased frequency of central apnea episodes. In clothed, preterm newborns, Bader et al. (60) reported that central apnea increased during transient departures of the air temperature from thermoneutrality but only in QS for preterm infants and only in AS for term infants. Thus, thermal stress could act on ventilation via the central control mechanism (by disruption of respiratory drive). During heat stress, the observed increase in periodic breathing has been related to a fall in the partial pressure of blood arterial CO2 due to temperatureinduced hyperventilation. The larger increase in periodic breathing observed in AS when compared with QS could be due to the relative lack of damping providing by oxygen stores, since the functional residual capacity is lower in AS (61). A tonic, thermometabolic drive, which stimulates cardiorespiratory control, has also been postulated and could override a weak chemoreceptor response in the first few days of life (54). Thus, in a hot environment, the metabolic rate is reduced and the metabolic drive needed to ensure phasic respiratory activity is weak. Thermal stress and sleep stages are important modulators of this metabolic drive. Another explanation relates to the fact that high peripheral chemoreceptor gain could increase breathing instability (62). In contrast to Rigatto et al. (63), Chardon et al. (64,65) have shown that the initial drop in ventilation in response to a hyperoxic test (which reflects the strength of the peripheral chemoreceptor drive) (66) is stronger in AS than in QS in neonates (postconceptional age: 36 1 weeks). The discrepancy between these findings may be related to differences in the methods used by various authors to calculate the magnitude of the ventilatory response to the hyperoxic test. However, Rigatto et al. (63) found that sleep modifies the response to low oxygen concentrations. The early increase in ventilatory response to hypoxia is better sustained in QS than in AS. The biphasic response to hypoxia is altered (at least in part) by behavioral influences on respiratory control, which are more pronounced during AS. The strength of
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Figure 4 Mean percentage change in ventilation (VE) at the response time to a hyperoxic test in AS (open box) and QS (hatched box) at thermoneutrality (TN: 32.28C 0.58C), warm (W: 34.08C 0.58C), and cool (C: 30.58C 0.58C) conditions. I: 0.10 < p < 0.05; ***: p < 0.001. Abbreviations: AS, active sleep; QS, quiet sleep. Source: Modified from Ref. 65.
peripheral chemoreceptor activity may contribute to amplification of staterelated changes in ventilation (67). In AS, small changes in thermal stress increase the ventilatory response to a hyperoxic test in neonates (Fig. 4) (65). Since metabolism is predominantly an aerobic process, it is obvious that there is a close relationship between oxygen consumption and ventilation. Accordingly, temperature changes often have an effect on oxygen consumption (68). It could be held that the respiratory chemoreflex’s gain changes upon exposure to environmental temperatures, which modify the metabolic drive to respiration. This reflex (related to metabolic drive) involves peripheral chemoreceptors, which exert feed-forward control on respiration (69). Although neonates are particularly vulnerable to hypothermia (which rapidly increases metabolic heat production and ventilation), few studies have dealt with the influence of cold stress on respiratory control in the different sleep states. Body cooling may reduce the ventilatory response to hypoxia because resting ventilation is often maximal, whereas hypoxia slows metabolism. This hypometabolic response not only conserves oxygen but also lowers CO2 production, thus decreasing the respiratory drive (70). The rise in oxygen consumption with mild cold stress is significantly greater in AS than in QS (45,71). The apparent depression of the thermoregulatory mechanisms in REM sleep seen in various mammals is not, therefore, a feature of AS in neonates. Moreover, the ventilatory response to a hyperoxic test measured during cold exposure in AS is enhanced, whereas oxygen consumption increases (65). Metabolic heat production provides an important tonic sensory input, which directly influences the stability of breathing. This stability could also be mediated by the peripheral chemoreceptor activity.
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Neural Sites
In 1979, Parmeggiani (72) suggested that phasic influences of nonrespiratory structures affect also phrenic motoneurons during REM sleep in cats. The mechanism involves a complex network, which remains to be defined. A subset of nervous structures in the basal forebrain (near the amygdale) appears to be implicated in the control of QS initiation, arousal, body temperature, and respiration. Breathing regulation is mediated at multiple hierarchical levels in the brain stem, notably by medullary structures, which appear to be the dominant constituents. These structures receive descending arousal influences from the limbic system that help control breathing patterns and blood pressure. There is also evidence that descending hypothalamic contributions influence respiratory patterning (73), also illustrated by the fact that the preoptic area appears to be essential for many inhibited fetal functions, including non-shivering thermogenesis and breathing. During wakefulness and NREM sleep, warming the thermosensitive hypothalamic-preoptic area in cats exposed to thermoneutral environment elicits tachypnea (74). This response disappears during the transition period from synchronized to desynchronized sleep. Finally, the discovery of oxygen-sensing neurons in the caudal hypothalamus and their role in cardiorespiratory control (75,76) reinforces the evidence for an interaction between thermoregulatory processes, sleep stages, and oxygen chemoreceptor function in neonates. These hypothalamic neurons could generate additional respiratory drive during thermal challenges and, like the peripheral chemoreceptors, could be switched out by the hyperoxic test. Respiratory rate and effort are profoundly influenced by the core or anterior hypothalamic temperature, an effect that is greatly reduced in REM sleep in both the cat and the developing kitten (74,77). Tamaki and Nakayama (78) also showed that in anesthetized rats, hypoxia increased the activity of warm-sensitive neurons in the preoptic-anterior hypothalamus. An appropriate, rapid-breathing response to hypothalamic warming needs time to develop in the kitten; very young animals cannot maintain adequate ventilation and switch intermittently to slower breathing—thus increasing the likelihood of hyperthermic damage (77). However, thermoregulation during AS is efficient in neonates (35; see above). Hence, anterior hypothalamic influences are probably present during this sleep stage. The paraventricular hypothalamus projects toward the ventral medullary surface (VMS), which integrates (via the nucleus tractus solitarius) the neural output originating from peripheral chemoreceptors (79). Changes in VMS responsiveness to hypothalamic influences may explain the alterations in breathing pattern seen during thermal stress, particularly during AS (57,65). During REM sleep, enhanced responses to depressor challenges suggest a loss of dampening of evoked activity (80). VMS responses to ventilatory challenges are also sleep state dependent. Hypoxia increases VMS activity in the anesthetized goat, and the response is strongly accentuated during waking. Cooling of the rostral VMS area induces marked apnea during sleep but not during waking (81). Sleep state-related
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changes in hypothalamic influences on baseline VMS activity could underlie the state-dependent responses to challenges. There remains the question of the mechanisms underlying central changes in chemoreflex gain during warm and cool exposures. As pointed out by Johnson and Andrews (54), a thermometabolic drive related to metabolic rate provides (via the hypothalamus) a tonic central stimulus to the respiratory brain stem, which could then reset the central neural thresholds for cardiorespiratory function. Watanabe et al. (82) questioned this hypothesis, since the kitten’s chemoreflex response to hypoxia is not modified by an increase in the metabolic rate. Moreover, the metabolic rate increases during cool exposure in both AS and QS (65), although the ventilatory response to a hyperoxic test is not enhanced in QS. Therefore, we have assumed that the chemoreflex gain is linked to the metabolic drive in AS only—probably as a result of VMS-level amplification of peripheral chemoreceptor output. In a heat-gaining environment, the peripheral thermosensor inputs themselves could also be involved in the ventilatory response. The change in environmental temperature can act via skin thermosensors to reset the thermostats at the VMS level. This could modify the respiratory chemoreflex, in the absence of any changes in metabolism. Moreover, a pathway including the nucleus tractus solitarius (a primary projection area for the peripheral chemoreceptor inputs) would be consistent with earlier work, indicating that the effects of hypothalamic warming on breathing are probably mediated through descending projections to the same area (83). V.
Summary
Within the central neural network, the hypothalamus is a key structure that drives subordinate brain stem and spinal mechanisms. Since the suprapontine changes during early life are substantial and require time to develop during homeostatic challenges, fatal events could involve a “functional crisis” in neurally compromised circumstances—probably related to developmental abnormalities associated with resetting of the central nervous structures. Defects in morphological and functional developments in the various hierarchically connected nervous structures involved in the control of the above-described functions could produce respiratory system failure. The stability of the respiratory function remains maximal as long as this function is controlled by the diencephalic areas, i.e., when the functional dominance of telencephalic structures is depressed. Following exposure to heat stress, one could also assume that there is a loss of blood pressure due to body water loss (hypovolemia) and peripheral vasodilatation, which may be followed by a life-threatening decrease in brain perfusion. This decrease could be crucial in AS, during which there is a tonic increase in cerebral blood flow (84) that reduces the effectiveness of local vasodilatatory responses. As a result, the compensatory cerebral vasodilatation response to acute hypotension is limited and
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the risk of intracerebral ischemic hypoxia rises. A decrease in the efficiency of compensatory responses (i.e., those related to maintenance of blood brain perfusion and respiratory efforts) could be a source of fatal events. The infant’s physiological vulnerability is probably reduced in AS, which is a sleep stage well protected against thermal stress. At present, we can only conjecture as to the mechanisms underlying this functional crisis. Given the strong links between thermal stress, respiratory control, and sleep state when a vital system is compromised, we should focus our attention on the status of cardiorespiratory control systems during sleep in general and during AS in particular. Hence, thermal stress itself may not lead directly to death by hyperthermia, but could act via the central control mechanisms as an exogenous, precipitating factor, which disrupts respiratory drive during sleep.
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54. Johnson P, Andrews DC. The role of thermometabolism on cardiorespiratory function in postnatal life. In: Gaultier C, Escourrou P, Curzi-Dascalova L, eds. Sleep and Cardiorespiratory Control. Colloque, vol. 217. Paris: INSERM/John Libbey Eurotext, 1991:45–53. 55. Parmeggiani PL, Sabattini L. Electromyographic aspects of postural, respiratory and thermoregulatory mechanisms in sleeping cats. Electroencephalogr Clin Neurophysiol 1972; 33:1–13. 56. Riesenfeld T, Hammarlund K, Sedin G. The effect of a warm environment on respiratory water loss in fullterm newborn infants on their first day after birth. Acta Paediatr Scand 1990; 79:893–898. 57. Berterottie`re D, D’Allest AM, Dehan M, et al. Effects of increase in body temperature on the breathing pattern in premature infants. J Dev Physiol 1990; 13:303–308. 58. Riesenfeld T, Hammarlund K, Norsted T, et al. Irregular breathing in young lambs and newborn infants during heat stress. Acta Paediatr 1996; 85:467–470. 59. Franco P, Szliwowski H, Dramaix M, et al. Influence of ambient temperature on sleep characteristics and autonomic nervous control in healthy infants. Sleep 2000; 23:401–407. 60. Bader D, Tirosh E, Hodgins H, et al. Effects of increased environmental temperature on breathing patterns in preterm and term infants. J Perinatol 1998; 18:5–8. 61. Henderson-Smart DJ, Read DJ. Reduced lung volume during behavioral active sleep in the newborn. J Appl Physiol 1979; 46:1081–1085. 62. Dunai J, Kleiman J, Trinder J. Ventilatory instability during sleep onset in individuals with high peripheral chemosensitivity. J Appl Physiol 1999; 87:661–672. 63. Rigatto H, Kalapesi Z, Leahy FN, et al. Ventilatory response to 100% and 15% O2 during wakefulness and sleep in preterm infants. Early Hum Dev 1982; 7:1–10. 64. Chardon K, Bach V, Telliez F, et al. Peripheral chemoreceptor activity in sleeping neonates exposed to warm environments. Neurophysiol Clin 2003; 33:196–202. 65. Chardon K, Telliez F, Bach V, et al. Effects of warm and cool thermal conditions on ventilatory responses to hyperoxic test in neonates. Respir Physiol Neurobiol 2004; 140:145–153. 66. Dejours P. Chemoreflexs in breathing. Physiol Rev 1962; 42:335–358. 67. Dunai J, Wilkinson M, Trinder J. Interaction of chemical and state effects on ventilation during sleep onset. J Appl Physiol 1996; 81:2235–2243. 68. Mortola JP. Influence of temperature on metabolism and breathing during mammalian ontogenesis. Respir Physiol Neurobiol 2005; 149:155–164. 69. Fleming PJ, Levine MR, Azaz Y, et al. Interactions between thermoregulation and the control of respiration in infants: possible relationship to sudden infant death. Acta Paediatr Suppl 1993; 82(suppl 389):57–59. 70. Frappell PB, Leon-Velarde F, Aguero L, et al. Response to cooling temperature in infants born at an altitude of 4,330 meters. Am J Respir Crit Care Med 1998; 158:1751–1756. 71. Stothers JK, Warner RM. Thermal balance and sleep state in the newborn. Early Hum Dev 1984; 9:313–322. 72. Parmeggiani PL. Integrative aspects of hypothalamic influences on respiratory brain stem mechanisms during wakefulness and sleep. In: von Euler C, Lagerkrantz H, eds. Central Nervous Control Mechanisms in Breathing, Wenner-Gren Center International Symposium. Series 32. Oxford, UK: Pergamon Press, 1979:53–68.
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73. Parmeggiani PL, Calasso M, Cianci T. Respiratory effects of preoptic-anterior hypothalamic electrical stimulation during sleep in cats. Sleep 1981; 4:71–82. 74. Parmeggiani PL, Franzini C, Lenzi P, et al. Threshold of respiratory responses to preoptic heating during sleep in freely moving cats. Brain Res 1973; 53:189–201. 75. Boden AG, Harris MC, Parkes MJ. The preoptic area in the hypothalamus is the source of the additional respiratory drive at raised body temperature in anaesthetised rats. Exp Physiol 2000; 85:527–537. 76. Bodineau L, Larnicol N. Brainstem and hypothalamic areas activated by tissue hypoxia: Fos-like immunoreactivity induced by carbon monoxide inhalation in the rat. Neuroscience 2001; 108:643–653. 77. Ni H, Schechtman VL, Zhang J, et al. Respiratory responses to preoptic/anterior hypothalamic warming during sleep in kittens. Reprod Fertil Dev 1996; 8:79–86. 78. Tamaki Y, Nakayama T. Effects of air constituents on thermosensitivities of preoptic neurons: hypoxia versus hypercapnia. Pflu¨gers Arch 1987; 409:1–6. 79. Richard CA, Rector DM, Harper RK, et al. Optical imaging of the ventral medullary surface across sleep-wake states. Am J Physiol 1999; 277:R1239–R1245. 80. Rector DM, Richard CA, Staba RJ, et al. Sleep states alter ventral medullary surface responses to blood pressure challenges. Am J Physiol Regul Integr Comp Physiol 2000; 278:R1090–R1098. 81. Forster HV, Gozal D, Harper RM, et al. Ventral medullary surface activity during hypoxia in awake and anesthetized goats. Respir Physiol, 1996; 103:45–56. 82. Watanabe T, Kumar P, Hanson M.A. Elevation of metabolic rate by pyrogen administration does not affect the gain of respiratory peripheral chemoreflexes in unanaesthetized kittens. Pediatr Res 1998; 44:357–362. 83. Holstege G. Some anatomical observations on the projections from the hypothalamus to brainstem and spinal cord: an HRP and autoradiographic tracing study in the cat. J Comp Neurol 1987; 260:98–126. 84. Zoccoli G, Bojic C, Franzini C. Regulation of cerebral circulation during sleep. In: Parrmeggiani PL, Velluti RA, eds. The Physiologic Nature of Sleep. London, UK: Imperial College Press, 2005:351–369.
7 Behavioral Influences on Sleep in Children and Adolescents
KRISTIN T. AVIS University of Alabama Birmingham, Birmingham, Alabama, U.S.A.
JODI A. MINDELL St. Joseph’s University, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.
I.
Introduction
Sleep is one of the primary activities of a child from infancy to adolescence. During this time, sleep is profoundly influenced by a wide array of behavioral, developmental, environmental, and emotional factors. Although a physiological process, sleep is continually shaped by a multitude of factors, including developmental and health status, social and emotional factors, and characteristics and sleep practices of both the caregiver and child (Fig. 1). Any of these factors, alone or in any combination, may either precipitate or maintain sleep patterns that prevent children from functioning at their optimal level, affecting numerous aspects of their growth, health, behavior, and development, as well as overall quality of life. This chapter discusses those behavioral influences, most often associated with specific ages, in further detail. II.
Infants, Toddlers, and School-Aged Children
Infancy, toddlerhood, and childhood are complex times in which maturational, parental, environmental, developmental, cognitive, social, and emotional factors 159
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Figure 1 Factors influencing sleep in children.
significantly influence sleep. Sleep itself is an isolated construct that is undergoing rapid biological and maturational changes beginning in infancy. As the sleep-wake cycle matures, numerous influences shape the process or contribute to problems in sleep. The following sections discuss in detail several of the behavioral influences on sleep across these ages. A.
Developmental Status
Sleep in young children is largely influenced by the developmental status of the child and the ongoing changes experienced over the course of the developmental process. Especially throughout young childhood, sleep is sensitive to virtually all aspects of skill development. For example, cognitive, motor, and language development all contribute to sleep patterns in infants, toddlers, and school-aged children. Cognitive, Motor, and Language Development
Piagetian cognitive development provides a framework for understanding some of the cognitive changes in children that contribute to specific sleep issues. Development of cognitive abilities allows children to assimilate more information from the world around them, with some of these changes negatively impacting sleep. For example, as children progress through different stages of cognitive development, their newly acquired cognitive processing abilities and thinking patterns contribute to the development of separation anxiety, fears, and worries, all factors that influence sleep (1–5). By the end of the first year, the development of object permanence contributes to separation anxiety, which can lead to what appears to be bedtime resistance. The infant understands that the
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parent exists even though out of sight and wants to actively seek the presence of the parent at naptime or bedtime. Separation anxiety peaks at 18 months and typically lasts until 24 months, causing increased stress at naptime and bedtime when the child must separate from the parent (6,7). As children aged four to six years enter the preoperational stage, fears remain immediate but magical thinking develops, and fears often involve imaginary creatures. Around age seven, children enter the concrete operational stage and are able to infer cause and effect and to imagine multiple outcomes, positive and negative, allowing a wider array of fears and worries. Often, the development of anxiety and fears may lead to attempts to delay bedtime or secure the presence of parents during the night. Parental responses to this wide array of fears may reinforce or shape changes in the child’s sleep patterns (8). For example, children with nighttime fears are more likely to bedshare with their parents (9), likely decreasing sleep quality. Motor skill development can also be associated with sleep issues, primarily prolonged onset to sleep and nightwakings. For example, crawling has been associated with changes in sleep patterns. Scher and Cohen (10) investigated the relationship between sleep patterns and motor skill development in 107 infants aged five to eight months. Crawlers experienced significantly more frequent nightwakings and night wakings of longer duration than precrawlers, even of the same age. The child’s mobility alone accounted for 17% of the variance associated with nightwaking. They and others (11) argue that motor skill development may alter sleep regulation and change the level of parental involvement at sleep onset. Specifically, Scher and Cohen found that mothers of crawlers (88%) were found to be more involved in settling their child at bedtime than mothers of precrawlers (54%). Mothers of precrawlers also were more likely to describe their infant as able to self-soothe. In addition, walking allows the child to more actively resist bedtime and to change locations during the night, particularly once the child is transitioned out of the crib (8). Motor skill development allows the child to actively resist bedtime and to seek parental presence in the middle of the night, particularly in the context of attachment, proximity seeking, and separation anxiety (12). For example, as children progress in motor skills from ages one to three years, there is an increase in the length of the bedtime routine and in bedtime resistance (13,14), as well as the number of children who share the bed with their parents (15). Whether motor skill development is associated with more frequent nocturnal awakenings or whether the increased parental presence and involvement at bedtime maintains the nightwakings remains unclear (10). In addition to cognitive and motor development, language development allows the child to actively delay bedtime, most often in recurrent calling to parents and delaying sleep onset. For example, Beltrami and Hertzig (14) found that overall 75% of children aged one to five years regularly called to their parents a minimum of one time after being put to bed. Prior to age two, most children played alone once put to bed. Only 1% of one-year-old children and 26% of two-year-old children called to their parents. By three years, children
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were significantly more likely to call to their parents and to have longer time to sleep onset, and this trend continued to increase with age. That is, 42% of threeyear-old children, 49% of four-year-old children, and 50% of five-year-old children regularly called to their parents. Again, parental responses to ‘‘curtain calls’’ may serve to reinforce the behaviors, delaying sleep onset, maintaining nightwakings, and shortening total sleep duration. B.
Family and Parental Factors
There are many family and parental factors that can influence sleep. One such factor that has an impact on sleep is parental mental health. The majority of the research conducted in this area focuses on maternal depression. It has been found that infant and childhood sleep problems are strongly correlated with maternal depression (16,17). This relationship between maternal depression and child’s sleep problems is bidirectional. Mothers with depressive symptoms are less likely to implement good sleep practices, increasing the likelihood of having a child with sleep problems. For example, mothers with depressive symptoms are less likely to engage in behaviors such as playing, reading, talking with, and holding their child, as well being less emotionally available—all factors that promote healthy attachment (18). Mothers with depressive symptoms are also less likely to engage in behaviors that promote good sleep habits, such as following routines (19–21). In addition, mothers with depressive symptoms often have more negative or ambivalent cognitions with regard to parenting, which are associated with sleep problems, particularly during infancy (22). However, it is important to understand that this relationship is bidirectional, in that depressive symptoms may develop as a result of sleep deprivation related to infant and childhood sleep problems (23). Thus, maternal depression may compromise the mother’s ability to implement good sleep and parenting practices, either precipitating or and maintaining the infants sleep difficulties (23). Finally, although the association between maternal depression and sleep problems in children has been investigated, the role of paternal characteristics and depression has received scarce attention and is less understood (24). Liu et al. (25) did find the presence of paternal psychiatric history to be highly correlated with dyssomnias in a sample of 2004 elementary age children. In addition, aside from the parent-child relationship, marital conflict is associated with sleep problems in children. In two recent studies, marital conflict predicted total sleep time and quality of children’s sleep (26) and increases in children’s emotional insecurity (27). In addition, marital conflict increases vigilance or anger in children (28), which is incompatible with, or disruptive to, sleep (29). Family stress is another factor impacting children’s sleep. In addition to sleep in infants, toddlers, and children being sensitive to stress in general (30), family stress can be a primary factor. Sadeh et al. (30,31) investigated sleep in kindergarten and school-aged children and found that family stress predicted sleep quality as measured objectively by actigraphy. More specifically, in their
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sample of 140 children from second to sixth grade, family stress was associated with lower sleep efficiency and increased nightwakings. It has been suggested that parents in stressed families tend to have less effective parenting practices, creating a more disorganized environment (32). Owens-Stively et al. (33) found that sleep disturbances were associated with lax parenting. Parents who tended to enforce few rules and have difficulty setting limits, or who have difficulty implementing limits consistently with their children are more likely to have children with sleep disturbances (33). Finally, parental level of education has also been associated with sleep problems in children. Rona (34) found that lower maternal education was associated with poor sleep. Research by Sadeh et al. (30) supported these earlier findings, noting that children of parents of higher education level had highest sleep quality. C.
Emotional Factors
Attachment processes have been associated with childhood sleep problems. Most often, it is reported that there is a high association between insecure attachment and sleep problems (35–37). Children who are insecurely attached are more likely to show distress with separation from caregivers (38). Separation is required at bedtime and during the night, increasing the arousal level of the child. However, McNamara et al. (39) suggested that it may be the type of insecure attachment that is most associated with sleep problems, rather than insecure attachment in general. In their sample of 342 infants, those with secure-resistant attachment had nightwakings that were significantly more frequent and of longer duration than infants with insecure-avoidant attachment. On the other hand, there have been a few studies indicating that insecure attachment does not result in negative effects on sleep in young children. For example, Scher (12) investigated the relationship between insecure attachment and sleep problems in 12-month-old infants and found that poor sleep patterns were only weakly associated with insecure attachment. Results indicated that 55% of secure infants and 60% of insecureresistant (avoidant) awakened during the night, showing only a minimal difference between the two groups. He concluded that at the end of the first year, nightwakings are a ‘‘common developmental phenomenon,’’ rather than a significant result of the quality of attachment. Another emotional factor related to sleep is child temperament. Studies indicate that children with sleep disturbances are more likely to be described by their parents as being temperamentally ‘‘difficult’’ (33). It has been well established that during infancy, mothers of children with sleep problems are more likely to describe their baby as fussy or difficult in temperament (7,40–42). Scher et al. (43) found a significant relationship between toddlers’ sleep and mother-reported child temperament, especially between short sleep duration and less adaptability. Atkinson et al. (44) found that toddlers with increased nightwaking had more difficult temperaments. Bates et al. (32) also found that
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children who are more negative in their behavior are more likely to resist bedtime. Temperamental difficulties often persist through childhood and continue to be associated with sleep problems. Sadeh et al. (45) investigated sleep patterns in nine-year-old children and, on the basis of actigraphy, found that children who spent a lower percentage of time in sleep had higher levels of internalizing behavior problems and hopelessness, as well as lower self concept, temperamental sociability, and activity. Finally, an additional emotional factor related to sleep is exposure to stressors and traumatic situations, other than family or parental stressors discussed above. Maternal separation, whether brief or regular, has been associated with increased nightwakings. Field and Reite (46) found that brief (~3 days) separations during the birth of another sibling resulted in increases in negative affect, activity level, nightwakings, and crying in young children. Van Tassel (47) found that maternal employment was associated with increased nightwakings in children in their second year of age. As thoroughly reviewed by Sadeh (48), sleep problems in children, most often increases in nighttime fears, difficulty initiating sleep, and increased nightwakings, have also been associated with traumatic experiences (49–51), illness or injury (52), and natural disasters (53,54). D.
Health Status
As reviewed in chapters 11 and 12, the health status of infants and children significantly affects sleep. Sleep of infants is often disrupted by the presence of ear infections, colds, reflux, and a variety of relatively mild medical conditions. In addition, the presence of chronic illnesses, mental health disorders, and neurological and developmental disorders significantly influence sleep (8,45,55,56). Children with chronic illnesses frequently experience sleep disturbances related to their particular illness or disease status, shorter sleep periods due to arduous medical regimens, and/or changes in sleep schedules due to frequent hospitalizations. High levels of stress related to coping with their disease or anticipatory anxiety prior to or after treatments, surgeries, or hospitalizations often contribute to shorter sleep duration and sleep disturbance (57,58). In addition, caregivers of children with chronic illness also experience significant sleep deprivation, increasing family stress, and risk for maternal depression (59). Children with mental health disorders such as attention-deficit/hyperactivity disorder (ADHD), mood, and anxiety disorders often experience sleep disturbances, including delayed sleep onset, increased nocturnal awakenings, time awake after sleep onset, and early morning awakenings. Finally, medications for disease improvement and management of mental health or behavioral symptoms can contribute to sleep disturbance and require careful monitoring (8). E.
Sleep Environment and Sleeping Arrangement
The bedroom environment itself can significantly impact sleep. Rooms of comfortable temperature that are quiet with a low level of light are recommended
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to promote good quality sleep. Of these environmental factors, light has been the most studied. Light functions as a zeitgeber, cueing the child to sleep when it is dark and to increase arousal during the day when the environment is brighter. The presence or absence of light also impacts melatonin production, the primary hormone regulating the sleep-wake cycle. Another common contributor to sleep issues is stimuli in the bedroom, with the most studied being television viewing. Studies consistently find that having a television in the bedroom significantly influences a child’s sleep. The number of children with a television in their bedroom is increasing. In the early 1990s it was reported that slightly more than 10% of children between the ages of 3 and 10 years had a television in the bedroom (60). In the late 1990s, Owens et al. (61) surveyed parents of 495 children in kindergarten through the fourth grade and found that 25% of the children had a television in the bedroom. Results from the 2004 National Sleep Foundation (NSF) study found an even higher estimate, with 40% of school-aged children having a television in their bedroom. According to this study, the presence of a television in the bedroom predicts sleep disturbance in children, and those children who have a television in their bedroom have increased bedtime resistance and decreased total sleep time, initiating sleep 20 minutes later than their peers without a television in the bedroom. Sleeping arrangements also influence sleep patterns in children at any age. Cosleeping, as discussed in chapter 8, is a widely debated cultural practice with the decision ultimately based on family beliefs and values. However, studies have shown an association between cosleeping and sleep in general (15,62). More specifically, bedsharing has been associated with increased nocturnal awakenings (62). In one longitudinal study, Jenni et al. (15) investigated the relationship between bedsharing and sleep problems in 493 children up to the age of 10 years. Previous studies had reported that the percentage of bedsharing children gradually decreases with age (63); however, Jenni et al. found that bedsharing tendencies actually increased after infancy in their sample, peaking at 4 years, and then gradually decreasing as the child reached 10 years. The increasing trend of bedsharing up to four years was concordant with an increasing trend in the frequency of nightwakings, shortening sleep duration. Finally, results from the NSF 2004 study indicated that children who share a room or bed are more likely to take longer to fall asleep, to exhibit bedtime resistance, to have difficulty initiating and maintaining sleep, and to awaken too early in the morning. F.
Sleep Practices
Sleep Schedules
Parental practices for instituting a sleep schedule are influenced by their view on how much sleep their child should obtain, the timing at which sleep initiation and naps should begin, and the consistency with which children are put to bed. For
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example, overestimating developmental need for sleep often results in increased bedtime resistance, increased nocturnal awakenings, and early morning awakenings (64–67). Adjusting the bedtime so that sleep efficiency is maximized can reduce the frequency and severity of bedtime resistance and improves sleep quality overall (65). On the other hand, underestimating a child’s sleep need leads to a sleepdeprived child who is often behaviorally difficult during the day and at bedtime. A sleep-deprived child is also more likely to awaken during the night, resulting in poor sleep quality. The timing of sleep initiation must not only be developmentally appropriate, but also consistent so that the sleep-wake cycle is regulated. Children who are put to bed at irregular times are more likely to exhibit bedtime resistance, sleep onset delay, and sleep disturbance. Napping
Children under the age of five years who nap regularly tend to have longer attention spans and fewer behavioral difficulties during the day (8). The number of naps needed per day changes as the child develops and varies depending on individual need. According to the 2004 NSF study, by 11 months, 75% of children have decreased to two naps per day. Between 12 and 17 months of age, 60% of children take one nap, and 40% of children take two naps per day. Between 18 and 35 months, 80% to 87% of children have shifted to one nap per day. There is a linear decline in the number of children who nap once a day until age six (68). There is some evidence that napping is not only related to developmental status, but also race. For example, there are racial differences in napping behavior in preschool children, independent of psychosocial functioning (68). African-American children are more likely to maintain their daily nap longer, up to eight years, in comparison with Caucasian children. Crosby et al. (67) found that 95% of Caucasian children took more than one nap per week at age two, which declined linearly until eight years, when less than 10% of these children were napping more than once a week. In contrast, the percentage of African-American children who took more than one nap per week remained the same until five years. At eight years, close to 40% of African-American children still took naps. Total sleep time in both groups was similar, but was distributed differently across the 24-hour day. Parental practices regarding napping remain a strong influence on children’s sleep behavior. Parents, caregivers, and day-care providers may have expectations of napping that may be outside of a child’s developmental need. For example, implementing inconsistent or inappropriate naps may cause difficulty in regulating the child’s sleep-wake schedule and contribute to difficulty with sleep onset and bedtime resistance. Eliminating the nap at an inappropriate age can also disturb nocturnal sleep. Many parents eliminate the nap in the hope that their child will fall asleep earlier in the evening or sleep through the night, instead resulting in increased behavioral difficulties, bedtime resistance, and sleep disturbance.
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Bedtime Routines, Sleep Onset Associations, and Parental Responses
Children thrive on structure, routines, and familiarity. Having a consistent bedtime routine is recommended to develop and improve children’s sleep habits at all ages. By teaching a familiar pattern each night, each activity becomes a discriminative stimulus for the next behavior, building a behavioral chain of events. Knowing what to expect decreases the likelihood of testing limits and bedtime resistance and reduces anxiety from unclear or inconsistent situations. Other major influences on sleep are behaviors associated with sleep onset. Children become conditioned to associate falling asleep with certain circumstances and are then reliant on these circumstances to initiate sleep. Children with poor sleep onset associations have difficulty putting themselves to sleep at night and returning to sleep in the middle of the night. Sleep onset associations may consist of a place (couch or parent’s bed), a person’s presence (mom or dad), or an activity (feeding from a bottle, being rocked, watching television). Studies consistently find that parental presence and involvement in soothing a child to sleep have been associated with sleep problems, including initiating sleep and maintaining sleep (69,70). In one study of 122 mothers of nine-month-old infants, it was found that infants whose parent was present at sleep onset experienced significantly more nightwakings, requiring parental presence to return to sleep during the night (70). Ottaviano et al. (6) surveyed parents of two four-year-olds and found that 52% required the presence of a parent at sleep onset. These children were more likely to bedshare, have increased nightwakings, longer time to sleep onset, and shorter total sleep times when compared with children who initiated sleep alone. As children age, parents are less likely to remain in the room at bedtime, thus the child initiates sleep independently and is less likely to signal to the parent in the middle of the night. For example, Tikotzky and Sadeh (31) found that kindergarten children awaken during the night as often as during infancy, but that parents are unaware of the awakenings because children re-initiate sleep independently. Behavioral interventions are recommended to help children initiate and maintain sleep independently, resulting in increased total sleep time and improved sleep quality. An American Academy of Sleep Medicine standards of practice review found that behavioral interventions produce both reliable and lasting improvements in bedtime problems and night wakings in infants and young children (71). Behavioral approaches improved children’s sleep problems in 94% of the 54 studies reviewed. Over 80% of children benefited from the treatment, with most continuing to show improvements for three to six months. Extinction, graduated extinction, and parent education/prevention received strong support after empirical review.
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Adolescence
Adolescence is a complex time in which physiological changes, increased independence, and environmental (including social and academic) demands significantly impact sleep. The previously discussed factors influencing sleep remain applicable for this age; however, changing developmental, social, and emotional factors bring new stressors and challenges. Although sleep is important at all ages, sleep is particularly important during adolescence, as sleep is necessary for learning and higher level thinking, regulation of emotions, growth and development, and numerous other aspects of daytime functioning. We know that adolescents do not obtain the sleep that they need because of developmental and behavioral factors discussed in this section. Particularly in adolescence, studies have found that sleep problems, particularly insufficient sleep, result in impaired executive function and attentional skills and increased risk for symptoms of ADHD, anxiety, depression, and oppositional disorders (72–74), Other studies have found an association between risk-taking behavior and sleep in adolescents (75), as well as an impact on academic performance (76,77). A.
Development
Regardless of the behavioral factors influencing adolescent sleep, they need to be considered within the context of significant biological changes that contribute to changing sleep patterns and difficulties during adolescence. It is a common misconception that children require less sleep as they get older. Rather, in the classic study by Carskadon et al. (78) it was clearly demonstrated that when the opportunity for sleep is held constant, adolescents do not sleep less. In addition, across all adolescent ages, sleep time is observed to be consistent at 9.2 hours. Additional studies have continued to document that adolescents need as much, if not more, sleep than younger, prepubescent children (79,80). In addition, Carskadon et al. have published several studies documenting the association between maturation and phase preference (78,80–82). As discussed in chapter 4, adolescents experience a maturational shift in their circadian rhythm, shifting towards falling asleep and returning to wakefulness at later times. Although psychosocial and behavioral factors exist, changes in circadian rhythm associated with puberty have been documented in controlled laboratory settings, indicating that biological changes occur in adolescent sleep patterns regardless of psychosocial influences (83). The result of these biological changes is a phase delay, with adolescents endorsing more eveningness type patterns, preferring to stay up late and sleep late (84,85). Adolescents are more likely to feel most sleepy in the morning hours upon early arrival to school (80,81). Ratings of optimal alertness shift to later periods of the day, most often after 3 PM (86–88). The later bedtime and difficulty awakening in
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the morning likely make adolescents more apt to be influenced by psychosocial factors that further exacerbate the problem (76). As discussed in the next section, sleep practices change, with adolescents delaying bedtime further with age, curtailing sleep to participate in other activities, and attempting to catch up on sleep on weekends. B.
Sleep Practices
Parental Involvement
Parental involvement and awareness of adolescent’s sleep pattern significantly decreases throughout adolescence. Parents are likely to practice and implement good sleep hygiene habits for their younger child, focusing on improving or maintaining good sleep patterns in their child’s early years. As the child ages, parents become less vigilant and the children themselves become increasingly responsible for their own sleep-related and daytime behavior with less parental supervision. During this time of increased independence, not only do parents become less involved in managing their child’s sleep, they also become less aware of their child’s sleep practices, particularly in older adolescents. For example, Giannotti and Cortesi (88) found that parental involvement at bedtime decreased from 3% at 15 years to 0.9% at 18 years. Furthermore, in the NSF 2006 poll of over 1500 adolescents (age, 11–18 years), 9 out of 10 parents described their adolescent as obtaining sufficient amount of sleep, despite the fact that more than half of the adolescents themselves reported obtaining less than adequate sleep. In addition, only 7% of the parents reported that their adolescent had a sleep problem compared with 16% reported by the adolescents. Carskadon found that very few parents implemented a set bedtime for their older children. At that time, it was reported that about half of the children aged 10 to 11 years were put to bed at set bedtimes by their parents. This number decreased gradually with increasing age. By high school, 5% of children had a bedtime set by their parents (75,80,81,90). A current survey is somewhat more positive in that older children are now more likely to have a set bedtime on school nights. Results from the NSF 2006 poll indicate that up to 95% of adolescents in the sixth grade have a set bedtime on school nights, with numbers decreasing to 39% in the 12th grade. Not surprisingly, those adolescents with a set bedtime obtain significantly more sleep than those adolescents whose parents do not institute an established bedtime. Sleep Schedules
Although adolescents are more likely to have a set bedtime during the week, they are still going to bed too late. Wolfson and Carskadon (75) surveyed 3120 high school students and found that 40% of these adolescents went to bed after 11 PM on school nights and 97% went to bed after 11 PM on weekends. In contrast,
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91% of students woke by 6:30 AM during the school week. O’Brien and Mindell (74) surveyed 388 adolescents and found an average bedtime of 11:13 PM during the school week and approximately 1:00 AM on weekends. Not surprisingly, a later bedtime coupled with an early rise time for school leads to insufficient sleep. Across the board, studies have shown that adolescents obtain shortened amounts of sleep, particularly during the school week (67,75,76,84,91–94). In general, the majority of adolescents obtain less than the recommended 9.2 hours of sleep. Studies have documented that adolescents obtain approximately seven to eight hours of sleep on school nights. Wolfson and Carskadon found in their study of over 3000 students that the average total sleep time was between 7 hours, 4 minutes and 7 hours, 42 minutes. These total sleep times decrease significantly as the child progresses to upper grades (67,76,89). For example, Wolfson and Carskadon found that total sleep time decreased by 40 to 50 minutes from age 13 to 19 years. Bedtimes consistently became later, while rise time remained consistent during the week. Similar patterns across age were found in the study by O’Brien and Mindell. Sleep delay on weekends is commonly reported among adolescents. Wolfson and Carskadon reported that adolescents typically go to bed on average two hours later on weekends. O’Brien and Mindell reported a delay of 110 minutes with an oversleep time of 130 minutes. Several other studies have continued to demonstrate sleep schedule variability in adolescents (88,93,94). Lazaratou et al. (92) surveyed over 2000 adolescents and found that bedtime and rise times were later on weekends, with total sleep time increasing by over an hour. The impact of shortened and variable sleep schedules is significant. Wolfson and Carskadon found that adolescents with grades of C or lower obtained approximately 25 minutes less sleep and had a bedtime 40 minutes later than those with grades of As or Bs. Students with lower grades had a significantly later delay to bedtime on weekends. In addition, students who obtained the shortest amounts of sleep were more likely to report daytime sleepiness and depressed mood. Carskadon et al. (94) found a high association between irregular sleep schedules and academic difficulties, attention problems, daytime sleepiness, and falling asleep in school. Irregular sleep schedules are also associated with higher rates of substance use, risk-taking behavior, vulnerability to accidents, and mental health disorders (75,81,96). Napping
As we know, adolescents are not obtaining enough sleep at night. Morrison et al. (71) reported that approximately 25% of 943 adolescents surveyed reported they need more sleep than they obtain. Other more recent studies indicate that this percentage has significantly increased. Wolfson and Carskadon found that 87% of over 3000 adolescents surveyed stated they needed more sleep. O’Brien and Mindell found that 67% of adolescents surveyed felt they needed more sleep.
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In an effort to obtain more sleep and to counteract the effects of this nighttime sleep deprivation, many teenagers rely on naps. NSF 2006 data indicated than one-third of adolescents take naps regularly, with studies indicating that daytime naps typical last well over one hour (93,97). Another study found even a higher prevalence of napping during adolescence. Lazaratou et al. surveyed adolescents and found that almost 70% napped at least three times a week and that the average nap was 2.7 hours. Furthermore, the percentage of adolescents who nap has been shown to steadily increase with age (74,93), likely as a result of a similar trend for decreased sleep with age. Insufficient sleep and variable sleep schedules, later bedtimes, and early school start times are strongly associated with napping (74,76,97). For some sleep-deprived adolescents, a short nap may be beneficial, but adolescents who regularly take long naps will likely experience prolonged sleep initiation at bedtime, further disrupting the sleep-wake cycle. Thus, napping has a significant impact on sleep, and not always in a positive manner. C.
Sociocultural Influences
School Start Times
During a period in which adolescents tend to initiate sleep and wake at later times, high school start times advance progressively earlier in the morning, shortening the total sleep time of adolescents during the academic year (81,95). Wolfson (98) reported that 48% of high schools in the United States begin at or before 7:30 AM and research documents that students who attend schools that start at or before 7:30 AM obtain less sleep on school nights (76). When the influence of an early school start time is removed, adolescents obtain more sleep. Szymczak et al. (99) found that Polish students aged 10 to 14 years increased total sleep time on weekends and vacations because they were allowed to wake up later. When the influence of an early school start time is in place, adolescents total sleep time significantly decreases. In a laboratory setting, Carskadon et al. (94) implemented a 65-minute advance in school start time for 40 ninth graders to investigate how transitioning from a junior high to a high school schedule would impact the students. Simply advancing the start time from 8:25 AM to 7:20 AM resulted in a 40-minute sleep loss per night and a significant increase in daytime sleepiness. Hansen et al. (100) followed 60 high school seniors prior to and during the first few weeks of the school year. Adolescents lost up to 120 minutes of sleep per night once school began, and to offset the sleep debt, slept approximately 30 minutes longer on weekends. Interestingly, there was no difference between weekday sleep during summer and weekend sleep during the school year. The result of early school start times is not only insufficient sleep, but also impaired attention, learning, and academic functioning. Hansen et al. found that student reported levels of fatigue, and alertness significantly improved as the
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school day progressed. For example, global ratings of ‘‘feeling vigorous’’ differed significantly, with higher ratings obtained during the afternoon classes compared with early morning ratings. In addition, performance on computer vigilance tasks significantly improved when administered during a 3 PM to 4:30 PM test period, rather than during a 6:30 AM to 8 AM test period. This is consistent with prior studies showing that cognitive performance peaks in the afternoon hours (101) and adolescents report feeling that they function best in the afternoon (88) with optimal alertness after 3 PM (86). To further investigate the impact of school start time on sleep as well as daytime functioning, the school start time was delayed in the Edina school district in the Minnesota-St. Paul area from 7:25 AM to 8:30 AM. Results from student and teacher interviews generally indicated that delaying school start time resulted in higher attendance in morning classes and increased levels of alertness during academic instruction. Total sleep time increased and students noted improvement in cognitive functioning, specifically in attentional skills. Teachers observed improvement in student affect, mood, and work completion. Furthermore, students began eating breakfast more often, while reports of somatic complaints and stress decreased (102). It is clear that earlier school start times significantly impact the amount of sleep of adolescents obtain, resulting in impaired daytime functioning. Extracurricular Activities, Leisure Activities, and Employment
Engaging in extracurricular activities can also have a significant impact on adolescent sleep. Whether for social reinforcement, social pressure, resume building at a time of competitive college admission rates, innate drive, or a multitude of other reasons, adolescents are scheduling more activities each day, compromising total sleep time (8). Employment also significantly affects sleep and daytime functioning. It has been shown that working more than 20 hours per week results in a later sleep onset time, increased daytime fatigue, and higher levels of caffeine and alcohol intake (81). Wolfson (98) reported that in a 1994 survey of 1712 students from the 11th and 12th grades, 56% worked more than 20 hours a week. These students obtained less total sleep, averaging 6 hours and 57 minutes. Ten percent of the 11th and 12th graders reported struggling to remain awake and/or falling asleep while driving, compared with 8% of those with a work schedule of less than 20 hours, placing them at higher risk for daytime fatigue and accidents. Dorofaeff and Denney (93) also investigated the relationship between hours of employment and sleep patterns in over 9000 adolescents. The number of hours of employment was highly correlated with total sleep time. Less sleep was observed in adolescents engaging in just three or more hours of employment. A similar relationship has been found between leisure activities and sleep. Access to electronic equipment increases, and the number of hours spent using these items is on the rise. All but 3% of adolescents report having at least one
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electronic item, such as a television, computer, phone, or music device, in their bedroom, as documented by the recent NSF 2006 poll of adolescents in the United States. As expected, the number of electronic items in the bedroom increases with age from two items in 6th grade to four items in 12th grade, and significantly impacts sleep. Those adolescents with four or more electronic items in their bedroom get approximately 30 minutes less sleep per night and are twice as likely to fall asleep in school and while doing homework. Dorofaeff and Denny found that as the number of hours of computer use, television watching, or computer game use increases, total sleep time decreases. Adolescents with five or more hours of computer use obtain significantly less sleep than their peers, losing at least 30 minutes of sleep each night. Van den Bulck (103) surveyed adolescents to investigate the relationship between the presence of a television set, a gaming computer, and/or an Internet connection in the room of adolescents and sleep patterns. Adolescents who watched more television, spent more time on the Internet, and who spent more time playing video games had a later bedtime. Van den Bulck (104) also surveyed 2546 adolescents aged 13 to 16.3 years and found that text messaging is a common activity of teenagers that significantly disrupts sleep. As age increased, the number of times adolescents were awakened by a text message significantly increased. In the youngest grade, 13.4% reported being awakened one to three times a month, 5.8% were awakened once a week, 5.3% were awakened several times a week, and 2.2% were awakened every night. In the oldest grade, 20.8% of adolescents were awakened one to three times a month, 10.8% at least once a week, 8.9% several times a week, and 2.9% every night. D.
Social and Emotional Factors
Finally, there are a number of social and emotional factors that impact sleep, including stress, mental health, and substance use. The relationship is bidirectional in that the above factors influence sleep, most often shortening sleep time, and at the same time, insufficient sleep also puts adolescents at risk for increased stress, substance use, and mental health disorders (8). Stress
Data from the NSF 2006 survey suggest that approximately one-half of adolescents report feeling stressed out or anxious or that they were affected by feeling nervous or tense within the past two weeks, all factors that impact sleep. Common stressors during adolescence include autonomy, identity formation, issues regarding intimacy and sexuality, peer and social relationships, status, and development of goals for the future (105). Individual coping skills and personality factors moderate how well the adolescent responds to the challenges and how likely the stressors are to impact sleep (105,107). For example, Chen et al. (108) surveyed 656 adolescents between the ages of 13 and 18 years and found that the ability of the adolescent to manage stress effectively was negatively
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correlated with obtaining adequate sleep. Studies also have demonstrated a strong association between sleep disturbance and children and adolescents with internalizing tendencies (45,108–110), placing them at risk for developing sleep disturbances as a reaction to stress (105). Sadeh (48) has long argued that sleep is sensitive to both transient and chronic stress. Assimilating Selye’s (111) model of stress with a review of the relevant literature, Sadeh (48,105) proposed two models of how the sleep-wake system responds to stress. The first type of response is hyperarousal, a protective response in which the individual is alarmed and allowed to focus and cope with stress. The second response is a ‘‘shut-off’’ response in that in order to remove itself from stress, particularly stress that is unmanageable or unchangeable, the individual attempts to deepen or extend sleep. Thus, with the numerous stressors that adolescents face, sleep is likely compromised in that it may be harder to relax so that sleep may be initiated or maintained. Sleep, however, may also be extended in some cases as a response to stress as well (48,105). Mental Health
Sleep deprivation is associated with increased attentional and mood disturbances. This relationship is bidirectional, each complicating the other, and affecting quality of life and well-being (106). Sleep problems are common in children with psychiatric disorders, as discussed in chapter 12. For example, prevalence rates in studies report that up to 50% of children with ADHD have sleep problems and between 40% and 50% of children and adolescents with mood disorders have sleep problems (8). In addition, sleep problems also place the child or adolescent at risk for developing mental health symptoms, such as depression or anxiety (8,76). Wolfson and Carskadon found that adolescents who obtained fewer hours of sleep were more likely to report feelings of depressed mood. As stated earlier, irregular sleep schedules are also associated with higher rates of substance use, risk-taking behavior, vulnerability to accidents, and mental health disorders as well (75,81,96). On a more general level, 17% of adolescents report high depressive mood that is associated with delays in sleep onset on school nights, shortened sleep time, and daytime sleepiness. Negative mood is also strongly correlated with sleep difficulties. Of the adolescents who endorse feeling unhappy or tense, 73% feel they obtain less than adequate amounts of sleep and 59% experience excessive daytime sleepiness. On the other hand, positive mood is associated with obtaining sufficient sleep. In addition, it has been well established that insufficient sleep significantly impacts executive functioning, attention, memory, and learning processes (106). Substance Use
Sleep disturbance and deprivation are also associated with substance use. As with the above factors, the relationship between sleep issues and substance use is
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bidirectional, with studies indicating that sleep deprivation contributes to increased substance use. Adolescents with significant sleep disturbance may be more likely to self-medicate with substances to improve sleep difficulties, mood, or daytime fatigue (112). Giannotti et al (91) surveyed over 6000 adolescents aged 14 to 18 years. Adolescents who preferred a later bedtime and risetime, particularly on weekends, were more likely to consume caffeinated beverages and substances to promote sleep initiation. One study found adolescents with sleep difficulties were 6.5 times more likely to report using inhalants, 2.6 times more likely to report using alcohol, 2.4 times more likely to report using marijuana, and 2.2 times more likely to report using cigarettes within one year of the study (113). Adolescents are more likely to consume caffeine, which affects the ability to fall asleep and to obtain good quality sleep. In middle and high schools, caffeinated beverages are often readily available from machines with no dispensing limitations. It has also been suggested that adolescents are more likely to attend social and extracurricular activities where caffeinated beverages are readily available (114). Children who consume caffeinated beverages experience less sleep and more disrupted sleep (114). Pollak and Bright (114) examined the caffeine consumption patterns of seventh to ninth graders and found that caffeine intake increases after Wednesday and peaks on Saturday. They concluded that whether intake increases later in the week to counteract increasing sleep deprivation over the course of the week or that caffeinated beverages are available at many weekend functions remains unclear. IV.
Conclusion
As outlined in this chapter, a multitude of factors exist that continually shape and influence sleep patterns from infancy throughout adolescence. Most often, these influences either shorten total sleep duration or disturb the sleep period, resulting in significant consequences in growth, learning, development, and behavior in young children. As the child enters adolescence, evidence that new physiological, behavioral, and environmental factors result in curtailed or disturbed sleep is compelling. Given the importance of sleep to the well-being of both children and adolescents, the continuing study of factors that can affect this important activity is critical. References 1. Bauer DH. An exploratory study of developmental changes in children’s fears. J Child Psychol Psychiatry 1976; 17(1):69–74. 2. Vasey MW, Crnic KA, Carter WG. 1994 Worry in childhood: a developmental perspective. Cognit Ther Res 1994; 18:529–549. 3. Ollendick TH, Hagopian LP, King NJ. Specific phobias in children. In: Davey GC, ed. Phobias: A Handbook of Theory, Research, and Treatment. Chichester, UK: Wiley, 1997:201–225.
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103. Van den Bulck J. Television viewing, computer game playing, and Internet use and self-reported time to bed and time out of bed in secondary-school children. Sleep 2004; 27(1):101–104. 104. Van den Bulck J. Text messaging as a cause of sleep interruption in adolescents, evidence from a cross-sectional study. J Sleep Res 2003; 12(3):263. 105. Sadeh A, Gruber R. Stress and sleep. In: Carskadon MA, ed. Adolescent Sleep Patterns: Biological, Social, and Psychological Influences. Cambridge, UK: Cambridge University Press, 2002:236–253. 106. Dahl RE. The impact of inadequate sleep on children’s daytime cognitive function. Semin Pediatr Neurol 1996; 3(1):44–50. 107. Bertelson AD, Monroe LJ. Personality patterns of adolescent poor and good sleepers. J Abnorm Child Psychol 1978; 7:191–197. 108. Chen MY, Wang EK, Jeng YJ. Adequate sleep among adolescents is positively associated with health status and health-related behaviors. BMC Public Health 2006; 6:59. 109. Achenbach TM, Edelbrock CS. The classification of child’s psychopathology: a review and analysis of empirical efforts. Psychol Bull 1978; 85:1275–1301. 110. Fisher BE, Rinehart S. Stress, arousal, psychopathology, and temperament: a multidimensional approach to sleep disturbance in children. Pers Individ Dif 1990; 11(5):431–438. 111. Selye H. The Stress of Life. New York: McGraw Hill, 1956. 112. Stevens SJ, Murphy BS. Ethnic and gender differences in drug use and sleep disorders among adolescent drug users. Presented at The Center for Substance Abuse Treatment Adolescent Treatment Models Grantee Meeting; September 25–27, 2000; Washington, D.C. 113. Johnson EO, Breslau N, Roehrs T, et al. Insomnia in adolescence: epidemiology and associate problems. Sleep 1999; 22:S1–S22. 114. Pollak CP, Bright D. Caffeine consumption and weekly sleep patterns in US seventh-, eighth-, and ninth-graders. Pediatrics 2003; 111(1):42–46.
8 Cultural Influences on Infant and Childhood Sleep Biology, and the Science That Studies It: Toward a More Inclusive Paradigm II
JAMES J. MCKENNA and LEE T. GETTLER University of Notre Dame, Notre Dame, Indiana, U.S.A.
I.
Introduction
We try to keep in mind cultural influences on the advice we give. We remind ourselves that much of what comes to the pediatrician’s attention, as problematic sleep behavior— children who have difficulty falling asleep alone at bedtime, who wake at night and ask for parental attention, or who continue to nurse at night—is problematic only in relation to our society’s expectations, rather than to some more general standard of what constitutes difficult behavior in the young child. Our pediatric advice on transitional objects, breast feeding, cosleeping may be unknowingly biased toward traditional Euro American views of childrearing, especially those about bedtime and nighttime behavior. Thus, in giving advice about sleep, pediatric health professionals might do well to be aware of their own cultural values, to examine closely their patients cultural and family contexts, and to assess parental reactions to children’s sleep behaviors. (1) Who sleeps by whom is not merely a personal or private activity. Instead it is social practice, like burying the dead or expressing gratitude for gifts or eating meals with your family, or honoring the practice of a monogamous marriage, which (for those engaged in the practice) is invested with moral and social meaning for a person’s reputation and good standing in the community. (2) In clinical pediatrics, cosleeping is the political third rail. If you touch it, you die. (3)
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In this chapter, we have contributed a new conclusion to the first version published in the earlier edition, slightly modified and updated recent developments as regards research into mother-infant cosleeping in the form of bedsharing, and have contributed a new last section that critiques recommendations against any and all bedsharing. But mostly, we provide here (without modification) a cultural background to our thinking about what constitutes ‘‘normal, healthy, and desirable’’ infant sleep and show the interconnectedness between scientific research, cultural values, concerns for morality, and sleeping arrangements that are characteristic of Western society. Specific biological and psychological evidence is put forth supporting the views of Sadeh and Anders (4,5) and Anders (6) on the importance of understanding what is ‘‘appropriate’’ infant sleep on the basis of the overall social and physical context within which it occurs. To illustrate and supplement this more professional viewpoint, we add at the top of many sections parental quotes from an Internet survey on parents’ views of their infants’ sleep and sleeping arrangements. In this way parents’ voices can be heard as they share their views, experiences, and interpretations of their own choice of sleeping arrangement and their evaluations of their infants sleep. As before, selected data on a variety of topics is used to demonstrate how culturally guided parental childcare choices, including those involved in sleeping arrangements, set in motion a cascade of interconnected changes that affect the biology and behavior of the participants, appropriate to those choices. We suggest that clinicians generally fail to convey to parents the legitimacy of different choices, and that the widely accepted research paradigm fails scientifically to include alternatives to the model of the solitary sleeping, bottle- or minimally breast-fed infant. The diversity of sleep-related arrangements and practices alter infant sleep development significantly in the first years of life and this argues against a simple cultural definition of infant sleep progression implied by the widely accepted (traditional) model. Perhaps no other issue has been so often misrepresented and grossly oversimplified as parent-infant cosleeping, and especially for this chapter, many parental views and attitudes are made crystal clear on the subject. New data on the subject highlights the extent to which cultural ideologies, cultural judgments, and concerns for morality are often mistaken for science, in the area of infant sleep research and the recommendations that emerge from it. For example, data collected exclusively on the solitary sleeping, bottle-fed infants continue to provide the basis for definitions of, and research into, clinically ‘‘normal’’ infant sleepwake patterns. These data continue to serve as the gold standard against which, eventually, parents and professionals evaluate infant sleep development, despite significant contextual differences that may invalidate the comparisons. Almost no consideration is given to other sleeping arrangements, however healthy they are. New data from psychology are presented which raise the possibility that clinicians have overestimated the need for infants to sleep separately in order to assure ‘‘independence’’ from their parents, and recent biological data described
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here suggest that sleep researchers underestimate the importance of maternal proximity and breast-feeding in regulating infant sleep physiology, and thus, fulfilling infantile nighttime needs. By using data from only one type of sleeping arrangement and implying that there is only one context within which healthy infant sleep emerges, i.e., the solitary one, pediatric sleep research is thus held captive by Western ethnocentrism. As before, we conclude that to forge effective partnerships between parents and health professionals in our ever increasingly multicultural society, pediatric sleep medicine must come to terms with cultural biases embedded in sleep research medicine in general and clinical interpretations and advice in particular. At this point in the history of Western societies, where an unprecedented convergence of cultural practices is underway—not the least of which involves sleeping arrangements—it is critical that clinicians and researchers broaden their thinking about what constitutes appropriate and desirable childhood sleep practices. Failure to do so will continue to limit both the accuracy of pediatric sleep science and the effectiveness of care. II.
