Swaiman s Pediatric Neurology - E-Book
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6339 pages
English

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Description

Swaiman’s Pediatric Neurology, by Drs. Kenneth Swaiman, Stephen Ashwal, Donna Ferriero, and Nina Schor, is a trusted resource in clinical pediatric neurology with comprehensive, authoritative, and clearly-written guidance. Extensively updated to reflect advancements in the field, this fifth edition covers new imaging modalities such as pediatric neuroimaging, spinal fluid examination, neurophysiology, as well as the treatment and management of epilepsy, ADHD, infections of the nervous system, and more. The fully searchable text is now available online at www.expertconsult.com, along with downloadable images and procedural videos demonstrating intraventricular hemorrhage and white matter injury, making this an indispensable multimedia resource in pediatric neurology.

  • Gain a clear visual understanding from the numerous illustrations, informative line drawings, and summary tables.
  • Tap into the expertise of an authoritative and respected team of editors and contributors.
  • Get comprehensive coverage of all aspects of pediatric neurology with a clinical focus useful for both the experienced clinician and the physician-in-training.
  • Access the fully searchable text online at www.expertconsult.com, along with 16 additional online-only chapters, downloadable images, videos demonstrating intraventricular hemorrhage and white matter injury, and links to PubMed.
  • Stay current on recent developments through extensive revisions: a new chapter on paraneoplastic syndromes in children; a new section on congenital brain malformations written by leading international authorities; and another one on cutting-edge pediatric neuroscience concepts relating to plasticity, neurodegeneration of the developing brain, and neuroinflammation.
  • Apply the latest information on diagnostic modalities, including pediatric neuroimaging, spinal fluid examination, and neurophysiology

Sujets

Ebooks
Savoirs
Medecine
Médecine
Brain Death
Miastenia gravis
Genoma mitocondrial
Epilepsy in children
Editorial
Electroencephalography
Amnesia
Smell
Meningitis
Metabolic myopathy
Narcolepsy
Mental retardation
Viral disease
Organic acidemia
Guillain?Barré syndrome
Paraneoplastic syndrome
Tonic?clonic seizure
Resource
Dihydrolipoamide dehydrogenase
Caregiver
Generalised epilepsy
Chromosome abnormality
Hypoxia
Peroxisomal disorder
Anterior horn of spinal cord
Neurological examination
West syndrome
Myositis
Temporal lobe epilepsy
Neurodevelopmental disorder
Arachnoid cyst
Partial seizure
Tic disorder
Neurofibromatosis type II
Channelopathy
Agenesis of the corpus callosum
Visual impairment
Gait abnormality
Status epilepticus
Medical history
Craniosynostosis
Myopathy
Neoplasm
Sensorineural hearing loss
Traumatic brain injury
Dermatomyositis
Spinal cord injury
Tetrahydrobiopterin
Hyperkalemic periodic paralysis
Degenerative disease
Hypotonia
Duchenne muscular dystrophy
Congenital heart defect
Ketogenic diet
Subdural hematoma
Subarachnoid hemorrhage
Neuromuscular junction
Dystonia
Myoclonus
Prenatal diagnosis
Nephropathy
Stroke
Peripheral neuropathy
Tuberous sclerosis
Lysosomal storage disease
Intracranial pressure
Prosencephalon
Myosin
Pain management
Dysautonomia
Encephalopathy
Carbohydrate metabolism
Absence seizure
Lumbar puncture
Congenital disorder
Palliative care
Cerebrovascular disease
Brainstem
Macrocephaly
Microcephaly
Neural tube
Hydrocephalus
Neural development
Physical exercise
Pleasure
Poisoning
Glycogen storage disease
Mitochondrial disease
Urination
Motor neuron
Febrile seizure
Medical ultrasonography
Spasticity
Defecation
Headache
Heart disease
Cardiopulmonary resuscitation
Attention deficit hyperactivity disorder
Cardiac arrest
Tourette syndrome
Rett syndrome
Ménière's disease
Clinical neurophysiology
Adrenoleukodystrophy
Mood disorder
X-ray computed tomography
Cerebral palsy
Multiple sclerosis
Cerebellum
Hearing impairment
Phenytoin
Sleep disorder
Morality
Encephalitis
Brain tumor
Infection
White matter
Urea
Epileptic seizure
Plasticity
Pediatrics
Paralysis
Nervous system
Neurotransmitter
Neurologist
Neurology
Microgyrus
Magnetic resonance imaging
Muscular dystrophy
Hypoglycemia
Genetic disorder
Epilepsy
Diet
Major depressive disorder
Dyslexia
Down syndrome
Cerebrospinal fluid
Bipolar disorder
Autism
Motor
Ataxia
Concussion
Necrosis
Blindness
Brain
Gene
Sleep
Carbamazépine
Vaccine
Polysaccharide
Mutation
Coma
Vertigo
Menstruation
DNA
Syncope
Copyright

Informations

Publié par
Date de parution 11 novembre 2011
Nombre de lectures 0
EAN13 9780323089111
Langue English
Poids de l'ouvrage 36 Mo

Informations légales : prix de location à la page 0,1612€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

Swaiman’s Pediatric Neurology
Principles and Practice Volume 1
Fifth Edition

Kenneth F. Swaiman, MD
Director Emeritus, Division of Pediatric Neurology
Professor Emeritus of Neurology and Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA

Stephen Ashwal, MD
Distinguished Professor of Pediatrics, Chief of the Division of Child Neurology and Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA

Donna M. Ferriero, MD MS
W.H. and Marie Wattis Distinguished Professor and Chair Department of Pediatrics Physician-in-Chief UCSF Benioff Children’s Hospital University of California San Francisco San Francisco, CA, USA

Nina F. Schor, MD
William H. Eilinger Chair of Pediatrics, Professor, Departments of Pediatrics, Neurology, and Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Saunders
Front matter
Swaiman’s Pediatric Neurology
Commissioning Editor: Lotta Kryhl
Development Editor: Janice Gaillard
Editorial Assistant: Emma Cole
Project Manager: Frances Affleck
Design: Kirsteen Wright
Illustration Manager: Karen Giacomucci
Illustrator: Dartmouth Publishing and Joe Chovan
Marketing Manager (UK/USA): Gaynor Jones/Helena Mutak

Swaiman’s Pediatric Neurology

Principles and Practice
FIFTH EDITION
Volume 1
Kenneth F. Swaiman MD , Director Emeritus, Division of Pediatric Neurology Professor Emeritus of Neurology and Pediatrics University of Minnesota Medical School Minneapolis, MN, USA
Stephen Ashwal MD , Distinguished Professor of Pediatrics Chief of the Division of Child Neurology and Pediatrics Loma Linda University School of Medicine Loma Linda, CA, USA
Donna M. Ferriero MD MS , W.H. and Marie Wattis Distinguished Professor and Chair Department of Pediatrics Physician-in-Chief UCSF Benioff Children's Hospital University of California San Francisco San Francisco, CA, USA
Nina F. Schor MD PhD , William H. Eilinger Chair of Pediatrics Professor, Departments of Pediatrics, Neurology, and Neurobiology and Anatomy University of Rochester School of Medicine and Dentistry Rochester, NY, USA
Dedication
With pleasure and appreciation we dedicate this book to our spouses, Phyllis Sher, Eileen Ashwal, Thomas Rando, and Robert Schor, who made it possible for us to spend the enormous amount of time planning, reading, and editing that was necessary to bring this text to fruition. It is impossible to describe the value of their encouragement and support adequately.
Furthermore, no dedication of a book embracing this field would be meaningful without a tribute to the courage and perseverance of neurologically impaired children and their caretakers.
Copyright

SAUNDERS is an imprint of Elsevier Inc.
© 2012, Elsevier Inc. All rights reserved.
First edition 1989
Second edition 1994
Third edition 1999
Fourth edition 2006
Fifth edition 2012
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher's permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions .
This book and the individual contributions contained in it are protected under copyright by the Publisher.

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Saunders
British Library Cataloguing in Publication Data
Swaiman's pediatric neurology. -- 5th ed.
1. Pediatric neurology.
I. Ashwal, Stephen, 1945- II. Swaiman, Kenneth F., 1931-
III. Pediatric neurology.
618.9'28-dc22
ISBN-13: 9781437704358
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Preface to the First Edition
It is concurrently tiring, humiliating, and intellectually revitalizing to compile a book containing the essence of the information that embraces one’s life work and professional preoccupation. For me, there is a certain moth-to-the-flame phenomenon that cannot be resisted; therefore this new book has been produced.
Pediatric neurology has come of age since my initial interest and subsequent immersion in the field. Concentrated attention to the details of brain development and function has brought much progress and understanding. Studies of disease processes by dedicated and intelligent individuals accompanied by a cascade of new technology (e.g., neuroimaging techniques, positron emission tomography, DNA probes, synthesis of gene products, sophisticated lipid chemistry) have propelled the field forward. The simultaneous increase of knowledge and capability of pediatric neurologists and others who diagnose and treat children with nervous system dysfunction has been extremely gratifying.
Although once within the realm of honest delusion of a seemingly sane (but unrealistic) devotee of the field, it is no longer possible to believe that a single individual can fathom, much less explore, the innumerable rivulets that coalesce to form the river of knowledge that currently is pediatric neurology. Streams of information in certain areas sometimes peacefully meander for years; suddenly, when knowledge of previously obscure areas is advanced and the newly gained information becomes central to understanding basic pathophysiologic entities, a once small stream gains momentum and abruptly flows with torrential force.
This text is an attempt to gather the most important aspects of current pediatric neurology and display them in a comprehensible manner. The task, although consuming great energies and concentration, cannot be accomplished completely because new conditions are described daily.
The advancement of the field necessitated that preparation of this text keep pace with current knowledge and present new and valuable techniques. My colleagues and I have made every effort to discharge this responsibility. Because of continuous scientific progress, controversies are extant in some areas for varying periods; wherever possible, these areas of conflict are indicated.
This book is divided into four unequal parts. Part I contains a discussion of the historic and clinical examination. Part II contains information concerning laboratory examination. Chapters relating to the symptom complexes that often reflect the chief complaints of neurologically impaired children compose Part III. Part IV provides detailed discussion of various neurologic diseases that afflict children.
Although every precaution has been taken to avoid error, bias, and prejudice, inevitably some of these demons have become embedded in the text. The editor assumes full responsibility for these indiscretions.
It is my fervent hope that the reader will find this book informative and stimulating and that the contents will provide an introduction to the understanding of many of the conditions that remain mysterious and poorly explained.

Kenneth F. Swaiman, MD
Autumn 1988
Preface to the Fifth Edition
Since publication in 2006 of the fourth edition of Pediatric Neurology: Principles & Practice , the discipline of child neurology has progressed and reached new levels of complexity. Advances in molecular biology and neuroimaging have fueled an explosion of knowledge that has translated into a richer understanding of nervous system development and function. Researchers and clinicians alike believe that, during the next decade, novel and targeted treatments will be the product of such fundamental advances in knowledge. Successful treatment of children with both common and rare neurologic disorders is becoming a reality.
This fifth edition reflects the enormous growth and intricacy of the basic and clinical neurosciences. The entire text has been revised and reorganized. Many chapters have undergone extensive updating, as they reflect clinical areas of child neurology that are becoming even more relevant (e.g., neurogenetics, neuropsychopharmacology, neurorehabilitation), and new chapters are included on diseases that previously were given little attention in child neurology (e.g., channelopathies). Many chapters have new authors who bring to these discussions new insights into disease mechanisms. Also, the editors of the 2006 edition are extremely fortunate to have Nina Schor join us to provide her expertise to enhance the quality of this publication.
Several major and important changes are present in this edition. The first is that purchasers of the book will be able to access all chapters online through a website established by Elsevier. This innovation will allow readers to access contents from any location and it will also provide an online ability to search the text for specific topics – finding particular information about a disease or syndrome will be much easier. Second, because of the continued explosion in knowledge, we have decided to publish a group of chapters exclusively in the online version of the book (see below). This change will allow the hard-copy version to remain a two-volume work. The chapter on congenital malformations has been converted to a “book within a book” – contained as nine chapters in Part V of the text. Finally, we also have included three chapters on cutting edge neuroscience devoted to concepts of plasticity, cell-death mechanisms, and neuroinflammation, written by several of the leading authorities in their respective fields.
The two volumes are divided into 17 parts, encompassing 108 chapters as outlined in the table of contents. Parts I and II will be published on the book's website and contain information regarding selected aspects of the pediatric neurologic examination, as well as the different motor and sensory systems, and these discussions are followed by a comprehensive review of the pertinent neurodiagnostic testing procedures and their clinical application. Part III is a new section devoted to important concepts in the developmental neurosciences related to plasticity, cell-death mechanisms, and neuroinflammation – topics that are complex but very important for clinicians to understand as they try to apply this information to diseases that their patients endure. Part IV covers important aspects of neonatal neurology and the long-term sequelae of acquired and developmental abnormalities that can result in chronic disorders, such as cerebral palsy, developmental delay, and epilepsy. Part V is a new expanded section devoted to brain malformations. It includes an overview and classification of brain development, five chapters on specific groups of developmental malformations, and chapters on hydrocephalus, congenital skull anomalies, and prenatal diagnosis. Part VI documents the vast array of genetic and neurometabolic disorders that occur in infants and children; this section also provides many of the fundamental concepts of molecular biology and neurochemistry that constitute the scientific basis of these diseases. Part VII describes the major neurobehavioral disorders of childhood and includes chapters on autism and the neuropsychiatric problems that accompany Tourette's syndrome, and a newly revised chapter on neuropsychopharmacology. Part VIII focuses on pediatric epilepsy and contains revised chapters on the neurophysiology and neurogenetics of pediatric epilepsy. Also included are chapters on the various types of pediatric epilepsy, epileptiform disorders with cognitive symptomatology, the ketogenic diet, surgical treatment, and the learning and behavioral problems associated with epilepsy.
The second volume encompasses many of the serious and complex central and peripheral nervous system diseases that present to child neurologists and allied health professionals. Part IX reviews the nonepileptiform paroxysmal disorders, including headache, syncope, and sleep disorders. Parts X and XI deal with conditions that are degenerative in nature and cause severe loss of motor and mental function. These conditions include disorders of balance and movement in Part X (e.g., cerebellar disorders and hereditary ataxia, movement disorders, cerebral palsy, and Tourette's syndrome) and metabolic-genetic disorders, as well as acquired disorders of the white matter in Part XI. Part XII contains chapters on traumatic and nontraumatic brain injury in infants and older children. As neurologists frequently are asked to provide consultation for many of these conditions, chapters on disorders of consciousness, nonaccidental trauma, anoxic brain injury, and traumatic brain and spinal cord injury are included, as well as a current review of the issues related to brain death determination. Parts XIII (infection) and XIV (tumors and cerebrovascular and vasculitic disorders) extensively cover the major diseases that, directly or indirectly, cause serious neurologic symptoms and are discussed from a clinical perspective. In addition, a new chapter on paraneoplastic syndromes is included. The neuromuscular diseases are reviewed in Part XV, which contains chapters on the classic neuromuscular disorders, including the anterior horn cell diseases, disorders of the peripheral nervous system and neuromuscular junction, inflammatory neuropathies, metabolic myopathies, and channelopathies. Part XVI covers systemic and autonomic nervous systemic disorders. These include important chapters that review many pediatric systemic conditions (e.g., endocrine, renal, cardiac, gastrointestinal) that are known to cause neurologic symptoms, as well as chapters on poisonings, complications of immunizations, and autonomic nervous system disorders. This volume concludes with Part XVII, which is Web-based, and reviews the care of the child with neurologic diseases, revised extensively, and including updated chapters on pediatric neurorehabilitation, pain and palliative care management, ethical issues in child neurology, and the Internet as it relates to child neurology.
We hope that the reader will find this book a useful resource and that the information will benefit the many children who suffer from these conditions. It is our wish that the greater world community will increase support for the care of neurologically impaired children and the research necessary to provide further understanding of, and improved treatment and preventive measures for, neurologic diseases. This support will improve the survival and quality of life of these brave children and their families.

Kenneth F. Swaiman, Stephen Ashwal, Donna M. Ferriero, Nina F. Schor
Contributors

Amal Abou-Hamden, MB BS BMedSc (Hons) FRACS , Paediatric Neurosurgery Fellow, Neurosurgery Hospital for Sick Children, Toronto, Ontario, Canada

Anthony A. Amato, MD , Vice-Chairman, Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Stephen Ashwal, MD , Distinguished Professor of Pediatrics, Chief of the Division of Child Neurology and Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA

Felicia B. Axelrod, MD , Carl Seaman Family Professor of Dysautonomia Treatment and Research, Pediatrics and Neurology, New York University School of Medicine, New York, NY, USA

James F. Bale, Jr. , MD , Professor and Associate Chair, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

Brenda Banwell, MD FRCPC , Associate Professor of Pediatrics (Neurology), Director, Pediatric Multiple Sclerosis Clinic, Senior Associate Scientist, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Kristin W. Baranano, MD PhD , Instructor, Department of Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

A. James Barkovich, MD , Professor of Radiology, Neurology, Pediatrics, and Neurosurgery, University of California San Francisco, San Francisco, CA, USA

Richard J. Barohn, MD , Chairman Gertrude and Dewey Ziegler Professor of Neurology, University of Kansas Medical Center, Kansas City, KS, USA

Mark L. Batshaw, MD , Chief Academic Officer, Children’s National Medical Center, Professor and Chair, Department of Pediatrics, Associate Dean for Academic Affairs, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

Liat Ben-Sira, MD , Doctor, Pediatric Radiology Unit, Tel-Aviv Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Angela K. Birnbaum, PhD , Associate Professor, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

Rose-Mary N. Boustany, MD , Professor of Pediatrics and Biochemistry, American University of Beirut, Adjunct Professor of Pediatrics, Professor of Neurobiology and Associate in Medicine, Duke University Medical Center, Beirut, Lebanon

Amy Brooks-Kayal, MD , Chief and Ponzio Family Chair in Pediatric Neurology, Children’s Hospital of Colorado, Professor of Pediatrics, Neurology and Pharmaceutical Sciences, University of Colorado Schools of Medicine and Pharmacy, Aurora, CO, USA

Lawrence W. Brown, MD , Associate Professor of Neurology and Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Carol S. Camfield, MD , Professor Emeritus, Department of Pediatrics, Dalhousie University and the IWK Health Centre Halifax, Nova Scotia, Canada

Peter R. Camfield, MD FRCP(c) , Professor, Pediatrics, Dalhousie University and IWK Health Centre, Halifax, Nova Scotia, Canada

Margaretha L. Casselbrant, MD PhD , Eberly Professor of Pediatric Otolaryngology, University of Pittsburgh School of Medicine, Director, Division of Pediatric Otolaryngology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

Claudia A. Chiriboga, MD MPH , Associate Professor, Clinical Neurology and Pediatrics, Interim Program Director of Pediatric Neurology, Columbia University Medical Center, New York, NY, USA

Susan L. Christian, PhD , Laboratory Director, Center for Integrative Brain Research, Seattle Childrens Research Institute, Seattle, WA, USA

Maria Roberta Cilio, MD PhD , Faculty, Bambino Gesù Children’s Hospital, Rome, Italy, Associate Professor in Neurology, University of California San Francisco, San Francisco, CA, USA

Anne M. Connolly, MD , Professor of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, MO, USA

Jeannine M. Conway, PharmD , Assistant Professor, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

Susannah Cornes, MD , Assistant Professor of Clinical Neurology, Department of Neurology, University of California San Francisco, San Francisco, CA, USA

David L. Coulter, MD , Associate Professor, Neurology, Harvard Medical School, Boston, MA, USA

Tina M. Cowan, PhD , Associate Professor, Pathology, Stanford University, Stanford, CA, USA

Soma Das, PhD , Professor of Human Genetics, University of Chicago, Chicago, IL, USA

Darryl C. De Vivo, MD , Sidney Carter Professor of Neurology, Professor of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA

Linda S. de Vries, MD , Professor in Neonatal Neurology, Department of Neonatology, Wilhelmina Children’s Hospital, UMCU, Utrecht, The Netherlands

Jay Desai, MD , Fellow, Division of Neurology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Maria Descartes, MD , Associate Professor Genetics and Pediatrics, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

Gabrielle deVeber, MD MHSc , Director, Children’s Stroke Program, Neurology, Hospital for Sick Children, Toronto, Ontario, Canada

Salvatore DiMauro, MD , Lucy G. Moses Professor of Neurology, Department of Neurology, Columbia University Medical Center, New York, NY, USA

William B. Dobyns, MD , Professor, Departments of Pediatrics and Neurology, University of Washington and, Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA

Qing Dong, MD PhD , CEO and President, Sound Pediatrics, Daly City, CA, USA

James M. Drake, BSE MBBCh MSc FRCSC FACS , Professor and Divisions Head, Pediatric Neurosurgery, Harold Hoffman/Shopper’s Drug Mart Chair, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Ann-Christine Duhaime, MD , Professor of Neurosurgery, Harvard Medical School, Attending Neurosurgeon, Massachusetts General Hospital, Boston, MA, USA

Adre J. du Plessis, MBChB , Chief of Fetal and Transitional Medicine, Children’s National Medical Center, Professor of Pediatrics and Neurology, George Washington University Medical School, Washington, DC, USA

Mohamad K. El-Bitar, c/o Rose-Mary N. Boustany

Gregory M. Enns, MD , Associate Professor, Stanford School of Medicine, Palo Alto, CA, USA

Diana M. Escolar, MD , Associate Professor of Neurology, Johns Hopkins School of Medicine, Neurology Department, Kennedy Krieger Institute, Baltimore, MD USA

Owen B. Evans, Jr, MD , Professor of Pediatrics and Neurology, Department of Pediatrics, University of Mississippi School of Medicine Jackson, MS, USA

S. Ali Fatemi, MD , Assistant Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Pediatric Neurologist, Division of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, USA

Donna M. Ferriero, MD MS , W.H. and Marie Wattis Distinguished Professor and Chair Department of Pediatrics, Physician-in-Chief, UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, USA

Pauline A. Filipek, MD , Director, Autism Center at the Children’s Learning Institute, Professor of Pediatrics, Children’s Learning Institute and, Division of Child and Adolescent Neurology, UT Health Sciences Center at Houston, Houston, TX, USA

Yitzchak Frank, MD , Professor, Pediatrics and Neurology, Mount Sinai Medical School, New York, NY, USA

Douglas R. Fredrick, MD , Clinical Professor of Ophthalmology and Pediatrics, Department of Ophthalmology, Stanford University, Stanford, CA, USA

Hudson H. Freeze, PhD , Professor and Director, Genetic Disease Program, Sanford Children’s Health Research Center, Burnham Institute for Medical Research, La Jolla, CA, USA

Neil R. Friedman, MBChB , Staff Center for Pediatric Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Joseph M. Furman, MD PhD , Professor, Departments of Otolaryngology and Neurology, University Of Pittsburgh, Pittsburgh, PA, USA

Bhuwan P. Garg, MB MS , Professor Emeritus, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

Debabrata Ghosh, MD DM , Staff, Center for Pediatric Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Elizabeth E. Gilles, MD , Assistant Professor of Pediatrics, University of Minnesota, Medical Director, Pediatric Neurology, Children’s Hospitals and Clinics, St. Paul, MN, USA

Christopher C. Giza, MD , Associate Professor in Residence, Division of Pediatric Neurology and Department of Neurosurgery, UCLA Brain Injury Research Center, David Geffen School of Medicine at UCLA, Mattel Children’s Hospital – UCLA, Los Angeles, CA, USA

Carol A. Glaser, DVM MPVM MD , Chief of Encephalitis and Special Investigations Section, Communicable Disease and Emergency Response Branch, Division of Communicable Disease Control, California Department of Public Health, Richmond, CA, USA

Joseph G. Gleeson, MD , Professor, Neurosciences and Pediatrics, University of California San Diego, La Jolla, CA, USA

John M. Graham, Jr. MD ScD , Director of Clinical Genetics and Dysmorphology, Professor of Pediatrics and Biomedical Sciences, Cedars Sinai Medical Center, Professor of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Pierre Gressens, MD PhD , Laboratory Chief, Paris 7 University, Hôpital Robert Debré, Paris, France, Professor of Perinatal Neurology, Hammersmith Hospital, Imperial College of London, London, UK

Renzo Guerrini, MD , Pediatric Neurology Unit and Laboratories, Children’s Hospital, A. Meyer-University of Florence, Florence, Italy

Nalin Gupta, MD PhD , Associate Professor, Neurological Surgery and Pediatrics, Chief, Pediatric Neurosurgery, UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, USA

Jin S. Hahn, MD , Professor of Neurology and Pediatrics, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA

Chellamani Harini, MBBS MD , Clinical Instructor, Department of Neurology, Children’s Hospital, Boston, MA, USA

Chad Heatwole, MD , Assistant Professor of Neurology, Neurology, University of Rochester, Rochester, NY, USA

Deborah G. Hirtz, MD , Program Director, Office of Clinical Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

Gregory L. Holmes, MD , Chair, Department of Neurology, Professor of Neurology and Pediatrics, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

Barbara A. Holshouser, PhD , Professor of Radiology, Radiology, Loma Linda University Medical Center, Loma Linda, CA, USA

Rebecca N. Ichord, MD , Associate Professor, Neurology and Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Paymaan Jafar-Nejad, MD , Post-doc fellow, Dr. Huda Zoghbi’s laboratories, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX, USA

Frances E. Jensen, MD , Professor of Neurology, Neurology, Children’s Hospital and Harvard Medical School, Boston, MA, USA

Michael V. Johnston, MD , Chief Medical Officer, Kennedy Krieger Institute Children’s Hospital, Professor of Neurology, Pediatrics and Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Lori Jordan, MD , Assistant Professor of Neurology and Pediatrics, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Yasmin Khakoo, MD , Pediatric Neurologist/Neuro-Oncologist, Departments of Pediatrics and Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Mustafa Khasraw, MD MRCP FRACP , Clinical Fellow, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Adam Kirton, MD MSc FRCPC , Assistant Professor, Pediatrics and Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada

John T. Kissel, MD , Professor of Neurology and Pediatrics, Ohio State University and Nationwide Children’s Hospital, Columbus, OH, USA

Ophir Klein, MD PhD , Assistant Professor, Departments of Orofacial Sciences and Pediatrics, University of California San Francisco, San Francisco, CA, USA

Kelly Knupp, MD , Neurology and Neurodiagnostics, Assistant Professor of Pediatrics, Children’s Hospital, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

Bruce R. Korf, MD PhD , Wayne H. and Sara Crews Finley Chair in Medical Genetics, Professor and Chair, Department of Genetics, Director, Heflin Center for Genome Sciences, University of Alabama, Birmingham, AL, USA

Suresh Kotagal, MD , Professor, Division of Child Neurology, Consultant, Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, MN, USA

Steven Leber, MD PhD , Professor, Pediatrics and Neurology, University of Michigan, Ann Arbor, MI, USA

Ilo E. Leppik, MD , Professor of Pharmacy, Adjunct Professor of Neurology, Director, Epilepsy Research and Education Program, University of Minnesota, Minneapolis, MN, USA

Tally Lerman-Sagie, MD , Associate Professor, Head, Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel

Jason T. Lerner, MD , Assistant Professor, Director of Training, Division of Pediatric Neurology, Mattel Children’s Hospital at UCLA, Los Angeles, CA, USA

Robert T. Leshner, MD , Health Sciences Clinical Professor, Department of Neurosciences, University of California San Diego, San Diego, CA, USA

Richard J. Leventer, MBBS BMedSci FRACP PhD , Consultant Pediatric Neurologist, Children’s Neuroscience Centre and Murdoch Children’s Research Institute, Royal Children’s Hospital and Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia

Donald W. Lewis, MD , Professor and Chairman, Department of Pediatrics, Children’s Hospital of the King’s Daughters, Eastern Virginia Medical School, Norfolk, VA, USA

Paul F. Lewis, MD , Associate Professor, Pediatrics, Oregon Health and Sciences University, Portland, OR, USA

Uta Lichter-Konecki, MD PhD , Director of the Metabolism Program, Children’s National Medical Center, Associate Professor of Pediatrics, Department of Pediatrics, George Washington University, Washington, DC, USA

Catherine Limperopoulos, PhD , Director, MRI Research of the Developing Brain, Associate Professor of Pediatrics, Diagnostic Imaging and Radiology, George Washington University Health Center, Children’s National Medical Center, Washington, DC, USA

Janice K. Louie, MD MPH , Chief, Surveillance and Epidemiology Section, Division of Communicable Disease Control, California Department of Public Health, Richmond, CA, USA

Quyen N. Luc, MD , Clinical Fellow in Pediatric Movement Disorders, Division of Neurology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Tobey J. MacDonald, MD , Director, Pediatric Neuro-Oncology Program Associate Professor of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA

Naila Makhani, MD FRCPC , Clinical Research Fellow, Pediatric Demyelinating Disease Program, Hospital for Sick Children, Toronto, Ontario, Canada

Gustavo Malinger, MD , Professor, Fetal Neurology Clinic, Department of Obstetrics and Gynecology Wolfson Medical Center, Holon, Israel, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