Culture and Childhood Sleep
They moved into their own bedrooms at their own speed. We never pressured them into moving out of our bed. They slept with us when they wanted to and in their own beds when they felt like it . . . I will not change that cosleeping relationship for anything in the world!!! It was the most wonderful sight to wake up to my children, lying there in our arms, smiling peacefully at us, or playfully tugging our hair. TN, Toledo The importance of local cultural influences, including health professional and family values on infant and childhood sleep, were anticipated more than a decade ago by Lozoff et al. (1). In the first of the four passages quoted above, Lozoff and her colleagues acknowledge as eloquently as any group of anthropologists or psychologists the critical, if not pivotal, role that personal beliefs, experiences, and societal values can play in pediatric research. The same applies to the advice given to parents regarding a range of nighttime sleep-related issues, problems, and possible solutions. Across different cultures, ideas vary about how, where and why infants and children should sleep, as well as what constitutes ‘‘normal’’ sleep and ‘‘sleep problems’’ (2,7,8). Ethnographic studies of this variability worldwide are important because the data help to establish the extent to which species-wide sleep biology and development are subject to environmental manipulation and regulation. Local customs and traditions, irrespective of whether the society is industrialized or is structured around a hunting-andgathering economy, all play roles (9–14).
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Even within a single society, infant and childhood sleeping patterns and the social values and relationships that influence them are diverse, and significant differences cut across subgroups in unexpected but important ways (15–17). For example, infants and children not able to sleep alone and ‘‘through the night’’ are not uniformly regarded in our own culture as having a ‘‘sleep problem’’ (8). Most conceptualizations of ‘‘sleep problems’’ are based on culturally and parentally constructed definitions and expectations, not biology. In reality, infant sleep development plays out extraordinarily differently in diverse family settings in which infant feeding and nighttime nurturing behaviors, and parental needs and goals, vary. These, in turn, affect both long-and short-term developmental processes. Yet, the legitimacy of these variations continue to be largely ignored in both professional as well as popular discourse and a ‘‘one size should fit all’’ approach to sleeping arrangements continues to be advocated (18). A.
How Do Social Values and Cultural Goals Influence Infant Sleep Practices?
Both of our two children coslept with us from infancy up until around ages 5 to 5 ½. . . . Today, at ages 10 and 6, they are bright, imaginative, independent, emotionally well-adjusted young people with no sleep disturbances or problems whatsoever. I am confident that cosleeping, in the context of attachment parenting, played an important part in the successful emotional development of our children. JJ, Chicago That a critical relationship exists between the cultural ideologies that underlie sleep practices and desired developmental outcomes (even when they are not achieved) is made dramatically clear when one compares Asian, Guatemalan, and American values, conceptualizations of infants at birth, and desired developmental outcomes. For example, interdependence and group harmony are positively valued in Japan, where parent-child cosleeping is practiced. As Christopher describes it, ‘‘One monkey that does perch on the back of nearly all Japanese is a deeply engrained feeling that individual gratification is possible only in a group context—a feeling which, like the taste for dependence, clearly stems from childhood experiences’’ (19). American children are presumed to be trained to be self-reliant and to display their individuality by sleeping alone, and Japanese children are taught to ‘‘harmonize with the group’’ and, hence, ‘‘cosleep’’ with their parents. These observations relate to the different attitudes that Japanese and American parents have concerning the ‘‘nature’’ of the infant at birth, what developmental outcomes are desired, and what sleeping arrangement are presumed necessary to
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achieve them. For example, Caudill and Weinstein (20) cited in Shand (21) state that in Japan the infant is seen more as a separate biological organism who from the beginning, in order to develop, needs to be drawn into increasingly interdependent relations with others. In America, the infant is seen more as a dependent biological organism who in order to develop, needs to be made increasingly independent of others.
Indeed, according to Brazleton (22), ‘‘The Japanese think the US culture rather merciless in pushing small children toward such independence at night.’’ Kawakami’s (23,24) describes American and Japanese differences this way: An American mother-infant relationship consists of two individuals . . . On the other hand, a Japanese mother infant relationship consists only one individual i.e. mother and infants are not divided.
Japanese infants and children usually sleep adjacent to their mothers on futons with space availability playing a minor role in this arrangement, and in general, children sleep with someone (fathers or extended family members) through the age of 15 years (24,25). Similar to the Japanese, Mayan mothers from Guatemala do not believe in separate sleeping quarters for infants, children, and parents. In fact, sleeping alone is considered so difficult for adult Guatemalans that in the absence of family members it is not uncommon for adults to seek out friends with whom they can share sleep (24). Upon hearing that American babies are made to sleep alone Mayan women respond with ‘‘shock, disapproval, and pity’’ and think of the practice as ‘‘tantamount to child neglect’’ (24). This evaluation contrasts dramatically with one offered by Ferber of the United States who advocates that all infants should be taught to sleep alone. In his popular selling book, How To Solve Your Child’s Sleep Problems, Ferber provides mothers who may be emotionally predisposed to sleep with their infants with a reason to ponder the status of their own mental health. He advises, ‘‘If you find that you actually prefer to have your child in bed, you should examine your feelings very carefully’’ (26). The study of Guatemalan (Mayan) women is one of the best cross-cultural (comparative) studies of childhood sleep to date. Morelli et al. examined a group of middle class American (Caucasian) and contemporary Mayan (Guatemalan) mothers and found that all the 14 Mayan mothers slept in the same bed with their infants, and eight older toddlers slept with their fathers. In the middle class American sample, none of the newborn infants regularly slept with its mothers. Mayan parents believe that cosleeping is the only ‘‘reasonable way’’ for a parents and infants to sleep, while the Americans in the sample of Morelli et al. felt comfortable keeping newborns and neonates next to their beds ‘‘to make sure that they were still breathing’’ (24), but were not comfortable having them in the same bed. After their children’s third to sixth month of life, American parents
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felt their infants were no longer so vulnerable. Fearful of interfering with the infant’s progress toward independence and autonomy, most American parents in the sample moved the infants to a separate room. In another study, conducted in Australia, an immigrant Vietnamese mother was told about the sudden infant death syndrome (SIDS), with which she was unfamiliar. She surmised that ‘‘the custom of being with the baby must prevent this disease. If you are sleeping with your baby, you always sleep lightly. You notice if his breathing changes. . . . Babies should not be left alone.’’ To further the point, another of the Vietnamese mothers added, ‘‘Babies are too important to be left alone with nobody watching them’’ (27). Of 40 Chinese women interviewed (in Chinese) at Guagzho University Hospital by Wilson (28) over 66% of new mothers were intending to have their infants sleep with them in the marital bed, and all of her sample were planning to have the infant sleep alongside the bed. One informant represented many when she stated that the baby is ‘‘too little to sleep alone,’’ and that cosleeping ‘‘make babies happy.’’ Another Chinese informant told Wilson that ‘‘the parents breathing effects the baby, so cosleeping is good’’ and, later, cosleeping permits mothers to know ‘‘if the baby {was} too hot or too cold . . . to hear baby’s sounds’’ (28). B.
Is Moral Character a Function of the Sleep Environment?
I believe his knowing we are always available to him has made him emotionally independent and socially very confident. He makes friends easily, has never been clingy or needy and enjoys new situations and environments. He takes criticism fairly well and he is nonaggressive but stands up for himself verbally and loudly. LM, Morgantown What might come as a surprise to some researchers is the work of cultural psychologist Shweder and his colleagues at the University of Chicago (second passage at the top of chapter i.e. ‘‘Who sleeps by whom’’). They show explicitly that concerns for ‘‘moral goods’’ (taken here to mean concerns or preferences for particular personal qualities or behavior and personality or character outcomes) are deeply embedded in and reflective of notions about proper sleeping arrangements, regardless of whether these notions are scientifically based or simply folk assumptions (2). Their cross-cultural comparisons reveal that in choosing sleeping arrangements parents feel a powerful concern for what ‘‘looks’’ morally acceptable and for practices they’ve come to believe lead to certain moral traits. At least initially, not only is it believed that certain ‘‘types’’ of sleeping arrangements produce certain ‘‘types’’ of children, but also that they reflect certain ‘‘types’’ of parents (i.e., good or moral parents) who are themselves judged by family, friends, and community, depending on where they place their infants or children for nighttime sleep (2,29). Shweder et al. showed specifically that where and with whom some American children are allowed to sleep is guided by concerns for three specific
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moral issues: the sacredness-separateness (from children) of the husband-wife relationship; the appearance of incest avoidance, and the importance of teaching the child self-reliance and independence by enforcing the infant or child to sleep alone. Perhaps the overriding importance of these moral goods in certain segments of American society helps explain why culture-based ‘‘folk’’ and scientific understandings of infant and childhood sleep often intermingle, and mutually reinforce each other. In pediatric sleep medicine, for example, it is often difficult to distinguish between what is passed on to parents as proven scientific findings— in relation to how sleeping arrangements affect marriages, personality development, self confidence, independence, and/or overall satisfaction with life—and what is simply personal judgment on the part of the advice giver (18,22). Interestingly, the ‘‘moral’’ outcomes parents desire to instill in their children through choices for particular sleeping arrangements contrast and often conflict with the sleep management strategies parents think they need to employ to obtain those outcomes. For example, Western parents generally seek to instill sensitivity, kindness, trust, and empathy in their children (30), at the same time, also wanting to create separateness, self-reliance, and/or autonomy through enforced solitary sleep, which can be facilitated through first withdrawing and then eliminating nighttime feeds and parental contact (26). Such emotionally conflicted parents will often display inconsistent (on-again, off-again) enforcement of solitary sleep, alternating between some form of cosleeping and separate sleeping arrangements, an important phenomenon called reactive cosleeping first introduced by Madansky and Edelbrock (31). But reactive cosleeping only exacerbates parent-child sleep struggles, and certainly does not eliminate them, as their study illustrates (31). C.
Do Solitary? Or Social? Infant Sleeping Arrangements Produce Independent, Satisfied, (Moral) Children and Adults? Is This the Right Question?
I love our story because of all the people who cautioned me that he would never learn to sleep on his own, would never leave our bed, etc. He proved all the experts wrong! GB, Boston I credit cosleeping with his increasing ability to handle new things, because I believe it fosters the kind of independence only feeling secure can give. I believe that babies and children left alone too much can learn to present an independent nature, but it is one based on insecurity and bravado, and leads to an insecure and needy adult. JG, Walnut Creek
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The absence of systematic studies on the relationship between acquired infant or child personality characteristics and routine sleeping arrangements, probably explain why Western conventional understandings about the relationship between solitary infant sleeping arrangements and early independence are imprecise and misleading at best. Recent systematic studies are beginning to provide evidence that contradicts conventional wisdom on solitary sleep in early childhood. Consider: l
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Heron (17) found that in England, it was the solitary sleeping children who were harder to handle (as reported by their parents) and who dealt less well with stress, and who were rated as being more (not less) dependent on their parents than were the cosleepers. Heron’s (17) recent cross-sectional study of middle class English children showed that among the children who ‘‘never’’ slept in their parents’ bed there was a trend to be harder to control, less happy, exhibit a greater number of tantrums. Moreover, he found that those children who never were permitted to bedshare were actually more fearful than children who always slept in their parents’ bed for all of the night. In a survey of adult college age subjects, Lewis and Janda (32) reported that males who coslept with their parents between birth and five years of age had significantly higher self-esteem, experienced less guilt and anxiety, and reported greater frequency of sex. Boys who coslept between 6 and 11 years of age also had higher self-esteem. For women, cosleeping during childhood was associated with less discomfort about physical contact and affection as adults. (While these traits may be confounded by parental attitudes, such findings are clearly inconsistent with the folk belief that cosleeping has detrimental long-term effects on psychosocial development. Crawford (33) found that women who coslept as children had higher self-esteem than those who did not. Indeed, cosleeping appears to promote confidence, self-esteem, and intimacy, possibly by reflecting an attitude of parental acceptance (32). A study of parents of 86 children in clinics of pediatrics and child psychiatry (aged 2–13 years) on military bases (offspring of military personnel) revealed that cosleeping children received higher evaluations of their comportment from their teachers than did solitary sleeping children, and they were under-represented in psychiatric populations compared with children who did not cosleep. The authors state: Contrary to expectations, those children who had not had previous professional attention for emotional or behavioral problems coslept more frequently than did children who were known to have had psychiatric intervention, and lower parental ratings of adaptive functioning. The same
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finding occurred in a sample of boys one might consider ‘‘Oedipal victors’’ (e.g., 3 year old and older boys who sleep with their mothers in the absence of their fathers)—a finding which directly opposes traditional analytic thought (16). l
And in the largest and possible most systematic study to date conducted on five different ethnic groups from Chicago and New York involving over 1400 subjects, Mosenkis (34) found far more positive adult outcomes for individuals who coslept as children, among almost all ethnic groups (African-Americans and Puerto Ricans in New York, Puerto Ricans, Dominicans, and Mexicans in Chicago) than there were negative findings. An especially robust finding, which cut across all the ethnic groups included in the study, was that cosleepers exhibited a feeling of satisfaction with life.
But Mosenkis’s main finding went beyond trying to determine causal links between sleeping arrangements and adult characteristics or experiences. Perhaps his most important finding was that the interpretation of the ‘‘outcome’’ of cosleeping had to be understood within the context specific to each cultural milieu, and within the relational matrix within which it occurs. For the most part, cosleeping as a child did not correlate with anything in any simple or direct way. Mosenkis concluded that outcomes associated with bedsharing, whether good, bad or benign, depended on the overall nature of the social relationships brought to the bed to share (34). D.
Beliefs About the Consequences of Nontraditional Sleeping Arrangements: Science or Religion?
At least judging from public discourse, the validity of predicted outcomes associated with particular sleeping arrangements need not be demonstrated or proven scientifically, as long as people believe that they do, or that the outcomes promised reflect, compliment, or in some way support the prevailing values and goals that justified the recommended practice in the first place. For example, in contrast with situations where parents and children sleep together (cosleep), solitary childhood sleeping arrangements are believed to foster more independent infants and children. The problem is that no study has ever defined what exactly is meant by independence, or how it should be measured or, assuming it can be measured, or, assuming it can or could be achieved at a young age, whether this quality or characteristic is causally linked to childhood satisfaction, competence, or happiness. Furthermore, no study has ever determined if the ability to sleep alone through the night at an early age relates to the emergence of other skills or personality characteristics unavailable to infants and children sleeping under different conditions. When discussions turn to nontraditional sleeping arrangements, much is presumed, but little or nothing is proven. For example, it is often implied or stated
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outright that cosleeping exacerbates or creates parent-child sleep problems, but this appears to be true where parents do not value cosleeping, such as when parents permit a child to sleep in their bed as a response to ongoing sleep difficulties. Furthermore, Hayes et al. (35) studied cosleeping among 51 three- to five-yearolds and found that in the subgroup that were considered difficult sleepers, all but one (of the 51) had developed sleep problems in the context of sleeping alone; that is, originally all the children that developed into ‘‘problem sleepers’’ as defined by their parents, had been placed in a separate bed from infancy. And even where cosleeping parents report problems, this does not necessarily mean that it is not still the preferred sleeping arrangement. Whether sleeping alone or socially, the functions of the sleep environment for a child change in relationship to age (36,37) and/or changing circumstances. For example, the physiological consequences of a mother sleeping beside her one-month-old infant are enormously different from the physiological consequences associated with her sleeping with this same child 13 months later when cognitive and psychological systems are much more mature. At one month, and owing to the human infant’s extreme neurological immaturity at birth and continuing slow development, the mother’s body acts as a cue or trigger in regulating the baby’s body temperature, breathing, arousal patterns, cortisol levels, and sleep architecture (38–41). But at 2, 5, or 13 years of age, children will actively interpret the relational meaning and affects of cosleeping with their parents although the initial important physiological effects will diminish. Indeed, whether the consequences of the sleeping arrangement is beneficial, benign, or deleterious (at any given age) will depend not simply on the location, where the sleep occurs, but on the social meaning and psychological content of the relationship of the participants, as expressed within the family, of which sleeping arrangement, per se, is but a small reflection and part. Such critical analytic distinctions are mostly absent when the potential value of nontraditional sleeping arrangements (especially cosleeping) is addressed (42). III.
Conventional Western Understandings of ‘‘Healthy, Normal’’ Infant and Childhood Sleep: Where Did They Come From? Is One Form of Sleep as Good as Any Other?
It is tempting to use the concept of cultural relativism to argue that regardless of differences in the ways infants or children sleep worldwide, each culture-based strategy is equally valid and appropriate. Such a simplistic perspective is fallacious, however, in a number of ways. First, it presumes that parents in all societies are equally satisfied with the way their infants and children sleep, or that parents (and children) are equally well rested despite differences in how or where they sleep. Though it is hard to compare across all cultures, the impression by many anthropologists is that (in general) parents living in Western industrialized societies are much less satisfied with how their children sleep than are
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parents in non-Western societies, and that in industrialized societies nightly infant and childhood sleep comes about under more stressful conditions (43,44). A second fallacy is the erroneous assumption that any society (including our own) necessarily produces a sleep management strategy that is appropriate for all, and that it is optimal (promote maximum health) for all, or is always compatible with the short-or long-term biological needs of the infant. Parental caregiving choices that satisfy parental best interests are not, for example, necessarily the same as those that best serve the infant’s (40). And while modern lifestyles and/or technology offer some effective substitutes for parental nurturing (contact, protection, and support) it is worthwhile to recall Bruner’s warning that ‘‘it would be a mistake to leap to the conclusion that because human immaturity makes possible high flexibility in later adjustment, anything is possible for the species . . . we would err if we assumed a priori that man’s inheritance places no constraint on his power to adapt (45). A third problem with the relativist perspective is that it erroneously implies that within any given society each family’s values and goals are the same, and that publicly preferred or ‘‘ideal’’ sleeping arrangements are those which are actually practiced. We now have evidence there is much more variability regarding sleep practices especially in the United States and the United Kingdom than has ever been acknowledged (16,46–48). Obviously, each culture is unique, and there must be some compatibility between family behaviors and the society within which they live. My criticism is that the pediatric sleep community continues to make it uncomfortable for many parents to practice sleeping and nighttime feeding arrangements that differ from their own. More importantly, I regret that the ‘‘science’’ of infant sleep continues, for the most part, to disregard the significance of the mother’s presence as a biological regulator of infant sleep as it unfolds and develops within the cosleeping/breast-feeding adaptive complex. I argue that this situation precludes a full understanding on infant sleep physiology and development and, therefore, a full understanding of the likely etiology of so many sleep-related problems infants, children, and parents experience. In my own work, no particular sleeping arrangement is advocated to any particular family. Rather my colleagues and I advocate a perspective from which other kinds of analyses and concerns can proceed. An evolutionary perspective provides a more objective context, I believe, for understanding infant responses to the diverse sleep environments cultures provide (49–51). As a conceptual tool evolution offers a beginning point to consider how social factors come to predominate over and influence infant and childhood sleep biology and development (42). Anthropological studies which incorporate and evolutionary framework reveal that infant sleep physiology evolved in the context of continuous maternal contact including baby-controlled nighttime breast-feeding (52,53). This fact permits us to argue that in order to understand species-wide infant sleep-wake patterns and/or sleep architecture, infant sleep must be studied under conditions that mimic this ‘‘environment of adaptedness’’ (54).
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In Western cultures (as described above), generally, clinicians continue to advocate only one form of sleep for infants and children (i.e., solitary sleep) and sleep management strategies aimed at sharply reducing parental handling and feeding of infants at bedtime as early in life as possible. Parents are encouraged not to permit infants to associate falling asleep with food (including breastfeeding) or parental touch (18,26,55,56), the very context within which the infant’s ‘‘falling asleep,’’ in relation to parental emotions evolved. Breast-feeding rates are increasing in the United States (57). If falling asleep at the breast is as common and, apparently, as biologically appropriate as cross-cultural data suggest (43), then this recommendation will prove problematic for many mothers and infants. Given the Western cultural and historical context within which infant sleep studies were begun, these contemporary recommendations are understandable. First, both clinicians and pediatricians encounter parents who need simple, practical solutions to immediate, on-going problems associated with solitary infant sleep. Thus, a clinician’s impressions are colored by, and mostly limited to, families in crisis. They hear little testimonies from parents who have found alternative sleeping arrangements (to the solitary model), and who enjoy their alternative choices. Second, infant sleep studies were first conducted by researchers in the 1950s and 1960s when breast-feeding was at an all-time low and cosleeping was regarded as being aberrant, and definitely to be avoided. Since the significance of mother-infant cosleeping with nighttime breast-feeding was considered neither biologically nor culturally appropriate, it is not surprising that patterns of childhood sleep development considered clinically ‘‘healthy’’ and ‘‘normal’’ were those patterns expressed by bottle-fed infants sleeping alone in sleep laboratories. A.
The Traditional Sleep Research Paradigm Is Inadequate for the Diversity of Family Sleep Practices It Must and Should Accommodate
It is hypothesized that the progressive organization of sleep and wakefulness at night in infancy reflects the integration of constitutional propensities of the infant (temperament) in interaction with the infants multiple contexts . . . Contextual relationships are mediated by the infants primary relationships which are different from, but have their origins in, the infant’s social dyadic interactions. (6)
Anders (6) suggests, in the quote above, that patterns of ‘‘normal’’ and ‘‘appropriate’’ infant sleep development are extremely variable and responsive to a variety of environmental i.e., contextual, processes. Some of these processes involve family interactional factors, which characterize the nature and affectional structure of the social relationships parents experience with their infants or children during the day (58). If fully realized by researchers and clinicians alike, the ‘‘transactional’’ model that Anders (6) and Sadeh and Anders (4) envision offers a revolutionary approach to studying and understanding infant sleep development, and for creating the inclusive paradigm for which this chapter argues.
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Indeed, a transactional approach takes Lozoff and her colleagues one step further. The approach acknowledges at the outset that ‘‘normal’’ infant sleep development can not only vary within different cultural subgroups but also from one infant to the next, depending upon the interplay of intrinsic and extrinsic variables significant to each developing child. Intrinsic factors can include, but are not limited to, infant temperament, growth rate, and neurological status (constitutional needs) at birth. Extrinsic factors, with which intrinsic variables interact, can involve such things as whether infants are breast- or bottle-fed (59), whether the infant feeds on its own or on its parent’s schedule (60), whether the infant sleeps in the same bed, same room, or different room (alone) (61,62), whether the infant sleeps on its back, side, or belly (63), whether the family generally favors nighttime contact or discourages or resists it (17), and whether the infant has siblings or is an only child. All of these factors (and others) can alter the trajectory of infant sleep development in important ways. Harkness et al. (64) point out that the traditional theoretical models, explanations, and clinical treatments of infants with dyssomnias and parasomnias continue to be predicated on the notion that the ontogeny or maturation of infant sleep is, in the vernacular, fairly predictable, clean, and neat. Changes in infant sleep architecture, particularly the reversal of the predominance of active to quiet sleep, is reported to follow an orderly, unfolding pattern dominated by endogenous mechanisms. For example, during the first year of life a more stable ‘‘adult-like’’ pattern of sleep emerges. The infant sleeps for longer and longer (relatively uninterrupted) periods in increasingly deeper (delta wave) sleep which is thought to reflect an increase in the level of ‘‘integrity and maturity’’ of the central nervous system (64). Indeed, the ability of infants to return to sleep unassisted after awakening (to self soothe), to ‘‘sleep through the night’’ as early in life as possible with minimal parental contact continues to be a developmental benchmark against which infants and their caregivers are evaluated, even when ‘‘sleeping through the night’’ is not an important issue for the parents. Such a criteria if used to evaluate ‘‘developmental progress,’’ may do more harm than good if the sleeping arrangements actually practiced are not the same as the one for which the evaluation was intended. B.
Examples of How Culturally Guided ‘‘Choices’’ Concerning Sleeping Arrangements and Related Sleep Practices Matter Biologically to the Infant, and Change ‘‘Normative’’ Sleep Development
Infant Sleep Position and SIDS Susceptibility
Consider how sensitive the infants sleep behavior, physiology, and health is to culturally guided decisions about how, where, with whom (if anyone) infants should sleep. Indeed, while Lozoff and her colleagues hinted at it, they never could have predicted the degree to which culturally based decisions regarding infant and childhood sleep affects development and nightly sleep physiology,
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including the chances of an infant dying from SIDS. In fact, the sleeping position of the infant has proven to be the single most important factor for reducing the chances of an infant dying of SIDS (65), although the reasons for increased risk remain unknown. The discovery that, merely by placing infants in the supine, rather than in the prone sleep position, SIDS rates could decline as much as 90% in some countries continues to astonish many SIDS researchers worldwide (66). The decision to recommend what turned out to be the dangerous prone sleeping position for term infants, emerged from the widely accepted belief that if prone sleeping helped premature infants to breathe and sleep better then it could probably do the same for older term infants. The possibility that supine infant sleep could make the infant vulnerable to choking (esophageal reflux) only added to the resolve of physicians to lay infants prone for sleep (67). Do infantile arousal mechanisms needed to protect infants during respiratory crises follow the same time course of development as the neurological mechanisms that promote longer periods of deeper sleep (delta wave, stages 3 and 4)? This is an important question, as pertains to the susceptibility to SIDS (68). Over 20 years ago, Douthitt and Brackbill (69) found that prone sleeping newborns slept longer and deeper (aroused less and slept longer) than did supine sleeping infants. That is, infants sleeping on their backs experienced twice as many motor activities during sleep and more awakenings than did prone sleeping newborns, findings recently confirmed by Kahn et al. (70). Since the goal of both parents and health professionals in Western societies was and continues to be to promote sleep and not awakenings, it is easy to understand why these earlier data provided evidence for why infants should be placed in the prone position. Yet, it has been suggested that some infants who die of SIDS perhaps cannot arouse or awaken easily or fast enough to terminate a cardio-respiratory crisis during sleep, especially while in deep sleep where arousal thresholds are higher (68). These findings raise the possibility that the supine sleep might well be safer precisely because of the increased arousal and motor activity which accompanies it, even though the implications of this possibility conflict with cultural strategies to promote early ‘‘deep’’ sleep in infants as early in life as possible. There are other parent-controlled ‘‘social’’ precautions that lower the risks of SIDS. Mitchell (71) found that the presence of a responsible adult sleeping in the same room as an infant reduced by four fold the chances of infants dying from SIDS. This protective effect did not generalize to cosleeping among siblings, indicating that a responsible role played by the caregiver is likely critical in reducing the chances of the infant dying. Moreover, the largest epidemiological study to date conducted in Great Britain, also shows increased risks for infants sleeping in rooms alone, as well as for babies sleeping in their mother’s beds, if the mother smokes. Other dangerous conditions include the use of duvets pulled up over the infant’s head, and the use of soft mattresses. Overheating by overwrapping an infant also significantly increased SIDS risks. All of these new data illustrate the extent to which infant sleep physiology is directly mediated by parental intervention (see Chap. 13).
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Feeding Practices
Bottle-fed infants exhibit significantly different nightly sleep profiles than do breast-fed infants and infants breast-fed for a year or more, develop different sleep patterns than do infants breast-fed for only the first three months (15). Recall that Oberlander et al. (72) found that among newborns a complete milk formula feed increased post-feed sleep by 46% and 118%, compared to water or carbohydrate-only feedings. Furthermore, the most recent Ross surveys indicate that 62% of contemporary mothers in the United States are breast-feeding when they leave the hospital (57). New evidence suggests that at least among Latinos, mothers continue to provide their infants with at least two breast-feeds or more from midnight through to the morning (59). That so many more mothers are now breast-feeding their infants for increasingly longer periods makes sleep models based only on data from infants fed artificial or cow’s milk (from bottles) highly problematic for at least half of the population of contemporary American infants. And while breast-feeding drops to 26% at six months, the number of mothers breast-feeding is continuing to rise in the United States (59). This rise is particularly significant since, as described below, in addition to sleep differences induced by breast versus Cow’s milk, sleep proximity to mother also influences the frequency and duration of feeding bouts (59). Maternal proximity in the form of bedsharing, in addition to breast-feeding, especially changes the infant’s nightly sleep architecture including arousals and sleep period time. Developmental models of infant sleep in the first year of life that do not consider feeding method and frequency in relationship to sleeping arrangements are not therefore appropriate for many infants. Over 20 years ago, Harper et al. (73) argued that feeding behavior asserts an underestimated role in regulating infant sleep physiology and sleep architecture, even though most pediatric sleep research papers rarely include data on feeding method and frequency. For example, he and his colleagues found that among bottle-fed, solitary sleeping infants, the waking periods associated with feeding increased the probability of a subsequent REM period, a finding consistent with previous work on small mammals. They suggested that because REM sleep and quiet sleep followed each other in a sequential fashion, a change in the relative distribution of REM sleep altered the likely sequence of state. Their laboratory research on bottle-fed infants showed that feeding tended to entrain the subsequent REM-QS cycle in that the percentage of REM increased after feeding and then dropped sharply approximately 20 minutes later, with a corresponding increase in quiet sleep. They concluded that ‘‘the interpretation of behavior resulting from maternal-infant interaction should be viewed within the framework of incorporation of food, in that satiety play a large role in regulation of state integration and cardiac response’’ (73). ‘‘Choice’’ of sleeping arrangement was found to greatly increase not only the number of breast-feeds but also the total nightly durations of breast-feeding and the average intervals between the feeding sessions. For example, among 70
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Figure 1 For the breast-fed infant, ‘‘choice’’ of sleeping arrangement sets in motion a cascade of potentially beneficial biobehavioral effects for the mother–infant dyad (from the infant’s perspective).
nearly exclusively breast-feeding Latina mothers and their two- four-month-old infants, we found that when bedsharing the average interval between the breastfeeds was approximately 1.5 hours, but when sleeping apart in separate bedrooms (but still within earshot), the interval was at least twice as long (about 3 hours). Moreover, on their bedsharing nights, we reported that babies breastfed twice as often for three times the total nightly duration than they did when they slept alone (59). These differences in feeding were part of a broader complex of differences, a cascade of interconnected changes induced by the presence of the mother. Sleeping together altered not only feeding behavior within what was supposed to be a homogenous breast-feeding group, but also infant and maternal arousal patterns (75), and sleep architecture (61 and below) mother-baby body orientations in bed (77), infant respiratory behavior (78), and almost every major parameter important in understanding infant and maternal sleep physiology (Figs. 1 and 2 and discussion below). Infant and Maternal Arousals, Temporal Correspondences, and Sleep Architecture Among Solitary and Bedsharing Mother-Baby Pairs
‘‘Separate normative values for infant sleep need to be developed for infants who bedshare, and existing norms should be reinterpreted within the cultural context in which they were established (61).’’ I’ve always found that mother’s intuition and ‘‘mommy radar’’ is on when my kids are right there beside me in bed. Any change in their breathing or
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Figure 2 Cosleeping sets in motion a cascade of biobehavioral effects and events relevant to mothers (from the mother’s perspective).
their well-being and I am instantly awake. I’ve even found that when they started having a fever in the middle of the night, I woke up—perhaps I could sense even these few degrees of difference and knew subconsciously that something was wrong. In three in-house laboratory studies of one form of mother-infant cosleeping, bedsharing, we used standardized polysomnography and infrared photography. We quantified differences in the behavior and physiology of mother-infant pairs as they shared a bed or slept apart. The data show that while bedsharing, a significant amount of temporal correspondence occurred between the sleeping pair’s transient (brief) arousals, and between their larger epochal awakenings (75). We also found that bedsharing mother-infant pairs exhibited a trend toward greater simultaneous overlap in all sleep stages (i.e., stages 1–2, 3–4, and REM). This synchronization of sleep states was not explained by chance and is not found when the sleep/wake activity of infants is compared to randomly selected mothers with whom they did not cosleep (50,79). In our most extensive study, we reported that, in general, small EEGdefined transient infant arousals are facilitated in the bedsharing environment, selectively, and even when routinely bedsharing infants slept alone, they continued to exhibit more transient arousals than do routinely solitary sleeping infants, sleeping alone (75). Furthermore, bedsharing significantly shortened the amount of time per episode infants remained in deeper stages of sleep (stage 3–4) compared with when they slept alone, with increases in the amount of time spent in stages 1 and 2, and more total time asleep (61), since among other things,
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infants cried significantly less while sleeping with their mothers, compared with when they slept apart (51). We also documented an acute sensitivity on the part of the routine bedsharing mothers to their infant’s presence in the bed. That is, compared to the number of overlapping arousals (in which the infant aroused first), routinely solitary sleeping mothers on their bedsharing night in the laboratory exhibited significantly less overlapping arousals than the routinely bedsharing mothers did, indicating that bedsharing mothers do not habituate to the presence of their babies, but become more sensitized to their behavior (75). And while routinely bedsharing mother aroused and fed their infants more frequently while sleeping next to them, on average they received as much sleep as solitary breast-feeding mothers, and routinely bedsharing mothers evaluated their bedsharing sleep experiences (in the laboratory) at least as positively as did routinely solitary sleeping mothers following the night when they slept in their routine (solitary) condition (76). Altogether, these documented differences between the bedsharing and solitary sleep environments suggest the possibility that the presence or absence of the mother routinely in bed with the infant, should lead to significant changes in sleep development over the infant’s first year of life—a ‘‘normative’’ trajectory of sleep development not represented by the traditional paradigm. Culture (Vis a` Vis Sleeping Arrangements) Regulates Infant Breathing?
Sleeping next to them I just find anything different that’s happening wakes me straight up. I just snuggle up to them and they breathe rhythmically again. CH, Kansas I have loved knowing where my babies are and being able to immediately meet their nighttime needs without disturbing the family’s sleep and without myself having to fully awaken. Babies fall back to sleep much more quickly, because most of the time they haven’t even had to work up a cry to have their needs met. BB, Austin In this same study, Richard et al. (78) showed that the decision to sleep with an infant in the same bed, or to place it in a separate room for sleep, contributes to differences in the infant’s nightly breathing patterns. For example, the bedsharing environment is associated with more central apneas, fewer obstructive apneas, and more periodic breathing in infants than the solitary environment. During bedsharing, irrespective of the routine sleeping arrangement at home, the infant experiences a higher frequency of central apneas during stages 1 to 2 and REM (and overall). Among routinely solitary sleeping infants, who slept with their mothers in the same bed in the laboratory, this increase largely reflected an
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increase in the shortest apneas (3–5.9 seconds) while in stages 1 to 2; in routinely bedsharing infants, it reflected increases in apneas in the 6–8.9 second range during REM, and in the apnea range of 9 to 11.9 seconds during stages 1 to 2. In contrast to central apneas, however, obstructive apneas were decreased by bedsharing, but only among routinely solitary sleeping infants (while bedsharing) who had a lower frequency overall and specifically in stages 1 to 2 and REM (78). The amount of periodic breathing was also significantly increased in the bedsharing environment. Routinely bedsharing infants had a higher frequency of periodic breathing and a longer mean duration over the entire night (overall) while bedsharing and specifically during REM. Routinely solitary sleeping infants exhibited more frequent periodic breathing only during stages 3 to 4, while bedsharing in the laboratory with their mothers (78). Social Determinants of Total Infant Sleep Time and Average Bout Lengths
The ethnographic studies of infant sleep in diverse settings confirm just how extensively the infant’s endogenous mechanisms transact with parental behavior. Outside of the laboratory, it is clear that the total amount of daily sleep an infant experiences is regulated by the environment, and cannot be considered dependent on endogenous factors at all. For example, in a recent in-home longitudinal study, Harkness et al. (64) studied 36 American families from Cambridge, Massachusetts. The children ranged in age from birth to 36 months and were studied for over a year. Sleep behavior of the children was compared to a Dutch sample of 66 families with children (living near Leiden and Amsterdam) from different age groups ranging from six months to eight years. Analysis was based on diaries kept by parents in both settings. They found that, on average, Dutch babies slept two hours longer (15 hours vs. 13 hours) than American infants, and the parent infant sleep ‘‘struggles’’ ubiquitous among the Americans was not as familiar to the Dutch (64). The authors explained these differences between the American and Dutch infants’ sleep behavior in terms of the importance of the ‘‘three Rs’’ of Dutch childrearing: rust (rest), regelmaat (regulation) and rein held (cleanliness). The Rs represent the complex social values that underlie and validate the preferred context of solitary and prolonged infant sleep behavior. Harkness et al. (64) describe how Dutch parents bring to their child rearing an ‘‘ethnohistory’’ or set of beliefs, which explain why infants need a great deal of sleep and must not be over stimulated neither during the day nor night. Not only are babies put down to sleep earlier in the evenings, but rather than worrying about whether their infants are receiving enough intellectual stimulation during the day—as American parents do—Dutch parents are concerned that they may be receiving too much stimulation, potentially threatening the infant’s ability to sleep at night (64). In another study, Elias et al. (15) compared the development of sleep in infants of ‘‘standard-care’’ mothers (those following Dr. Spock’s recommendations to minimize contact and feeding during the night), with the sleep of
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infants whose mothers practice care recommended by La Leche League, a worldwide health profession committed to promoting prolonged breast-feeding, physical contact, and cosleeping. Among infants receiving standard, minimal, nighttime contact care, the maximum sleep bout length increased from an average of 6.5 hours at two months of age to 8 hours at four months and to greater than 8 hours during the second year. At two months of age, infants of La Leche League mothers slept an average of 5 hours during their longest sleep bout. Not until they were 20 months old did these infants sleep significantly longer than 5 hours during their longest sleep bout. In contrast to the consolidated sleep of the standard-care infants, their sleep was characterized by shorter bouts and frequent awakenings at night. In addition to bout length, total sleep time developed differently for cosleepers. La Leche League infants slept a total of 15 hours at two months, 12.5 hours at four months, and just over 11 hours by two years. Standard-care infants continued to sleep 13 to 14 hours per day throughout the two-year monitoring period (15). As such, Elias et al. concluded that weaning status and bedsharing have major effects on the development of sleep patterns. Indeed, in their sample, these two factors explained 67% of the variance in bout length (80,81). These data are consistent with babies born to mothers from a very different society, but whose patterns of nighttime sleep and feeding were approximately the same as infants whose mothers practiced the La Leche League recommended baby care. For example, for the first year of life and more, Super and Harkness (43) documented significant nighttime infant sleep behavior differences between the Kipsigis people of rural Kenya and infants living in Los Angeles. Ten Kipsigis infants were observed over a 24-hour cycle on a series of days during the first eight months of life with records kept on their sleep-wake state and feeding patterns, while comparison data for the Los Angeles sample was provided by work conducted by Parmelee, Wenner, and Schultz (82). Kipsigis babies breast-feed throughout the night in close contact with their mothers in one-room dwellings, while American babies slept either in their own rooms or in their own beds. Whereas the American babies averaged eight hours of nighttime sleep by 16 weeks of age, the Kipsigis babies continued to wake at intervals of three to four hours up to eight months of age, the oldest age for which we kept data. They also found that over the 24-hour cycle by the third and fourth month of age American babies were sleeping about two hours longer (43). Thumbsucking and Transitional Objects
Winnicott (83) first described the use of ‘‘sleep aids’’ by young children as part of the process by which they learn to sleep alone. In the absence of a parent or attachment figure, a young child might adopt a ‘‘special object’’ (blanket, favored toy, or stuffed animal) to which they attribute special qualities. These objects serve to comfort a young child during awakenings or while falling asleep (4). In Western cultures transitional objects are so ubiquitous that
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current psychological models of development imply that their use is a natural stage through which all children pass. Use of such objects, however, is not universal, but again dependent upon the social context within which a child’s nightly sleep experience begins and ends. As discussed in their review, Wolf and Lozoff (84) report that American toddlers (mean age 21.7 months) who had an adult present when they fell asleep were significantly less likely to use an attachment object (such as a blanket or doll) or to suck their thumbs, practices that appear to provide a sense of security in the absence of parental contact. In Japan and Korea, where cosleeping is the norm, as a general rule children do not suck their thumbs at night or use transitional objects. One of the most convincing arguments that thumbsucking may well reflect the results of solitariness in young children comes from a study conducted among Turkish children, 96% of whom were thumbsuckers between the ages of one and seven years. These children had been left alone as infants to fall asleep, while all of the children on the non-thumbsucking group (the majority of the total sample) had some type of adult contact or body contact, such as either being held or breastfed while falling asleep (in infancy). Even in American samples, children whose parents stayed with them at bedtime were less likely to suck their thumbs than were children who fell asleep alone (84–86). Among contemporary Mayan children, on only a rare occasion were objects used to ease the transition to sleep and there were no preparations for bedtime or bed time rituals, including special nighttime clothes. Babies mostly fell asleep in their mothers’ arms or were breast-fed to sleep, and only one child observed by Morelli et al. (24) used a security (transitional) object while falling asleep. As they explain, among the Mayans, infant sleep occurred in the same company with whom the babies spend their days and ‘‘no coaxing of any type was needed to get the infant to sleep’’ (24). In sum, culture (including medical views) guide parental decisions regarding infant sleep position, feeding method, and distribution, whether the baby sleeps alone or with its mother, and parental notions concerning infant vulnerabilities. In turn, parental decisions influence infant sleep behavior and physiology. This includes: infant sleep architecture, arousals, sensitivity to the presence of the mother, breathing, amount of feeding, amount of sleep, nightly infant crying time, as well as thumbsucking, and the use of transitional objects. These documented, interrelated effects support Anders’ (6) ‘‘transactional model,’’ which sees the emergence of infant sleep patterns in terms of a ‘‘transaction’’ between extrinsic and intrinsic factors. He hypothesizes that: ‘‘the progressive organization of sleep and wakefulness at night in infancy reflects the integration of constitutional propensities of the infant (temperament) in interaction with the infant’s multiple contexts . . . Contextual influences are mediated by the infant’s primary relationships, which are different from, but have their origins in, the infant’s social dyadic interactions.’’
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My first child, who slept in his own crib and own room, was a ‘‘high-need’’ child who kept my husband and me in sleep deprivation for many months until I finally let him ‘‘cry it out’’ at the age of nine months, something I regret bitterly to this day . . . So I decided my next child would sleep with me. At that point I didn’t care if she were in bed with me until she was 21 years old; I was not going through again what I went through with the first child. HT, New Haven That infant sleep biology changes much more slowly than do the cultural values that underlie and regulate them, raises the possibility that sleep environments optimal for infants may not be the ones encouraged by the culture within which an infant’s family lives. And, of course, it is highly likely that widely accepted infant sleep management strategies are sufficient for some infants and children, but unsuitable for others who vary emotionally or psychologically. Moreover, some families may apply widely accepted developmental sleep norms established for one kind of sleep environment to their own when it is inappropriate to do so. This adaption can have the effect of disappointing parents leading them to conclude that either their parenting skills are deficient or that their infant or child is uncooperative. Ironically, this situation best describes what occurs in developed countries, the United States, Great Britain, and Australia where 35%, possibly as many as one out of every three otherwise healthy children have problems falling or staying asleep, after having first been conditioned to sleep alone (17,35,87). Such high percentages probably do not reflect infant or caregiver deficiencies, but perhaps over confidence in the validity of our definitions and expectations about how infants should sleep, and perhaps the rigidity by which parents hear, interpret, and apply the message offered by health professionals. Indeed, the rigidity by which parents are socialized to hold on to these expectations concerning how their infants should sleep can be used to predict the relative likelihood that infant-child sleep problems will manifest themselves. The more rigid the parental expectations, the more likely parents report dissatisfaction with their child’s sleep behavior (17,80). And as Anders and Taylor (4,5,8) astutely point out, night awakenings constitute a problem for only those parents who expect their children to sleep through the night at very definite ages. Only in the last 100 years or so, in a relatively small number of world cultures, have parents and health professionals become concerned with how infants should be conditioned to sleep. And only in Western cultures are infants thought to need to ‘‘learn’’ to sleep, in this case, alone and without parental contact. Most cultures simply take infant sleep for granted. Consider this remarkable insight offered by Harkness et al.:
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In the sense that normal children everywhere will eventually sleep throughout the night, will need less sleep as they get older and will go to bed and get up at approximately the same hours as other members of the family, and they will eventually fall asleep (and wake up) without immediate support from their mothers or fathers, all four of the major behavioral stages or components of infant sleep are ‘‘developmentally based.’’ (64)
IV.
Infant-Parent or Child Cosleeping: ‘‘The Political Third Rail?’’ Why So Controversial?
Although taking your child into bed with you for a night or two may be reasonable if he is ill or very upset about something, for the most part this is not a good idea. (26) The parents have to be firm and committed to returning the child to bed . . . parents have to learn to ignore crying until the child falls asleep. Sometimes children can cry for a couple of hours . . . . Children may vomit with crying and so parents need to be prepared to go in to clean up the child and change the bedclothes quickly and, with the minimum of fuss, put the child back to bed, and walk out. (56) Sleeping in your bed can make your child feel confused and anxious rather than relaxed and reassured. Even a young toddler may find this repeated experience overly stimulating. (26) Advice against cosleeping may be overly simplistic. (88)
Infant-parent cosleeping is a generic concept referring to the diverse ways in which a primary (responsible) caregiver usually the mother sleeps within close proximity (arms reach) of the infant or child. This proximity permits each to detect and respond to a variety of each other’s sensory stimuli (sound, movement, smells, sights, touch). Cosleeping represents the universal (species specific) evolved context of human infant sleep development. The breast-feeding or mother-infant cosleeping arrangement is for the majority of contemporary people inevitable and inseparable, it is not a choice. This fact suggests that any universal biological understanding of infant sleep physiology and sleep-related difficulties that neglects the evolved connections between nighttime mother-infant proximity, breast-feeding and infant neurological status including emotional needs, must be regarded as inaccurate, incomplete and/or fundamentally flawed. Bedsharing is but one form of cosleeping. Others are: futon cosleeping, or infants sleeping alongside, but not on the same surface as the mother. This arrangement occurs, for instance, when infants sleep in a basket or in a hammock above or on the side of the mother, or when mothers and infants lie beside each other on a mat on the floor. There can be no one outcome associated with cosleeping—benign, beneficial, or deleterious—just as there can be no one outcome associated with solitary infant sleeping arrangements. Physiological or psychological outcomes depend on the infant’s or child’s age, as well as on the nature of the relational setting and social conditions and physical circumstances within which cosleeping occur.
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How Cultural/Scientific Bias Manifests Itself Against the Choice to ‘‘Cosleep’’: A Social Critique
The idea of parent-infant cosleeping as a legitimate and appropriate choice for parents remains controversial in Western societies probably because so many putative negative consequences are associated with it. However, these consequences are rarely contextualized or systematically documented. In popular parenting books, childcare bulletins, and childcare magazines cosleeping can be: (1) mostly described as if it were a unitary concept; (2) ignored completely; and (3) presented to parents in terms of the likely or inevitable ‘‘problems’’ that will, might, or could, arise, if it were practiced. Sometimes, it is explicitly discouraged (26); at other times the message is similar but more subtle (18). The usual reasons that separate sleeping quarters for parents and children are recommended over cosleeping include: marriages might best be nurtured and preserved; infant or child individualism and autonomy promoted; incest and suffocation avoided, social (childhood) competence maximized; gender and sexual identities strengthened; and life satisfaction (for all family members) potentially realized (47,29). Indeed, where a ‘‘problem’’ or potential problem with cosleeping can be identified, rather than being considered simply a ‘‘problem to be solved,’’ the putative problem becomes the argument against the practice, as if all families who cosleep will experience the same ‘‘problem.’’ Furthermore, possible problems associated with cosleeping are presented as if they cannot be solved in the same manner as, for example, problems associated with solitary sleep can be solved. Throughout the literature, cosleeping is described as the cause of marital discord (58), though recent data from Sweden refutes this notion, (89), or the cause of sibling jealousies . . . which, while possible, may be only one of many causes of sibling jealousy. Moreover, without considering whether the particular parents involved consider cosleeping a ‘‘bad’’ or a ‘‘good’’ habit, parents are warned that cosleeping creates a ‘‘bad habit,’’ one that’s ‘‘difficult to break.’’ Furthermore, cosleeping is said to ‘‘confuse’’ the infant or child emotionally or sexually, or to induce ‘‘over’’ stimulation. But no evidence is offered which specifies how, when, and under what circumstances (26). A child needs to sleep alone, it is also recommended in order to create a sense of self and comfort with aloneness, or skills that presumably foster self-reliance—all ‘‘moral goods (26). Again, no specifics are given, however, as to how this arrangement only produces these outcomes, leaving the readers to assume that solitary sleep is the only way. Certainly, concerns for infant safety top the list of reasons why some health professionals suggest that all cosleeping should be avoided, and it is true that modern beds were not designed for infant safety. Suffocation and SIDS, which are mostly indistinguishable from each other, are argued to be two potential consequences of parent-infant cosleeping (71). Indeed, where mattresses are soft, the mother smokes, and/or any adult cosleeper is desensitized by drugs, bedsharing should definitely be avoided. And, there are many other conditions that would make bedsharing less than an ideal choice, including the parents’
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discomfort with the idea. But recognizing when and where cosleeping in the form of bedsharing should be avoided is different from assuming that all bedsharing is dangerous—as laboratory (49,59,61,75,76,90,91), home (46), and epidemiological studies of unexpected deaths in infants (see chap. 13) are making clear. Cosleeping/bedsharing is not synonymous with dangerous sleep environments, although dangerous conditions are used inappropriately as a proxy for the act itself i.e., mothers and infants lying side-by-side), as current debates about cosleeping are beginning to reveal (92,93). The exaggerated fear of suffocating an infant while cosleeping may, in part, stem from Western cultural history. Over the past 500 years, many economically destitute women living in Paris, Brussels, Munich, and London (to name but a few locales) confessed to Catholic priests of having murdered by overlaying their infants to control family size (94–96). Led by the priests who threatened excommunication, fines, or imprisonment (for actual deaths), infants were banned from parental beds. The legacy of this particular historical condition in Western history probably converged with other changing social mores and customs (values favoring privacy, self-reliance, individualism) providing a philosophical foundation for contemporary cultural beliefs. This foundation makes it far easier to find dangers associated with cosleeping than to find (or assume) hidden benefits. The proliferation and expansion of the idea of ‘‘romantic love’’ throughout Europe, coupled with the belief in the importance of the ‘‘conjugal’’ (husbandwife) relationship probably also promoted separate sleeping quarters. It has been proposed that this physical separation, especially of the father from his children, maximized his ability to dispense religious training and to display moral authority (96,97). As with many relational issues, parent-child cosleeping may require unique solutions to assure, in this case, safety and ‘‘private adult time.’’ However, that ‘‘problems’’ in need of solving can be associated with cosleeping is no more an argument against its legitimacy, than is the fact that thousands of parents purchase books to solve the ‘‘problems’’ associated with solitary infant sleep. As Kuhn noted, scientific paradigms change neither quickly nor easily (98). The controversy surrounding cosleeping and the value of mother-infant cosleeping studies might partially be explained by these topics being part of a new paradigm that is not readily or necessarily easily assimilated by those who have worked all of their scientific lives documenting the normality of solitary infant sleep and accepting, uncritically, the alleged deleterious consequences of infant-parent cosleeping. Researchers, clinicians, and parents alike share many common cultural experiences. This common background probably means that most or very few of them routinely coslept with their own parents, which strongly influences ones comfort with the practice (99). Perhaps an appreciation of diverse childcare practices, including cosleeping, will come only when non-European immigrants come to dominate Western countries. As demographics on that score suggest, the question is not if the paradigm will change, but how soon.
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Cosleeping/Bedsharing in Western Societies: How Often? How Much of the Night? Who Really Knows?
Infant-parent cosleeping represents the universal, species-wide pattern of sleep for children worldwide. Barry and Paxson (10) surveyed the sleeping practices of 186 independent societies in a sample representative of all known major cultural types in the world. Of the 119 cultures with reliable ethnographic data on parental nighttime sleeping proximity to infants, mothers slept in the same bed with their infants in 76 cultures (64%). In 20% of these cases, the father slept in the same bed as well. In none of the cultures was the infant actually isolated at bedtime. The baby was always placed in sensory proximity of another person, but not necessarily made to sleep on the same surface. Few studies have addressed the prevalence of parent-infant cosleeping in the United States and most surveys are now dated. It is a difficult subject on which to collect accurate information. Some American subgroups are comfortable reporting that they cosleep, while others are not. Fear of censure and/or parental perceptions that bedsharing is outside of the cultural norm probably leads to underreporting (58,99,100). Until recently, popular parenting books and magazines warned parents about the psychological consequences of colseeping. That parents might fear disapproval and be reluctant to admit to cosleeping is justified. One survey in 1984, found that 94% of pediatricians disapproved of cosleeping. Although that number is likely considerably lower today, negative opinions about cosleeping probably remain high (88). That said, even within Western industrialized cultures, it appears that diverse forms of cosleeping are not uncommon. For example, Abbott (29) found that in Eastern Kentucky (Appalachia), infant-parent cosleeping is prevalent among white Americans who seem not ‘‘to care what doctors say’’ believing rather that ‘‘it is best for the mother and child to be together.’’ Says another informant, ‘‘These new mothers are losing two of the greatest blessings that God gave mothers: the pleasure of sleeping with your child and letting it nurse’’ (29). Abbot argues that Eastern Kentucky practice of parents sleeping with or near their infants throughout the first two years of life is a strategy used by parents in this subgroup to induce interdependence, which is preferred to independence. As one Eastern Kentucky woman phrased it, ‘‘how can you expect to hold on to them later in life if you begin their lives by pushing them away’’ (29). In the well-cited study conducted of parent-infant cosleeping among urban Americans in Cleveland, Lozoff et al. (88) found that 35% of poor urban whites and 79% of poor urban blacks routinely slept with their children, who ranged in age from six months to four years. In contrast, Anders and Keener (36) recorded the nighttime sleep of 40 newborns and found that between the time the infant was initially laid in the crib and the time it was removed in the morning, at two and four weeks of life, the infant spent less than 20% of the night outside of the crib. After the age of 20 weeks (5 months) through to the first birthday, infants spent less than 3% of the night outside their cribs.
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Of the 150 mothers in the Cleveland area, 71% of the mothers indicated that they did not practice cosleeping during the month before the interview, and 65% disclosed that they did not provide any body contact to their child at bedtime (88). However, what parents say and what they actually do are often two different things. For example, in this same survey, fewer than 35% of these mothers indicated that they were ‘‘firm’’ in adhering to these stated practices when their child continued to awaken during the night, was ill, or was frightened. In the Boston metropolitan area (Worcester), Madansky and Edelbrock (31) found similar differences between black and white families. The majority of parents in the sample, 55% reported that their two- to three-year-olds had slept in their bed at least once in the last two months, and 14% reported cosleeping several times a week. Seventy-six percent of the black families coslept, while 53% of the white families did. Black families were more than twice as likely as whites to cosleep more than twice a week (50% to 21% respectively). A relatively recent study of cosleeping in Harlem by Schacter-Fuchs et al. reveals that 20% of Hispanic Americans slept with their children all night at least three nights a week, compared with only 6% of the white families sampled there (48). Among US La Leche League mothers, there was frequent bedsharing with their infants and children. Elias et al. (15) showed that between 2 to 13 months of age, 60–90% of La Leche League infants slept with their mothers. Especially for upper middle class families, nighttime nurturing in the form of cosleeping is one way that mothers and fathers feel they can compensate for time spent apart from children during the day. Says one career woman interviewed in Southern California: ‘‘Sleeping with my baby lets me make up some time I couldn’t spend with her during the day, since my husband and I do not return to the house until early evening. Cosleeping gives me more time to feel and nurture my baby.’’ Among middle to upper class (Caucasian) families, cosleeping no longer appears to be taboo, as it was just a decade ago (46). The fact that over half of all American mothers are breast-feeding for between three and six months or longer (57) makes it even more likely that increasing numbers of mothers are sleeping with or near their infants or children to facilitate nighttime feeds. Breast-feeding promotes bedsharing (100). Still, fear of censure by pediatricians, family, and friends prevent many parents from discussing their nighttime caregiving practices, if they happen to vary from the expected ‘‘norms’’ (88,99,101). C.
Closet Cosleepers, Changing Demographics of Cosleeping Families and Dear Abby?
Recent anthropological field studies in Great Britain further indicate that many more parents sleep with their infants or children in Western societies than is ever reported. Ball and Hooker (46) studied a white working class community in northeast England. They found that parents often respond to questions regarding the place where the infant sleeps at night by identifying the place where the
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infant starts the night, or where the infant ‘‘is supposed to sleep’’ but not necessarily with where the infant spends most of the night. Ball and Hooker filmed nighttime parenting behavior using infrared cameras placed in the parents’ bedroom. In addition, they conducted two sets of interviews—one before the infant’s birth, the other when the infant was two months old. Their study revealed that unless researchers specifically asked parents if the babies were moved during the night possibly as many as half the infants would not have been identified as cosleepers, who actually were (46). Attitudes regarding the validity of the choice to ‘‘cosleep’’ are changing in Western countries. Perhaps advice columnist Abigail van Buren (Dear Abby) reflects where popular culture is headed on this issue. Recently a ‘‘Dear Abby’’ letter published in the Chicago Tribune was received from a husband who signed his letter: ‘‘Crowded Bed’’. He complained to Abby about his wife’s insistence that their 16-month-old daughter be permitted to sleep in their bed and he asked for Abby’s opinion. She responded with: Dear Crowded Bed: In some cultures it is normal for a baby to share the parents bed until mid-childhood. . . . An infant will adjust to the style parents choose . . . but Alicia can learn to sleep comfortable in her own bed, if that is what you choose to teach her. (102)
V.
Conclusions/Recommendations/Afterthoughts----Getting Mothers and Infants Together for Nighttime Sleep and Breast-feeding: Still Crazy After All These Years
To every complex problem there is one, simple, wrong solution H.L. Mencken As discussed throughout this chapter, cross-cultural (global) data on infant sleep, sleeping arrangements, and nighttime breast-feeding patterns remind us that how we, in the industrialized West, define from a medical point of view, normal, safe, and healthy infant sleep, i.e., infants sleeping outside bodily contact with their mothers, actually conflicts with our species evolutionary history, including present worldwide infant sleep behavior. One irrefutable fact still remains: human infants are designed to sleep next to their mothers in and out of bodily contact. This fact is especially being verified since breast-feeding behavior, which is biologically and behaviorally interdependent with mother-infant cosleeping, is yet again part of the parental experiences of Western mothers. It should not be surprising then that a shift first to breast-feeding has led to a shift to sleeping closer to baby (104). As is obvious from the material presented in this chapter, specific breastfeeding and cosleeping patterns will vary extraordinarily with some bedsharing practices being far safer than others, but it is naı¨ve to think, and as a strategy to
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respond to these differences, that everyone should be told not to practice it or that simply by suggesting that mothers and infants should never sleep on the same surface that this advice can or even should be followed. We suggest that such advice is not only scientifically flawed but also dangerous, insofar as it prevents parents from being able to openly discuss their cosleeping choices with those who can help them practice it in the safest possible manner. The recently promulgated and unqualified assertion by the American Academy of Pediatrics (AAP) (105) that contact during sleep between an infant and its mother in a Western bed is inherently dangerous, ultimately places Western mothers and infants at odds with their own biological propensities to seek out and secure nighttime bodily contact whether for nutritional or emotional purposes or both. Ultimately, the recommendation that emerged from this assertion, not to sleep on the same surface as the baby, will fail because the reasoning and rationale behind it is simply not true. We argue that the entire process by which ‘‘evidence’’ about bedsharing is generally collected, i.e., questions formulated and questions omitted, and subsequently how the data are evaluated often reflects a traditional, if not highly limiting, way of thinking—a one-size must-fit-all way with a simplistic solution proposed for a very diverse, complex, and heterogeneous practice—an approach that, as this chapter has shown, has tenacious cultural and historical roots. It is fascinating to think that while medical institutions are formalizing their arguments against the safety of bedsharing, and since the first publication of this chapter eight years ago, more Western families are bedsharing than ever before. One recent survey conducted in the United States by the National Institutes of Child Health and Human Development found that during the 1990s, the number of mothers sharing their bed with their infants for part or all of the night doubled and may reach as high as 50% (intermittent or part-time bedsharing is considered) (106). That same survey involving over 10,000 families revealed that breast-feeding mothers were three times more likely than bottle feeding mothers to bedshare (106) and similar findings have been documented in Great Britain (104), Australia (107), and New Zealand (108). In fact, it may be that bedsharing is much higher than is reported in these surveys. In northern England, Ball et al. (109) found that they would have missed half of the routine cosleepers (bedsharers) had the researchers not asked if the baby was moved or relocated to sleep in a different location at some point in the night. They describe why working class parents in North Tees, England, changed their sleeping arrangements from the crib to bedsharing. The authors state, ‘‘Bringing the baby into their bed to sleep was described as an ‘intuitive’ strategy by many new parents.’’ This research raises the possibility that the true frequency of cosleeping has been grossly underestimated in Western countries where parents traditionally confront social criticisms for bedsharing (109). It appears then that the biology underlying breast-feeding behavior—the new Western feeding norm—acts as a ‘‘hidden regulator’’ practically assuring increased nighttime mother-infant proximity whether sleeping in the same bed or
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within arms’ reach, on a different surface (110). A standard reason given for why breast-feeding mothers bedshare is that it simply makes breast-feeding easier. It is important to understand the full context within which the unqualified recommendation against cosleeping in the form of bedsharing by the AAP was made. In the new SIDS Guidelines, bedsharing is not recommended and is described as ‘‘hazardous’’ regardless of who practices it and how. The good news is (from these authors perspective), that for the first time in Western medical contexts, while bedsharing is not supported, mother-infant cosleeping in the form of roomsharing is. In other words, the data show that a committed adult sleeping in the room with an infant significantly reduces that infant’s chances of dying from SIDS, possibly by as much as one half. It would appear that the life-saving function of cosleeping where sensory exchanges between the adult caregiver and infant occur is supported empirically as long as mothers and infants do not (apparently) get too close. Still, while the recommendation against separate room sleeping for infant and parent is appreciated and is historically important, the assumption that parents, no matter what, cannot construct a safe bedsharing environment for their infant has never been demonstrated and there is much evidence contradicting the committees assertion that a sleeping mother is unable to respond to protect her infant through the night. The very fact that the data from laboratory studies discussed earlier showing mothers capacity to emerge from sleep in response to her infants activity (sounds or movements) provides further evidence for considering the reality of deep-seated scientific bias which is embedded within the SIDS and infant sleep paradigm. There is no doubt that the AAP’s recommendation against bedsharing is preventing families interested in bedsharing from receiving advice and counseling on how to maximize bedsharing safety. Since the recommendation came out, information about safe bedsharing previously found on hospital health brochures are being rescinded all across the United States possibly leading to preventable bedsharing accidents or deaths. It may seem that a recommendation by the AAP means that there is scientific consensus within the organization itself and that, in addition to the six individuals who made the recommendation, thousands of scientists and/or pediatricians studied the issue and concur that no bedsharing can be made safe. This is not the case. The recommendation against bedsharing was approved without scientific consensus within the AAP and lacked support from many other medical organizations, especially those involved in the human lactation sciences and/or the promotion of breast-feeding (111,112). Criticisms of the unqualified recommendation against bedsharing center around the sub-committee’s singular over reliance on population-wide epidemiological studies characterized in many cases by inconsistent definitions of bedsharing, and studies which infer causation and make recommendations without having controlled for critical independent factors, such as sleep position and other risk factors alcohol or drug use, or even, in one study, where the infant actually died (111).
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The complete dismissal of the importance of any and all contrary scientific lines, particularly physiological-behavioral or laboratory bedsharing research that demonstrate potential positive (clinical) trade-offs associated with bedsharing, and/or benefits including protective aspects of combining breast-feeding and bedsharing are also problematic (112). In making such a decision to exclude all but epidemiological studies, the committee fails to follow the rules of evidence-based medicine, which requires that all lines of evidence and research be considered and not simply epidemiology. Perhaps this decision also confuses a social judgment with a scientific one. That is, the committee apparently believes that problems or hazards associated with crib sleeping (recall at least 350,000 infant deaths in Western countries have occurred there) are worth solving, while problems or hazards associated with bedsharing are not. To come to its assessment of the ‘‘data’’ that bedsharing is always, if not inevitably, a risk factor for SIDS, the committee chose to ignore cross-cultural evidence to the contrary, data showing that some of the low SIDS awareness countries and those with the lowest SIDS rates in the world practice the most bedsharing (113). The committee also chose to ignore the fact that the most rapid and precipitous declines in SIDS rates occur among the very groups for which the greatest increases in bedsharing behavior are taking place: middle class whites who breast-feed (104,107). Nobody can deny that a high and disproportionate number of babies die in unsafe bedsharing contexts, or that successful outcomes associated with bedsharing can be seen to increase as socioeconomic status improves. The urban poor among us fare much less well as regards infant survival while bedsharing. But the solution to this unfortunate dilemma is not to gloss over the complexities in favor of a ‘‘one simple message’’ i.e., ‘‘Don’t do it.’’ Not only does it dismiss the ultimate rights of parents to make decisions that are only theirs to make and to receive the information they need to make those decisions wisely, but it dismisses the significance of parental-infant biology, and mostly, it dismisses the capacities of parents to respond to their infants and what their infants need to make them safe, in the most effective way possible which cannot or should not emerge from external medical authorities. Along these lines, and still just as timely as they were in 2000 for the first publication of this chapter, many different ideas and issues are proposed which are worth highlighting and some additional ones are called for in light of the unqualified AAP recommendation against bedsharing with which we and many others disagree. 1. In pediatric practice, physicians should be prepared to give advice relevant to culturally diverse parental childcare goals, attitudes, desires, and approaches, and attempts should be made to inform parents about a broad range of sleeping and feeding patterns, which means discussing choices that might differ from those chosen by the physician. The potential advantages and disadvantages of all sleeping
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2.
3.
4.
5.
6.
arrangements should be raised, and mention of safety precautions for all choices should be included in discussions. Problems associated with nontraditional sleeping arrangements, such as cosleeping, do not by themselves constitute arguments against the validity of the choice. Nor does the existence of ‘‘problems’’ suggest that they cannot be solved, or that particular problems are intrinsic to the practice and inevitable. The human infant’s extreme neurological immaturity at birth makes social care (including sleeping arrangements of young infants) practically synonymous with physiological regulation. This regulation is an extraordinarily important and unique aspect of the importance of the sleep environment for the human infant—a significance that is not acknowledged by the traditional paradigm or, in general, by pediatricians and sleep clinicians. Unless it is determined that mothers want to reduce nighttime breastfeeding, sleep clinicians or pediatricians should not automatically assume that the best approach is: the fewer the feeds earlier in life, the better. The benefits of breast milk, including nighttime breast-feeds, are far too significant, as recent scientific studies have revealed. The choice belongs to fully informed parents, not to advice givers. Regardless of where parents want their children to sleep, as a beginning point for understanding, parents should be reminded that, biologically and psychologically, infants, children, and they are designed to sleep close. It is perfectly appropriate that some parents, perhaps many, may choose not to do so. However, it should be explained to parents that the infant’s inability to ‘‘sleep through the night’’ or to sleep alone easily should not be interpreted as a deficiency or as manipulation on the part of the infant. Such an understanding may help prevent parents from evaluating their own caregiving skills negatively and/or their infants or children’s behavior as abnormal, bizarre, or deficient. A more scientifically accurate or ‘‘user-friendly’’ approach to infantchildhood sleep problems and potential solutions requires sensitivity to the legitimacy of diverse choices parents might make. The transactional model described by Anders (6) and Sadeh and Anders (4,5) can guide both research and clinical practice into the new millennia. They describe a model that can accommodate biological as well as sociocultural and psychological influences on sleep development and, indeed, it is a model that sees these factors as being inseparable. This model can help researchers to formulate new questions, further demonstrating how culturally guided choices influence infant sleep and potentially induce significant physiological regulatory effects—some of which can be life saving, as discussed.
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7. As Baddock argues, following a qualitative study of caregiving practices in relationship to SIDS risk factors among four different cultural groups in New Zealand (114): i. To be effective, ‘‘safe infant sleep’’ guidelines need to be delivered in a way that is appropriate to family goals as expressed in specific cultural contexts. ii. Unqualified recommendations against bedsharing risk, alienating those at the highest risk for SIDS (in this case single mothers), by making them feel what they are doing is wrong only produces a reluctance to openly discuss childcare behaviors, thus preventing parents from receiving access to current and proper safety guidelines. iii. Bedsharing is not a coherent or homogenous (discrete) behavior, but composed of many different behaviors; hence, epidemiological studies need to incorporate many more qualitative questions to capture what makes bedsharing safe or what transforms it into something dangerous. iv. Research that treats bedsharing as a single entity or fails to take into account the context of the bedsharing, or the values families place upon it, will likely prove inadequate. v. Identification of specific risk factors in the context of bedsharing (rather than assuming that bedsharing is always hazardous and dangerous) has a better chance of understanding the variation in risk between cultural groups who practice bedsharing, but with radically different outcomes (115–117). References 1. Lozoff B, Wolf A, Davis NS. Sleep problems seen in pediatric practice. Pediatrics 1985; 75(3):477–483. 2. Shweder R, Jensen LA, Goldstein WM. Who sleeps by whom revisited: a method for extracting moral goods implicit in practice. In: Goodnow JJ, Miller PJ, Kessel F, eds. Cultural Practices As Contexts for Development. San Francisco, CA: JosseyBass, 1995:21–40. 3. Shifrin D. A nod to family togetherness. In: Feeney S, ed. New York Daily News. August 1997:32 (personal communication). 4. Sadeh A, Anders TF. Infant sleep problems: origins, assessment, interventions. Infant Ment Health J 1993; 14(1):17–34. 5. Sadeh A, Anders TF. Sleep disorders. In: Zeanah CH, ed. Handbook of Infant Mental Health. New York, NY: Guilford Press, 1993:305–316. 6. Anders TF. Infant sleep, nighttime relationships, and attachment. Psychiatry 1994; 57(1):11–21. 7. Anders TF, Eiben LA. Pediatric sleep disorders: a review of the past 10 years. J Am Child Adolesc Psychiatry 1997; 36(1):9–20.
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92. McKenna J. Bedsharing promotes breast feeding and the AAP task force on infant positioning and SIDS. Pediatrics 1998; 102(3):663–664. 93. Hauck F, Kemp J. Bedsharing promotes breast feeding and the AAP task force on infant positioning and SIDS. Pediatrics 1998; 102(3):662–663. 94. Flandrin J-L. Families in Former Times: Kinship, Household and Sexuality. New York: Cambridge University Press, 1979. 95. Kellum BA. Infanticide in England in the later middle ages. Hist Child Q (J Psychohist) 1974; 1(3):367–388. 96. Stone L. The Family, Sex and Marriage in England, 1500–1800. New York: Harper and Row, 1977. 97. Aries P. Centuries of Childhood. New York: Vintage, 1962. 98. Kuhn TS. The Structure of Scientific Revolutions. Chicago, IL: University of Chicago Press, 1962. 99. Hanks CC, Rebelsky FG. Mommy and the nighttime visitor: a study of occasional co-sleeping. Psychiatry 1977; 40(3):277–280. 100. Mitchell EA, Scragg L, Clements M. Factors related to infant bedsharing. NZ Med J 1994; 107:466–467. 101. Oleinick MS, Bahn AK, Eisenberg L, et al. Early socialization experiences and intrafamilial environment: a study of psychiatric outpatient and control group children. Psychiatry 1966; 15(4):344–353. 102. Dear Abby Column. Chicago Tribune. January 27, 1998. 103. Douglas M, Wildarsky A. Risk and Culture. Berkeley, CA: University of California Press, 1982. 104. Blair P, Ball HL. The prevalence and characteristics associated with parent-infant bed-sharing in England. Arch Dis Child 2004; 89(12):1106–1110. 105. American Academy of Pediatrics Task Force on Sudden Infant Death Syndrome. The changing concept of Sudden Infant Death Syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables to consider in reducing risk. Pediatrics 2005; 116(5):1245–1255. 106. Willinger M, Ko CW, Hoffman HJ, et al. Trends in infant bed sharing in the United States, 1993–2000: the national infant sleep position study. Arch Pediatr Adolesc Med 2003; 157(1):43–49. 107. McCoy RC, Hunt CL, Lesko SM, et al. A frequency of bed sharing and its relationship to breast feeding. J Dev Behav Pediatr 2004; 25(3):141–149. 108. Rigda R, McMillen IC, Buckley P. Bed sharing patterns in a cohort of Australian infants during the first six months after birth. J Pediatr Child Health 2002; 36 (2):117–121. 109. Hooker HE, Kelly P. Where will baby sleep? Attitudes and practices of new and experienced parents regarding cosleeping with their newborns. Am Anthropol 1999; 101(1):141–151. 110. McKenna JJ, Mosko S, Richard C, et al. Mutual behavioral and physiological influences among solitary and co-sleeping mother-infant pairs; implications for SIDS. Early Hum Dev 2004; 38:182–201. 111. McKenna JJ, McDade T. Why babies should never sleep alone: a review of the co-sleeping controversy in relation to SIDS, bedsharing and breastfeeding. Paediatr Respir Rev 2005; 6(2):134–152. 112. Fleming P, Blair P, McKenna J. New knowledge, new insights, new recommendations. Arch. Dis Child 2006; 91(10):799–801.
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9 Pediatric Parasomnias
THORNTON B. A. MASON II The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.
ALLAN I. PACK University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
I.
Introduction
Parasomnias are defined as ‘‘undesirable physical events or experiences that occur during entry into sleep, within sleep, or during arousals from sleep’’ (1). The large number of parasomnias underscore that sleep is not simply a quiescent state, but can involve complex episodes of movement, ranging from subtle to dramatic and complex. The obvious, prolonged, dramatic events are most likely to raise concerns of patients, relatives, and clinicians, prompting medical evaluation (1). As delineated by the International Classification of Sleep Disorders, Second Edition, parasomnias are classified as (i) disorders of arousal [from non– rapid eye movement (NREM) sleep], (ii) parasomnias usually associated with rapid eye movement (REM) sleep, and (iii) other parasomnias (1). II.
Disorders of Arousal from NREM Sleep
An important subset of pediatric parasomnias includes the disorders of arousal: sleepwalking, confusional arousals, and sleep terrors. As these parasomnias share overlapping features, they are often considered part of a continuum. While 223
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most often occurring in slow-wave sleep (SWS), (stages 3 and 4 of NREM sleep), these parasomnias can also occur in stage 2 NREM sleep (2). Importantly, these disorders share common aspects, such as incomplete transition from SWS, altered perception of the environment, automatic behavior, and variable degrees of amnesia for the event. In particular, because of the association with SWS, the arousal disorder parasomnias tend to occur in the first third of the night, when SWS is most prominent (1). The child’s sleep stage transition from SWS is abnormal, often when shifting into lighter NREM sleep (e.g., stage 2) just prior to the first REM sleep episode. The patient, in a sense, becomes ‘‘stuck’’ between deep sleep and wakefulness (3). The electroencephalogram (EEG) during these episodes demonstrates an admixture of theta, delta, and alpha frequencies. A.
Prevalence
The disorders of arousal parasomnias are more frequent in childhood than in adolescence or adulthood. Prevalence estimates in childhood for sleep terrors range from 1% to 6%, for sleepwalking up to 17% with a peak at 8 to 12 years, and for confusional arousals up to 17.3%(1). On the basis of structured telephone interviews, Ohayon et al. reported that the percentage of adolescents and adults (aged 15–24 years) with sleep terrors was 2.2%, sleepwalking 2%, and confusional arousals 4.2%; the prevalence significantly decreased after age 25, and no sex differences were observed (4). B.
Evaluation
The office evaluation of a child with any parasomnia should be thorough. Because parasomnias occur out of sleep, a child’s recollection of events is fragmented at best. Indeed, in most cases the child will not remember any details of what transpired. Parents, on the other hand, should be questioned regarding the spectrum of events that typically occur, how soon after sleep onset these events are noted, and whether episodes take place during naps as well as at night. Parents should also be asked to describe in detail the movements and behaviors that are typically seen. If possible, the parents should make a home video recording that can prove very valuable in diagnosing parasomnias (5). A detailed history may also be supported through the completion of sleep diaries, in which parents record sleep periods, arousals/awakenings, and possible parasomnia events. The sleep medicine practioner should keep in mind that some patients may have more than one parasomnia type. Information regarding whether the movements are rhythmic or stereotyped and whether the movements occur at different times through the night should be gathered; these features, if present, may support an epileptic origin to the events. Parents should be questioned if similar events have been noted during wakefulness. The sleep history should be accompanied by a comprehensive physical and neurological exam, to look for features that would be associated with an
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underlying sleep disruptor: for obstructive sleep apnea, features such as adenotonsillar hypertrophy, retrognathia, and mid-face hypoplasia; for periodic limb movements in sleep, features such as peripheral neuropathy or myelopathy. Sleepwalking
Sleepwalking (somnambulism) in childhood shares features with sleepwalking in adults, and may begin in infancy as soon as a child is able to walk. Sleepwalking may be either calm or agitated, with varying degrees of complexity and duration (6). Because of episodes that are unobserved or forgotten, the frequency of sleepwalking may be underestimated (7). In his landmark studies, Klackenberg reported that the presence of sleepwalking of variable frequency was highest at 11 to 12 years, with males and females equally affected (8). Children with somnambulism are usually calm and do not demonstrate fear. The child may be found walking into a parent’s room, bathroom, or different parts of the house. With mobility go concerns for safety, because subjects with sleepwalking are at risk of injury (6). The subject may climb through windows, wander in bathrooms, attempt to walk downstairs, and sometimes leave the house. Injuries to the child may include trauma from falls, lacerations from broken window/patio glass doors, even hypothermia from exposure (9). Confusional Arousals
Confusional arousals have more associated agitation than that usually expected with sleepwalking. Confusional arousals occur mainly in infants and toddlers. A typical episode may begin with movements and moaning, then evolve to confused and agitated behavior with calling out, crying, thrashing, or even combative behavior (10). Attempts to wake the child fully are unsuccessful. Physical injury is rarely seen (11). The child resists the parents’ efforts at consolation, and more forceful attempts to intervene may result in increased resistance and further agitation. A confusional arousal episode may last 5 to 15 minutes (although sometimes longer) before the child calms and returns to a restful sleep. In adults, rapid awakening from especially deep sleep may result in sleep drunkenness (schlaftrunkenheit). Factors that increase sleep drunkenness include sleep deprivation, medication effects, or other sleep disorders with excessive sleepiness or abnormal sleep/wake patterns (9). In a large sample of individuals ages 15 to 100 years, confusional arousals were self-reported by 4.2% of the sample; the prevalence was equal in males and females, and was highest in the 15- to 24-year-old age group, decreasing significantly with advancing age (4). Sleep Terrors
Sleep terrors are the most dramatic partial arousals from SWS. The child may sit up suddenly and scream, with an intense, blood-curdling ‘‘battle cry.’’ The episode is a fight-flight phenomenon. Autonomic activation is present, with
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mydriasis, diaphoresis, and tachycardia (12). There is an increased respiratory tidal volume (much more so than respiratory rate) and an intense look of fear on the face. Moreover, there is a ‘‘curious paradox’’ of endogenous arousal coexistent with external unarousability (13). With sleep terrors, children may report indistinct recollections of threats (monsters, spiders, snakes) from which they have to defend themselves (14). The differential diagnosis of sleep terrors includes nightmares, nocturnal panic attacks, epileptic events (see below), and cluster headaches. Sleep terrors are more prevalent in childhood than in later life; peak prevalence is between 5 and 7 years, and resolution typically occurs before adolescence. Sleep terrors affect approximately 3% of children between the ages of 4 and 12 years and <1% of adults (15). C.
Influencing Factors
Disorders of arousal (sleepwalking, confusional arousals, sleep terrors) can be thought of as being due to a faulty ‘‘switch’’ that prevents normal sleep cycle progression. The transition from SWS to lighter sleep, just prior to REM sleep onset, is abnormal. The patient is neither fully asleep nor fully awake (3). The EEG demonstrates an admixture of different EEG frequencies (16). There are multiple factors that may influence arousal parasomnias. Age is an important issue, as many parasomnias are much more likely to occur in childhood than later in life. Another contributing factor includes the homeostatic drive to sleep, with more frequent or more severe parasomnia episodes being associated with prolonged sleep deprivation. Sleep deprivation has been shown to increase the complexity and frequency of sleepwalking events in a sleep laboratory during subsequent recovery nights; thus, sleep deprivation may facilitate a polysomnographically-based diagnosis (17). Other factors that may trigger parasomnias include medications (e.g., neuroleptics, sedative hypnotics, stimulants, and antihistamines), a noisy or stimulating sleep environment, fever, stress, and intrinsic sleep disorders (such as obstructive sleep apnea and periodic limb movements in sleep) (18). Features in the child’s history that support obstructive sleep apnea include the presence of snoring, gasping in sleep, and pauses in breathing. Overnight polysomnography is indicated when there is concern for an intrinsic sleep disruptor (e.g., periodic limb movements, obstructive sleep apnea), rather than to document the parasomnia per se, as parasomnia events recorded in the sleep laboratory may be atypical, if indeed present at all. Reviewing questionnaire data, Owens et al. reported that parasomnias, such as sleepwalking and sleep terrors, appeared significantly more common in children with obstructive sleep apnea than in normal children (19). Guilleminault et al. reported that in children sleep disordered breathing or periodic limb movements in sleep/restless legs syndrome may trigger sleepwalking or sleep terrors, as these parasomnias disappeared after treatment of obstructive sleep apnea or periodic limb movements in sleep/restless legs syndrome (14). In another study, children with sleep-disordered breathing
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experienced more parasomnias than those without the problem (20). Psychopathology is thought to be extremely rare as an influencing factor for arousal parasomnias in childhood (2). In adults, there is controversy, but no close association has been established (21). Several studies support a genetic predisposition for arousal parasomnias. Some evidence draw from studies of sleep terrors, in which a possible autosomal dominant disorder was seen in a three-generation pedigree (22). Kales et al. reported that the prevalence of sleep terrors and sleepwalking in first degree relatives of individuals with sleep terrors was 10 times greater than in the general population. They estimated a 60% chance of a child being affected if both parents were affected (23). A study of monozygotic and dizygotic twins demonstrated that sleep terrors are under moderate to strong genetic control (24). Proposed modes of inheritance for sleepwalking include multifactorial models, autosomal recessive inheritance with incomplete penetrance, and autosomal dominant inheritance with variable penetrance (25). Working from the Finnish Twin Cohort, Hublin et al. reported that more than one-third of sleepwalking in adults and more than half in children is attributable to genetic factors; both additive and dominant genetic effects were proposed (7). Lecendreux et al., in a family-based study, found a positive association between the HLA-DQB1*05 subtype and sleepwalking, suggesting a possible further interaction between the immune system and sleep (25). D.
Clinical Studies
In evaluating arousal parasomnias, it is rare to capture a full, typical event during an overnight in-laboratory polysomnography. Nevertheless, polysomnography may play an important role. When there is a clinical suspicion, polysomnography can be used to assess whether other disorders of sleep are present, including obstructive sleep apnea, as well as whether there might be seizures. Features supporting epilepsy in the differential diagnosis of nocturnal paroxysmal events include stereotyped behavior, a history of seizures (even if purported to be well controlled), and multiple attacks per night. In some cases, seizures may be brief, with preserved consciousness. Typically, seizures do not necessarily predominate during the first third of the night (as with arousal parasomnias) and may occur on waking or falling asleep (26). If epilepsy is considered, an expanded EEG montage is needed; sleep-deprived EEG, video-EEG as inpatient, or ambulatory continuous EEG recording can be required. Although ambulatory continuous EEG recording for seizure detection and classification has the appeal of potentially greater convenience and lower cost, there are several limitations, including contamination of the EEG signal by artifacts (loose leads, muscle activity, movement), a decreased number of channels available for the recording, and a lack of video documentation to review behavioral manifestations (27). A routine daytime EEG that includes sleep may be valuable in demonstrating epileptiform discharges that adds support for an underlying seizure disorder.
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In the differential diagnosis of children with paroxysms of complex movements during sleep, nocturnal frontal lobe epilepsy should be considered. It can manifest in three patterns, that may lie along a continuum: (i) paroxysmal arousals, which involve abrupt, frequently recurring arousals from sleep with stereotyped movements (raising the head, sitting, screaming, or looking around as if frightened); dystonic posture of the limbs often occurs, with a typical event duration of less than 20 seconds; (ii) nocturnal paroxysmal dystonia, where sudden arousals occur with complex, stereotyped, and sometimes bizarre sequences of movements (asymmetric tonic or dystonic postures, cycling movements, kicking, twisting, or rocking of the pelvis); event duration is typically less than two minutes; and (iii) episodic nocturnal wanderings, where sudden awakenings with abnormal motor features are followed by agitated somnambulism (jumping, twisting around, moving aimlessly), possibly accompanied by screaming or agitated behavior; the duration is usually less than three minutes (28,29). The mean age of onset for nocturnal frontal lobe epilepsy is 10 to 12 years, and affected patients usually have a normal developmental history. As neuroimaging is usually normal and more than half the cases may not have ictal or interictal EEG changes, establishing the diagnosis may be difficult. Anticonvulsants are often effective, especially carbamezepine. There is a genetic form of nocturnal frontal lobe epilepsy that is autosomal dominant, and it has been linked to chromosome 20q13.2, with three mutations in the nicotinic acetylcholine receptor a4 subunit identified; another linkage to chromosome 15q24 has been reported (30,31). E.
Management
Treatment of disorders of arousal includes reassuring parents that parasomnias are common in childhood and can be effectively managed. Parents should be counseled, where appropriate, on instituting important safety measures, i.e., securing windows and outside doors, covering windows with heavy curtains, placing mattress on the floor, and using alarm systems and bells to alert parents should the child leave the room. Another important intervention is to ask parents and patients to maintain a sleep diary, which will foster routine notation of sleep times and may help to reinforce the principle of minimizing sleep deprivation to lessen the frequency and duration of parasomnias. Attention should be focused on ensuring that caffeine-containing beverages are eliminated completely, as caffeine may contribute to decreased sleep efficiency and thereby increase sleep debt. Parents should be advised not to try to restrain or waken the child during an episode. Not only is waking such a child difficult, it is unnecessary and may prolong/worsen the episode. If the child has no recollection of the episode, then there is no value in recounting events the following day, as this may promote anxiety (9). When arousal disorders occur consistently at a particular time, scheduled or anticipatory awakenings several minutes beforehand may help ameliorate the events (32–34). However, scheduled awakenings may be
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ineffective in children who do not have arousal parasomnias frequently and at a predictable time (5). Medications should be reserved for those rare, protracted cases with no associated sleep disorder, with frequent parasomnias, and with a threat of injury to the patients or others. Medications that have been used successfully in the past include benzodiazepines and tricyclic antidepressants (15). Low-dose clonazepam is often effective in controlling arousal disorders in children. Starting with 0.25 mg an hour before bedtime, the dose may be increased slowly with attention to symptoms of daytime sedation. In some cases, a three- to six-week course of treatment may be curative, allowing withdrawal of the medication (7). III. A.
Parasomnias Usually Associated with REM Sleep REM Sleep Behavior Disorder
REM sleep behavior disorder (also known as REM sleep motor disorder) involves ‘‘problematic behavioral release,’’ with enacting of unpleasant, combative dreams. Instead of the customary REM sleep atonia, patients with REM sleep behavior disorder have complex movements that can be vigorous and even violent. REM sleep behavior disorder in adults tends to have a male predominance, with onset usually in the sixth to seventh decade of life; in a major case series, 25% of patients experienced a prodrome with a mean duration of 22 years (range, 2–48 years), where vocalizations and partial limb movements without complex behavior occurred during REM sleep (28). Although REM sleep behavior disorder is uncommon in children, it may still occur. Affected patients with REM behavior disorder, while in a dream state, may injure themselves or their bed partners by punching, grabbing, or kicking (11,35). As a result, trauma can occur (e.g., lacerations, ecchymoses, and fractures) that may be at times severe and perhaps life threatening. Patients with REM sleep behavior disorder report that their dreams have more action, intensity, and violence than typical dreams (36). Although there is variable loss of the general muscle paralysis typically associated with REM sleep, all other major features of REM sleep remain intact in REM sleep behavior disorder. Other aspects of generalized anomalous motor control in REM sleep behavior disorder include nonperiodic limb twitching in NREM sleep and periodic limb movements. The differential diagnosis of REM sleep behavior disorder is long, and includes: nocturnal seizures; sleepwalking/sleep terrors; hypnogenic paroxysmal dystonia (attacks from sleep of extremity torsion, which when brief are likely partial motor seizures from the cerebral frontal lobe); episodic nocturnal wanderings (potentially another manifestation of nocturnal frontal lobe epilepsy); rhythmic disorders of NREM and REM sleep; obstructive sleep apnea with agitated arousals; nocturnal psychogenic dissociative disorders (complex and often injurious activity during apparent sleep, but with a concurrent waking EEG pattern, reported in patients with a prior history of physical or sexual abuse
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during childhood) and malingering (36,37). Dream enacting behaviors have been seen in adults with severe obstructive sleep apnea. Polysomnography has demonstrated that the apparent acting out of dreams (with kicking, gesturing, talking, and raising the arms) occurred during arousals that terminate obstructive sleep apnea episodes. Effective treatment of the sleep apnea with continuous positive airway pressure eliminates the unusual behavior, which has been termed ‘‘pseudo-REM sleep behavior disorder.’’ Although rare, children and adolescents have been documented to have REM sleep behavior disorder (subclinical, idiopathic, and symptomatic), with onset as early as 11 months of age (38). REM sleep behavior disorder in children may occur in the clinical setting of narcolepsy. REM sleep behavior disorder has also been documented in children with neurological disorders such as brainstem tumors, juvenile Parkinson disease, and olivopontocerebellar degeneration (36,39). Other pediatric disorders associated with REM sleep behavior disorder or subclinical REM sleep behavior disorder based on case reports include Tourette syndrome, xeroderma pigmentosum, and infantile spasms (36,38). Clues to REM sleep behavior disorder in children include nightmares associated with body movements and trauma from movements during sleep. The abnormal preservation of muscle tone during REM, with increased REM phasic muscle activity, can be identified in children on overnight polysomnography (38,40). In a series of five pediatric cases of REM sleep behavior disorder, clonazepam given in bedtime doses of 0.25 mg has been reported to be completely effective in eliminating the parasomnia (40). Rather than restoring REM atonia, clonazepam suppresses phasic EMG activity (with behavioral control) (36). Typically, relapse of REM behavior disorder occurs immediately with discontinuation of clonazepam (41). Melatonin given in a range of 3 to 9 mg in adults is reported to restore REM atonia, and may be effective as monotherapy for REM behavior disorder, or in combination with clonazepam (36). Melatonin apparently has its therapeutic activity in restoring REM atonia (as distinct from the phasic motor activity mechanism of clonazepam) (42,43). Melatonin may be considered for treatment of REM behavior disorder when there is an incomplete response to clonazepam, or concerns that clonazepam might potentially aggravate existing dementia in adults or exacerbate daytime sleepiness (43). No prospective, randomized, controlled trials of melatonin or clonazepam for REM behavior disorder have been performed to date. REM sleep behavior disorder can coexist with other sleep disorders, resulting in combined narcolepsy-REM sleep behavior disorder and parasomnia overlap disorder (36). Parasomnia overlap disorder refers to patients having combined (injurious) sleepwalking and/or sleep terrors with REM sleep behavior disorder; those cases that are idiopathic in origin have been reported to have an earlier onset (childhood) than a symptomatic subgroup (early adulthood), where cases develop secondary to some other underlying pathological process (44). Moreover, Schenck et al. describe status dissociatus, a most extreme manifestation of REM sleep behavior disorder, with apparent complete disruption of
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state-determining boundaries (36). On polysomnography, behavioral and selfperceived sleep actually consists of a simultaneous admixture of elements of wakefulness, NREM sleep, and REM sleep (45). These findings are similar to the clinical impression, where sleep is atypical with vocalizations, twitching, and reports of dream-like mentation on forced or spontaneous awakenings. Conditions potentially associated with status dissociatus include olivopontocerebellar degeneration, narcolepsy, protracted withdrawal from alcohol abuse, prior open-heart surgery, and fatal familial insomnia. Status dissociatus may respond to clonazepam (36). Recurrent Isolated Sleep Paralysis
Sleep paralysis is a generalized, fleeting inability to speak or to move the head, trunk, and limbs that occurs during the transitional period between sleep and wakefulness. The episodes are transient, lasting variably from one minute or less to several minutes (46). There is preservation of consciousness. Despite their relative brevity, episodes of sleep paralysis can be quite distressing, particularly if associated with hallucinations (46). The sleep paralysis phenomenon is known in many cultures, and has been named ‘‘Old Hag’’ in Newfoundland, ‘‘Kokma’’ in the West Indies, ‘‘Kanashibari’’ in Japan, and ‘‘being ridden by the witch’’ by some southern U.S. African-Americans (47). Sleep paralysis may occur as part of the classical tetrad of narcolepsy, in a familial form apparently under genetic control, or as an isolated form in otherwise healthy individuals (48). There are few reports that explore possible genetic factors in sleep paralysis (1); one study of 22 patients with sleep paralysis found a positive family history of sleep paralysis in 19 (86%) (49). Factors such as fatigue, stress, irregular schedules, shift-work, sleeping in a supine position, alcohol/caffeine use, and sleep deprivation may predispose individuals to sleep paralysis (46,48). Mental disorders associated with sleep paralysis include panic disorder, other anxiety disorders, bipolar disorder, post-traumatic stress disorder, and depression (47). Conditions that could mimic isolated sleep paralysis include hypokalemic periodic paralysis, atonic seizures, cataplexy, drug withdrawal/abuse (particularly anxiolytic medications, which can result in physical immobility on awakening because of their muscle relaxant properties), hysterical or psychotic states with immobility, and REM rebound (46,48). To diagnose recurrent isolated sleep paralysis, one needs to exclude the possibility that the parasomnia is not better explained by another sleep, mental, neurological, or medical disorder, or medication/substance use (1). While some reports suggest that isolated sleep paralysis begins in childhood or adolescence in most cases (48), others support onset across the lifespan (46). In a sample of European subjects aged 15 years or older studied by Ohayon et al. (4,46), 6.2% of the sample experienced at least one sleep paralysis episode during their lifetime; other surveys support higher lifetime prevalences of 15% to 40% (1). Ohayon et al. found that 12.4% of adult subjects with sleep paralysis
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had episodes that started during childhood, while 10.8% had onset during adolescence (prior to the age of 18 years) (46). Sleep-Related Hallucinations
Sleep-related hallucinations (another ICSD-2 parasomnia type) are perceptions not based in reality that can occur at sleep onset (hypnagogic hallucinations) or upon awakening (hypnopompic hallucinations). Although these hallucinations are primarily visual, they may also include auditory, tactile, or kinetic phenomena. Sleep-related hallucinations may be associated with episodes of sleep paralysis, concomitantly or on different nights. It is unclear currently whether sleep-related hallucinations are always associated with REM intrusion into wakefulness, as is this case with isolated recurrent sleep paralysis (1). B.
Nightmare Disorder
Nightmares are generally well known as vivid dreams that typically awaken a patient from sleep with intense feelings of terror or dread (50). While children may appear anxious after awakening, they can relay a developmentally appropriate description of sometimes very detailed dream imagery (unlike the vague descriptions, if any, that children offer after a sleep terror) (11). Although dreaming may occur in other sleep stages, nightmares with their characteristically complex storylines and increasingly frightening content usually occur during REM sleep (and accordingly are therefore common during the second half of a major sleep period). Prominent motor activity during nightmares rarely occurs, in contrast to REM behavior disorder and sleep terrors (51). However, phasic muscle twitches may be increased (11). Bad dreams are felt to be 3 to 4 times more prevalent than nightmares, may have similar dream content, but do not trigger awakenings from sleep (52). Between the ages of three and six years, nightmares are especially common, noted at least occasionally in 30% to 90% and often in 5% to 30% of children in this age group. During childhood, boys and girls are equally affected, but women appear to be significantly more affected in adulthood (51). Nielsen et al. reported that the recall of disturbing dreams was more prevalent in girls than boys when evaluated at ages 13 and 16 years (52). There is a carryover effect with maturation; those with nightmares in childhood (often or sometimes) have nightmares as adults weekly or monthly in 28.5% of males and 32.5% of females (51). As reviewed by Levin and Fireman, occasional nightmares in adults are quite common with 85% of respondents having at least one episode in the past year, and 2% to 6% respondents having weekly nightmares (50). C.
Associated Disorders
Although infrequent nightmares likely do not merit further evaluation or treatment, it is important to note that there is an increased prevalence of psychiatric disorders in patients with nightmares compared with controls. In particular,
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schizophrenic spectrum pathology has been described (borderline or schizoid personality disorder, schizotypal personality, and schizophrenia) (50,51). In children, psychiatric disorders have been seen more than three times as often in those with nightmares than those without nightmares. In adults, the proportion of patients with psychiatric disorders is about five times greater than among those without nightmares (51). Frequent disturbing dreams have been found to be associated with anxiety at age 13 years and separation anxiety, generalized anxiety disorder, and overanxious disorder symptoms in later adolescence (52). Nightmares may also be a specific marker for a history of sexual abuse in children and adolescents (53). Children with post-traumatic stress disorder (from direct violence, witnessed violence, accidents, or natural disasters, for example) may reexperience the trauma with trauma-specific reenactments, repetitive play involving trauma themes, and generalized nightmares, however dreams of the event may be nonspecific (54). Analysis in twins support persistent genetic effects that impact on the frequency of nightmares in both childhood and adulthood; a study estimated that approximately 44% of phenotypic variance in nightmares among children and 37% in adults was due to genetic effects (51). Environmental influences (e.g., television) appear to affect dream content in a majority of children (55). IV. A.
Other Parasomnias Enuresis
Nocturnal enuresis (bedwetting) refers to the passing of urine while asleep. In children less than five years of age, nocturnal enuresis is normal. It has been estimated that at five years, approximately 15% to 25% of children have nocturnal enuresis (56). Nocturnal enuresis occurs approximately 1.5 to 2 times more frequently in boys than girls (57). The percentage of children with nocturnal enuresis decreases by about 15% with each advancing year (56,58,59). This steady decrease may indicate interim maturation of bladder or central nervous system voiding mechanisms (60). In adolescence, only 1% to 3% still wet the bed. Enuresis can be classified according to time of day (diurnal enuresis, nocturnal enuresis,), periods of dryness, and the presence of other symptoms. Primary enuresis refers to enuresis in a child who has never been dry (continent) consistently since birth, whereas secondary enuresis is applicable to a child who has had at least six months of dryness prior to recurrence of enuresis. There are many possible etiologies for sleep enuresis. Three major (nonexclusive) pathologic factors are often involved. The first is polyuria, which at least in some cases is related to a diminished vasopressin peak during sleep (group 1, volume- or diuresis-dependent patients). The second mechanism can be sudden, involuntary detrusor contractions associated with a small nocturnal functional bladder capacity and daytime enuresis (group 2, detrusor dependent
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group). The third cause is felt to be a decreased arousability (group 3). Patients in group 1 may respond to DDAVP (1-deamino-8-D-arginine vasopressin; also known as desmopressin) (61). Patients in group 2 may respond to alarms. In the low arousability patients (group 3), one should consider whether patients have sleep disordered breathing. A significant percentage of children with obstructive sleep apnea also have nocturnal enuresis, with estimates ranging from 8% to 47% (60). In such subjects, enuresis may respond to adenotonsillectomy (62). Following adenotonsillectomy, resolution of enuresis has been reported in 55% to 77% of children; most cases resolve in the first month after surgery, with an additional minor resolution thereafter (60). There are several mechanisms whereby obstructive sleep apnea may be involved in enuresis. Obstructive respiratory events can be associated with swings of positive abdominal pressure and negative intrathoracic pressure. These pressure changes may affect bladder function directly through abdominal compression, contributing to enuresis. Cardiac distension in sleep apnea due to increased intrathoracic pressure results in enhanced secretion of atrial natriuretic peptide, which subsequently inhibits renin secretion and decreases aldosterone levels; consequently, there is a decrease in intravascular volume and increased urine and sodium output during sleep, also contributing to enuresis (58,63,64). Treatment of obstructive sleep apnea reduces levels of atrial natriuretic peptide and increases the mean levels of renin and aldosterone, thereby reversing this effect (64). Other factors that may play a role in enuresis include genetic and familial factors, infection, and anatomical variants. From a family history perspective, enuresis is increased in the progeny of parents who themselves had enuresis in childhood. It has been reported, for example, if both parents have a history of childhood enuresis, there is a 77% risk of their children also developing enuresis. If only one parent had enuresis, the risk decreases to 43%. In cases where neither parent had enuresis during childhood, a much lower risk of enuresis has been reported (15%) (65). Causes of complicated enuresis include urinary tract infection, ectopic ureter in females, posterior urethral valves in males, and spinal cord abnormalities with associated neurogenic bladder. Evaluation of these anatomic concerns includes a renal ultrasound and/or voiding cystourethrogram (56). A gastrointestinal evaluation may be indicated for work-up of chronic constipation or encopresis. Other factors contributing to enuresis have been reported to include diabetes, psychological stress, sexual abuse, and excessive evening fluid intake, particularly caffeinated beverages (63). Bader et al. studied children with enuresis and compared at-home sleep studies to controls. The sleep of children with enuresis was ‘‘polysomnographically normal,’’ although respiratory effort and flow data were not recorded. Compared to controls, children with enuresis had longer time in bed and increased number of sleep cycles. Enuresis occurred in non-REM sleep stages 2, 3, and 4 as well as REM sleep. Most episodes of enuresis occurred in
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the first half of the night. In a small study approximately 50% of children with enuresis episodes experienced tachycardia, evidence of an autonomic arousal preceding micturition (61). B.
Sleep-Related Dissociative Disorders
Dissociation is a separation of discrete mental processes from the mainstream of brain activity with a loss of integrated function and autonomous operation of the isolated elements. Dissociation plays a role in dissociative disorders, somatoform disorders, and post-traumatic stress disorder. Sleep-related dissociative disorder is a variant of dissociative disorders. They occur from wakefulness out of a sleep episode, or wakefulness in the transition to sleep, and involve a disruption of the usually integrated functions of memory, consciousness, identity, or perception of the environment. The three categories of dissociative disorders that have been documented with sleep-related dissociative disorder include dissociative fugue (a disturbed state of consciousness where a patient appears fully aware in performing activities, but subsequently has no recollection), dissociative identity disorder (formerly called multiple personality disorder), and dissociative disorder not otherwise specified. Most patients with sleep-related dissociative disorder have corresponding daytime episodes of disturbed behavior, confusion, and associated amnesia, as well as a current or past history of physical or sexual abuse (1). Childhood traumatic events may result in the development of dissociative symptoms, possibly functioning as a defense mechanism. There appears to be an association between nightmares and dissociative states or experiences. Agargun et al., for example, found a strong association in college students between nightmares and childhood traumatic experiences (66). Patients with dissociative disorders also often experience nightmare disorder; those patients with both disorders have been reported to have suicide attempts, a higher rate of self-mutilating behavior, and comorbidity with borderline personality disorder more than those without nightmare disorder (67). During the sleep-related behaviors, patients can scream, run, or display sexualized behavior. These activities may represent re-enactment of previous abuse situations; there is amnesia for the behavior the next day. The age of onset can range from childhood to middle adulthood. Other parasomnias, particularly disorders of arousal described earlier, must be differentiated from the dissociative episodes (1). Patients with dissociative disorders are challenging to treat, requiring a flexible approach that may include cognitive-behavioral therapy, sensorimotor psychotherapy, post-traumatic disorder treatment, and clinical hypnosis (68,69). Therefore, referral to an appropriate, experienced psychotherapist is recommended. Coping skills are taught that can be used by the patient to replace maladaptive responses. Because patients across the spectrum of dissociative disorders have difficulty with traumatic reenactment in the forms of self-injurious behavior, suicidal ideation, and revictimization safety planning is essential in management
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(68). Therapeutic modalities may include journal entries to complement therapy sessions as well as expressive artwork (68). The latter approach may be especially suited to younger children. C.
Exploding Head Syndrome
Exploding head syndrome (EHS) is a harmless, but potentially terrifying situation, which usually occurs while a patient is falling asleep and less often may occur on awakening. Patients report a terrifying loud noise, sometimes accompanied by myoclonic jerks or the perception of a flash of light. The episode lasts only for an instant and afterward, the patient may experience acute anxiety and palpitations (70). Typically, EHS is not associated with sudden pain or headache (71,72). Polysomnography has verified that attacks of EHS occur during wakefulness rather than during sleep. No pathological EEG changes have been found, specifically none indicating an epileptic etiology to this condition (72). Onset of EHS episodes may be during childhood, but most commonly begin in middle age or later (70). Attacks are variable, and may be sporadic. EHS episodes may recur in association with stressful situations at school, work, or home (72). Patients should be reassured about the harmless nature of the symptoms. Drug treatment is not needed. D.
Sleep-Related Eating Disorder
Sleep-related eating disorder has combined characteristics of sleepwalking and daytime eating disorders (such as the compulsive eating of bulimia nervosa or binge-eating disorder). Patients with sleep-related eating disorder experience a partial arousal from sleep, often two to three hours after sleep onset. Their subsequent eating is ‘‘out-of-control’’ (rapid and sloppy, often with high carbohydrate foods and sometimes taken in odd food combinations that may include nonnutritive substances). Patients may become angry or agitated if they are disturbed during an episode and have limited to no recall of the episode the following day (73). Common responses to nocturnal eating include restriction of daytime eating or morning anorexia. In a case series of 23 patients with sleeprelated eating disorder, Winkelman reported that 3 had onset before age 10 years, with the majority having onset in adolescence or early adulthood (73). E.
Associated Disorders
Most patients with sleep-related eating disorders have histories of other parasomnias (isolated sleepwalking, enuresis, sleep terrors, or some combination of these), and more than one-third had a daytime eating disorder (bulimia nervosa, anorexia nervosa, or binge-eating disorder) (73). Sleep-related eating disorder has also been reported in the setting of other primary sleep disorders, such as obstructive sleep apnea or periodic limb movement disorder. In some cases, an associated partial arousal from sleep may trigger a nocturnal eating episode in a
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susceptible individual (73). Medications that increase the risk of sleep-related eating disorder include triazolam abuse, olanzapine, respiridone, and zolpidem (74–76). In addition to sleep-related eating disorder, the differential diagnosis of nocturnal eating includes nocturnal eating syndrome (eating at night with full alertness), dissociative disorder with nocturnal eating (eating at night and altered level of awareness in the setting of disorders such as multiple personality disorder, post-traumatic stress disorder), binge-eating disorder or bulimia nervosa with nocturnal eating (eating at night with full alertness, combined with a daytime eating disorder), and Kleine-Levin Syndrome (73). Kleine-Levin syndrome is a rare disorder characterized by recurrent episodes of hypersomnia (each often lasting as long as a week or more), and frequently associated cognitive disturbances (attention and memory defects, prominent confusion, decreased concentration), changes in eating behavior (such as eating larger amounts of food), altered perceptions of reality, depressed mood, irritability, and hypersexuality (as well as other compulsive behaviors). Onset is often during adolescence, more commonly in males; Kleine-Levin syndrome usually abates by early adulthood (77). F.
Catathrenia
Catathrenia, or nocturnal groaning, may occur in NREM sleep (stage 2) and REM sleep (78). The moaning/groaning sounds occur exclusively during expiration, and typically last 2 to 20 seconds. The sounds tend to be repeated in clusters lasting two minutes to an hour, and occur several times per night. Polysomnography has shown that catathrenia is associated with a slightly decreased heart rate and moderately positive intra-esophageal pressure. The groaning ends in a snort, followed by rebound in heart rate. The onset of catathrenia may begin during childhood or adolescence (78). The etiology of this groaning is unclear, as no underlying psychiatric or respiratory disease has been found. While catathrenia may have an adverse impact on social and familial function, no specific therapy has been determined to be effective. In summary, parasomnias in childhood are common, and indeed often more frequent than in adults. Many pediatric parasomnias are benign, self-limited, and may not persist into late childhood or adolescence. Moreover, parasomnias in childhood often differ in type from adults (e.g., sleep terrors in childhood are much more likely than REM behavior disorder). Clinicians should be aware that while parasomnias in adults may portend significant psychiatric disturbances or neurodegenerative disorders, although these concerns are rarely supported in childhood. When evaluating pediatric parasomnias, a detailed history from parents (perhaps supported by home videotapes) is most helpful. Persistent, prominent, and complex cases require physician management, aided by the appropriate use
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of diagnostic studies (polysomnography, expanded EEG recordings) and possible pharmacotherapy. The further study of parasomnias in children may help elucidate the multifactorial etiologies of these fascinating conditions, shedding light on their potential genetic bases as well as environmental contributions. Acknowledgment This work was supported by an NIH award to Dr. Mason, K23 RR16566-01. References 1. AASM. International classification of sleep disorders. Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine, 2005. 2. Broughton R. NREM arousal parasomnias. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia: WB Saunders, 2000:693–706. 3. Fisher C, Kahn E, Edwards A, et al. A psychophysiological study of nightmares and night terrors. I. Physiological aspects of the stage 4 night terror. J Nerv Ment Dis 1973; 157(2):75–98. 4. Ohayon MM, Guilleminault C, Priest RG. Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry 1999; 60(4):268–276; quiz 77. 5. Mindell JA, Owens J. Sleepwalking and sleep terrors. In: A Clinical Guide to Pediatric Sleep. Philadelphia: Lipincott Williams & Wilkins, 2003. 6. Mahowald MW, Bornemann MC, Schenck CH. Parasomnias. Semin Neurol 2004; 24(3):283–292. 7. Hublin C, Kaprio J, Partinen M, et al. Prevalence and genetics of sleepwalking: a population-based twin study. Neurology 1997; 48(1):177–181. 8. Klackenberg G. Somnambulism in childhood—prevalence, course and behavioral correlations: a prospective longitudinal study (6–16 years). Acta Paediatr Scand 1982; 71(3):495–499. 9. Stores G. Dramatic parasomnias. J R Soc Med 2001; 94(4):173–176. 10. Rosen GM, Ferber R, Mahowald MW. Evaluation of parasomnias in children. Child Adolec Clin North Am 1996; 5:601–616. 11. Sheldon SH. Parasomnias in childhood. Pediatr Clin North Am 2004; 51(1):69–88, vi. 12. Mason TB II, Pack AI. Sleep terrors in childhood. J Pediatr 2005; 147(3):388–392. 13. Mahowald M. Arousal and sleep-wake transition parasomnias. In: Lee-Chiong TL, Sateia MJ, Carskadon MA, eds. Sleep Medicine. Philadelphia, PA: Hanley & Belfus, 2002:207–213. 14. Guilleminault C, Palombini L, Pelayo R, et al. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics 2003; 111(1):E17–E25. 15. Robinson A, Guilleminault C. Disorders of arousal. In: Chokroverty S, Hening W, Walters AS, eds. Sleep and Movement Disorders. Philadelphia, PA: Butterworth Heinemann, 2003:265–272. 16. Mahowald MW, Ettinger MG. Things that go bump in the night: the parasomnias revisited. J Clin Neurophysiol 1990; 7(1):119–143.
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17. Joncas S, Zadra A, Paquet J, et al. The value of sleep deprivation as a diagnostic tool in adult sleepwalkers. Neurology 2002; 58(6):936–940. 18. Mahowald MW, Schenck CH, Rosen GM, et al. The role of a sleep disorder center in evaluating sleep violence. Arch Neurol 1992; 49(6):604–607. 19. Owens J, Spirito A, Nobile C, et al. Incidence of parasomnias in children with obstructive sleep apnea. Sleep 1997; 20(12):1193–1196. 20. Goodwin JL, Kaemingk KL, Fregosi RF, et al. Parasomnias and sleep disordered breathing in Caucasian and Hispanic children—the Tucson children’s assessment of sleep apnea study. BMC Med 2004; 2(1):14. 21. Schenck CH, Mahowald MW. On the reported association of psychopathology with sleep terrors in adults. Sleep 2000; 23(4):448–449. 22. Hallstrom T. Night terror in adults through three generations. Acta Psychiatr Scand 1972; 48(4):350–352. 23. Kales A, Soldatos CR, Bixler EO, et al. Hereditary factors in sleepwalking and night terrors. Br J Psychiatry 1980; 137:111–118. 24. Ooki S. [Statistical genetic analysis of some problem behaviors during sleep in childhood—estimation of genetic and environmental factors influencing multiple health phenomena simultaneously]. Nippon Eiseigaku Zasshi 2000; 55(2):489–499. 25. Lecendreux M, Bassetti C, Dauvilliers Y, et al. HLA and genetic susceptibility to sleepwalking. Mol Psychiatry 2003; 8(1):114–7. 26. Malow BA. Paroxysmal events in sleep. J Clin Neurophysiol 2002; 19(6):522–534. 27. Kotagal P, Costa M, Wyllie E, et al. Paroxysmal non-epileptic events in children and adolescents. Pediatrics 2002; 110(4):E46. 28. Provini F, Plazzi G, Tinuper P, et al. Nocturnal frontal lobe epilepsy: a clinical and polygraphic overview of 100 consecutive cases. Brain 1999; 122(pt 6):1017–1031. 29. Provini F, Plazzi G, Lugaresi E. From nocturnal paroxysmal dystonia to nocturnal frontal lobe epilepsy. Clin Neurophysiol 2000; 111(suppl 2):S2–S8. 30. Saenz A, Galan J, Caloustian C, et al. Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene. Arch Neurol 1999; 56(8):1004–1009. 31. Zucconi M, Ferini-Strambi L. NREM parasomnias: arousal disorders and differentiation from nocturnal frontal lobe epilepsy. Clin Neurophysiol 2000; 111(suppl 2): S129–S135. 32. Lask B. Sleep disorders. ‘‘Working treatment’’ best for night terrors. BMJ 1993; 306(6890):1477. 33. Lask B. Novel and non-toxic treatment for night terrors. BMJ 1988; 297(6648):592. 34. Frank NC, Spirito A, Stark L, et al. The use of scheduled awakenings to eliminate childhood sleepwalking. J Pediatr Psychol 1997; 22(3):345–353. 35. Schenck CH, Bundlie SR, Ettinger MG, et al. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 1986; 9(2):293–308. 36. Schenck CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002; 25(2):120–138. 37. Chokroverty S, Hening W, Walters AS. An approach to the patient with movement disorders during sleep and classification. In: Chokroverty S, Hening W, Walters AS, eds. Sleep and Movement Disorders. Philadelphia: Butterworth-Heinemann, 2003:201–218.