David E. Mandelbaum, MD PhD , Professor, Neurology and Pediatrics, Alpert Medical School of Brown University, Providence, RI, USA

Charles J. Marcuccilli, MD PhD , Assistant Professor of Neurology, Division of Pediatric Neurology, Medical College of Wisconsin, Milwaukee, WI, USA

Stephen M. Maricich, MD PhD , Assistant Professor, Departments of Pediatrics, Neurosciences and Otolaryngology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

Lee J. Martin, PhD , Professor of Pathology and Neuroscience Departments of Pathology and Neuroscience Division of Neuropathology, Johns Hopkins University School of Medicine Baltimore, MD, USA

Julie A. Mennella, PhD , Member, Monell Chemical Senses Center, Philadelphia, PA, USA

Laura R. Ment, MD , Professor, Pediatrics and Neurology, Associate Dean, Yale University School of Medicine, New Haven, CT, USA

David J. Michelson, MD , Assistant Professor, Pediatrics, Division of Child Neurology, Loma Linda University School of Medicine, Loma Linda, CA, USA

Fady M. Mikhail, MD PhD , Assistant Director, Cytogenetics Laboratory, Assistant Professor, Department of Genetics, University of Alabama at Birmingham Birmingham, AL, USA

Kathleen J. Millen, PhD , Associate Professor, Department of Pediatrics, Seattle Children’s Hospital Research Institute, Center for Integrative Brain Research, University of Washington, Seattle, WA, USA

Steven P. Miller, MDCM MAS FRCPC , Canada Research Chair in Neonatal Neuroscience, Senior Clinician Scientist, Child and Family Research Institute, Associate Professor of Pediatrics (Neurology), University of British Columbia, Vancouver, British Columbia, Canada

Jonathan W. Mink, MD PhD , Professor of Neurology, Chief, Child Neurology, Interim Chief, Movement Disorders, University of Rochester, Rochester, NY, USA

Ghayda Mirzaa, MD FAAP , Fellow, Clinical Genetics, Department of Human Genetics, University of Chicago, Chicago, IL, USA

Wendy G. Mitchell, MD , Professor, Neurology and Pediatrics, Keck School of Medicine, University of Southern California, Acting Division Head, Pediatric Neurology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Manikum Moodley, MD FRCP , Staff, Center for Pediatric Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Lawrence D. Morton, MD , Professor, Neurology and Pediatrics, Director, Clinical Neurophysiology, Virginia Commonwealth University Health Systems, Richmond, VA, USA

Richard T. Moxley, III , MD , Professor of Neurology and Pediatrics, Director, Neuromuscular Disease Center, Associate Chair for Academic Affairs, Helen Aresty Fine and Irving Fine Professor of Neurology, University of Rochester, Rochester, NY, USA

Srikanth Muppidi, MD , Assistant Professor, Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA

Kendall Nash, MD , Pediatric Neurophysiology/Epilepsy Fellow, Department of Neurology, University of California San Francisco, San Francisco, CA, USA

Ruth Nass, MD , Professor of Child Neurology, Child and Adolescent Psychiatry and Pediatrics, NYU Langone Medical Center, New York, NY, USA,

Michael J. Noetzel, MD , Professor of Neurology and Pediatrics, Neurology and Pediatrics, Washington University School of Medicine, St. Louis, MO, USA

Douglas R. Nordli, Jr. , MD , Lorna S. and James P. Langdon Chair of Pediatric Epilepsy, Professor, Department of Pediatrics, Northwestern University-Feinberg School of Medicine, Director, Epilepsy Center, Children’s Memorial Hospital, Chicago, IL, USA

Frances J. Northington, MD , Associate Professor of Pediatrics, Department of Pediatrics, Eudowood Neonatal Pulmonary Division and Neonatal Research Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Robert Ouvrier, MD BS BSc (Med) , Petre Foundation Professor of Pediatric Neurology, Discipline of Pediatrics, University of Sydney, Children’s Hospital at Westmead, New South Wales, Australia

Roger J. Packer, MD , Senior Vice President, Neuroscience and Behavioral Medicine, Director, Brain Tumor Institute, Director, Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC, USA

Seymour Packman, MD PhD , Professor of Pediatrics, Department of Pediatrics, Division of Medical Genetics, University of California San Francisco, San Francisco, CA, USA

Julie A. Parsons, MD , Assistant Professor of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO, USA

John C. Partridge, MD MPH , Professor of Clinical Pediatrics, University of California San Francisco, San Francisco, CA, USA

Gregory M. Pastores, MD , Associate Professor, Neurology and Pediatrics, NYU School of Medicine, New York, NY, USA

Marc C. Patterson, MD FRACP , Professor of Neurology, Pediatrics, and Medical Genetics, Mayo Clinic College of Medicine, Chair, Division of Child and Adolescent Neurology, Departments of Neurology, Pediatrics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA

John M. Pellock, MD , Professor and Chairman, Division of Child Neurology, Virginia Commonwealth University/Medical College of Virginia Health System, Richmond, VA, USA

Ronald M. Perkin, MD MA , Professor and Chairman, Department of Pediatrics, Brody School of Medicine at East Carolina University, Greenville, NC, USA

Isabelle Rapin, MD , Professor, Saul R. Korey Department of Neurology and Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA

Gerald V. Raymond, MD , Professor of Neurology, Johns Hopkins University School of Medicine, Neurologist, Neurogenetics Research Center, Kennedy Krieger Institute, Baltimore, MD, USA

Rebecca Rendleman, MD CM , New York Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA

Jong M. Rho, MD , Senior Staff Scientist, Neurology Research, Barrow Neurological Institute, Associate Director, Child Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

Sarah M. Roddy, MD , Associate Professor, Department of Pediatrics and Neurology, Loma Linda University School of Medicine, Loma Linda, CA, USA

Stephen M. Rosenthal, MD , Professor of Pediatrics, Associate Program Director, Pediatric Endocrinology, Director, Pediatric Endocrine Outpatient Services, University of California San Francisco, San Francisco, CA, USA

N. Paul Rosman, BSc MD CM , Professor, Departments of Pediatrics and Neurology, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA

M. Elizabeth Ross, MD PhD , Professor, Neurology and Neuroscience, Weill Cornell Medical College, New York, NY, USA

Robert S. Rust, MA MD , Thomas E. Worrell Professor of Epileptology and Neurology, Professor of Pediatrics, Departments of Neurology and Pediatrics University of Virginia, Charlottesville, VA, USA

Pedro A. Sanchez-Lara, MD , Assistant Professor, Department of Pediatrics, University of Southern California, Keck School of Medicine, Director of Craniofacial Genetics, Medical Genetics, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Terence D. Sanger, MD PhD , Associate Professor, Department of Biomedical Engineering, Child Neurology and Biokinesiology, University of Southern California, Los Angeles, CA, USA

Oranee Sanmaneechai, MD , Pediatric Neurology Fellow, Neurology, Albert Einstein College of Medicine, Bronx, NY, USA, Assistant Professor in Pediatrics, Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok, Thailand

Urs B. Schaad, MD , Professor Emeritus, Pediatrics, Pediatric Infectious Diseases, University of Basel, Basel, Switzerland

Mark S. Scher, MD , Professor of Pediatrics and Neurology, Department of Pediatrics, Division Chief, Pediatric Neurology, Director, Rainbow Neurological Center, Neurological Institute of University Hospitals, Director, Pediatric Neurointensive Care Program/Fetal Neurology Program, Rainbow Babies and Children’s Hospital, University Hospitals Case Medical Center, CWRU School of Medicine, University Hospitals of Cleveland, Cleveland, OH, USA

Nina F. Schor, MD PhD , William H. Eilinger Chair of Pediatrics, Professor, Departments of Pediatrics, Neurology, and Neurobiology and Anatomy, University of Rochester School of Medicine, and Dentistry, Rochester, NY, USA

Michael M. Segal, MD PhD , Founder and Chief Scientist, SimulConsult, Inc., Chestnut Hill, MA, USA

Bennett A. Shaywitz, MD , Charles and Helen Schwab Professor in Dyslexia and Learning Development, Chief, Pediatric Neurology, Yale University School of Medicine, New Haven, CT, USA

Sally E. Shaywitz, MD , Audrey G. Ratner Professor in Learning Development, Co-Director, Yale Center for Dyslexia and Creativity, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA

Elliott H. Sherr, MD PhD , Associate Professor, Neurology, University of California San Francisco, San Francisco, CA, USA

Michael I. Shevell, MD CM FRCP FAAN , Professor, Departments of Neurology/Neurosurgery and Pediatrics, McGill University, Director, Division of Pediatric Neurology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada

Shlomo Shinnar, MD PhD , Professor of Neurology, Pediatrics, and Epidemiology and Population Health, Hyman Climenko Professor of Neuroscience Research, Director, Comprehensive Epilepsy Management Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

Stanford K. Shu, MD , Assistant Professor of Pediatrics and Neurology, Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA

Faye S. Silverstein, MD , Professor, Pediatrics and Neurology, University of Michigan, Ann Arbor, MI, USA

Harvey S. Singer, MD , Haller Professor of Pediatric Neurology, Johns Hopkins University School of Medicine, Director, Child Neurology, Johns Hopkins Hospital, Baltimore, MD, USA

John T. Sladky, MD , Professor of Pediatrics and Neurology, Pediatrics, Emory University School of Medicine, Atlanta, GA, USA

Stephen A. Smith, MD , Neurology, Gillette Children’s Specialty Healthcare, Pathology, Hennepin County Medical Center, Minneapolis, MN, USA

Janet S. Soul, MD CM FRCPC , Director, Clinical Neonatal Neurology, Director, Neonatal Neurology Clinic, Children’s Hospital Boston, Assistant Professor of Neurology, Neurology, Harvard Medical School, Boston, MA, USA

Carl E. Stafstrom, MD PhD , Chief, Pediatric Neurology, Professor, Neurology and Pediatrics, University of Wisconsin, Madison, WI, USA

Jonathan B. Strober, MD , Director, Pediatric MDA Clinic, Associate Clinical Professor, Neurology and Pediatrics, Division of Child Neurology, University of California San Francisco, San Francisco, CA, USA

Joseph Sullivan, MD , Director, UCSF Pediatric Epilepsy Center, Assistant Professor of Clinical Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, USA

Kenneth F. Swaiman, MD , Director Emeritus, Division of Pediatric Neurology, Professor Emeritus of Neurology and Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA

Matthew T. Sweney, MD MS , Child Neurology Fellow, Division of Pediatric Neurology, University of Utah, Salt Lake City, UT, USA

Kathryn J. Swoboda, MD FACMG , Associate Professor, Departments of Neurology and Pediatrics Director, Pediatric Motor Disorders Research Program, University of Utah, Salt Lake City, UT, USA

Martin G. Täuber, Dr. Med , Director and Chief, Institute for Infectious Diseases, University of Bern, and Inselspital University Hospital, Bern, Switzerland

Donald A. Taylor, MD , Director of Pediatric Clinical Neurophysiology, St. Mary’s Hospital, Richmond, VA, USA

Ingrid Tein, MD FRCP(C) , Associate Professor of Pediatrics, Laboratory Medicine and Pathobiology, Director, Neurometabolic Clinic and Research Laboratory, Staff Neurologist, Division of Neurology, Department of Pediatrics, Senior Scientist, Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Elizabeth A. Thiele, MD PhD , Director, Pediatric Epilepsy Program, Director, Herscot Center for Tuberous Sclerosis Complex, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Doris A. Trauner, MD , Professor, Neurosciences and Pediatrics, University of California San Diego, La Jolla, CA, USA

Roberto Tuchman, MD , Director, Autism Program, Neurology, Miami Children’s Hospital Dan Marino Center, Weston, FL, USA

Adeline Vanderver, MD , Assistant Professor of Neurology, Pediatrics and Integrative Systems Biology, Department of Neurology, Children’s National Medical Center, George Washington University School of Medicine, Washington, DC, USA

Michéle Van Hirtum-Das, MD , Attending Physician, Neurology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

V. Venkataraman Vedanarayanan, MD FRCPC , Professor of Neurology, Pediatrics, and Pathology, University of Mississippi Medical Center, Jackson, MS, USA,

Zinaida S. Vexler, PhD , Professor of Neurology, University of California San Francisco, San Francisco, CA, USA

Gilbert Vezina, MD , Director of Neuroradiology, Division of Radiology, Children’s National Medical Center, Washington DC, USA

Emily von Scheven, MD MAS , Professor of Clinical Pediatrics, Pediatric Rheumatology, University of California San Francisco, San Francisco, CA, USA

Ann Wagner, PhD , Chief, Neurobehavioral Mechanisms Branch, Division of Developmental Translational Research, National Institute of Mental Health, Bethesda, MD, USA

Mark S. Wainwright, MD PhD , Director, Pediatric Neurocritical Care Program, Children’s Memorial Hospital, Associate Professor, Department of Pediatrics, Divisions of Neurology and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

John T. Walkup, MD , Professor of Psychiatry, Vice Chair of Psychiatry and Director, Division of Child and Adolescent Psychiatry, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY, USA

Laurence E. Walsh, MD , Associate Professor of Clinical Neurology, Medical and Molecular Genetics, and Clinical Pediatrics, Child Neurology Section, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

Ching H. Wang, MD PhD , Associate Professor, Neurology and Pediatrics, Stanford University Medical Center, Stanford, CA, USA

James W. Wheless, MD , Professor and Chief of Pediatric Neurology LeBonheur Chair in Pediatric Neurology University of Tennessee Health Science Center Director, LeBonheur Comprehensive Epilepsy Program & Neuroscience Institute, LeBonheur Children’s Hospital, Clinical Chief & Director of Pediatric Neurology, St Jude Children’s Research Hospital, Memphis, TN, USA

Nicole I. Wolf, MD PhD , Assistant Professor, Child Neurology, VU University Medical Center, Amsterdam, The Netherlands

Gil I. Wolfe, MD , Dr. Bob and Jean Smith Foundation Distinguished Chair in Neuromuscular Disease Research, Professor of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Yvonne W. Wu, MD MPH , Professor, Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, USA

Nathaniel D. Wycliffe, MD , Associate Professor of Radiology, Division of Neuroradiology, Loma Linda University Medical Center, Loma Linda, CA, USA

Jerome Y. Yager, MD FRCP(C) , Director of Research, Department of Pediatrics, Section of Pediatric Neurosciences, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada

Jennifer A. Zimmer, MD , Assistant Professor, Department of Child Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

Huda Y. Zoghbi, MD , Investigator, Howard Hughes Medical Institute, Professor, Baylor College of Medicine, Department of Pediatrics, Molecular and Human Genetics, Neurology and Neuroscience, Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA

Mary L. Zupanc, MD , Professor, Department of Pediatrics and Neurology, University of California Irvine Children’s Hospital of Orange County, Chief, Division of Pediatric Neurology Director, Pediatric Comprehensive Epilepsy Program, Children’s Hospital of Wisconsin, Milwaukee, WI, USA
Acknowledgments
We wish to thank the editorial and publishing staff at Elsevier, especially Janice Gaillard, Charlotta Kryhl, Frances Affleck, and Wendy Lee. Without their diligence and persistence, we would have never been able to complete this project.
Table of Contents
Instructions for online access
Front matter
Dedication
Copyright
Preface to the First Edition
Preface to the Fifth Edition
Contributors
Acknowledgements
Part I: Clinical Evaluation
Chapter 1: General Aspects of the Patient’s Neurologic History
Chapter 2: Neurologic Examination of the Older Child
Chapter 3: Neurologic Examination after the Newborn Period until 2 Years of Age
Chapter 4: Neurologic Examination of the Term and Preterm Infant
Chapter 5: Muscular Tone and Gait Disturbances
Chapter 6: Vision Loss
Chapter 7: Hearing Impairment
Chapter 8: Vertigo
Chapter 9: Taste and Smell
Part II: Neurodiagnostic Testing
Chapter 10: Spinal Fluid Examination
Chapter 11: Pediatric Neuroimaging
Chapter 12: Pediatric Neurophysiologic Evaluation
Part III: Emerging Neuroscience Concepts
Chapter 13: Brain Plasticity and its Disorders
Chapter 14: Neurodegeneration in the Neonatal Brain
Chapter 15: Neuroinflammation
Part IV: Perinatal Acquired and Congenital Neurologic Disorders
Chapter 16: Neonatal Seizures
Chapter 17: Hypoxic-Ischemic Brain Injury in the Term Newborn
Chapter 18: Neonatal Brain Injury
Chapter 19: Injury to the Developing Preterm Brain: Intraventricular Hemorrhage and White Matter Injury
Chapter 20: Perinatal Metabolic Encephalopathies
Part V: Congenital Structural Defects
Chapter 21: Overview of Disorders of Brain Development
Chapter 22: Disorders of Neural Tube Development
Chapter 23: Disorders of Forebrain Development
Chapter 24: Disorders of Cerebellar and Brainstem Development
Chapter 25: Disorders of Brain Size
Chapter 26: Malformations of Cortical Development
Chapter 27: Hydrocephalus and Arachnoid Cysts
Chapter 28: Congenital Anomalies of the Skull
Chapter 29: Prenatal Diagnosis of Structural Brain Anomalies
Part VI: Genetic, Metabolic, and Neurocutaneous Disorders
Chapter 30: Introduction to Genetics
Chapter 31: Chromosomes and Chromosomal Abnormalities
Chapter 32: Aminoacidemias and Organic Acidemias
Chapter 33: Inborn Errors of Urea Synthesis
Chapter 34: Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism
Chapter 35: Disorders of Glycosylation
Chapter 36: Lysosomal Storage Diseases
Chapter 37: Mitochondrial Diseases
Chapter 38: Peroxisomal Disorders
Chapter 39: Neurotransmitter-Related Disorders
Chapter 40: Phakomatoses and Allied Conditions
Chapter 41: Degenerative Disorders Primarily of Gray Matter
Chapter 42: Channelopathies
Part VII: Neurodevelopmental Disorders
Chapter 43: Global Developmental Delay and Mental Retardation/Intellectual Disability
Chapter 44: Cognitive and Motor Regression
Chapter 45: Developmental Language Disorders
Chapter 46: Dyslexia
Chapter 47: Attention-Deficit Hyperactivity Disorder
Chapter 48: Autistic Spectrum Disorders
Chapter 49: Neuropsychopharmacology
Part VIII: Epilepsy
Chapter 50: Pediatric Epilepsy: An Overview
Chapter 51: Neurophysiology of Seizures and Epilepsy
Chapter 52: Genetics of Epilepsy
Chapter 53: Generalized Seizures
Chapter 54: Focal and Multifocal Seizures
Chapter 55: Epilepsy and Neurodevelopmental Disorders
Chapter 56: Myoclonic Seizures and Infantile Spasms
Chapter 57: Febrile Seizures
Chapter 58: Status Epilepticus
Chapter 59: Antiepileptic Drug Therapy in Children
Chapter 60: The Ketogenic Diet
Chapter 61: Epilepsy Surgery in the Pediatric Population
Chapter 62: Behavioral, Cognitive, and Social Aspects of Childhood Epilepsy
Part IX: Nonepileptiform Paroxysmal Disorders and Disorders of Sleep
Chapter 63: Headaches in Infants and Children
Chapter 64: Breath-Holding Spells and Reflex Anoxic Seizures
Chapter 65: Syncope and Paroxysmal Disorders Other than Epilepsy
Chapter 66: Sleep–Wake Disorders
Part X: Disorders of Balance and Movement
Chapter 67: The Cerebellum and the Hereditary Ataxias
Chapter 68: Movement Disorders
Chapter 69: Cerebral Palsy
Chapter 70: Tics and Tourette’s Syndrome
Part XI: White Matter Disorders
Chapter 71: Genetic and Metabolic Disorders of the White Matter
Chapter 72: Acquired Disorders Affecting the White Matter
Part XII: Brain Injury and Disorders of Consciousness
Chapter 73: Impairment of Consciousness and Coma
Chapter 74: Traumatic Brain Injury in Children
Chapter 75: Non-accidental Head Trauma
Chapter 76: Hypoxic-Ischemic Encephalopathy in Infants and Older Children
Chapter 77: Disorders of Intracranial Pressure
Chapter 78: Spinal Cord Injury
Chapter 79: Determination of Brain Death in Infants and Children
Part XIII: Infections of the Nervous Syste
Chapter 80: Bacterial Infections of the Nervous System
Chapter 81: Viral Infections of the Nervous System
Chapter 82: Fungal, Rickettsial, and Parasitic Diseases of the Nervous System
Part XIV: Tumors and Vascular Disorders of the Nervous System
Chapter 83: Tumors of the Brain and Spine
Chapter 84: Paraneoplastic Syndromes Affecting the Nervous System
Chapter 85: Cerebrovascular Disease in Children
Chapter 86: Neurologic Manifestations of Rheumatic Disorders of Childhood
Part XV: Neuromuscular Disorders
Chapter 87: Normal Muscle
Chapter 88: Anterior Horn Cell and Cranial Motor Neuron Disease
Chapter 89: Peripheral Neuropathies
Chapter 90: Inflammatory Neuropathies
Chapter 91: Diseases of the Neuromuscular Junction
Chapter 92: Muscular Dystrophies
Chapter 93: Congenital Myopathies
Chapter 94: Metabolic Myopathies
Chapter 95: Inflammatory Myopathies
Chapter 96: Channelopathies: Myotonic Disorders and Periodic Paralysis
Part XVI: Systemic and Autonomic Nervous System Disease
Chapter 97: Endocrine Disorders of the Hypothalamus and Pituitary in Childhood and Adolescence
Chapter 98: Disorders of the Autonomic Nervous System: Autonomic Dysfunction in Pediatric Practice
Chapter 99: Disorders of Micturition and Defecation
Chapter 100: Poisoning and Drug-Induced Neurologic Diseases
Chapter 101: Neurologic Disorders in Children with Heart Disease
Chapter 102: Interrelationships between Renal and Neurologic Diseases and Therapies
Chapter 103: Neurologic Disorders Associated with Gastrointestinal Diseases and Nutritional Deficiencies
Chapter 104: Neurologic Complications of Immunization
Part XVII: Care of the Child with Neurologic Disorders
Chapter 105: Pediatric Neurorehabilitation Medicine
Chapter 106: Pain Management and Palliative Care
Chapter 107: Ethical Issues in Child Neurology
Chapter 108: The Impact of Computer Resources on Child Neurology
Index
Part I
Clinical Evaluation
Chapter 1 General Aspects of the Patient’s Neurologic History

Kenneth F. Swaiman
There is no substitute for an accurate and thorough history. The critical role of obtaining the child’s neurologic history directly from the patient or a member of the patient’s family often is pivotal in developing a correct diagnosis. The history-taking procedure should elicit specific information and be directed so as to exclude or ensure inclusion of pertinent conditions in the differential diagnosis of the child’s disease. The information obtained during the history-taking session is crucial during the subsequent analysis and synthesis of all patient data. The clinician should be involved in a dynamic diagnostic quest throughout the interview and during the review of previous medical and other relevant records. A systematic approach to the medical history is mandatory; however, the clinician must be alert to significant clues that may prove essential to the diagnostic process. The history-taking session is not a random gathering operation with data to be subsequently sorted; rather, the data should be actively synthesized as they are collected and then used to alter the direction and the varying depth of the questioning process.
The process of identifying a differential diagnosis should begin at the outset of questioning. In a broad sense, certain umbrella categories encompass virtually all etiologic mechanisms that underlie the differential diagnosis. Inevitably, there is some overlap (e.g., vascular occlusion in MELAS, a metabolic condition; mass effect of a brain abscess, an infectious condition). The fundamental pathologic processes, simplistically identified, are infectious, traumatic, metabolic, endocrinologic, toxic (exogenous and endogenous), congenital structural malformations, vascular, neoplastic, degenerative (usually of unknown or obscure cause), and idiopathic. Each of these categories has many subsets with which the clinician who evaluates neurologic problems in children must be familiar. The likelihood that one of the broad umbrella classifications applies to the problem of the pediatric patient must be judged while the history is obtained, during which time some categories will gain in probability and some will become increasingly remote. The information gathered during the history-taking session may be vital in the process of literature and database searches that may subsequently prove necessary. The precise role of genetic determination (i.e., gene product formation and use) in all familial pathologic processes is exceedingly important particularly now that the human genome has been mapped [ Ali-Khan et al., 2009 ] and chromosomal microarray studies are available [Paciorkowsky and Fang, 2010]. Personalized genomic characterization will likely be utilized frequently in the immediate future [ Guttmacher et al., 2010 ]. Results of newborn screening tests may be known by the caretakers and provide pertinent information [ Duffner et al., 2009 ].
Most chronic neurologic complaints are complex, and the neurologist’s involvement is often preceded by involvement of other professionals and agencies. If the parents are the primary caregivers, both the mother and father should be present if possible. When grandparents or other caregivers are involved in attending to the child, they should be present.
Review of past medical and developmental histories is an essential component of a good history-taking session. Information should be sought from records and from questioning the mother about health problems, including infertility, and diseases that occurred during pregnancy. With increasing data accumulating regarding adverse pediatric outcomes with assisted reproductive technologies [ Jackson et al., 2004 ], it is important to ask whether conception was achieved naturally and, if not, what method of assisted reproductive technology was employed. Gestational information about infection, radiation, acute trauma, chronic illnesses such as diabetes mellitus, and toxins, including illicit drugs, tobacco, and alcohol, may prove invaluable. Further information about medications that the mother received, including over-the-counter preparations, should be probed.
It is important to record the expected and actual dates of delivery. Review of birth records, including prenatal and delivery records of the mother, may reveal information concerning difficulties with pregnancy and problems in the perinatal period that are not known or remembered by the parents. Details of the intrapartum period, including associated hypertension, drugs administered, length of stages of delivery, occurrence of chorioamnionitis, and if possible, information concerning placental pathology and the general appearance of the newborn at time of birth, may prove enlightening.
It is important to determine the status of the newborn infant. Information should be sought concerning Apgar scores, depression of activity, neonatal seizures, presence of hypotonia, and whether tracheal intubation and ventilatory support were needed. The presence and nature of neonatal difficulties should be ascertained.
The patient’s caregivers should be questioned carefully about the nature and results of previously performed tests, including electrodiagnostic tests, brain-imaging studies, biochemical studies (e.g., quantitative assays of amino acids, organic acids, lactic acid, and lysosomal enzymes), biopsies, and chromosomal/gene studies (including chromosomal microarray studies). The caregivers should also be asked about whether medication or other treatment has been administered or advised and about the result of such therapies.
The primary problem of the child is embodied in the chief complaint. A combination of chief complaints may prove more specific and narrows the diagnostic spectrum (e.g., a 6-month-old male with delayed development and cataracts). The differential diagnosis is based initially on the chief complaint, which should therefore be documented as accurately as possible. The caregiver’s or patient’s description should be quoted verbatim, when possible. The period of onset and whether the symptoms began acutely or gradually should be carefully determined. The clinician should not substitute medical terminology in place of the terms used by the caregivers or patient when recording the chief complaint. Medical terms must be explained fully so that responses are complete and pertinent.
Notwithstanding these goals, the actual complaint may be imprecisely described because the caregivers’ memories, language, or observations may be inaccurate and because the child may be unable to provide detailed information. The clinician should make every attempt to question the child directly. Even a preschool-aged child may provide helpful information. Sometimes, adults who participate in the session may not be objective or capable of accuracy. Most commonly, however, the observations and concerns of the caregiver should be given every consideration and essence of credibility. It is extremely unwise to disregard these components of the history when comments are somewhat unusual or incompatible with the clinician’s diagnostic bias.
The features associated with the chief complaint compose the history of the present illness. The questioning should provide an incisive interaction between caregiver (or patient) and clinician, and should be directed at formulating the differential diagnosis. This portion of the communication process requires skill and perseverance. An all-inclusive neurologic history is impossible; however, that which makes the history meaningful and complete may be the seemingly trivial information that is not readily recalled or divulged. The accomplished clinician can uncover this information by directed and specific inquiry.
The chief complaint should trigger the process of differential diagnosis in the examiner’s thinking, which begins as a listing of the disease conditions that could cause the chief complaint at the child’s age. The following four specific questions should be answered, if possible, in taking the history of the current illness:
1. Is the process acute or insidious?
2. Is it focal or generalized?
3. Is it progressive or static?
4. At what age did the problem begin?
The order in which disease findings develop and the precise time of onset of symptoms and signs may be critical factors in the process of accurate diagnosis. The presence of repeated episodes or associated phenomena should be determined. Detailed questions should be asked of the caregivers and child to elucidate the facts.
Sequelae of traumatic events develop over a period of minutes to a day ( Figure 1-1 ). Although the clinical manifestations of cerebrovascular events normally develop over minutes to hours, the underlying process may be long-standing; therefore, acute onset of vascular symptoms may be the result of a subacute or chronic process. Infectious processes, electrolyte imbalances, and toxic processes (endogenous or exogenous) usually reach their zenith within a day to several days. Degenerative diseases, inborn metabolic disorders, and neoplastic conditions usually progress insidiously over weeks or months.

Fig. 1-1 Patterns of onset and courses of neurologic conditions.
The arrow in each graph signifies the point of clinical recognition.
(Adapted from Baker AB. Outline of Clinical Neurology. Dubuque, Iowa: William C Brown, 1958.)
Based on the chronologic aspects of the history, the clinician should ask questions related to the most likely pathologic processes. For example, when the history suggests a subacute process, the clinician should probe for characteristics associated with an infectious process (e.g., exposure to a known infectious source, recent infection, vomiting, diarrhea, fever) or with specific toxins (e.g., over-the-counter medications, prescribed medications, insecticides, other toxins found around the home).
Evaluation of whether a condition is focal or generalized is embedded in the neurologic diagnostic process. A focal neurologic lesion is not necessarily one that causes focal manifestations but is one that can be related to dysfunction in a circumscribed neuroanatomic location. For example, a focal lesion in the brainstem may cause ipsilateral cranial nerve and contralateral corticospinal tract involvement. If the difficulties are not focal within this definition, they usually result from a generalized process or from several lesions (i.e., multifocal). Neoplastic and vascular diseases frequently result in focal processes; occasionally, trauma results in such abnormalities. Generalized or multifocal conditions are usually associated with degenerative, congenital, metabolic, or toxic abnormalities.
The clinician must always attempt to determine whether the condition is progressive or static. A detailed developmental history is often the best means of substantiating whether a condition is progressive or static. The history should include a log of motor milestones and should contain specific information regarding motor, language, and adaptive-social behavior. Questions should be crafted to obtain evidence that the child is no longer capable of motor or intellectual activities that were previously performed. This information is essential to the diagnosis of progressive disease, which is usually preceded by a period of normal development. Occasionally, previous formal neurologic and psychometric evaluations may be available. Documentation may be forthcoming from family photographs, family video tapes, or baby books. In progressive conditions, documentation of increasing loss of normal function or an increase in any symptoms, including pain, is essential. Conditions that are static or improve spontaneously are usually the result of traumatic or anoxic episodes, congenital abnormalities, acute toxicity, or resolving infection.
The Denver Developmental Screening Test (DDST) [ Frankenburg and Dodds, 1967 ], the revised form [ Frankenburg et al., 1981 ], the Denver II screening test ( Figure 1-2 ) [ Frankenburg et al., 1992 ], and other developmental surveys allow a more precise approach to the determination of whether gains or losses of skills have occurred and aid in the decision about whether a process is progressive or static.

Fig. 1-2 Denver Developmental Screening Test (Denver II) directions.
(From Frankenburg WK, Dodds JB, Archer P, et al. The Denver II: a major revision and restandardization of the Denver Developmental Screening Test. Pediatrics 1992;89:91.)
The DDST has undergone major revision and restandardization and is available as the Denver Developmental Screening Test II (DDST II, or Denver II). The DDST II has replaced the older versions of the DDST. Standardization testing for the Denver II included evaluating each item to determine if significant differences among different subpopulations existed. These subpopulations included gender, ethnic group (i.e., black, white, or Hispanic), maternal education (i.e., less than 12 grades completed or more than 12 grades completed), and place of residence (i.e., rural, semirural, or urban).
The Denver II differs from the DDST in the selected items, test form, and interpretation. The total number of items has been increased from 105 to 125, and items that were judged as difficult to administer or interpret have been modified or eliminated. Most of the new items are in the language section. The technical manual should be consulted if a delay is identified because it may be caused by sociocultural differences. The DDST II has been modified for use in different language and cultural norms [ Lejarraga et al., 2002 ; Lim et al., 1994 , 1996 ].
The test form for the Denver II resembles the DDST in the vertical placement of items. Key Denver items have been eliminated so that the age scale coincides with the American Academy of Pediatrics’ suggested schedule for health maintenance examinations to facilitate use of the Denver II during these visits. The norms for the distribution bars are in accordance with the new standardization data. A valuable addition to the front of the form is a checklist for documentation of the child’s behavior during testing.
Scoring and interpretation changes have also been made. If a child is able to perform an item depicted to the right of the age line, the performance is designated as advanced. If a child fails or refuses an item that is depicted completely to the right of the age line, the score for the item is deemed normal. If the child passes, fails, or refuses an item on which the age line falls between the 25th and 75th percentile lines, performance is designated as normal. If the child refuses or fails an item on which the age line falls on or between the 75th and 90th percentile lines, performance is designated as a caution. If the child is unable to pass an item depicted entirely to the left of the age line, performance is designated as a delay. Sufficient items should be administered to establish basal and ceiling levels in each sector. To screen only for developmental delays, only items located completely to the left of the child’s age line should be administered. Retesting is recommended after 1–3 months for performance scored as a caution. Retesting for one or more delays, as well as refusals, should be performed within 2 weeks.
It is essential that examiners, caregivers, and educational personnel recognize that the Denver II provides an evaluation of the child’s current developmental level and is not a predictor of the future rate of development or eventual maximum attainment. The test may be used for early identification of neurologic deficits [ Hallioglu et al., 2001 ]. Abnormalities in more complex and abstract functioning may not be recognizable until a later age and will require more sophisticated testing vehicles. Alteration in the child’s biologic or environmental status may affect developmental rate and achievement, and should be investigated and taken into account in the evaluation if appropriate.
The clinician should ask specific questions regarding the age of attainment of developmental landmarks and should make every attempt to discern whether the child is delayed in many areas of development or has developed normally in some areas but not in others. Children who have normal motor development but also have hearing impairment may have delayed speech. However, the presence of neuromuscular disease may cause obvious retardation of motor development but may allow normal development of social and language skills.
Various developmental screening instruments are available and their uses can be summarized briefly ( Table 1-1 ) [ Aly et al., 2010 ]. These instruments are useful when utilized in appropriate situations.

Table 1-1 Major Available Screening Tools
A specific form may be used by the examiner as a guideline to the history-taking procedure ( Figure 1-3 ). There are many systems for recording history and the subsequent examination. The form printed in this chapter may be modified to the specific needs of the patient and the clinician.

Fig. 1-3 General history form.
This can be used for obtaining the medical history, developmental history, and family history of children with neurologic problems.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
The question of hyperactivity is often at the core of the caregiver’s complaint. A rating scale may be completed by teachers to aid the clinician in diagnosis ( Figure 1-4 ) [ Connors, 1969 ]. The problem is discussed in more detail in Chapter 47 . School behavior can also be assessed by caregivers, as shown in Box 1-1 .

Fig. 1-4 Teacher questionnaire for behavioral assessment.
(Adapted from Conners CK. A teacher rating scale for use in drug studies with children. Am J Psychiatry 1967;126:884.)

Box 1-1 Parents/Caretaker Questionnaire—School Behavioral Assessment


Many children are involved in some planned day activity, day care, or school program after the age of 2 or 3 years. A questionnaire, as in Figure 1-5 , can be devised that will allow supervisory personnel to record intellectual, motor, and emotional characteristics.

Fig. 1-5 School information form.
This can be used to obtain the child’s school history from school, day care center, or day activity center.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
It is essential that an adequate family history be recorded. Ages of siblings (including those who have died and those aborted), parents, grandparents, uncles, and aunts should be available. It is particularly helpful to gain health history details of deceased siblings and relatives, because familial conditions that might otherwise go undiscovered are often revealed.
Questions concerning neurologic diseases initially should be specific; then more generalized questions should be asked because caregivers may not understand the more specific approach. The presence of epilepsy, cerebral palsy, deafness, mental retardation, movement disorders, blindness, ataxia, weakness, or progressive intellectual and motor deterioration must be determined. Less sophisticated names, such as fainting spells, nervous breakdowns, strokes, and palsies, may strike a responsive chord. It is imperative that the clinician ask if any family members suffer from the same problems that affect the patient.
Autosomal-dominant traits may be present in successive generations, although the degree of expressivity may vary. Autosomal-recessive traits often do not manifest in successive generations but may be present in siblings. Consanguinity must be considered when autosomal-recessive disease is part of the differential diagnosis. X-linked recessive conditions are manifest in male siblings, male first cousins, and maternal uncles. Careful questioning of the mother, if possible, is highly desirable. Although mitochondrial diseases may be inherited through transmission of maternal DNA, paternal inheritance patterns are also possible [ Schwartz and Vissing, 2003 ]. If a genetic condition is suspected, it is wise to examine siblings, parents, and other family members to augment the history.

References
The complete list of references for this chapter is available online at www.expertconsult.com .
See inside cover for registration details.

References

Ali-Khan S.E., Daar A.S., Shuman C., et al. Whole genome scanning: resolving clinical diagnosis management amidst complex data. Pediatr Res . 2009;66:357-363.
Aly Z., Taj F., Ibrahim S. Missed opportunities in surveillance and screening systems to detect developmental delay: A developing country perspective. Brain Dev . 2010;32:90.
Conners C.K. A teacher rating scale for use in drug studies with children. Am J Psychiatry . 1969;126:152.
Duffner P.K., Caggana M., Orsini J.J., et al. Newborn screening for Krabbe Disease: the New York State Model. Pediatr Neurol . 2009;40:245-252.
Frankenburg W.K., Dodds J.B. Denver developmental screening test. J Pediatr . 1967;71:181.
Frankenburg W.K., Fandal A.W., Sciarillo W., et al. The newly abbreviated and revised Denver Developmental Screening Test. J Pediatr . 1981;99:995.
Frankenburg W.K., Dodds J.B., Archer P., et al. The Denver II: A major revision and restandardization of the Denver Developmental screening test. Pediatrics . 1992;89:91.
Guttmacher A.E., McGuire A.L., Ponder B., et al. Personalized genomic information: preparing for the future of genetic medicine. Nat Rev Genet . 2010;11:161-165.
Hallioglu O., Topaloglu A.K., Zenciroglu A., et al. Denver developmental screening test II for early identification of the infants who will develop major neurological deficit as a sequelae of hypoxic-ischemic encephalopathy. Pediatr Int . 2001;43:400.
Jackson R., Gibson K.A., Wu Y.W., et al. Perinatal outcomes in singletons following in vitro fertilization: A meta-analysis. Obstet Gynecol . 2004;103:551.
Lim H.C., Chan T., Yoong T. Standardisation and adaptation of the Denver Developmental Screening Test (DDST) and Denver II for use in Singapore children. Singapore Med J . 1994;35:156.
Lim H.C., Ho L.Y., Goh L.H., et al. The field testing of Denver Developmental Screening Test Singapore: A Singapore version of Denver II Developmental Screening Test. Ann Acad Med Singapore . 1996;25:200.
Lejarraga H., Pascucci M.C., Krupitzky S., et al. Psychomotor development in Argentinean children aged 0–5 years. Paediatr Perinat Epidemiol . 2002;16:47.
Paciorkowsky A.R., Fang M. Chromosomal microarray interpretation: What is a child neurologist to do? Pediatr Neurol . 2009;41:391-398.
Schwartz M., Vissing J. New patterns of inheritance in mitochondrial disease. Biochem Biophys Res Commun . 2003;310:247.
Chapter 2 Neurologic Examination of the Older Child

Kenneth F. Swaiman
As it is usually feasible to perform a more rigorous examination of older children, detailed discussion of the conventional neurologic examination of children is provided in this chapter, including evaluation of the cranial nerves.
Examination of a child older than 2 years should be as informal as possible while maintaining a basic flow pattern to permit complete evaluation. The older child has acquired a large repertory of skills since infancy ( Box 2-1 ). For children between 2 and 5 years old, the Denver Developmental Screening Test II may be useful in evaluating various motor skills [ Frankenburg et al., 1992 ] (see Chapter 1 ). Many neurologic functions of children between the ages of 2 and 4 years are examined in the same manner as those of children younger than 2 years. As is the case with younger children, some patients between 2 and 4 years old may be most comfortable sitting on a caregiver's lap. The examining room should be equipped with small toys, dolls, and pictures with which to interest the child and provide for ease of interaction. Observation and play techniques are essential means of monitoring intellectual and motor function. Children may choose to move about the examining room and may be attracted to these various playthings. After 4 years of age, the components of the neurologic examination are more conventional and routine, and by adolescence, the examination is much the same as the adult examination.

Box 2-1 Emerging Patterns of Behavior from 1 to 5 years of Age

15 months

Motor: Walks alone; crawls up stairs Adaptive: Makes tower of two cubes; makes line with crayon; inserts pellet into bottle Language: Jargon; follows simple commands; may name familiar object (ball) Social: Indicates some desires or needs by pointing; hugs parents

18 months

Motor: Runs stiffly; sits on small chair; walks up stairs with one hand held; explores drawers and waste baskets Adaptive: Piles three cubes; initiates scribbling; imitates vertical stroke; dumps pellet from bottle Language: Ten words (average); names pictures; identifies one or more parts of body Social: Feeds self; seeks help when in trouble; may complain when wet or soiled; kisses parents with pucker

24 months

Motor: Runs well; walks up and down stairs one step at a time; opens doors; climbs on furniture Adaptive: Makes tower of six cubes; circular scribbling; imitates horizontal strokes; folds paper once imitatively Language: Puts three words together (subject, verb, object) Social: Handles spoon well; tells immediate experiences; helps to undress; listens to stories with pictures

30 months

Motor: Jumps Adaptive: Makes tower of eight cubes; makes vertical and horizontal strokes but generally will not join them to make a cross; imitates circular stroke, forming closed figure Language: Refers to self by pronoun “I”; knows full name Social: Helps put things away; pretends in play

36 months

Motor: Goes up stairs alternating feet; rides tricycle; stands momentarily on one foot Adaptive: Makes tower of nine cubes; imitates construction of “bridge” of three cubes; copies circle; imitates cross Language: Knows age and gender; counts three objects correctly; repeats three numbers or sentence of six syllables Social: Plays simple games (in “parallel” with other children); helps in dressing (unbuttons clothing and puts on shoes); washes hands

48 months

Motor: Hops on one foot; throws ball overhand; uses scissors to cut out pictures; climbs well Adaptive: Copies bridge from model; imitates construction of “gate” of five cubes; copies cross and square; draws man with 2–4 parts besides head; names longer of two lines Language: Counts four pennies accurately; tells a story Social: Plays with several children with beginning of social interaction and role playing; goes to toilet alone

60 months

Motor: Skips Adaptive: Draws triangle from copy; names heavier of two weights Language: Names four colors; repeats sentences of ten syllables; counts ten pennies correctly Social: Dresses and undresses; asks questions about meanings of words; domestic role playing
(Adapted from Behrman RE, et al. Nelson Textbook of Pediatrics, 14th edn. Philadelphia: WB Saunders, 1992.)

Observation
The examiner should take the opportunity to observe the child during the history-taking session. Older children should sit in a chair or perform tasks, such as reading or drawing with crayons or colored pencils. If the child participates actively in the history-taking procedure, the child's understanding and contribution to the session allow the examiner to make judgments about the child's intellectual skills. The child's language skills can be assessed. Stuttering, dysarthria, nasal speech, dysphonia, and problems of articulation are evident. This session also provides an additional opportunity to evaluate facial and eye movements. Head nodding, lip twitching, eye blinking, and staring may be evidence of epilepsy. Movement disorders involving the face, such as chorea or tics, and other movement disorders involving the neck, limbs, and trunk (i.e., athetosis, chorea, dystonia, myoclonus, tics, and spasms) may be noticeable.
This portion of the examination provides an opportunity to assess the child's behavior. Impulsivity, short attention span, and relative dependence may be evident. The child may be unable to sit or play quietly. Distractibility may be evident in response to minor external stimuli. The caregiver–child interaction may also be scrutinized during this time. The caregiver may threaten or use physical force or obsequiously cajole the child. The child's response may be inappropriate.
The following questions must be answered. Does the child respond positively to the caregiver's interaction? Does the child attempt to manipulate the caregiver? Is the response transient or persistent? Is the caregiver's attitude one of caring or hostility?

Screening Gross Motor Function
Sometime between 4 and 6 years of age, most children of normal intelligence participate in a motor screening examination. A rapid screening component is advisable because the child may lose interest, become slowly or abruptly distractible, or become tired and uncooperative. The child should stand before the examiner. Whenever possible during the entire examination, the examiner should demonstrate each of the various motor acts with precision and good humor. A smiling examiner is much more likely to be accepted by the child. Then, for example, the examiner should ask the child to watch as he or she hops on either foot. The child should then be asked to hop in place on each foot (first one then the other), “just the way I did.” The same technique should then be used to have the child tandem-walk forward and backward, toe-walk, and heel-walk. The child should be asked to rise from a squatting position. The child should then be asked to stand with the feet close together, eyes closed, and arms and hands outstretched. This maneuver allows simultaneous assessment of Romberg's sign and adventitious movements, particularly of the face, arms, and hands. The child should then be asked to perform finger-to-nose movements with the eyes closed and finger-to-finger-to-nose movements with the eyes open. After this rapid screening procedure, the examiner can begin a more detailed and systematic evaluation, bearing in mind any suggested or obvious abnormalities evident during the screening process.

Physical Examination

Deep Tendon Reflexes
Deep tendon reflexes (i.e., muscle stretch reflexes) are readily elicited by conventional means with a reflex hammer while the child is sitting quietly. In the case of the biceps reflex, it may be helpful for the examiner to place his or her thumb on the tendon and strike the positioned thumb to elicit the reflex. If the child is crying or overtly resists, the examiner should postpone this portion of the examination. The child may be reassured if the examiner taps the brachioradialis reflex of the caregiver before performing the same act on the child. Deep tendon reflexes customarily examined include the biceps, triceps, brachioradialis, patellar, and Achilles reflexes. Each tendon reflex is mediated at a specific spinal segmental level or levels ( Table 2-1 ) [ Haymaker and Woodhall, 1962 ; Hollinshead, 1969 ].
Table 2-1 Muscle Stretch (Tendon) Reflexes Reflex Nerve Segmental Level Biceps Musculocutaneous C5, C6 Brachioradialis Radial C5, C6 Gastrocnemius and soleus (ankle jerk) Tibial L5, S1, S2 Hamstring Sciatic L4, L5, S1, S2 Jaw Trigeminal Pons Quadriceps (knee jerk) Femoral L2–L4 Triceps Radial C6, C8
The response to elicitation of deep tendon reflexes can be characterized as follows:
1. no response
2. hyporeflexic response
3. normal response
4. hyperreflexic response or unsustained clonus
5. sustained clonus.
The findings for each elicited reflex can be noted (e.g., 3/5 or 4/5) as appropriate. A stick man figure can be used to indicate the position of each quantitated reflex. Obviously, the examiner will to some extent have individual quantitation standards, but consistency will develop over time. Hyperactive reflexes or clonic responses to tapping of the reflex usually result from corticospinal dysfunction. Hyperreflexia may also be indicated by an abnormal “spread” of responses, which includes contraction of muscle groups that usually do not contract when a specific reflex is being elicited (i.e., crossed thigh adductor or finger flexor reflexes). Although a bilateral brisk reflex response may be normal, particularly when only one reflex is involved, unilateral hyperreflexia virtually always signals a pathologic process.
Hyporeflexia may be associated with lower motor unit involvement (e.g., anterior horn cell disease, peripheral neuropathy, myopathy). However, hyporeflexia may occasionally be found with central depression, impaired central control of the gamma loop (central hypotonia), or involvement of the posterior root (intramedullary or extramedullary). With anterior horn cell involvement (e.g., infantile spinal muscular atrophy), the patellar reflexes are greatly diminished or absent early because the cells subserving the proximal muscles of the legs are profoundly involved first. Sensory involvement, particularly peripheral, is often detectable in patients with neuropathies. Similarly, the distal deep tendon reflexes tend to be involved earlier and to a greater degree. Tendon reflexes may be normal early in the course of certain myopathies, including the muscular dystrophies, and may become absent later.
Disease generally decreases muscle tone and may decrease tendon reflexes because of effects on the gamma loop. Enhancement of tendon reflex responses when reflexes are seemingly absent can be promoted by having the child squeeze an object such as a block or ball or perform the more traditional Jendrassik maneuver (i.e., hooking the fingers together while flexed and then attempting to pull them apart).

Other Reflexes
A flexor (plantar) toe sign response is normal in children. Impairment of corticospinal tract function leads to extensor responses. The Babinski reflex is elicited by firm, steady, slow stroking from posterior to anterior of the lateral margin of the sole with an object such as a key or a tongue blade. The stimulus should not be painful. A positive response is a slow, tonic hyperextension of the great toe. This is the constant and necessary feature of a positive response. The other four toes may also hyperextend, or they may slowly spread apart (i.e., fanning).
Flicking the patient's nail (second or third finger) downward with the examiner's nail (i.e., the Hoffmann reflex) results in flexion of the distal phalanx of the thumb. No response or a muted response occurs in normal children; a brisk or asymmetric response occurs in the presence of corticospinal tract involvement.
Abdominal reflexes are obtained by stroking the abdomen from lateral to medial with strokes beginning just above the umbilicus, lateral to the umbilicus, and just below the umbilicus directed toward the umbilicus. Unilateral absence of the reflex usually is associated with acquired corticospinal tract dysfunction. However, in 50 percent of normal individuals, no response is elicited in any of the four quadrants.
The cremasteric reflex is elicited in males by stroking the inner aspects of the thigh in a caudal–rostral direction and observing the contraction of the scrotum. The reflex is normally present and symmetric. Absence or asymmetry may indicate corticospinal tract involvement.
Developmental reflexes are discussed in Chapter 3 . The persistence of developmental reflexes beyond the expected age of extinction is usually an indication of corticospinal tract impairment [ Zafeiriou, 2004 ].

Cerebellar Function
Head tilt may be associated with tumors of the cerebellum. The tilt is usually ipsilateral to the involved cerebellar hemisphere, but exceptions are common. Herniation of the cerebellar tonsils through the foramen magnum resulting from increased intracranial pressure may cause head tilt; neoplasms that induce increased intracranial pressure, other than those of the cerebellum, may cause head tilt. Cerebellar function is also evaluated during testing of station and gait (see Chapter 5 ). Cerebellar dysfunction is usually associated with hypotonia.
Tremor in cerebellar disease occurs with action (intention). Cerebellar function is assessed in a number of ways. Hand patting (i.e., alternating pronation and supination of the hand on the thigh while the other hand remains stationary on the other thigh) is a good method for assessing dysdiadochokinesis. The maneuver is repeated with each hand separately to assess the presence of mirror movements (i.e., synkinesis). Other tests that monitor cerebellar integrity include repetitive finger tapping (thumb to forefinger), foot tapping, and finger-to-nose, finger-to-finger (examiner's)-to-nose, and heel-to-knee-to-shin stroking. These movements are an index of cerebellar function when limb strength and sensation are intact. Breaks in rhythm and nonfluidity of movement, as well as dysmetria, which is suggestive of cerebellar dysfunction, are evident during this phase of the examination.

Cranial Nerve Examination
In older children, the cranial nerve examination may be performed in a systematic fashion, beginning with the first cranial nerve and testing through the twelfth. Examination of infants and younger children usually requires some modification of the sequence and may need some ingenious improvisation of the procedure, according to the degree of cooperation of the child. As is the case with all examinations of infants and young children, the less threatening portions of the examination should be performed first.

Olfactory Nerve: Cranial Nerve I
Olfactory nerve function is rarely impaired in childhood. Cranial nerve I can be evaluated by having the child smell pleasant aromas (e.g., chocolate, vanilla, peppermint) through each nostril while the other is manually occluded. Olfactory sensation is intact if the child appreciates a change in odor; precise identification is often impracticable. Anosmia occurs most commonly in children with upper respiratory infections or after head trauma, often occipital. Neoplasms in the inferior frontal lobe or cribriform plate regions can cause anosmia. Unilateral anosmia is more worrisome than bilateral anosmia because of the possibility of a unilateral neoplasm.

Optic Nerve: Cranial Nerve II
Examination of cranial nerve II, the optic nerve, is one of the critical portions of the neurologic examination because of the long anterior-to-posterior span of the visual pathways within the brain. Formal visual acuity testing is possible with a Snellen chart or a “near card” in older children. Visual acuity and visual field testing should be performed in an appropriately lit room. The visual test objects should be easily visible and without glare. Occasionally, when subtle changes are being investigated, it is efficacious to hold the visual field test object against a background of less contrast, increasing the difficulty of identification.
Function can be difficult to evaluate in the very young child. Gross vision can be assessed in children younger than 3 or 4 years of age by their ability to recognize familiar items of various sizes, shapes, and colors. Beyond 4 years of age, the E test is useful. The child is taught to recognize the E, and to discern the direction in which the three “arms” are pointing and point a finger accordingly. Most older children can be taught the essentials of the test in less than a minute. During the acuity evaluation, Es of different sizes, rotated in different directions, are presented to the child.
For each eye, the visual field (range of vision) is assessed by confrontation with an object that is moved from a temporal to nasal direction along radii of the field. A small (3-mm), white or red test object or toy can be used. A modification of the same procedure can be used for double simultaneous testing by moving two test objects or penlights simultaneously from the temporal to the nasal fields and then from the superior and inferior portions of the temporal and nasal fields while the child looks directly at the examiner's nose. Finger counting can be used if acuity is grossly distorted. In cases of extreme impairment, perception of a rapidly moving finger can be used.
Visual acuity is rarely affected by papilledema until there is scarring of the optic nerve head. This lack of acuity change is in marked contrast to the early loss of visual activity that accompanies inflammation of the optic nerve.
The optic disc (i.e., optic nerve head) of the older child is sharply defined and often salmon-colored, which differs from the pale gray color of the disc in an infant. In the presence of a deep cup in the optic disc, the color may appear pale, but the pallor is localized to the center of the disc. The pallor of optic atrophy occurs centrally and peripherally, and is accompanied by a decreased number of arterioles in the disc margins. Most commonly, papilledema is associated with elevation of the optic disc, distended veins, and lack of venous pulsations. Hemorrhages may surround the disc. Before papilledema is obvious, there may be blurring of the nasal disc margins and hyperemia of the nerve head.
Pupils should be observed in light that allows them to remain mildly mydriatic. The diameter, regularity of contour, and responsivity of the pupils to light should be examined. When the pupil is dilated and is minimally reactive or unresponsive to light, the patient may suffer from Adie's pupil. The upper lid is usually at the margin of the pupil. In Horner's syndrome, impairment of the sympathetic pathway results in a miotic pupil, mild ptosis, and defective sweating over the ipsilateral side of the face ( Figure 2-1 ). Dragging a finger over the child's forehead may aid in the recognition of anhidrosis. The fixed, dilated pupil usually is associated with other signs of oculomotor nerve dysfunction and may signify cerebral tonsillar herniation.

Fig. 2-1 Bilateral oculomotor nerve paralysis.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
The presence or absence of the pupillary light reflex differentiates between peripheral and cortical blindness. Lesions of the anterior visual pathway (i.e., retina to lateral geniculate body) result in the interruption of the afferent limb of the pupillary light reflex, producing an absent or decreased reflex. Anterior visual pathway interruption can cause amblyopia in one eye. In this situation, the pupil fails to constrict when stimulated with direct light; however, the consensual pupillary response (i.e., response when the other eye is illuminated) is intact. Various degrees of visual loss may modify this phenomenon so that the full response to direct stimulation is delayed, but the consensual reflex is brisk. The deficient pupillary reflex is revealed by alternately aiming a light source toward one eye and then the other. In the eye with decreased vision, consensual pupillary constriction is greater than the response to direct light stimulation (Marcus Gunn pupil); the pupil of the affected eye may dilate slightly during direct stimulation.

Oculomotor, Trochlear, and Abducens Nerves: Cranial Nerves III, IV, and VI
The oculomotor, trochlear, and abducens cranial nerves control extraocular motor movements; these nerves must operate synchronously or diplopia ensues. Cranial nerve III innervates the superior, inferior, and medial recti; the inferior oblique; and the eyelid elevator (levator palpebrae superioris). Cranial nerves IV and VI innervate the superior oblique muscle and the lateral rectus muscle, respectively. Unfortunately for purposes of understanding, the function of extraocular muscles depends somewhat on the direction of gaze. The lateral and medial recti are abductors and adductors of the globe, respectively. The superior rectus and inferior oblique are elevators, and the inferior rectus and superior oblique are depressors. The oblique muscles act in the vertical plane while an eye is adducted. The recti muscles serve this function when an eye is abducted ( Figure 2-2 ). When directed forward (i.e., primary position), the oblique muscles effect torsion around the anteroposterior axis (rotation) of the globes [ Cogan, 1966 ]. The eye position that results from paralysis of each eye muscle is listed in Table 2-2 .