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38. Kohyama J, Shimohira M, Kondo S, et al. Motor disturbance during REM sleep in group A xeroderma pigmentosum. Acta Neurol Scand 1995; 92(1):91–95. 39. Rye DB, Johnston LH, Watts RL, et al. Juvenile Parkinson’s disease with REM sleep behavior disorder, sleepiness, and daytime REM onset. Neurology 1999; 53(8):1868–1870. 40. Sheldon SH, Jacobsen J. REM-sleep motor disorder in children. J Child Neurol 1998; 13(6):257–260. 41. Ferini-Strambi L, Zucconi M. REM sleep behavior disorder. Clin Neurophysiol 2000; 111(suppl 2):S136–S140. 42. Schenck CH, Bundlie SR, Ettinger MG, et al. Chronic behavioral disorders of human REM sleep: a new category of parasomnia, 1986 [classical article]. Sleep 2002; 25(2):293–308. 43. Boeve BF, Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003; 4(4):281–284. 44. Schenck CH, Boyd JL, Mahowald MW. A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed cases. Sleep 1997; 20(11):972–981. 45. Mahowald MW, Schenck CH. Status dissociatus—a perspective on states of being. Sleep 1991; 14(1):69–79. 46. Ohayon MM, Zulley J, Guilleminault C, et al. Prevalence and pathologic associations of sleep paralysis in the general population. Neurology 1999; 52(6):1194–1200. 47. Paradis CM, Friedman S. Sleep paralysis in African-Americans with panic disorder. Transcult Psychiatry 2005; 42(1):123–134. 48. Buzzi G, Cirignotta F. Isolated sleep paralysis: a web survey. Sleep Res Online 2000; 3(2):61–66. 49. Dahlitz M, Parkes JD. Sleep paralysis. Lancet 1993; 341(8842):406–407. 50. Levin R, Fireman G. Nightmare prevalence, nightmare distress, and self-reported psychological disturbance. Sleep 2002; 25(2):205–212. 51. Hublin C, Kaprio J, Partinen M, et al. Nightmares: familial aggregation and association with psychiatric disorders in a nationwide twin cohort. Am J Med Genet 1999; 88(4):329–336. 52. Nielsen TA, Laberge L, Paquet J, et al. Development of disturbing dreams during adolescence and their relation to anxiety symptoms. Sleep 2000; 23(6):727–736. 53. Krakow B, Sandoval D, Schrader R, et al. Treatment of chronic nightmares in adjudicated adolescent girls in a residential facility. J Adolesc Health 2001; 29(2):94–100. 54. Stein MT, Heyneman EK, Stern EJ. Recurrent nightmares, aggressive doll play, separation anxiety and witnessing domestic violence in a 9-year-old girl. J Dev Behav Pediatr 2004; 25(6):419–422. 55. Muris P, Merckelbach H, Gadet B, et al. Fears, worries, and scary dreams in 4- to 12-year-old children: their content, developmental pattern, and origins. J Clin Child Psychol 2000; 29(1):43–52. 56. Thiedke CC. Nocturnal enuresis. Am Fam Physician 2003; 67(7):1499–1506. 57. Kajiwara M, Inoue K, Kato M, et al. Nocturnal enuresis and overactive bladder in children: an epidemiological study. Int J Urol 2006; 13(1):36–41. 58. Tietjen DN, Husmann DA. Nocturnal enuresis: a guide to evaluation and treatment. Mayo Clin Proc 1996; 71(9):857–862.
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10 Narcolepsy in Childhood
SURESH KOTAGAL Mayo Clinic, Rochester, Minnesota, U.S.A.
I.
Introduction
Narcolepsy is a life-long neurological disorder of rapid eye movement (REM) sleep in which there are attacks of irresistible daytime sleepiness, cataplexy (sudden loss of muscle control in the legs or neck in response to emotional triggers like laughter, fright, or rage, leading to head dropping or falls), hypnagogic hallucinations (vivid and often terrifying dreams at sleep onset), and sleep paralysis (a momentary inability to move as one is drifting off to sleep). Thomas Willis can possibly be credited with the first description of narcolepsy in the 17th century (1). He described persons with “a sleepy disposition— they eat and drink well, go abroad, take care well enough of their domestic affairs, yet whilst talking or walking, or eating, yea their mouths being full of meat, they shall nod, and unless roused by others, fall fast asleep” (1,2). The term narcolepsie was coined by Jean Baptiste Edouard Gelineau in 1880 (3). He recognized the
Adapted with permission in part from: Kotagal S. Narcolepsy in Childhood. In Pediatric Sleep Medicine. Principles and Practice. Sheldon SH, Ferber R, Kryger MH (eds), Elsevier Saunders, 2005, pp 171–182.
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sudden, brief attacks of sleepiness in patients with this disorder and the recurrent falls or astasias accompanying it, which were subsequently termed cataplexy. He characterized narcolepsy as a “rare neurosis . . . characterized by an urgent necessity to sleep” Adie (4) was also impressed by the likely psychiatric basis for the disorder and wrote: “True narcolepsy is a functional disorder of the nervous system, probably an undue fatigability of nerve cells, in individuals with a peculiar kind of nervous activity that allows excessive responses to emotional stimuli and favours the spread of inhibitions” (4,5). The actual appreciation of the biological basis for narcolepsy began with the discovery of REM sleep by Aserinsky and Kleitman in 1953 (6). In 1963, Rechtschaffen et al. observed REM onset sleep on polysomnograms of patients with narcolepsy (7). They determined that daytime sleep attacks in patients with narcolepsy resulted from superimposition of REM sleep onto wakefulness. Significant progress in our understanding of the disorder came in 1999 when Mignot et al. found canine narcolepsy to be associated with mutations in the gene for the hypocretin (orexin) receptor (8). The following year, human narcolepsy-cataplexy was found to be linked to hypocretin deficiency in the cerebrospinal fluid (9,10). II.
Epidemiology
The incidence rate in the United States is 1.37 per 100,000 persons per year: 1.72 for men and 1.05 for women (11). It is highest in the second decade of life, followed by a gradual decline thereafter. The prevalence rate in the United States has been estimated at 56 persons per 100,000 persons (11). In Japan, the prevalence is around 1 in 600 persons (12), and in Israel around 1 in 500,000 persons (13). While the disorder has often been diagnosed as late as the third and fourth decades of life, a meta-analysis of 235 subjects derived from three studies (14) found that 34% of all subjects have onset of symptoms prior to 15 years of age, 16% prior to 10 years of age, and 4.5 % prior to 5 years of age (Fig. 1). It is likely that over the next decade, owing to the increasing awareness of this disorder among pediatricians and family physicians, we will see a shift of the peak age of onset into the first, second and third decades. Cataplexy, one of the most reliable clinical features of narcolepsy, is present in only 50–70% of all subjects. Some epidemiologic studies have required the presence of cataplexy as a prerequisite for the diagnosis, whereas others have not made this stipulation. This lack of uniformity in clinical diagnostic criteria has lead to some uncertainty in estimating the exact prevalence. III.
Pathophysiology
Patients with narcolepsy tend to fall asleep more often during a 24-hour day as compared with healthy controls, but do not necessarily have an increase in sleep quantity. They have unstable sleep-state regulation, with frequent intrusion of REM sleep into wakefulness. Cataplexy, sleep paralysis, and hypnagogic
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Figure 1 The age of onset of narcolepsy, based on an analysis of 250 cases. Source: From Ref. 14.
hallucinations are all the result of intrusion of fragments of REM sleep into wakefulness. Cataplexy is accompanied by the hyperpolarization of spinal alpha motor neurons, with resultant active inhibition of skeletal muscle tone and suppression of the monosynaptic H-reflex and tendon reflexes. A.
Initial Studies in Animals
Attempts at understanding the pathophysiologic basis of human narcolepsy began initially with the study of narcolepsy in animals. About 15 breeds of dogs, cats, miniature horses, quarter horses, and Brahman bulls with narcolepsy have been described, with a confirmed, autosomal recessive pattern in Doberman pinschers and Labrador retrievers (15). Narcoleptic cats have served as a useful model for the study of cataplexy. In this model, the instillation of carbachol, an acetylcholine like substance, into the paramedian pontine reticular formation triggers cataplexy, thus confirming its cholinergic basis (16). A relative deficiency of the monoamines dopamine and norepinephrine has also been postulated to explain the hypersomnolence. B.
Genetic Predisposition
The presence of the histocompatibility antigens (HLA) DQB1*0602 in close to 100% of human narcolepsy patients, as compared with a 25% prevalence in the general population, points to a genetic susceptibility for narcolepsy (17). HLA class II molecules, such as DQB1, are expressed on B cells, dendritic cells, and activated T cells (17,18). This genetic predisposition per se, however, is insufficient to trigger narcolepsy. Despite being HLA DQB1*0602 positive, monozygotic twins have
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shown significant discordance in the age of onset of narcolepsy. Life stresses may play a role as trigger factors—bereavement or systemic viral illness may precede the onset of narcolepsy symptoms in about 70% of subjects. Human narcolepsy is best explained on the basis of a two-hit hypothesis, with interplay between genetic susceptibility and environmental factors. C.
Hypocretin Deficiency
A dramatic advance in the understanding of narcolepsy came in 1999, with the identification of mutations in the preprohypocretin gene receptor in canine narcolepsy and in a single case of human narcolepsy (8). Hypocretin (synonymous with orexin) is a peptide that is synthesized from preprohypocretin by neurons of the dorsolateral hypothalamus. The hypocretin neurons project widely to the ventral forebrain and the brainstem, and thereby regulate arousal, muscle tone, locomotor activity, and feeding behavior (19). Hara et al. (20) generated transgenic mice in which orexin-containing hypothalamic neurons were selectively ablated. The hypocretin knock-out mice showed features resembling human narcolepsy, with cataplexy-like behavioral arrests, premature onset of REM sleep, and fragmentation of sleep. This finding underscores the central role of hypocretin neurotransmission in the pathogenesis of narcolepsy. Unlike various animal species, humans with narcolepsy-cataplexy do not show abnormalities in the hypocretin receptors, but rather a significant reduction in the concentration of hypocretin-1 in the cerebrospinal fluid (CSF) (9,10). Using a radioimmunoassay, Nishino et al. (9) showed that the mean CSF level of hypocretin-1 in healthy controls was 280.3 33 pg/mL, in controls with miscellaneous neurological disorders it was 260.5 37.1, whereas in patients with narcolepsy-cataplexy, the hypocretin-1 was either below 100 pg/mL or undetectable. The diagnostic sensitivity of low levels of hypocretin-1 (<100 pg/mL) for narcolepsy was 84.2%. Postmortem examination of the hypothalamus in patients with narcolepsy shows a significant drop out of hypocretin neurons, while adjacent neurons that secrete melanin concentrating hormone remain unaffected, with little in the way of inflammatory change (21). This selective degeneration suggests a localized neurodegenerative process. Owing to the strong association of human narcolepsy with HLA DQB1*0602, an immunemediated susceptibility for this degeneration has been suggested, though not established (18). Patients who have narcolepsy without cataplexy show normal levels of CSF hypocretin-1 (22), suggesting that there are alternate pathogenetic mechanisms for narcolepsy, besides hypocretin deficiency (Fig. 2). D.
The Association Between Childhood Narcolepsy and Obesity
Children, adolescents, and adults with narcolepsy-cataplexy, in general, tend to show a higher body mass index (BMI) as compared with age-matched controls (23–25) (Fig. 3). The increased BMI can be seen at diagnosis, and is not linked to
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Figure 2 A comparison of the levels of cerebrospinal fluid hypocretin-1 in patients with narcolepsy-cataplexy who are HLA DQB1*0602 positive (N–C, HLAþ), narcolepsycataplexy subjects who are HLA DQB1*0602 negative (N–C, HLA–), narcolepsy without cataplexy (N) and idiopathic hypersomnia (IH). Abbreviations: HLA, histocompatibility antigens; C, cataplexy. Source: Adapted from Ref. 22.
treatment with medications, such as tricyclic agents, that have the side effect of weight gain (23). Orexin-deficient mice also tend to become obese (20). As compared with controls, young adults with narcolepsy-cataplexy have reduced circulating levels of the appetite-suppressing hormone, leptin, and fail to demonstrate the physiological rise in nocturnal levels of leptin (26). The hypothalamic hypocretin neurons normally have receptors for dynorphin and neuronal activity–related pentraxin (NARP), a secreted protein that regulates adenosine monophosphate (AMPA) receptor clustering. Loss of these signaling molecules may contribute to the lack of appetite control in animals and human subjects with narcolepsy (27), consequent hyperphagia and weight gain. E.
Symptomatic Narcolepsy
While the majority of cases of narcolepsy are idiopathic, structural lesions involving the posterior hypothalamus or midbrain may on rare occasions precipitate symptomatic narcolepsy in subjects with an underlying biological predisposition, possibly from disruption of the secretion of hypocretin. Nishino and Kanbayashi indicate that 117 cases of symptomatic narcolepsy have been reported thus far (28) (Fig. 4). Brain tumors, such as craniopharyngomas and gliomas, head injury, inflammatory disorders such as sarcoidosis, and inherited
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Figure 3 A comparison of the body mass index at the time of diagnosis of children with narcolepsy in comparison with that of unaffected controls. For each group, the top horizontal line represents the maximum value, the bottom horizontal line the minimum value, and the middle line the mean value. Source: From Ref. 23.
Figure 4 The etiology of symptomatic narcolepsy, based on the analysis of 117 cases. Source: From Ref. 28.
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disorders have been implicated (29). Disorders that are associated with cataplexy, though with no clear hypersomnolence, include Niemann-Pick Type C disease, Norrie disease, Coffin-Lowry syndrome, and Mobius syndrome (30). Daytime hypersomnolence, REM onset sleep periods, and a mild lowering of CSF hypocretin levels have also been reported in cases of the Prader-Willi syndrome (31). In this disorder, the CSF hypocretin levels have been in the 164 46.8 pg/mL range, and not below 100 pg/mL as is usually observed in narcolepsy-cataplexy. The hypersomnolence that is seen occasionally in acutely ill patients with multiple sclerosis, acute disseminated encephalomyelitis, or acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome) is not associated with cataplexy. Patients with these disorders may show a mild reduction in levels of CSF hypocretin, which seems to normalize with the remission of the clinical symptoms (28). IV. A.
Clinical Features Preschool-Age Children
Narcolepsy is rare in preschool-age children. Yoss and Daly observed that 11.7% of a group of 85 subjects were below the age of five years (32). In their metaanalysis of 235 children, Challamel et al. found that 4.6% were below the age of five years at the time of diagnosis (14) Sharp and D’Cruz have described a 12-month-old with hypersomnia who was subsequently confirmed to have narcolepsy (33). Nevsimalova et al. have described a 2.5-year-old who developed hypersomnolence at the age of 6 months, with the presence of as many as 30 cataplectic attacks per day that mimicked atonic seizures, but these subsided after treatment with chlorimipramine (34). In general, it is difficult to diagnose narcolepsy prior to the age of four to five years, as even unaffected children of this age tend to take habitual daytime naps and are not able to provide an accurate history of cataplexy, hypnagogic hallucinations, or sleep paralysis. The diagnosis may, however, be facilitated by the documentation of cataplexy attacks on video-polysomnography, which shows loss of muscle tone and bursts of rapid eye movements, coinciding with low-voltage, mixed-frequency activity on the electroencephalogram (EEG). B.
School-Age Children
Daytime sleepiness is the invariant and most disabling feature of narcolepsy. It may develop as early as five to six years of age. There is a background of a constant, foggy feeling from drowsiness, superimposed on which are periods of more dramatic sleep attacks. Habitual afternoon napping is uncommon in most healthy five- to six-year-olds and should raise suspicion. The naps in children with narcolepsy tend to be longer (30 to 90 minutes) than those in adult patients, and are not consistently followed by a refreshed feeling (35). These attacks of sleepiness are most likely to occur when the patient is involved in sedentary
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activities, such as sitting in the classroom, riding in an automobile for short distances, and reading a book. Daytime sleepiness is frequently accompanied by automatic behavior of which the subject is unaware, impaired consolidation of memory, decreased concentration, executive dysfunction, and emotional problems. Mood swings are also common (35). Children with daytime sleepiness may be mistakenly labeled “lazy” and targeted with negative comments from their peers. Parents may also overlook excessive sleepiness until it starts adversely impacting the child’s mood, behavior, or academic performance. Adults who have been diagnosed with narcolepsy sometimes give a history of an “attention deficit disorder” in childhood (36). On the basis of studies of narcolepsy subjects evaluated after the elimination of time cues, Pollack et al. found in them a tendency to sleep more often, but not longer than subjects without narcolepsy (37). The major sleep episode of six or more hours still occurred at night. Cataplexy is seen in over 70% of children with narcolepsy. It consists of attacks of sudden loss of muscle tone in the extensor muscles of the thighs, back, or neck in response to emotional triggers, such as fright, rage, excitement, surprise, or laughter. The pathophysiological basis is the intrusion of the skeletal muscle atonia of REM sleep into wakefulness (38,39). A history of cataplexy may be difficult to elicit in nonverbal children. This author recalls a six-year-old girl with proven narcolepsy who denied any episodic muscle weakness, but would repeatedly fall down whenever she jumped on a trampoline. Consciousness remains fully intact during the cataplexy episodes, which can last 1 to 30 minutes. Respiration and cardiovascular functions remain unaffected. Challamel et al. (14) found cataplexy in 80.5% of idiopathic narcolepsy and in 95% of symptomatic narcolepsy subjects. Hallucinations at sleep onset (hypnagogic) or upon awakening from sleep (hypnopompic) are seen in 50–60% of patients with narcolepsy and may have an unpleasant, frightening quality to them. They may be auditory or visual in nature. Sleep paralysis is a sudden momentary inability to move as one is drifting off to sleep or awakening from sleep. Like cataplexy, both sleep paralysis and hypnagogic hallucinations are caused by the intrusion of fragments of REM sleep into wakefulness. Nighttime sleep is also disturbed in narcolepsy, with frequent awakenings. Young et al. attributed sleep fragmentation, in part, to periodic limb movements, which were found in five (63%) of eight children with narcolepsy in their series (40). Sleep fragmentation in narcolepsy can also occur unrelated to periodic limb movements, restless legs syndrome, or obstructive sleep apnea. Neuropsychological and behavioral manifestations are common in childhood narcolepsy, but they have not been adequately studied, partly because of difficulties in developing valid yet succinct batteries of neuropsychological tests for sleepy children. It is not uncommon for children with narcolepsy to present with inattentiveness or mild depression. Adult patients with narcolepsy have demonstrated selective cognitive deficits in response latency, word recall, and estimation of frequency (41). Rogers and Rosenberg (42) performed a battery of
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neuropsychological studies on 30 adults with narcolepsy and age-matched controls. The subjects with narcolepsy experienced more difficulty in maintaining attention than controls, as evidenced by more perseveration errors on Strub and Black’s List of Letters. It is unclear whether children with narcolepsy exhibit similar deficits. Stores et al. evaluated the psychosocial problems of children with narcolepsy (mean age, 12 years; n ¼ 42), children with daytime sleepiness of uncertain origin (mean age, 14 years; n ¼ 18) and healthy controls (mean age, 11 years; n ¼ 23) (43). They used the Strengths and Difficulties Questionnaire, the Child Depression Inventory, and the Child Health Questionnaire. No differences were found in the degree of psychosocial impairment among subjects with narcolepsy and those with sleepiness of uncertain origin, suggesting that sleepiness per se rather than narcolepsy underlies the psychosocial problems. V.
Diagnosis
A.
Nocturnal Polysomnogram
The diagnosis is usually established on the basis of the characteristic sleep-wake history combined with the nocturnal polysomnogram (NPSG) and multiple sleep latency test (MSLT) (44). Two weeks of wrist actigraphy combined with sleep logs obtained prior to the NPSG and MSLT can help exclude the possibility of sleepiness being caused by inadequate sleep hygiene or circadian rhythm sleep disorders (author’s opinion). NPSG helps exclude sleep pathologies, such as obstructive sleep apnea and the periodic limb movement disorder. In conjunction with the MSLT, the NPSG helps exclude disorders like idiopathic hypersomnia that can mimic narcolepsy. A reduced nocturnal REM latency (time between sleep onset and the appearance of the first epoch of REM sleep) of 70 minutes or below (reference value in adolescents generally around 140 minutes) may serve as a useful marker for narcolepsy (45) (Fig. 5). B.
Multiple Sleep Latency Test
When narcolepsy is suspected to be the basis for daytime sleepiness, the patient should undergo an MSLT on the morning after the NPSG (44,46). The MSLT consists of four or five opportunities to fall asleep in a darkened, quiet room during the daytime at two-hour intervals, e.g., at 0900, 1100, 1300, 1500, and 1700 hours, during which eye movements, chin electromyogram, and EEG are monitored simultaneously. Sleep is scored in 30-second epochs. The MSLT provides quantitative and qualitative information about the transition from wakefulness into sleep. The time interval between “lights out” and sleep onset is termed the sleep latency. The mean sleep latency is the average of the sleep latencies of all the naps (4 or 5). The mean sleep latency in healthy control adolescents is between 14 and 23 minutes (Table 1). It is shortened to less than eight minutes in patients with narcolepsy. Furthermore, unaffected children usually show a transition from wakefulness into non–rapid eye movement sleep.
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Figure 5 Diagram showing the usefulness of nocturnal REM latency in the assessment of childhood narcolepsy. For each patient, the gray bar depicts nocturnal REM latency at a time when the diagnosis of narcolepsy was suspected but not confirmed. The solid black bar depicts REM latency at the time of definitive diagnosis of narcolepsy (based on the nocturnal polysomnogram and multiple sleep latency test). Abbreviation: REM, rapid eye movement.
Table 1 Reference Values for the Multiple Sleep Latency Test Tanner stage Stage I Stage II Stage III Stage IV Stage V Older adolescents (age, 17–20 yr)
Mean sleep latency (min) Standard deviation 18.8 18.3 16.5 15.5 16.2 15.8
1.8 2.1 2.8 3.3 1.5 3.5
Data obtained from the MSLT conducted following the first of three successive nights of nocturnal polysomnographic recording. Abbreviation: MSLT, multiple sleep latency test. Source: Adapted from Ref. 47.
Narcoleptic subjects, however tend to shift from wakefulness directly into REM sleep (sleep-onset REM period or SOREMP). Normative data for the MSLT has been gathered from small series of patients and not on a multicenter basis. For the diagnostic assessment of narcolepsy, the normative data derived on adolescents and preadolescents from the studies of Mary Carskadon at the Stanford University summer sleep camps (Table 1) (47) is useful. The mean age of preadolescents (Tanner stage I of sexual development) in this study was 11.6 years (range, 10.1–14.6; n ¼ 11). This cohort of preadolescents showed a mean sleep latency on the MSLT of 18.8 minutes. In another MSLT study of preadolescents, Gozal et al. (48) found a much longer mean sleep latency of 23.7 3.1 minutes. It
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should be pointed out, however, that these children were much younger than the Carskadon study subjects, i.e., mean age of 6.1 0.2 years. The MSLT is prone to show a “floor effect” in the sense that the mean sleep latency does not help to further stratify subjects who have already been established as being pathologically sleepy. The diagnostic feature of two or more SOREMPs is not consistently present in the early stages of the disorder in children and young adults, and sometimes serial sleep studies are needed to establish a definitive diagnosis (49). How reliable is the MSLT? Aldrich et al. evaluated 2083 studies on patients aged 6 to 79 years (50). Criteria for the diagnosis of narcolepsy included daytime sleepiness, definite cataplexy, no other medical, psychiatric, or sleep disorder, two or more SOREMPs on the initial MSLT, and a mean sleep latency of less than eight minutes. These criteria were 78% sensitive and 95% specific for the diagnosis of narcolepsy, with a positive predictive value of 63%, i.e., 37% of subjects with these findings did not have narcolepsy. False positives in the diagnosis of narcolepsy may occur in the context of circadian rhythm disorders, obstructive sleep apnea, inadequate sleep hygiene, and substance abuse. C.
Maintenance of Wakefulness Test
The maintenance of wakefulness test (MWT) is useful in determining the degree of response to pharmacological therapy (46). It consists of four to five trials of trying to stay awake in a darkened, quiet environment, while seated upright and dressed in street clothes. In this regard, it is the mirror-image opposite of the MSLT. The length of the trials is 40 minutes and they are provided at two-hour intervals. Most nonsleepy controls demonstrate a mean sleep latency from the trials of 30 minutes or more.
D.
CSF Hypocretin Analysis
This assay is helpful when the patient is already receiving pharmacological agents such as selective serotonin reuptake inhibitors and when it is unsafe or impractical to discontinue these drugs for obtaining the MSLT. Levels of CSF hypocretin-1 are not influenced by age, gender, or time of collection of the sample; the levels are defined as low (<110 pg/mL), intermediate (110–200 pg/ mL), or normal (>200 pg/mL) (28). The diagnostic sensitivity of low levels of hypocretin-1 (<100 pg/mL) for narcolepsy is 84.2%. Arii et al. studied CSF hypocretin-1 levels in 132 patients with pediatric neurological disorders, six of whom had narcolepsy-cataplexy (29). They noted markedly reduced levels (<110 pg/mL) in all 6 patients (100%) with narcolepsy-cataplexy, but in only 7 of 126 (5.5%) of the non–narcolepsy control group, which included intracranial tumors, head trauma, acute infectious polyneuritis, and acute disseminated encephalomyelitis.
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Table 2 Pharmacological Agentsa Used in the Treatment of Narcolepsy-Cataplexy Symptom
Medication (trade name)
Dose
Daytime sleepiness
Methylphenidate hydrochloride (Ritalin) (Ritalin SR) (Concerta) (Metadate) Dextroamphetamine (Dexidrine) Amphetamine/dextroamphetamine mixture (Adderall) Modafinil (Provigil)
10–60 mg/day in 2–3 divided doses 20–60 mg/day in 1–2 doses 18–54 mg/day in 1–2 doses 20–60 mg/day in 1–2 doses 20–30 mg/day in 1–2 doses 10–40 mg/day in 2 doses
Clomimipramine (Anafranil)
25–75 mg/day in 1–2 divided doses 25–100 mg/day in 1–2 divided doses 2.5–10 mg/day in 1–2 divided doses 3–9 g in 2 divided doses at night 10–20 mg/day in a single dose 10–20 mg/day in a single dose 25–75 mg/day
Cataplexy
Imipramine Protryptiline (Vivactil) Sodium oxybate (Xyrem) Fluoxetine (Prozac) Citalopram (Celexa) Venlafaxine (Effexor/Effexor extended release) Emotional problems, Fluoxetine (Prozac) depression Sertraline (Zoloft)
100–400 mg/day in 1–2 doses
10–30 mg in the morning 25–100 mg in 2 divided doses
a
Not listed in any specific order of efficacy.
VI.
Management
Narcolepsy requires life-long treatment, thus it is important that to the extent possible, the diagnosis be established definitely. Medications commonly used for treatment are listed in Table 2. A.
Sleepiness
Daytime sleepiness is countered using modafinil or stimulants like methyphenidate (regular or extended release) and various formulations of amphetamine (51). The mechanism of action of methylphenidate/amphetamines is the enhanced release of catecholamines from the presynaptic vesicles. Side effects include loss of appetite, nervousness, tics, headache, and insomnia. For
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maintaining alertness adequately throughout the day, administration may need two to three divided doses. Regular and extended formulations of methylphenidate may be taken in combination to maintain a stable level of alertness throughout the day. The evidence regarding therapeutic efficacy of methylphenidate/amphetamines includes three level II and four level V studies (51). The practice parameter published by the American Academy of Sleep Medicine states that the benefit to risk ratio of stimulants has not been well documented because published clinical trials are composed of small numbers of patients. Mittler evaluated the efficacy of pemoline, methylphenidate, and dextroamphetamine in adults with narcolepsy and age-matched controls by using the maintenance of wakefulness test as an objective measure of daytime alertness (52). The digit symbol substitution test was used to measure neuropsychological function. None of the drugs improved the level of alertness of narcolepsy subjects above the 81st percentile of the alertness level of the controls. Further, this occurred only with methylphenidate 60 mg/day. Modafinil (trade name Provigil), a drug with an unspecified mode of action, has proved effective in enhancing alertness in 64–90% of subjects in randomized, controlled clinical trials (53). The dose varies from 100 to 400 mg in one to two divided doses. The side effects include headache, nervousness, anxiety, and nausea. A systematic chart review of 13 children prescribed modafinil for daytime sleepiness documented a favorable response in terms of a reduction in the number of sleep attacks (54). There was an exacerbation of seizures and psychosis in 2 of 13 subjects who had preexisting conditions. Hematological and hepatic functions were unaltered. In older teens, one may be able to utilize the MWT in order to optimally titrate the medication dose and time of administration (author’s opinion). If the daytime sleepiness of narcolepsy does not improve satisfactorily despite adequate dosing with modafinil/methylphenidate/dextroamphetamine, coexisting conditions like inadequate sleep hygiene, depression, delayed sleep phase syndrome, periodic limb movement disorder, restless legs syndrome, and obstructive sleep apnea should be considered (51). B.
Cataplexy
Mild cataplexy may not require therapy during childhood. When it becomes bothersome, selective serotonin reuptake inhibitors or anticholinergic medications have been commonly prescribed (there is a propensity of cholinergic stimulation of the brainstem in the precipitation of cataplexy in animals). Commonly used agents include venlafaxine, protryptiline, and clompiramine. The side effects of venlafaxine include decreased appetite, dizziness, headache, and nervousness. Common side effects of protryptiline and clomimipramine include drowsiness, weight gain, dry mouth, and constipation. Monitoring for cardiac conduction defects like prolongation of the QT-interval is important with tricyclic agents. Fluoxetine, by virtue of REM suppressant effect, is also useful in treating cataplexy, especially when combined with a tricyclic agent. g-Hydroxybutyrate
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(sodium oxybate) has also been approved by the Food and Drug Administration to treat cataplexy in adults (55). It seems to work by stabilizing nocturnal sleep architecture, which might indirectly reduce the frequency of REM sleep intrusions onto wakefulness during the daytime. It also leads to improvement in daytime sleepiness (56). Potential side effects include the precipitation of confusional arousals, sleep apnea, enuresis, depression, tremor, respiratory depression, and constipation. In a retrospective study of eight children with narcolepsycataplexy who had been treated with sodium oxybate, Kotagal et al. (57) found that seven of the eight subjects had an improvement in cataplexy, and all had improvement in daytime sleepiness. The mean age at initiation of treatment was 13.75 years (range, 9–16 years). Suicidal ideation, dissociative episodes, tremor, and constipation occurred in one subject each. C.
General Measures
One to two planned naps per day of 10 to 60 minutes also help enhance daytime alertness and improve psychomotor performance. Supportive psychotherapy and fluoxetine or sertraline may be indicated if patients develop emotional and behavioral problems. The Narcolepsy Network (telephone 973-276-0115; E-mail:
[email protected]) is a useful private, nonprofit resource for patients, families, and health professionals. Because of the increased risk of accidents from sleepiness, patients should be cautioned against driving long distances and working near sharp, moving machinery. D.
Immunotherapy
Owing to the possible role of dysregulation of the immune system in the pathogenesis of narcolepsy-cataplexy (17,18), Dauvilliers et al. have treated a group of four hypocretin deficient narcolepsy-cataplexy patients with intravenous immunoglobulin soon after the diagnosis was established (58). The oldest subject was 54 years at the time of diagnosis. There was significant and sustained improvement in cataplexy which minimized the need to use other medications to treat cataplexy (59). They acknowledge the limitations of the study, which include small sample size, open label design, and lack of adequate information about the natural history of narcolepsy-cataplexy in older adults. VII.
Conclusions
While many aspects of the narcolepsy of childhood and adolescence resemble those of adults, some differences do stand out. These include the subtle and relatively nonspecific initial manifestations of fatigue, mood swings, and weight gain. While some children show SOREMPs right away at the time of the onset of sleepiness, others have gradual progressive intrusion of the REM sleep phenomena into wakefulness, which evolves over months. The significance of these
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two clinical presentations is unclear. Do children with narcolepsy-cataplexy have a different outcome than those with narcolepsy without cataplexy? Do children with idiopathic narcolepsy fare better or worse than those with symptomatic narcolepsy? Does early intervention with immunological therapy definitely alter the long-term prognosis? These issues remain unresolved. With regard to diagnosis, in North America, CSF hypocretin assays are available only after enrollment in research protocols but not routinely through clinical laboratories (owing to a combination of administrative and methodological hurdles). Pharmacokinetic, safety, and efficacy studies pertaining to drug therapy in children and adolescents are lacking, and consequently, so are evidence-based treatment guidelines. There is no denying, however, that over the past decade, advances in the neurosciences have had a major impact on our understanding of narcolepsy, and there will undoubtedly be further progress. References 1. Pearce JMS. Willis on narcolepsy: historical note. J Neurol Neurosurg Psychiatry 2003; 74:76. 2. Lennox WC. Thomas Willis on narcolepsy. Arch Neurol Psychiatry 1939; 41: 348–351. 3. Gelineau J. De la narcolepsie. Gaz des Hop (Paris) 1880; 53:626–628. 4. Adie WJ. Idiopathic narcolepsy: a disease sui generis; with remarks on the mechanism of sleep. Brain 1926; 49:257–306. 5. Culebras A. Sleep and narcolepsy. Arch Neurol 1999; 56:117–118. 6. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena during sleep. Science 1953; 118:273–274. 7. Rechtschaffen A, Wolpert EA, Dement WC, et al. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol 1963; 15:599–609. 8. Lin L, Faraco J, Li R, et al. The sleep disorder, canine narcolepsy, is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98:365–376. 9. Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355:39–40. 10. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brain. Nat Med 2000; 6:991–997. 11. Silber MH, Krahn LE, Olson EJ, et al. The epidemiology of narcolepsy in Olmstead County, Minnesota: a population based survey. Sleep 2002; 25:197–202. 12. Honda Y. Clinical features of narcolepsy: Japanese experiences. In: Honda Y, Juji T, eds. HLA in Narcolepsy. Berlin: Springer-Verlag, 1988:24–57. 13. Lavie P, Peled R. Narcolepsy is a rare disease in Israel. Sleep 1987; 10:608–609. 14. Challamel MJ, Mazzola ME, Nevsimalova S, et al. Narcolepsy in children. Sleep 1994; 17:S17–S20. 15. Foutz AS, Mitler MM, Cavalli-Sforza LL, et al. Genetic factors in canine narcolepsy. Sleep 1979; 1:413–421. 16. Mitler MM, Dement WC. Cataplectic-like behavior in cats after microinjection of carbachol in the pontine reticular reticular formation. Brain Res 1974; 68:335–343.
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39. Guilleminault C, Pelayo R. Narcolepsy in prepubertal children. Ann Neurol 1998; 43:135–142. 40. Young D, Zorick F, Wittig R, et al. Narcolepsy in a pediatric population. Am J Dis Child 1988; 142:210–214. 41. Henry GK, Satz P, Heilbronner RL. Evidence of a perceptual encoding deficit in narcolepsy. Sleep 1993; 16:123–127. 42. Rogers AE, Rosenberg RS. Tests of memory in narcoleptics. Sleep 1990; 13:42–52. 43. Stores G, Montgomery P, Wiggs L. The psychosocial problems of children with narcolepsy and those with excessive daytime sleepiness of uncertain etiology. Pediatrics 2006; 118:e1116–e1123. 44. Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986; 9:519–524. 45. Kotagal S. A developmental perspective on narcolepsy. In: Loughlin GM, Carroll JL, Marcus CL, eds. Sleep and Breathing: A Developmental Approach. New York: Marcel Dekker, 2000:347–362. 46. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005; 28(1):113–121. 47. Carskadon MA. The second decade. In: Guilleminault C, ed.: Sleeping and Waking Disorders: Indications and Techniques. Menlo Park, CA: Addison Wesley, 1982: 99–125. 48. Gozal D, Wang M, Pope DW Jr. Objective sleepiness measures in pediatric obstructive sleep apnea. Pediatrics 2001; 108:693–697. 49. Kotagal S, Swink TD. Excessive daytime sleepiness in a 13 year old. Semin Pediatr Neurol 1996; 3:170–172. 50. Aldrich MS, Chervin RD, Malow BA. Value of the multiple sleep latency test for the diagnosis of narcolepsy. Sleep 1997; 20(8):620–629. 51. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep 2001; 24(4):451–466. 52. Mitler MM. Evaluation of treatment with stimulants in narcolepsy. Sleep 1994; 17(suppl 1):103–106. 53. Billiard M. Modafinil: pharmacology and therapeutic perspectives. Rev Neurol (Paris) 2003; 159(1):122–125. 54. Ivanenko A, Tauman R, Gozal D. Modafinil in the treatment of excessive daytime sleepiness in children. Sleep Med 2003; 4(6):579–582. 55. Scharf MB. Sodium oxybate for narcolepsy. Expert Rev Neurother 2006; 6(8): 1139–1146. 56. Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 2006; 29(7):939–946. 57. Murali H, Kotagal S. Off-label treatment of severe narcolepsy-cataplexy in childhood with sodium oxybate. Sleep 2006; 29(8):1025–1029. 58. Dauvilliers Y, Carlander B, Rivier F, et al. Successful management of cataplexy with intravenous immunoglobulin at narcolepsy onset. Ann Neurol 2004; 56(6): 905–908. 59. Dauvilliers Y. Follow up of four narcolepsy patients treated with intravenous immunoglobulin [letter]. Ann Neurol 2006; 60(1):153.
11 Sleep in Children with Neurologic Disease
MARCO ZUCCONI Sleep Disorders Centre, Department of Neurology, H San Raffaele Institute, Milan, Italy
OLIVIERO BRUNI University La Sapienza, Rome, Italy
I.
Introduction
In the last few years, sleep researchers focused their attention on pediatric neurologic diseases and mainly on specific neuropsychiatric syndromes such as Down, Fragile-X, Rett, Prader-Willi, Angelman, Tourette, or autism, attentiondeficit disorders, tuberous sclerosis, etc. (1). However, extensive and comprehensive studies on sleep disorders in children with neurologic diseases are scarce: developmental disorders, epilepsies, and organic brain syndromes constituted more than 35% of total cases of children referred to a neuropsychiatric center for sleep problems (2). Any child with a brain disorder may be at risk for the development of sleep-wake rhythm disorders. Mentally retarded and brain-impaired children may have altered perception of ‘‘common zeitgeber’’ (light-dark cycle, food schedule, maternal inputs, etc.) and may also exhibit endogenous dysfunction in hormone release, important in synchronizing circadian rhythms, and can therefore interfere with the development of a normal sleep-wake cycle. The behavioral manifestations of sleep disruption in neurologically impaired children are mainly represented by difficulty in settling at night (51%) 261
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and nocturnal awakenings (67%) (3); institutionalized mentally retarded children had irregular and fragmented sleep throughout the day and night and exhibited daytime sleepiness or low level activity and, in some cases, showed complete reversal of the night-day cycle for sleep (4,5). The main features of sleep architecture in severely brain-injured infants were represented by an anomalous cyclic organization of sleep with prolonged duration of the sleep cycles, which can be regarded as an index of pathological sleep-wake organization, abnormally high percentage of wake time and anomalous interrelations between electromyographic, electrooculographic, cardiorespiratory, and electroencephalogram (EEG) patterns that did not allow to clear determination of active versus quiet sleep (6,7). In these cases, scoring sleep stages following the standard criteria could be very difficult; epochs are often scored as ‘‘undifferentiated’’ or ‘‘undetermined/transitional’’ sleep and it may even be impossible to distinguish sleep stages (monostage sleep) (8). In the cases in which sleep architecture can be identified, the most important polysomnographic features were the alteration of rapid eye movement (REM) sleep (increased REM sleep latency, decreased REM density, number of REM cycles, and REM stage duration) and the alteration of sleep spindles; either absence, overrepresentation, or prolonged duration (5,9). These sleep characteristics of neurologically impaired children did not seem to be specific to a particular etiology but positively correlated to the severity of mental retardation (10). The first observation of Petre-Quadens of a decrease in the number of rapid eye movements, decreased REM density in mentally retarded children and the correlation with level of intelligence (11,12) suggested the importance of REM sleep in learning and memory processes: REM sleep deprivation in animals causes a deficit of mnemonic and learning abilities (13), while intensive learning sessions were associated with an increase of REM sleep percentage (14). Considering that one of the main functions of REM sleep is an endogenous activation of the brain that influences neuronal growth, synaptic plasticity, learning, and unlearning (15,16), the deficit of REM sleep in neurologically ill infants could be the consequence of brain damage and could also contribute to low plasticity and low organization of the brain structures of these subjects. II.
Sleep in Children with Pervasive Developmental Disorders
Several studies showed that sleep disorders are common in children and adults with pervasive developmental disorders (PDD) including Asperger syndrome and high functioning autism (HFA) (17–27). In general, parents of PDD children report a prevalence of sleep problems ranging from 44% to 83%, mainly represented by difficulty in falling asleep, restless sleep, frequent awakenings, and reduced total sleep time during the night
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(28) and these sleep disturbances could have a predictive role on the autistic behavior during the day (29). Further, PDD children with sleep problems are more likely to exhibit daytime behavior problems and/or daytime sleepiness that may interfere with their educational and behavioral development (18,19). A recent study on 167 PDD children, including 108 with autistic disorder, 27 with Asperger syndrome, and 32 with other diagnoses of PDD, showed that about 86% of children had at least one sleep problem almost everyday, including bedtime resistance (54%), insomnia (56%), parasomnias (53%), sleep-disordered breathing (25%), morning rise problems (45%), and daytime sleepiness (31%). In this study, the type of PDD was not found to be significantly related to sleep problems and all the sleep pattern parameters did not significantly differ among children with autism, Asperger syndrome, and other PDD. Comorbid epilepsy, insomnia, and parasomnias were associated with increased risk for daytime sleepiness. (30). Further another new questionnaire study showed that parents of autism spectrum disorder (ASD) children reported a high prevalence of disorders of initiating and maintaining sleep, enuresis, repetitive behavior when falling asleep, and daytime sleepiness (31). Sleep problems are also frequent in children with Asperger syndrome and HFA, including difficulties in falling asleep, lower sleep efficiency, lower parent-rated sleep quality, and daytime sleepiness (32); these disturbances have been confirmed by actigraphy (33). Several studies on parasomnias in autism have reported inconsistent results (17,19,21). Most polysomnographic (PSG) studies of sleep in children with PDD have focused on abnormalities related to REM sleep in PDD (decreased quantity, more undifferentiated sleep, more immaturity in the organization of eye movements into discrete bursts). Old studies focused mainly on REM sleep, reporting an increase in fast EEG components and spindling, reduction in the duration but not in the number of REM bursts and a lower ratio of REM bursts to REMs out of bursts in autistic children (age up to 62 months) compared with normal controls (34,35). Elia et al. (36) showed that most sleep parameters were not significantly different between the two groups except the reduction of stage 2 non–rapid eye movement (NREM) sleep and higher values of REM density and oculomotor activity during REM sleep. The same research group, in a larger study, suggested that information processing (related to REM sleep) might be different in autistic mentally retarded subjects from subjects with mental retardation alone. Mentally retarded children seem to present a deficit in the production of REMs, while autistic children show a deficit in the modulation of REMs (37). A review analysis of PSG studies in PDD children showed a reduced total sleep time (38–40) as the main feature of sleep architecture in autism. Few studies tried to analyze sleep structure in order to characterize better the sleep of PDD children and almost all of them were performed on PDD children with associated mental retardation. Diomedi et al. (41) found a higher density of
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spindle activity not only during sleep stage 2 NREM, but also during slow-wave sleep (SWS) and REM sleep; during REM sleep, other authors found a higher density of muscle twitches (38) that apparently related to pontine-tegmentum alterations (42), and briefer bouts of REMs (39). A comprehensive PSG study over two consecutive nights on ASD children showed that the ASD poor sleepers differed significantly from the ASD good sleepers and normal children, having lower sleep efficiency and prolonged sleep latency. The ASD good sleepers and the control children did not differ on any of the sleep architecture parameters (43). This study also documented a relative absence of other sleep disorders on PSG, including sleep apnea, parasomnias, and sleep-related seizures. Few studies have tried to analyze sleep microstructure in order to characterize better sleep in autistic children. A recent study reported a reduction in the time in bed, total sleep time, sleep period time, and REM latency in ASD children. Sleep microstructural measures showed subtle alterations of NREM sleep, which could be detected with an appropriate methodology such as cyclic alternating pattern (CAP). ASD subjects had a lower CAP rate during slow-wave sleep than normal controls, together with a lower percentage of A1 subtypes. The authors hypothesized that the reduction of A1 subtypes during slow-wave sleep might play a role in the impairment of cognitive functioning in these subjects (31). III. A.
Sleep in Other Forms of Mental Retardation Down Syndrome
In Down syndrome (DS), children’s sleep recordings showed an increase in wake after sleep onset and body movements, a decrease in REM sleep with low REM sleep density, and fewer spindle bursts (44,45). Children with DS are prone to develop obstructive sleep apnea (OSA) because of many predisposing factors, such as midfacial and mandibular hypoplasia (46) macroglossia, glossoptosis and hypoplastic trachea (47), tonsillar and adenoid hypertrophy (48,49), obesity, and hypotonia. Several reports indicate a percentage of OSA between 50% and 80% in this type of mental retardation (50,52). A more recent report showed that the prevalence of OSA was 59% in DS children and 32% in snoring controls and out of 13 DS children with OSA, eight of them (61.5%) had no habitual snoring (53). Ferri emphasized the finding of central as opposed to obstructive apneas (89.4% vs. 9.4%) in a series of 10 DS subjects without obesity or upper airway pathology (54). These central events were preceded by sighs, but they provoked significant oxygen desaturation. The authors hypothesized that brainstem abnormalities may be responsible for the centrally impaired control of respiration during sleep. More recently a study assessed the leg motor activity of infants with DS showing that they produced more low-intensity activity and more fragmented sleep than typically developing infants (55).
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Rett Syndrome
Rett syndrome is a peculiar form of severe mental retardation characterized by autistic tendencies during infancy associated with particular stereotyped behaviors, ventilatory abnormalities during wakefulness (alternating apnea and hyperventilation), and motor apraxia of unknown etiology. Irregular sleep-wake rhythms have been observed frequently (56–58) as well as breathing disorders during wakefulness consisting of intermittent hyperventilation and prolonged apnea associated with severe oxygen desaturation (59,60). During sleep respiratory pattern is usually normal (59,61), although some central or obstructive events were also reported (50), indicating an impairment of the behavioral (waking) respiratory control while automatic ventilatory control is spared. Alterations in sleep architecture have been described, such as low sleep efficiency, long sleep-onset latency, and short and fragmented total sleep time, decreased REM sleep, decreased total sleep time, fewer spindles, and decreased K complexes (58,60,61), similar to other forms of mental retardation. C.
Fragile X Syndrome
Fragile X syndrome, a genetic disorder caused by a mutation in a specific gene located on the X chromosome, is characterized (in the case of full mutation) by mild to severe mental retardation, behavioral components, such as social deficits with peers, abnormalities in language and communication, unusual responses to sensory stimuli, stereotypic behaviors, hyperactivity, epilepsy, and cognitive dysfunction with deficits in visual–spatial skills, attention, and executive functioning. Distinctive physical features include an elongated face, large ears, and protruding jaw. Recently an increased risk for OSA was shown in a group of male children and young adults (62). However, a subsequent report of seven fragile X children, using polysomnography, found no obstructive apnea/hypopnea and only a few central respiratory events, preceded by sighs and without oxygen desaturation (63). Fragile X syndrome children do not seem at particular risk for OSA, which differs from the other genetic forms of mental retardation (Down and Prader-Willi syndromes). Concerning sleep neurophysiology, a study of nine fragile X patients showed reduced total sleep time, decreased REM sleep percentage, and an increase in the first REM latency, and in the stage 3–4 NREM percentage (64). Moreover, in the same study, an increase in twitch movements was observed during both stage 2 NREM and REM sleep. This may indicate a dysregulation of the cholinergic monoaminergic system during sleep, leading to an imbalance between the two neurochemically different mechanisms, which are known to be involved in other clinical manifestations of this genetic syndrome (65). Behavioral intervention for sleep problems (mainly extinction) seemed to be effective in fragile X subjects reducing settling problems, night wakings, and cosleeping; while early morning waking and night rocking did not improve (66).
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Angelman Syndrome
Angelman syndrome (AS) is a genetic disorder characterized by psychomotor delay, severe speech impairment, profound mental retardation, ataxic gait, and/or tremulous movements of limbs, a peculiar behavior with frequent laughter, apparently happy temperament, hand flapping, and jerky movements (puppet like movements), and severe epilepsy (67,68). The few studies available on sleep disorders in AS show a high frequency of disorders of initiating and maintaining sleep, prolonged sleep latency, prolonged wakefulness after sleep onset, high number of night awakenings, and reduced total sleep time. In addition, snoring and parasomnias were frequently reported including enuresis, bruxism, sleep terrors, somnambulism, and nocturnal hyperkinesia (69). Complete polysomnographic studies described a significant reduction in sleep efficiency and in the percentage and duration of REM sleep, while the percentage of SWS was significantly higher because of the presence of the 1- to 3-Hz bursts that represented the typical EEG pattern of the syndrome (70). Further, no respiratory abnormalities were found, but a tendency for AS subjects to present a higher PLMI than other two control groups with epilepsy and mental retardation (71). Finally, treatment with sleep hygiene, behavioral therapy, and reinforcing of the sleep-wake rhythm was documented to be as effective as hypnotic drugs (72). E.
Prader-Willi Syndrome
Prader-Willi Syndrome, a congenital disorder usually associated with a mutation on the chromosome 15q11–13, is characterized by perinatal hypotonia, hyperphagia, hypogonadism, and learning difficulties as well as dysmorphic traits such as hypotelorism, high arched palate, and downturned mouth. Daytime sleepiness is a very common symptom associated with the syndrome and was recently listed, together with sleep apnea, as a minor characteristic in the consensus on diagnostic criteria (73). These characteristics, along with weight gain, lead to an increased risk for OSA, well documented by several authors (74–77). Several authors reported daytime sleepiness as the main behavioral characteristic of these children (74,78–80), increasing with the age and weight, and severe in cases with OSA or obesity hypoventilation. Clift et al. (77) found daytime sleepiness to be present in 70% of children and young adults with the syndrome, severe in 50% and related to OSA severity. In addition, they found atypical REM sleep with a short latency after sleep onset. Because of the presence of daytime sleepiness also in children without respiratory disturbances, they concluded that in Prader-Willi syndrome, excessive daytime sleepiness is mainly of central origin (hypothalamic involvement?) but OSA may increase it, particularly in obese subjects. For this reason, they recommended screening for sleep apnea, independent of the subjective complaint of daytime somnolence (77). Hertz et al. studied developmental changes in sleep and respiration among a group of children and
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adults with the Prader-Willi syndrome and found minor sleep apnea and frequent REM-related oxygen desaturation (only two out of nine children had overt OSA) that correlated with the degree of obesity. They described REM sleep abnormalities (both in children and adults), such as REM sleep fragmentation, variable REM latency, and sleep-onset REM periods on the multiple sleep latency test (MSLT), but none of the patients had clinical symptoms of narcolepsy and cataplexy. Moreover, these sleep alterations appeared to be independent of disordered breathing, nocturnal oxygen desaturation, and daytime sleepiness. The authors postulated a dysfunction in the posterior hypothalamus as responsible for sleep findings, while obesity was correlated with respiratory and oxygen saturation abnormalities (76). Continuous positive airway pressure (CPAP) has been shown to be useful in the management of severe OSA and daytime sleepiness but is more difficult in children with mental retardation and behavioral learning disabilities (75,77). Concerning the REM sleep abnormalities, which are similar to those of narcolepsy, two recent reports exclude an association between HLA haplotype DR2(15) and DQ1(16) and the syndrome, even though these associations are typical for narcolepsy (81,82). A novel study evaluated sleep architecture and NREM sleep microstructure abnormalities in PWS adults showing a reduced MSLT score and mean latency of sleep, increased REM sleep periods and increased mean CAP rate in Prader-Willi syndrome that corresponded to a higher NREM sleep instability. They also found a negative correlation between A1 phases of CAP (slow oscillations events) and growth hormone (GH) deficiency (83). Since several cases of sudden death in GH-treated and non-GH-treated, mainly young Prader-Willi syndrome patients were reported, a study investigating the effects of GH on respiratory parameters in prepubertal Prader-Willi syndrome children reported that children with this syndrome have a high apnea-hypopnea index (AHI), mainly due to central apneas and that six months of GH treatment does not aggravate the sleep-related breathing disorders (84). To summarize, in Prader-Willi syndrome somnolence during the day is a common symptom that becomes severe when associated with sleep-disordered breathing. There are no typical and consistent sleep architecture modifications but, probably, hypothalamic dysfunction acts on the central component of daytime sleepiness and obesity worsens the upper airway obstruction during sleep. It is possible that OSAs may contribute to neurocognitive and psychosocial deficits in PWS and treatment of OSA may have potential benefits in improving neurocognitive performance and behavior in PWS (85). F.
Smith-Magenis Syndrome
The Smith-Magenis syndrome is a rare, complex multisystemic disorder caused by a heterozygous interstitial deletion of chromosome 17p11.2 and is characterized by infantile hypotonia and lethargy in infancy, minor skeletal (brachycephaly,
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brachydactyly) and craniofacial features, ocular abnormalities, middle ear and laryngeal abnormalities, as well as marked early expressive speech and language delays, psychomotor and growth retardation, and a 24-hour sleep disturbance. The diagnosis of the Smith-Magenis syndrome is based on the clinical recognition of a constellation of physical, developmental, and behavioral features in combination with a sleep disorder characterized by inverted circadian rhythm of melatonin (MLT) secretion with peaks during the day (86). Sleep disturbance occurs in all cases of the Smith-Magenis syndrome from infancy into adulthood. In infants, the sleep disturbance is manifest by excessive daytime lethargy as well as decreased 24-hour sleep. Older toddlers and children manifest fragmented and shortened total sleep cycles, frequent and prolonged nocturnal awakenings, early morning awakening, excessive daytime sleepiness, daytime napping, snoring, and enuresis (87). The decreased nocturnal sleep, early awakenings, and daytime naps extend into adolescence. Recent objective sleep data derived from actigraphy indicate a sleep disturbance in infancy that continues into later childhood and beyond. Data on three infants under one year of age indicate fragmented sleep with reduced 24-hour total sleep time as early as six months of age (88). Reduced sleep begins at infancy with reduced 24-hour sleep compared with healthy control subjects. The pattern continues with preschool (3 years), early school (5 years), and later school children (6–8 years), who sleep 1 to 2 hours less per 24 hours than healthy age-matched control children. Reduced 24-hour sleep stems largely from the reduction of night sleep in each of the age groups. The sleep debt is compensated for by daytime napping (86). PSG studies documented reduced sleep time in virtually all Smith-Magenis syndrome patients studied. Further abnormalities of REM sleep have been reported in 43–50% of patients with the Smith-Magenis syndrome, with REM disrupted by arousals in all children (89,90). Individuals with the Smith-Magenis syndrome have an abnormally reduced latency for falling asleep during the daytime, a finding that is consistent with increased daytime napping (89). The therapeutic approach using b-blockers in the morning (to inhibit MLT secretion during the day) and exogenous MLT administration in the evening, resets circadian rhythm of MLT, improves behavior and restores sleep (86,91). IV.
Nocturnal Frontal Lobe Epilepsy and Abnormal Motor Behaviors of Epileptic Origin: Differentiation from Parasomnias
Experimental studies in rats showed that amygdala kindling determined sleep modifications that appear early in the development of kindling before the occurrence of seizures, and also persist after their cessation (92). This observation demonstrated that even in the absence of clinical effects, sleep is one of the first functions affected and, sharing a common neuroanatomical substrate, can modulate the occurrence of other disorders. An example of sleep modulation in neurologic
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disorders is represented by the activating effect of the CAP on interictal epileptiform discharges. CAP is represented by a repetitive EEG pattern either in synchronization and linked to a higher arousal level (phase A) or in desynchronization and linked to a lower arousal level (phase B). CAP phase A has an activating effect on the epileptiform discharges in primary generalized epilepsy and in lesional epilepsies with frontotemporal focus while phase B has an inhibitory action (93). Another example of the sleep influence on epilepsy is represented by the improvement of seizure control after treatment of sleep apneas either in adults (94,95) or in children (96). In nine children with neurodevelopmental disorders, who had well-documented sleep apneic episodes and seizure disorders, treatment for sleep apnea greatly reduced seizure frequency in five patients. Oxygen saturation did not correlate with baseline seizure frequency or seizure outcome after apnea treatment. A.
Nocturnal Frontal Lobe Epilepsy
Frontal lobe epilepsy is very well studied and large series on patients have been published in the past literature (97–101). Seizures are characterized by a wide spectrum of clinical features, but the motor manifestations and the nocturnal (sleep) preponderance are the main and common aspects of these seizures. Supplementary motor area (assumption of postures, rhythmic movements, and rapid uncoordinated movements), cyngulate gyrus (complex repetitive movements involving arms and legs, vocalization) or orbitofrontal (pelvic thrusting, wandering) origins are difficult to evaluate with a conventional EEG. Only the dorsolateral regions of the frontal lobe are detectable with surface electrodes. Moreover, during attacks motor artifacts often cover electrical abnormalities and only intracranial or, in some cases sphenoidal and zygomatic leads may disclose epileptic critic and intercritic paroxysmal abnormalities (98,101,102). For these reasons frontal seizures, when evaluated during wakefulness, can be misdiagnosed as pseudoseizures (103,104) and, when observed during sleep, are often misdiagnosed as movement disorders or sleep disturbances (105–109). Only recently, a distinct form of clear-cut nocturnal attacks originating from epileptic foci located in the frontal lobe (in particular in mesial and orbital cortex) and emerging almost exclusively from sleep (NREM sleep) has been described (109–115). Seizures are characterized by a wide spectrum of clinical features but the motor manifestations and the nocturnal preponderance are the main and common aspects of these types of seizures. Before video recording, the epileptic origin of these paroxysmal arousals with atypical motor behaviors and, in some cases, of a more pronounced complex dystonic-dyskinetic motor attack was only postulated but not confirmed (116,117). Only since the mid-1980s and in the last 10 years, with the aid of detailed analysis of video-polysomnographic recordings (103,109,111,113,114,118,119) and intracranial or sphenoidal electrodes (110,112) was the epileptic origin of some unusual motor manifestations from mesial and orbital regions of the frontal lobes clearly demonstrated.