Fig. 2-2 Extraocular muscle movement.
A, In primary position. B, In abduction and adduction.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
Table 2-2 Extraocular Muscle Paralysis Paretic Muscle Cranial Nerve Eye Deviation Inferior oblique III Down and out Inferior rectus III Up and in Lateral rectus VI Medial Medial rectus III Lateral Superior oblique IV Upward and outward (head tilted) Superior rectus III Down and in
In heterophorias, also called phorias, both globes are directed normally on near or far objects during fixation; however, one or both deviate when one eye is occluded while the other eye fixes. Forcing fixation of the uncovered eye by alternately covering each eye confirms the diagnosis of heterophorias. This predisposition may be evident when the child is febrile or fatigued. Exophoria is a predisposition to divergence, whereas esophoria is a predisposition to convergence.
Eye deviations detectable during binocular vision are heterotropias, also called tropias. Adduction tropias are esotropias; abduction tropias are exotropias. Tropias are most often caused by compromised extraocular muscle innervation. Extraocular palsies can frequently be detected by observation of eye movements. A red glass is placed in front of an eye, and a focused, relatively intense white light is aimed at the eyes from various visual fields while the child fixes on the light. A merged, solitary, red–white image is perceived when extraocular movements are normal; however, when muscle paresis is present, the child reports a separation of the red and white images when looking in the direction of action of the affected muscle. The farthest peripheral image is the one perceived by the abnormal eye; this eye can be identified by the color of the image. Minimal extraocular muscle palsies may be heralded by delayed eye movement to the appropriate final position. Volitional turning of the head accompanies paresis of the lateral rectus muscle to forestall diplopia; the head is deviated toward the paretic muscle, and the eyes are directed ahead. In superior oblique or superior rectus muscle palsies, tilting of the head toward the shoulder opposite the side of the paretic eye muscle occurs.
Extraocular muscle dysfunction is associated with many conditions that affect the brainstem, cranial nerves, neuromuscular junction, or muscles. Among the diseases are ophthalmoplegic migraine, cavernous sinus thrombosis, brainstem glioma, myasthenia gravis, and congenital myopathy. Cranial nerve VI function may be impaired by increased intracranial pressure, irrespective of cause. Squint, usually esotropia, often accompanies decreased visual acuity in infants and young children [ Smith, 1967 ].
Ptosis and extraocular muscle paralysis accompany dysfunction of cranial nerve III. Ptosis resulting from oculomotor nerve compromise is usually more pronounced than is the malposition of the lid associated with Horner's syndrome. This symptom is a great diagnostic aid because the lid does not significantly elevate when the patient is asked to look up. Complete oculomotor nerve paralysis, although uncommon, causes the eye to position downward and outward. Poor adduction and elevation are also evident (see Figure 2-1 ).
Version eye positioning may accompany irritative or destructive brainstem lesions and cerebral hemispheral lesions. In destructive brainstem conditions the conjugate eye movement (version) deviation is toward the opposite side. Destructive cerebral hemispheral lesions will cause the eyes to deviate toward the side of the lesion; conversely, an irritative cerebral hemispheral lesion causes the eyes to turn away from the side of the lesion.
Eye-movement deviations of the binocular disconjugate (nonparallel) type caused by brainstem dysfunction also occur in children. Vertical gaze paresis results from dysfunction of the tectal area of the midbrain. Patients with a pineal tumor or hydrocephalus may be unable to elevate the eyes for upward gaze.
Brainstem lesions, especially those in the midbrain or pons, may disrupt the medial longitudinal fasciculus. The resultant impairment of conjugate eye movement is referred to as an internuclear ophthalmoplegia. These lesions engender weakness of medial rectus muscle contraction of the adducting eye, which is accompanied by a monocular nystagmus in the abducting eye. Occasionally, paresis of lateral rectus muscle movement in the abducting eye may occur. Medial longitudinal fasciculus involvement may be unilateral or bilateral, and may be associated with a number of brainstem conditions, including hemoglobinopathies, demyelinating disease, or brainstem vascular disease [ Cogan, 1966 ].
Internal ophthalmoplegia consists of a fully dilated pupil that is unreactive to light or accommodation. Extraocular muscle function is normal when each muscle is tested separately. The oculomotor nerve, nucleus, or ciliary ganglion may be a site of involvement.
External ophthalmoplegia results in ptosis and paralysis of all extraocular muscles. Pupillary reactivity is normal. This pattern of involvement may accompany myasthenia gravis, hyperthyroidism, ocular myopathy, Möbius' syndrome, tumors or vascular lesions of the brainstem, Wernicke's disease, botulism, and lead intoxication.
Opticokinetic nystagmus is a useful test in evaluating the eye movements of children. A drum or tape with stripes or figures is slowly rotated or drawn before the child's eyes in horizontal and vertical directions. With fixation, the child should visually track the object in the direction the tape is being drawn, with a rapid, rhythmic movement (refixation) of the eyes in the reverse direction to enable fixation on the next figure or stripe. Absence of such a response may result from failure of fixation, amaurosis, or disturbed saccadic eye movements.
The child who appears clinically blind because of a conversion reaction usually exhibits a normal opticokinetic nystagmus response. Children who manifest congenital nystagmus and have an opticokinetic nystagmus response in the vertical plane likely have adequate functional sight. Absence of opticokinetic nystagmus in the presence of congenital nystagmus heralds reduced visual acuity. If asymmetry of an opticokinetic nystagmus response is evident, lateral lesions in the posterior half of the cerebral hemisphere are likely present. The lesion is on the side that manifests reduced or absent opticokinetic nystagmus reactivity. The area of involvement is generally in the posterotemporal, parietal, or occipital areas. Hemianopic field defects may exist.
Spontaneous nystagmus (i.e., involuntary oscillatory movements of the eye) may be horizontal, vertical, or rotary; a patient can exhibit all three types. The movements may consist of a slow and a fast phase, giving rise to the term jerk nystagmus. However, the phases may be of equal duration and amplitude, appearing pendular.
Nystagmus, especially vertical nystagmus, is most commonly induced by medications (e.g., barbiturates, phenytoin, carbamazepine, benzodiazepines). Such nystagmus often has a jerk component and is usually most prominent in the direction of gaze. Vertical nystagmus that is not associated with medications indicates brainstem dysfunction. A few beats of horizontal nystagmus with extreme lateral gaze are usually normal. Persistent horizontal nystagmus indicates dysfunction of the cerebellum or brainstem vestibular system components; the nystagmus is coarser (i.e., the amplitude of movements are greater) when the direction of gaze is toward the side of the lesion. A rare condition, seesaw nystagmus, is characterized by disconjugate (alternating) movement of the eyes, which move upward and downward in a seesaw motion. This type of nystagmus accompanies lesions in the region of the optic chiasm (see Chapter 6 ).

Trigeminal Nerve: Cranial Nerve V
Cranial nerve V, the trigeminal nerve, has motor and sensory functions. The motor division of the trigeminal nerve innervates the masticatory muscles: masseter, pterygoid, and temporalis. Temporalis muscle atrophy manifests as scalloping of the temporal fossa. The masseter muscle bulk may be assessed by palpation while the patient firmly closes the jaw. Pterygoid muscle strength is evaluated by having the patient open the mouth and “slide” the jaw from one side to the other while the examiner resists movements with the hand to assess muscle strength. The jaw reflex is elicited when the examiner places a finger on the patient's chin while the mouth is slightly open and taps the finger to stretch the masticatory muscles. A rapid muscle contraction with closure of the mouth is the reflex response. This stretch reflex receives its afferent and efferent nerve control from cranial nerve V; the segmental level is located in the midpons. The expected reflex reaction is absent with motor nucleus and peripheral trigeminal nerve compromise. Conversely, this reflex is overactive in the presence of supranuclear lesions; rarely, jaw clonus may be evident. Because of weakness of the ipsilateral pterygoid muscles, unilateral impairment of the trigeminal nerve causes deviation of the jaw toward the side of the lesion.
Cranial nerve V is also responsible for sensation involving the face and the anterior half of the scalp ( Figure 2-3 ). Brainstem compromise can effect clearly delineated laminar sensory deficits; however, mapping of such deficits is difficult in children. The corneal reflex, provided its sensory input by the trigeminal nerve, may be diminished or absent after trauma, in cerebellopontine angle tumors, brainstem tumors, cavernous sinus thrombosis, Gradenigo's syndrome, or childhood collagen–vascular diseases.

Fig. 2-3 Facial sensation supplied by the trigeminal nerve.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Facial Nerve: Cranial Nerve VII
Taste sensation over the anterior two-thirds of the tongue, secretory fibers (parasympathetic) innervating the lacrimal and salivary glands, and innervation of all facial muscles are accomplished by cranial nerve VII. Complete motor dysfunction on one side of the face ensues when the cranial nerve VII pathway is disrupted in the nucleus, pons, or peripheral nerve. The patient is unable to move the forehead upward, close the eye forcefully, or elevate the corner of the mouth on the side of the affected nerve ( Figure 2-4 and Figure 2-5 ).

Fig. 2-4 Right facial paralysis of the peripheral type.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Fig. 2-5 Möbius' syndrome is manifested by bilateral palsy of cranial nerves VI and VII.
Central (supranuclear) facial nerve impairment produces only paresis of the muscles involving the lower face, with resultant drooping of the angle of the mouth, disappearance or diminution of the nasal labial fold, and widened palpebral fissure. The muscles of the forehead, which are innervated bilaterally, are unaffected. Cardiofacial syndrome is a congenital weakness that causes failure of depression of the angle of the mouth and is unrelated to facial nerve palsy (see Chapter 4 ).
Taste sensation in the anterior two-thirds of the tongue is in part provided by the chorda tympani nerve, which traverses the path of the facial nerve for a short distance. Testing of taste sensation is difficult. Evaluation of taste requires that the patient extend the tongue and that the examiner hold the tip of the tongue with a piece of gauze and place salty, sweet, acidic, and sour and bitter materials, usually represented by salt, sugar, vinegar, and quinine, on the anterior portion of the tongue. The patient's tongue must remain outside of the mouth until the test is completed. An older patient should be able to identify each substance.

Auditory Nerve: Cranial Nerve VIII
Function and evaluation of cranial nerve VIII are discussed in detail in Chapters 7 and 8 . Although cranial nerve VIII is known as the auditory nerve, it has auditory and vestibular functions. Gross auditory impairment may be suspected during the history-taking session while the child is in the room. The child may not respond directly to questions or to directions from the caregivers. More specific testing with whispered language, the ticking of a watch, a party noisemaker, or a tuning fork may be used to gain more information.
Patients who fail to develop speech or who have slow speech development, as well as those who have difficulty with fluency and articulation, may have hearing impairment. Older children can cooperate with formal audiometric testing. Such testing may not be possible in younger infants, but brainstem auditory-evoked potentials may provide the necessary information concerning hearing impairment and the level of dysfunction within the nervous system.
Clinical evaluation and caloric testing can be used for gross assessment of vestibular function. More complex evaluation should be undertaken if the screening tests or the complaint indicate a need for more detailed assessment. Complaints of nausea, ataxia, vertigo, or unexplained vomiting, singly or in combination, may indicate labyrinthine and vestibular pathologic origins. Caloric testing can be performed with relative ease. While the patient is in the supine position, the head is flexed at 30 degrees. Ice water (10 mL) is injected over 30 seconds into one external auditory canal at a time. The conscious patient develops coarse nystagmus toward the ipsilateral ear; no eye deviation occurs. If the patient has some degree of obtundation, there is a modification of the response. The eyes become tonically deviated ipsilaterally, with accompanying nystagmus occurring contralaterally. If the patient is comatose, cold water stimulation usually causes tonic deviation ipsilaterally and no nystagmus; if the coma is profound or the patient is brain-dead, no eye changes occur.

Glossopharyngeal and Vagus Nerves: Cranial Nerves IX and X
Examination of the larynx, pharynx, and palate provides most of the desired information concerning the function of cranial nerves IX and X. Unilateral paresis of the soft palate causes an ipsilateral droop, even when the patient is expelling air through the open mouth or gagging in response to a tongue blade. Bilateral involvement causes a flaccid soft palate bilaterally. With bilateral paresis, the voice becomes nasal, and regurgitation of fluids occurs during drinking. During evaluation of swallowing, the child should be asked to swallow up to ten times to determine the efficacy of swallowing and stamina. The examiner can evaluate the difficulty and the relative movements of the hyoid during swallowing.
The gag reflex is mediated through cranial nerve IX and is elicited by touching the posterior pharyngeal mucosa with a tongue blade. Normal individuals may have absence or a seemingly disproportionately violent response; assessing the importance of changes in the gag reflex is difficult in the absence of other findings. The integrity of cranial nerves IX and X is necessary for a gag response. Although the larynx can be studied under direct or indirect laryngoscopy, the presence of stridor, hoarseness, or dystonia suggests the need for more detailed examination of the brainstem and cranial nerve IX integrity.

Spinal Accessory Nerve: Cranial Nerve XI
Cranial nerve XI provides innervation for the trapezius and sternocleidomastoid muscles. Cranial nerve XI comprises some fibers from C1 and C2, and some from the motor nucleus in the brainstem, and is unique in combining brainstem and cervical cord origins. The trapezius muscles are assessed when the patient is asked to shrug the shoulders against resistance exerted by the examiner. Atrophy of the muscle and drooping of the shoulder provide further information on the status of the trapezius. The sternocleidomastoid muscle is tested by exerting resistance against the child's head while the child attempts rotation to one side. Weakness of the sternocleidomastoid muscle results in an inability to rotate the head to the contralateral side. Muscle bulk of the sternocleidomastoid muscle is readily palpable and is readily visible in the presence of moderate to severe atrophy. Congenital or acquired lesions in the area of the foramen magnum most commonly cause difficulties of cranial nerve XI.

Hypoglossal Nerve: Cranial Nerve XII
The tongue muscle is the primary responsibility of cranial nerve XII. Atrophy and fasciculation of the tongue occur when the ipsilateral hypoglossal nucleus or hypoglossal nerve is involved. The protruded tongue deviates toward the involved side because contraction of the normally innervated tongue muscle causes protrusion and is unopposed. The child cannot push the tongue against the cheek of the unaffected side. Speech may be muffled or dysarthric. Bilateral involvement of hypoglossal nuclei or cranial nerve XII may be severely incapacitating. The tongue muscle may be markedly atrophied, and fasciculations of the tongue may be very prominent ( Figure 2-6 ). The patient may be unable to protrude the tongue beyond the lips, and there is marked dysarthria with unintelligibility of speech. Although chewing and swallowing are somewhat affected by unilateral tongue weakness, bilateral involvement results in gross difficulty.

Fig. 2-6 Fasciculation of the tongue, especially of the right lateral border, in a patient with group 2 Werdnig–Hoffmann disease.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
Cranial nerve XII dysfunction may result from supranuclear bulbar palsy from unilateral or bilateral corticobulbar tract involvement. Although the signs and symptoms may resemble those of involvement of the hypoglossal nucleus or nerve, lower motor unit signs such as fasciculations and atrophy are absent. Certain movement disorders, particularly dystonia, may interfere with normal tongue movements and confound the examiner.

Sensory System
Cooperation of the pediatric patient is paramount to the success of the sensory examination. Vibration sense and joint and position sense are usually easily tested in all four limbs. Touch may be assessed by a single stimulus or by double simultaneous stimulation of two skin areas. The latter tests extinction of perception over an involved area. Testing should include areas of the face, trunk, and limbs. The ability to localize the area of contact of a tactile stimulus, topagnosis, is monitored by touching the patient, whose eyes are closed, on the face, arm, hand, leg, or foot with the examiner's finger or a cotton swab; the child is asked to point to the area or identify it verbally. The loss of ability to localize the stimulus is associated with parietal lobe dysfunction.
In a more sophisticated test, the patient is touched on two parts of the body simultaneously (i.e., double simultaneous stimulation test). Extinction is the term used to denote failure of the child to perceive both stimuli. The contralateral parietal lobe to the side on which the unidentified stimulus was applied is the site of dysfunction. Pain, as tested with pinprick, must be assessed gently, rapidly, and in a nonthreatening and playful manner.
Testing for segmental sensory level during childhood is sometimes an essential portion of the examination. Because the patient must be attentive and cooperative, the examination often has to be repeated for corroboration. Segmental sensory innervations of the arm and leg are illustrated in Figure 2-7 , Figure 2-8 , and Figure 2-9 [ Keegan and Garrett, 1948 ]. The nipples are at approximately the T5 level and the umbilicus at the T10 level.

Fig. 2-7 Segmental sensory innervation of the arm.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School; adapted from Keegan JJ, Garrett FD. The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 1948;102:409. Reprinted with permission of Wiley–Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Fig. 2-8 Segmental sensory innervation of the leg.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School, adapted from Keegan JJ, Garrett FD. The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 1948;102:409. Reprinted with permission of Wiley–Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Fig. 2-9 Radicular cutaneous fields.
Cortical sensory function can be tested in the older child. So-called cortical sensory functions require attentiveness and cooperation, and involve complex processing. Because the tests are primarily of parietal lobe function, testing of these functions assumes and requires intact sensory neurologic pathways from the diverse cutaneous specialized nerve endings, muscles, and joints, and subsequent connections with the parietal lobe.
Stereognosis is the recognition of familiar objects by touch. After the patient closes the eyes, objects are placed by the examiner in one of the child's hands and then the other. The patient should recognize the objects by size, texture, and form. Objects may include a button, safety pin, or key. Coins are particularly useful because older patients can be asked to differentiate among them. The patient must be able to manipulate the objects freely with the fingers and palms. Absence of stereognosis is astereognosis. Astereognosis usually results from lesions of the parietal lobe.
Graphesthesia is the ability to recognize numbers, letters, or other readily identifiable symbols traced on the skin. It is necessary to ascertain that the child is capable of identifying the symbols. This ability can be determined best by tracing the symbols in a preliminary trial while the child's eyes are open. When the patient's eyes are closed, the figures are traced over the palm or forearm. Failure to identify the symbols is called dysgraphesthesia. By 8 years of age, most children are able to identify all single digits correctly.
The ability to distinguish between closely approximated stimulation at two points is two-point discrimination. The minimal distance between two simultaneous points of stimulation is determined. Normal findings have been reported for children 2–12 years old [ Cope and Antony, 1992 ]. Testing of this modality is frequently performed over the fingertips. Differences in perception over homologous areas on both sides are sought. Absence or impairment of two-point discrimination results from parietal lobe dysfunction.

Skeletal Muscles
Tone, bulk, and strength of the skeletal muscles should be determined during this portion of the examination. The segmental innervation patterns of the trunk muscles and the extremities and the motor functions of the spinal nerves are described in Table 2-3 , Table 2-4 , and Table 2-5 .
Table 2-3 Motor Functions of the Spinal Nerves Nerves Muscles * Function CERVICAL PLEXUS (C1–C4) Cervical Deep cervical Flexion, extension, and rotation of neck Phrenic Scalene Elevation of ribs (inspiration)   Diaphragm Inspiration BRACHIAL PLEXUS (C5–T1) Anterior Pectorales major and minor Adduction and depression of arm downward and medially Long thoracic Serratus anterior Fixation of scapula on raising arm Dorsal scapular Levator scapulae Elevation of scapula   Rhomboid Drawing scapula upward and inward Suprascapular Supraspinatus Outward rotation of arm   Infraspinatus Elevation and outward rotation of arm Subscapular Latissimus dorsi     Teres major Inward rotation and abduction of arm toward the back   Subscapularis Inward rotation of arm Axillary Deltoid Raising of arm to horizontal   Teres minor Outward rotation of arm Musculocutaneous Biceps brachii Flexion and supination of forearm   Coracobrachialis Elevation and adduction of arm   Brachialis Flexion of forearm Median Flexor carpi radialis Flexion and radial deviation of hand   Palmaris longus Flexion of hand   Flexor digitorum sublimis Flexion of middle phalanges of second through fifth fingers   Flexor pollicis longus Flexion of distal phalanx of thumb   Flexor digitorum profundus (radial half) Flexion of distal phalanges of second and third fingers   Pronator quadratus Pronation   Pronator teres Pronation   Abductor pollicis brevis Abduction of metacarpus I at right angles to palm   Flexor pollicis brevis Flexion of proximal phalanx of thumb   Lumbricals I, II, III Flexion of proximal phalanges and extension of other phalanges of first, second, and third fingers   Opponens pollicis brevis Opposition of metacarpus I Ulnar Flexor carpi ulnaris Flexion and ulnar deviation of hand   Flexor digitorum profundus (ulnar half) Flexion of distal phalanges of fourth and fifth fingers   Adductor pollicis Adduction of metacarpus I   Hypothenar Abduction, opposition, and flexion of little finger   Lumbricals III, IV Flexion of first phalanx and extension of other phalanges of fourth and fifth fingers   Interossei Same action as preceding. Also spreading apart and bringing together of fingers Radial Triceps brachii Extension of forearm   Brachioradialis Flexion of forearm   Extensor carpi radialis Extension and radial flexion of hand   Extensor digitorum communis Extension of proximal phalanges of second through fifth fingers   Extensor digiti quinti proprius Extension of proximal phalanx of little finger   Extensor carpi ulnaris Extension and ulnar deviation of hand   Supinator Supination of forearm   Abductor pollicis longus Abduction of metacarpus I   Extensor pollicis brevis Extension of proximal phalanx of thumb   Extensor pollicis longus Abduction of metacarpus I and extension of distal phalanges of thumb   Extensor indicis proprius Extension of proximal phalanx of index finger THORACIC NERVES Thoracic Thoracic and abdominal Elevation of ribs, expiration, abdominal compression, etc. LUMBAR PLEXUS (T12–L4) Femoral Iliopsoas Flexion of leg at hip   Sartorius Inward rotation of leg together with flexion of upper and lower leg   Quadriceps femoris Extension of lower leg Obturator         Adduction of leg           Adduction and outward rotation of leg SACRAL PLEXUS (L5–S5) Superior gluteal Abduction and inward rotation of leg; also, under certain circumstances, outward rotation       Tensor fasciae latae Flexion of leg at hip   Piriformis Outward rotation of leg   Gluteus maximus Extension of leg at hip Inferior gluteal     Sciatic     Outward rotation of leg       Biceps femoris Flexion of leg at hip   Semitendinosus     Semimembranosus   Peroneal Tibialis anterior Dorsiflexion and supination of foot Deep Extensor digitorum longus Extension of toes   Extensor hallucis brevis Extension of great toe Superficial Peroneus Pronation of foot Tibialis Plantar flexion of foot       Tibialis posterior Adduction of foot   Flexor digitorum longus Flexion of distal phalanges II–V   Flexor hallucis longus Flexion of distal phalanx I   Flexor digitorum brevis Flexion of middle phalanges II–V   Flexor hallucis brevis Flexion of middle phalanx I   Plantar Spreading, bringing together and flexion of proximal phalanges of toes Pudendal Perineal anal sphincters Closure of sphincters of pelvic organs; participation in sexual act; contraction of pelvic floor
* Various muscles may receive still other nerve supplies than those mentioned. The following are the principal accessory nerve supplies: the brachial muscle receives fibers from the radial nerve; the flexor digitorum sublimis, from the ulnar; the adductor pollicis, from the median; the pectineus, from the femoral; the adductor magnus, from the tibial.
(From Haymaker W. Bing's Local Diagnosis in Neurological Diseases, 15th edn. St. Louis: Mosby, 1969.)
Table 2-4 Segmental Innervation of Muscles of Extremities



Table 2-5 Segmental Innervation of Trunk Muscles

The strength of limb muscles is assessed, when possible, by testing the child's ability to counteract resistance imposed by the examiner on proximal and distal muscle groups or individual muscles. Norms cited for gross motor outcomes in young children with brain injury are useful in assessing children with apparent motor difficulties [ Golomb et al., 2004 ].

Muscle Testing
The skeletal muscles selected in the subsequent text are responsible for primary movements ( Table 2-6 ). The material presented is adapted from Baker [1958] . Frequently, more than one muscle participates in the movement. For this reason, while testing the selected muscles, the examiner should observe and palpate surrounding muscles to detect any substitution of action of other muscles.

Table 2-6 Muscle Testing
The following scoring system is useful for recording muscle power * :
5: normal power
4: inability to maintain position against moderate resistance
3: inability to maintain position against slight resistance or gravity
2: active movement with gravity eliminated
1: trace of contraction
0: no contraction.
While testing for muscle function, it is most convenient for the patient to maintain a fixed position against force. The examiner can assess the strength of various muscles by instituting the action of the antagonist. This strategy obviates the necessity for providing new directions for each muscle tested and simplifies the procedure for patient and examiner. The fixed positions depicted in Figure 2-10 are used routinely here and are referred to by the following letters:
Position A: The arm is adducted, the forearm flexed at the elbow, and the wrist placed across the xiphoid process.
Position B: The child lies on the back with the lower extremity flexed at 90 degrees at the hip and knee. The examiner should support the lower limb at the ankle.
Position C: The child lies on the back with the leg and foot in normal extension.

Fig. 2-10 Position of the limbs for muscle strength (see Table 2-6 ).
When the weakness of any muscle group prevents the use of any of these positions, substitute positions should be improvised.
Unfortunately, while examining young children, problems with cooperation or coordination may make it difficult to evaluate maximal strength; only gross testing may be possible, during which various functions are tested by using game playing or gross maneuvers, such as the “wheelbarrow” maneuver (i.e., walk on the hands while the examiner holds the child's feet and moves slowly forward).
Arm and shoulder strength can also be assessed by using functional operations. The child is asked to lean against a wall with the legs placed a foot or two from the wall edge and the arms outstretched with the palms against the wall. Strength of the shoulder girdle and arm extension can be evaluated. Winging of the scapulas also is evident. Alternatively, the child can be placed on the floor and asked to “wheelbarrow.” The child should be placed on the floor and asked to rise without assistance. The normal child will spring erect. The child with weakness of the hip extensors will engage in Gowers' maneuver, and climb up the legs and push off into the erect position ( Figure 2-11 ).

Fig. 2-11 Gowers' maneuver indicates weakness of truncal and proximal lower extremity muscles.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
During examination of gait, the examiner must be aware of the presence of normal associated movements of the arms, circumduction of the legs, footdrop, unusual positions of the feet, and waddling (see Chapter 5 ). The presence of a limp may also be evident.
Muscle bulk is evaluated by gentle palpation and observation. Abnormalities include atrophy and fasciculations that accompany anterior horn cell disease and muscle hypertrophy, particularly of the gastrocnemius and deltoid muscles associated with Duchenne's muscular dystrophy and other dystrophies, as well as myotonia congenita. Muscle tenderness, nerve tenderness, and nerve hypertrophy can also be assessed by palpation. Myotonia can be elicited by tapping over the thenar eminence and deltoid muscles. Tapping the tongue should be performed at the end of the examination and only when other elements of the history or examination make this evaluation essential. Tapping individual muscles with the reflex hammer elicits the myotatic reflex, which may be useful in the detection of myopathy because the reflex is absent in myopathies.
Muscle tone is evaluated when the child is relaxed so that resistance to passive movement can be monitored. Aside from passive movement of limbs at joints, the examiner also assesses the extensibility of muscles by shaking the limbs and determining the range of motion.
Tone may be decreased in the presence of cerebellar disease and anterior horn cell disease. Tone may be increased because of the rigidity associated with basal ganglia disease and spasticity associated with corticospinal tract dysfunction.

Gait evaluation
The evaluation of gait is discussed in detail in Chapter 5 , but a brief outline is presented here. The child should be asked to walk back and forth normally, preferably in a corridor, and up and down steps. The examiner should observe whether the gait is wide- or narrow-based, whether there are symmetric reciprocal movements of the arms, and whether the legs and feet move in a symmetric and normal fashion. The child should also be asked to run because running exaggerates neurologic impairment. Flexion or extension of an arm with subsequent athetosis not present during walking may be apparent during running.
Among the abnormal gaits are those that can be characterized as cerebellar, spastic, waddling, and steppage. These gait types are discussed further in Chapter 5 .

References
The complete list of references for this chapter is available online at www.expertconsult.com .
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References

Baker A.B. An outline of clinical neurology. Dubuque, Iowa: William C Brown, 1958.
Cogan D.G. Neurology of the ocular muscles. Springfield, Ill: Charles C Thomas, 1966.
Cope E.B., Antony J.H. Normal values for two-point discrimination. Pediatr Neurol . 1992;8:251.
Frankenburg W.K., Dodds J.B., Archer P., et al. The Denver II: A major revision and restandardization of the Denver Developmental screening test. Pediatrics . 1992;89:91.
Golomb M.R., Garg B.P., Williams L.S. Measuring gross motor recovery in young children with early brain injury. Pediatr Neurol . 2004;31:311.
Haymaker W. Bing's local diagnosis in neurological diseases, ed 15. St. Louis: CV Mosby, 1969.
Haymaker W., Woodhall B. Peripheral nerve injuries. Philadelphia: WB Saunders, 1962.
Hollinshead W.H. Functional anatomy of the limbs and back, ed 3. Philadelphia: WB Saunders, 1969.
Keegan J.J., Garrett F.D. The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec . 1948;102:409.
Smith J.L., editor. Neuro-ophthalmology: Symposium of the University of Miami and the Bascom Palmer Eye Institute, vol 3. St. Louis: CV Mosby, 1967.
Zafeiriou D.I. Primitive reflexes and postural reactions in the neurodevelopmental examination. Pediatr Neurol . 2004;31:1.

Suggested reading

Brett E.M.. Normal development and neurological examination beyond the newborn period. Paediatric Neurology. ed 3. London: Churchill Livingstone; 1997.
Dekaban A. Examination. In: Dekaban A., editor. Neurology of early childhood . Baltimore: Williams & Wilkins, 1970.
Dodge P.R. Neurologic history and examination. In: Farmer T.W., editor. Pediatric neurology . New York: Paul B Hoeber, 1964.
Egan D.F. Developmental examination of infants and preschool children. Clinics in developmental medicine. Oxford: MacKeith Press, 1990. no. 112
Fenichel G.M. Clinical pediatric neurology: a signs and symptoms approach, ed 5. Philadelphia: WB Saunders, 2005.
Haerer A.F. Dejong's the neurologic examination. Philadelphia: Lippincott, 1992.
Iannetti P., Spalice A., Iannetti L., et al. Residual and persistent Adie's pupil after pediatric ophthalmoplegic migraine. Pediatr Neurol . 2009;41:204.
Illingworth R.S. The development of the infant and young child, ed 9. Baltimore: Williams & Wilkins, 1987.
Kestenbaum A. Clinical methods of neuro-ophthalmologic examination. New York: Grune & Stratton, 1961.
Menkes J.H., Sarnat H.B., Maria B. Textbook of Child Neurology, ed 7. Baltimore: Williams & Wilkins, 2005.
Nellhaus G. Composite international and interracial graphs. Pediatrics . 1968;41:106.
Paine R.S. Neurologic examination of infants and children. Pediatr Clin North Am . 1960;7:41.
Paine R.S. Neurologic conditions in the neonatal period: diagnosis and management. Pediatr Clin North Am . 1961;8:577.
Paine R.S. The evolution of infantile postural reflexes in the presence of chronic brain syndromes. Dev Med Child Neurol . 1964;6:345.
Paine R.S., Brazelton T.B., Donovan D.E., et al. Evolution of postural reflexes in normal infants and in the presence of chronic brain syndromes. Neurology . 1964;14:1036.
Paine R.S., Oppe T.E. Neurological examination of children. London: William Heinemann, 1966.
Peiper A. Cerebral function in infancy and childhood. New York: Consultants Bureau Enterprises, 1963.
Popich G.A., Smith D.W. Fontanels: Range of normal size. J Pediatr . 1972;80:749.
Sauer C., Levinsohn M.W. Horner's syndrome in childhood. Neurology . 1976;26:216.
Volpe J.J. The neurological examination: Normal and abnormal features. In Volpe J.J., editor: Neurology of the newborn , ed 5, Philadelphia: WB Saunders, 2008.

* Adapted from Medical Research Council. War memorandum, no. 7. Aids to the investigation of peripheral nerve injuries, 2nd edn. London, His Majesty's Stationery Office, 1943 (reprinted 1960).
Chapter 3 Neurologic Examination after the Newborn Period until 2 Years of Age

Kenneth F. Swaiman, Lawrence W. Brown
The first two years of life are a time of rapid changes in the acquisition of development skills and responses based on maturation of physiologic processes and anatomic structures of the developing central and peripheral nervous systems. Visual, sensory, and motor pathways are the most rapidly evolving in the first year of life, but the bases of social communication and language are also becoming more orgainized and sophisticated with each passing month. Neurologic assessment depends on comparing the results of the infant’s examination with established norms ( Box 3-1 ) [ Gesell and Amatruda, 1956 ; Illingsworth, 1987 ; Zafeiriou, 2004 ]. In some ways the examination is easier than that of a neonate because older infants and toddlers maintain alertness for much longer periods and can interact meaningfully with the examiner, but sudden or painful manipulation and stranger anxiety can lead to a screaming child and upset parents. As it is critical that the infant remain calm and cooperative for the longest possible time during the examination, the least intrusive portions of the examination should be done first. A review of Chapter 2 can assist in understanding the material in this chapter.

Box 3-1 Child Development from 2 Months through 2 Years

2 months

Keeps hands predominantly fisted
Lifts head up for several seconds while prone
Startles in response to loud noise
Follows with eyes and head over 90-degree arc
Smiles responsively
Begins to vocalize single sounds

3 months

Occasionally holds hands fisted
Lifts head up above body plane and holds position
Holds an object briefly when placed in hand
Turns head toward object, fixes and follows fully in all directions with eyes
Smiles and vocalizes when talked to
Watches own hands, stares at faces
Laughs

4 months

Holds head steady while in sitting position
Reaches for an object, grasps it, brings it to mouth
Turns head in direction of sound
Smiles spontaneously

5–6 months

Lifts head while supine
Rolls from prone to supine
Lifts head and chest up in prone position
Exhibits no head lag
Transfers object from hand to hand
Babbles
Sits with support
Localizes direction of sound

7–8 months

Sits in tripod fashion without support
Stands briefly with support
Bangs object on table
Reaches out for people
Mouths all objects
Says “da-da,” “ba-ba”

9–10 months

Sits well without support, pulls self to sit
Stands holding on
Waves “bye-bye”
Drinks from cup with assistance
Uses pincer grasp

11–12 months

Walks with assistance
Uses 2–4 words with meaning
Creeps well
Assists in dressing
Understands a few simple commands

13–15 months

Walks by self, falls easily
Says several words, uses jargon
Scribbles with crayon
Points to things wanted

18 months

Climbs stairs with assistance, climbs up on chair
Throws ball
Builds 2–4-block tower
Feeds self
Takes off clothes
Points to 2–3 body parts
Uses many intelligible words

24 months

Runs, walks up and down stairs alone (both feet per step)
Speaks in 2–3-word sentences
Turns single pages of book
Builds 4–6-block tower
Kicks ball
Uses pronouns “you,” “me,” and “I”
(Data from Frankenburg et al., 1981 ; Illingsworth RS, 1987 ; Knobloch H et al., 1980 .)

Approach to the Evaluation
There is no one way to organize the examination of an infant. Experienced examiners develop individual techniques and sequences for the evaluation [ Brett, 1997 ]. The following is a sequence that has been successful for many individuals, using a staged approach for examination of the infant.
The first stage of the examination is observation. Alertness, eye contact, cry, and posture can be seen from the moment the child enters the examining room, and infant–parent interaction is often apparent from the outset. The child should remain comfortable in the stroller or on the caregiver’s lap. No direct contact is initiated by the examiner except for reassuring gestures as he or she completes the history portion of the visit, questioning the caregivers about pertinent aspects of the history; typically, the child becomes reassured that the clinician means well. Such passive observation allows limited assessment of cranial nerve function, unusual facies, gross structural deformities (including those of the head and neck), symmetry of strength and movements of the extremities, and unusual posturing.
In the second stage, the head, muscle tone, superficial and deep sensation, gross response to sound, and visual fields can be evaluated while the child remains on the caregiver’s lap. Older infants can be given blocks or a crayon, and examiner or parents can try to speak with them. Examination of the deep tendon reflexes and plantar responses (e.g., Babinski’s reflex) also can be done or can be incorporated after the child is placed on the examining table for a more interactive assessment of muscle function and further assessment of the developmental reflexes, traction response, parachute response, and sitting and standing abilities takes place. The sensory examination is best done at this time.
The third stage becomes more invasive, and may require help from a caregiver or assistant. At this point, a general examination is performed with attention to the skin, heart, chest, abdomen, back, genitalia, and anal area. Examination of the oropharynx, tongue and sternocleidomastoid muscles should also be done. If previously deferred, measurement of the occipitofrontal circumference (OFC) is mandatory. The fundi and ears must be examined.
Before the examination can be considered complete, the child’s spontaneous motor abilities must be assessed. In the fourth stage of the examination, the child is placed on the floor and encouraged to crawl, walk, and run, if possible.
It is important to recognize that the examination of the infant and toddler can be a challenge even for the experienced clinician. Less experienced individuals may find it almost impossible: one study of medical students reported that more than 90 percent found the neurologic examination challenging and that children were uncooperative and difficult to examine [ Jan, 2007 ]. This discomfort appears to remain an issue when one considers that more than 50 percent of pediatricians referred more than 90 percent of patients with neurologic complaints to neurologists, and those who refer the most have the least self-confidence in their own neurologic examinations [ Maria and English, 1993 ].

Evaluation of the Patient

Stage 1
The evaluation should be initiated with a welcoming smile and the family brought into the consulting room with confidence and a relaxed manner. The examiner should avoid quick movements that could be interpreted as threatening, make friendly facial expressions and gestures, and speak in soft and reassuring tones. This is the time to bring out toys rather than medical instruments. It is preferable that the child sit on the caregiver’s lap facing the examiner during the history-taking session so that he or she becomes familiar with the room and comfortable with the examiner.
Observations made during the initial conversation with the caretaker may provide important information. The sequence of examination should be flexible and should be determined by the child’s comfort level and temperament. The examiner must be highly sensitive to the child’s mood and defer those parts of the examination that appear to upset the child. Flexibility on the part of the examiner may be the key to a successful session. However, the clinician must not lose sight of the need for all pertinent data to be collected; it is essential to perform a complete examination, even if the child is resistant. It is imperative that the clinician comprehensively conduct that aspect of the examination related to the chief complaint.
The clinician should make judgments concerning the facial and extraocular movements and the asymmetry and character of limb movements. The child’s state of alertness, awareness of surroundings, and affect should be evident. Expressive and receptive communication skills should be compared to age-appropriate expectations.

Head
Examination of the head must be done systematically, looking for asymmetry, indentations, and protuberances. Evaluation of the fontanels and cranial sutures should be performed with gentle palpation. The dimensions of the anterior fontanel should be carefully recorded [ Pedroso et al., 2008 ]. The examiner should determine by observation and palpation the presence of frontal bossing, bulging fontanel, sutural synostosis or diastasis (separation), and unusual head shapes such as trigonocephaly, marked dolichocephaly or brachycephaly. Positional plagiocephaly has become increasingly common with the current “back to sleep” approach, and is the most common cause of abnormal head shape; it can often be distinguished from isolated craniostenosis by prominence of the contralateral forehead, which leads to a rhomboidal appearance [ Bialocerkowski et al., 2008 ]. Unusual masses under the scalp and gross asymmetries of the skull should be sought.
The occipitofrontal circumference should always be measured. If the child becomes agitated, the measurement could be deferred until later in the examination (stage 3). The largest measured circumference incorporating nasion and inion should be recorded and plotted on a standardized graph of normative data, preferably incorporating serial measurements. The size of the anterior fontanel, which is typically closed by 12 months of age, should be recorded. The anterior fontanel pulsates in unison with the heartbeat, and becomes fuller or bulging when the child cries, and this must be distinguished from disease states in which there is increased intracranial pressure. The tenseness of the anterior fontanel should be evaluated when the child is sitting comfortably in an upright position. The posterior fontanel usually admits only a finger at time of birth and is usually closed by 2 months of age. Other fontanels are usually difficult to palpate, except in pathologic states. Occasionally, accessory fontanels may be found along the sutures, particularly the sagittal suture; these are usually benign variants. The head should be auscultated for the presence of unusual intracranial bruits. Intracranial bruits occur commonly in childhood, and cautious interpretation is advised; asymmetric bruits and those that can be suppressed by carotid artery suppression are frequently pathologic. Vascular abnormalities, such as vein of Galen malformations, can produce extremely loud bruits, and are often heralded by prominent scalp veins. The vein of Galen malformation is typically associated with increasing occipitofrontal circumference, high-output cardiac failure, and infant distress while in the supine position.

Cranial Nerves
Most of the examination of cranial nerve function of the infant and toddler can be completed by observation with minimal invasive procedures. More details concerning examination of each cranial nerve can be found in Chapter 2 . Toys or colorful objects can facilitate the assessment of extraocular movements in young children. Visual fixation and pursuit will bring out nystagmus and strabismus. If the child appears uninterested in bright objects, the possibility of a visual defect or an underlying intellectual defect must be considered. Rolling eye movements and dysconjugate gaze suggest gross visual impairment. Double simultaneous stimulation (i.e., simultaneously bringing two bright objects into both temporal fields) normally causes the child to look from one object to the other; failure to take notice of one object may indicate homonymous hemianopsia. An opticokinetic tape (with repetitive bars or objects) should be drawn horizontally and then vertically across the child’s field of vision. An absent response results from lack of visual fixation or from gross impairment of vision. Unusual transient deviations of the eyes may occur in the first year of life [ Echenne and Rivier, 1992 ].
A beam from a small flashlight should be directed at each eye to allow evaluation of pupil size (noting colobomas and anisocoria), pupillary responses and the red retinal reflex. To avoid frightening the child, the examiner could use the light in a playful manner such as directing the light beam at the child’s hand or abdomen while trying to avoid restraining the child or forcibly opening the eyes. There are many eye features to be noted, including symmetry of the palpebral fissures, relative size of the two globes, angulation of the eyes compared with other facial components (i.e., mongoloid or antimongoloid slant) and with the ears, cataracts, conjunctival telangiectases, colobomas of the iris, ptosis, proptosis, and malformed or eccentrically placed pupils. Hair color, patterning distribution, including unusual whorl patterns, and texture should be assessed.
The examiner should observe the child’s facial movements closely throughout the entire examination. Smiling at the child, tickling the child, or making unusual noises or facial grimaces often causes the child to smile or laugh, allowing observation of the nasolabial folds. Widening of the ipsilateral palpebral fissure or inability to bury the limbus when crying is indicative of facial nerve weakness. If facial weakness is found, one must distinguish central from peripheral cranial nerve VII dysfunction. The latter includes involvement of the muscle that raises the ipsilateral eyebrow. In the younger infant, sucking and rooting reflexes should be obtained. Tongue thrusting, drooling, and unusual shapes of the lips should be evident. Sometimes, the child can be induced to protrude the tongue if the examiner urges the child to imitate the examiner’s tongue movements. Deformity, atrophy, or abnormal positioning of the tongue can be observed. Tongue fasciculations should be evaluated with the tongue in the resting position, and by gently elevating the tongue with a depressor and examining the undersurface.
Basic responses to the sound made by a tuning fork, rubbing fingers together, ringing a bell, or using a toy noisemaker that generates noise at a modest volume may provide much information. The examiner must be careful not to confuse response to a visual cue (e.g., the movement needed to elicit noise from a toy) with response to the sound. Typically, the young infant orients toward the sound by turning the head with arrest of motor activity, while the child older than 6 months usually reaches for the noisemaker. If the child fails to perform satisfactorily, formal audiometry and auditory-evoked response testing should be obtained.

Motor Evaluation
As with all other parts of the evaluation, the motor examination begins with observation. Even before touching the child, the examiner should systematically observe the general posture and the symmetry of movements of arms and legs, and look for any gross discrepancies in muscle bulk or limb length. Definite hand preference (such as reaching across the midline to avoid using the contralateral hand) before 24 months suggests a central or peripheral nervous system impairment of the opposite hand and arm. In this situation, leg movement and use should be carefully studied to detect the presence of hemiparesis. Typically, there is also a decrease in spontaneous movement of the affected limb. Unusual posturing of the limbs may indicate paresis or evolving extrapyramidal disease.
Decreased muscle bulk may not be appreciated because of the large amount of subcutaneous fat, and muscle atrophy may be undetected. The examiner should be careful to palpate muscle mass beneath the fat and not to misinterpret the subcutaneous tissue as muscle.
Palpation is the next step; this allows for evaluation of muscle tone, the resistance of muscle to passive stretch. Muscle tone and range of motion of the arms and legs are best assessed when the child is in the relaxed state by gently shaking and moving the hands and feet in flexion and extension. Pronation and supination of the hands and forearms provide further information about range of motion and the presence of spasticity or rigidity. Greater than normal resistance to passive movement indicates hypertonia, whereas less than normal resistance indicates hypotonia. This portion of the examination is most difficult for the novice because reasonable experience is required to make accurate judgments. It is important to distinguish increased tone from limitation of movement due to joint contracture. Spontaneous muscle movements, particularly those against gravity, provide the most information concerning muscle strength. Active resistance to attempted movement of the extremities will provide the examiner with an estimate of muscle strength.
Upper motor neuron unit involvement, such as that in hemiparesis, may manifest by decreased movement of the entire extremity or more specific involvement such as limited flexion of the arm at the elbow, persistent fisting, or adduction of the thumb against the palm. Children with Erb’s brachial plexus injury commonly hold the arm against the chest in a position of internal rotation and adduction at the shoulder. Interacting with the infant using toys and other interesting objects may facilitate the evaluation of limb strength, range of motion, and coordination. In the older cooperative child, individual muscle testing should be carried out when appropriate.
There is a normal developmental sequence of fine motor control as the child becomes more adept at reaching for objects. Grasping things with both hands and holding the object before the face or immediately placing it in the mouth is later superseded by transferring the object from hand to hand and manipulating the toy. The infant’s grasping skills are best demonstrated in the response to small objects. The 4–5-month-old infant is able to grasp an object with the entire hand ( Figure 3-1 ); at 7 months the thumb and the neighboring two fingers are used ( Figure 3-2 ); and the pincer grasp (using only the thumb and forefinger) should be present by 9–11 months ( Figure 3-3 ). The palmar grasp reflex (i.e., obligate grasp reflex) should gradually diminish from 3–6 months of age. Teleologically, this allows the infant to develop the ability to transfer objects from hand to hand. The persistence of the obligate grasp reflex beyond 6 months of age may signal corticospinal tract dysfunction. Observation of the child’s ability to raise the arms and to abduct and adduct the arms while reaching for a proffered object provides valuable information concerning proximal muscle strength. Simultaneously, the presence of intention tremor and of the avoidance response of early athetosis may be evident. Congenital malformations of the fingers and hands from webbing to clinodactyly can be readily determined during this portion of the examination.

Fig. 3-1 Entire hand grasp of a 4-month-old infant.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Fig. 3-2 Use of two fingers and thumb in the grasp of a 7-month-old infant.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Fig. 3-3 Pincer grasp with the thumb and forefinger of an 11-month-old infant.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
Direct examination of the hips should include assessment of the range of motion; decreased excursion may signify spasticity or subluxation of the hip joints. Subluxation may exist separately or as a result of spasticity. Conversely, increased excursion may represent hypotonia or ligamental laxity.
Initial examination of the legs should consist of assessment of muscle symmetry and mass. The presence and symmetry of spontaneous motor movements should be evaluated. Assessment of tone is similar to that done with the arms and hands – one should gently shake the feet and passively move the joints of the lower extremities from hip to knee to ankle. Tight Achilles tendon is shown by decreased range of motion and inability of the feet to dorsiflex readily beyond neutral (90 degrees).
Deep tendon reflexes that are excessively brisk may indicate upper motor neuron unit disease, especially when associated with clonus. Asymmetry is particularly worrisome because of the association with pathologic conditions. Absent deep tendon reflexes are seen with anterior horn cell disease or peripheral neuropathy. The crossed adductor reflex is elicited when the patellar reflex is stimulated and resultant contraction of the adductor muscles occurs in the opposite leg. This response can be normal until approximately 1 year of age. However, persistence of the response, particularly unilaterally, suggests the presence of corticospinal tract involvement.
The plantar response can be as important in infants as in adults. There is no consensus of opinion about the latest time at which an extensor response is a normal finding. One report found an extensor response in 50–75 percent of 1-year-old infants [ Dodge, 1964 ]. Others claimed that the usual response in the newborn period is flexor in origin and that the initial response is flexor in 93 percent of normal infants [ Hogan and Milligan, 1971 ]. All would agree that asymmetric extensor toe signs or extensor toe signs that persist beyond 12 months should be considered pathologic. A pathologic extensor plantar sign is indicative of upper motor neuron unit disease. Unsustained ankle clonus up to six beats is often present in the neonatal period. Ankle clonus should disappear by 2 months of age. The persistence of ankle clonus and extensor plantar response suggests upper motor neuron unit disease even in the absence of hyperreflexia.
Cerebellar function is difficult to assess in infants; assessment is easiest in a cooperative child capable of sitting, standing, walking, or reaching for objects. The examiner can also observe the child during play to see resting or intention tremor, dysmetria, titubation or truncal sway while sitting, and fine motor coordination. Decreased tone may accompany other signs of cerebellar dysfunction.

Sensory Testing and Cutaneous Examination
Light touch can be tested by gently stroking the extremities; this should lead to a reaction with signs of recognition ranging from eye deviation and facial response to anxious withdrawal of the limbs ( Figure 3-4 ). Application of a tuning fork often causes arrest of motion and a wide-eyed look of wonder in the child who cannot otherwise describe the feeling. Proprioception cannot be directly evaluated at this age, but observations of sitting positions, gait, and posture may provide some clues. Pain response from light application of a pin or gentle pinching should be reserved until late in the examination. The child may cry or make short, whimpering sounds. Careless use of the pin can destroy rapport with the patient and loss of confidence on the part of the caregivers.

Fig. 3-4 Segmental distribution of the cutaneous nerves of an infant.
(Modified from Fanaroff AA, Martin RJ. Neonatal-perinatal medicine: diseases of the fetus and infant, 5th edn. St. Louis: Mosby, 1992.)
The skin of the infant is observed for obvious areas of abnormality that may suggest certain conditions, including neuroectodermal neurocutaneous disorders. Examination of the spine may indicate the presence of scoliosis, sinus tracts, scars, dimples, and hemangiomas. Unusual skin lesions or hair growth over the spine suggest the presence of an underlying mesodermal defect, including diastematomyelia. The spine should be palpated along its entire course for defects.
Abdominal and cremasteric reflexes are present at birth. The abdominal reflex is elicited by stroking the skin of the upper, middle, and lower portions of the abdomen laterally from the midline. Each stroke elicits a muscle contraction mediated by a different group of thoracic nerves from T8 to T12. The response results in the retraction of the umbilicus toward the stimulated side. The cremasteric reflex is elicited by upwardly stroking the inner thigh, beginning 3–5 cm below the inguinal crease. The cremasteric reflex results in an elevation of the testicles due to contraction of the overlying smooth muscles. Cremasteric reflexes are mediated by spinal nerves L1–L2.

Stage 2
For stage 2 of the evaluation the child should be placed on an examining table with the caregiver close by to provide reassurance to the child and assistance to the examiner, if necessary. Motor evaluation of the older child can also be carried out on a larger, carpeted surface. By 3 months of age, an infant in the prone position should be able to hold the head and chest off the table. Good head control when held in the sitting position should be evident by 4 months of age. The child should be able to sit unsupported and maintain adequate balance by 8–9 months of age. Independent achievement of the sitting position should occur by 10 months of age. The child should crawl by 10 months, pull to a standing position by 10 months, and creep by 11 months. The child should walk with support by 12 months and without support by 13–14 months. Delayed acquisition of these abilities must be evaluated in coordination with other findings.
Trunk, shoulder, and pelvic girdle tone and strength should be directly evaluated. The child is observed while held in vertical and horizontal suspension. A hypotonic infant often droops over the examiner’s arm when held in horizontal suspension (“the inverted comma position”). In vertical suspension, the hypotonic child may slide through the examiner’s hands. The child may be unable to maintain a standing posture when the feet are placed on the table surface – this must be distinguished from active withdrawal of the legs that may also prevent successful standing. Increased tone, or hypertonicity, usually the result of spasticity, may manifest by arching of the extended head, neck, and back) while in horizontal suspension. Extensor thrusting with legs extended and “scissoring” with excessive abduction can be seen when the child is held in vertical suspension, and the child may stand on the toes when the feet are allowed to touch the table ( Figure 3-5 ).

Fig. 3-5 Extended legs, scissoring, toe stance, and fisting in an infant with spastic quadriplegia.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Motor Performance Instruments
Through the years, several instruments have been devised that are useful for evaluating motor performance in relation to chronologic age. These instruments have provided norms for evaluating the expected rate of motor development for a number of different assessments and maneuvers [ Zafeiriou, 2004 ]. The instruments that are most commonly used are listed in Box 3-2 .

Box 3-2 Most Commonly Used Motor Performance Tools

Developmental scales

Amiel-Tison [ Amiel-Tison, 1968 ]
Amiel-Tison [ Amiel-Tison, 2002 ]
Bayley [ Bayley, 1969 ]
Brazelton [ Brazelton and Nugent, 1995 ]
Dubowitz [ Dubowitz et al., 1999 ]
Haataja [ Haataja et al., 1999 ]
Peabody [ Reed, 1985 ]
Prechtl [ Prechtl and Beintema, 1964 ]

Developmental screening tests

Denver Developmental Screening Test (Denver II) [ Frankenburg et al., 1992 ]
Battelle Screening Test [ Glascoe and Byrne, 1993 ]
Clinical Adaptive Test (CAT)/Clinical Linguistic and Auditory Milestone Scale (CLAMS) [ Leppert et al., 1998 ]
Knobloch Revised Screening Inventory [ Knobloch et al., 1980 ]
General Movements (GMs) Assessment [ Dargassies, 1997 ; Prechtl, 1997 ; Prechtl et al., 1997 ]

Motor assessment instruments

Alberta Infant Motor Scale (AIMS) [ Piper et al., 1992 ]
Early Motor Pattern Profile (EMPP) [ Morgan, 1988 ]
Gross Motor Function Measure (GMFM) [ Russell et al., 2002 ]
Movement Assessment Inventory (MAI) [ Kaye and Whitfield, 1988 ]
Test of Infant Motor Performance (TIMP) [ Campbell et al., 1993 ]
(Adapted from Zafeiriou DI. Primitive reflexes and postural reactions in the neurodevelopmental examination. Pediatr Neurol 2004;31:1.)

Developmental Reflexes
Developmental reflexes are patterned responses that are ontogenetically determined at certain ages. They represent maturational stages of the developing nervous system, and therefore they can be helpful in assessing neurologic development. Occasionally, they can have localizing value, but usually, they are non-specific. Abnormal findings include the absence or poor manifestation of the expected response, persistence of a reflex that should have disappeared, or an asymmetric response. These reflexes and the means of elicitation are listed in Table 3-1 and Table 3-2 [ Zafeiriou, 2004 ].

Table 3-1 Eliciting Primitive Reflexes
Table 3-2 Eliciting Postural Reactions Reaction Position Method Traction Supine Placing the examiner’s index finger in the infant’s hand and pulling the infant at a 45-degree angle to the examination bed Horizontal suspension Prone Suspending the infant by placing the hands around the infant’s thorax without providing support for the head or legs Vertical suspension Vertical Placing both hands in the axillae without grasping the thorax and lifting the infant straight up facing the examiner Vojta response Vertical Suspension from the vertical to the horizontal position facing the examiner by placing both hands around the infant’s thorax Collis horizontal suspension Prone Placing one hand around the upper arm and the other around the upper leg and suspending the infant in the horizontal position, parallel to the examination bed Collis vertical suspension Prone Placing one hand around the upper leg and suspending the infant in the vertical position with the head directed downward Peiper–Isbert vertical suspension Prone Placing the examiner’s hands around the upper leg of the infant and suspending the infant in the vertical position with the head directed downward
(Data from Vojta, 1988 ; Zafeiriou et al., 1998 ; Zafeiriou, 2004 .)
The Moro reflex presents in an incomplete fashion with an attenuated adduction phase at 2 months, and is seen in its complete fashion until 5 or 6 months of age. Although the Moro reflex may be demonstrated by different maneuvers, correctly eliciting it requires holding the infant in the supine position, lifting the head and then allowing it to fall approximately 30 degrees while cradling the head in the examiner’s hands [ Parmelee, 1964 ]. The expected response is initial extension and abduction of the arms with extension of the fingers, followed by adduction of the arms at the shoulder ( Figure 3-6 ). An abnormal Moro reflex usually represents diffuse central nervous system depression, generalized weakness, or severe spasticity rather than a specific area of involvement. An asymmetric Moro reflex can be caused by unilateral brachial plexus palsy, fractures of the humerus or clavicle, or spastic hemiplegia. An exaggerated Moro reflex may indicate pathologic central nervous system (CNS) irritability. The Moro reflex can be distinguised from similarly presenting extensor infantile spasms since the normal developmental reflex is always associated with a postural change and never occurs spontaneously or in clusters.

Fig. 3-6 The Moro response to rapid extension of the neck in a 2-day-old infant.
The abduction phase of arm movement is illustrated. A cry usually accompanies the response, and the leg position varies.
The asymmetric tonic neck reflex (ATNR) may be detected in the neonatal period but reaches its peak at 2 months. It gradually diminishes and is absent by 6 months of age. The tonic neck reflex has been described in great detail in animals and humans [ Shevell, 2009 ]. To elicit the reflex, the head is turned to one side while the infant is lying in the supine position. There is extension of the arm and leg on the side toward which the face is turned, while the contralateral extremities flex (“fencer’s posture”). The degree of response varies widely but is usually seen to the same degree in each direction. In any event, a normal infant should not maintain the position beyond a few seconds (i.e., obligate ATNR). This reflex should disappear by 6 months of age [ Paine et al., 1964 ]. When the ATNR can only be elicited to one side, it may indicate a lesion in the hemisphere opposite the direction in which the face is turned. The same consideration holds true if the response is obligate or persists beyond the expected age. Severe muscle weakness secondary to central or peripheral motor unit involvement may lead to an abnormally diminished response. Athetoid and spastic infants may also have an exaggerated response, and this may contribute to their difficulty in sitting or standing.
The palmar grasp reflex is elicited by placing an object or the examiner’s finger in the palm of the infant’s hand; this leads to an involuntary flexion response. This reflex subsides by 3–6 months of age, and is replaced by voluntary grasping, which is necessary to allow transfer of objects from hand to hand. The obligatory involuntary grasp reflex may persist and is often one of the earliest signs of infantile hemiplegia [Paine et al., 1964].
In slightly older infants, the Landau reflex can be first elicited between 5 and 10 months of age, and can usually be seen up to 2 years of age. With one hand supporting the abdomen in the prone position, the examiner flexes the infant’s head with his other hand. The normal response is flexion of the legs and trunk. When held in horizontal suspension, 55 percent of infants spontaneously elevate their heads above the horizontal plane by age 5 months and 95 percent by 6 months [ Paine et al., 1964 ].
The placing reflex response can be demonstrated by holding the upright infant in a manner that causes the dorsal surface of the infant’s feet to touch the underside of a tabletop. The infant flexes the legs at the hips and knees so that contact with the underside of the surface ceases.
One of the most useful maneuvers is the traction response. This is elicited with the infant in the supine position; the examiner grasps both hands and pulls the infant gently and slowly upward, to a sitting position. Marked head lag with little resistance to the examiner’s pulling efforts characterizes the newborn response ( Figure 3-7 ). By 1 month, the infant’s head shows transient neck flexion followed by extension as the infant is pulled forward. Usually, by 3–5 months of age at the latest, the infant is able to participate actively with arm flexion at the elbow, as well as holding the head and trunk in a straight line as the examiner pulls him or her to the upright position. At this point there should be no head lag, and little or no forward motion of the head as the child reaches the upright position. Asymmetry signals a neurologic difficulty. Superimposition of leg extension with standing as the infant is pulled to sitting suggests bilateral corticospinal tract difficulty.