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Attacks are generally restricted to NREM sleep (both deep and light NREM) emerging with or during arousals with various EEG activities: background flattening, rhythmic theta or delta activity, and sharp waves predominantly on frontal regions. Sleep structure is generally conserved in terms of percentages of sleep stages and in the sleep maintenance parameters (115,121). However in some cases, because of the high number of motor attacks during the night (even of minimal duration) the microstructure analysis reveals sleep fragmentation with increase in arousals and augmented sleep instability in all the NREM sleep stages (121,122). Utilizing CAP parameters according to Terzano et al. criteria (123), we found a significant increase in sleep instability in a group of nocturnal front lobe epilepsy (NFLE) patients complaining also of daytime symptoms such as difficulty in morning awakening, performance decrease and particularly daytime sleepiness (122). These motor attacks, known as nocturnal paroxysmal dystonia, paroxysmal awakenings or arousals, paroxysmal nightmares, episodic nocturnal wanderings, represent a spectrum of the same epileptic syndrome, NFLE, with a heterogeneous group of sleep-related complex motor attacks. Moreover, the description of a number of family history cases have led to the delineation of an autosomal dominant form of NFLE (ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy), which has been linked to chromosome 20q13 in a large Australian family and in other Japanese and European families (124–126), to chromosome 15q24 in an English family (127) and recently to chromosome 1q21 in two other (one Italian) families (128,129). The different mutations (three for the CHRNA4 gene, and two for the CHRNB2) code for the different subunits of the neuronal nicotinic acethylcoline receptor (nAChR). Genetic results in European pedigrees showed autosomal dominant inheritance with reduced penetrance; however, locus heterogeneity has been hypothesized since the absence of linkage on chromosomes 20q13, 15q24, and 1q21 for the majority of the families (130–132). The electroclinical picture of ADNFLE is not different from sporadic forms: motor and/or behavioral phenomena mainly during sleep starting in childhood/adolescence (mean age, 10–12 years) with interictal and ictal EEG during sleep often normal or uninformative; absence of lesions from neuroimaging (only 10–14% with some abnormalities at brain TC or MRI); normal development in the majority of the cases; frequent misdiagnosis with classical parasomnias (sleepwalking and sleep terrors) or other pathologies (psychiatric disorders); a generally good response to antiepileptic drugs (carbamazepine, topiramate), although in around 30% of the cases the motor attacks are resistant to drug treatment, and persist during adulthood in some cases (113,115,130,132,133). B.
Nocturnal Motor Behaviors in Children
Motor behaviors during sleep and nocturnal motor agitation are very frequent in children. The clinical features of the main NREM parasomnias (sleep walking, sleep terrors, and confusional arousals) and of NFLE are often overlapping or
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difficult to ascribe to one or the other sleep phenomena. Also, the similar clinical manifestations of arousal disorders and seizures (ADNFLE) renders them of low utility in the differential diagnosis. We recently observed a series of consecutive children, coming to our Sleep Center from pediatricians or neurologists, to evaluate repetitive motor behaviors during sleep or nocturnal motor agitation (134). Thirty-seven (25 males; 12 females; mean age, 10.0 3.7 (SD) years; range, 3–15 years) children underwent nocturnal video-polysomnography, including at least eight bipolar EEG leads. They were video monitored by a splitscreen audiovisual circuit, and arousals or awakenings with motor activity or motor behaviors were analyzed by two expert physicians, with very low interobserver and intraobserver variability of scoring (<5%) (113,114,130). The mean age at onset of motor episodes was 4.9 2.3 years (range, 1–11 years) and the mean frequency of episodes 15.9 12.3 per month, but in 13 children, the frequency was almost nightly. Analysis of video-polysomnography allowed a diagnosis in 29 cases (78.4%) whilst in eight children the recording showed only normal motor behaviors and gross body movements that were inconclusive. Among the 29 diagnosed cases, 23 (79.3%) met the criteria for NFLE and eight of them for the genetic form (ADNFLE). The diagnosis of NFLE was reached on the basis of motor episodes and EEG analysis as follows: (1) presence of several paroxysmal arousals (ranging 5–30 seconds in duration) with atypical motor behaviors of different types: prolonged, major, minor, and minimal (113,114,118,130); (2) stereotypy and repetitiveness of the motor attacks; (3) presence of at least one major or prolonged attack; and (4) sudden and abrupt start of motor behaviors with dystonic and dyskinetic components. Interictal epileptiform abnormalities were found in 51.4 % of the cases and ictal discharges in 40%. The other diagnoses were: sleep terrors (2 cases), sleep enuresis (3 cases), and rhythmic movements of sleep onset (1 case). No difference both in age at onset and in sleep parameters (sleep initiation, maintenance, and architecture) between NFLE and the other cases was found. Stage 2 NREM percentage (increased in NFLE) and stage 3–4 NREM percentage (decreased in NFLE) showed a trend, but did not reach the statistical difference. Our results suggest that children referred to a Sleep Disorders Center complaining of repeated nocturnal motor and/or behavioral and/or autonomic phenomena are likely to suffer from NFLE rather than parasomnias. In most cases, we diagnosed NFLE on the basis of abnormal motor manifestations during sleep (wanderings, dystonic/dyskinetic movements, complex behaviors, and vocalizations). Therefore, a complete video-polysomnographic study is of utmost importance in children with nocturnal motor attacks in order to provide a correct diagnosis and to delineate the real prevalence and clinical impact of parasomnias. Clinical and, particularly, video-polysomnographic criteria are needed to distinguish normal movements during sleep from motor parasomnias and epileptic phenomena.
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Diagnostic Differentiation Between NFLE and Arousal Disorders: Theoretical Implications
In order to improve discrimination of these disorders, recently a clinical-anamnestic scale has been proposed to examine its reliability for distinguishing sleep disorders (in particular, arousal disorders) from seizures. The Frontal Lobe Epilepsy and Parasomnia scale is based on questions to address features useful in discriminating the two entities: age at onset, duration of the typical event, clustering, timing, symptoms, stereotypy, recall, vocalization. Responses favoring epilepsy scored positively and those favoring parasomnias scored negatively; greater weighting was given to features considered to be strong indicators of either condition. This scale showed a sensitivity of 1 and specificity of 0.9 with a good interrater reliability in diagnosing NFLE or parasomnia with a small degree of overlap for the two groups compared with the ‘‘gold standard’’ video-polysomnography and/or an expert interview when necessary (135). Concerning the differentiation between arousal disorders and NFLE, there are some clinical/anamnestic and video-polysomnographic features leading to differential diagnosis (Table 1). On the basis of clinical history, although some overlap may exist, the start of episodes during pre-school age (3–6 years), the rare frequency (usually <1/mo, with no clustering), the long duration of episodes (usually >5 minutes), the prevalent occurrence in stage 3–4 NREM during the first half of the night (1–2 hours after sleep onset), and the disappearance before the ages of 16 to 18 years are the main features characterizing arousals disorders (sleepwalking and sleep terror). The motor pattern and the signs of the attacks are intriguing and more suggestive of NFLE when: the motor episodes are brief (<2 minutes in duration), stereotypic and repetitive in the same subject, in different recordings or in the same polysomnography; the continuity and the spreading from minimal or minor attacks to the more rapidly and typical major episode (sudden elevation of head and trunk with fear expression and dystonic posture of head or limbs, dyskinetic agitation of arms, vocalization, or screaming) and to the more complex and prolonged dystonia involving arms, legs, and trunk, or to so-called ‘‘agitated’’ somnambulism (with a sort of repetitive jump or a disordered and grotesque dance); the elevated number of episodes, both minimal, minor, and major attacks, with sleep disruption and daytime symptoms (difficulty with waking up, daytime fatigue or sleepiness) in some cases and a possible lucid recall of a proportion of events. These features are quite different from the rare episodes of parasomnias and the absence of sleep complaints in arousal disorders (135–139). Independent of the motor pattern there are some characteristics belonging to both disorders; the wake-EEG is normal and the interictal sleep-EEG shows some epileptiform abnormalities frontally, dominant only in about 50% of the cases of NFLE (114,115). Concerning ictal-EEG or EEG during parasomnia episodes, the data in arousal disorders are uncertain, because of the limited number of EEG leads during the recording or to the absence of video-polysomnographic simultaneous recording (126,138). Thus the differences are not so striking: for ictal
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Table 1 Clinical and Video-Polysomnographic Characteristics of Nocturnal Frontal Lobe Epilepsy (NFLE) and Parasomnias (Arousal Disorders).
Age at onset (mean) Positive family history for parasomnias Episode frequency/mo (mean) Episode frequency/night (mean) Clinical course over years Age at disappearance Episode duration Movements semeiology Triggering factors Ictal EEG Autonomic activation Episode onset after sleep onset Sleep stages during which episodes appear
Parasomnias (Sleepwalking-sleep terrors)
NFLE
typically <10 yr 62–96%
14 10 59%
<1–4
20 11
1
33
tend to disappear 7–14 yr from 15 sec to 20 min complex, non-stereotypic Yes high amplitude slow waves Present first third of night
increased frequency ? from 2 sec to 3 min violent, stereotypic none in 79% normal in 43% epileptic activity in 3% Present Anytime
3–4 NREM
2 NREM in 65%
EEG no change, artifacts, partial arousal to lighter sleep, arousal to awake pattern EEG, dissociative patterns (posterior alpha rhythm mixed with sleep elements), prevalence of background flattening of EEG or focal rhythmic activity of delta or theta bands, bursts of delta activity preceding or initiating the episode may be recorded in both types of motor episodes (113–115,130). These patterns have been described in typical arousal disorders and in frontal lobe seizures as ictal or post-ictal phenomena (140). Less than 10% of NFLE cases show typical epileptic discharges during the attacks, and only with deep stereo-EEG leads clear-cut paroxysms of epileptic origin have been shown (110,141,142). Even large changes in vegetative parameters (e.g., heart rate, respiratory rate) are not useful because of their presence both in arousal disorders and NFLE (115,143). The more elaborate arousal behaviors of parasomnias are unusual in NFLE, as well as myoclonic jerks, trembling, and shivering. The fearful or distressed expressions in parasomnias are usually highly emotive and, in general, sobbing or crying is not seen in NFLE. Also, the motor pattern is complex and non-stereotyped in parasomnias compared with NFLE. Another potential source of misdiagnosis is the recording of brief arousals from sleep without major or complex episodes. It remains to be delineated which criteria are useful to distinguish paroxysmal arousal with atypical motor behaviors from normal and physiologic body
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or segmental movements. Up to now, what we know is that the differences between patients and controls is in the number of motor arousals, especially of minimal attacks, occurrence of major episodes, and stereotypy of most of the attacks in patients, but not in controls (114). However, this feature does not invariably indicate an epileptic disorder; the onset of parasomnias may be similarly stereotyped. Some relatively new concepts and theories are coming from observations and analyses of data in the literature. The behaviors, both in NFLE and arousals and sometimes in healthy subjects may represent a common nonspecific response to internal or external stimuli, variable in expression (brief subclinical seizures in NFLE, loud noise, internal alerting signals, etc.) capable of evoking a nonspecific arousal and, in turn, triggering major seizures, full-blown parasomnias, or arousal/ awakening with motor behaviors. This theoretical speculation fits well with the unifying model proposed by Tassinari and colleagues (144) suggesting that the characteristic features of NFLE, temporal lobe epilepsy during sleep, arousals with motor behaviors, parasomnias, and other movement or motor behaviors during sleep result from the activation of central motor patterns from common motor pattern generators in the CNS. Both epilepsy and sleep can lead to temporary disinhibition of elementary motor patterns, genetically determined and situated from mesencephalon to spinal cord. A different trigger (seizure, normal arousal, or confusional arousal) involves the same central motor pattern generator leading to a common semiology of the episode/attack (144). The sleep microstructure, with the CAP measures, shows oscillation and instability in both the motor disorders (NFLE and arousal disorders), indicating periodic arousal oscillation as a trigger factor in motor phenomena during sleep. V.
Achondroplasia
Achondroplasia (AP) is the most common form of dwarfism (with prevalence between 1 in 25,000 and 1.5 in 10,000 live births). This autosomal dominant condition is caused by a mutation in fibroblast growth factor receptor-3 (FGFR-3), leading to a defect of endochondral bone formation, consisting of short stature, lumbar lordosis, protuberant abdomen, short hands, and craniofacial deformities, such as macrocephaly, frontal bossing, small foramen magnum, short cranial base, and severe midface hypoplasia (145). The bony modifications may lead to neurologic problems like hydrocephalus or myelopathy. Recent literature describes a high prevalence of respiratory disturbances during sleep, both central and obstructive in origin, in children with achondroplasia (146–151). Our group observed a consecutive series of children with AP, and evaluated sleep and respiration by PSG, correlating the results with clinical, magnetic resonance imaging or computer tomography brain imaging and cephalometry (where possible) (152). Almost all the children studied had a history of habitual snoring and/or suspected sleep apnea and daytime symptoms predicting respiratory disturbances during
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sleep. Sleep parameters were normal for age and no different from a group of normally developed children with habitual snoring. In 75% of the children with AP, we found breathing disorders during sleep ranging from obstructive sleep apneas with significant oxygen desaturations, obstructive hypopnea, continuous and loud snoring with increased respiratory effort, brief obstructive events, and an increase of breathing rate during sleep (152). Twenty five percent of the patients studied showed rare central apnea events during REM sleep, generally of short duration and without significant oxygen desaturation. There was no correlation between the size of the foramen magnum and the AHI. These findings likely indicate that the morphological features of achondroplasia such as craniofacial deformity are more important in the pathogenesis of breathing disorders than any possible dysfunction of central respiratory control. Our data on prevalence of sleep disordered breathing are similar to a recently published series on children with AP, studied by PSG, and indicating a wide spectrum of respiratory disorders during sleep; almost 50% presented signs of obstruction and hypoxemia though only a substantial minority were affected by severe sleep-disordered breathing (151). Our children did not exhibit respiratory complications during wakefulness and might represent a relatively benign phenotypic expression of the disease. In fact, in a recent prospective study, the authors tried to identify different groups of AP children; the less affected group usually presenting only with obstructive sleep apnea due to midfacial predisposition to upper airway obstruction (and adenotonsillar hypertrophy); the median affected group with OSA due to upper airway muscle weakness along with hydrocephalus (due to a small foramen magnum); the most severely affected group with upper airway obstruction but also with cor pulmonale and severe respiratory failure leading to death. It has been postulated that these different degrees of severity may be related to different specific regions in the chondrocranium development or to different time of development; caudal or early defects may be responsible for severe phenotypic defects (with foramen magnum and hypoglossal foramen abnormalities), rostral or late defects produce only midface problems (and only OSA), while intermediary defects may produce hydrocephalus and jugular foramen stenosis (150). In conclusion, our results confirmed other studies concerning the degree of upper airway obstruction during sleep in most children with AP (149–151). The crucial role of craniofacial deformity with reduction in the sagittal dimension of the nasopharynx and probably an increase in upper airway resistance seems to be the more important factor in explaining sleep disordered breathing. The high incidence of sleep-disordered breathing and malocclusion before the school age in AP has been further confirmed by a questionnaire survey (153) and correlated with cephalometry data (154). The authors found upper airway stenosis, a retruded position of the chin, and an increased mandibular plane angle due to partial ossification of cranial bones. Moreover, an increased lower facial height due to an increased mandibular angle has been found, similar to a group of children with OSA and adenoids hypertrophy and different from a control group (154,155).
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Neuromuscular Diseases
Among the various types of diseases involving neuromuscular pathology, the more frequently encountered sleep-related findings are respiratory problems due to respiratory muscle weakness (diaphragm, intercostals, and accessory respiratory muscles) and/or impairment of central breathing control. Respiratory insufficiency will be most marked in sleep and will first appear during periods of REM sleep (156,157). Obstructive or central apneas together with hypoventilation are the more commonly described abnormalities during sleep in children with neuromuscular diseases (NMD). Obstruction can occur at the upper airway level because of primary bulbar involvement or as a consequence of the inability of the diaphragm and intercostal muscles to overcome the normal change in airway resistance that is produced by progression from wake to sleep. REM sleep is the crucial period during which sleep-disordered breathing occurs because there is a physiologic inhibition of the chest wall and accessory muscles involved in respiration, while diaphragm function is relatively spared. Hypoventilation and central apnea in REM sleep can be recorded in diaphragm palsy without respiratory compromise during wakefulness. Usually, at least at the beginning of the disease, ventilation during NREM sleep is not compromised. When hypoventilation extends to NREM sleep, it is a sign of possible hypoventilation in the waking state too (with hypercapnia) and, consequently, a first step toward respiratory failure if left untreated. In addition, at this stage, the progression of the neuromuscular disease may play a role in increasing the hypoventilation during sleep and wakefulness by a worsening of muscle weakness (156,157). If upper airway obstruction is superimposed on sleep hypoventilation due to an underlying weakness, the two overlap and worsen the hypoventilation during sleep. The severity of the respiratory disturbances is related to age, type of the disease, and degree of involvement of respiratory or upper airway muscles. To date, there is no single predictor factor for detection of early abnormalities in sleep: only mild hypercapnia and REM hypoventilation (by means of PSG) are the first abnormalities detected. In-laboratory PSG or, at least, sleep studies using ambulatory equipment (158) should be performed on most patients in view of the high frequency of sleep-disordered breathing in neuromuscular diseases (159). Sleep-disordered breathing often precedes diurnal respiratory failure in NMD patients, requiring timely recognition and management with noninvasive ventilation (NIV). Moreover the severity, duration, and type of NMDs influence the pattern of sleep disturbances. While there is general agreement that NIV improves quality of life and survival in children with NMDs, there is no definite agreement on the timing of the investigation with PSG or how to determine the optimal timing for initiating NIV to treat sleep-disordered breathing. To date, several long-term studies show significant improvements in sleep quality, morning headaches, mood swings and daytime sleepiness with NIV in NMD children, besides the resolution of objective
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respiratory disorders (160,161). Moreover, children spend less time in hospital and intensive care after starting NIV (161). The neuromuscular disease associated with respiratory failure and sleeprelated breathing disorders that has received the most study is Duchenne’s muscular dystrophy (DMD). Both in children and in young adults, central and obstructive apnea/hypopnea, hypoventilation, and nocturnal oxygen desaturations have been observed in almost all the patients studied, usually preceding daytime respiratory failure. Problems tend to be worse during REM sleep, with simple decreases of SaO2 or apnea/hypopnea associated with significant O2 desaturation (162). The magnitude of oxyhemoglobin desaturation appears to be significantly correlated to functional residual capacity (162), vital capacity (in supine vs. the erect position, if possible) as an index of diaphragm weakness, daytime PaO2, PaCO2 (163), or decreased maximum inspiratory pressure (164). Besides the inhibition of intercostal and accessory muscle activity and the relative preservation of the diaphragm function in REM sleep, upper airway obstruction in these patients may decrease chest wall motion sufficiently to produce apparent central apnea (pseudocentral apnea) that is actually obstructive in origin (165–167). In a study considering daytime predictors of sleep hypoventilation, the authors concluded that PSG should be considered when PaCO2 is more than 45 mmHg. Moreover, improvement of awake PaCO2 after the institution of nighttime ventilation implicates sleep hypoventilation in the etiology of the respiratory failure (168). As a consequence of this amount of data, the periodic assessment of pulmonary function during wakefulness and respiration during sleep in children affected by DMD is to be considered an essential component of the effort to improve long-term survival, morbidity, and quality of life (169). Disturbances of cardiac rhythm during sleep (170) as well as a decrease in the heart rate variability, similar to adult DMD patients, are also described in these children (171). With respect to nocturnal mechanical ventilation as the first choice in the treatment of respiratory disorders during sleep, several studies, both in young adults and in children, confirm the efficacy of nocturnal ‘‘elective’’ ventilation, with immediate benefit on nocturnal blood gas abnormalities, preservation of residual respiratory function, and delay in the increase in chronic hypercapnia (172). The ventilation may be initially a bilevel positive airway pressure (173) in either spontaneous/timed mode or eventually nocturnal nasal intermittent positive pressure ventilation (174). Such pressure ventilation may produce an improvement in respiratory drive both in sleep and wake periods and improve arousal responses to abnormal blood gases (174). Long-term domiciliary nasal or facemask ventilation produces good results in terms of compliance and of nocturnal and diurnal blood gases also in children less than five to six years old (175). Myotonic dystrophy is another potential myopathy associated with sleeprelated breathing problems, which may present in the child early stages of the disease. Besides the presence of frequent central apnea, not only in REM sleep, but occurring throughout all the sleep stages (176), and less frequent obstructive events (177), there is an impairment of neural respiratory control indicated by the
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abnormal response to hypoxia and hypercapnia (156), which is due to the CNS involvement. Excessive daytime sleepiness, often described in children in the initial stage of myopathy (177), is probably independent from the AHI, the oxygen desaturations and the sleep fragmentation occurring because of the direct effect of the CNS lesions as suggested by the cognitive and neuropsychological deficits (178,179). Concerning other less frequent neuromuscular diseases, respiratory disorders during sleep have been described in congenital myasthenic syndrome (180), congenital myopathies (181) in particular nemaline myopathy (182), spinal muscular atrophy (159,169), and mucopolysaccharidoses (183). The treatment for these disorders is the same as for DMD, with nocturnal mechanical ventilation. VII.
Cerebral Palsy
Structural brain lesions in infants and children are often associated with sleep disruption. Different sleep problems can occur: either disorders of initiating and maintaining sleep, parasomnias, or even respiratory disturbances. In children with cerebral palsy (CP), sleep may be affected by several factors. Muscle spasms, other forms of musculoskeletal pain, and the decreased ability to change body position during the night may all contribute to sleep difficulties. Epilepsy, which is frequently associated with CP, is likely to predispose to sleep disorders, and the antiepileptic drugs can cause daytime sleepiness. Blindness or severe visual impairment, which may coexist with CP, can affect the timing and maintenance of sleep through an effect on MLT secretion and the lack of light perception. A questionnaire-based survey of 233 CP children investigated the prevalence of respiratory disturbances during sleep; habitual snoring was reported in 63% and sleep apnea in 19.7%. In 48 of these children whose questionnaires revealed habitual snoring and sleep apnea, a screening sleep study using pulse oximetry showed that 27% of the children had an AHI >5, and 58% had a level of SaO2 lower than 85% (184). A recent study determined the frequency and predictors of sleep disorders in 173 children with CP through the Sleep Disturbance Scale for Children questionnaire. Of the children in our study, 23% had a pathological total sleep score in comparison with 5% of children in the general population. Difficulty in initiating and maintaining sleep, sleep-wake transition, and sleep-breathing disorders were the most frequently identified problems. Active epilepsy was associated with the presence of a sleep disorder. Disorders of initiation and maintenance of sleep were more frequent in children with spastic quadriplegia, those with dyskinetic CP, and those with severe visual impairment (185). One of the first reports exploring sleep organization in CP children showed that 12 out of 23 patients exhibited some abnormal sleep EEG patterns such as absence of EEG characteristics indicative of wakefulness, NREM sleep and
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REM sleep, absence of REM sleep, extremely low incidence of sleep spindles or presence of ‘‘extreme spindles,’’ or abnormally high percentage of wake after sleep onset (186). In order to explore specific patterns associated with respiratory events, Kotagal et al. (187) studied nine subjects with severe CP (spastic quadriparesis and severe psychomotor retardation). Although scoring of sleep stages was technically difficult because of the presence of spike and slow-wave activity, no significant differences had been found in sleep parameters versus a control group; a higher arousal index indicated that the CP group had more sleep fragmentation, although not statistically significant. A considerably greater number of respiratory events (central and obstructive) per hour of sleep have been found in CP children (5.39 vs. 2.16; p <0.01). These patients also had significantly fewer changes in body position despite frequent and severe oxygen desaturation events. The treatment of sleep respiratory disorders in these patients resulted in a better sleep for these patients and also a decreased irritability during the day. Supporting these results, a more recent study (188) on 56 children with persistent snoring and OSA, 16 of whom were neurologically abnormal (2 of them with CP), showed that neurologically abnormal children had significantly increased obstructive apnea indices, increased desaturation events and lower mean arousal indices compared to their neurologically normal OSA peers. These reports raised the importance of treating sleep disorders and respiratory disturbances during sleep in children with neurologic disorders, especially children with CP. In 1997, Tanaka and his colleagues (189) reported three patients with severe brain damage (a 14-year-old boy, an 8-year-old girl, and a 9-year-old boy), and spastic quadriplegia that were treated with flunitrazepam (2 cases) and oral 5 mg MLT (1 case). After the correction of the chronic sleep-wake cycle disorder, the spasticity was reduced in all patients as showed by the F-wave analysis. Although the relaxing properties of flunitrazepam should be taken into account, the improvement of hypertonicity was also achieved with MLT and the authors speculated that the effect on muscle tone were not caused by direct action of benzodiazepine but by improved sleep quality produced by the treatment. Therefore, treatment for sleep disturbance occurring in brain damage is important in view of the improvement of increased muscle tone. On the other hand, the reduction of spasticity in CP patients with sleep apnea can lead to an improvement of respiratory function through the reduction of respiratory muscle spasticity. A patient with mixed spastic athetoid quadriparetic cerebral palsy with dystonia and who had sleep apnea, requiring nightly CPAP, was treated with intrathecal baclofen therapy that resulted in a reduction of spasticity and dystonia, as well as improvement of sleep apnea (190). Improved respiratory function can be explained by the enhancement in the vital capacity through reduction in spasticity of the respiratory musculature. The obstructive sleep apneic episodes were likely reduced by lowering the nasal resistance, thus decreasing the subatmospheric pressure in the pharynx, and by
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improving the synchronicity of the respiratory muscles through reduction in dystonia. The quality of sleep was also likely helped by a reduction in the number of restless leg movements that were caused by severe spasticity. Surgical techniques for the treatment of sleep respiratory disturbances have been used in several patients with CP or anoxic brain injury with documented obstructive sleep apnea; improvement of respiratory symptoms was achieved in most of the patients treated, with a significant reduction of AHI (184,191). A more recent study on sleep nasendoscopy evaluated four CP children before and after intervention. Two patients underwent uvulopalatoplasty and the remaining two were treated with tonsillectomy and laser supraglottoplasty. Three did extremely well with abolition of their sleep apneas and one child was able to have his gastrostomy removed due to the marked improvement in his swallowing (192). VIII.
Headaches
Sleep and headache are interrelated in different ways (193); sleep can be a relieving factor or trigger factor for headache (excessive, reduced or disrupted, increased deep sleep); sleep disorders (i.e., sleep apnea) can cause headache; headache patients are more prone to suffer from specific sleep disorders (parasomnias, sleepwalking); different forms of headache can be sleep-related (during or after sleep) or sleep-stage linked. This relationship is strongly evident even in nonclinical populations. A large community study on 622 children and adolescents with pain (60% with headache) reported that pain caused restrictions in daily activities and the most common complaint was sleep disturbances (53.6%) followed by inability to pursue hobbies (53.3%), eating problems (51.1%), and absence from school (48.8%). Further, one of the most frequent self-perceived subjective triggers of pain was the lack of sleep (194). Hyperreactivity syndrome during infancy (often associated with night awakenings and falling asleep difficulties) and periodic syndromes of infancy and childhood have been reported as risk and predisposing factors for migraine (195,196). Further, early sleep disorders have been found to be predictive of headache persistence from infancy to childhood. They were present in 78% of children with enduring headache versus 25% of children showing headache remission (197). Parasomnias are the sleep disorders most commonly associated with headache; history of sleepwalking has been reported in different groups of migraine patients with prevalence ranging from 30% (198,199) to 21.9% (200). Also pavor nocturnus and enuresis have been found to be commonly associated with headache (201). A case control study in school-age children confirmed this strong association (202). Migraine and tension-type headache children showed a higher prevalence of disorders of initiating and maintaining sleep: they exhibited a shorter sleep duration, a longer sleep latency, more difficulty in getting to sleep and
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bedtime struggles and a higher number of night awakenings. Regarding parasomnias, sleeptalking, bruxism, and reports of frightening dreams were more prevalent, while no differences were found for the prevalence of sleepwalking, bed-wetting, and sleep terrors. Sleepwalking, however, was more frequent in children with migraine with aura, according to the only report that attempted to differentiate between headache subgroups (199) and found a higher occurrence of sleepwalking in ophthalmic migraine. Sleep-breathing disorders were more frequent only in migraine subjects versus controls. Both migraine and tension-type headache were described as restless sleepers and presented daytime sleepiness. More recently two other studies supported these initial findings. Miller et al. (203) showed a high rate of sleep disturbances in children, including sleeping too little (42%), bruxism (29%), cosleeping with parents (25%), and snoring (23%). Moreover, they performed a hierarchical multiple regression analyses to identify predictors of children’s sleep disturbances. Headache characteristics independently predicted sleep anxiety ( p <0.05), parasomnias ( p <0.03), bedtime resistance ( p <0.03), sleepwalking ( p <0.03), and bruxism ( p <0.01), after controlling for the effects of child demographics; specifically, while the frequency of migraine predicted parasomnias, its duration predicted sleep anxiety and bedtime resistance. Along the same lines, other authors performed a logistic regression analysis showing that migraine without aura is a sensitive risk factor for disorders of initiating and maintaining sleep and chronic tension-type headache for sleepbreathing disorders, but headache disorder is a cumulative risk factor for disorders of excessive somnolence (204). Luc et al. (205) confirmed the higher prevalence of excessive daytime sleepiness, narcolepsy, and insomnia in children with headaches, but they did not find a significantly higher prevalence of symptoms of sleep apnea, restlessness, and parasomnias. Headache has been described as related to biological cycles and there is evidence of the relationship of different headache syndromes to a variety of cyclic phenomena (206). In childhood, the precursors of migraine called ‘‘migraine variants,’’ such as colic and periodic syndromes showed a recurrent circadian pattern. The behavioral regulation of sleep-wake rhythm in 35 migraine children through the application of the sleep hygiene guidelines resulted in a reduction of duration and frequency of migraine attacks (207). A further report showed that in three children, the head pain complaints resolved after a modification of bad sleep habits, notably problems with falling asleep, confirming that awareness of this connection could provide the clue to a successful treatment of headache (208). Analyzing circadian rhythms to assess the relationships with migraine, a preliminary report evaluated the sleep-wake cycle in 10 subjects with migraine versus controls on a long-term basis (2 weeks) using the actigraph, which allows an activity-based assessment of the sleep-wake cycle. A decrease in the average duration of each sleep episode, in the mean activity during the night and of sleep efficiency and an increase in wake after sleep onset was reported in migraine versus control children, indicating an alteration of the sleep
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continuity. Correlating the actigraphic data with the temporal occurrence of migraine attacks has revealed reduced movement activity and wake after sleep onset in the nights preceding and following the diurnal migraine attack (209). Several PSG studies analyzed sleep organization in adult headache and did not find any peculiar characteristics of sleep architecture in the adult population except for the association of particular subgroups with specific sleep stages, mainly REM stage (193). In children, there is a real paucity of PSG studies. In a preliminary work, our group analyzed the sleep structure in 10 migraine children compared with 10 age-matched controls and found differences in the number of stage shifts, the movement time and time spent in stage 1 NREM, while no differences have been found in the time in bed, total sleep time, total sleep period, sleep latency, time in stages 2 and 3–4 NREM and REM latency (210). These data demonstrated that the main feature of sleep organization in migraine children was represented by a high degree of sleep instability. In a study of adults with headache (211), nocturnal PSG led to a change in diagnosis in nearly half of the patients (periodic limb movements of sleep, fibromyalgia syndrome, and obstructive sleep apnea syndrome), suggesting the possibility that the headache is because of a sleep disorder in pediatric patients. It has been reported that morning headache could also be one the major signs of sleep apnea in children. Since, in a previous study (201), we found a high prevalence of sleep-disorder breathing in migraine children versus controls, we analyzed the respiratory pattern in 10 migraine subjects in order to evaluate the presence of sleep apnea; respiratory analysis revealed that two out of 10 patients had a higher prevalence of obstructive/mixed apneas (212) and reported habitual snoring and associated sleep disturbances such as restless sleep and hypnic jerks. Although parents may not associate headache with these symptoms in their children, the report of habitual snoring and restless sleep could be a reliable marker of sleep apnea in migraine children. Treating sleep disturbances, therefore, could result in the improvement of headache pain. Treatment with L-5-hydroxytryptophan in migraine subjects led to the improvement of both conditions—headache and sleep disorders, in particular frequent awakenings and some parasomnias (213). Also MLT treatment in five patients with different kinds of headache (migraine without aura, cluster headache, and chronic tension type headache) associated with delayed sleep phase syndrome was successful (214). IX.
Use of Melatonin in Children with Neurologic Disorders
In the last few years several authors reported beneficial effects of melatonin (MLT) for chronic sleep problems and irregular sleep-wake patterns in children with neurologic disorders (215). These sleep problems were often associated with an
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anomalous secretion of MLT: difficulties in sleep induction and maintenance are associated with lower levels of endogenous MLT; delayed sleep onset alone may or may not be associated with delayed onset of MLT secretion; free-running sleep rhythm is associated with a daily delay of sleep onset and MLT secretion (216). The most effective dose is between 5 and 10 mg given shortly or some hours before the desired bedtime; the nocturnal sleep onset correlates well with the onset of rising MLT levels (216,217). Fast release MLT is most useful for sleep induction, in view of the short half-life of the hormone (<1 hour); the slow release form is more useful for sleep maintenance (218). The speed of response to treatment varies: in some children the sleep difficulties disappear after the first dose, while in others the improvement takes days and occasionally weeks; however, in some patients, MLT does not have the desired effect (219). Once improved circadian control is established, it may be possible to successfully withdraw the treatment after few months. Because of the safety profile, MLT has been also used for obtaining sleep EEGs in children, providing a good alternative to pharmacological sedation and a complementary method to sleep deprivation (220). A.
Neurologic Syndromes and Mental Retardation
Pillar et al. (221) demonstrated that in mentally retarded children, MLT levels were low compared with the normal peak levels, no consistent day/night differences were present, and the level peaked at unexpected times. In these cases, exogenous administration of MLT did not change the 24-hour total sleep time, but consolidated nocturnal sleep periods—evident from the decrease in the amount of daytime sleep and simultaneous increase in nocturnal sleep. In two of five patients, the discontinuation of MLT did not induce recurrence of the sleep disturbances. The authors speculated that, in these patients, MLT had reset their circadian pacemaker, which remained synchronized even after the treatment was stopped. The other two children required ongoing therapy because any brief interruption resulted in sleep deterioration. An improvement in sleep disturbances has been reported in an open, prospective trial of MLT administration in 10 children with disability (mental retardation, epilepsy, and visual impairment) that presented sleep disorders for at least six months and that had not responded to at least one hypnotic drug. The therapeutic response was observed after the initial few nights and persisted in all responders. Most children (80%) showed a significant decrease in the average number of awakenings per night, average number of nights with delayed sleep onset and early morning arousals (222). In a five-year-old boy with non-24-hour sleep-wake syndrome and mental retardation, sleep-wake pattern improved after oral administration of MLT. The circadian variation in MLT secretion was extremely low, and it was speculated that the non-24-hour sleep-wake syndrome was due to a congenital deficiency of MLT secretion (223).
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McArthur et al. (224), in a double-blind placebo-controlled crossover protocol, tested the safety and efficacy of MLT treatment (2.5–7.5 mg) for sleep dysfunction in Rett syndrome. MLT significantly decreased sleep-onset latency during the first three weeks of treatment and improved total sleep time and sleep efficiency in the patients with the worse baseline sleep quality. In another investigation, a beneficial effect of 5 mg MLT treatment was observed in two patients with Rett syndrome and severe sleep disorders. MLT dramatically improved the sleep-wake cycle in the first patient, and in the second showed a hypnotic effect but early morning awakenings still occurred sometimes (225). O’Callaghan et al. (226) used a randomized double-blind placebocontrolled crossover design to investigate the efficacy of MLT treatment (5 mg) in seven patients with tuberous sclerosis complex who also had severe sleep problems (delayed sleep onset and fragmented sleep patterns). Results showed a small but clinically significant improvement in total sleep time (mean improvement 0.55 hours) and on sleep-onset latency. MLT did not have any discernible effect on sleep fragmentation and the significant increase in total sleep time resulted from an improvement in sleep onset rather than a reduction in the total number of awakenings per night. The authors suggested that MLT may work in patients with tuberous sclerosis because it modifies their epilepsy or moderates the sleep disruption caused by the epilepsy. More recently the same authors reported that normal patterns of MLT excretion were seen in tuberous sclerosis patients responding to MLT treatment suggesting that exogenous MLT can act by a simple sedative action and that an initial trial of 5 mg MLT is worth considering in patients with tuberous sclerosis complex and sleep disorder (227,228). Zhdanova et al. (229) used 0.3 mg MLT in 13 children (2–10 years) with AS and monitored serum MLT and motor activity. In three of their patients, they observed delayed MLT peaks. Although a small dosage of MLT was used compared to other studies, sleep-wake pattern of all children improved significantly with both a decrease in motor activity and an increase in the duration of the total sleep period. B.
Blindness
The cause of the sleep-wake disturbance in visually impaired children may be linked to the lack of perception of the light-dark cycle leading to a desynchronization of the 24-hour sleep-wake rhythm (219). Espezel et al. (230) treated 70 visually impaired children, aged 1 to 20 years old, with oral MLT (2.5–10 mg) at bedtime because of chronic sleep disorders. Sleep patterns improved dramatically without side effects, and patients became more alert and sociable and showed developmental gains. In eight children with functional visual impairment and severe circadian sleep-wake disturbances, MLT secretion peak times were delayed in seven patients and body temperature variation was out of phase in relation to sleep and MLT levels in five; MLT administered in the evening improved the sleep-wake pattern in all the patients and the effect was maintained
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for those between one and six years in six patients, with a reduction of night waking and daytime sleepiness (231). Of the 15 multiply handicapped children with severe persistent sleep disorders, nine had ocular or cortical visual impairment; 2 to 10 mg of oral MLT resulted in improvement of sleep patterns, with associated health, behavioral, and social benefits (219). References 1. Stores G. Annotation: sleep studies in children with a mental handicap. J Child Psychol Psychiatry 1992; 33:1303–1317. 2. Muratorio A, Massetani R, Baracchini G, et al. Sleep disorders in neuropsychiatric children. Res Commun Psychol Psychiatry Behav 1984; 9:285–306. 3. Quine L. Sleep problems in children with mental handicap. Am J Ment Defic 1991; 35:269–290. 4. Landesman-Dwyer S, Sacckett GP. Behavioral changes in nonambulatory, profoundly mentally retarded individuals. Monogr Am J Ment Defic 1978; 3:44. 5. Okawa M, Sasaki H. Sleep disorders in mentally retarded and brain-impaired children. In: Guilleminault C, ed. Sleep and Its Disorders in Children. New York: Raven Press, 1987:269–290. 6. Monod N, Guidasci S. Sleep and brain malformation in the neonatal period. Neuropaediatrie 1976; 7:229–249. 7. Dreyfus-Brisac C, Monod N. Sleep and brain malformation in abnormal newborn infants. Neuropaediatrie 1970; 1:354–366. 8. Sasaki H, Tamagawa K, Okawa M. Sleep of ‘‘acerebrate’’ patients. Clin Electroencephalogr 1978; 20:672–676. 9. Espie CA, Tweedie FM. Sleep patterns and sleep problems amongst people with mental handicap. J Mental Defic Res 1991; 35:25–36. 10. Grubar JC. Sleep and mental deficiency. Rev Electroenceph Neurophysiol Clin 1983; 13:107–113. 11. Petre-Quadens O, Jouvet M. Paradoxical sleep and dreaming in the mentally retarded. J Neurol Sci 1966; 3:608–612. 12. Petre-Quadens O, Jouvet M. Sleep in the mentally retarded. J Neurol Sci 1967; 4:354–357. 13. Fishbein W. Disruptive effects of rapid eye movement sleep deprivation on longterm memory. Physiol Behav 1971; 6:279–282. 14. Leconte P, Hennevin E. Augmentation de la duree du sommeil paradoxal consecutif a un apprentissage chez le rat. C R Acad Sci (Paris) 1971; 273:86–88. 15. Mirmiran M. The function of fetal/neonatal rapid eye movement sleep. Behav Brain Res 1995; 69:13–22. 16. Marks GA, Shaffery JP, Oksenberg A, et al. A functional role for REM sleep in brain maturation. Behav Brain Res 1995; 69:1–11. 17. Richdale AL, Prior MR. The sleep-wake rhythm in children with autism. Eur Child Adolesc Psychiatry 1995; 4:175–186. 18. Wiggs L, Stores G. Severe sleep disturbances and daytime challenging behavior in children with severe learning disabilities. J Intellect Disabil Res 1996; 40:518–528.
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174. Piper AJ, Sullivan CE. Effects of long-term nocturnal nasal ventilation on spontaneous breathing during sleep in neuromuscular and chest wall disorders. Eur Respir J 1996; 9:1515–1522. 175. Simonds AK, Ward S, Heather S, et al. Outcome of paediatric domiciliary mask ventilation in neuromuscular and skeletal disease. Eur Respir J 2000; 16:476–481. 176. Cirignotta F, Mondini S, Zucconi M, et al. Sleep related breathing impairment in myotonic dystrophy. J Neurol 1988; 235:80–85. 177. Guilleminault C. Sleep disorders in children. In: Berg BO, ed. Neurological Aspects of Pediatrics. Boston, MA: Butterworth Heinemann, 1992:617–626. 178. Broughton R, Stuss D, Kates M, et al. Neuropsychological deficits and sleep in myotonic dystrophy. Can J Neurol Sci 1990; 17:410–415. 179. Ono S, Kurisaki H, Sakuma A, et al. Myotonic dystrophy with alveolar hypoventilation and hypersomnia: a clinicopathological study. J Neurol Sci 1995; 128:225–231. 180. Iannaccone ST, Mills JK, Harris KM, et al. Congenital myastenic syndrome with sleep hypoventilation. Muscle Nerve 2000; 23:1129–1132. 181. Khan Y, Heckmatt JZ, Dubowitz V. Sleep studies and supportive ventilatory treatment in patients with congenital muscle disorders. Arch Dis Child 1996; 74:195–200. 182. Sasaki M, Takeda M, Kobayashi K, et al. Respiratory failure in nemaline myopathy. Pediatr Neurol 1997; 16:344–346. 183. Leighton SE, Papsin B, Vellodi A, et al. Disordered breathing during sleep in patients with mucopolysaccharidoses. Int J Pediat Otorhinolaryngol 2001; 58:127–138. 184. Shintani T, Asakura K, Ishi K, et al. Obstructive sleep apnea in children with cerebral palsy. Nippon Jibiinkoka Gakkai Kaiho 1998; 101:266–271. 185. Newman CJ, O’Regan M, Hensey O. Sleep disorders in children with cerebral palsy. Dev Med Child Neurol 2006; 48:564–568. 186. Shibagaki M, Kiyono S, Takeuchi T. Nocturnal sleep in mentally retarded infants with cerebral palsy. Electroencephalogr Clin Neurophysiol 1985; 61:465–471. 187. Kotagal S, Gibbons VP, Stith JA. Sleep abnormalities in patients with severe cerebral palsy. Dev Med Child Neurol 1994; 36:304–311. 188. Masters IB, Harvey JM, Wales PD, et al. Clinical versus polysomnographic profiles in children with obstructive sleep apnoea. J Paediatr Child Health 1999; 35:49–54. 189. Tanaka H, Araki A, Ito J, et al. Improvement of hypertonus after treatment for sleep disturbances in three patients with severe brain damage. Brain Dev 1997; 19:240–244. 190. McCarty SF, Gaebler-Spira D, Harvey RL. Improvement of sleep apnea in a patient with cerebral palsy. Am J Phys Med Rehabil 2001; 80:540–542. 191. Kosko JR, Derkay CS. Uvulopalatopharyngoplasty: treatment of obstructive sleep apnea in neurologically impaired pediatric patients. Int J Pediatr Otorhinolaryngol 1995; 32:241–246. 192. Myatt HM, Beckenham EJ. The use of diagnostic sleep nasendoscopy in the management of children with complex upper airway obstruction. Clin Otolaryngol 2000; 25:200–208. 193. Sahota PK, Dexter JD. Sleep and headache syndromes: a clinical review. Headache 1990; 30:80–84. 194. Roth-Isigkeit A, Thyen U, Sto¨ven H, et al. Pain among children and adolescents: restrictions in daily living and triggering factors. Pediatrics 2005; 115:E152–E162.
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195. Guidetti V, Ottaviano S, Pagliarini M. Childhood headache risk: warning signs and symptoms present during the first six months of life. Cephalalgia 1984; 4:236–242. 196. Del Bene E. Multiple aspects of headache risk in children. Adv Neurol 1982; 33:187–198. 197. Balottin U, Termine C, Nicoli F, et al. Idiopathic headache in children under six years of age: a follow-up study. Headache 2005; 45(6):705–715. 198. Barabas G, Ferrari M, Matthews WS. Childhood migraine and somnambulism. Neurology 1986; 33:948–1048. 199. Giroud M, D’Athis P, Guard O, et al. Migraine et somnambulisme: une enquete portant sur 122 migraineux. Rev Neurol 1986; 142:42–46. 200. Pradalier A, Guittard M, Dry J. Somnambulism, migraine and propranolol. Headache 1987; 27:143–145. 201. Dexter JD. The relationship between disorders of arousal from sleep and migraine. Headache 1986; 26:322. 202. Bruni O, Fabrizi P, Ottaviano S, et al. Prevalence of sleep disorders in childhood and adolescence headache: a case-control study. Cephalalgia 1997; 17:492–498. 203. Miller VA, Palermo TM, Powers SW, et al. Migraine headaches and sleep disturbances in children. Headache 2003; 43:362–368. 204. Carotenuto M, Guidetti V, Ruju F, et al. Headache disorders as risk factors for sleep disturbances in school aged children. J Headache Pain 2005; 6:268–270. 205. Luc ME, Gupta A, Birnberg JM, et al. Characterization of symptoms of sleep disorders in children with headache. Pediatr Neurol 2006; 34:7–12. 206. Fox AW, Davis RL. Migraine chronobiology. Headache 1998; 38:436–441. 207. Bruni O, Galli F, Guidetti V. Sleep hygiene and migraine in children and adolescents. Cephalalgia 1999; 19:58–60. 208. Feikema WJ. Headache and chronic sleep deprivation: an often missed relationship in children and also in adults. Ned Tijdschr Geneeskd 1999; 143:1897–1900. 209. Guidetti V, Bruni O, Violani C, et al. Sleep wake cycle variations in migrainous children. Cephalalgia 1999; 19:278. 210. Guidetti V, Bruni O, Canitano R, et al. Migraine and headache in childhood: sleep disorders and sleep organization. Cephalalgia 1995; 16:S10–S12. 211. Paiva T, Batista A, Martins P, et al. The relationship between headaches and sleep disturbances. Headache 1995; 35:590–596. 212. Bruni O, Miano S, Galli F, et al. Sleep apnea in childhood migraine, J Headache Pain, 2000; 1:169–172. 213. De Giorgis G, Miletto R, Iannuccelli M, et al. Headache in association with sleep disorders in children: a psychodiagnostic evaluation and controlled clinical study-L-5-HTP versus placebo. Drugs Exp Clin Res 1987; 13:425–433. 214. Nagtegaal JE, Smits MG, Stuart AC, et al. Melatonin-responsive headache in delayed sleep phase syndrome: preliminary observations. Headache 1998; 38:303–307. 215. Gordon N. The therapeutics of melatonin: a paediatric perspective. Brain Dev 2000; 22:213–217. 216. Jan JE, Freeman RD, Fast DK. Melatonin treatment of sleep-wake cycle disorders in children and adolescents. Dev Med Child Neurol 1999; 41:491–500. 217. Zhdanova IV, Lynch HJ, Wurtman RJ. Melatonin: a sleep-promoting hormone. Sleep 1997; 20:899–907. 218. Jan JE, Hamilton D, Seward N, et al. Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res 2000; 29:34–39.
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219. Jan JE, Espezel H, Appleton RE. The treatment of sleep disorders with melatonin. Dev Med Child Neurol 1994; 36:97–107. 220. Wassmer E, Quinn E, Whitehouse W, et al. Melatonin as a sleep inductor for electroencephalogram recordings in children. Clin Neurophysiol 2001; 112:683–685. 221. Pillar G, Etzioni A, Shahar E, et al. Melatonin treatment in an institutionalised child with psychomotor retardation and an irregular sleep-wake pattern. Arch Dis Child 1998; 79:63–64. 222. Jan MM. Melatonin for the treatment of handicapped children with severe sleep disorders. Pediatr Neurol 2000; 23(3):229–232. 223. Akaboshi S, Inoue Y, Kubota N, et al. Case of a mentally retarded child with non-24 hour sleep-wake syndrome caused by deficiency of melatonin secretion. Psychiatry Clin Neurosci 2000; 54(3):379–380. 224. McArthur AJ, Budden SS. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol 1998; 40:186–192. 225. Miyamoto A, Oki J, Takahashi S, et al. Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome. Brain Dev 1999; 21:59–62. 226. O’Callaghan FJ, Clarke AA, Hancock E, et al. Use of melatonin to treat sleep disorders in tuberous sclerosis. Dev Med Child Neurol 1999; 41:123–126. 227. Hancock E, O’Callaghan F, Osborne JP. Effect of melatonin dosage on sleep disorder in tuberous sclerosis complex. J Child Neurol 2005; 20(1):78–80. 228. Hancock E, O’Callaghan F, English J, et al. Melatonin excretion in normal children and in tuberous sclerosis complex with sleep disorder responsive to melatonin. J Child Neurol 2005; 20(1):21–25. 229. Zhdanova IV, Wurtman RJ, Wagstaff J. Effects of a low dose of melatonin on sleep in children with Angelman syndrome. J Pediat Endocrinol Metab 1999; 12:57–67. 230. Espezel H, Jan JE, O’Donnell ME, et al. The use of melatonin to treat sleepwake-rhythm disorders in children who are visually impaired. J Vis Imp Blind 1996; 90:43–50. 231. Palm L, Blennow G, Wetterberg L. Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol 1997; 39:319–325.
12 Sleep and Psychiatric Disorders in Children: A Complex Reciprocal Relationship
DANIEL S. LEWIN and CANDICE A. ALFANO Children’s National Medical Center, The George Washington University School of Medicine, Washington, D.C., U.S.A.
I.
Introduction
During the past decade and since the publication of the first edition of this volume, there has been an exponential increase in published reports of comorbid sleep and psychiatric disorders. As a result, there is now compelling evidence for linkages between the regulation of sleep, emotion, attention, and behavior in both children and adults. The majority of published reports on children have focused on sleep problems associated with specific psychiatric disorders. In particular, many early reports focused on depression (1,2), while subsequent focus shifted to sleep in children with attention deficit hyperactivity disorder (ADHD) (3). More recently, there has been an increasing interest in examining sleep among children with anxiety disorders, pervasive developmental disorders (PDD), and other developmental disorders associated with genetic syndromes. Collectively, however, few studies have addressed the neurobehavioral and psychiatric sequelae of sleep disturbance during childhood, including the shared pathophysiology of sleep and psychiatric disorders. In this chapter, we will review the pediatric literature that has addressed the relationship between sleep, anxiety disorders, depression, ADHD, and developmental disorders, with a 297
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particular focus on assessment and treatment. When relevant, we will also discuss findings from the adult literature, which is significantly better developed, particularly for the affective disorders. Among adults, risk of developing an anxiety or depressive disorder is significantly higher among individuals with insomnia than the general population (4,5). Among patients with a primary psychiatric disorder, up to 80% complain of difficulty initiating and/or maintaining sleep some time during the course of their illness (6). Direct links between adult affective disorders and both subjective (e.g., reports of difficulty initiating and maintaining sleep) and objective (e.g., polysomnographic) evidence of sleep disturbance most commonly involve complaints of insomnia, decreased rapid eye movement (REM) sleep, and increased REM latency. Data also indicate that, in many cases, adult sleep disorders both originate and persist from childhood (7), suggesting that early intervention may be critical. Although research on sleep in child and adolescent psychiatric disorders is more limited, many findings are consistent with adult data in terms of depression (8,9), anxiety disorders (10), and ADHD (11). A majority of youths presenting with a primary complaint of insomnia meet criteria for a psychiatric disorder or have elevated levels of emotional and behavioral problems (12). Additionally, increases in negative affective responses (including anger, sadness, and fear) following mild to moderate amounts of sleep restriction have been reported in otherwise healthy children and adolescents (13,14), behavioral and academic problems, as well as decrements in cognitive function, have been associated with sleep related breathing disorders (15–18). Together, data highlight the reciprocal nature of these relationships and underscore a need for clinicians to evaluate sleep among youths presenting with psychiatric disorders or emotional and behavioral difficulties. Compared to research documenting the co-occurrence of sleep and psychiatric disorders in children and adolescents research examining specific mechanisms and factors underlying this common overlap is quite limited. A bidirectional model of sleep, emotional and behavioral regulation (19) would have to account for the impact of insufficient sleep on the regulation of affect, attention and behavior; psychiatric problems on sleep regulation; and underlying temperament and regulatory mechanisms that are early prognosticators of both sleep and psychiatric disturbances. In general, nonpharmacologic treatments for the behavioral insomnias of childhood (ICSD-2) (20) are highly effective in young children (21); however, few studies have systematically evaluated the impact of these interventions on daytime behavior and mood. At present, there are only a few well-controlled studies assessing the efficacy of pharmacologic or behavioral interventions for sleep problems in school-age children and adolescents, and no studies documenting the efficacy of these interventions for comorbid sleep and psychiatric disorders. Because medications used to treat both sleep and psychiatric problems may produce significant changes in nighttime as well as daytime behavior, these data are critically needed. While a thorough discussion of the impact of different
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classes of psychotropic medications on sleep is beyond the scope of this chapter, we will point toward some of their effects. II.
Sleep and Anxiety Disorders
Children’s fears and anxiety are frequently associated with the presence of sleep disruption. Transient fears (e.g., monsters under the bed, the dark, a robbery) are considered to be developmentally appropriate and occur in a majority of children (22,23). Although such fears generally subside with age, inadvertent parental reinforcement of children’s nighttime fears may lead to more chronic sleep problems. The most effective treatments for these problems include extinction techniques (21) aimed at correcting maladaptive sleep-onset associations and setting appropriate limits at bedtime. However, severe nighttime fears and sleep problems that are persistent and/or impairing may be symptomatic of an underlying anxiety disorder. Anxiety disorders, consisting of physiologic (e.g., rapid heart beat, sweating), cognitive (e.g., catastrophizing thoughts and worry), and behavioral (i.e., avoidance) symptoms, occur in 12–20% of children (24,25). The most common anxiety disorders include separation anxiety (SAD), generalized anxiety (GAD), and social anxiety (SOC) disorders. Approximately 85% of children and adolescents with anxiety disorders experience intermittent sleep disturbances, while one half experience a persistent sleep problem (10,26). Although individual difficulties vary depending on the specific disorder and age of the child, some of the most common types of problems include insomnia, difficulty sleeping alone, recurrent nightmares, and parasomnias. In the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (27), sleep disturbance is included as a specific feature of several anxiety disorders, including SAD, GAD, and post-traumatic stress disorder (PTSD). For example, children with SAD commonly exhibit reluctance or refusal to sleep alone or away from home and report the presence of nightmares (26,28), while children with PTSD may exhibit nightmares, hyperarousal at bedtime, and parasomnias (e.g. enuresis and night terrors) (29). Among children with GAD, insomnia is most common (10). Approximately one half of children with GAD experience moderate to severe insomnia, a rate that is similar to that found among adults with GAD. Specific mechanisms underlying sleep disturbances and anxiety in children are yet to be examined, but likely involve the role of physiologic (e.g., autonomic arousal, muscle tension), cognitive (e.g., worry, rumination), and/or environmental factors (e.g., cosleeping, poor sleep hygiene). Despite extensive clinical reports of sleep disturbance among children with anxiety disorders, data based on the use of objective methods of assessment are lacking. An earlier study by Rapoport et al. (30) reported reduced sleep efficiency and increased sleep latency among nine adolescents (age, 13–17 years) with obsessive compulsive disorder (OCD) compared with matched healthy controls based on the use of polysomnography (PSG). Adolescents with OCD required
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twice as long as control adolescents to initiate sleep onset. In addition, two studies have examined sleep patterns among children with PTSD based on the use of wrist actigraphy. Glod et al. (31) and Sadeh et al. (32) found poorer sleep efficiency among children with PTSD who were exposed to physical abuse compared with those exposed to sexual abuse. Glod et al. also reported that children with PTSD, but not depression, exhibited more nocturnal activity, longer sleep-onset latencies, and reduced sleep efficiency compared with children with both PTSD and depression. Although the frequent presentation of sleep problems in children exposed to traumatic events may be attributed to increased levels of arousal and hypervigilance, it is also important to note that decreased sleep has been shown to result in increased levels of daytime anxiety in both anxious and nonanxious populations (13,33,34). From a clinical standpoint, a bidirectional relationship between sleep and anxiety suggests a potential worsening of both problems and associated impairments over time. Few studies have specifically examined the impact of treatment for childhood anxiety disorders on co-occurring sleep problems. Alfano et al. (26) reported that fluvoxamine produced significantly greater reductions in sleep problems among youth with anxiety disorders after eight weeks of treatment compared with placebo. However, more than 10% of youth reporting at least moderate levels of insomnia at pretreatment continued to experience insomnia at posttreatment, suggesting that in some cases, direct intervention may be necessary. Because other studies have reported sleep disturbance (most commonly insomnia) as a common side effect of treatment with selective serotonin reuptake inhibitors (SSRIs) (35), more research is ultimately needed to determine the impact of pharmacologic interventions for childhood anxiety on sleep. Available case reports have revealed significant reductions in anxiety and sleep problems following the use of behavioral treatments (28,36). In many cases, use of behavioral interventions may be more appropriate based on attention to familial and parenting factors within the home. In particular, because observational studies reveal anxiety-disordered parents and parents of anxious children to commonly exhibit ‘‘anxiety-promoting’’ parenting behaviors (37–39), these factors appear to be highly salient in understanding and treating anxious children’s sleep problems. Providing excessive reassurance, over-involvement in bedtime routines, and/or permitting cosleeping with parents or siblings as a means of reducing anxiety may serve to reinforce children’s fears and worries and may ultimately interfere with the development of necessary self-regulatory skills. Thus, identifying and eliminating parental reinforcement of children’s anxiety are important foci of treatment (21,40). In summary, insomnia and problems of sleep onset and maintenance commonly co-occur with symptoms of anxiety and anxiety disorders. The primacy of these problems can be difficult to disentangle, though probable underlying causes include the role of pathophysiologic factors, poor self-regulatory skills (based on temperamental characteristics) and parental reinforcement. Careful evaluation of these problems should include gathering information from multiple
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informants and assessing potential patterns of reinforcement within the home. Such assessment data are paramount to designing and choosing effective interventions. At present, interventions that have demonstrated efficacy primarily involve behavioral strategies, although other intervention techniques, including a focus on sleep hygiene training and positive routines, may also produce significant improvement in sleep problems among anxious children (40). III.