Fig. 3-7 The traction maneuver causes little response in a 2-day-old infant.
There is little or no perceptible flexion of the neck or the arms at the elbows.
A stereotypic “elbowing” movement in newborns has been described. A curved wooden model of an ultrasonographic probe is gently used to exert pressure on the right and left subcostal regions. The newborn reacts with a particular defensive arm movement in which there is a three-phase response [ Saraga et al., 2007 ].
A valuable measure of vestibular function in the newborn can be obtained by holding the infant in a supine position with the feet closest to the examiner. As the examiner rotates the infant laterally in each direction, the eyes of the infant deviate in the direction of rotation, accompanied by intermittent nystagmus to the opposite side. This maneuver also allows extraocular movements to be assessed.
It is essential that the examiner take into account the overall pattern of developmental responses. An isolated delay or irregularity of one reflex does not indicate significant neurologic abnormality. There are other developmental reflexes, but those discussed here appear to be the most often evaluated and the most useful.

Stage 3
Examination of the optic fundi should be performed with the infant supine, possibly lying in the caregiver’s lap or held over the caregiver’s shoulder with the infant’s head held tightly against the caregiver’s head. Abnormalities of the fundi, including vascular changes, elevation of the optic disc, and retinal changes, as well as abnormalities of the lens and media, should be assessed (see Chapter 6 ). Mydriatic agents and sedation are rarely employed in the office evaluation, although they are both occasionally necessary. During the first few months of life, the optic discs may be somewhat gray. This normal finding should not be confused with optic atrophy. Retinal abnormalities that can be seen during a routine fundoscopic examination include hypoplasia, papilledema, chorioretinitis and retinitis pigmentosa.
The general portion of the examination follows. A heart murmur may signify congenital structural anomalies more widespread than just in the heart. Stridor heard on auscultation may accompany weakness of the upper respiratory musculature. The presence of hepatosplenomegaly should be determined because many storage diseases, which also affect the brain, may be the cause of organ enlargement. When spinal lesions are suspected, the anal sphincter should be examined for tone and the presence of an anal cutaneous reflex. Congenital anomalies of the genitalia should be sought. The remainder of the general examination, particularly the intrusive aspects, such as evaluation of the auditory meati, tympanic membranes, mouth, and teeth, should be done at this time.

Stage 4
The crawling child should be put on a carpeted floor or a suitable pad; if the child stands, or walks, he or she should be placed on the floor. The child should be allowed to ambulate or encouraged by rolling a ball across the room or having him follow a parent across the room. Spastic diparesis, hemiplegia, waddling, footdrop, limp, or ataxia may be evident. The manner in which the child stoops and bends to retrieve a ball or block may show premature hand dominance, athetosis, tremor, or weakness of the legs. Whenever there is a question of proximal weakness, the child should be observed when arising from the floor to a standing position to determine the presence of Gowers’ maneuver (see Figure 2-11 ).
Unlike in the examination of older children, the testing of individual muscle groups in infants is usually impracticable. Nevertheless, evaluation of spontaneous movements and use of some specific maneuvers (e.g., traction response, wheelbarrow maneuver, standing from the floor or a seated position) can provide information about spasticity, weakness, and incoordination. As always, a comparison of the examination findings must be made with expected age-related norms.
Further examination of muscle strength can be accomplished by using the parachute response; the examiner holds the child in the prone position over an examining table and gently thrusts the patient toward the table surface. A fully developed response (expected at 8 months) consists of arm and wrist extension, allowing the outstretched palms to make contact with the table as the infant supports the body weight with arms and shoulders. Each upper extremity can be tested individually if one arm is pulled from the table by the examiner, forcing the child to support most of the body weight on the opposite arm and shoulder. Somewhat older infants may be induced to support their weight on their hand as they move forward in the “wheelbarrow” maneuver ( Figure 3-8 ) (see Chapter 2 ). The child should then be asked to crawl. Formal individual muscle testing can be used in the older child whenever necessary.

Fig. 3-8 Abnormal parachute response.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
The sensory examination is difficult and is usually limited to rather gross evaluation of touch and pain; however, much can be accomplished with persistence and patience ( Box 3-3 ). Examination of touch, position sense, and vibration sense should be done first. When a tuning fork is placed on the appropriate bony prominence, a look of surprise or bemusement appears. Evaluation of pain should be done last and only after the examiner demonstrates to the child the method that will be used.

Box 3-3 Tips for Examining Poorly Cooperative Children

During history-taking

Keep the child next to the parent
Observe the child carefully
Smile, be friendly, and maintain eye contact
Avoid wearing a white lab coat
Start interacting with the child

Beginning of interaction

Present a toy
Keep hands off; use observation
Keep the younger child in the caregiver’s lap
Let the parents do the undressing
Try not to show all your tools

During examination

Start with the most relevant system
Be focused
Use your observational skills, starting with gait
Demonstrate some testing on the parents
Leave threatening or painful tests to the end
[ Jan, 2007 ].
The older child should be asked to stand in one place with the feet together and then asked to close the eyes to be evaluated for Romberg’s sign. The examiner should observe the child for titu-bation, nystagmus, and dysmetria while reaching for objects. Cooperative children older than 3 years should be able to perform finger-nose testing with eyes closed. The heel-shin test is frequently not possible in children younger than 4 years. Many of the maneuvers suggested in Chapter 2 for the older child are applicable, depending on the maturity and abilities of the older infant.
Assessment of the deep tendon reflexes is best carried out with the infant or toddler in the caregiver’s lap. The biceps response in most infants can be difficult to elicit, but the triceps and brachioradialis reflexes are usually readily detected. Patellar and Achilles responses are typically present and easy to elicit. Toe signs can be evaluated as in older children.

General Considerations
Throughout the examination, the clinician should evaluate the child’s alertness, interest in the surroundings, and ability to learn during the examination. The child’s speech pattern should also be assessed. By 15 months of age, the child should have a consistent vocabulary of 2–6 words; by 18 months, up to 20 words. Short phrases consisting of two or three words are usually part of the child’s repertoire by 21–24 months. By 2 years of age, most children have a vocabulary of up to 50 words. Using specific scales to evaluate intelligence and development levels is of some help but a single office assessment may not be reliable. It is therefore important that the examiner become proficient in informal means of evaluating these characteristics. A new website, PediNeuroLogicExam ( http://library.med.utah.edu/pedineurologicexam/html/download_by_exam.html ), provides text and movies demonstrating the changing examination as the child matures, along with an approach to examining the young patient.

References
The complete list of references for this chapter is available online at www.expertconsult.com .
See inside cover for registration details.

References

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Suggested Reading

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Haymaker W. Bing’s local diagnosis in neurological diseases, ed 15. St. Louis: CV Mosby, 1969.
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Paine R.S., Oppe T.E. Neurological examination of children. London: William Heinemann Medical Books, 1966.
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Chapter 4 Neurologic Examination of the Term and Preterm Infant

Kenneth F. Swaiman

The Term Infant
Fetal monitoring during the labor process is difficult, but certain variables can be studied. The fetal biophysical profile includes fetal heart rate reactivity, fetal breathing movements, gross body movements, fetal tone (flexor-extensor movements and posture), and amniotic fluid volume. Ultrasonography has enabled this type of evaluation [ Manning et al., 1998 ]. Other methods of evaluating the fetus are also utilized in various settings [ Devoe, 2008 ]. Fetal central nervous system malformations detected by magnetic resonance imaging (MRI), performed when suspicion of malformations exists, are of value [ Herman-Sucharska et al., 2009 ]. Injury of the developing brain may be offset by the plasticity inherent in the nervous system during the early stages of maturation [ Johnston et al., 2009 ]. Assessment also routinely takes place by means of electronic fetal monitoring [ Volpe, 2008a ]. Alterations in fetal heart rate patterns may be valuable in assessing fetal status.
The term infant is examined, when possible, immediately after birth. Apgar scores are routinely obtained for term infants at the time of birth ( Apgar, 1953 ). The categories for scoring are described in Table 4-1 . Details of the scoring and the total scores often provide useful information concerning the newborn’s status for the examiner and subsequent health-care providers. Use of the Sarnat score is of value in assessing term infants who are encephalopathic at birth ( Table 4-2 ) [ Sarnat and Sarnat, 1976 ].

Table 4-1 Apgar Scoring

Table 4-2 Encephalopathy Scoring System in Term Neonates with Hypoxic-Ischemic Brain Injury
The neurologic examination of a term infant should be conducted in a quiet and evenly lit area that is suitably warmed so that the infant remains comfortable after removal of clothing and covering. When the infant is in a stable condition, a thorough examination during the first day is customary. If possible, another examination should be performed on the second or third day of life several hours after feeding so that the infant is optimally responsive. This examination is usually performed just before discharge. In emergent situations, the infant should be evaluated after stabilization has been achieved. It is often necessary to examine the infant on several occasions to confirm the presence and monitor the evolution of abnormal findings. Many protocols for the examination of the term infant (gestational age of 38–42 weeks) have been written [ Amiel-Tison, 2002 ; Ashwal, 1995 ; Brazelton, 1973 ; Dubowitz and Dubowitz, 1981 ; Paine, 1960 ; Peiper, 1963 ; Prechtl, 1977 ]; some investigators have addressed the subject as part of the discussion of neonatal neurology [ Fenichel, 2001 ; Volpe, 2008b ]. Estimation of gestational age is discussed later in this chapter.
It is essential that the examination of the term infant be conducted in a systematic manner. Examination of the sick neonate may be difficult because of the presence of monitoring wires, sensors, catheters, eye shields, and infusion lines; however, systematic order in the sequence and extent of examination must be maintained to provide optimal information. These sick infants often must be examined on multiple occasions for sequential monitoring purposes and to complete portions of the examination not possible at the first encounter. The examiner should bear in mind that by 6 weeks post term, neurologic signs, particularly those related to muscle tone and posture, should reflect maturation of the nervous system [ Guzzetta et al., 2005 ]. Furthermore, prediction of long-term development may be possible with the use of a combination of multiple complementary tools, including achieved milestones, neurological examination, and assessment of the quality of motor behavior [ Heineman and Hadders-Algra, 2008 ].

Observation
A proper examination begins with observation. The infant’s clothing should be removed slowly and gently, and the diaper should be opened only for the period in which the covered area is evaluated. The examiner should make no quick moves. It is a common error to begin handling the infant before an adequate and systematic observation period.
The examiner should delineate the presence of congenital abnormalities, including midline defects of the cranium, face, palate, and spine. Midline defects are often associated with abnormalities of the neural tube. Abnormalities of the trunk, limbs, and skin are readily observed. Skin pigmentation changes are important because of the shared ectodermal beginnings of the integument and the nervous system. In particular, the presence of abnormalities associated with neurocutaneous syndromes should be ascertained, even though manifestations may not be present in the newborn. Freckling in the axillary areas is highly suggestive of neurofibromatosis.
Assessment of most cranial nerves can be accomplished in part through observation. The cranial nerves enabling eye movements and facial movements can be readily monitored.
Gross motor abilities of the newborn infant can be partially evaluated by observation. The head is preferentially turned to the right for longer periods than to the left. Term infants have predominant flexor tone, with resultant flexion of the arms at the elbows and of the legs at the knees. Bilateral fisting of the hands, including adduction and infolding of the thumbs (i.e., cortical thumbs), is expected. Limb position and posturing should be roughly symmetric. While supine, the infant manifests spontaneous limb movements that are often asymmetric and have a rapidly jerking quality. Jitteriness or tremulousness of the hands or jaw is sometimes spontaneous. These movements may indicate hyperexcitability of the central nervous system (CNS). Causes of hyperexcitability are discussed later in this chapter.
The examiner should mentally quantitate frequency and amplitude of limb movements. Diminished frequency or amplitude of arm movements may indicate brachial plexus injury; involvement of an arm and ipsilateral leg may indicate hemiparesis. While prone, the infant normally maintains a flexed posture of the arms and legs, with resultant elevation of the pelvis and flexion of the hips and knees.
The infant’s respiratory rhythm and chest movement should be observed to indicate adequate contraction of intercostal muscles. Although diaphragmatic breathing is normally accentuated in the newborn, the absence of intercostal muscle participation and a “sucking in” of the sternum may indicate anterior horn cell disease, neuromuscular junction disease, or spinal cord injury. The presence of a pectus excavatum deformity in the newborn should not be regarded as an isolated congenital deformity until neuromuscular conditions in which the diaphragm overpowers the intercostal muscles have been excluded.
The level of alertness increases with CNS maturation. At 37 weeks’ gestation, crying is common during wakefulness. At term, the infant remains alert for reasonable periods and responds to visual, auditory, and tactile stimulation. Crying is often forceful. Sleep and wake periods are clearly delineated.

Cranial Vault Evaluation
Among the most important facets of the examination is the measurement of the occipitofrontal (head) circumference. For the most part, this measurement is a reflection of brain growth. However, undue enlargement may be associated with cephalohematoma, subdural fluid collection, hydrocephalus, hydranencephaly, macrocephaly, or megalencephaly ( Chapters 21 – 28 ). Serial measurements provide an index of brain growth in sick neonates. Microcephaly may be associated with many conditions, including intrauterine infection, hereditary abnormalities, maternal substance abuse, and poor nutrition.
The measurement of the occipitofrontal circumference should be performed carefully. An assistant may be necessary to stabilize the head during measurement. The measuring tape should be moved up and down the head until the largest circumference is obtained. The shape of the head influences the measure of the circumference. The nearer the head shape approximates a perfect circle, the smaller is the head circumference compared with the circumference of a noncircular head, despite the fact that the area of a plane through the maximal circumference and the brain volumes are the same. A similar relationship exists between a perfect sphere and the volume contained within it. The occipitofrontal circumference should be plotted on a graph standardized for gender, race, and gestational age to determine if the measurement falls within the normal range (i.e., two standard deviations above or below the mean) ( Figure 4-1 ) [ Braun et al., 2004 ]. On average, occipitofrontal circumference increases 2 cm during the first month of life, 6 cm during the first 4 months, 7 cm during the first 6 months, and 12 cm during the first 12 months of life [ Fujimura and Seryu, 1977 ].

Fig. 4-1 Head circumference charts.
(From Nellhaus G. Composite international and interracial graphs. Pediatrics 1968;41:106.)
Infants delivered vaginally may have some deformity of the head because of scalp and subcutaneous edema with resulting caput succedaneum formation; vacuum extraction delivery often results in caput formation. Infants delivered by cesarean section usually have relatively round heads. The caput deformity, usually transient, produces an increased diameter and may confound accurate occipitofrontal circumference measurements. Cephalohematomas, which are delimited by the periosteum of the individual cranial bones, produce asymmetry of the head and increase the occipitofrontal circumference. Most occur over the parietal bones. A caput succedaneum, unlike a cephalohematoma, extends over two or more cranial bones and is not restricted to the subperiosteal (subgaleal) space. Subgaleal hematomas result from bleeding under the scalp aponeurosis and are often preceded by forceps or vacuum-assisted delivery space [ Kilani and Wetmore, 2006 ]. The scalp may be edematous and boggy because of underlying blood. Although most subgaleal hematomas are benign, hypovolemic shock may ensue if a large amount of blood is sequestered in the subgaleal space.
The anterior fontanel, readily palpable at birth, is concave or flat in relation to the surrounding cranium. The fontanel should be assessed with the child held in the sitting position if there is any question of increased pressure. The fontanel may bulge during crying or in the presence of pathologic increased intracranial pressure. Unfortunately, the presence of normal conformation of the fontanel does not guarantee normal pressure; conversely, a bulging anterior fontanel strongly suggests increased intracranial pressure. The anterior fontanel varies in size but usually ranges from 1 to 3 cm in its longest dimension [ Popich and Smith, 1972 ]. The fontanel pulsates synchronously with the infant’s pulse. The posterior fontanel in the neonate usually is open but admits only a fingertip. The presence of an enlarged posterior fontanel suggests the possibility of intrauterine increased intracranial pressure. From time to time, particularly in the presence of wormian bones, auxiliary fontanels may be palpable. A detailed discussion of the infant skull can be found in Chapter 28 .
The cranial sutures (e.g., sagittal, metopic, lambdoidal, squamosal) are readily palpable in the newborn. Infants delivered vaginally may manifest overriding of the sutures that, with normal head growth, resolves during the first week of life. The sagittal and lambdoidal sutures are most frequently involved. The sutures are readily separated from one another with palpation. The abrupt steplike contour of the overriding bone at the suture interface distinguishes this condition from that of premature closure of the sutures. When a suture closes prematurely, growth continues along the line of apposition of the bones across the suture. For example, sagittal synostosis causes an increase in the anteroposterior diameter (i.e., scaphocephaly). Increased bitemporal diameter occurs in the presence of coronal synostosis (i.e., brachycephaly). Asymmetric suture closure may lead to grossly asymmetric head shape (i.e., plagiocephaly).
Auscultation over the infant skull, particularly the anterior fontanel and neck vessels, usually reveals a venous hum in a number of locations. Rarely, systolic-diastolic bruits, particularly those that are focal and asymmetric, indicate the presence of an arteriovenous malformation [ Dodge, 1956 ]; however, these bruits may be heard in normal infants.
Cranial ultrasound, computed tomography (CT), and MRI are informative concerning subdural hematomas, cystic lesions, hemorrhages, and enlarged ventricles.

Developmental Reflexes
Developmental reflexes are primitive reflexes with complex responses, and largely reflect the integrity of the brainstem and spinal cord; the role of higher centers, although of importance, is not fully known. Many of these reflexes are present at birth and undergo modification during the first 6 months of life. Detailed discussion of these reflexes is presented in Chapter 3 . Their persistence beyond the expected date of dissipation suggests maturational lag or impaired CNS function. This group includes the Moro, rooting, grasping, tonic neck, stepping, and placing reflexes. Generalized diminution of the manifestation of these reflexes suggests diffuse depression of brain function. Asymmetry indicates central or peripheral nervous system dysfunction that must be further localized. It is likely that infants born after breech presentation may have significant suppression of active movements when examined at the second and fourth days of life [ Sekulic et al., 2009 ]. A stereotypic “elbowing” movement in newborns has been described. A curved wooden model of an ultrasonographic probe is gently used to exert pressure on the right and left subcostal regions. The newborn reacts with a particular defensive arm movement in which there is a three-phase response [ Saraga et al., 2007 ].

Motor Function
Gentle manipulation of the infant’s limbs allows for assessment of muscle tone and strength. Tone is defined as resistance to passive movement (see Chapter 5 ). Tone at each large joint should be evaluated while the infant is at rest. Spontaneous movements and resistance of the infant to limb and trunk movement provide a measure of muscle strength. The examiner should recall any clues from the observation period suggesting muscle weakness and corroborating changes in tone and strength at this time. The infant should be supine with the head in the midposition while tone is evaluated so that the tonic neck reflex does not augment tone unilaterally.
The newborn infant should be held in the horizontal position while attitude and posture of the limbs and trunk are observed. The infant should then be held in vertical suspension again to determine whether the expected flexor tone of the limbs is present and symmetric. When held in the vertical position, the hypotonic and weak infant tends to slide through the examiner’s hands. The infant’s arms are held loosely at the sides, and the expected configuration of the shoulder girdle is poorly maintained. In the horizontal position, the infant appears to be looped over the examiner’s arms. Infants with increased tone manifest an opisthotonic position in conjunction with obligate extension in both vertical and horizontal positions. Although it usually manifests in older infants, scissoring (i.e., crossing of the legs because of excessive, involuntary adductor magnus contraction) may be evident. The most common cause of generalized decreased tone is depression of CNS function, which may result from hypoxic-ischemic encephalopathy, neonatal sepsis, intraventricular hemorrhage, subdural hemorrhage, or metabolic abnormalities (e.g., hypoglycemia). Congenital malformations, including neuronal migration disorders, may be associated with hypotonia. Tone and strength may be decreased in a number of neuromuscular conditions, including spinal muscular atrophy, neonatal myasthenia gravis, congenital myopathies, and neonatal myotonic dystrophy. Muscle tone may be increased in a variety of conditions that cause a neonatal encephalopathy, including many metabolic disorders, hypoxic-ischemic encephalopathy, neonatal stroke, intrauterine infection, congenital malformations, and trauma.
While the infant is being handled, stimulation may engender jittery or tremulous movements of the jaw or limbs. Such movements are arrhythmic and do not have a definite phasic composition. The movements usually terminate when stimulation ends, although noises or abrupt changes in light may trigger them. Sometimes, there may be spontaneous tremulousness. Crying enhances the frequency and range of the movements. Such tremulousness may indicate metabolic abnormalities (e.g., electrolyte imbalance), bleeding, congenital CNS defects (structural or functional), infections, or drug withdrawal syndromes. Exaggerated and persistent tremulousness may indicate relative irritability of the cerebral cortex and potential risk for subsequent, significant neurologic dysfunction including seizures.
Deep tendon reflexes are elicited using a reflex hammer and are often brisk in the newborn, although they may be normally absent [ Critchley, 1968 ]. They may be inordinately enhanced by upper motor neuron abnormalities and are further facilitated by crying. CNS depression may be associated with reduced deep tendon reflexes. The examiner should confirm that the deep tendon reflexes are symmetric, because asymmetry may indicate central or peripheral nervous system impairment. If previous examination has suggested the possibility of hemiparesis, deep tendon reflexes should be carefully evaluated for asymmetry; they are usually increased on the affected side. Deep tendon reflex asymmetry in the arms may be associated with upper motor neuron abnormality, but asymmetrically absent deep tendon reflexes suggest peripheral involvement, possibly the result of brachial plexus injury. Nerve conduction studies in newborns may provide an index of neurologic maturity [Dubowitz et al., 1968 ].
Controversy remains over the significance of the plantar response in the newborn period in term infants. Although some investigators have reported that the Babinski sign is flexor and symmetric in the newborn period [ Hogan and Milligan, 1971 ], this finding is more likely caused by obtaining a plantar grasp than a Babinski response if only the sole of the foot is used to elicit the response. The plantar response is extensor for at least the first month of life and usually through the first year of life. However, at all times, the response should always be bilaterally symmetric. Persistence of extensor toe-sign responses beyond infancy suggests corticospinal tract impairment and may be associated with alterations in tone and other deep tendon reflex abnormalities. Ankle clonus is frequently elicited in the newborn; rarely are there more than eight beats in normal infants. The clonus is enhanced during crying and may be facilitated during hyperexcitable states, such as those associated with metabolic abnormalities, infection, and subarachnoid hemorrhage. Sustained ankle clonus has the same significance in term newborns as in later life and suggests dysfunction of the corticospinal tracts.
A reflex akin to the plantar response has been described for the hand in term and preterm newborns. The examiner strokes the ulnar aspect of the infant’s palm with the thumb, beginning distally and stroking proximally from the small finger to the hypothenar eminence. The normal response is gradual extension of the fingers, beginning with the small finger and continuing to the middle fingers [ Modanlou, 1988 ]. Lack of response or gross alteration of response may be observed in the presence of corticospinal tract dysfunction.

Cranial Nerve Examination
A more detailed discussion of the cranial nerve examination is found in Chapter 2 . Cranial nerve I, the olfactory nerve, is infrequently tested but may be evaluated by the use of pleasant but definitive aromatic substances, such as cinnamon and cloves [ Sarnat, 1978 ]. The infant usually manifests an arrest of activity, arousal, and sucking activity when exposed to these aromas. Virtually all neonates born after more than 32 weeks’ gestation respond [ Sarnat, 1978 ].
Evaluation of cranial nerves II, III, IV, and VI involves assessment of the eyes. The pupils should be symmetric, and there should be an equal bilateral response to light. A bright light causes the infant to blink or hold the lids closed. The presence of ptosis or increased height of the palpebral fissure should be evaluated. The examiner should ascertain the presence of heterochromia, although it may not be evident until later.
Examination of the optic fundi may be difficult but is necessary. Numerous changes, including chorioretinitis (i.e., salt-and-pepper pigmentary changes), may be observed. Hemorrhages are commonly detected after vaginal delivery, even in the absence of traumatic delivery. The optic nerve may be hypoplastic, as manifested by a small, pearl-colored optic disc. The color of the optic disc in the newborn infant is grayish white. Retinal hemorrhages may be found in a large percentage of otherwise normal infants who have no history of abnormal delivery and who later prove to be neurologically normal [ Besio et al., 1979 ]. Further discussion of funduscopic characteristics is presented in Chapter 6 .
The newborn infant turns toward a light of moderate intensity and fixes on a bright object or the examiner’s face. Most often, the newborn’s eyes are symmetrically open or closed. If one eye is open and the other closed, there should be a shifting from one side to the other. Width of palpebral fissures should be equal; if not, the presence of ptosis should suggest an abnormality of cranial nerve III function, sympathetic innervation dysfunction, neuromuscular junction difficulty, weakness of the levator muscle of the lid, or abnormality of the lid connective tissue. Among the conditions to be considered are congenital myasthenia gravis, myotonic dystrophy, Horner’s syndrome ( Figure 4-2 ), Möbius’ syndrome, congenital myopathies, and Duane’s syndrome. Occasionally, central or peripheral seventh nerve paresis may result in asymmetry of the palpebral fissure.

Fig. 4-2 Horner’s syndrome (left eye).
Miosis and ptosis are plainly evident.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
Extraocular movements should be monitored while a child is lying quietly. Slight lapses of conjugate gaze are common in the newborn period. Newborn visual acuity is difficult to assess, but black and white-patterned objects can be used. The examiner’s face is often the best “target.” The intended object of focus is moved slowly in the infant’s field of vision, less than a foot from the infant’s eyes. The infant slowly follows with eye movement, particularly in lateral directions. Prolonged gaze may occur in the newborn period [ Brazelton et al., 1976 ]. Opticokinetic nystagmus may be elicited by using a striped, rotating drum or striped cloth strip, which is slowly pulled across the infant’s visual field in the vertical and horizontal directions. The response is the same as in older children (see Chapter 2 ).
Although small-excursion, lateral-gaze nystagmus may be present in the newborn, the coarser to-and-fro pattern of congenital nystagmus, which is oscillatory in nature, is usually unmistakable. Although unusual, nystagmus associated with mild esotropia or exotropia may be evident in the newborn. Wild, jerky nystagmus of congenital opsoclonus is a startling and readily discernible finding suggesting midbrain involvement.
Doll’s-eye movement is elicited by the examiner gently rotating the infant’s head from one side to the other when the infant is asleep. The eyes move conjugately in the direction opposite to the rotation of the head. Movement of the head in the vertical position (upward and downward) causes similar movements in the vertical plane. Failure of the eyes to move in the expected manner or direction indicates abnormalities of the cranial nerves or brainstem nuclei. Failure of abduction is associated with cranial nerve VI impairment or lateral rectus muscle impairment. Failure of normal movement in the medial direction implicates medial rectus muscle or cranial nerve III impairment.
To gain further information, the infant may be held supine on the examiner’s arm as the examiner rotates and watches the infant’s eyes. This oculovestibular maneuver causes movement so that there is lateral conjugate deviation in the direction of the rotation. When the rotational movement is terminated abruptly, the eye movements reverse. It is possible to assess the integrity of cranial nerves III and VI with this maneuver.
Cranial nerve VII involvement may be the result of the position of the infant in the maternal pelvis and delivery by pressure incurred during forceps delivery, or by agenesis of the motor nucleus of cranial nerve VII. Facial movements are readily observed during crying; an asymmetry of mouth movement may indicate cranial nerve VII involvement. During crying, the angle of the mouth is depressed on the normal side. The syndrome referred to as asymmetric crying facies may manifest this way [ Nelson and Eng, 1972 ]. This syndrome results from weakness of the lower lip caused by hypoplasia of the depressor muscle of the mouth angle. This phenomenon is a congenital abnormality and does not signal cranial nerve VII involvement. This condition also may be associated with somatic atrophy, vertebral and rib abnormalities, renal dysgenesis, and most importantly, cardiac defects (i.e., atrial or ventricular septal defect; cardiofacial syndrome) [ Pape and Pickering, 1972 ].
Hearing in term infants has been evaluated by sophisticated testing techniques that indicate some ability to localize and discriminate. However, meaningful hearing evaluation during routine neurologic examination is difficult to accomplish because of simultaneous visual cues and variable responses. The use of brainstem auditory-evoked potential testing has greatly improved the ability to evaluate hearing response during the neonatal period. Vestibular function can be monitored by the oculovestibular maneuver described previously.
Assessment of cranial nerves IX, X, and XII may be facilitated by evaluating the infant’s cry; however, impairment of crying may occur because of central rather than peripheral abnormalities. An infant with generally depressed CNS function often cries infrequently, and the cry is weak and may be high-pitched. The volume and tone of the cry should be assessed. An irritable child with a hyperexcitable nervous system may have a high-pitched shriek, whereas unusual cries, such as that associated with the cri du chat syndrome, are similar to a cat’s cry.
Observation of the infant during crying is a valuable adjunct to certain portions of the examination. During the lusty segments of crying, the infant’s tongue and palate may be readily inspected. Asymmetry or loss of tongue bulk may indicate abnormalities of cranial nerve XII or its nucleus. The presence of fasciculations may indicate spinal muscular atrophy. More complex forms of Möbius’ syndrome may also involve the tongue. Tongue fasciculations must be identified when the child is quiet and not crying. The fasciculations occur along the lateral margins and underside of the tongue.
Cranial nerves V, VII, IX, X, and XII are involved in sucking and swallowing. Swallowing dysfunction requires close scrutiny to determine which cranial nerve or nerves are involved. The gag reflex is present in term newborns and requires normal function of cranial nerves IX and X.
Tests for pain and sensation are imprecise at this age, and the gross response of infants to stroking and pinprick with withdrawal, crying, and change in sucking rates may be the only information possible. More sophisticated testing can be devised during which heart and respiratory rates are monitored.
If necessary, in the presence of olfactory, gustatory, visual, tactile, or auditory stimuli, sophisticated monitoring and scoring of body activity may be performed [Brazelton et al., 1976]. All such sensory stimuli produce habituation in the newborn [ Lipsitt, 1977 ]. Lack of habituation or failure to respond to these stimuli is abnormal; however, the abnormality may be specific for the sensory mechanism or merely may be a reflection of generalized CNS depression.

The Preterm Infant
The neurologic evaluation of the preterm infant is a major challenge to the clinician. Much of the information in this chapter concerning the term infant is applicable to the preterm infant. The fragility of the patient, the changing developmental norms coupled with the uncertainty of the length of gestation, and the frequent need for life-support systems and associated paraphernalia, which interfere with the examination and the spontaneity of movement, all complicate the process. Modern imaging techniques permit correlation of clinical examination and image alterations never before available. The use of cranial ultrasound examination and, when feasible, CT has permitted the timely diagnosis of intraventricular and hemispheral hemorrhage and early hydrocephalus in preterm infants. The information provided is greater in quality and quantity than has been available previously.
The designation of an infant as preterm is related primarily to length of gestation. Term gestation is 38–42 weeks from conception, and preterm therefore is any period less than 38 weeks, although most clinicians would not consider a baby preterm or premature between 36 and 38 weeks. Expected developmental milestones are based on gestation [ Mercuri et al., 2003 ]. The clinician must estimate gestational age to facilitate interpretation of the observations and findings made during the neurologic examination. An infant whose birth weight is low compared with length of gestation (e.g., intrauterine growth retardation, small for gestational age) exhibits different growth patterns or neurologic findings than the infant whose weight is appropriate for gestational age. In a parallel fashion, preterm infants born of diabetic mothers may weigh more than 2500 g, but these infants manifest findings consistent with their preterm status during the neurologic evaluation.
The designation of extremely low birth weight infants has been assigned to those infants who weigh less than 1000 g at birth [ Doyle et al., 2004 ; Kilbride, 2004 ]. Most of these infants are at 28 weeks’ gestation or less. The very low birth weight infants are those who weigh less than 1500 g at birth. In the absence of intrauterine growth retardation, most infants of this birth weight are born after 31–32 weeks’ gestation [ Lubchenco et al., 1966 ]. The neurologic examination of these infants is reviewed in this portion of the chapter; the expected results of the examination should be based on the gestational age as determined from the various tables and illustrations.

General Examination
It is not possible with any great assurance to estimate gestational age from the date of the first day of the mother’s last menstrual period [ Lubchenco, 1970 ]. Nevertheless, a number of physical findings evident during the examination can prove helpful in this evaluation [ Farr et al., 1966a , 1966b ; Lubchenco, 1970 ; Usher and McLean, 1969 ]. Among the most valuable findings are skin texture and color, quantity of breast tissue and ear cartilage, and the stage of development of the external genitalia. No single characteristic can determine the gestational age. The estimate should be based on the average of expected findings ( Table 4-3 ). The combination of findings based on physical characteristics and neurologic examination has proved of value in the estimation of gestational age [ Dubowitz et al., 1970 ]. This method is discussed with the specifics of the neurologic examination.

Table 4-3 External Characteristics Useful for Estimation of Gestational Age

Electrophysiologic Assessment
Motor nerve conduction velocity studies of the ulnar and posterior tibial nerves may corroborate the clinical estimation of gestational age because nerve velocity becomes more rapid with maturation. Such studies also differentiate infants of short gestation from those with intrauterine growth retardation, including those at high risk and with very low birth weight [ Dubowitz et al., 1968 ; Cruz-Martinez et al., 1983 ; Miller et al., 1983 ; Moosa and Dubowitz, 1972 ].
Electroencephalographic (EEG) patterns also appear to be a function of maturity. Comparison of EEG, anatomic, and clinical criteria provides one means of estimating gestational age [ Scher and Barmada, 1987 ]. EEG correlates are listed in Box 4-1 [ Scher and Barmada, 1987 ] and are further discussed in Chapter 12 .

Box 4-1 Selected Gestational Age-dependent Electroencephalographic Patterns Based on Convolutional Measurements

Less than 28 weeks

Prominent occipital theta/alpha
Prominent vertex-central delta brush
Rhythmic occipital delta (<6 seconds) *
Prominent bitemporal attenuation
Diffuse theta/delta slowing
Interburst intervals (<40 seconds)
Brief continuous portions (<1 minute)

28–29 weeks

Prominent occipital delta (<10 seconds)
Appearance of temporal delta brush
Occasional temporal attenuation
Diffuse theta/delta slowing
Interburst intervals (<40 seconds)
Continuous portions (>1 minute)

30–31 weeks

Prominent temporal theta bursts
Prominent temporal delta brushes
Prominent occipital delta brushes (>10 seconds)
Interburst intervals (<30 seconds)
Continuous portions (several minutes)

* Parentheses contain observed duration of electroencephalographic pattern.
(Adapted from Scher MS, Barmada MA. Estimation of gestational age by electrographic, clinical, and anatomic criteria. Pediatr Neurol 1987;3:256.)

Neurologic Examination
Although estimation of gestational age should be made as soon after birth as possible, the neurologic examination may be postponed for 1–2 days, depending on the condition of the infant and the need for physiologic support. The examination should be performed while the infant is awake and approximately 1 hour before the next scheduled feeding. The child may become fussy shortly before a feeding and often becomes somnolent after a feeding, resulting in decreased muscle tone.

Environmental Interaction
Periods of apparent wakefulness are rare before 28 weeks. Arousal by external stimulation is often necessary for the 28-week preterm infant [ Illingworth, 1972 ]. Nevertheless, small preterm infants respond to environmental factors, such as temperature, light, and feeding. Periods of wakefulness and somnolence are relatively brief and change swiftly in the preterm infant. The waking periods of preterm infants of 25–30 weeks’ gestation are short compared with those of term infants [ Fenichel, 1978 , 1985 ]. A readily recognizable level of alertness during wakeful stages occurs even in infants of 31 weeks’ gestation [ Hack et al., 1976 ]. In infants of 32 weeks’ gestation, external stimulation is usually unnecessary. Responsiveness increases with CNS maturation; suck rate increases, and sucking persists for longer periods. In those born after 37 weeks’ gestation, crying is commonly present during wakefulness. By 40 weeks’ gestational age, the preterm infant continues to be alert for reasonable periods and responds to visual, auditory, and tactile stimulation. Sleep and wakeful periods are easily identified. Sleep is discussed in detail in Chapter 66 .

Formal Scale of Gestational Assessment
Using a systematic evaluation of body and neurologic characteristics, Dubowitz and colleagues [ 1970 ] were able to achieve a high correlation with gestational age, making this method of assessment most valuable. The evaluation was based on 10 neurologic and 11 external (e.g., skin texture, breast size, ear form) characteristics. The external evaluation was adapted from Farr and colleagues [ 1966a , 1966b ]. The scoring scheme is detailed in Figure 4-3 and Figure 4-4 and in Table 4-4 [ Dubowitz et al., 1970 ].

Fig. 4-3 A, Scoring system for neurologic criteria.
(From Dubowitz L, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970;77:1.)

Fig. 4-3 B, Description of techniques used to assess neurologic signs.
(From Dubowitz L, Dubowitz V Goldberg. Clinical Assessment of gestational age in the newborn infant, J Pediatr 1970; 77:1.)

Fig. 4-4 Graph for reading gestational age from total score obtained from scores derived from Figure 4-3 .
(Redrawn from Dubowitz LMS, Dubowitz V, Goldberg C. J Pediatr 1970;77:1.)

Table 4-4 Scoring System for External Criteria

Deep Tendon Reflex Assessment
The assessment of deep tendon reflexes in preterm infants can be of value in the presence of many conditions, such as spinal cord anomalies, peripheral nerve injuries, congenital myopathies, and infantile spinal muscular atrophy. A standard method of deep tendon reflex examination for preterm infants has been proposed [ Kuban et al., 1986 ]. The methods of elicitation are described in Table 4-5 and depicted in Figure 4-5 [ Kuban et al., 1986 ]. Deep tendon reflexes differ in healthy and ill preterm infants of 33 weeks’ gestation; the elicitation rate and intensity of deep tendon reflexes vary with maturity (i.e., less than and greater than 33 weeks’ gestation) [ Kuban et al., 1986 ]. In a study of preterm infants of more than 27 weeks’ postconceptional age, the pectoralis major reflex was elicited in all, regardless of maturity. In 98 percent of the infants of more than 33 weeks’ gestation, the Achilles, patellar, biceps, thigh adductor, and brachioradialis reflexes were obtained. Infants of less than 33 weeks’ gestation had decreased elicitation rates for patellar and biceps reflexes and had overall decreases in reflex intensity compared with their older counterparts. For all infants in the study, the following tendon reflexes were found to be present (in decreasing order): finger flexors, jaw, crossed adductors, and triceps. Contrary to conventional wisdom, head position had no effect on the reflexes [ Kuban et al., 1986 ].
Table 4-5 Deep Tendon Reflexes Evaluated in Preterm Infants Deep Tendon Reflexes Innervation Technique of Elicitation Jaw Cranial nerves V and VII The point of the finger is placed over the chin so that the jaw is slightly open. The hammer strikes the index finger tip Pectoralis major Predominantly C7 and C8, lateral pectoral nerve The examiner’s index finger is firmly placed in a caudad (or cephalad) direction on to the axilla over the pectoralis major Biceps C5 and C6, musculocutaneous nerve The examiner’s index finger is placed on to the biceps tendon in the superomedial aspect of the antecubital fossa with the arm flexed at the elbow Brachioradialis C5, C6, radial nerve The tendon of the muscle is struck directly over the distal third of the radius while slowly flexing and extending the arm Triceps C7, C8, radial nerve The examiner’s finger is placed over the triceps tendon at its distal aspect proximal to the elbow. The triceps tendon also may be struck directly while flexing and extending the arm Finger flexors C8, T1, median nerve The examiner’s finger is placed horizontally across the base of the infant’s fingers to elicit a partial grasp. The examiner’s finger is then struck Patellar L3, L4, femoral nerve The reflex hammer strikes the examiner’s finger placed across the patellar tendon, or the latter is struck directly while flexing and extending the leg at the knee Thigh adductors and crossed adductors L3, L4, obturator nerve The examiner’s index finger to be struck is placed diagonally across the medial aspect at the knee (thigh adductor) with the little finger placed on the contralateral leg to maintain a 45- to 60-degree angle (crossed adductor) Achilles L5, S1, tibial nerve The examiner’s finger to be struck is placed horizontally across the plantar aspect of the infant’s foot, which is partially dorsiflexed
(From Kuban KCK, Skouteli HN, Urion DK, et al. Deep tendon reflexes in premature infants. Pediatr Neurol 1986;2:266.)

Fig. 4-5 Elicitation of deep tendon reflexes in a preterm infant of 32 weeks’ gestation.
A and B, Pectoralis major. C, Brachioradialis. D, Thigh adductors and crossed adductors. E, Achilles.
(From Kuban KCK, Skouteli HN, Urion DK, et al. Deep tendon reflexes in premature infants. Pediatr Neurol 1986;2:266.)

Body Attitude
During maturation, preterm infants adopt typical postures that correspond to gestational age. These postures have been charted and are very useful for evaluation of gestational age [ Dubowitz et al., 1970 ; Dubowitz and Dubowitz, 1981 ].

Muscle Tone
Assessment of muscle tone in the preterm infant is requisite to completion of a satisfactory neurologic evaluation [ Paro-Panjan et al., 2005 ; Amiel-Tison, 1968 , 2002 ; Saint-Anne Dargassies, 1966 ]. The muscle tone of small-for-gestational-age infants differs from that of infants with only a short gestation.
At 26–28 weeks’ gestation, the infant is extremely hypotonic. When held by the examiner in vertical suspension, the infant does not extend the head, limbs, or trunk ( Figure 4-6 ). The change from the hypotonia of the preterm infant to the flexion posture of the term infant manifests first in the legs and then in the arms and head. At 34 weeks’ gestation, the infant lies in the frogleg position while supine; the legs are flexed at the hip and knee, but the arms remain extended and relatively hypotonic ( Figure 4-7 ).

Fig. 4-6 Preterm baby, 26–28 weeks’ gestation.
Notice the hypotonic posture with lack of extension of the spine and head, and lack of flexion of the extremities.

Fig. 4-7 Two weeks after birth.
The frogleg position of a preterm infant of 34 weeks’ gestation.
Measurement of various limb angles offers some objective evidence for the degree of tone. The popliteal angle, measured by maximum extension of the leg at the knee with the hip fully flexed, decreases from 180 degrees at 28 weeks’ gestation ( Figure 4-8 ; see also Figure 4-14 ) to less than 90 degrees at term [ Kato et al., 2005 ]. Similarly, the adductor and dorsiflexion angle of the foot diminishes to almost 0 degrees at term ( Figure 4-9 ).

Fig. 4-8 The popliteal angle is 180 degrees in a preterm infant of 28 weeks’ gestation.

Fig. 4-14 Measurement of the popliteal angle in an infant who was 8 months old (corrected age).
The popliteal angle is evaluated by bringing the infant’s knees to the chest and by extending the legs with the use of gentle pressure behind the ankles. The popliteal angle was approximately 180 degrees in this case.
(From Kato T, Okumura A, Hayakawa F, et al. Popliteal angle of low birth weight infants during the first year of life. Pediatr Neurol 2004;30:244.)

Fig. 4-9 The adductor angle of the thighs is almost 180 degrees in a preterm infant of 30 weeks’ gestation.
During the traction maneuver, the head lags considerably, with little resistance until after 30 weeks’ gestation. The head extensors develop gradually, followed by the flexors. By 38 weeks, the head follows the trunk, is maintained briefly, and then falls forward when the infant is pulled from a supine to a sitting position during the traction maneuver.
In small preterm infants, the scarf sign, which is elicited by folding the arm across the chest toward the opposite shoulder, is present if the elbow reaches the opposite shoulder ( Figure 4-10 ). In term infants, the elbow cannot be brought beyond the midline.

Fig. 4-10 An infant of 32 weeks’ gestation demonstrates the scarf sign, with the elbow approximating the opposite shoulder.
The extreme hypotonia of preterm infants permits the legs to be flexed at the hip so that the heel can be passively brought to the side of the face (i.e., heel-to-ear maneuver). Understandably, this positioning is restricted in the older infant because of increasing tone ( Figure 4-11 ).

Fig. 4-11 Diminished tone in the very small preterm infant of 30 weeks’ gestation allows the heels to reach the head easily.
The pelvis should be flat on the table.
Tone may also be monitored while postural and righting reflexes are assessed. During the stepping maneuver, the 28-week preterm infant will not support weight ( Figure 4-12 ). However, over the next few weeks, there is gradual support of weight, and by 34 weeks, a good supporting response is present. Tremors and even clonic movements manifest in the small preterm infant but are not normally discernible after 32 weeks’ gestation. Stretching movements of the limbs are common in small preterm infants while they are awake but somewhat less common during sleep. These movements may spread to include the trunk and head.

Fig. 4-12 A preterm infant of 28 weeks’ gestation supports his or her weight briefly.
Toe-walking may be evident.
Serial measurements may indicate the likelihood of developing spasticity. A “tight” (<120 degrees) angle was found at 4 months in infants with birth weights ranging from less than 999 g up to 1999 g. Infants who had birth weights ranging from 2000 to more than 2500 g had only an 8 percent incidence of tight popliteal angle ( Table 4-6 ).

Table 4-6 The Rates of Infants with a Tight Popliteal Angle

Cranial Nerves
Some features of the preterm infant examination are different from features of the older infant’s examination. Head position is unpredictable in the small preterm infant, but by 35 weeks’ gestation, there is a preference for the head to be held to the right. By 39 weeks’ gestation, the head is held to the right approximately 80 percent of the time while the infant is at rest [ Gardner et al., 1977 ].
The small preterm infant may cry in response to provocation [ Fenichel, 1978 ], but crying often occurs when the infant is unprovoked. By 36–37 weeks’ gestation, the cry is more vigorous, frequent, and persistent, and it is easily elicited by noxious stimuli.
The pupillary light reflex is not fully mature before 29–30 weeks’ gestation, and in the resting state, the infant’s pupils are usually miotic. The reflex becomes progressively evident and is mature by 32 weeks.
Although they may forcefully close their eyes when a bright light is directed toward them, infants of 28 weeks’ gestation or less do not turn in the direction of the light. By using a large target (e.g., large, red ball; hoop; handful of yarn), visual fixation and even rudimentary scanning and tracking may be evident in infants of 31–32 weeks’ gestation [ Hack et al., 1976 ]. Associated with this response, there may be widening of the palpebral fissure. By 36–38 weeks’ gestation, the infant rotates the head toward a light and closes the eyes forcefully when a strong light stimulus is presented.
The doll’s-eye reflex is elicited in the 28- to 32-week preterm infant who has no compromise of consciousness. The ease of eliciting a response is enhanced because infants do not visually fixate. By 36 weeks’ gestation, this response is not elicited in the normal infant.

Developmental Reflexes
Observation and description of the major reflex changes peculiar to the preterm infant have been undertaken by many investigators ( Table 4-7 ) [ Amiel-Tison, 1968 , 2002 ; Fenichel, 1985 ; Lubchenco, 1970 ; Saint-Anne Dargassies, 1966 ].

Table 4-7 Neurologic Maturation
The rooting and sucking reflexes in small preterm infants are perfunctory but become vigorous in infants of 34 weeks’ gestation. The Moro reflex, first present in fragmentary form at 24 weeks, is well developed by 28 weeks, although it fatigues easily and lacks a complete adduction phase. Not until 38 weeks’ gestation is the entire response characteristic of the term infant observed.
At 28 weeks’ gestation, the grasp reflex is evident just in the fingers, and by 32 weeks, the palm and fingers participate. Slightly later, contraction of the muscles of the shoulder girdle and elbows occurs during the traction maneuver when the infant is pulled from a supine to a sitting position.
The tonic reflex is elicited by turning of the head to one side. The arm on the side to which the head is turned extends, and the other arm flexes. The legs may follow suit, but the response is often absent or subtle. This “fencing” position often can be elicited in the 35-week preterm infant.
The crossed-extensor reflex is obtained by stroking the sole of one foot while holding the leg firmly in extension. The response occurs in the opposite leg and comprises rapid flexion at the hips and knees with attendant withdrawal, followed by extension, adduction, and fanning of the toes. The complete response, elicited in infants of about 36 weeks’ gestation, is informative when asymmetric. Otherwise, it only establishes that some degree of primitive function is present.
The stepping response (i.e., automatic walking) is usually present by 37 weeks’ gestation and can be induced by resting the infant’s soles on a mattress and rocking the infant gently from one foot to the other. This procedure usually initiates a walking sequence, which is facilitated by the examiner supporting the infant’s weight and tilting the infant forward. The preterm infant usually walks on the toes, whereas the term infant uses a heel-to-toe sequence. The response manifests at 32–34 weeks’ gestation.
Ongoing neurologic examinations of the preterm infant are most important for the assessment of development and neurologic status. When the preterm infant reaches the equivalent of 40 weeks’ gestation, the neurologic examination results are not the same as those of a term newborn [ Illingworth, 1972 ]. After reaching 40 weeks’ gestation the preterm infant lies with relatively less elevation of the pelvis, and so the prone body profile is flatter than that of the term newborn ( Figure 4-13 ). The preterm infant continues toe-walking and, even at 40 weeks, manifests relative hypotonia, incomplete dorsiflexion of the foot, and a greater popliteal angle compared with the term newborn.

Fig. 4-13 The hips are abducted and the pelvis is low in a prone preterm infant of 32 weeks’ gestation.
Tone can also be evaluated by measurement of the popliteal angle in preterm infants. These data provide useful information in assessing tone ( Kato et al., 2004 ). The angle is assessed as shown in Figure 4-14 . Data documenting preterm infants and popliteal angle changes are found in Table 4-6 .

Assessment of Head Growth Patterns
It is essential to measure and plot growth data to facilitate early detection of abnormal patterns. The shape of the head changes markedly with growth in preterm infants. The ratio of anteroposterior diameter to biparietal diameter increases rapidly in preterm infants during the first few months of life [ Baum and Searls, 1971 ].
There are known differences between the extrauterine body growth patterns of preterm infants and the extrauterine body growth patterns of the term infant [ Babson et al., 1970 ; Gardner and Pearson, 1971 ; Lubchenco et al., 1966 ; Usher and McLean, 1969 ]. The occipitofrontal circumference of preterm infants often shrinks during the first few days of life. Expected patterns of extrauterine head growth are reasonably well documented, making diagnosis of hydrocephalus or microcephaly in the preterm infant possible. Frequent serial occipitofrontal circumference measurements should be obtained to allow early diagnosis. A standard plotting curve must be used to monitor head growth in the preterm infant. A useful standard plot is depicted in Figure 4-15 [ Babson and Benda, 1976 ]. Conventional symptoms and signs of hydrocephalus are not immediately evident, even though the presence of ventricular dilatation is documented with imaging techniques [ Korobkin, 1975 ; Volpe et al., 1977 ].

Fig. 4-15 A fetal-infant growth graph for infants of various gestational ages.
This can be used for plotting growth from birth until 1 year of age after term status has been reached.
(From Babson SG, Benda GI. Growth graphs for the clinical assessment of infants of varying gestational age. J Pediatr 1976;89:814.)
The presence of certain characteristics should alert the clinician to the presence of hydrocephalus [ Sher, 1982 ]; these include full fontanel with separation of the cranial sutures, abnormally high rate of occipitofrontal circumference increase, frontal bossing, scaphocephaly, and increased ratio of head size to body length.
The preterm infant’s state of health is a major determinant of head growth [ Sher and Brown, 1975a , 1975b ]. Mean occipitofrontal circumferences for small and large, healthy, preterm infants and for sick infants are graphed [ Sher and Brown, 1975a ] for comparison with the data of O’Neill [ 1961 ]. Irrespective of gestational age, sick infants were designated as those who were maintained with mechanical ventilation and intravenous therapy for various periods up to 2 weeks [ Sher and Brown, 1975a , 1975b ]. Infants with easily correctable metabolic abnormalities or minimal degrees of hyperbilirubinemia not requiring exchange transfusion were excluded from the sick group. On the basis of the study of Sher and Brown [ 1975a , 1975b ], some conclusions are possible [ Sher, 1982 ].
The rate of occipitofrontal circumference increase in the healthy preterm infant is approximately double (1.1 cm/week) that of the term infant in the first and second months after delivery ( Figure 4-16 ). The rate of increase of occipitofrontal circumference in the healthy preterm infant is approximately equal (0.5 cm/week) to that of the term infant in the third and fourth months. The average rate of occipitofrontal circumference for ill preterm infants is 0.25 cm/week for the first 3 months.

Fig. 4-16 Head circumference growth record for preterm infants.
Preterm infants with a short gestation have more rapid rates of occipitofrontal circumference increase than infants with a longer gestation. Preterm infants with rates of occipitofrontal circumference increase greater than the expected rate should be evaluated for the presence of hydrocephalus. Preterm infants who are healthy and who fail to achieve the least expected rate of occipitofrontal circumference increase may have intrinsic brain disease.
When comparisons are made based on postconceptional age, the occipitofrontal circumference of preterm infants is greater than that of the term infant, at least for the first 5 postnatal months [ Fujimura et al., 1977 ]. The maximum velocity of head growth in healthy, preterm infants with good caloric intake occurs shortly postpartum and decreases thereafter.
In general, the prognosis for normal development of low birth weight infants is much improved since the advent of focused obstetric practices related to the preterm infant and neonatal intensive care units [ Hutson et al., 1986 ; Kitchen and Murton, 1985 ]; however, the increase in the number of very low birth weight infants has resulted in an increase in the prevalence of cerebral palsy in this population [ Pharoah et al., 1990 ]. The clinician must be cognizant of the normal, rapid rate of head growth and avoid unnecessary procedures designed to diagnose hydrocephalus.
Caution should be exercised in placing undue emphasis on isolated neurologic findings that deviate from expected findings in preterm infants. Variations from infant to infant and from time to time in the same infant are common. The infant’s general pattern of responses should weigh heavily in the assessment of CNS integrity at any one moment.

References
The complete list of references for this chapter is available online at www.expertconsult.com .
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References

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Suggested Reading

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Beintema D.J. A neurological study of newborn infants. London: William Heinemann Medical Books, 1968.
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Knobloch H., Pasamanick B. Predicting intellectual potential in infancy. Am J Dis Child . 1963;166:43.
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Rawlings G., Reynolds E.O.R., Stewart A., et al. Changing prognosis for infants of very low birth weight. Lancet . 1971;1:516.
Robinson R.J. Assessment of gestational age by neurologic examination. Arch Dis Child . 1966;41:437.
Saint-Anne Dargassies S. Long-term neurological follow-up study of 286 truly premature infants. Dev Med Child Neurol . 1977;19:462.
Sustersic B., Paro-Panian D. Assessment of general movements in relation to neurologic signs at age two years. Pediatr Neurol . 2008;39:108.
Chapter 5 Muscular Tone and Gait Disturbances

Kenneth F. Swaiman, Lawrence W. Brown
Muscular tone is conventionally separated into phasic and postural types. Phasic tone is the result of rapid stretching of a tendon, attached muscle, and most importantly, the muscle spindle. The response is rapid and short-lived. Postural tone is the result of a steady, restrained stretch on tendons and attached muscles, with resultant protracted contraction of the involved muscle. Gravity is the most common stimulus for this response. Postural tone is the topic primarily discussed in this chapter, and it is referred to simply as tone.
Tone is functionally defined as resistance to passive movement (i.e., resistance experienced by the examiner while the patient’s relaxed limbs are moved about the joints). Hypotonia is decreased resistance to passive movement. Hyperextensibility is an abnormally increased range-of-joint movement. Hyperextensibility of the elbows, wrists, knees, and ankles usually accompanies hypotonia but is not pathognomonic. The combination of hypotonia and hyperextensibility allows an infant to adopt unusual and awkward-appearing postures.
The term “floppy” is frequently used to describe hypotonic infants. This term is useful only as a shorthand description of clinical manifestations and is not a formal diagnosis.
Hypotonia must not be equated with hyporeflexia or muscle weakness. For example, patients with Down syndrome commonly have normal deep tendon reflexes and normal strength but are usually hypotonic. Conversely, patients with anterior horn cell disease are weak and manifest hypotonia and hyporeflexia.

Pathology
The central and peripheral nervous systems modify tone, but intrinsic physical characteristics of the tendons, joints, and muscles and the anatomic interrelationships of these structures also contribute significantly to tone. In childhood central nervous system (CNS) dysfunction, upper motor neuron (unit) disease may cause increased or decreased muscle tone [ Teddy et al., 1984 ]. Disease involving the lower motor neuron (unit) results in hypotonia and weakness.
The final common pathway of upper or lower motor unit modification of tone is through the gamma loop (fusimotor) system [ Gordon and Ghez, 1991 ; Granit, 1975 ]. Intimately involved with monitoring and effecting tone are the two stretch-sensitive muscle receptors – the muscle spindles and the Golgi tendon organs ( Figure 5-1 ). It also has become evident that nonreflex, mechanical mechanisms are involved in the maintenance of resting muscle tone. Spinal cord reflex responses depend on ongoing activity in interneurons [ Davidoff, 1992 ].