Sleep and Depression
Depressive disorders, which may include symptoms of anhedonia, hopelessness, malaise, and neurovegetative symptoms, are commonly associated with sleep disturbance both during childhood and adulthood. More than 90% of depressed children and adolescents report problems with sleep (8,9). The vast majority of depressed youth report symptoms of psychophysiologic insomnia, defined as difficulty initiating and/or maintaining sleep, and/or poor sleep quality that is associated with daytime impairment. Even in the absence of significant sleep problems, report of diurnal tiredness or fatigue may occur in depressed adolescents (9). These adolescents also may present with a circadian rhythm disorder, most commonly, delayed sleep phase syndrome, and in rare cases, advanced sleep phase syndrome (41). With the onset of puberty there is a tendency for a delay in circadian phase (42). When this biologically mediated delay is coupled with decreased motivation and school/social avoidance (common problems in affective disorders), the circadian phase delay may become entrenched and refractory to treatment. Over time, these adolescents may shift to increasingly more delayed sleep-wake schedules, resulting in greater impairments in academic and social functioning, as well as increased family conflict. In extreme cases, legal problems may arise based on truancy laws. Because fewer than six hours of sleep per night has been shown to result in significant increases in depressed mood among healthy adolescents (14), it may be difficult to differentiate depressive symptoms and daytime impairments associated with ongoing sleep disruption. Assessments should therefore incorporate several methods, various informants, and thorough evaluation of the persistence and severity of individual symptoms. Despite the presence of sleep-related complaints among depressed youths and robust findings of objective changes in sleep macro-architecture (i.e., sleep schedules, sleep-onset latency, and wake time after sleep onset) among depressed adults (43), several investigations have found no objective evidence of changes in sleep micro-architecutre (i.e., distribution and percentage of sleep stages) among adolescents with major depression (44,45). The basis for this difference is presently unclear. One possibility involves the fact that the sleep drive of children and adolescents is particularly high and may be protected as an epiphenomenon of neurophysiologic and physical development (19). As such measurable sleep changes
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associated with the presence of psychopathology may not emerge until late adolescence or early adulthood. However, Dahl et al. (46) have provided evidence that a more severe form of psychiatric illness may be a critical factor in the presentation and detection of sleep disturbance during childhood. A few studies using PSG have reported objective evidence of sleep differences among depressed teens compared with controls (47). Emslie et al. (48) reported the presence of reduced REM latencies and increased sleep-onset time among a sample of depressed youths. Following remission of their depressive symptoms, children had significantly shorter REM latencies and an increased number of REM periods as compared with when they were in a depressed state. In another study, Emslie et al. (49) reported that among children and adolescents who had recovered from an initial episode of major depression, those who exhibited delayed sleep onset greater than 10 minutes were significantly more likely to experience a recurrence of depressive symptoms within 12 months than those with shorter sleep-onset latencies. Findings reported by Emslie et al. are consistent with longitudinal data showing sleep disturbance to be a specific risk factor for the onset of depressive and anxiety disorders during both adolescence (50,51) and adulthood (5,52). Collectively, these data reveal sleep disturbance to be an important predictor in the early course of depressive illness, as well as the onset of other forms of psychopathology. In terms of assessment, it is important to note that although PSG may provide reliable data regarding sleep micro-architecture, it does not provide a reliable or valid measure of sleep macro-architecture. Home-based assessments of sleep (e.g., sleep diaries and actigraphy) provide more ecologically valid findings in this regard. Use of actigraphy has revealed the presence of poor sleep quality and abnormal circadian rhythms among depressed youth (53,54). While there also are reliable and valid parent and self-report questionnaires that assess sleep disturbances and depression in children and adolescents [e.g., CHSQ (55), PSQ (56), CDI, (57)], there are no studies demonstrating the convergent reliability of these measures. There are several reports of the impact of pharmacologic interventions for depressed youths on sleep. In one study where the effects of fluoxetine were examined in a small sample of depressed adolescents, findings revealed significant increases in stage 1 non-REM sleep, number of arousals, periodic limb movements, and oculomotor abnormalities (58). Also, based on self-report data, a majority of adolescents reported longer sleep latencies and rated their sleep on fluoxetine as being of poorer quality. SSRIs have been shown to induce similar sleep disturbances in adults with major depression (59,60). Although few studies have examined the impact of tricyclic antidepressants (TCAs) on sleep, REM sleep suppression, increases in stage 2 sleep, and decreases in stage 4 sleep have been reported among depressed adolescents treated with imipramine (61). The significance of these changes is not fully understood and more research in this area is needed.
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Similar to findings among anxious youths (26), at least 10% of depressed children and adolescents continue to experience sleep problems after their depressive symptoms have remitted (1). However, treatment outcome data are limited and long-term follow-up studies are needed. In some cases, treatment of sleep disturbance alone may have a positive impact on depression, while resolution of depressive symptoms may produce significant improvements in sleep in other patients. Adult studies have, nonetheless, highlighted the importance of treating both depressive symptoms and sleep disturbance simultaneously so as to achieve the best clinical outcomes and reduce the possibility of relapse. In this manner, cognitive behavioral therapies (CBT) that include strategies specifically targeting factors associated with both problems, (such as rumination and dysfunctional cognitions, decreased daytime activity, and poor sleep hygiene) have been shown to be particularly efficacious for insomnia with comorbid depression (see Ref. 62 for a review). CBT has also been shown to produce superior improvement in sleep compared with pharmacologic interventions (63). However, treatment outcome data are limited to adult populations. Mindfulness techniques that include relaxation, deep breathing, guided imagery, and progressive muscle relaxation also may help improve sleep disturbances, though studies demonstrating the efficacy of these techniques for comorbid sleep and depressive disorders in children or adults are needed. IV.
Sleep and ADHD
ADHD and its subtypes (inattentive, hyperactive, and combined types) usually present during childhood and are disorders with hallmark features of overactive behavior, sustained inability to maintain attention, attend to relevant stimuli, and control impulses (27). Prevalence rates for ADHD are 2–17% among children (64), making it the most common psychiatric disorder. It also is well established that ADHD causes significant impairment in academic, occupational, social, and interpersonal functioning. The most widely studied interventions for ADHD are psychostimulants, which most commonly include various preparations of methylphenidate. Behavioral treatments also have been shown to be efficacious among children with ADHD, particularly for children with other comorbid psychiatric disorders (65). Sleep disturbance was included in the definition of ADHD in the DSM-II and DSM-III, but was removed in the most current edition of the DSM (27) on the basis of concerns that it represented a nonspecific symptom of the disorder. Recent reports suggest that sleep problems occur in at least 50% of children with ADHD (11) and typically involve difficulty initiating and/or maintaining sleep. The causes of sleep-onset difficulties are, nonetheless, complex and multifactorial. For example, a subgroup of children with ADHD appears to experience difficulty regulating their behavior 24 hours a day (3,11,66). For this group, difficulty settling, engaging in a regular bedtime routine, and gradually decreasing vigilance
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at bedtime may be as challenging as regulating daytime behavior. This pattern of difficulty settling also may be complicated by parent-child interactions at bedtime including problems related to limit setting, inadequate bedtime routines, conflict, and frustration; all of which contribute to increased arousal and delayed sleep onset. ADHD also is commonly comorbid with both depressive and anxiety disorders (67). This subgroup of children with multiple psychiatric problems may exhibit similar sleep problems to those observed among children with affective disorders (68), and commonly include difficulty decreasing nighttime arousal and worry. Similar to findings among depressed youths, several studies have failed to find consistent evidence changes in the micro-architecture of sleep among children with ADHD compared with controls on the basis of polysomnographic evaluation (69,70). Actigraphy has produced similarly inconsistent findings in terms of differences in sleep-onset latency, nighttime awakenings, and sleep efficiency (71,72). However, findings based on the use of both actigraphy and inhome videography do suggest increased activity, including both the frequency and duration of movements, to be a distinctive feature of sleep among children with ADHD (73). Moreover, several investigations have found greater night-to-night variability in the sleep patterns of ADHD children (74,66). These authors hypothesize that inconsistent sleep patterns among children with ADHD reflect more global impairments in arousal regulation. Another potential cause of sleep problems in ADHD is the lingering effect of stimulant medications. For example, in a head-to-head comparison of methylphenidate and Strattera (75), the former was associated with sleep-onset problems, while the latter was associated with a slight increase in disrupted nocturnal sleep. In general, findings regarding the effects of stimulants on sleep in individuals with ADHD have been quite mixed (76). There are anecdotal reports that sleep may be improved for some children on the basis of a late afternoon dose of a psychostimulant. It is also a common practice to add a bedtime dose of an a agonist (e.g., clonodine) that causes somnolence and helps to decrease arousal. However, research has not consistently examined ADHD subtypes or adequately differentiated types of sleep disturbances and sleep-related behaviors. Careful observation of pharmacologic interventions for ADHD is required to assure that treatment with a stimulant does not interfere with sleep, and conversely, to determine whether a longer acting stimulant may promote more regulated behavior that is conducive to a smooth wake-to-sleep transition. Nonpharmacologic approaches to treating ADHD are well established, but at present there are no published reports of controlled studies examining concurrent changes in sleep. In a case report by Dahl et al. (77) involving a 10-yearold child diagnosed with ADHD, symptoms of ADHD remitted following a standard set of behavioral interventions for limit-setting sleep disorder (78). As with other interventions for sleep problems, approaches to improving sleep in ADHD children may involve establishing regular routines and sleep-wake schedules, identifying parent-child interactions that result in the reinforcement of delayed sleep onset and other undesirable behaviors, practicing relaxation skills
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that can be implemented at bedtime, using rewards or tokens as a means of reinforcing positive sleep hygiene practices, and, finally, limiting exposure to electronic media. It also is particularly important to consider the extent to which the phenotypic expression of ADHD and sleep disorders is comparable. In two separate studies (79,80) unmedicated children with ADHD had significantly shorter sleep-onset latencies on multiple sleep latency tests, suggesting an underlying problem with diurnal arousal or increased sleep propensity. This supports Weinberg’s (81) hypothesis that some psychiatric disorders should be defined as disorders of arousal. However, chronic sleep disruption or inadequate sleep also may lead to patterns of behavior that mimic ADHD symptoms. For example, based on the presence of a physiologically based sleep-related breathing problem (e.g., obstructive sleep apnea syndrome), or a movement disorder [e.g., restless legs syndrome (RLS) and periodic limb movement disorder (PLMD)], a child may appear inattentive and hyperactive and respond well to stimulants. Ruling out the presence of a sleep disorder prior to diagnosing and treating ADHD should be a high priority. Recent evidence provided by several investigators (82–85) has suggested a link between ADHD and RLS/PLMD (see Chap. 13, for more information). Decreased dopamine may account for at least some symptoms of both of these disorders (86,87). As evidence of the role of dopamine, Walters et al. (88) treated children aged 8 to 13 years diagnosed with comorbid ADHD and PLMD with a dopamine agonist and found modest improvement in symptoms of both disorders. Dopamine agonists may prove to be a promising treatment for comorbid ADHD and PLMD, but safety and efficacy studies are needed before this approach can be recommended. One additional link implicating dopamine involves serum ferretin (89). Ferretin plays a critical role in the cellular synthesis of dopamine and preliminary evidence points toward the improvement of RLS/PLMD symptoms and some improvement in behavior with iron supplementation. When serum ferretin levels fall below 50 mg/mL, supplementation with ferrous gluconate or ferrous sulfate (3–6 mg/kg of elemental iron) may be appropriate (90). While the risk of gastrointestinal side effects and iron overdose are relatively low, the efficacy of this approach also requires further investigation in children. V.
Sleep and Developmental Disorders
Sleep problems are quite common among children with pervasive developmental disorders (e.g., autism spectrum and Asperger’s disorder) as well as other syndromes associated with cognitive deficits and developmental disorders (Down syndrome, Prader-Willi) (91–94). As is the case with ADHD and affective disorders, the causes of sleep disturbances in these children are multifactorial. For all children, the transition from wake to sleep requires learning a routine and
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developing self-regulatory skills that promote the letting down of vigilance—a prerequisite to making an independent transition from wake to sleep. Children with developmental disorders may have more difficulty learning these behavioral sequences because of specific or global cognitive deficits, as well as deficits in the ability to read and/or respond to social cues. In contrast, for normally developing children, close proximity to parents and other social cues (e.g., a transitional object) often facilitate a smooth wake-to-sleep transition at bedtime and in middle of the night. Thus, in addition to bedtime problems, children with developmental disorders also commonly awaken during the night and have trouble making the transition back to sleep (92–95). Extended periods of unsupervised wakefulness can be dangerous for a child and therefore place a significant burden on family members to stay awake with the child and assure their safety or implement precautionary measures. Assessment of sleep problems among developmentally delayed children also should include consideration of children’s level of anxiety, which may present differently than in normally developing children. For example, because children with developmental delays may experience greater difficulty understanding and expressing specific nighttime fears, behaviors such as temper tantrums, avoidance, and irritability may be observed. Finally, craniofacial characteristics and body habitus of some children with developmental delays should be considered, as these may place the child at increased risk of sleeprelated breathing disorders (96–98). Treatment approaches for sleep problems in children with developmental disorders do not differ significantly from those other children, although the duration and pace of treatment may vary considerably on the basis of the specific characteristics of the child. Positive routines (99,100) and sequencing of behaviors should be modified so as to match individual levels of development, cognitive function, and specific deficits. For example, children with pervasive developmental disorders may require greater amounts of demonstration and reinforcement of bedtime routines before consistent changes in sleep patterns are observed. These children may respond better to visual rather than verbal cues. For children with more profound cognitive delays, concrete, immediate, and frequent reinforcement may be most effective in establishing a consistent nighttime routine (101–103). Finally, as with normally developing children, extinction and graduated extinction techniques are particularly effective in establish appropriate sleep-wake habits (21) and the specific aspects of these programs should be tailored for each child. VI.
Case Discussion
This section contains two case examples that specifically highlight some of the complex issues and problems reported by children (and their parents) presenting with both sleep problems and psychiatric disorders or behavior problems. These
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vignettes are intended to provide clinicians with an introduction to relevant clinical issues, as well as assessment and treatment approaches. A.
Case 1
Susan is an 11-year-old female who is in the sixth grade. She has a history of difficulty initiating and maintaining sleep and excessive daytime tiredness. Susan’s bedtime is at 9:30 PM, although she lies in bed for between 60 and 90 minutes prior to sleep onset on four or more nights per week. Between bedtime and sleep onset, Susan lies in bed staring at the ceiling, checking the clock, and feeling like her mind is racing. During this time she reports being worried about a variety of topics that might include not feeling rested the next day, performing poorly on tests, her parents’ health, and someone breaking into the house. Susan lives in an old house that she reports is ‘‘full of creaking and groaning sounds.’’ These noises make her heart race because they sound as if ‘‘someone is breaking in.’’ She awakens at least once every night at approximately 4 AM, and while she usually falls back asleep within 10 minutes, at least twice per month she lies awake for several hours. Susan finds it easiest to get back to sleep when she turns on the clock radio that is next to her bed because the music drowns out other noises in the house and helps her relax. However, she and her parents argue about whether or not she should be allowed to turn on the radio in the middle of the night. Susan’s parents are concerned because her grades have recently dropped. She was an honors student during the prior year. Susan has missed 12 school days this term because of difficulty waking in the morning. This is also a great cause for worry as Susan believes that she will be unable to make up the work she has missed. Assessment procedures within a sleep speciality clinic included: (i) a clinical interview with Susan and her parents, involving assessment of sleep behaviors, current stressors, overall functioning, psychiatric symptoms, medical history, development and academic history; (ii) completion of several child-parent report questionnaires [e.g., the Children’s Depression Inventory (57), the Screen for Childhood Anxiety Related Emotional Disorders (104) parent report sleep questionnaire (55,56,105), Child Behavior Checklist (106)]; and (iii) completion of a daily sleep log during a two-week period prior to the clinical assessment. Evaluation procedures led to a diagnosis of psychophysiologic insomnia, including difficulty both initiating and maintaining sleep related to somatized tension, worry, and conditioned arousal at night. A behavioral intervention protocol was implemented targeting Susan’s unique sleep problems. First, principles of sleep hygiene were reviewed with the family, including use of stimulus control techniques (e.g., removing the clock from Susan’s bedroom, getting out of bed if unable to initiate sleep 30 minutes after getting into bed, or waking during the night) and sleep-promoting behaviors (e.g., reducing intake of caffeinated foods and beverages, engaging in calm, quiet activities prior to bedtime, such as reading or listening to soft music). A temporarily delayed bedtime of 10:30 PM was set in
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order to increase Susan’s natural sleep drive and reduce frustration and anxiety surrounding bedtime. She also was prohibited from ‘‘sleeping in’’ on weekends or taking long afternoon naps in order to help regulate her sleep schedule. In addition, Susan was instructed to set aside 15 to 20 minutes each afternoon for writing down her specific fears and worries in a journal. She also was taught to challenge and problem solve these worries, including examining the evidence for her fears, considering realistic worst-possible outcomes, and weighing the likelihood of feared outcomes (107). Finally, progressive muscle relaxation (108) was demonstrated and practiced over the course of several sessions to help Susan focus on relaxing her body instead of her thoughts at bedtime. Treatment progress was assessed on the basis of a daily sleep log and child and parent report of daytime and nighttime behavior. Although Susan’s sleep problems were significantly reduced within three weeks of beginning treatment (including a more regular sleep-wake schedule, and a reduction in sleep-onset latency and nighttime worries), she continued to experience daytime worries and somatic tension. Susan was, therefore, referred to a clinical psychologist for further evaluation and treatment of her anxiety. The psychologist diagnosed Susan with GAD and used CBT to help her face and cope with her general fears and worries, and to reduce somatic symptoms. Initially, both clinicians worked together to coordinate Susan’s treatment and ensure consistency across settings (i.e., in the use of daytime and nighttime cognitive and relaxation techniques). Both clinicians also supported the family in working with the school to implement a specific plan for helping Susan to make up the work she previously missed during absences from school. B.
Case 2
Jessie is a 5.5-year-old boy diagnosed with pervasive developmental disorder-not otherwise specified (PDD-NOS). He presented to a sleep disorders clinic with parental complaints of multiple and extended nighttime awakenings. At three years of age, Jessie was diagnosed with PDD and probable autism (including significant delays in verbal and social skills and mild mental retardation). His vocabulary was developing, but at a delayed pace, and at four years he began speaking simple sentences. Fine and gross motor delays were observed as early as six to eight months of age. Jesse also had a history of mild gastroesophageal reflux disease (GERD), but was otherwise healthy. Jessie’s parents had established a regular and appropriate nighttime routine and bedtime. He was put to bed at 6:30 PM and fell asleep independently in his own bed within 15 minutes. On some evenings however, Jesse indicated that he wanted to go to bed even earlier. Jessie had at least one awaking every night between 3 AM and 5 AM. If he awakened before 4:30 AM, his parents would sometimes succeed in getting him back to bed. When he awakened during the night, Jesse would either go to his parents’ room and wake them, wander around the house, or play quietly in his
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own room. He never tried to leave the house nor was injured during his early morning wanderings. His parents stated that they were exhausted and that Jesse’s sleep schedule had begun to take a significant toll on their work. They also indicated that on days when Jesse did not fall back to sleep, he was irritable and out of sorts. They tried later bedtimes, an over the counter antihistamine, and closing his bedroom door, but none of these interventions resulted in improvement. Prior to the assessment, Jesse’s parents completed a two week sleep log, a children’s sleep questionnaire, and the Child Behavior Checklist (106). Jessie was diagnosed with a behavioral insomnia of childhood (limit-setting sleep disorder) and a mild circadian rhythm disorder (advanced sleep phase syndrome). His sleep problem was attributed to a learned early morning awakening, a failure to identify his early awakenings as atypical and socially unacceptable (e.g., everyone in the house was asleep except for Jesse), and intermittent parental reinforcement during early morning awakenings. An advance in sleep phase is not unusual in young children of Jesse’s age. The treatment approach consisted of a multicomponent intervention to address the circadian and behavioral components of his sleep disorder. Intervention targeting the circadian phase advance included: (i) increased exposure to bright light during one hour prior to bedtime, (ii) an incremental, 10-minute delay in his bedtime (with a target bedtime of 7:30 AM) to be gradually implemented over the course of a week and then maintained for one month, (iii) blackout shades in his bedroom, and (iv) a 30-minute late afternoon (2–4 PM) rest period. Interventions targeting the behavioral insomnia of childhood included: (i) repeated rehearsal and reminders during the daytime and at bedtime that Jesse is to stay in his bedroom until his parents wake him in the morning, (ii) a series of pictures hung in his bedroom that depict a sequence of behaviors associated with bedtime so that if he wants to leave his bedroom he is required to take his ‘‘wake-up picture’’ to his parents, (iii) gradually fading the extent of parental interactions with Jesse during the night (e.g., days 1–3, take Jesse back to his bed and tell him to get into bed and lie quietly; days 4–6, tell Jesse to return to bed and then check on him after he has returned; days 7–14, tell Jesse to return to bed, close his bedroom door if he is not compliant, and check on him periodically), (iv) maintain a sleep log documenting his early morning awakenings, and (v) provide positive verbal reinforcement of Jesse’s progress in the morning and at bedtime. Sleep logs completed by Jesse’s parents provided evidence of gradual improvement in the frequency and duration of early morning awakenings. At six weeks follow-up Jesse had two early morning awakenings during which he went to his parents’ room and was taken back to his own room by his mother before falling back asleep. There was little change in his morning wake-up time, which ranged from 6 AM to 6:30 AM. His parents and teacher reported improvement in his daytime behavior, including less irritability and more responsiveness to their prompts and directives. Importantly, Jesse’s parents also reported feeling more rested.
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Summary and Conclusions
There is compelling evidence for links between the regulation of behavior, emotion, attention, and sleep. The reciprocal effects of these relationships are complex in that psychiatric problems may exacerbate sleep problems, the effects of insufficient sleep may diminish regulation of attention, affect, and behavior and these problems my continue in cyclical fashion for extended periods of time. Links between sleep and psychiatric disorders also may be related to shared underlying regulatory mechanisms, neurotransmitters, and neurohormones. Sleep and psychiatric disorders may indeed share pathophysiologic mechanisms, and the early presentation of problems in either domain may be an early marker for problems in the other. In some cases sleep disorders may cause psychiatric symptoms, and, for clinicians with less experience in evaluating sleep disturbances, the potential exists that the underlying cause of such problems may be overlooked. In other cases, the presence of psychopathology may result in chronic difficulty initiating and maintaining sleep, a problem that may persist despite adequate treatment of the psychiatric illness. Additionally, potential iatrogenic effects must be considered for all children, and it is particularly important that the effects of medication on sleep be monitored based on the use of state-of-the-art techniques and measures (i.e., PSG, actigraphy, sleep diaries, and sleep questionnaires). In sum, there are many efficacious treatment approaches for comorbid sleep and psychiatric disorders, though controlled studies of interventions for childhood sleep problems are only beginning to emerge. The majority of nonpharmacologic interventions for both sleep and psychiatric disorders involve behavioral and cognitive-behavioral techniques, which have been shown to be efficacious (21,109,110). There are several approved and efficacious pharmacologic approaches to treating child and adolescent psychiatric disorders, currently however, no approved pharmacologic interventions for sleep problems exist. In addition to behavioral sleep problems, sleep-disordered breathing, sleep-related movement disorders, and more rarely, narcolepsy, are associated with daytime behavioral disturbances as well, and should be treated aggressively. However, thorough assessment of both nighttime and daytime behaviors is required prior to implementing any particular treatment approach. Assessment that includes multiple informants and methods for evaluating sleep-related problems and psychiatric symptoms can provide substantial guidance in this regard. References 1. Puig-Antich J, Goetz R, Hanlon C, et al. Sleep architecture and REM sleep measures in prepubertal major depressives: studies during recovery from the depressive episode in a drug-free state. Arch Gen Psychiatry 1983; 40(2):187–192. 2. Puig-Antich J. Sleep and neuroendocrine correlates of affective illness in childhood and adolescence. J Adolesc Health Care 1987; 8(6):505–529.
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13 Restless Legs Syndrome and Periodic Limb Movements in Sleep in Children
ARTHUR S. WALTERS New Jersey Neuroscience Institute, Seton Hall University School of Graduate Medical Education, Edison, New Jersey, U.S.A.
I.
Introduction
The restless legs syndrome (RLS) was probably described over 300 years ago by Willis (1). Descriptions were then sporadic until the 1940s when Ekbom described all of the primary and secondary features of RLS minus periodic limb movements in sleep (PLMS), which were subsequently described by Lugaresi et al. when polysomnography became available in the mid-1960s (2,3). Subsequent descriptions of RLS through various versions of the International Classification of Sleep Disorders (4,5) and the International Restless Legs Syndrome Study Group (IRLSSG) (6,7) were attempts to discriminate essential from nonessential diagnostic features. The first full case reports of RLS appeared in 1994 (8). Two pedigrees with clinically significantly affected children and adolescents were reported, and RLS appeared to be inherited in an autosomal dominant fashion. In pedigree 1, two boys and a girl were reported of ages 6.5 years, 4 years, and 1.5 years (Fig. 1). In pedigree 2, an adolescent girl aged 16 years was reported. Kotagal and Silber (9) later reported 32 children with definite or probable RLS. Sleep-onset or
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Figure 1 A pedigree compatible with an autosomal dominant mode of inheritance in familial restless legs syndrome. Males are designated by squares and females by circles. Filled-in squares or boxes indicate that the individual is affected. And non-filled-in squares indicated that the individual is not affected. Abbreviation: RLS, restless legs syndrome.
maintenance insomnia was present in 87.5% of the children and a family history of RLS was present in 73%. The first full cases of PLMS in children were reported in 1999 (10). PLMS can sometimes be in the severe range in children. In this series, 16 of 129 children with PLMS index of >5/hr of sleep had PLMS index of >25/hr of sleep. All these 16 children had sleep disturbance and 7 of 16 had daytime somnolence that resolved with dopaminergic medications. II.
Epidemiology of Adult and Childhood RLS
As a whole, the large individual epidemiologic studies involving at least 15,000 subjects each indicate that RLS exists in 10–15% of adults in Western civilizations, but that in 2.5% it occurs at least two days/wk and seriously impacts the quality of life. Thus, 2.5% represents the real patient population (11,12). It has recently been observed that RLS may occur in children. A retrospective recall of RLS symptoms by adults in two separate series found that 12–20% recalled symptom onset below the age of 10 years and 38.3–45%, below the age of 20 years (13,14). In a survey of 10,523 children, it was found that RLS occurs at least twice per week and significantly impacted quality of life in 0.5% of children and 1% of adolescents (15). A recent study suggested that the prevalence of childhood RLS was 1.3% in 1084 unselected children in pediatric practices (16). In a study of 538 subjects in a sleep disorder center, 32 subjects (5.9%) received a diagnosis of
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RLS. Twenty-three (4.2%) of these subjects were found to have definite RLS and 9 (1.7%) were found to have probable RLS by the aforementioned NIH consensus criteria (9). Another study found consistent leg restlessness in 6.1% of 1353 children aged 11 to 13 years over a 3-year period (17). III.
Essential Clinical Features of Adult RLS
The essential criteria for the diagnosis of adult RLS are accepted by both the IRLSSG (7) and ICSD (5). In adults, the RLS consists of four obligatory features as follows: 1. An urge to move the legs, which is usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. 2. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying or sitting. 3. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues. 4. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. All four of the essential features are necessary to make the diagnosis. There are sometimes some subtleties in making this diagnosis. For example, if a patient has severe RLS, there may not be relief by activity that is acknowledged by the patient, but if relief by activity is acknowledged by the patient to have been present at an earlier time during the clinical course, criterion 3 is fulfilled. Similar concerns apply to the worsening of symptoms at night, i.e., if a patient has severe RLS, symptoms may be equally bad day and night, but if the patient acknowledges that the symptoms were worse later in the day or in the evening at an earlier time during the clinical course, criterion 4 is fulfilled. In addition, some patients will say that they get no relief by activity, but what they actually mean is that the minute they sit or lie down again that the symptoms come right back. One must then rephrase the question to ask whether the patient gets at least partial and temporary relief while they are actually moving. If such is the case, the appropriate response is often obtained. IV.
Nonessential Features of Adult Restless Legs Syndrome
The IRLSSG also developed a list of things that are frequently seen in RLS, but are not essential for the diagnosis as outlined in Tables 1 and 2. One of these features needs special emphasis.
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Table 1 Nonessential Clinical Features of Restless Legs Syndrome: Supportive Clinical Features . Positive family history of RLS Usually compatible with an autosomal dominant mode of inheritance. Several chromosomes have been isolated in RLS families but no genes to datea Improvement with dopaminergic therapy PLMS PLMW In RLS they can be elicited by having the patient lie perfectly still (suggested immobilization test). As with other RLS symptoms, they disappear with movement. In about 15% of RLS patients they are very prominent and cause insomniab a
Refer Figure 1. Ref. 86. Abbreviations: PLMS, periodic limb movements in sleep; PLMW, periodic limb movements in wakefulness; RLS, restless legs syndrome. b
Table 2 Nonessential Clinical Features of Restless Legs Syndrome: Associated Clinical Features Sleep disturbance Neurological examination Normal in idiopathic or familial cases. Evidence of peripheral neuropathy or radiculopathy in ‘‘secondary cases’’a Serum ferritin <50 mg/L (ferritin is an iron binding protein and indicative of iron deficiency) Clinical course Most adult patients middle to older age, but may be seen at any age Usually progressive, but static course may be seen. Remissions of a month or more may be seen in 15% of cases a
Ref. 87.
A.
Periodic Limb Movements in Sleep
To be classified as PLMS, there must be at least four movements in a row—25% as high as the electromyography (EMG) calibration signal, 0.5 to 5 seconds in duration and 5 to 90 seconds apart as determined by polysomnography. PLMS are seen in 80% of adult RLS patients and may commonly be seen without RLS as an incidental finding on polysomnography. When PLMS are present without RLS they are usually not disruptive to the sleep of the patient, but are often disruptive to the sleep of the bed partner. If PLMS in the absence of RLS are accompanied by sleep disruption that can definitely be attributed to the PLMS, the diagnosis of periodic limb movement disorder is made (4,5,18). PLMS are illustrated in Figure 2.
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Figure 2 PLMS are demonstrated. To be classified as PLMS there must be at least four movements in a row—25% as high as the EMG calibration signal, 0.5 to 5 seconds in duration and 5 to 90 seconds apart as determined by polysomnography. Abbreviations: PLMS, periodic limb movements in sleep; EMG, electromyography.
V.
Essential Clinical Criteria for Childhood RLS
Clinical criteria for childhood RLS have been recently developed. To be diagnosed as having definite RLS, children must have all four of the essential adult criteria for RLS and either 1. be able to describe the leg sensations in their own words, or 2. if unable to describe the leg sensations in their own words, they must still meet all four adult criteria for RLS, and must meet two of the three following criteria: i. sleep disturbance for age, ii. a PLMS index of >5/hr sleep, and iii. a first-degree relative (parent or sibling) with definite RLS. Note that the adult RLS criteria do not require that actual leg sensations be described, but only that the patient have an urge to move the legs. The childhood criteria require that the child be able to describe the leg sensations in his or her own words. The IRLSSG has also proposed criteria for probable and possible Childhood RLS (7) as outlined in Tables 3 and 4. The probable and possible categories are intended for young children or cognitively impaired children who do not have sufficient language to describe the sensory component of RLS.
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Table 3 Clinical Criteria for Probable Childhood Restless Legs Syndrome. 1. The child meets all essential adult criteria for RLS, except criterion 4 (the urge to move or sensations are worse in the evening or at night than during the day) AND 2. The child has a biologic parent or sibling with definite RLS OR 1. The child is observed to have behavior manifestations of lower-extremity discomfort when sitting or lying; accompanied by motor movement of the affected limbs, the discomfort has characteristics of adult criteria 2, 3, and 4 (i.e., is worse during rest and inactivity, relieved by movement, and worse during the evening and at night) AND 2. The child has a biologic parent or sibling with definite RLS Abbreviation: RLS, restless legs syndrome.
Table 4 Clinical Criteria for Possible Childhood Restless Legs Syndrome. 1. The child has periodic limb movement disorder AND 2. The child has a biologic parent or sibling with definite RLS, but the child does not meet definite or probable childhood RLS definitions Abbreviation: RLS, restless legs syndrome.
VI. A.
Pathophysiology Iron
The strongest pathophysiological evidence suggests that iron deficiency exists in RLS patients. The fact that RLS patients respond to iron therapy implies that this iron deficiency is also causal to symptomatology. Ferritin is an ironbinding protein and a low ferritin level is one of the most sensitive indicators of iron deficiency. Serum and cerebrospinal fluid (CSF) ferritin levels are low in RLS patients (19). Iron is low in the substantia nigra in RLS patients’ magnetic resonance imaging (MRI), and the MRI iron values of this area correlate inversely with RLS severity (20). In addition, intracellular iron is low in the substantia nigra in both primary and secondary RLS patients at autopsy (21). The relationship between iron deficiency and RLS has also been explored in children (22). Although the studies are more limited in children, the evidence suggests that relative iron deficiency with levels of serum ferritin lower than 35 to 50 mg/L may exacerbate the symptoms of RLS/PLMS in children and that RLS/ PLMS in children may be responsive to iron therapy (9,22–24). In Kryger’s study, three teenagers with low serum ferritin levels and RLS showed improvement in
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RLS and PLMS with iron therapy (22). In Simakajornboon’s prospective study, 39 children with an average age of 7.5 years, who had a PLMS index of >5/hr of sleep, were researched (24). Low serum iron levels were significantly correlated with a higher PLMS index, and iron therapy over three months resulted in a reduction of the PLMS index from 27.6/hr to 12.6/hr ( p < 0.001). In Kotagal and Silber’s study, serum ferritin levels were measured in 24 of 32 RLS subjects, which were below 50 mg/L in 20 of 24 subjects (83%) (9). All of this suggests that low iron is pathogenetic to RLS and PLMS in children also.
B.
Dopamine
The very powerful therapeutic effect of dopaminergic agents on the symptoms of RLS and PLMS suggests hypofunction of the endogenous dopaminergic system in RLS and PLMS (25–30) This therapeutic effect has also been explored in children, but to a much more limited extent (see section below). It is interesting that iron serves as a cofactor in the conversion of L-dopa to dopamine via tyrosine hydroxylase. Thus, one possibility is that there is an accompanying hypofunction of the endogenous dopamine system in RLS patients that is secondary to the iron deficiency. This hypothesis is further strengthened by the strong improvement in RLS symptoms by dopaminergic therapy. However, basic scientific evidence suggests that dopaminergic hypofunction, although present, is rather minimal. This evidence comes from rather extensive studies of autopsy material, CSF, and also from positron emission tomographic (PET) scan studies (21,31–34). All of these suggest that although dopaminergic hypofunction is present in RLS, it is not the primary cause of RLS. C.
Other Less Well-Explored Hypotheses
These include hypofunction of the endogenous opioid system (35,36) and autonomic dysfunction (37). VII.
Relationship of Childhood RLS to Growing Pains
RLS can be misdiagnosed as ‘‘growing pains.’’ In a retrospective review of the literature on growing pains where symptoms of RLS were not considered, many of the reported children had all four of the essential features for the diagnosis of RLS and a nonpainful form of RLS was even reported in this case series (38). In a retrospective study of adults with RLS, some of these adults reported being diagnosed with growing pains in childhood, but the childhood growing pains persisted unabated and became adult RLS. In the vast majority of cases, symptoms are mild in childhood and medical attention is not usually sought, but
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in this series, where some children did seek medical attention, growing pains was a frequent misdiagnosis (13). Rajaram et al. described 10 children diagnosed with growing pains who met clinical criteria for RLS (39). One parent in four of eight available families of these children had RLS, suggesting that some of these cases of childhood growing pains were likely to persist into adulthood, and not disappear. In a much earlier study of the relationship of growing pains to RLS, Ekbom, on the basis of limited evidence, suggested that RLS may not be the same thing as growing pains because the retrospectively recalled symptoms of growing pains experienced as a child had a different characteristic than the RLS discomfort felt as an adult (40). However, Brenning, a contemporary of Ekbom, studied 257 children aged 6 to 7 years and 419 children aged 10 to 11 years and their respective parents. In these children, he determined the prevalence of growing pains and ‘‘RLS-like’’ symptoms (41). He found that adults with RLS-like symptoms were much more likely to have experienced growing pains as children than adults without RLS-like symptoms (39.7% vs. 12%). He also discovered that the parents of children with growing pains were much more likely to have experienced growing pains as children than the parents of children without growing pains (51% vs. 12.5%). His third discovery was that the parents of children with growing pains were much more likely to have RLS-like symptoms than the parents of children without growing pains (47% vs. 19.7%). The essence of Brenning’s studies, thus, was that growing pains and RLS may be the same in at least a subpopulation of patients because of a common inheritance pattern. One of the weaknesses of the study, however, was that it did not use our modern definition of RLS, and disorders other than RLS may have been included in the analysis. VIII.
Relationship of Childhood RLS to ADHD
Much recent literature has focused on the possible relationship between RLS, PLMS, or both and attention-deficit/hyperactivity disorder (ADHD). The initial interest in this area came about as a result of studies establishing a possible link between ADHD and other sleep disorders, such as sleep apnea and narcolepsy, the theory being that sleep disruption leads to symptoms of ADHD (42–46). Although there are some contradictions in the literature (47), the overall body of evidence from this literature suggests that RLS and PLMS, either separately or together, occur more frequently in ADHD and vice versa. A video analysis of patients with ADHD revealed that they move around much more in sleep compared with controls (48). In two different series, between 26% and 64% of children with ADHD had a PLMS index of >5/hr of sleep (49,50). In the first of these series where 69 ADHD patients were studied, 8 of 18 children with ADHD and a PLMS index of >5/hr of sleep had both a personal and parental history of RLS (44.4%) (49). In the second of these series, 8 of 25 parents of the children
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with ADHD (32%) had symptoms of RLS as opposed to none of the control parents (50). In that same study, six of the nine children who had both ADHD and a PLMS index of >5/hr of sleep had a parent with RLS (67%) (50). These data suggest a possible genetic link between RLS/PLMS and ADHD. In a recent survey, 44% of ADHD children with a mean age of 9.2 years met criteria for RLS (51). In a large community-based cross-sectional survey of 866 children, symptoms of ADHD, as measured by objective indices, were almost twice as likely to occur with symptoms of RLS than would be expected by chance alone (45). There was a high hyperactivity index in 18% of children with RLS and 11% of children without RLS. The odds ratio between a high hyperactivity index and other parameters was 1.6 for PLMS, 1.9 for RLS, and 1.9 for growing pains. Results were similar for inattention. In the aforementioned study by Kotagal and Silber 8 of 32 or 25% of patients with childhood RLS demonstrated inattentiveness (9). Martinez and Guilleminault showed that 7 out of 11 prepubertal children with ADHD had PLMS (52). Golan et al. showed that 5 of 34 ADHD patients (15%) but none of the 32 controls had PLMS (53). Snoring and obstructive sleep apnea are also highly associated with ADHD (54,55). In a separate study in 113 children with ADHD, obstructive sleep apnea, and PLMS, it was the PLMS that had closer association with ADHD, and the obstructive sleep apnea seemed to act only as an effect modifier of this association as shown in Figure 3 (56). Not only do children with ADHD have more PLMS, but children with PLMS also have more ADHD. Approximately 44% of children with PLMS have been found to have symptoms of ADHD (57). The reverse prevalence also seems to hold for RLS, and the link between RLS and ADHD may persist into adulthood. In one study, 26% of adults with RLS had symptoms suggestive of ADHD as opposed to only 5% of normal controls and 6% of insomnia controls (58). Interestingly, a preliminary study showed that dopaminergic drugs caused an improvement not only in RLS/PLMS but also in ADHD in children who had both disorders (59).
Figure 3 Increasing severity of PLMS and sleep apnea may correlate with increasing severity of ADHD. PLMS may have a more direct effect on ADHD with sleep apnea playing a modifying role in this interaction. Abbreviations: PLMS, periodic limb movements in sleep; ADHD, attention deficit hyperactivity disorder; RLS, restless legs syndrome.
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Other behavioral problems, such as conduct disorder, also seem to be highly associated with RLS/PLMS (60). Another interesting observation spurred by the RLS/PLMS and ADHD connection is the subsequent observation that ADHD may also be characterized by iron deficiency (51,61). Konofal’s first study showed that low serum ferritin levels correlated with ADHD severity in 43 children with ADHD, 44% of whom met criteria for RLS (51). Iron has also proven to be effective in the treatment of ADHD in children without RLS in a yet unpublished double-blind study (Konofal, personal communication). The following are theoretical, causal relationships that may exist between RLS/PLMS and ADHD: 1. Children with RLS/PLMS have leg discomfort at their school desks. They, therefore, cannot pay attention and must get up to walk around. This has been reported in some of our childhood RLS patients (8,59). 2. The chronic sleep disruption from RLS/PLMS leads to symptoms of ADHD. Precedent—ADHD is also associated with i. Sleep apnea (54,55): RX of apnea may improve behavior. ii. Narcolepsy (46): RX of narcolepsy may improve behavior. 3. ADHD and RLS/PLMS may share a common dopaminergic deficit. i. Ritalin, which helps ADHD, promotes dopamine (62). ii. L-Dopa responsiveness of ADHD and RLS/PLMS (59). iii. ADHD shows genetic association to the dopamine receptor transport system and there is a variation in dopamine receptor subtypes (63,64). iv. PET scan studies in both ADHD and RLS/PLMS show dopaminergic abnormalities (33,65,66). 4. ADHD and RLS/PLMS both run in families and may share genetic linkage (67–70). 5. Children with ADHD move around more in wakefulness. In sleep they show more aperiodic movements in addition to the PLMS; perhaps the PLMS are coincidental. IX.
Treatment Options
Only small open-label treatment trials to date have been published in children with RLS (see section below). What is known about the treatment of adult RLS is summarized below and in Table 5. In children the therapeutic options are similar except that we have avoided opioids and have used clonidine instead because of its ability to suppress ADHD as well as RLS/PLMS symptoms (71).
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Table 5 Therapeutic Options in the Treatment of Adult RLS. First Line Dopaminergic agents L-Dopa Nonergot preparations pramipexole ropinirole Ergot preparations bromocriptine pergolide cabergoline Second Line Opioids oxycodone codeine methadone Anticonvulsants gabapentin Benzodiazepines clonazepam diazepam
A.
Dopaminergic Drugs
Dopaminergic agents are considered to be the first line of treatment for patients with RLS. Akpinar was the first to observe improvement in RLS symptoms with dopaminergic therapy (72). L-Dopa was the first dopaminergic agent proven in double-blind studies to be successful in the treatment of RLS (27). Subsequently, all dopaminergic agonists were found to be successful in the treatment of RLS (25,26,28–30). L-Dopa and all dopaminergic agonists cause augmentation in RLS patients, but the frequency of augmentation is higher in L-dopa treated patients. Therefore, the tendency has been to go more to dopamine agonists as a first-line treatment. In augmentation, RLS symptoms are pushed to an earlier time of day and become more severe after treatment with dopaminergic drugs. The tendency has also been to use the nonergot dopaminergic agonists, pramipexole and ropinirole, more than the ergot dopaminergic agonists, bromocriptine and pergolide, because of the rare but potentially serious complication of cardiac valvular fibrosis with the ergot agonists. Pramipexole and ropinirole are the first FDA-approved medication for the treatment of RLS. For other side effects of L-dopa and the dopamine agonists in general, as in Parkinson’s disease, nausea, and light-headedness, are common, and daytime drowsiness or sleep attacks occur as they sometimes do in Parkinson’s disease. However, unlike the situation in Parkinson’s disease, chorea, hallucinations, and mental confusion are rare.
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Augmentation should be distinguished from rebound (73,74). In augmentation, RLS symptoms appear at a time incompatible with the half-life of the drug. For example, if RLS symptoms originally began at 10 PM and a dopaminergic agonist with a half-life of four hours is given only at 9:30 PM for the treatment of symptoms, the symptoms may start to appear at 7:30 PM. This scenario is incompatible with rebound since the drug would be out of the system for 18 hours when the symptoms appear at 7:30 PM. However, morning rebound of the symptoms of RLS can also occur after an evening dose of a dopaminergic drug. For the treatment of augmentation, one can sometimes get by with adding an earlier dose of the medication, but if the symptoms subsequently appear even earlier, the drug should be discontinued or the dose lowered, and one should not add earlier dosages of medication (73). B.
Opioids
Opioids have been shown to be helpful in the treatment of RLS. In a doubleblind study, oxycodone was found to be successful employing an average of approximately 15 mg/day in divided dosages (75). Among the other opioids that have been found to be useful in RLS, codeine 30 mg may be titrated up to 90 mg/ day in divided dosages and for the most severe unresponsive cases methadone up to 20 mg/day may be used in divided dosages (76). With regard to side effects, there is surprisingly little addiction, tolerance, or long-term dose escalation, and constipation is only a minor problem. However, one must watch for the development or exacerbation of sleep apnea with long-term treatment (77). C.
Gabapentin
Gabapentin has also been found to be successful in the treatment of RLS in dosages up to 3000 mg/day in divided dosages, although the usual dosages utilized in double-blind studies are between 300 and 1200 mg/day. Ataxia and drowsiness may be side effects (78). D.
Benzodiazepines
The most effective benzodiazepine for the treatment of RLS is clonazepam, most useful because of its long half-life (79). Diazepam may be useful for similar reasons. Dosage for clonazepam ranges from 0.5 to 4.0 mg in divided dosages. As with the other therapeutic modalities, the drug may help leg discomfort, the need to move, sleep disturbance, and PLMS. There are no good direct comparisons of benzodiazepine therapy with other therapies for RLS, but the general feeling among experts is that the direct effect of benzodiazepines upon leg discomfort is weak compared with that of other classes of medication. As the dose of clonazepam gets higher, patients may get more drowsy in the morning from a carry-over effect of the drug because of its long half-life. As the dose gets higher, the patient may also show decreased cognition in the morning for the
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same reasons. As with the opioids, addiction and tolerance are low in the long term (80). E.
Iron Therapy
Iron therapy should only be given in the presence of a relative iron deficiency with a serum ferritin of <50 mg/L (81,82). Also, iron should never be administered as an initial monotherapy since it depends on raising the serum ferritin level to >50 mg/L, and this takes a long time since iron crosses the blood-brain barrier poorly. Iron may be given 325 mg t.i.d., with vitamin C 500 mg given with each dose to help absorption through the GI tract and theoretically to keep the iron in the active reduced ferrous form. If facilities are available, intravenous iron is probably more effective than oral iron because of problems of absorption, etc. (83). X.
Treatment of Restless Legs and Periodic Limb Movements of Sleep in Children
Iron therapy in children with RLS has already been reviewed in the section on pathogenesis. With regard to dopaminergic therapy, in one study dopaminergic agents improved not only the RLS/PLMS symptoms but also the ADHD symptoms in children with both RLS/PLMS and ADHD (age, 6–14 years) (59). This further supports a link between RLS/PLMS and ADHD. L-Dopa or pergolide were employed. There was an improvement in RLS leg discomfort and a statistically significant decrement in the PLMS index and associated arousals. The PLMS index fell from 11.7 to 2.1/hr of sleep ( p = 0.018), and the total number of PLMS associated arousals per night fell from 21.4 to 1.8 per hour ( p = 0.042). Because Walters et al. were also treating daytime ADHD symptoms, dosing was usually t.i.d. or q.i.d. (59). In another study of 10 children with RLS, originally misdiagnosed as having growing pains (mean age 10.4 years), four were treated with one tablet of carbidopa/levodopa 25/100 controlled release (CR) prior to bedtime. Symptomatic improvement in the IRLS rating scale for RLS severity was found in three patients. There was a decrement in scores from 30, 28, and 33 to 15, 12, and 10, respectively (39). Note that because the authors were only treating nighttime RLS symptoms, dosage was lower than that in the aforementioned study. Ropinirole has been reported in one child to have resulted in significant improvement of RLS, ADHD, and sleep symptoms (84). Guilleminault et al. treated two children with RLS/PLMS and confusional arousals (sleepwalking or sleep terrors) with pramipexole (Mirapex) (85). The PLMS arousal index decreased from 11 and 16 per hour to 0 and 0.2 per hour, respectively. The confusional arousals resolved with pramipexole treatment as well, suggesting that RLS/PLMS triggered the confusional arousals. In another study by the same authors five of six prepubertal children with PLMS were treated with pramipexole with complete resolution of the PLMS (52).
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14 Gastroesophageal Reflux During Sleep
GERALD M. LOUGHLIN Weill Medical College of Cornell University, New York, New York, U.S.A.
I.
Sleep, Gastroesophageal Function and Dysfunction
Gastroesophageal dysfunction, as evidenced by the reflux of gastric contents into the esophagus, has been implicated in a broad range of clinical symptoms (1). Some of these clinical problems ascribed to reflux, such as sleep disruption, apparent life-threatening events (apnea and bradycardia), and nocturnal asthma may occur primarily, or exclusively, during the night as a result of the reflux episode. In addition, reflux during sleep, coupled with a sleep state– related loss of normal airway and esophageal mucosal protective mechanisms may contribute to the severity of the gastroesophageal reflux disease (GERD)– related esophagitis, laryngeal irritation, and asthma. Finally, conditions associated with increased work of breathing during sleep, such as obstructive sleep apnea and nocturnal asthma, may also predispose to gastroesophageal reflux (GER), which may then produce esophagitis and other complications such as wheezing. These complications may, in turn, become more severe because they occur during sleep (2,3).
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Sleep, Circadian Rhythms, and Gastroesophageal Function
Most likely, it is the combination of changes in the gastroesophageal function that are under circadian influences and functional changes in the aerodigestive physiology induced by the sleep state that contribute both to the pathogenesis of the symptoms associated with gastroesophageal dysfunction and to enhancing the severity of these symptoms or complications (4). Much of the information on the physiologic changes in gastroesophageal function that occur with sleep come from studies on adults; however, the limited data from children have demonstrated that gastroesophageal function during sleep is similar across all ages, including in premature infants. That said, there are significant developmental influences during sleep on some aspects of esophageal function, such as the upper esophageal sphincter and swallowing (5,6). During sleep, the transient lower esophageal sphincter relaxations that are the cause of reflux when children are awake are decreased. In normal infants, this results in a reduction in reflux episodes from approximately 1.4 per hour to 0.4 episodes per hour. In infants, most reflux episodes are seen during active or indeterminate sleep (7,8). Reflux episodes are rare during quiet sleep and are often associated with movements (9). In older children and adults, the pattern is similar. When a reflux episode occurs, it is usually seen in stage 2 sleep. Reflux episodes are rare in REM and slow-wave sleep in normal subjects and are most often associated with arousals (1,10). However, Sondheimer et al. reported a pattern of reflux characterized by a drifting onset of a drop in pH rather than the typical abrupt onset seen with the transient lower esophageal sphincter relaxations (11). This pattern of reflux appears to be unique to sleep and is thought to be secondary to a gradual leakage of small amounts of gastric acid during a period when the buffering capacity and acid clearance mechanism of the lower esophagus are depressed. These episodes apparently occur without appreciable changes in lower esophageal sphincter tone and are unaffected by sleep states. The function of the upper esophageal sphincter (UES), on the other hand, is altered by sleep state in a potentially negative fashion if reflux occurs (12,13). Although data regarding the affects of specific sleep states are limited, it appears that UES tone decreases during sleep, with the lowest values seen at the end of expiration during slow-wave sleep (12). This may predispose to aspiration, or at a minimum, laryngitis, by permitting the passage of the refluxed material into the upper airway. Work by Bajaj et al. also demonstrated an interaction between sleep states and the esophago-upper esophageal sphincter contractile reflex (EUCR) and secondary esophageal peristalsis (14). The EUCR is a reflex triggered by the reflux of gastric contents that is manifested by the contraction of the upper esophageal sphincter and secondary peristalsis. EUCR and secondary peristalsis are elicited in stage 2 and REM, but are preempted by arousals during slow-wave sleep. The volume of refluxed material needed to trigger the reflex was less in REM than during wakefulness or stage 2 sleep. Finally, even though
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the resting upper esophageal sphincter pressure declines with sleep, it can still mount reflex contraction when challenged (14). However, these data were obtained from adult volunteers and it is not clear how age and developmental status further affect upper esophageal sphincter function during sleep. It would appear that there is a clear circadian controlled pattern to the production of gastric acid, with the most acid production in the late hours of the evening and the least in the early morning (4,15,16). This increased production of gastric acid at night could potentiate the negative consequences of any reflux episodes that occur during sleep. It is not known how the changes in meal patterns of children as they age affect this pattern of acid production and the risks of acid reflux (17). Infants who may eat as often as every three to four hours may mitigate this increased nocturnal acid production by more frequent eating. However, even this is complicated by factors such as the composition of the feeding. Breast milk empties from the stomach more rapidly than formula, thus reducing the buffering capacity of the feeding. Gastric pH decreases more rapidly after a meal of expressed breast milk, which results in a predisposition to acid reflux (8,18). Similarly, there appears to be both diurnal and sleep state influences on gastric motility, with decreased gastric emptying also noted in the late evening hours (19). In addition, sleep state–related changes in gastric muscle activity, as measured by electrogastrography, demonstrate the instability of gastromyoelectric activity and increased gastric muscle dysrhythmia during slow-wave sleep when compared with the awake state (20). This pattern, coupled with the above-noted changes in acid production, adds to the vulnerability of sleep. In addition, decreased gastric emptying will affect the delivery of medications to the small intestine, which in turn will affect drug delivery and, thus, the effectiveness of drug therapy for reflux. In contrast, the limited data available in adults suggest that esophageal motility is unaffected by sleep (4). Esophageal clearance is biphasic, consisting of volume clearance (primarily the result of peristalsis) and chemical clearance (neutralization of acid by swallowed saliva and perhaps buffering secretions from the esophageal mucosa) (6,21). Chemical clearance is prolonged during fasting periods, perhaps secondary to reduced efficiency of acid clearance mechanisms, such as salivation, peristalsis, or mucosal secretion (3,4). Both salivation and swallowing frequency are decreased during sleep. The swallow rate decreases during sleep by fivefold (3,21). Swallowing does not appear to be directly influenced by specific sleep state in infants, but is influenced by the presence of apnea and arousals (22). Development also appears to play an important role (21). Jeffrey et al. have shown that there is a dramatic difference between the manner in which preterm versus term infants respond to reflux episodes during active sleep (9). In active sleep, term infants clear acid reflux by increasing swallowing and secondary peristalsis. Preterm infants, on the other hand, respond by increasing propagated swallows, resulting in decreased duration of reflux episodes. In this study, the findings in term infants were equivalent to those seen in adults, suggesting a
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rapid maturation of this physiologic response. Work by Sondheimer et al. has shown that, in patients with pathologic reflux, acid clearance is dramatically reduced during sleep compared to a control group (23). Body position during sleep may also have a role in exacerbating or reducing reflux during sleep. The right lateral decubitus position has been associated with prolonged periods with pH < 4 and prolonged acid clearance compared to the supine prone and left lateral position, with the left lateral position associated with the best acid clearance. Interestingly, reflux episodes were more common in the supine position (24). This is the sleep position recommended for reduction of sudden infant death syndrome (SIDS) risk, yet despite this increase in reflux, the benefits in terms of the impact on SIDS far outweigh the risks of increased reflux (25,26). The net result of these circadian and sleep state–related effects is a situation that presents an interesting paradox. On the one hand, GER is reduced during sleep, but if it occurs during sleep, there is an increased risk that it will cause trouble because of the physiologic changes in the defenses against reflux (decreased acid clearance and UES function) that occur during sleep. II.
Sleep-Related Clinical Manifestations of GER
Although it is certainly in vogue to blame GER for a wide range of respiratory and nonrespiratory complaints during sleep, the link between a number of these conditions and reflux has yet to be clearly established. In many clinical reports, objective documentation of reflux, both acid and nonacid, as well as objective correlation with the symptom, has not been obtained, and when objective measures have been recorded, a strong correlation has not been established for many of the symptoms or conditions linked to GER. In many instances, pH/ impedance probe studies, which are considered the gold standard for diagnosing both acidic and weakly or nonacidic reflux, have not been coordinated with polysomnography data, which would thus increase the yield from these studies. A.
Sleep Disturbance
In contrast to studies in adults, the role of GER in producing sleep disturbance in children is inconclusive. In surveys of adults with reflux, a significant number of subjects report sleep disturbance secondary to heartburn, and a negative impact of nocturnal reflux on their quality of life (27–29). In children, however, this association is less clear. This may reflect a higher threshold for arousal from sleep in children compared with adults. On the basis of pH probe data, a study by Sondheimer et al. in a group of infants with histories of apnea or chronic lung disease demonstrated no difference in sleep patterns of infants with and without pathologic reflux. A slight body movement accompanied the reflux episode in both patients and controls (30). EEG arousal occurred with equal frequency in both groups. There were no differences in sleep patterns, nor was there a
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decrease arousal response in those with pathologic reflux. Similarly, Heine et al. did not find an increased occurrence of sleep disturbance in infants less than three months of age with pathologic reflux (31). However, in a recent study of 50 normal infants with occasional regurgitations, studied at eight weeks of age, using more detailed polysomnography documentation of the state of sleep and arousals, Kahn et al. concluded that proximal GER can act as a strong stimulus for arousal from sleep (32). In a related questionnaire study administered to the parents of 102 infants with pH probe documented GER, Ghaem et al. demonstrated that sleep interruption occurs more frequently in infants and children with reflux disease than in controls (33). They found a significantly greater occurrence of nighttime waking, delayed onset of sleeping through the night, and a greater prevalence of daytime naps beyond 24 months of age in the group of subjects with GER. Thus, at this point, it is difficult to draw any conclusions regarding the relationship between reflux and disturbed sleep in infants and children. More studies linking detailed polysomnography data with recordings of both acidic and nonacidic reflux episodes are needed. It would also strengthen the relationship if the studies employed detectors in both the upper and lower esophagus. It is possible, since heartburn and pain associated with reflux is a variable finding even when the patient is awake, that it is only the episodes of reflux that reach the upper esophagus and thus approach the pharyngeal airway that trigger arousal and disturb sleep. B.
Respiratory Findings
GER, especially if it occurs during sleep when respiratory and gastrointestinal defenses are diminished, has been thought to cause or contribute to a broad range of respiratory symptoms (cough, stridor, laryngitis, nasal pain, and apnea) and also to contribute to exacerbations of sinusitis and asthma (3,34). Data supporting a link between reflux and supraesophageal complications is marginal and the role of reflux during sleep is unclear (35,36). In addition, GER may be exacerbated by respiratory conditions that result in the increased work of breathing and increased intrathoracic pressure swings such as laryngomalacia (37). This chapter will focus on conditions associated with changes in breathing during sleep (nocturnal asthma, apnea in infants, and obstructive sleep apnea) where reflux is thought to play a role. GER has been reported in increased numbers of patients with asthma, and reflux has been suggested as a factor contributing to exacerbations of nocturnal exacerbations of asthma (38,39). The association appears to be more solid in children (40). Microaspiration and/or vagally mediated reflex bronchoconstriction triggered by reflux into the distal esophagus are thought to be responsible. This association was confirmed in a study that involved infusion of acid into the lower esophagus at midnight and between 4 AM and 5 AM. The earlymorning infusion produced significant changes in lung function as well as wheezing in children with nocturnal asthma and who also had a positive
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Bernstein test (pain in response to acid infusion into the lower esophagus). This effect was less apparent if the acid was infused at midnight (41). Treatment of reflux has generally been successful in improving nocturnal asthma symptoms and reduces exacerbations (42,43). In a child with persistent asthma, especially if symptoms occur at night, an evaluation for reflux (acidic and nonacidic) is indicated. As with all respiratory conditions in which reflux during sleep is thought to play a role, these patients require a study that records both acid and nonacid reflux in combination with polysomnography to monitor changes in respiration during sleep. Unfortunately, impedance monitoring for nonacid reflux is not routinely available, but may be useful in patients with persistent respiratory symptoms during sleep despite adequate control of acid production. In addition, in older patients capable of performing lung function tests, measurement of lung function at onset and end of the sleep period, as well as documentation of lung function changes associated with nocturnal awakenings may be useful if objective documentation of an association between a reflux episode and respiratory signs and symptoms is required. Various investigators have proposed a link between apnea in infants, manifested as either apnea of prematurity or as an apparent life-threatening event (ALTE), and GER during sleep. Again, the frequency of reflux in this age group, coupled with alterations in the respiratory system and airway defenses that occur during sleep, makes investigating this potential link quite attractive. Unfortunately, this link also remains unproven. A study by DiFiore et al. could not establish a temporal relationship between GER and apnea, either central or obstructive, in premature infants (44). In addition, reflux did not prolong apnea or make the associated heart rate slowing or decrease in oxygen saturation worse. Work by Peter et al. demonstrated that while both apnea and GER, including nonacidic reflux, are common in premature infants, they did not appear to be linked temporally (45). This study is significant in that it monitored both acidic and nonacidic or weakly acidic reflux, which is more common in premature infants. In a study of infants who were being evaluated following an ALTE, Kahn et al. could not establish a link between reflux and apnea. There was no correlation between the duration or the lowest esophageal pH and the number or duration of apneas. No obstructive apnea, bradycardia, or arousal was triggered by the reflux (46). However, Wenzl et al., using a similar technique, found an association between apnea and nonacid reflux and concluded that a standard pH probe study is not sufficient to diagnose a potential relationship between reflux and apnea (47). Unfortunately, this issue was complicated by the study of Mousa et al. who also measured both acid and nonacid reflux episodes in a group of infants being evaluated for an ALTE (48). They concluded that GER did not play a role in ALTE. The differences between these studies most likely stem from the differences in how ALTE were defined in the study populations. More work is needed, but at this point there is no compelling evidence that reflux during sleep plays a major role in causing ALTEs.
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The nature of the relationship between reflux and obstructive sleep apnea syndrome (OSAS) remains in question. Considering the changes in transdiaphragmatic pressures that occur with obstructive sleep apnea, it is certainly tempting to think that OSAS may make reflux worse (49,50). By the same token, if extraesophageal reflux occurs (passage of refluxate above the UES), it is possible that this could cause inflammation and airway wall edema, thus increasing airways resistance, an important factor in determining obstructed breathing during sleep. It may also contribute to the sleep disturbance associated with OSAS. Demeter et al. demonstrated a relationship between the endoscopically determined severity of the esophagitis and the apnea-hypopnea index (51). Work by Ing et al. in adults has demonstrated that patients with OSAS had significantly more reflux episodes than controls, but only half of the reflux episodes were temporally related to the episodes of obstructive apnea or hypopnea (52). In addition, medical management of the reflux reduced arousals from sleep but had no effect on OSAS. Interestingly, nasal continuous positive airway pressure (CPAP) reduced OSAS and reflux. The mechanism underlying the reduction in reflux by the application of CPAP is not known, and is nonspecific in that it reduces reflux even in controls without OSAS (49,52). At this point, the body of evidence, primarily from adults, suggests that the relationship between GERD and OSAS is one of mutual reinforcement (50). Support for this comes from observations that treatment of either condition appears to have a positive effect on the other one. This relationship needs to be explored in more detail in children, but there is no reason to think that the same relationship will be seen in the pediatric population. References 1. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines. J Pediatr Gastroenterol Nutr 2001; 32(suppl 2):S1–S31. 2. Orr WC. Sleep and gastroesophageal reflux: what are the risks?. Am J Med 2003; 115(suppl 3a):S109–S113. 3. Bandla H, Splaingard M. Sleep problems in children with common medical disorders. Pediatr Clin North Am. 2004; 51(1):203–227, viii. 4. Pasricha PJ. Effect of sleep on gastroesophageal physiology and airway protective mechanisms. Am J Med 2003; 115(suppl 3a):S114–S118. 5. Jadcherla SR, Duong HQ, Hofmann C, et al. Characteristics of upper oesophageal sphincter and oesophageal body during maturation in healthy human neonates compared with adults. Neurogastroenterol Motil 2005; 17(5):663–670. 6. Jeffery HE, Ius D, Page M. The role of swallowing during active sleep in the clearance of reflux in term and preterm infants. J Pediatr 2000; 137:445–448. 7. Kawahara H, Dent J, Davidson G. Mechanisms responsible for gastroesophageal reflux in children. Gastroenterology 1997; 113:399–408. 8. Davidson G. The role of the lower esophageal sphincter function and dysmotility in gastroesophageal reflux in premature infants and in the first year of life. J Pediatr Gastroenterol 2003; 37(suppl 1):S17–S22.
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9. Jeffery HE, Heacock HJ. Impact of sleep and movement on gastro-oesophageal reflux in healthy, newborn infants. Arch Dis Child 1991; 66:1136–1139. 10. Freidin N, Fisher MJ, Taylor W, et al. Sleep and nocturnal acid reflux in normal subjects and patients with reflux esophagitis. Gut 1991; 32:1275–1279. 11. Sondheimer JM, Hoddes E. Gastroesophageal reflux with drifting onset in infants: a phenomenon unique to sleep. J Pediatr Gastroenterol Nutr 1992; 15(4):418–425. 12. Eastwood PR, Katagiri S, Shepard KL, et al. Modulation of upper and lower esophageal sphincter tone during sleep. Sleep Med 2007; 8:135–143. 13. Avots-Avotins AE, Ashworth WD, Stafford BD, et al. Day and night esophageal motor function. Am J Gastroenterol 1990; 85:683–685. 14. Bajaj JS, Bajaj S, Dua KS, et al. Influence of sleep stages on esophago-upper esophageal sphincter contractile reflex and secondary esophageal peristalsis. Gastroenterol 2006; 130:17–25. 15. Moore JG. Circadian dynamics of gastric acid secretion and pharmacodynamics of H2 receptor blockade. Ann N Y Acad Sci 1991; 618:150–158. 16. Moore JG, Englert E Jr. Circadian rhythm of gastric acid secretion in man. Nature 1970; 226:1261–1262. 17. Cresti F, De Sanctis L, Savino F, et al. Relationship between gastro-esophageal reflux and gastric activity in newborns assessed by combined intraluminal impedance, pH metry and epigastric impedance. Neurogastroenterol Motil 2006; 18:361–368. 18. Heacock HJ, Jeffery HE, Baker JL, et al. Influence of breast versus formula milk on physiological gastroesophageal reflux in healthy newborn infants. J Pediatr Gastroenterol Nutr 1992; 14:41–46. 19. Goo RH, Moore JG, Greenberg E, et al. Circadian variation in gastric emptying of meals in humans. Gastroenterology 1987; 93:515–518. 20. Elsenbruch S, Orr WC, Harnish MJ, et al. Disruption of normal gastric myoelectric functioning by sleep. Sleep 1999; 22:453–458. 21. Woodley FW, Fernandez S, Mousa H. Diurnal variation in the chemical clearance of acid gastroesophageal reflux in infants. Clin Gastroenterol Hepatol 2007; 5:37–43. 22. Don GW, Waters KA. Influence of sleep state on frequency of swallowing, apnea and arousal in human infants. J Appl Physiol 2003; 94:2456–2464. 23. Sondheimer JM. Clearance of spontaneous gastroesophageal reflux in awake and sleeping infants. Gastroenterology 1989; 97(4):821–826. 24. Khoury RM, Camacho-Lobato L, Katz PO, et al. Influence of spontaneous sleep positions on nighttime recumbent reflux in patients with gastroesophageal reflux disease. Am J Gastroenterol 1999; 94:2069–2073. 25. Task Force on Sudden Infant Death Syndrome, The changing concept of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleep environment and new variables to consider in reducing risk. Pediatrics 2005; 116:1245–1255. 26. Byard RW, Beal SM. Gastric aspiration and sleeping position in infancy and early childhood. J Paediatr Child Health 2000; 36:403–405. 27. Shaker R. Nighttime GERD: clinical implications and therapeutic challenges. Best Pract Res Clin Gastroenterol 2004; 28:31–38. 28. Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux on health-related quality of life. Arch Intern Med 2001; 161:45–52.
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29. Shaker R, Castell DO, Schoenfeld PL, et al. Nighttime heartburn is an underappreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003; 98:1487–1493. 30. Sondheimer JM, Hoddes E. Electroencephalogram patterns during sleep reflux in infants. Gastroenterology 1991; 101:1007–1011. 31. Heine RG, Jaquiery A, Lubitz L, et al. Role of gastroesophageal reflux in infant irritability. Arch Dis Child 1995; 73:121–125. 32. Kahn A, Rebuffat E, Scottiaux M, et al. Arousals induced by proximal esophageal reflux in infants. Sleep 1991; 14:39–42. 33. Ghaem M, Armstrong KL, Trocki O, et al. The sleep patterns of infants and young children with gastro-esophageal reflux. J Paediatr Child Health 1998; 34:160–163. 34. Halstead LA. Role of gastro-esophageal reflux in pediatric upper airway disorders. Otolaryngol Head Neck Surg 1999; 120:208–214. 35. Weaver EM. Association between gastroesophageal reflux and sinusitis, otitis media, and laryngeal malignancy: a systemic review of the evidence. Am J Med 2003; 115(suppl 3A):81S–89S. 36. Rudolph CD. Superesophageal complications of gastroesophageal reflux in children: challenges in diagnosis and treatment. Am J Med 2003; 115(suppl 3A): 150S–156S. 37. Hadfield PJ, Albert DM, Bailey CM, et al. The effect of aryepiglottoplasty for laryngomalacia on gastro-esophageal reflux. Int J Otorhinolaryngol 2003; 67:11–14. 38. Shapiro GG, Christie DL. Gastro-esophageal reflux in steroid-dependent asthmatic youths. Pediatrics 1979; 63:207–212. 39. Martin ME, Grunstein MM, Larsen GL. The relationship of gastro-esophageal reflux to nocturnal wheezing in children with asthma. Ann Allergy 1982; 49(6):318–322. 40. Harding SM. Nocturnal asthma: role of nocturnal gastro-esophageal reflux. Chronobiol Int 1999; 16:641–642. 41. Davis RS, Larsen GL, Grunstein MM. Respiratory response to intraesophageal acid infusion in asthmatic children during sleep. J Allergy Clin Immunol 1983; 72:393–398. 42. Wong CH, Chua CJ, Liam CK, et al. Gastroeoesophageal reflux disease in ‘difficult to control’ asthma: prevalence and response to treatment with acid suppression therapy. Aliment Pharmacol Ther 2006; 1:1321–1327. 43. Khoshoo V, Haydel R Jr. Effect of antireflux treatment on asthma exacerbations in nonatopic children. Pediatr Gastroenterol Nutr 2007; 44:331–335. 44. Di Fiore JM, Arko M, Whithouse M, et al. Apnea is not prolonged by acid gastroesophageal reflux in preterm infants. Pediatrics 2005; 116:1059–1063. 45. Peter CS, Sprodowski N, Bohnhorst B, et al. Gastroesophageal reflux and apnea of prematurity: no temporal relationship. Pediatrics 2002; 109:8–11. 46. Kahn A, RebuffatE, Sottiaux M, et al. Sleep apneas and acid esophageal reflux in control infants and in infants with an apparent life-threatening event. Biol Neonate 1990; 57:144–149. 47. Wenzl TG, Schenke S, Peschgens T, et al. Association of apnea and nonacid reflux in infants: investigations with the luminal impedance technique. Pediatr Pulmonol 2001; 31(2):144–149. 48. Mousa H, Woodley FW, Methane M, et al. Testing the association between gastroesophageal reflux and apnea in infants. J Pediatr Gastroenterol Nutr 2005; 41:169–177.
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49. Kerr P, Shoenut JP, Millar T, et al. Nasal CPAP reduces gastroesophageal reflux in obstructive sleep apnea syndrome. Chest 1992; 101:1539–1544. 50. Demeter P, Pap A. The relationship between gastroesophageal reflux disease and obstructive sleep apnea. J Gastroenterol 2004; 39:815–820. 51. Demeter P, Visy KV, Magyar P. Correlation between severity of endoscopic findings and apnea-hypopnea index in patients with gastroesophageal reflux disease and obstructive sleep apnea. World J Gastroenterol 2005; 11:839–841. 52. Ing AJ, Ngu MC, Breslin AB. Obstructive sleep apnea and gastroesophageal reflux. Am J Med 2000; 108(suppl):120S–125S.
15 Assessing Neurobehavioral Outcomes in Childhood Sleep-Disordered Breathing: A Primer for Nonneuropsychologists
DEAN W. BEEBE University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
I.
Introduction
Although qualitative descriptions of scholastic and behavioral difficulties associated with sleep-disordered breathing (SDB) in children date back over a century (1), it has only been in the past three decades that reproducible, objective measures have been used to document this association. Since then, interest in the cognitive, behavioral, and scholastic outcomes of children with SDB has increased nearly exponentially, both broadly and in pediatric-focused journals (Fig. 1), with the number of articles published in the past few years rivaling or exceeding the volume that had been cumulatively published before. The products of this exciting, cross-disciplinary research expansion can, however, be misleading if professionals from one discipline do not have a good understanding of the other. The goal of this chapter is to contribute to that understanding, acting as a primer for nonpsychologists who wish to understand the daytime outcomes of children with SDB, and a focused refresher for psychologists who may not be immersed in neurobehavioral assessment on a regular basis. The term ‘‘neurobehavioral’’ has been applied to overt behaviors, cognitive abilities, and covert thoughts, experiences, and emotions that are mediated 345
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Figure 1 Publications on pediatric SDB and neurobehavioral functioning. The solid line and left vertical axis refer to the number of PubMed citations yielded via the search ‘‘([sleep AND (breathing OR apnea]) AND (children OR pediatric OR child OR childhood) AND (neuropsychological OR psychological OR behavior OR cognitive OR neurobehavioral OR psychological OR psychiatric)’’ on August 21, 2006. The dotted line and right vertical axis refer to the same search, further limited to articles published in the Journal of Pediatrics or Pediatrics. Abbreviation: SDB, sleep-disordered breathing.
by the brain. In emphasizing the neural mediation of psychological phenomena, this term has the advantage of disavowing mystical, disembodied notions of psychology that have little basis in science. Other than this, the terms neurobehavioral, neuropsychological, and psychological are synonymous, so neurobehavioral researchers are well advised to consider the science of psychological measurement that has developed over the past century. This science, known as psychometrics, has its own terminology, which the early portion of this chapter will review. In doing so, it will focus on broad conceptual issues; readers who are interested in more in-depth, technical expositions are referred to several excellent reference texts (2–5). The chapter will then summarize psychometric issues that have unique relevance to child assessment, highlighting potential pitfalls to avoid. Finally, to act as a launching point for future researchers, the chapter will summarize the available research on the associations between pediatric SDB and neurobehavioral functioning as of mid-2006. II.
Psychometric Terms
A.
The ‘‘Reliable and Valid’’ Instrument
Research articles frequently include the cryptic statement that a given measure is ‘‘reliable and valid.’’ Although often driven by legitimate pressures to limit
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article length, such sweeping statements can offer false reassurance. Readers who are unfamiliar with a test or measure are well advised to hunt down the citations offered up as support—too often the reader will discover that the evidence is weak. The vast majority of conventional psychometricians work off of the ‘‘true score model.’’ This model assumes that a given person at a given time has a ‘‘true score’’ on a theoretical psychological construct—for example, how sleepy Neil Armstrong was five minutes before takeoff to the moon, or how good his vocabulary was that day or any other. Reliability and validity estimates reflect comparisons against this theorized true score. There is no singular ‘‘best way’’ to establish the psychometric characteristics for all tests across all constructs and contexts. As a result, simple statements about ‘‘reliable and valid’’ instruments beg the questions: reliable how? valid for what? Reliability
Broadly speaking, in psychometrics the term ‘‘reliability’’ refers to how consistent a test score is, or how free the measure is from random measurement error. There are several points at which measurement error can occur in psychological testing, including item selection, administration factors, and scoring. To test Armstrong’s vocabulary, one would have to choose from millions of words in the English language, some of which would be more familiar to him than to an equally verbally endowed individual of different background. Because by necessity, one cannot present all possible potential items, test designers introduce a potential source of measurement error, that is, from item selection. Administration factors—unique aspects of the situation in which the measurement occurs—are also important. Even if Armstrong’s vocabulary truly did not change between when he sat on the launch pad and a month later, his score on a vocabulary test probably would have changed because of the unique assessment contexts. Finally, since the accuracy of a given vocabulary definition is somewhat subjective, different scorers might assign different amounts of credit to his responses, thereby introducing measurement error across scorers. Different techniques have been designed to address these different sources of potential measurement error, as listed in Table 1. Not all forms of reliability are appropriate for all types of measurement. It would be useful to know that a test of a vocabulary—a theoretical construct that is considered fairly homogeneous and stable in adults, yet in practice might have some subjectivity in scoring—has strong test-retest, internal consistency, and interscorer reliabilities. However, it would be inappropriate to expect that a test of a more dynamic construct, such as immediate sleepiness, should have strong testretest reliability. Armstrong was probably much less sleepy just before takeoff than he was at 3 AM, a few nights before. Any measure of sleepiness obtained at those two times might show little correspondence, not because of poor reliability, but because of real change in the measured construct. Similarly, a measure of a
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Table 1 Conventional Forms of Reliability Form of evidence
Key questions asked
Source of error accounted for
Coefficienta
When appropriate
Test-retest
How do scores across two separate administrations of the same test compare?
Administration
Correlation
Measured construct is theoretically stable over time.
Internal How well do consistency all of the items measure the same construct?
Item selection
Measured Alpha, construct is KR-20, homogeneous. corrected split-half correlations
Inter-scorer
How well do different scorers agree?
Scoring
Kappa, intra-class correlation
There is subjectivity in how items are scored.
Alternate forms
Administration, How well item selection do different versions of the same test agree?
Correlation
Different versions of the test are needed to avoid practice or reactance effects.
a
Additional details on these coefficients can be found in Refs. 3, 4, or 5. Source: Adapted from Ref. 5.
broad, multifactorial construct (e.g., general academic ability) would be expected to yield lower estimates of internal consistency than a measure of a more tightly focused, homogeneous construct (e.g., single-word decoding/reading). However, if that multifaceted construct is assumed to be fairly stable over time, then it is reasonable to expect solid evidence of test-retest reliability. Note that decisions about which forms of reliability can be appropriately applied rely heavily on a strong theoretical model of the construct being measured. They are also somewhat relative. An excellent test-retest reliability estimate over a 10-minute interval for a stable construct is not very reassuring, but strong reliability over the course of months or years is impressive indeed. Along the same lines, because internal consistency estimates tend to increase as tests lengthen, having good internal consistency on a 5-item measure is remarkable, whereas very high internal consistency for a 50-item test may signal a need to cut redundant items. It is not that there are no rules that apply to reliability, but rather that the process of determining whether a test is ‘‘reliable’’ is more complex than the phrase ‘‘reliable and valid’’ would suggest.
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Validity
There is also more to validation than meets the eye. In psychometrics, ‘‘validity’’ refers to how well a test measures what it is supposed to measure. Defined this way, validity is predicated on reliability. For example, a bathroom scale that fluctuates wildly each time it is stepped on over a five-minute period cannot be a valid measure of body weight, assuming that true body weight is stable during that period. This definition of validity also matches well with what has been called ‘‘construct validity’’—the notion that what happens in the real world on a measure should correspond with what we think happens on the theoretical level. It subsumes the other traditional forms of validity, often called content validity and criterion validity (the latter of which has been further parsed into concurrent and predictive validity). These forms of validity, the questions they are designed to address, ways of approaching them, and potential pitfalls are summarized in Table 2. A good example of content validation is provided in the manual for the Behavior Rating Inventory of Executive Functioning (BRIEF) (6), which has been found to be sensitive to pediatric SDB (7). The BRIEF authors laid out definitions of the theoretical subdomains that they wished to cover, then asked experts to identify which subdomain each of many preliminary items fit into best. On average, 85% of the experts said each item selected for the final version of the test fit best with the subdomain to which it was assigned. In the field of pediatric sleep medicine, an excellent example of criterion validity was presented by Chervin et al. (8) when they described the SDB subscale of their Pediatric Sleep Questionnaire (PSQ). They compared scores on their subscale with objective evidence of SDB based on polysomnography using logistic regression and receiver operating curve analyses first to select the items that differed most across SDB versus no-SDB groups, then to demonstrate the sensitivity and specificity of the overall scale. Both these questionnaires also had further evidence of validity. For example, evidence of construct validity on the BRIEF was gathered by correlating subscales with measures of similar and dissimilar constructs and by comparing scores across groups known to have differing degrees of executive functioning (or dysfunction), such as healthy children, those with attention-deficit/hyperactivity disorder (ADHD), traumatic brain injuries, and Tourette’s disorder (6). Both questionnaires also avoided key hazards that can arise in scale validation. For example, the defining characteristics of content validation include the use of a quantitative, systematic approach that integrates expert opinion. In the absence of such an approach, what might initially appear to content validity is in fact ‘‘face validity’’—the scientifically untested sense that items ‘‘look like’’ they measure a construct based on the casual observations of the test taker. By systemically and quantitatively gathering expert opinion, the authors of the BRIEF gathered true evidence of content validity. The content validity of the SDB subscale of the PSQ was not explicitly examined, but its authors took an important step that is often overlooked: they cross-validated scores in two separate samples. Such
Key questions asked
Do test items representatively sample the relevant dimensions of the construct?
Concurrent validity: Do test scores correlate well with an external criterion measured around the same time? Predictive validity: Do test scores correlate well with an external criterion that will be measured in the future?
Does the test ‘‘behave’’ in a manner that fits with our theoretical notion of the construct it purports to measure?
Form of evidence
Content validity
Criterion validity
Construct validity
Table 2 Conventional Forms of Validity
Correlate items on a sleepiness questionnaire with the Multiple Sleep Latency Testa Use receiver-operating curves to examine the sensitivity and specificity of scores on an SDB screener compared to polysomnogramdefined obstructive sleep apnea Assess how well an SDB screener predicts subsequent diagnosis of sleep apnea Any of the above techniques Look for strong correlations between measures of identical or closely-tied constructs (e.g., two sleepiness forms); aka ‘‘convergent validity’’
l
l l
l
l
Do experts rate the items on relevance to construct?
l
Sample ways of addressing
l
l
l
l
l
Each form of evidence has its own limitations Because definition is broad, the ‘‘big picture’’ can be missed if too much weight is placed on one piece of evidence, ignoring others
Only as good as the criterion Inflated correlations occur when knowledge of one score affects the other (contamination) or if some items are identical on the test and criterion (overlap)
No well-accepted statistical index
Potential pitfalls
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Ref. 29.
a
Form of evidence
Key questions asked
Table 2 Conventional Forms of Validity (Continued )
l
l
l
l
‘‘Shared method variance’’ can inflate correlations between two tests obtained in the same way or from the same source There is the risk of adjusting the theoretical model of the construct to match the test (rather than vice versa)
l
l
Look for weak correlations between measures of different constructs that might be confounds (e.g., a measure of impulsivity and a measure of extraversion); aka ‘‘discriminant validity’’ Compare test scores across groups known to differ on the construct Examine sensitivity of test to an intervention that changes levels of the construct Test items statistically reduce to factors that correspond to theoretically defined aspects of the construct
Potential pitfalls
Sample ways of addressing
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cross-validation is important because, due to capitalization on chance variation within any given sample, validity estimates are often artificially inflated when the same sample’s data that were used to ‘‘weed out’’ poor items are also then used to validate the remaining items. A full exposition of reliability and validity extends beyond the scope of this chapter (2–5). However, it is hoped that this brief account highlights the need to move beyond simple statements about ‘‘reliable and valid’’ measures. There are different forms of reliability and validity, and in fact it is probably more true to talk about a measure having greater or lesser evidence for reliability and validity. Indeed, even the most extensively validated measures available— intelligence tests—remain the subject of intense scrutiny and debate. B.
Scores and Norms
Scores on a given measure can be expressed in several ways. The simplest is the ‘‘raw score’’—usually either a sum or mean of individual item’s scores, without any transformation. Raw scores preserve the full variability in the sample, and can be useful in tracking an individual’s or group’s change on a construct over time (e.g., the progress Armstrong made in vocabulary from the ages of 2–10 years). Raw scores can also be used to compare across individuals, so long as at least one of the following is true: (1) the age range of the sample is small, (2) there is little to no correlation between raw score and age, or (3) there is a linear association between raw score and age, and age is used as a covariate. A drawback inherent in raw scores is that they do not provide a reference to what is typically expected for individuals. This is particularly problematic when working with children, as there is often a dramatic developmental shift in such expectations. This is obvious with many cognitive constructs (e.g., vocabulary), and research has demonstrated developmental shifts in sleep constructs as well (e.g., chronotype) (9). Close cousins of the raw score include grade and age equivalents, which refer to the academic level or age at which a given score is at the middle of the normative distribution. For example, a vocabulary raw score of 18 may represent the mean score for nine-year-olds in the normative sample, so a person who scores 18 on that test would be said to have an age equivalent of 9. Although intuitively appealing, grade and age equivalents have many drawbacks. These include: (1) having different distributions and variance across ages, (2) having meaning only for constructs that show linear change across the relevant age range; nearly every construct is curvilinear if you cover a broad enough age range, (3) giving the appearance of equal intervals across ages, when in practice age and grade equivalents typically provide only a rough ordinal gradient. For these reasons, grade and age equivalents are rarely used in research and should be viewed with skepticism in clinical practice. When development itself is not of interest, most often raw scores are transformed into standardized scores. Standardized scores reflect a comparison
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of a given raw score against what is ‘‘normal,’’ usually for an individual of a given age or academic grade level, and sometimes for individuals of a given sex as well. Standardized scores obliterate developmental effects (an average 2-yearold will score the same as an average 10-year-old), but have the important advantage of having means and standard deviations that do not vary with age. The most basic standardized score, the z-score, is defined as the difference between an individual’s raw score and the norm group’s mean raw score, all divided by the norm group’s raw score standard deviation. The result is a distribution with a mean of 0 and a standard deviation of 1. All other standardized scores can be computed by multiplying the z-score by the standard deviation of the new standardized score, then adding this product to the mean of the new standardized score. For example, since the T-score distribution has a standardized mean of 50 and standard deviation of 10, a z-score of 2 is equivalent to a T-score of 70 (i.e., 2 10 þ 50). The most commonly used standardized scores are z, T, IQ scores (also known as ‘‘standard scores’’; M ¼ 100, SD ¼ 15), and scaled scores (M ¼ 10, SD ¼ 3). Figure 2 illustrates the relationships between these standardized scores relative to the Gaussian or normal curve. Standardized scores can be computed regardless of how raw scores are distributed, resulting in a distribution that mirrors the original. If the raw scores in the norm group are skewed, the standardized scores will also be skewed. This has several implications. First, the more skewed the normative distribution, the more distorted the mean and standard deviation. For example, an ongoing study
Figure 2 Standardized scores and percentile ranks associated with various points on the normal curve.
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of the relationship between sleep and daytime functioning in overweight adolescents has yielded z-scores of –3.5 or worse on a computerized measure of impulse control in two of the first 100 subjects. If this measure yielded normally distributed scores, the odds of this occurring would be well beyond 1 in a million. In reality, the negatively skewed distribution of scores on this measure resulted in a normative standard deviation that does not fairly represent the full dispersion of scores. A second, related implication is that, if two measures have differently shaped distributions, it can be misleading to compare standardized scores across the tests. A z-score of –3.5 on that skewed attention task is not equivalent to a z-score of –3.5 (i.e., an IQ of 48) on a normally distributed intelligence test. Finally, in non–normal distributions, one cannot expect that the percentage of individuals scoring at or below a given level (percentile rank) will conform to the pattern shown in Figure 2. Many behavior questionnaires use a T-score of 70 as a cutoff for suggesting pathology. If the distribution of scores is normal, this cutoff seems reasonably stringent, falling at the 98th percentile. However, the same T-score might fall at the 85th or lower percentile in a positively skewed distribution, or may never occur in a negatively skewed distribution. Given that many neuropsychological tests have skewed distributions, researchers should consider this skew before drawing conclusions about the performance of an individual or group. Researchers should also appraise the quality of the normative group on which standardized scores are based. Not all norm groups are created equal. Because of their commercial backing and widespread use, conventional intelligence and academic achievement tests tend to have well-developed norm groups, with great pains taken to obtain representative data across a range of geographic regions, degree of urbanization, racial and ethnic groups, gender, and ages. Many other tests sold by the same publication houses, however, have much less welldeveloped norms. Until only a few years ago, the test protocol for the venerable Boston Naming Test (10) listed a ‘‘norm group’’ for 18-year-olds that was comprised of a single individual who, to make matters worse, scored poorly compared with his younger or older counterparts. As of this writing, some of the most commonly used neuropsychological instruments (e.g., Grooved Pegboard, Boston Naming Test, Judgment of Line Orientation) had no published norms whatsoever for adolescents (11). The situation is getting better with time, but many pediatric neuropsychology norm groups remain weak (11). III.
Psychometric Issues in Child Assessment
There are a number of issues that, although relevant to all psychological assessment, are particularly so when assessing the neurobehavioral functioning of children. This section will summarize some of these issues, with illustrations of potential pitfalls to avoid. To avoid unduly maligning others, the examples of mistakes described below are those of this chapter’s author.
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To begin, one cannot assume that a test of a construct in one age group measures the same construct in another. For example, it was a mistake to include the Stroop Color-Word Interference Test (12), a purported measure of response inhibition, in the test battery for a research project that examined the impact of SDB on the neurobehavioral functioning of children aged 6 to 12 years. Some of the younger children in the sample were not fluent readers, which is requisite to validly interpret the Stroop as a measure of response inhibition. Because the Stroop was consequently measuring one construct in older children and another in young children, the data from the young children had to be dropped from some analyses (7). Such concerns are not limited to small-scale research projects. In the most recent revision of the Wechsler Intelligence Scale for Children (WISC-IV) (13), the ‘‘Picture Concepts’’ subtest was added to measure visual conceptformation ability. However, factor analyses indicate that, while Picture Concepts loads reasonably well with other core visual tasks in children aged 8 to 16 years, it loads better with verbal tasks in children aged 6 to 7 years (13). Even this extensively and expensively developed measure has a subtest that seems to be measuring different constructs at different ages. Child development also affects test ‘‘floors’’ and ‘‘ceilings.’’ A ‘‘floor’’ effect occurs when either a test’s raw or normed scores cannot go any lower because of a lack of appropriate items or normative data. A ceiling effect occurs where a test’s raw or normed score cannot go any higher for similar reasons. These effects are particularly relevant when assessing children because of the dramatic variations in skills that can occur developmentally. For example, the Gordon Diagnostic System (14) was included in a study of the relationship between sleep and daytime attentional functioning in 10- to 16-year-olds. In clinical practice, the Gordon has the advantage with braininjured children of differentiating errors from correct but slow responses. Unfortunately, it also has a low ceiling with non-brain-injured adolescents. One result of this is illustrated in Figure 3. Figure 3A shows the association between actigraphy-defined sleep efficiency across a one-week interval and impulsivity as measured on the Gordon. Although the correlation was statistically significant, the impulsivity distribution was truncated at less than one standard deviation above the mean. It is likely that some individuals’ true ability was actually higher than the test ceiling. If this were systematic, as shown in Figure 3B, the effect would be an association that is not only statistically stronger but also more amenable to parametric analyses. When working with children, it is absolutely essential to develop adequate rapport. The children’s comfort level, motivation, affective state, and comprehension of what is being asked of them are critical in obtaining accurate results. Examiners need to have both clinical and technical skills. Jerome Sattler’s books (2,3) provide guidance on how to train examiners to balance the rigorous standardization of the assessment process with the human touch needed to obtain accurate scores from children. Even the most skilled examiners, however, occasionally have problems establishing rapport with a given child.
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Figure 3 Obtained and possible association between actigraphy-defined sleep efficiency after the onset of sleep and impulsivity on the Gordon Diagnostic System (14). (A) The actual scores obtained (30), reflecting the truncation of impulsivity scores below 1 standard deviation. (B) Reflection of what might have been found if the ceiling effect reflected in this truncation had not occurred. Note that rp refers to Pearson’s correlation coefficient for parametric data, while rs refers to Spearman’s correlation coefficient for rank-ordered data. Source: From Refs. 14 and 30.
Consequently, it is a good idea to systematically gather examiner ratings of the validity of an assessment based on their interaction with each child. Ideally, these ratings should be formally coded and analyzed. For example, such ratings were considered in a pair of studies that examined the validity of two sets of purported measures of executive functioning in a group of inner-city adolescents (15,16). In preliminary analyses with the sample as a whole, the correlations between conceptually related measures were surprisingly weak. However, these correlations improved substantially after dropping the data from the approximately 10% of the sample whose assessments had been rated by the examiners as having been of questionable validity due to an apparent lack of test-taker effort. In writing about neuropsychological test findings, it is important to steer clear of phrasing that implies that test scores are homologous with brain functioning. True, modern science assumes that all thought arises from the brain and, particularly in adults, some neuropsychological tests are relatively sensitive to injuries in specific brain regions (e.g., finger tapping tends to ‘‘map’’ well to the contralateral precentral gyrus, about midway between the Sylvian and longitudinal fissures). However, even such well-defined relationships can be readily violated. Poor finger tapping performance can, for example, reflect injuries or degeneration at various points along the corticospinal tract, as well as nonneural muscular or connective tissue injuries. More complex cognitive processes are even less neurotopographically specific. This is especially true in children, whose brains may have developed atypically in response to a challenge (e.g., an
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early or ongoing injury), or who may show developmental shifts in how a cognitive process is conducted within the brain (17). This is not to say that one should abandon our scientific knowledge about brain-behavior relationships. Rather, it is a reminder that neurobehavioral test results are like direction signs from a substantial distance. Neurobehavioral findings are best interpreted in the context of solid theory building, taking into account developmental issues and other sources of information, including neurophysiological and imaging data in humans, as well as experimental animal models. Although neurobehavioral assessment has often been linked to officebased standardized cognitive testing, in fact a wide range of tools may be used. Table 3 lists the most common modalities of neurobehavioral assessment: officebased standardized testing, structured clinical interview, questionnaires (parent, teacher, child), and direct observations. Each means of gathering information has inherent strengths and weaknesses. Most early research on the neurobehavioral functioning of children with SDB relied heavily on parent report, probably because of the relative ease of data collection and the availability of psychometrically well-developed instruments. However, as shown in Table 3, parentreport questionnaires can suffer from various reporting biases and are not particularly adept at parsing out specific skill deficits. The second-most commonly used modality, office-based standardized cognitive tests, overcomes these weaknesses. However, some constructs, particularly attention and executive functioning (e.g., planning, organization, self-monitoring, mood regulation, behavior regulation) may be very difficult to assess in the tightly regulated office-based testing environment (6,11). Consequently, when assessing attention and executive functioning, it is important to gather complementary data from multiple sources. For example, although they have their own drawbacks, teacher reports are only minimally influenced by parent-report biases and can yield a sense of a child’s attention and executive functioning skills in an applied setting. In general, the combined findings across multifactorial assessment procedures can result in much more confident and comprehensive conclusions than those from any single procedure alone. Certain neurobehavioral assessment tools have been underutilized in the pediatric sleep research literature. As of this writing, only three articles had presented data from standardized, validated teacher-report behavioral questionnaires among children with SDB (7,18,19). Standardized clinical interviews—the ‘‘gold standard’’ for psychiatric diagnosis, have similarly been underutilized, despite the fact that multiple authors have noted the behavioral similarities between children with SDB and those diagnosed with ADHD (20). Finally, to the author’s knowledge, no SDB study has used direct observation (either in the natural environment or in a ‘‘simulated classroom’’) as a tool, despite its proven utility in research on children with ADHD and other behavioral disorders (21). These tools offer unique strengths that are not shared by other assessment modalities, and warrant greater use as the field moves forward.
Psychometric qualities well established Good control of contextual factors Can parse out specific cognitive skills Resistant to reporter/administrator biases Convenient for researcher Convenient for family Inexpensive (e.g., labor, time) Can gather information on ‘‘usual’’ performance or behavior over protracted time frame Considers real-life challenges that stress attention, executive functioning, coping Can record child’s spontaneous behaviors Can gather information on real-world settings Data source thoroughly familiar with child
Measurement characteristic
Structured diagnostic interview þ þ/ þ/ þ þ þ þ þ/
Office-based standardized testing þ þ þ þ
þ/
þ
þ
þ
þ þ þ þ
þ/
þ
Parent questionnaire
þ/
þ
þ
þ þ þ þ
þ/
þ
Teacher questionnaire
Table 3 Comparison of Major Tools for Assessing a Child’s Neurobehavioral Functioning
þ
þ
þ
þ þ þ þ
þ
Self-report questionnaire
þ/
þ
þ
þ
þ/ þ/
þ/
þ/
Direct observations
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þ þ/ þ þ þ/ þ þ/ þ/ þ
þ
þ/ þ þ
þ
þ/
þ
þ/
þ/ þ/
þ
Parent questionnaire
þ/
þ
þ/
þ/
þ
Teacher questionnaire
þ
þ
þ/ þ/
þ/
Self-report questionnaire
þ/
þ
þ þ/
þ/
Direct observations
A plus sign (þ) denotes strength of the assessment modality, a minus sign () denotes weakness, and both (þ/) denote that the modality may be strong or weak in a given area depending on the circumstances.
There are established instruments that assess many different constructs Can cater content to increase rapport Can stop the evaluation to clarify questions or answers to ensure accuracy Minimizes skipped or missing items Good choice for psychiatric diagnostic purposes Good choice to measure cognitive skills Good choice to measure overt behaviors Good choice to measure child’s thoughts/beliefs Good choice to measure child’s mood Good choice to measure parent attitudes
Measurement characteristic
Structured diagnostic interview
Office-based standardized testing
Table 3 Comparison of Major Tools for Assessing a Child s Neurobehavioral Functioning (Continued )
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Beebe IV.
The State of the Field Circa 2006
Whereas previous sections of this chapter have focused on issues that apply to neurobehavioral assessment beyond sleep medicine, the goal of this section is to provide a quick overview of what we have learned about the association between pediatric SDB and neurobehavioral functioning as of this writing, in mid-2006. An extensive review is beyond the scope of this chapter, and would further be redundant with a recent comprehensive review published in the journal Sleep (22). Only the main conclusions of that review will be summarized here; details, including an extensive citation list, can be found in the original. The review concluded that research strongly supports an association between SDB and children’s behavioral and emotional functioning in the natural setting (22). Impulsivity/hyperactivity and other ‘‘externalizing’’ behaviors such as aggression have been most consistently associated with SDB, though inattention of similar magnitude has also been reported (Fig. 4). A quick reading of the literature might imply that emotional problems are also associated with SDB, but a second look suggests that these conclusions are often based on composite ‘‘internalizing’’ scales that include somatic items, which may reflect sleepiness rather than negative mood. Although not always as obvious in childhood SDB as it is in adult SDB, daytime sleepiness is often present in children with this condition. As shown in Figure 5, there is reason to believe that children with SDB are at much greater risk for problems with emotion regulation (i.e., tempering emotional ups and downs) than for more ‘‘steady state’’ negative mood. This association between childhood SDB and problems with behavior and emotion regulation is not as evident in adults, reflecting a developmental shift that has not yet been adequately explained (23). As shown in Figure 6, many studies that have suggested links between SDB and office-based tests of intelligence may have capitalized upon recruitment techniques that yield control groups with above average intelligence. In fact, most studies have shown that school-age children with SDB tend to have average overall intelligence that only looks weak in comparison with potentially biased control groups. This would be consistent with adult studies that have shown little association between obstructive sleep apnea and intellectual test scores (24). However, well-constructed studies of very young children seem to be yielding different results. These studies, which used identical recruitment techniques for children in the SDB and control groups, suggest that intellectual weakness is associated with SDB during the preschool—first-grade years (25–28). It is not clear whether this represents a developmental vulnerability to SDB or a methodological artifact, since the content of intelligence tests varies somewhat across age groups (22,23). The 2006 review (22) further suggested that SDB did not appear to be related to expressive language, though children with SDB may have problems following oral instructions and diminished phonological processing skills. There was little evidence of an association between SDB and visual perception or
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Figure 4 Effect of SDB on parent-reported attention, hyperactivity/impulsivity, and other externalizing behaviors. Shown are standardized effect sizes derived from publications that included detail on all three behavioral domains (7,18,26,31,32). By convention, an effect size of 0.2 is considered small, 0.5 is considered medium, and 0.8 is considered large (33). The pooled effect sizes were computed using a random effects meta-analytic model (34), with the standard error of measurement represented by the line above each bar. Abbreviation: SDB, sleep-disordered breathing. Source: From Ref. 22.
Figure 5 Effect of SDB on parent-reported mood and emotional stability. Shown are standardized effect sizes. For Beebe et al.(7), the typical mood score represents the mean effect size from the anxiety and depression subscales of the Behavior Assessment System for Children (35), while the emotional stability score represents the effect size of the emotional control subscale of the Behavior Rating Inventory of Executive Functioning (6). For Rosen et al. (31), the typical mood score represents the mean effect size for the anxiety/depression subscale from the Child Behavior Checklist (36) and anxiety subscale from the Conners Parent Rating Scale (37), while the emotional stability score represents the effect size of the Conners emotional lability subscale. By convention, an effect size of 0.2 is considered small, 0.5 is considered medium, and 0.8 is considered large (33). Abbreviation: SDB, sleep-disordered breathing. Source: From Ref. 22.
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Figure 6 Association between SDB and overall IQ in 12 studies (7, 25–28, 38–44). The population mean is defined as 100, with a standard deviation of 15. Source: From Ref. 23.
construction, although complex line drawings may be affected. Some memory test processes may be vulnerable to SDB, but memory test findings have been surprisingly mixed. Similarly, at the time of this writing, inconsistent measures and findings precluded conclusions regarding higher-level reasoning skills. Tests of short-term working memory appear not to be related to SDB in children. However, multiple studies have suggested that SDB adversely impacts continuous performance tests that rely on sustained attention and inhibition, as well as cancellation tests that require speed, visual scanning, and selective attention. Such in-office findings are at least partially consistent with the problems with attention and behavior regulation noted above. It is possible that these deficits contribute to poor school performance, as numerous studies have shown SDB to be related to diminished school performance, despite evidence that scores on tests of basic academic knowledge are normal in school-age children with SDB. Proposed mechanisms by which childhood SDB might result in neurobehavioral morbidity generally start with its primary features—sleep disruption and intermittent hypoxia—then move to several adverse neural pathways. At the time of this writing, several proposed mechanisms have supportive evidence, but none has been demonstrated to be both necessary and sufficient for generating the pattern of findings observed in children with SDB (22,23). A few studies have examined the natural history of SDB and neurobehavioral functioning. Taken together, the data suggest that childhood snoring imparts a long-term risk for daytime behavior and scholastic problems. Nonrandomized treatment trials suggest considerable reversibility of neurobehavioral
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deficits with effective treatment. However, long-term prospective treatment outcome studies and randomized treatment trials with neurobehavioral outcomes have not yet been conducted. In light of this, it is concerning that long-term observational studies suggest that the risk for behavioral and scholastic deficits may persist even after snoring spontaneously resolves (22). Clearly, there is more work to be done before we have a solid understanding of the relationship between childhood SDB and neurobehavioral functioning, both immediately and over time. V.
Concluding Comments
The tone of much of this review has been cautionary. Given that the target reader is one who is not familiar with the details of neurobehavioral assessment, a key goal was to highlight potential pitfalls so that these could be successfully avoided. However, it is equally important to recognize that, despite these pitfalls and limitations, psychometric assessment remains the foundation upon which the science of neurobehavioral research is built. It is hoped that this chapter provides a greater appreciation of the assessment aspects of that science, including its terminology, a glimpse at its breadth and depth, and examples of how it may be applied in the study of children with SDB. If this appreciation sparks a passion, the reader is strongly recommended to review authoritative texts by Anastasi (4), Sattler (2,3), and Baron (11). This is an exciting time of interdisciplinary collaboration in pediatric sleep research. As with other interdisciplinary research, the degree to which each discipline understands the other will be a major determinant of the success of the enterprise, as a whole. Acknowledgment Preparation of this chapter was supported in part by grant K23 HL075369 from the National Institutes of Health. References 1. Hill W. On some causes of backwardness and stupidity in children: and the relief of these symptoms in some instances by nasopharyngeal scarifications. BMJ 1889; 2:711–712. 2. Sattler JM. Assessment of Children: Behavioral and Clinical Applications. 4th ed. San Diego, CA: Author, 2001. 3. Sattler JM. Assessment of Children: Cognitive Applications. 4th ed. San Diego, CA: Author, 2001. 4. Anastasi A. Psychological Testing. New York: Macmillan, 1988. 5. Cohen RJ, Swerdlik M. Psychological Testing and Assessment: An Introduction to Tests and Measurement. 6th ed. New York: McGraw-Hill, 2004.
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6. Gioia GA, Isquith PK, Guy SC, et al. BRIEF—Behavior Rating Inventory of Executive Function Odessa. FL: Psychological Assessment Resources, 2000. 7. Beebe DW, Wells CT, Jeffries J, et al. Neuropsychological effects of pediatric obstructive sleep apnea. J Int Neuropsychol Soc 2004; 10:962–975. 8. Chervin RD, Hedger KM, Dillon JE, et al. Pediatric sleep questionnaire (PSQ): validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Med 2000; 1:21–32. 9. Carskadon MA. Factors influencing sleep patterns of adolescents. In: Carskadon MA, ed. Adolescent Sleep Patterns: Biological, Social, and Psychological Influences. Cambridge, UK: Cambridge University Press, 2002:4–26. 10. Kaplan E, Goodglass H, Weintraub S. The Boston Naming Test. 2nd ed. Philadelphia, PA: Lea & Febiger, 1983. 11. Baron IS. Neuropsychological Evaluation of the Child. New York: Oxford University Press, 2004. 12. Golden CJ. Stroop Color and Word Test. Chicago, IL: Stoelting, 1978. 13. Wechsler D. WISC-IV Manual. San Antonio, TX: The Psychological Corporation, 2003. 14. Gordon M. The Gordon Diagnostic System. DeWitt, NY: Gordon Systems, 1983. 15. Beebe DW, Ris MD, Dietrich KN. The relationship between CVLT-C process scores and measures of executive functioning: lack of support among communitydwelling adolescents. J Clin Exp Neuropsychol 2000; 22:779–792. 16. Beebe DW, Ris MD, Brown TM, et al. Executive functioning and memory for the Rey-Osterreith complex figure task among community adolescents. Appl Neuropsychol 2004; 11:91–98. 17. Anderson V, Northam E, Hendy J. Developmental Neuropsychology: A Clinical Approach. Philadelphia, PA: Psychology Press, 2001. 18. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance, and behaviour in 4–5 year olds. Arch Dis Child 1993; 68:360–366. 19. Arman AR, Ersu R, Save D, et al. Symptoms of inattention and hyperactivity in children with habitual snoring: evidence from a community-based study in Istanbul. Child Care Health Dev 2005; 31:707–717. 20. Owens JA. The ADHD and sleep conundrum: a review. J Dev Behav Pediatr 2005; 26:312–322. 21. Anastopoulos AD, Shelton TL. Assessing Attention-Deficit/Hyperactivity Disorder. New York: Kluwer Academic/Plenum Publishers, 2001. 22. Beebe DW. Neurobehavioral effects of childhood sleep-disordered breathing (SDB): a comprehensive review. Sleep 2006; 29:1115–1134. 23. Beebe DW. Neurobehavioral effects of obstructive sleep apnea: an overview and heuristic model. Curr Opin Pulm Med 2005; 11:494–500. 24. Beebe DW, Groesz L, Wells C, et al. The neuropsychological effects of obstructive sleep apnea (OSA): a meta-analysis of norm-referenced and case-controlled data. Sleep 2003; 26:298–307. 25. Gottlieb DJ, Chase C, Vezina RM, et al. Sleep-disordered breathing symptoms are associated with poorer cognitive function in 5-year-old children. J Pediatr 2004; 145:458–464. 26. O’Brien LM, Mervis CB, Holbrook CR, et al. Neurobehavioral correlates of sleepdisordered breathing in children. J Sleep Res 2004; 13:165–172.
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27. O’Brien LM, Mervis CB, Holbrook CR, et al. Neurobehavioral implications of habitual snoring in children. Pediatrics 2004; 114:44–49. 28. Montgomery-Downs HE, Crabtree VM, Gozal D. Cognition, sleep and respiration in at-risk children treated for obstructive sleep apnoea. Eur Respir J 2005; 25:336–342. 29. Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986; 9:519–524. 30. Beebe DW, Kalra G, Bailie J, et al. Performance on a computerized vigilance task correlates with actigraphy-defined sleep disruption but not psg indexes of sleep disruption in obese adolescents. Sleep 2006; 29(suppl):A97 (abstr). 31. Rosen CL, Storfer-Isser A, Taylor HG, et al. Increased behavioral morbidity in school-aged children with sleep-disordered breathing. Pediatrics 2004; 114:1640–1648. 32. Mulvaney SA, Goodwin JL, Morgan WJ, et al. Behavior problems associated with sleep disordered breathing in school-aged children—the Tucson Children’s Assessment of Sleep Apnea study. J Pediatr Psychol 2006; 31:322–330. 33. Cohen CK. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988. 34. Lipsey MW, Wilson DB. Practical Meta-Analysis (Applied Social Research Methods), vol 49. Thousand Oaks, CA: Sage, 2001. 35. Reynolds CR, Kamphaus RW. BASC—Behavioral Assessment System for Children Manual. Circle Pines, MN: American Guidance Service, 1992. 36. Achenbach TM, Edelbrock C. Manual for the Child Behavior Checklist and Revised Child Behavior Profile. Burlinton, VT: Univerisity of Vermont, 1981. 37. Conners CK. Conners’ Ratings Scales-Revised: Technical Manual. North Tonawanda, NY: Multi-Health Systems, 1997. 38. Blunden S, Lushington K, Kennedy D, et al. Behavior and neurocognitive performance in children aged 5–10 years who snore compared to controls. J Clin Exp Neuropsychol 2000; 22:554–568. 39. Ali NJ, Pitson DJ, Stradling JR. Sleep disordered breathing: effects of adenotonsillectomy on behaviour and psychological functioning. Eur J Pediatr 1996; 155:56–62. 40. Lewin DS, Rosen RC, England SJ, et al. Preliminary evidence of behavioral and cognitive sequelae of obstructive sleep apnea in children. Sleep Med 2002; 3:5–13. 41. Kaemingk KL, Pasvogel AE, Goodwin JL, et al. Learning in children and sleepdisordered breathing: findings of the Tucson Children’s Assessment of Sleep Apnea (TuCASA) prospective cohort study. J Int Neuropsychol Soc 2003; 9:1016–1026. 42. Friedman BC, Hendeles-Amitai A, Kozminzki E, et al. Adenotonsillectomy improves neurocognitive function in children with obstructive sleep apnea syndrome. Sleep 2003; 26:999–1005. 43. Blunden S, Lushington K, Lorenzen B, et al. Neuropsychological and psychosocial function in children with a history of snoring or behavioral sleep problems. J Pediatr 2005; 146:780–786. 44. Emancipator JL, Storfer-Isser A, Taylor HG, et al. Variation of cognition and achievement with sleep-disordered breathing in full-term and preterm children. Arch Pediatr Adolesc Med 2006; 159:1–8.
16 Structural and Functional Magnetic Resonance Imaging as a Research Tool in Pediatric Sleep Research
RONALD M. HARPER, PAUL M. MACEY, and RAJESH KUMAR David Geffen School of Medicine, UCLA, Los Angeles, California, U.S.A.
I.
Introduction
The remarkable development of magnetic resonance imaging (MRI) procedures in the last few years has provided significant enhancements over other imaging approaches for both clinical care as well as research in pediatrics. Innovations in both structural and functional MRI (fMRI) techniques have contributed to this enhanced potential to evaluate sleep-related processes; it is the objective of this chapter to demonstrate current procedures and future potential for imaging techniques. Examples will be directed principally toward issues confronted in pediatric sleep research and, especially, breathing-related aspects of neural function and structure; airway morphology and action will also be considered, and particular constraints in imaging techniques for very young pediatric cases will be discussed. II.
Structural Imaging
A.
Upper Airway Morphology
The evaluation of upper airway morphology, especially in cases of obstructive sleep apnea (OSA), has received much attention in adults and children with 367
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diagnoses of sleep-disordered breathing (1–4). Earlier studies have principally used static or cine X ray, and computed tomography (5,6) imaging procedures, and have been useful for indicating gross deformations of the airway. Rapid structural MRI procedures, made possible by higher field-strength magnets and other technology enhancements, allow nonionizing radiation cine procedures to be applied to pediatric airway structure, evaluation of airflow (7) and turbulence in compromised airways (8), and transitions of soft tissue positions during waking and sleep states (9). The capability to image soft tissue structure, and especially the MR propensity for proton visualization in fat deposits, which is a special concern in sleep-disordered breathing in obese pediatric cases, is particularly valuable, as is the capability to establish changes in airway morphology with the onset of sleep (1,10). B.
Brain Morphology
Routine MRI
Magnetic resonance (MR) studies of the brain in very young infants pose unique problems, since infants have reduced lipid-laden myelin in axons of long fiber tracts, especially to the forebrain, altering the capability to visualize such axonal structures. MR studies for clinical examination have heavily used T2-weighted scans to more readily visualize tumors, tuberculomas, brain abscesses, and other gross pathologies, and T1-weighted scans to provide highresolution detail of gray and white matter. However, visibility of lesions on T2- and T1-weighted images depends on signal differences between the lesion and the surrounding normal parenchyma (11), and subtle tissue changes may not appear on routine MRI. The sources of injury frequently encountered by pulmonary physicians include intermittent hypoxia associated with sleep-disordered breathing, in addition to chronic hypoxia exposure or carbon monoxide or other asphyxiation. Tissue changes due to these exposures may be subtle, and not visible on routine MRI. T2 Relaxometry
Some of the injuries that result from suspected perfusion and hypoxia-induced changes accompanying sleep-disordered breathing are among those that do not appear as gross lesions, and thus require more specialized procedures for detection. A useful procedure for determination of tissue injury accompanying cell loss, demyelination, or loss of cell membranes is T2 relaxometry, which assesses the relative proportion of free to bound water content (12). This index changes in tissues affected by several disease processes, and has been implemented to study a number of disorders (12–14). The use of T2 relaxometry is illustrated in Figure 1, which demonstrates injury associated with congenital central hypoventilation syndrome (CCHS), and shows unique specificity of
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Figure 1 (See color insert.) Regions of structural damage as indicated by increased T2 relaxation time in 12 CCHS patients compared with 28 control subjects, color coded according to significance level (scale on right) and overlaid onto a single subject’s T1weighted anatomical scan. Damage extending from the lamina terminalis through the hypothalamus is noted by ‘‘a’’; injury damage also appears in the cerebellum, posterior cingulate, mid corpus callosum, and ventral frontal cortex. Abbreviation: CCHS, congenital central hypoventilation syndrome.
damage in, for example, thermoregulatory areas likely responsible for poor body temperature control in the syndrome (15). This example is of significance, since the American Thoracic Society description of CCHS (16) makes note that no significant lesions are detected by routine MRI which would result in the physiological characteristics of CCHS. Clearly, diffuse injury, as well as alterations in regional sites, are present in the syndrome and can be visualized using these specialized procedures. Diffusion Tensor Imaging
Diffusion tensor imaging (DTI), which allows direct examination of tissue architecture (17), is of great value in determining pathology where diffusion of water is altered. Water molecule diffusion is characterized by Brownian motion, and given an absence of tissue barriers (such as cell membranes and myelin), the direction of motion of a molecule is random. The movement of water molecules over time is described by a Gaussian distribution, and is called isotropic diffusion when motion is equal and unrestricted in all directions (17). However, tissue barriers limit Brownian motion of water molecules, resulting in the restriction of the total amount of diffusion (diffusion will, for example, be more restricted perpendicular to fibers than parallel to them), and is known as anisotropic
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diffusion (18). Changes in tissue microstructure will alter tissue barriers and thus diffusion properties, which can be determined by DTI procedures. DTI is especially useful for specialized applications, such as determination of axonal integrity and fiber tracking. The characteristics of nerve fibers, with fluid surrounded by myelin, constraining diffusion of fluid along the axis of the fiber (Fig. 2), allow assessment of fiber integrity, provide indications of directionality, and enable assessment of fiber tracking. Other characteristics of fibers also contribute to determination of directionality and tracking (19). An indication of the usefulness of the technique can be seen in assessment of fractional anisotropy (FA) and fiber tracking in CCHS (Fig. 3). The average diffusivity of water, mean diffusivity (MD), can also indicate possible tissue damage in the brain. An illustration of the use of MD can be seen in Figure 4, which shows injury in brainstem regions of CCHS patients (20).
Figure 2 Schematic illustration of changes in DTI indices with possible pathologies in gray and white matter. Fractional anisotropy ranges from 0 (no directionality, as in CSF) to 1 (water constrained to propagate only in one direction). Mean diffusivity is highest in CSF, and lower in gray and white matter. Abbreviations: FA, fractional anisotropy; MD, mean diffusivity.
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Figure 3 (See color insert.) Two-dimensional DTI representation of axonal projections in a CCHS (left) and control (right) subject, suggesting a diminution of axonal integrity in anterior cingulum bundle fibers in the patient group (arrow, top panels). The circular color scale indicates fiber direction (colors viewed on a sphere from above, i.e., green is anterior posterior, red medial lateral, etc.). For each voxel, the intensity of the color is scaled according to the fractional anisotropy at that point, with dark colors or black indicating no directionality, and bright colors indicating high directionality. A region of interest drawn in the cingulum (mid panels, white squares) can provide a set of characteristics of fibers within that region, including fiber number, and length and number of fibers/voxel characteristics. (Lowest panels): Fiber tracking in one 13-year-old male CCHS case and a matched control. Diminished fiber distribution to the cerebellum (circle) occurs in CCHS (b) over the control (a), and altered cortical fiber dispersion in the CCHS case also occurs (region of interest drawn in the pons). The background gray-scale images are diffusion images with no gradient (‘‘b0’’ images), and illustrate the distortion inherent in such acquisitions. Abbreviations: DTI, diffusion tensor imaging; CCHS, congenital central hypoventilation syndrome.
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Figure 4 (See color insert.) Significantly increased MD values in 12 CCHS cases versus 28 age- and gender-matched controls indicated by colored areas; damage appears in the ventral brainstem (arrow), other affected regions appear in the basal forebrain, corpus callosum, posterior cingulate, deep cerebellar nuclei, and cortical sites. Abbreviation: MD, mean diffusivity; CCHS, congenital central hypoventilation syndrome.
Magnetization Transfer Imaging
Magnetization transfer imaging (MTI) is another contrast mechanism involving free and bound water proton pools. Different biological tissues have different amounts of free and bound water protons, and only the free water proton pool contributes to the measurable MR signal (21). However, a continuous exchange of protons occurs between these proton pools through dipole–dipole interactions, indicating that bound protons also contribute indirectly to the MR signal (22). Using MTI procedures, bound water protons can be saturated without disturbing the free water proton pool, and the contribution of the bound water proton pool into the free water proton pool can be quantified in terms of the magnetization transfer ratio (MTR) (22). In general, during disease processes, bound protons decrease because of cell loss, membrane injury, and demyelination, and free protons increase, resulting in decreased MTR values. This contrast mechanism can be implemented in T2-, T1-, or proton density–weighted imaging. The procedures have been successfully used in several central nervous system diseases, such as traumatic brain injury (23), temporal lobe epilepsy (24), tuberculomas (25), and especially in white matter disease, including multiple sclerosis (26). The procedure has excellent potential for describing neural changes in sleep-related syndromes, especially where development of a disorder is an issue. Figure 5 illustrates MTI.
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Figure 5 Raw scans (A, B) used for calculation of magnetization transfer ratio (C ). (Panel A): A PD-weighted image; (Panel B): a PD-weighted image with magnetization transfer preparation; and (Panel C ): an MTR map showing bright white matter (15-year-old control subject). Abbreviation: MTR, magnetic transfer ratio.
Magnetic Resonance Spectroscopy
Brain metabolites from localized portions of the brain, including choline (Cho), creatine (Cr), and N-aceytlaspartate (NAA), can be measured using magnetic resonance spectroscopy (MRS). NAA is a marker for neuronal integrity or functionality, choline for cell density, and creatine for energy metabolism. These measures are often valuable for evaluation of tissue changes associated with hypoxia, and have been successfully used to show injury in the hippocampus of pediatric OSA cases (27); a pattern of metabolic changes in the insula of one pediatric OSA case is shown in Figure 6. Spectroscopic procedures continue to develop; the assessment of glutamate/glutamine is now possible (28), and the determination of other neurotransmitter levels will likely follow. III. A.
Functional Imaging Bold fMRI
Blood oxygen level dependent (BOLD) imaging, which assesses the relative proportion of oxygenated blood versus deoxygenated blood, is currently the most common fMRI procedure (29,30). The BOLD signal is directly related to the blood volume and the deoxyhemoglobin level, so that alterations in local deoxyhemoglobin that occur with neural activation cause small, but statistically significant, changes in signal intensity. Neural activation is followed by an inflow of oxygenated blood, a consequent decrease in deoxyhemoglobin and thus, increased BOLD signal intensity. Therefore, BOLD fMRI detects neurovascular changes rather than electrophysiological neural activation. However, work on animals demonstrates a strong correlation between the two, indicating that changes in BOLD signal correlate with local field potentials, and therefore
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Figure 6 Example of spectral peaks of NAA, Cr, and Cho of magnetic resonance spectroscopy plots from the right insular cortex in one OSA and in one control subject. Abbreviations: NAA, N-aceytlaspartate; Cr, creatine; Cho, choline; OSA, obstructive sleep apnea.
reflect input and intracortical processing that occur within a given area (31). BOLD imaging has been instrumental in demonstrating localized functional deficits in developmental disorders such as CCHS, and for illustrating normal pediatric responses to ventilatory and cardiovascular challenges (32–36). B.
Spin Label Procedures
Another fMRI procedure, arterial spin labeling (ASL), labels blood electromagnetically with a tracer that allows visualization of blood flow (37); this procedure infers activity somewhat reminiscent of procedures used for positron emission tomography (PET) imaging, i.e., inferring activity by assessment of perfusion aspects. This approach can measure directly a well-characterized physiological perfusion parameter, and can be sampled using imaging sequences that preserve signal in regions where artifact from surrounding tissue may be present (e.g., frontal and orbitofrontal cortices) (38). In this procedure, perfusion measurements are derived from pair-wise subtractions of images acquired with and without spin labeling. The pair-wise subtraction and subsequent calibration processes produce an absolute measure of cerebral blood flow (CBF); the slow drifts in BOLD contrast images are eliminated in ASL (39). Measurements of resting CBF from ASL are stable across time intervals from a few minutes to a few days, and comparison between ASL and BOLD contrast data suggests that
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ASL is better than BOLD contrast for task periods more than one minute (39). The procedure has been used in applications such as visualizing adult ischemic stroke effects, but its use in pediatric sleep research is still developing. C.
DTI Functional Imaging
Cellular discharge is accompanied by multiple alterations in physical characteristics of the cell membrane and changes in ionic flow, including expansion of the cell associated with the inflow of ions. The property of cellular swelling accompanying ionic flux changes with neural discharge has been used for high temporal resolution neural optical imaging of in vivo animal preparations (40,41). The transitory ionic and membrane alterations with neural firing can be used for DTI-based functional MR imaging, allowing a much higher temporal resolution data collection than hemodynamic-based BOLD techniques (19,42). Functional imaging using DTI procedures has not yet entered mainstream research, but offers considerable potential for imaging of rapidly-changing signals, especially those encountered in sleep research. IV. A.
Analytic Procedures Structural MRI
Voxel-Based Analysis
Voxel-based analysis (VBA), a generalization of voxel-based morphometry (VBM), provides for whole-brain analysis of large samples, as opposed to the manual definition of regions on a subject-by-subject basis. VBM has been used to identify gray matter loss in adult OSA (43). VBA consists of several processing steps, including normalization of each subject’s images into a common space, segmentation of different tissue types if required, smoothing those images, and performing statistical analyses at each voxel. Spatial Normalization and Segmentation
Spatial normalization is the procedure of warping an individual subject’s brain images into a common space. A standard adult template, such as the Montreal Neurological Institute (MNI) atlas, is typically used. This normalization process is an important step in the analysis, and standardizes brain sizes and shapes of different subjects. Most algorithms involve optimizing a series of nonlinear warping functions to best match the warped brain to a template. Another successful approach is a unified spatial normalization, bias correction, and segmentation procedure, implemented in a common freely available statistical package for MRI data analysis, Statistical Parametric Mapping (SPM) (44). The unified procedure is included in SPM version 5, and combines spatial normalization, intensity correction due to field inhomogeneity, and tissue segmentation into different types (this step is not necessary for all types of data), using a priori
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knowledge of the likely distribution of gray matter, white matter, and cerebrospinal fluid (CSF). Smoothing
Since different subjects have different brain sizes, spatial normalization has limited accuracy, and smoothing is required to minimize such confounds. Smoothing improves the signal-to-noise ratio for changes similar in size to the smoothing kernel, but the size of the smoothing kernel can impact results (45). Most studies use a smoothing kernel size from 10 to 12 mm. Statistical Analyses and Display
The normalized and smoothed images can be compared voxel-by-voxel to determine group differences. Covariates such as age or gender can be evaluated with an extension of two-sample t-tests. A ‘‘brain’’ mask, based on the segmented gray and white matter maps, can be used to remove any regions outside the brain from gray and white volumes. Once differences are detected by VBA, visualization techniques can be used, including: (1) a ‘‘glass brain’’ display which shows tissue damage/neural changes depending on the study in three 2-dimensional views—sagittal, coronal, and axial, with extent of change coded in gray or color scale density; (2) three-dimensional views with significant extent of change indicated as pseudocolored overlays on a reconstructed brain; and (3) overlays of significant regions of pseudocolored tissue damage/neural change onto a structural image, typically the mean image derived from all subjects’ normalized T1-weighted images. These images can be combined with cine techniques to show progressive changes over time. Defined Areas of Analysis: Volume of Interest
Volume-of-interest (VOI) analysis can be performed on structural data. For VOI analysis, manual definition of regions on a subject-by-subject basis is performed. Using these VOI, mean or median values of corresponding measures are calculated. Morphometry
An extension of VOI analysis is detailed regional examination of shape. Structures may be examined using specialized morphometric techniques, most of which are specific to certain brain structures such as the hippocampus (46). Figure 7 illustrates regions of the hippocampus that are reduced in volume in a pediatric OSA subject relative to five matched controls. B.
Functional MRI
Functional magnetic resonance imaging data analysis consists of several processing steps, including slice timing correction (necessary, depending on repetition time, an MRI scanning parameter), and motion correction; the remaining
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Figure 7 (See color insert.) Surface map of hippocampal volume ratio of one OSA patient relative to mean of five age- and gender-matched controls; white regions indicate reduced volume in the OSA patient of more than 20%, and colored (blue-red ) regions indicate no major difference in volume (see color key). Abbreviation: OSA, obstructive sleep apnea.
steps are similar to those for structural data analysis using VBA approaches. Using the normalized and smoothed functional images, two types of statistical analyses can be performed. Cluster Analysis
A common analytic technique for functional image analysis consists of detecting clusters of voxels that match a predefined pattern, or model, highlighting regions of signal increase or decrease throughout a challenge. A second-level population analysis, also known as random-effects analysis, can be performed to determine regions of significantly different neural responses between groups. Typically, adjustment for multiple comparisons using a modified Bonferroni correction is employed (47). VOI Analysis
The cluster analysis procedure only detects responses matching a model; therefore, to assess values changing with time, a second fMRI image analysis method, VOI, is used. The VOI analysis requires the investigator to manually identify the VOI areas for analysis, and to use repeated-measures ANOVA to compare the averaged time trend of all voxels within each VOI. VOI analysis allows for detection of responses within each group relative to baseline, and differences in response between groups, and does not assume a predetermined
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Figure 8 (See color insert.) Regions of significant increase or decrease in fMRI signal to a hypercapnic gas (CO2/O2) challenge in 14 pediatric subjects overlaid onto a single subject’s high resolution anatomical scan. The arrows indicate a region of signal increase in the cerebellum, with the time-trend shown in the graph (mean ± SE). An initial baseline 3-minute 30-second series was collected, followed at least 7 minutes later by a second series with hypercapnic gas mixture administered at time 0 (30 second into the fMRI series). Abbreviation: fMRI, functional magnetic resonance imaging.
pattern of response, unlike cluster analysis. An example of a VOI analysis applied to a sleep-disordered breathing problem is shown in Figure 8, and shows responses to CO2 in a control group of children (32). The CO2 challenge poses an additional issue for analysis since CO2 induces vasodilation, producing large global changes in the MR signal. These global signals can be removed (48), leaving signal changes in regional areas to indicate brain areas responding to the CO2 stimulation. V.
Physiological Data Acquisition
Functional MRI studies related to sleep frequently require concurrent acquisition of physiological signals to examine effects of challenges or state on activity within the autonomic nervous system, electroencephalograph (EEG) or breathing. Such acquisition poses significant logistic problems, since the high, changing magnetic fields of the scanner can readily introduce signals in electrodes and metallic leads, which can overwhelm physiological signals that are the objects of interest. Moreover, changing magnetic fields have the potential to induce large currents in the recording electrodes that can elicit unwanted electrical stimulation or even burn the subject. Finally, currents induced in local amplifiers and leads can lead to signals that interfere with image acquisition and elicit considerable artifacts on those images.
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Typically, scanners are equipped with electrocardiogram (ECG) amplifiers and, often, respiratory bellows to allow cardiac tracings and measures of thoracic wall movements. However, other signals are frequently required. Commercial manufacturers have introduced MR-compatible devices for acquisition of O2 saturation, EEG acquisition, and airflow; however, these instruments can be relatively high cost (pulse O2 saturation devices excepted). To reduce costs, laboratory-built systems, consisting of high commonmode rejection and low-noise operational amplifiers, coupled by fiber optic cables to receivers located outside the scanner area, have been used to reduce contamination from magnetic fields (49). When cables cannot be passed through the scanner magnetic shield, infrared transmission systems (50) can be used to send signals through the observation window and transfer EEG, ECG, O2 saturation, thoracic movement, and other physiologic signals. Cloth belts overlying air-filled plastic bags that are connected through noncompliant tubing to an external pressure transducer can readily acquire thoracic wall movement signals. Airflow can be assessed by MR-compatible flowmeters. Currently, small CO2 MR-compatible sensors capable of being locally placed are being developed, avoiding the long transmission of sample lines. VI.
Movement Control
The bane of MR imaging is movement of the imaged structure. This issue becomes especially important in pediatric imaging, with patients who may be unable or unwilling to comply with instructions to remain still, and who may become upset with restraint typically used to restrict head or other body movement. Procedures used to overcome such movement can include sedation for structural imaging, but the effects of such sedation on functional imaging may preclude such use, especially since certain sedatives can exert marked effects on brain activity and upper airway muscle tone. Some groups have developed specialized restraint procedures for very young infants which, when combined with more rapid imaging sequences, allow short-term acquisition of data from such subjects (51,52). Specialized head restraint devices have been developed for animals (53). Image sequences are normally visually evaluated for motion artifact, and subjected to motion correction procedures for removal of such artifact; such motion correction is incorporated in the SPM analysis software. VII.
Imaging Resources and Shared Access
A significant, but sometimes overlooked issue in MRI-based research is image storage. Functional MRI, in particular, poses formidable storage requirements; rapid acquisition of images over the entire brain for a sustained period requires attention to image transmission, storage media, and archiving. Standard image formats (e.g., DICOM) have been established to ease data sharing.
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Several public-domain image resources are being established to assist pediatric brain research investigations, including a structural database, which includes a developmental DTI atlas (54) (http://www.pediatricdti.org/), and a National Institutes of Health MRI study on normal brain development (http:// www.brain-child.org/). The latter study, currently in progress, will enroll approximately 546 children ranging in age from infancy to young adulthood who will be imaged at different time points over a six-year period. The data will include 3D T1-weighted volume imaging and T2-weighted imaging; subpopulations will also include MRS and DTI data, and the images are accompanied by neuropsychological evaluations. A multicenter consortium (http:// www.brainmapping.org/) provides a significant resource for imaging, with links to multiple imaging centers. Databases for adult populations have been developed or are in progress, and links to these databases are in the brain-mapping site. Several image resources for analysis, including SPM (44) (http://www.fil. ion.ucl.ac.uk/spm/) and for image display MRIcro (http://www.sph.sc.edu/comd/ rorden/mricro.html) also have been developed; another U.K. site with software resources is that at Oxford (http://www.fmrib.ox.ac.uk/). DTI analysis has especially benefited from tracking software offered by Mori and colleagues (H. Jiang and S. Mori, Johns Hopkins University, http://cmrm.med.jhmi.edu). VIII.
Summary
Pediatric sleep research has the potential to benefit substantially from recent developments in imaging technology and the concurrent implementation of physiological and data management procedures for support of those imaging procedures. The MR field is undergoing development of remarkable imaging innovations, with procedures now available to study neurotransmitter levels, e.g., glutamate/glutamine, in addition to classic cellular and fiber attributes. The field has benefited substantially by sharing of resources in imaging databases, analytic techniques, and display procedures, all of which are readily available through Internet access. Acknowledgment Supported by NIH HD-22695 and HL-60296. References 1. Arens R, McDonough JM, Costarino AT, et al. Magnetic resonance imaging of the upper airway structure of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2001; 164(4):698–703. 2. Iida-Kondo C, Yoshino N, Kurabayashi T, et al. Comparison of tongue volume/oral cavity volume ratio between obstructive sleep apnea syndrome patients and normal adults using magnetic resonance imaging. J Med Dent Sci 2006; 53(2):119–126.
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24. Tofts PS, Sisodiya S, Barker GJ, et al. MR magnetization transfer measurements in temporal lobe epilepsy: a preliminary study. Am J Neuroradiol 1995; 16(9):1862–1863. 25. Gupta RK, Husain M, Vatsal DK, et al. Comparative evaluation of magnetization transfer MR imaging and in-vivo proton MR spectroscopy in brain tuberculomas. Magn Reson Imaging 2002; 20(5):375–381. 26. Schmierer K, Scaravilli F, Altmann DR, et al. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol 2004; 56(3):407–415. 27. Halbower AC, Degaonkar M, Barker PB, et al. Childhood obstructive sleep apnea associates with neuropsychological deficits and neuronal brain injury. PLoS Med 2006; 3(8):E301. 28. Hattori N, Abe K, Sakoda S, et al. Proton MR spectroscopic study at 3 Tesla on glutamate/glutamine in Alzheimer’s disease. Neuroreport 2002; 13(1):183–186. 29. Kwong KK, Belliveau JW, Chesler DA, et al. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci U S A 1992; 89(12):5675–5679. 30. Ogawa S, Lee TM, Nayak AS, et al. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn Reson Med 1990; 14(1): 68–78. 31. Logothetis NK, Pauls J, Augath M, et al. Neurophysiological investigation of the basis of the fMRI signal. Nature 2001; 412(6843):150–157. 32. Harper RM, Macey PM, Woo MA, et al. Hypercapnic exposure in congenital central hypoventilation syndrome reveals CNS respiratory control mechanisms. J Neurophysiol 2005; 93(3):1647–1658. 33. Macey KE, Macey PM, Woo MA, et al. fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome. J Appl Physiol 2004; 97(5):1897–1907. 34. Macey PM, Macey KE, Woo MA, et al. Aberrant neural responses to cold pressor challenges in congenital central hypoventilation syndrome. Pediatr Res 2005; 57(4): 500–509. 35. Macey PM, Woo MA, Macey KE, et al. Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital central hypoventilation syndrome. J Appl Physiol 2005; 98(3):958–969. 36. Woo MA, Macey PM, Macey KE, et al. FMRI responses to hyperoxia in congenital central hypoventilation syndrome. Pediatr Res 2005; 57(4):510–518. 37. Detre JA, Alsop DC. Perfusion fMRI with arterial spin labeling (ASL). In: Moonen CTW, Bandettini PA, eds. Functional MRI. Heidelberg: Springer-Verlag, 1999:47–62. 38. Wang J, Aguirre GK, Kimberg DY, et al. Arterial spin labeling perfusion fMRI with very low task frequency. Magn Reson Med 2003; 49(5):796–802. 39. Aguirre GK, Detre JA, Zarahn E, et al. Experimental design and the relative sensitivity of BOLD and perfusion fMRI. Neuroimage 2002; 15(3):488–500. 40. Poe GR, Rector DM, Harper RM. Hippocampal reflected optical patterns during sleep and waking states in the freely behaving cat. J Neurosci 1994; 14(5 pt 2): 2933–2942. 41. Rector DM, Rogers RF, Schwaber JS, et al. Scattered-light imaging in vivo tracks fast and slow processes of neurophysiological activation. Neuroimage 2001; 14(5): 977–994.
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42. Darquie A, Poline JB, Poupon C, et al. Transient decrease in water diffusion observed in human occipital cortex during visual stimulation. Proc Natl Acad Sci U S A 2001; 98(16):9391–9395. 43. Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002; 166(10):1382–1387. 44. Friston KJ, Frith CD, Liddle PF, et al. The relationship between global and local changes in PET scans. J Cereb Blood Flow Metab 1990; 10(4):458–466. 45. Jones DK, Symms MR, Cercignani M, et al. The effect of filter size on VBM analyses of DT-MRI data. Neuroimage 2005; 26(2):546–554. 46. Thompson PM, Hayashi KM, de Zubicaray GI, et al. Mapping hippocampal and ventricular change in Alzheimer disease. Neuroimage 2004; 22(4):1754–1766. 47. Worsley KJ, Marrett S, Neelin P, et al. A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp 1996; 4:58–73. 48. Macey PM, Macey KE, Kumar R, et al. A method for removal of global effects from fMRI time series. Neuroimage 2004; 22(1):360–366. 49. Parker JM, Alger JR, Woo MA, et al. Acquisition of electrophysiologic signals during magnetic resonance imaging. Sleep 1999; 22(8):1125–1126. 50. Harper RM, Parker JM, Frysinger RC, et al. Infrared transfer of electrophysiologic signals during magnetic resonance imaging. Sleep Res Online 2001; 4(1):13–15. 51. Bluml S, Friedlich P, Erberich S, et al. MR imaging of newborns by using an MRcompatible incubator with integrated radiofrequency coils: initial experience. Radiology 2004; 231(2):594–601. 52. Vigneron DB. Magnetic resonance spectroscopic imaging of human brain development. Neuroimaging Clin N Am 2006; 16(1):75–85, viii. 53. Henderson LA, Frysinger RC, Yu PL, et al. A device for feline head positioning and stabilization during magnetic resonance imaging. Magn Reson Imaging 2001; 19 (7):1031–1036. 54. Hermoye L, Saint-Martin C, Cosnard G, et al. Pediatric diffusion tensor imaging: normal database and observation of the white matter maturation in early childhood. Neuroimage 2006; 29(2):493–504.
Index
Acetylcholine, 4 Achondroplasia (AP), 274–275 Acid clearance mechanism, 337, 338 of lower esophagus, 336 Actigraph, 281–282 Actigraphy, 304 wrist, 300 Actigraphy-defined sleep efficiency and impulsivity, 355, 356 Active sleep (AS), 116 Adenotonsillar hypertrophy, 275 ADHD. See Attention-deficit/ hyperactivity disorder ADNFLE. See Autosomal dominant nocturnal frontal lobe epilepsy Adolescents behavioral influences, on sleep development, 168–169 sleep practices, 169–171 social and emotional factors, 173–175 sociocultural influences, 171–173 depressive disorders in, 301 maturation of sleep patterns circadian timing system, 98–102 implications, 107–108 sleep-wake homeostasis, 102–105 working model, 105–106 melatonin secretion, 97 multiple sleep latency test (MSLT), 105 sleep-delaying pattern, 107 sleep-wake homeostasis, 102–105 slow wave sleep (SWS), 102–103
Adults anxiety or depressive disorder in, 298 RLS in approval of ICSD and IRLSSG for diagnosis of, 319 diagnosis of, 319–320 epidemiological studies in, 318, 319 impacts on quality of life, 318 options for treatment of, 327 PLMS in, 320 symptoms, retrospective recall of, 318 with sleep-disordered breathing, 367, 368 Aerodigestive physiology, functional changes in, 336 a Agonist, 304 ALTE. See Apparent life-threatening event (ALTE) American Sleep Disorders Association (ASDA) arousal criteria, 117–119 Angelman syndrome (AS), 266 Anisotropic diffusion, 369, 370 Antiepileptic drugs, 270, 278 Anxiety disorders, 299 AP. See Achondroplasia Apnea, sleep, 122–123, 150, 152, 266–267, 277, 279, 280, 282, 324, 340. See also Obstructive sleep apnea cardiac distension in, 234 index, 57, 123 Apnea-hypopnea index (AHI), in children with Prader-Willi syndrome, 267
385
386 Apoptosis, 65 Apparent life-threatening event (ALTE), 340 Armstrong’s vocabulary, 347 Arousability, 58 Arousal disorders and NFLE, 272–274. See also Parasomnias Arousal mechanisms, in children and infants from airway occlusion, 121 definitions and scoring methodologies, 117–120 determination of thresholds, 120 hierarchy of, 116–117 influencing factors environmental, 126–128 experimental conditions, 120–124 infant and children characteristics, 124–126 Arousal parasomnias in childhood disorders of arousal, office evaluation of, 224–225 disorders of arousal, prevalence, 223 factors influencing, 226–227 genetic predisposition for, 227 treatment of, 228–229 Arousal periods, 51 Arterial spin labeling (ASL), 374–375 Attention-deficit/hyperactivity disorder (ADHD), 164 characterization of, 326 and childhood PLMS, 324, 325, 326 and childhood RLS, 324–326 and other sleep disorders, 324, 325 severity and PLMS severity, 325 severity and serum ferritin levels, 326 and sleep, 303–305 symptoms of, 324, 325 video analysis of patients with, 324, 325 Auditory arousal challenges, 120–121 Autism spectrum disorder (ASD) children, PSG study on, 264 Autonomic behaviors, during sleep heart rate and heart rate variability, 59–60 respiratory patterns, 57–59 Autonomic dysfunction, 323 Autonomic functions, 1
Index Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), 270, 271 Awakening, 24–27 Awakening (hypnopompic hallucinations), 232
Basic rest/activity cycle (BRAC), 53 Bedsharing and sleep, 127 Behavioral influences, on sleep adolescence development, 168–169 sleep practices, 169–171 social and emotional factors, 173–175 sociocultural influences, 171–173 infants, toddlers and school-aged children developmental status, 160–162 emotional factors, 163–164 family and parental factors, 162–163 health status, 164 sleep environment and sleeping arrangement, 164–165 sleep practices, 165–167 Behavioral states in animals, 9–11 brain structures involved in control of, 3 in infants, 1 in sleep state, 2 Behavior Rating Inventory of Executive Functioning (BRIEF), 349 Benzodiazepines, 229 for RLS treatment, 328–329 Bernning’s study, 324 Bernstein test, 340 b-blockers and melatonin administration, 268 Binge-eating disorder, 237 Biorhythmic processes, 53 Blood oxygen level dependent (BOLD), 374–375 fMRI uses, 373, 374 imaging, 373, 374 signal, blood volume and deoxyhemoglobin level, 373
Index Body position during sleep, effect on reflux of gastric contents, 338 Body temperature rhythm, 98–99 BOLD. See Blood oxygen level dependent Bonferroni correction, modified, 377 Boston naming test, 354 Brain metabolites, 373 spectral peaks of, 374 BRIEF. See Behavior Rating Inventory of Executive Functioning Brown adipose tissue (BAT), 141 Brownian motion, 369 Bruxism, 281 Bulimia nervosa. See Binge-eating disorder
Carbamezepine, 228 Cardiac distension in sleep apnea, 234 Catathrenia, 237–238 CBF. See Cerebral blood flow Cerebral blood flow (CBF), 374 Cerebral cortex neurons, in macaque monkeys, 7 Cerebral palsy (CP), 278–280 Cerebrospinal fluid (CSF), 376 Chemical clearance, 337 Children. See also specific entries with autism spectrum disorder, 263 PSG study on, 264 Down syndrome, prevalence of obstructive sleep apnea (OSA) in, 264 gastric contents in, reflux of, 336 migraine and tension-type headache in, 280–281 multiple sleep latency test (MSLT) in, 119 with neurological disorders, REM sleep behavior disorder in, 230 night-waking problems, in older, 79 nocturnal motor behaviors in, 270–271 nocturnal sleep in, 78–79 periodic limb movements in sleep (PLMS) treatment of, 329 polysomnographic (PSG) studies of sleep in, 263
387 [Children] with post-traumatic stress disorder and nightmare disorder, 233 with Prader-Willi syndrome, apneahypopnea index (AHI), in, 267 with SDB, 367, 368. See also Sleepdisordered breathing (SDB) in children with sleep disturbance, role of GER in, 338 sleep disturbance in, due to gastroesophageal reflux, 338 sleep in, with pervasive developmental disorders (PDD), 262–264 upper airway obstruction in, with AP, 274–275 visual concept formation ability in, 355 Cholecystokinin (CCK-8), 8 Choline (Cho), 373 Chromosome 17p11.2, 267–268 Chromosome 15q11–13, 266 Chromosome 15q24, 270 Chromosome 20q13, 270 Circadian clock, 7 Circadian influences effect on gastroesophageal function, 336 Circadian rhythms, 52, 60 among depressed youth, 302 associated with migraine, 281–282 classic theory, 99 Circadian sleep-wake rhythms, 6, 22 Circadian timing system, 98–102 Clonazepam, 230, 231 Clonodine, 304 Cluster analysis, 377, 378 CNS structures, in states control, 2, 138 Cognitive behavioral therapies (CBT), 303 Cognitive functioning and sleep maturation, 85–87 Colic syndromes, 281 Common zeitgeber, 261 Comorbid epilepsy, 263 Computational analyses, of complex physiologic behaviors, 65 Computed tomography imaging procedures, 368 Computer analyses, of EEG-sleep during infancy, 61–64
388 Confusional arousals in infants and toddlers, 225 Congenital central hypoventilation syndrome (CCHS), 368 American Thoracic Society description of, 369 assessment of fiber tracking in, 370 assessment of fractional anisotropy (FA) in, 370 localized functional deficits in, 374 physiological characteristics of, 369 Congenital myasthenic syndrome, 278 Congenital myopathies, 278 Construct validity, 349 Content validation, defining characteristics of, 349 Continuous positive airway pressure (CPAP), 267, 341 Controlled Pulsatile Air Jets, 121 CPAP. See Continuous positive airway pressure Craniofacial deformities, 274–275 Creatine (Cr), 373 Criterion validity, 349 Cross validation, 349, 352 Cultural influences, on sleep American and Japanese differences, 187 beliefs about consequences of nontraditional sleeping arrangements, 191–192 conventional wisdom on solitary sleep in early childhood, 190–192 infant-parent cosleeping arrangements, 205–210 Mayan beliefs, 187 moral characteristics, 188–189 relationship between solitary infant sleeping arrangements and early independence, 189–191 social values and goals, 186–188 South Asian group beliefs, 188 Western understandings arousal mechanisms and bedsharing practice, 198–201 fallacies, 192–193 feeding practices, 197–198
Index [Cultural influences, on sleep Western understandings] interplay of intrinsic and extrinsic variables, 194–195 recommended sleeping practice, 194 sleep environment, 203–205 sleeping arrangements and practices, 195–197 social determinants, 201–202 thumbsucking and other sleep aids, 202–203 Cyclic alternating pattern (CAP), 264 on interictal epileptiform discharges, 269
Data acquisition, 378–379 Daytime eating disorders, 236 associated disorders, 236–237 Daytime sleepiness associated with Prader-Willi Syndrome, 266 DDAVP (1-deamino-8-D-arginine vasopressin), 234 Decubitus, right lateral position, 338 Delta brush patterns, EEG sleep, 44–45 Delta-sleep-inducing peptide (DSIP), 8 Delta wave patterns, EEG sleep, 45–46, 55 Depressive disorders, 301 Desmopressin. See DDAVP (1-deamino8-D-arginine vasopressin) Developmental disorders, sleep and, 305–306 case studies, 306–309 Diffusion tensor imaging (DTI), 369–370 examination of tissue architecture by, 369 functional imaging, 375 illustration of changes in, 370 two-dimensional representation of, 371 uses of, 370 Dopamine, 305 Dopaminergic agents effect on PLMS symptoms, 323 effect on RLS symptoms, 323 use in treatment of RLS patients, 327–328 Dopaminergic agonists, 327, 328
Index Dopaminergic therapy’s effect on RLS symptoms, 323 Dopamine system, endogenous, 323 Down syndrome (DS), 264 DS. See Down syndrome DSM-IV on sleep disturbance, 299 DTI. See Diffusion tensor imaging Duchenne’s muscular dystrophy (DMD), 277 Dysmorphic traits, 266
Electrocardiogram (ECG), 379 EEG. See Electroencephalograph EEG behaviors, of sleep in newborns and infants, 1 assessment of state organization in the full-term infant, 50–54 of autonomic behaviors during sleep heart rate and heart rate variability, 59–60 respiratory patterns, 57–59 brain adaptation to stress as reflected in sleep reorganization, 60–61 caveats of neurophysiologic interpretation, 40–41 computer-assisted analyses of, 61–64 maturation of electrographic patterns in the delta brush patterns, 44–45 delta wave patterns, 45–46 EEG discontinuity, 43–44 during fetal life through infancy periods, 54–57 of noncerebral physiologic behaviors that define state in the preterm infant, 47–50 occipital theta/alpha rhythms, 45 synchrony/asynchrony, 44 temporal theta rhythm, 45 midline theta/alpha activity, 46–47 and neural plasticity, 64–65 recording techniques and instrumentation, for neonates and infants, 41–42 visual interpretations of, 51 Electroencephalograph (EEG), 227, 378 arousal index, 119
389 Electrogastrography, 337 Electromyography (EMG) calibration signal, 320 Emotional factors, influencing sleep, 163–164 Employment, impact on sleep, 172 Enuresis. See Nocturnal enuresis (bedwetting) Epilepsy, 278 Episodic nocturnal wanderings, 228 Epworth Sleepiness Scale, 119 Esophageal clearance, 337 Esophageal motility, effect of sleep on, 337 Esophageal mucosal protective mechanism, 335 Esophageal peristalsis, secondary, 336 Esophago-upper esophageal sphincter contractile reflex (EUCR), 336 Estimated gestational age (EGA), 41 Exploding head syndrome (EHS), 236
Family influences, on sleep, 162–163 Feeding rhythms and sleep-wake rhythms, 23 Ferritin, 305, 322 Fetal circadian rhythmicity, 22 Fetal sleep cycle animals, 9 humans, 11–12 Fibroblast growth factor receptor-3 (FGFR-3), 274 Finnish Twin Cohort, 227 ‘‘First-night effect’’ phenomenon, 85 Flunitrazepam, 279 Fluoxetine, 302 Fluvoxamine, 300 Forced desynchrony (FD) conditions, 98 Fragile X syndrome, 265 Frontal Lobe Epilepsy and Parasomnia scale, 272 Functional magnetic resonance imaging (fMRI), 367, 376–378 BOLD, 373–374 cluster analysis, 377, 378 effects of sedation on, 379 image storage requirements in, 379
390 [Functional magnetic resonance imaging (fMRI)] significant increase or decrease in, 378 statistical analyses using, 377 steps of, 376–377 studies related to sleep, 378 VOI analysis, 377–378
Gabapentin for RLS treatment, 328 Gastric acid, 337 Gastric contents, reflux of clinical symptoms of, 335 effectiveness of drug therapy for, 337 effect of body position during sleep, 338 effect of CPAP on, 341 effect of development on, 337 into esophagus, 335 negative consequences of, 337 and obstructive sleep apnea syndrome, 341 in preterm versus term infants, 337 during REM, 336 during sleep, 335 during slow wave sleep, 336 during stage 2 sleep, 336 during supine sleep position, 338 treatment of, 340 Gastric contents in adults, reflux of, 338 Gastric contents in infants, reflux of during indeterminate sleep, 336 studies of, 338, 339 Gastric motility, 337 Gastric muscle activity, 337 Gastroesophageal dysfunction, 336 Gastroesophageal function, 336 Gastroesophageal reflux disease (GERD), 335 Gastroesophageal reflux (GER), 122 and ALTE in infants, 340 in asthma patients, 339 complications of, 335 effect of increased breathing during sleep on, 335 effect of sleep on, 336, 337, 338 respiratory and nonrespiratory complaints during sleep due to, 338
Index [Gastroesophageal reflux (GER)] respiratory symptoms due to, 339 role in producing sleep disturbance in children, 338 sleep related manifestations of, 338–341 Gastromyoeletric activity, instability of, 337 Gaussian distribution, 369 Gender differences, in sleep maturation, 84–85 Genetic-epigenetic interactions, of molecular pathways after stresses, 61 GER. See Gastroesophageal reflux GERD. See Gastroesophageal reflux disease Gordon diagnostic system, 355 Guinea pigs, behavioral states, 9–10
Habituation, 124 Headaches, 280–282 Head-Up Tilt Test, 121 Health status, influencing sleep, 164 Heart rate and heart rate variability, in newborns and infants, 59–60 Histamine, 4 HLA-DQB1*05 subtype and sleepwalking, 227 Hydrocephalus, 275 Hyperactivity index, 325 Hypercapnia, 121 Hyperoxic test, 150 Hyperreactivity syndrome during infancy, 280 Hyperventilation, 150 Hypochretin, 5 Hypoventilation, 276 Hypoxemia, 121 Hypoxia, 124, 151–152 chronic, 368 injuries due to, induced changes, 368 intermittent, and sleep-disordered breathing, 368 and tissue changes, 373
Index ICSD. See International Classification of Sleep Disorders Imipramine, 302 Infants. See also EEG behaviors, of sleep in newborns and infants with apparent life threatening events (ALTEs), 123 behavioral states in, 1 EEG behaviors, in sleeping, 1 melatonin secretion in, 78 monophasic sleep-wake rhythm in, 23 REM-NREM sleep distribution, 82–83 REM sleep, 47, 51, 55–56, 57 sleep conditions bedding conditions, 127 body and room temperature, 127 body position, 127 breast feeding, 128 pacifier use, 128 sleep development during early ontogenesis, 12–19 slow wave sleep (SWS), 83 sweating activity, 142 Insomnia, 263 Insomnias of childhood (ICSD-2), 298. See also ICSD Interictal epileptiform abnormalities, 271 International Classification of Sleep Disorders (ICSD), 317 approval for diagnosis of adult RLS, 319 International Restless Legs Syndrome Study Group (IRLSSG), 317 approval of clinical criteria for childhood RLS, 321 approval of clinical criteria for diagnosis of adult RLS, 319. Intrathecal baclofen therapy, 279 IRLSSG. See International Restless Legs Syndrome Study Group Iron deficiency, 322–323 therapy, 322, 329 Isotropic diffusion, 369 Kleine-Levin syndrome, 237
391 Laryngeal chemostimulation, 122 L-dopa conversion of, to dopamine, 323 effect on RLS augmentation, 327, 328 side effects of, 327 in treatment of RLS, 327 Leisure activity, impact on sleep, 172–173 L-5-hydroxytryptophan treatment in migraine, 282 Light functions, influence on sleep, 165 Magnetic resonance (MR) compatible devices, 379 effect of bound protons on, 372 global changes in, 378 movement control in, imaging, 379 studies of brain in infants, 368 T1-weighted scans, 368 T2-weighted scans in, 368 Magnetic resonance imaging (MRI) functional, 367, 376–378 image storage in, 379 structural, 367, 375–376 Magnetic resonance spectroscopy (MRS), 373 Magnetization transfer imaging (MTI), 372 Magnetization transfer ratio (MTR), 372 scans for calculation of, 373 Maternal sleep cycle, 9 Maternal smoking, 58 Mean diffusivity (MD) values, 372 Medical factors, influencing sleep maturation, 84 Melatonin (MLT), 230, 282 secretion in adolescents, 97 in CP, 278 cycle, 23 in infants, 78 inverted circadian rhythm of, 268 treatment for blindness, 284–285 in migraine, 282 for neurologic syndromes and mental retardation, 283–284 for sleep dysfunction in Rett syndrome, 284
392 Mental disorders associated with sleep paralysis, 231 Methylphenidate, 303, 304 Microaspiration, 339 Midline theta/alpha activity, of EEG sleep, 46–47 Migraine circadian rhythms associated with, 281–282 and tension-type headache in children, 280–281 Mindfulness techniques, 303 MLT. See Melatonin Monoaminergic systems, 10 Monophasic sleep-wake rhythm, in infants, 23 Montreal Neurological Institute (MNI) atlas, 375 Morphometry, 376 Mothers with depressive symptoms, influence on sleep practice, 162 Motor skill development, 161 MR. See Magnetic resonance Mucopolysaccharidoses, 278 Multifactorial construct, measurement of, 348, 357 Multiple sleep latency test (MSLT), 267 in adolescents, 105 in children, 119 Muscles spasms, 278 twitches, 264 Myotonic dystrophy, 277–278
N-aceytlaspartate (NAA), 373 Napping, 79, 104, 166, 170–171 Narcolepsy, 324 Nemaline myopathy, 278 Neonatal EEG-sleep study. See EEG behaviors, of sleep in newborns and infants Neonatal Individualized Developmental Care Assessment Program (NIDCAP), 17 Neural plasticity and EEG sleep, 64–65
Index Neurobehavioral functioning in children, 345, 346, 354 ceiling effect in, 355 floor effect in, 355 impact of SDB on, 355 modalities of, assessment, 357, 358–359 and pediatric SDB, 360–363 publications on pediatric SDB and, 346 a review from sleep, 360–363 tools for assessing, 358–359 Neuroimaging, 228 Neurologic syndromes and mental retardation, 283–284 Neuromuscular diseases, 276–278 Neuronal nicotinic acetylcoline receptor (nAChR), 270 Neurons in the cerebral cortex, of macaque monkeys, 7 role in REM sleep, 3–4 sleep-promoting, 5 Neuropeptide Y (NPY), 8 Neuropsychological test findings, 356 Neurotransmitters, activity in primates, 7 NFLE. See Nocturnal front lobe epilepsy Nightmare disorder, 232 associated disorders, 232–233 Nighttime sleep consolidation, 79 Night waking, 27 Night-waking problems, in older children, 79 Nocturnal eating syndrome, 237 Nocturnal enuresis (bedwetting) adenotonsillectomy and, 234 affect of sleep cycles on, 234–235 causes of, 234 etiologies for, 233–234 Nocturnal front lobe epilepsy (NFLE), 269–270, 270 and arousal disorders, 272–274 onset for, 228 Nocturnal motor behaviors in children, 270–271 Nocturnal paroxysmal dystonia, 228, 270 Nocturnal sleep, in children, 78–79 Noninvasive ventilation (NIV), 276–277 Non-rapid eye movement. See NREM
Index Noradrenaline, 4 NREM, disorders of arousal from clinical studies, 227–228 evaluation, 224–226 influencing factors, 226–227 management, 228–229 prevalence, 224 NREM parasomnias, 270–271 NREM sleep, 1–2, 4, 55–56 and age effects, 124–125 blood pressure and heart rates during, 59 cortical arousal in, 122 for pre- and early-pubertal and late-pubertal groups, 104–15 stable periods of, in fetal behavior, 11–12
Obesity hypoventilation, 266 Obsessive compulsive disorder (OCD), 299–300 Obstructive respiratory events, 234 Obstructive sleep apnea (OSA), 225, 226, 230, 227, 229, 234, 335, 341. See also Apnea associated with ADHD, 325–326 associated with Prader-Willi Syndrome, 266–267 and Down syndrome, 264 effect on GER, 335 evaluation of upper airway morphology in, 367, 368 and Fragile X syndrome, 265 gray matter loss in adult, 375 hippocampal volume ratio of, 377 and intellectual scores, 360 and neuromuscular diseases, 276–278 prevalence in DS children, 264 and Rett syndrome, 265 Obstructive sleep apnea syndrome (OSAS), 341 Occipital theta/alpha rhythms, 45 Oculomotor abnormalities, 302 Oculomotor activity during REM sleep, 263
393 Ontogeny, of EEG sleep. See EEG behaviors, of sleep in newborns and infants Ophthalmic migraine, sleepwalking in, 281 Opioids for RLS treatment, 328 system, endogenous, hypofunction of, 323 Orexin/hypocretin expression, in rats, 8 OSA. See Obstructive sleep apnea Overnight polysomnography, 226 Oxygenated blood versus deoxygenated blood, 373 Oxygen saturation, 269
Paradoxical breathing movements, 57–58 Paradoxical sleep. See Rapid eye movement (REM) sleep Parasomnia overlap disorder, 230–231 Parasomnias, 263, 280. See also Arousal disorders associated with REM sleep, 229–233 defined, 223 Parental influences, on sleep, 162–163, 169 Paroxysmal arousals, 228 Pediatric disorders, 230 Pediatric parasomnias, 223–224 Pediatric Sleep Questionnaire (PSQ), 349 Pediatric Sleep Questionnaire- Sleepiness Subscale, 119 Periodic limb movement disorder (PLMD), 305 Periodic limb movements in sleep (PLMS) and ADHD, 324, 325, 326 in adult RLS patients, 320 case reports of, 318 criteria to classify as, 320 demonstration of, 321 effect of dopaminergic agents on symptoms of, 323 effect on sleep disruption, 320 severity and ADHD severity, 325 treatment of children, 329 Periodic syndromes, 281
394 Permissive network, 2 Pervasive developmental disorders (PDD), 306 case studies, 308–307 sleep in children with, 262–264 Phase response curve (PRC), 98 Phasic muscle twitches, 232 Physiologic dysmaturity, of the newborn, 61 Piagetian cognitive development, 160 PLMS. See Periodic limb movements in sleep Polysomnographic (PSG) studies of sleep in children, 263 Polysomnography (PSG), 227, 230, 236, 237, 299–300, 317, 320, 338, 339, 340, 349 in newborns, 12–13 studies for Smith-Magenis syndrome, 268 and REM sleep behavior disorder, 231 Polyuria, 233–234 Pontine-tegmentum alterations, 264 Positron emission tomography (PET), 374 Postmenstrual age (PMA), 41–42, 45, 47–49, 55, 57 Post-traumatic stress disorder (PTSD), 299–300 Prader-Willi syndrome, 266–267 Programmed cell death. See Apoptosis Prone sleeping, 58 Proton pools, 372 Pseudo-REM sleep behavior disorder, 230. See also REM sleep behavior disorder PSG. See Polysomnography Psychiatric disorders in patients with nightmare disorder, 232–233 Psychological testing in children ceiling effect in, 355 criteria for rating, 355, 356 floor effect, 355 measurement errors in, 347–348 scores and norms of, 352–354 Psychometrics reliability in, 347–348 scores and norms in, 352–354 and brain function, 356 validity in, 349–352
Index Psychophysiologic insomnia, 301. See also Insomnia Psychosocial factors, influencing sleep maturation, 84 Psychostimulants, 303 Pulmonary infections, 58
Quiet sleep (QS), 116
Random-effects analysis, 377 Rapid eye movement. See REM Reliability in psychometrics, 347–348 REM atonia, 230 REM sleep, 1–2, 3–4, 276 and active sleep (AS), 145 and age effects, 124–125 blood pressure and heart rates during, 59 central control on brain stem and spinal cord, 148 in children with neuromuscular diseases (NMD), 276 cortical arousal in, 122 during the diurnal period, 21 motor disorder. See REM sleep behavior disorder and quite sleep (QS), 145–146 role in early brain development, 81–82 stable periods of, in fetal behavior, 11–12 REM sleep behavior disorder, 229 in children with neurological disorders, 230 differential diagnosis of, 229–230 dream enacting behaviors, 230 narcolepsy-, 230–231 parasomnia overlap disorder and, 230–231 pediatric disorders associated with, 230 polysomnography and, 231 trauma in, 229 Respiratory arousal, 121 Respiratory findings, 339–341 Respiratory infections and sleep deprivation, 126 Respiratory muscle weakness, 276
Index Respiratory patterns, in newborns and infants, 57–59 Respiratory tidal volume, increased, 226 Rest-activity cycle, 1 Restless legs syndrome (RLS), 305 augmentation, 327, 328 case reports of, 317, 318 inheritance of, 317 like symptoms, 324 nonessential clinical features of, 320 patients ferritin and cerebrospinal fluid (CSF) levels in, of, 322 ferritin and serum levels in, of, 322 iron deficiency in, of, 322–323 studies on iron deficiency in, 322, 323 treatment with dopaminergic agents, 327–328 pedigree compatible in familial, 318 sensory components of, 321 symptoms effect of dopaminergic agents on, of, 323 rebound in, of, 328 treatment, 328–329 Rett syndrome, 265 Rhythmic cycling, of motoric activity, 55 RLS. See Restless legs syndrome RLS/PLMS in children and ADHD, 324, 325, 326 and behavioral problems, 326 effect of serum ferritin on symptoms of, 322 response to iron therapy, 322
Salivation, effect of sleep on, 337 Science of psychological measurement. See Psychometrics SDB. See Sleep-disordered breathing Seismic REM sleep, 9 Seizures, 227, 269–270 Selective serotonin reuptake inhibitors (SSRIs), 300 Self-soothing abilities, of infants, 56–57 Separation anxiety, 161 Sheep, behavioral states, 9
395 Shivering, 138, 141–142 Single channel monitoring devices, 63 Sleep ADHD and, 303–305 and anxiety disorders, 299–300 apnea. See Apnea; Obstructive sleep apnea and depression, 301–303 deprivation, 125–126, 226 and developmental disorders, 305–306 case studies, 306–307 disruption, 261–262 drunkenness (schlaftrunkenheit), 225 duration, 79–81 effects of inadequate, 107–108 episodes, 23 latency, 80 maturation, in immature mammals, 10 modulation in neurologic disorders, 268–269 nasendoscopy, 280 onset, 79–81 onset (hypnagogic hallucinations), 232 paralysis, 231–232 regulation, 2 state scoring data, 13–15 switch, in the ventrolateral preoptic (VLPO) nucleus, 98 terrors, 225–226 terrors in monozygotic and dizygotic twins, 227 Sleep-delaying pattern, of adolescence, 107 Sleep development, during early ontogenesis animal studies development of behavioral states, 9–11 development of brain structures, 7–8 human studies fetal life, 11–12 first two to five years, 21–22 from premature to full-term newborns, 12–19 Sleep-disordered breathing (SDB) in children, 276–277 behavioral difficulties, 345 content validity of subscale of, 349
396 [Sleep-disordered breathing (SDB) in children] effect on parent-reported attention, 361 effect on parent-reported mood and emotional stability, 361 emotional problems and, 360 hypoxia-associated, 368–369 and neurobehavioral functioning, 360–363 versus non SDB, 349 and overall IQ, 362 scholastic difficulties, 345 and visual perception, 360, 362 Sleep disturbance, 338–339 associated with Smith-Magenis syndrome, 268 DSM-IV on, 299 Sleep patterns, maturation of in adolescents circadian timing system, 98–102 implications, 107–108 sleep-wake homeostasis, 102–105 working model, 105–106 electrographic patterns delta brush patterns, 44–45 delta wave patterns, 45–46 during fetal life through infancy periods, 54–57 of noncerebral physiologic behaviors that define state in the preterm infant, 47–50 occipital theta/alpha rhythms, 45 synchrony/asynchrony, 44 temporal theta rhythm, 45 in normal infants and children and cognitive functions, 85–87 consolidation of nocturnal sleep, 78–79 influencing factors, 83–85 sleep onset and sleep duration, 79–81 sleep state organization, 81–83 in young adults, 106–107 Sleep problems, in autism spectrum disorder (ASD) children, 263 Sleep-related dissociative disorder, 235–236 Sleep-related eating disorder, 236 Sleep-related hallucinations, 232
Index Sleep-related manifestations of GER, 338–341 respiratory findings, 339–341 sleep disturbance, 338–339 Sleep-wake control principles between-sleep state transition, 4–5 NREM sleep, 4 REM sleep, 3–4 waking and sleep onset promotion, 5–6 Sleep-wake cycle, 78 Sleep-wake homeostasis, in adolescents, 102–105 Sleep-wake regulation, early, 24 Sleep-wake rhythm, 22–23 Sleepwalking, 225, 281 HLA-DQB1*05 subtype and, 227 in ophthalmic migraine, 281 Slow wave sleep (SWS), 4 in adolescents, 102–103 in infants, 83 Smith-Magenis syndrome, 267–268 Smoothing, 376 Sociocultural influences, on sleep, 171–173 Somatostatin (SRIF), 7 Somnambulism, 228, 272 Somnolence, 304 Spastic quadriplegia, 279 Spinal muscular atrophy, 278 Spin labeled procedures, 374–375 Static or cine X-ray, 368 Statistical analyses and display, 376 Statistical parametric mapping (SPM), 375, 376 STOP rhythm (spontaneous theta activity in the occipital regions in the premature neonate), 45 Stress, impact on sleep, 173–174 Stroop color-word interference test, 355 Structural magnetic resonance imaging, 367, 375–376 procedures of, 368 sedation for, 379 Substance abuse, impact on sleep, 174–175 Sudden infant death syndrome (SIDS), 58, 60, 115, 125, 126, 188, 338 Supine prone position, 338
Index Suprachiasmatic nucleus, of the hypothalamus (SCN), 98 Swaddling, 127 Swallowing, effect of sleep on, 337–338 Sweating activity, 142–143 Synchronization, of the sleep-wake cycle, 78 Synchrony/asynchrony, in EEG sleep, 44
Tachypnea, 149 Temporal theta rhythm, EEG sleep, 45 Test-retest reliability, 347, 348 Thermoregulation, 1 Thermoregulation during sleep controlling system, 139–140 influences on respiratory patterning, 150–153 neonates concept of a set-point temperature, 143–144 theromoregulatory system, 137–143 role of skin’s thermosensors, 139–140 thermal responses in different sleep stages, 146–149 thermoregulatory effectors behavioral thermoregulation, 143 cutaneous vasomotricity, 140–141 non-shivering thermogenesis, 141–142 shivering thermogenesis, 141 sweating response, 142–143 Trace´ alternant pattern, 9, 16, 55 Transitional sleep (TS), 4–5, 15, 51 T2 relaxometry uses, 368–369 Tricyclic antidepressants (TCAs), 229, 302 True score model, 347 T-tests, 376 T1-weighted scans, 368, 376, 380
397 T2-weighted scans, 368, 380 Twitches, phasic muscle, 232
Ultradian sleep rhythm, 50–51, 51–52, 53–54 Upper airway morphology and sleep-related processes evaluation of, 367, 368 gross deformations, 368 Upper airway obstruction in children with AP, 274–275 superimposed on sleep hypoventilation due to an underlying weakness, 276 Upper esophageal sphincter (UES), 336
Vasoactive intestinal peptide (VIP), 8 Vasomotricity, 140–141 Ventral medullary surface (VMS), 152 Vibrotactile stimuli, 121 Video-polysomnographic study, 249, 271, 272 Visual concept formation ability in children, 355 Vocabulary test, 347 VOI. See Volume-of-interest (VOI) Volume clearance, 337 Volume-of-interest (VOI) analysis, 376, 377–378 Voxel-based analysis (VBA), 375, 376 Voxel-based morphometry (VBM), 375
Wakefulness, 5 Wechsler intelligence scale for children (WISC-IV), 355. See also Children Weinberg’s hypothesis, 305