Fig. 5-1 Muscle spindles and Golgi tendon organs are encapsulated structures found in skeletal muscle.
The main skeletal muscle fibers, or extrafusal fibers, are innervated by large-diameter alpha motor axons. The muscle spindle has a fusiform shape and is arranged in parallel with extrafusal fibers. It is innervated by afferent and efferent fibers. The Golgi tendon organ is found at the junction between a group of extrafusal fibers and the tendon; it is therefore in series with extrafusal fibers. Each tendon organ is innervated by a single afferent axon.
(Adapted from Houck JC, Crago PE, Rymer WZ. Functional properties of the Golgi tendon organs. In: Desmedt JE, ed. Spinal and supraspinal mechanisms of voluntary motor control and locomotion. Progress in Clinical Neurophysiology, vol. 8. Basel: Karger, 1980:33.)
Stationed in all areas of the skeletal muscle is the muscle spindle, a fusiform-shaped receptor structure ( Figure 5-2 ). The spindle is composed of contractile fibers at each end and a capsule covering a central fluid-filled dilatation. Sensory endings wrap around the central sections of the intrafusal fibers and monitor the stretch of these fibers; they communicate through the afferent axons that are described later in this chapter. Through efferent axons, gamma neurons within the anterior horn of the spinal cord innervate the contractile muscle portions on each end of the intrafusal fiber and enhance the sensitivity of the sensory endings to stretch [ Gordon and Ghez, 1991 ]. Gamma motor neurons that innervate muscle spindles comprise the fusimotor system.

Fig. 5-2 The main components of the muscle spindle are intrafusal fibers, sensory endings, and motor axons.
A, The intrafusal fibers are specialized fibers; their central regions are not contractile. The sensory endings spiral around the central regions of the intrafusal fibers and are responsive to stretch of these fibers. Gamma motor neurons innervate the contractile polar regions of the intrafusal fibers. Contraction of the intrafusal fibers pulls on the central regions from both ends and increases the sensitivity of the sensory endings to stretch. B, The muscle spindle contains three types of intrafusal fibers: dynamic nuclear bag, static nuclear bag, and nuclear chain fibers. A single group Ia afferent fiber innervates all three types of intrafusal fiber, forming a primary ending. A group II afferent fiber innervates chain and static bag fibers, forming a secondary ending. Two types of efferent axons innervate different intrafusal fibers. Dynamic gamma motor axons innervate only dynamic bag fibers; static gamma motor axons innervate various combinations of chain and static bag fibers.
(A, Adapted from Hullinger M. The mammalian muscle spindle and its central control. Rev Physiol Biochem Pharmacol 1984;101:1; B, Adapted from Boyd IA. The isolated mammalian muscle spindle. Trends Neurosci 1980;3:258. Reproduced with permission from Elsevier.)
The intrafusal muscle fibers are divided into three types: nuclear chain fibers, dynamic nuclear bag fibers, and static nuclear bag fibers. These fibers derive their names from the configuration of their nuclei in the fiber center. Chain fibers have nuclei arranged in a single column, whereas bag fibers have nuclei aligned in rows of two or three. A solitary Ia afferent fiber provides primary sensory innervation for all three types of intrafusal fibers. A group II afferent fiber innervates chain and static bag fibers providing secondary sensory endings. The various sensory endings on the different types of intrafusal fibers have different sensitivities to rate of change of length. Dynamic gamma motor axons innervate the contractile portions of dynamic nuclear bag fibers, and static gamma motor axons innervate the contractile portions of the static bag fibers [ Gordon and Ghez, 1991 ]. This intricate system of muscle spindle innervation allows the muscle stretch receptors to monitor muscle tension, length, and velocity of stretch, and provide input for maintenance of tone [ Carew, 1985 ].
It is through their effect on the gamma motor neuron that portions of the CNS (i.e., motor cortex, thalamus, basal ganglia, vestibular nuclei, reticular formation, and cerebellum) modify tone, with ensuing hypotonia or hypertonia (i.e., spasticity) [ Alexander and Delong, 1985 ; Brooks and Stoney, 1971 ; Carew, 1985 ; Ghez, 1985 ].
The Golgi tendon organs, unlike the muscle spindles, are found in series with the skeletal muscle fibers ( Figure 5-3 ), and are attached at one end to the muscle and at the other to the tendon. A number of individual skeletal muscle fibers enter a Golgi tendon organ through a constricted collar. The muscle fibers are attached to collagen fibers within the Golgi tendon organ. A single Ib axon enters each capsule and forms branches that are interlaced among the collagen fibers. The afferent axon branches are compressed when muscle contraction occurs and impulses are transmitted. Tendon organs are much more sensitive to muscle contraction than muscle spindles. Conversely, tendon organs are much less sensitive to stretch than muscle spindles. Each of these relative sensitivities plays a specific role during the performance of various motor tasks [ Gordon and Ghez, 1991 ].

Fig. 5-3 Golgi tendon organs are specialized structures found at the junctions between muscle and tendon.
Collagen fibers in the tendon organ attach to the muscle fibers. A single Ib afferent axon enters the capsule and branches into many unmyelinated endings that wrap around and between the collagen fibers. When the tendon organ is stretched (usually because of contraction of the muscle), the afferent axon is compressed by the collagen fibers (inset) and increases its rate of firing.
(Adapted from Schmidt RF. Motor systems. In: Schmidt RF, Thews G, eds. Human physiology [Biederman-Thorson MA, translator]. Berlin: Springer, 1983:81; inset, adapted from Swett JE, Schoultz TW. Mechanical transduction in the Golgi tendon organ: a hypothesis. Arch Ital Biol 1975;113:374.)

Evaluation of the Patient

History
The age at which hypotonia is first evident may be diagnostically crucial. The presence of hypotonia at birth or shortly thereafter can help differentiate among a number of conditions [ Brooke et al., 1979 ; Dubowitz, 1985 ]. The presence or absence of weak fetal movements or the change from apparently normal fetal movements to those of decreased amplitude and vigor should be determined. Hypotonia in the setting of polyhydramnios signals prenatal interference with swallowing.
A careful genetic history must be sought because several conditions characterized by hypotonia are hereditary. In a retrospective review of hypotonic infants, Birdi et al. reported a family history of neuromuscular or neurologic disorders in almost half [ Birdi et al., 2005 ].

Examination
Preterm infants, even when healthy, are normally hypotonic relative to a term newborn; therefore, corrected ages must be considered when assessing preterm infants during the first months of life. The finding of fixed contractures in the neonatal period suggests that hypotonia is associated with primary disorder of bone or muscle or an antenatal insult.
The infant’s tendency to assume unusual postures may indicate the presence of hypotonia – especially the “frogleg” position, in which the supine infant lies with the lower limbs externally rotated and abducted. Hypotonia is often associated with generalized weakness, with resultant poor suck, cry, and respiratory effort in addition to a paucity of spontaneous limb movements. Weakness should be suspected if the infant does not briskly withdraw a limb or cannot sustain the raised limb position in response to painful stimuli.
Tone should be assessed both in the active state and when the neonate is at rest; active tone of the extremities is normally higher than passive tone. Passive pronation, supination, flexion, and extension of the limbs and gently shaking the hands and feet are the best ways to assess tone. The hands move over a large amplitude when the arms are shaken gently at the wrists. Often, in the hypotonic infant, the elbows can be extended beyond their normal range. The scarf sign involves wrapping the infant’s arm across the chest toward the neck on the contralateral side and is positive when the elbow can be readily moved beyond the midline. While abnormal in the term infant, it can normally be seen in preterm infants. The traction maneuver is one of the best means to evaluate tone, since it allows simultaneous evaluation of head control, flexion of elbows during infant participation, and general body and back posture (see Figure 3-7 ). The hypotonic infant’s foot can be brought to the opposite ear, and extreme passive foot dorsiflexion may be possible when hypotonia is profound.
The hypotonic infant will slip through the hands of the examiner when held under the axillae (i.e., vertical suspension maneuver). If the hypotonic infant is supported by the trunk in an outstretched prone position (i.e., horizontal suspension maneuver), gravity causes flexion, or droop of the head and extremities (“inverted comma”). The normal response is anti-gravity with neck extension, straight back and limb flexion.
Weakness of facial muscles, weakness of muscles necessary for adequate suck and swallow, and paresis of the eyelid levators and extraocular muscles are often associated with genetic myopathies. The tongue should be carefully examined for atrophy and fasciculations. Evaluation of muscle weakness can be facilitated with the traction maneuver and by ascertaining the withdrawal response to appropriate stimuli and the ability to resist gravity. Paucity of movement signals the likely presence of concomitant weakness. If limb weakness is present, localization of the weakness to the proximal or distal extremities should be attempted. Older children may present with talipes planus, pronation at the ankles, and genu recurvatum.
The pectus excavatum deformity and a bell-shaped chest indicate relative weakness of intercostal muscles compared to better-preserved strength of the diaphragm during respiratory efforts. Skeletal deformities and fixed contractures are often present in congenital myotonic dystrophy and some congenital myopathies. Fixed contractures of the limbs may signal the presence of arthrogryposis multiplex congenita, which may result from dysfunction at a number of lower motor neuron unit sites [ Lebenthal et al., 1970 ; Yuill and Lynch, 1974 ] (see Chapter 88 ).
Fasciculations of limb muscles are difficult to observe in infants because of abundant subcutaneous tissue. However, the experienced examiner can usually palpate the underlying muscle beneath the fat and estimate the adequacy of muscle bulk.
Deep tendon reflexes should always be elicited at all ages. The triceps reflex may be difficult to elicit in preterm and term newborns; reflexes are variably present at the biceps, easier to obtain at the pectoralis, and usually present at the patellar and Achilles tendons.
Acute onset of progressive, profound weakness and hypotonia in previously normal infants suggests the possibility of infantile botulism [ Infant botulism, 2003 ; Kao et al., 1976 ; Pickett et al., 1976 ; Ravid et al., 2000 ; Thompson et al., 1980 ]. There is almost always accompanying constipation, poor feeding, and bulbar involvement.
In addition to most of the previously mentioned characteristics, hypotonia in the ambulatory child may manifest with a waddling gait, genu recurvatum, and talipes planus. There may be pronation of the feet at the ankles. The presence of scoliosis suggests associated weakness and neuromuscular disease.
Weakness is often readily diagnosed in the infant and younger child by observation; in the older child, more formal and discrete muscle testing is possible, as described in Chapter 2 . Examination also includes deep tendon reflexes, plantar reflexes, myotonic response to percussion and scrutiny of muscles for evidence of fasciculations.
When the lower motor unit is involved, the deep tendon reflexes range from hypoactive to absent. The reflexes are uniformly absent in infantile spinal muscular atrophy [ Bundey and Lovelace, 1975 ; Smith and Swaiman, 1983 ]. Reflexes tend to be increased or normal when the upper motor unit is involved, but may be decreased in the case of acute injury or concomitant involvement of the basal ganglia or their output tracts.
Further neurologic examination is necessary and should include the search for fasciculations, ptosis, squint, myotonia, and extensor plantar reflexes. The presence of squint or ptosis suggests the possibility of congenital myopathies [ Clancy et al., 1980 ; McComb et al., 1979 ; Riggs et al., 2003 ], myotonic dystrophy, myasthenia gravis [ Holmes et al., 1980 ; Namba et al., 1970 ], or mitochondrial myopathies (see Chapters 37 and 93 ). Knowledge about the congenital myopathies has grown considerably during the past decade, and the clinical and genetic complexities have become increasingly evident [ Bruno and Minetti, 2004 ; Kirschner and Bonnemann, 2004 ].
Specific laboratory studies may be essential in establishing the diagnosis. When lower motor unit diseases are considered, serum enzyme determinations, nerve conduction velocities, electromyography, and nerve or muscle biopsies may be of importance. However, there is increasing reliance for specific diagnosis on genetic analysis, which has been replacing the need for biopsy in cases where the clinical phenotype and other laboratory evidence are convergent. When upper motor unit diseases are involved, a careful history, electroencephalography, evoked potentials, brain imaging, specific endocrine evaluations, and specific enzyme determinations may be required.

Diagnosis
For didactic purposes and simplification, the motor pathway from the motor neuron in the motor strip to the skeletal muscle fiber can be divided into upper and lower motor neuron units. The upper motor neuron (unit) includes the pyramidal neuron in the motor cortex and the myelinated nerve fiber, which traverses the corticospinal tract and eventually terminates in the internuncial pool in the spinal cord adjacent to the anterior horn cell. The lower motor neuron (unit) consists of the anterior horn cell, peripheral nerve, neuromuscular junction, and muscle. Disorders affecting muscular tone are divided into upper and lower motor unit disorders. Combined disorders also occur. It cannot be overstressed that upper motor unit disease may result in increased or diminished muscle tone in infants and young children.
It is important to distinguish whether hypotonia is derived from a central or peripheral etiology. While there can be difficulty in distinguishing the localization, one study examined sensitivity and specificity of findings predictive of primary neuromuscular disorders. These included a history of reduced fetal movements with polyhydramnios, significant impairment or absence of antigravity movements, and presence of contractures [ Vasta et al., 2005 ]. Congenital hypotonia may be extremely difficult to categorize; however, certain characteristics may prove helpful in diagnosis ( Table 5-1 ) [ Harris, 2008 ].
Table 5-1 Differentiation of Central versus Peripheral Causes of Congenital Hypotonia Characteristic Central Peripheral Weakness Mild to moderate Significant (“paralytic”) Deep tendon reflexes Decreased or increased Absent Placing reaction Sluggish Absent Motor delays Yes Yes Antigravity movements in prone and supine Some (less than normal) Often absent Pull to sit Head lag (more than normal) Marked head lag Cognition/affect Delayed Typical Ability to “build up” tone, e.g., tapping under knees with infant in supine to assist him/her in holding hips in adduction Yes No
(From Harris S. Congenital hypotonia. Dev Med Child Neurol 2008; 50:889.)
Functional impairment of the lower motor unit causes hypotonia and weakness. Hyporeflexia, fasciculations, and muscle atrophy also result. Certain conditions (e.g., Krabbe’s disease) cause combined upper and lower motor unit impairment and produce initial hypotonia.
Inadequate brain control of the motor pathways, or central hypotonia, is the most common cause of decreased tone. The presence of normoactive or brisk deep tendon reflexes suggests that the child is probably not suffering from lower motor unit impairment. The examiner should be alert for other signs of brain dysfunction, such as lethargy, unresponsiveness to the environment (i.e., visual and auditory stimuli), lack of development of social skills in the early months of life, and delayed development of language and reasoning skills in older children.
Diseases of the upper motor unit may be classified according to pathophysiologic cause (i.e., metabolic, degenerative, traumatic, congenital-structural, infectious, or toxic). A similar classification may be used for lower motor unit diseases; such diseases also may be categorized by the anatomic site of involvement.
A number of specific diseases can be suggested by historic and physical findings. Marked arching of the back and irritability suggest Krabbe’s disease. Profound hypotonia with obesity, small male genitalia, and poor feeding in the neonatal period suggests Prader–Willi syndrome.
Down syndrome is often evident on clinical grounds alone, although confirmatory chromosomal analysis is necessary. Visceromegaly, particularly hepatomegaly, is found with some diseases associated with hypotonia, including Niemann–Pick disease and cerebrohepatorenal syndrome. Blindness, seizure activity, and hyperacusis in the older infant or toddler suggest Tay–Sachs disease. Marked muscle underdevelopment and flexion contractures are characteristic of arthrogryposis multiplex congenita.
The presence of hypothyroidism is suggested by decreased length and weight, large tongue, and developmental delay. Some conditions associated with hypotonia are listed in Box 5-1 and are discussed in detail elsewhere in this book.

Box 5-1 Selected Conditions Associated with Hypotonia

Adrenoleukodystrophy (neonatal)
Cerebellothalamospinal degeneration
Fukuyama’s muscular dystrophy and encephalopathy
Infantile neuroaxonal dystrophy
Krabbe’s disease (globoid cell leukodystrophy)
Metachromatic leukodystrophy
Zellweger’s syndrome

Upper Motor Unit Disease (Central Nervous System Diseases)

Acute cerebral insult
Cerebrovascular accident (e.g., hemorrhage, thrombosis, embolism)
Hypoxic-ischemic encephalopathy
Infection (e.g., viral, bacterial, fungal, parasitic)
Chromosomal abnormality
Angelman’s syndrome
Down syndrome
Prader–Willi syndrome
Congenital motor disease (cerebral palsy)
Ataxia
Atonic diplegia or paraplegia (periventricular leukomalacia)
Incontinentia pigmenti
Metabolic disease
Carnitine deficiency
Cytochrome c oxidase deficiency
Fucosidosis
Gangliosidosis (GM1)
Hyperammonemia
Hypercalcemia
Hyperglycinemia
Hyperlysinemia
Mannosidosis
Niemann–Pick disease
Oculocerebrorenal syndrome (Lowe’s syndrome)
Organic acidemias
Renal tubular acidosis
Tay–Sachs disease (and other GM2 gangliosidoses)
Toxicity
Bilirubin
Magnesium
Phenobarbital
Phenytoin
Sedative drugs
Trauma
Brain
Cord

Lower Motor Unit (Peripheral Nervous System Diseases)

Arthrogryposis multiplex congenita
Carnitine deficiency
Connective tissue disease, such as Ehlers–Danlos syndrome
Anterior horn cell
Infantile spinal muscular atrophy
Kugelberg–Welander disease
Poliomyelitis
Peripheral nerve
Familial dysautonomia
Guillain–Barré syndrome
Hereditary motor-sensory neuropathies
Polyneuropathy
Neuromuscular junction
Botulism
Myasthenia gravis
Myasthenic syndrome
Neonatal myasthenia gravis (immune- and nonimmune-mediated forms)
Neonatal transient myasthenia gravis
Muscle
Congenital myopathies (e.g., central core disease, congenital fiber type disproportion, myotubular myopathy, nemaline myopathy)
Glycogen storage disease (e.g., acid maltase deficiency, phosphofructose kinase deficiency, phosphorylase deficiency)
Hypothyroidism
Myotonic dystrophy
Polymyositis

Clinical Laboratory Studies
Conventional laboratory studies, such as hemogram, erythrocyte sedimentation rate, urinalysis, and serum electrolyte determinations, are usually not helpful in assessing hypotonia, although creatine kinase and thyroid studies should be performed. Hypothyroidism can be diagnosed from routine thyroid studies. Creatine kinase and other serum muscle enzymes (i.e., enzymes that have escaped the muscle cells and are detectable in serum) are rarely positive in infants with hypotonia, but elevated levels are found in certain congenital muscular dystrophies and mitochondrial myopathies. Some conditions linked to hypotonia require special tests to yield a precise diagnosis. Pertinent portions of this text should be consulted to determine special laboratory testing requirements.
Magnetic resonance imaging (MRI) has replaced computed tomography (CT) as the standard modality for the diagnosis of structural CNS abnormalities. MRI is of particular value in the diagnosis of white matter diseases, including leukodystrophies. Muscle ultrasonography can be helpful to distinguish upper motor from lower motor abnormalities.
Cerebrospinal fluid studies may demonstrate pleocytosis, increased levels of protein, or abnormal proteins, and specific patterns may point to demyelinating conditions or peripheral neuropathy. Assessment for leukocyte enzyme activities associated with certain lipid storage diseases may provide definitive diagnoses for conditions that affect the brain alone, the brain and anterior horn cells, or the brain and peripheral nerves. Some of these conditions affect some non-neural organs.
Some neuromuscular and mitochondrial diseases are associated with cardiomyopathies, and electrocardiography or echocardiography may be of assistance in establishing a diagnosis. Electromyography differentiates neurogenic from myopathic conditions, and should inspire more intense considerations of some diagnostic categories. Studies in infants and young children require patience and experience for optimal studies and interpretation. The conventional assessment of insertion potentials and potentials at rest and during movement is as essential in infants as it is in older children and adults.
The diagnosis of peripheral neuropathy, particularly in conditions that involve the central and peripheral nervous systems, may be readily overlooked without the determination of nerve conduction velocities. Normative data are available for all age groups [ Gamstorp, 1963 ].
The value of muscle biopsy is well established in the diagnosis of neuromuscular conditions and is discussed elsewhere in this book. It is essential that individuals specially trained and experienced in these endeavors are involved in all aspects of muscle biopsy from preparation of the specimens to specific light and ultramicroscopic studies.

Gait Impairment
Gait disturbances in children are often caused by neurologic disease, but it is overly simplistic to attribute all such abnormalities to neurologic dysfunction. Foot deformities are present in 4 percent of neonates, but the natural course of such congenital deformities is favorable, except for clubfoot which often requires surgical repair [ Widhe, 1997 ]. Congenital abnormalities such as hamstring muscle or plantar foot flexor tightness may result in difficulties with posture and back pain [ Jozwiak et al., 1997 ]. Clinical indices are available for the evaluation of gait pathology in children [ Romei et al., 2004 ].
Gait is a demanding, complicated skill that requires integration of many functional components of the nervous system and is the result of a repetitive sequence of limb movements. The walking pendulum mechanism seen in older children and adults is not yet developed when the toddler first learns to walk independently, but by 2 years of age mechanical energy data are already similar to adult patterns [ Ivanenko et al., 2004 ]. Significant changes in plantar pressure of the foot occur during the first year of standing and walking and the age of development of a mature pattern is highly variable [ Bertsch et al., 2004 ]. Sophisticated evaluation of foot kinetics during walking is useful in providing information about gait impairment [ MacWilliams et al., 2003 ]. Development of mature displacement of center of mass of the body during independent walking is a gradual neural process that evolves until the age of 7 years [ Dierick et al., 2004 ]. Optimal gait requires the least expenditure of energy possible. Mechanical energy must be generated and then dissipated in a controlled fashion during each cycle [ Gage et al., 1984 ; Õunpuu et al., 1991 ]. The encumbrance of additional weight can interfere with optimal walking posture; backpack load and walking distance do not affect stride, but a load of above 15 percent of body weight induces a significant increase in trunk inclination [ Hong and Cheung, 2003 ]. During the gait cycle, posture and balance must be maintained, and the feet must clear the ground without scraping. Quantitative gait evaluation is increasingly precise and useful [ Schwartz et al., 2004 ]. When children with pathologic gait characteristics are being compared with normal children, testing should involve patients and normal controls should be tested at the same walking speed [ van der Linden et al., 2002 ].
Gait must be assessed when the patient’s chief complaint focuses on walking or running; however, assessment of gait affords the clinician rapid appraisal of a number of significant nervous system units when patient complaints are other than those relating to gait. Acquired idiopathic gait difficulties may occur with some frequency in children admitted to some children’s hospitals. Some acquired gait disorders have a definite physical cause, and some are idiopathic [ Wassmer et al., 2002 ]. Further data documenting the incidence of these disorders is needed to evaluate their economic and social impact.

Physiologic Considerations
Skills required for standing must be synthesized into the walking procedure. The walking sequence requires that the non–weight-bearing leg moves forward while weight is shifted smoothly from leg to leg. The definitive components of support and forward movement require separate consideration; the rhythm and duration of each phase require monitoring [ Gage and Õunpuu, 1989 ; Paine and Oppe, 1966 ]. Conventionally, the period from one heel–ground contact to the next heel–ground contact of one foot is one gait cycle; walking can be divided into stance and swing phases. The instant from which heel–ground contact occurs until the instant when contact terminates is the stance phase. The stance phase can be divided into four parts: initial contact, loading response, midstance, and terminal stance ( Figure 5-4 and Figure 5-5 ). The period beginning immediately after the toe leaves the ground until the heel contacts the ground is the swing phase (see Figure 5-4 and Figure 5-5 ) [ Burnett and Johnson, 1971a , 1971b ; Norlin et al., 1981 ]. The swing phase can also be divided into four parts: preswing, initial swing, midswing, and terminal swing. Decreased knee flexion during the swing phase (i.e., stiff-knee gait) may be caused by overactivity of the rectus femoris [ Piazza and Delp, 1996 ]. Normally, the stance phase occupies 60 percent of the duration of the cycle, and the swing phase occupies 40 percent.

Fig. 5-4 Schematic representation of various phases of a child walking.
(Adapted from Õunpuu S, Gage JR, Davis RB. Three-dimensional lower extremity joint kinetics in normal pediatric gait. J Pediatr Orthop 1991;11:341.)

Fig. 5-5 Graphic representation of the phases of gait and their duration.
(From Õunpuu S, Gage JR, Davis RB. Three-dimensional lower extremity joint kinetics in normal pediatric gait. J Pediatr Orthop 1991;11:341.)
Elaborate methods for the assessment of phases of gait have been devised [ Burnett and Johnson, 1971a ; Õunpuu et al., 1991 ]. The center of gravity is affected by several factors during ambulation: pelvic rotation, pelvic tilt, knee flexion at midstance, foot and knee mechanics, and lateral displacement of the pelvis [ Saunders et al., 1953 ]. The center of gravity in older children shifts approximately 4.5 cm during the gait cycle. Pelvic rotation and pelvic tilt are usually necessary for development of independent gait [ Burnett and Johnson, 1971a , 1971b ]. Children usually acquire adult patterns of walking within 55 weeks of independent gait being achieved [ Burnett and Johnson, 1971a , 1971b ].
Because walking is such a complex skill, the normal participation of many motor system parts is vital; these include the basal ganglia; sensory cortex; neck proprioceptors; visual receptors; cerebellum; spinal cord motor and sensory tracts, and gray matter masses; peripheral nerves; neuromuscular junctions; and muscles [ Norlin et al., 1981 ; Winter, 1990 ]. The participation of various muscles varies greatly during each portion of the gait cycle ( Figure 5-6 ).

Fig. 5-6 Graphic representation of the involvement of various muscles during the phases of gait.
(From Õunpuu S, Gage JR, Davis RB. Three-dimensional lower extremity joint kinetics in normal pediatric gait. J Pediatr Orthop 1991;11:341.)
Indices have been devised to quantify deviations from normal gait and prove helpful in overall characterization of the patient’s degree of abnormal gait [ Schutte et al., 2000 ; Schwartz and Rozumalski, 2008 ].

Evaluation of the Patient
Neurologic assessment should be directed at a number of target points. It is important to determine whether abnormalities are focal or diffuse. Alterations from normal include abnormal muscle tone, weakness, nystagmus, titubation (involuntary head bobbing), and dysmetria. Extrapyramidal movements associated with basal ganglia dysfunction, including dystonia, chorea, and athetosis, may be evident. Extensor toe signs, usually Babinski’s sign, may also be present. Deep tendon reflexes can be assessed, with particular reference to the patient’s response to the tendon stretch elicited by a reflex hammer and to response asymmetry.
To evaluate gait fully, it is important that the examiner be able to see the entire picture, so the patient should be unencumbered by clothing and is best tested wearing only underwear. The child’s back should be carefully examined with special attention to the lower spine. This area should be searched for lipomas, hair patches, hemangiomas, and dimples, all of which may accompany spine and cord deformities. Café au lait spots may signal the presence of neurofibromatosis.
Scoliosis of the spine should be evaluated systematically. The child should bend at the waist while placing both feet together flat on the floor. The child should bend toward the examiner while the spine is examined. If scoliosis is suspected, the length from the anterior spine of the ilium to the midpoint of each medial malleolus should be measured to ascertain leg length discrepancy. A relatively small degree of scoliosis can result in an abnormal gait.
The hip, knee, and ankle joints should be moved through their entire range of motion, and the presence of contractures determined. Any pain associated with joint movement should be evaluated. In infants, congenital dislocation or subluxation of the hip is often associated with skin fold asymmetry along the medial thigh. This abnormality is best seen posteriorly. Abnormal placement of the head of the femur may result in limited range of motion or, alternatively, spasticity may result in subluxation of the femoral head.
Before the patient’s walk is observed, the Romberg test should be performed. Walking should be assessed while the patient is barefoot and while wearing shoes. Patients who wear braces should be examined with and without braces. The child needs an explanation of the walking procedure, which entails walking down the hallway, turning abruptly, and returning.
The clinician should systematically evaluate the components of the child’s gait and associated movements. Among the important characteristics are symmetry of gait from leg to leg; whether walking occurs on the balls of the feet, flat-footed, or on the heels; and the relative stability of the pelvis.
Associated movements of the arms should be carefully observed. The fingers and hands may flex in association with infolding of the thumbs, indicating possible corticospinal tract dysfunction. The arms should move so that the contralateral arm swings forward synchronously with the swing phase of each leg (see Figure 5-4 ). When the child runs, abnormal arm and hand postures and movements are frequently accentuated. It is important in gait evaluation to measure leg length accurately. Discrepancies of less than 3 percent are not associated with compensatory movements [ Song et al., 1997 ].
An older child should be asked to tandem-walk forward and backward (heel-to-toe); the examiner can facilitate compliance by demonstration. The child should be asked to pivot quickly when changing direction. The backward heel-to-toe walk should also be executed. The child should walk on the toes and reverse direction, remaining on the toes. This process needs to be repeated on the heels. A child who exhibits impaired heel walking may have an Achilles tendon contracture, equinovarus deformity, or foot dorsiflexor weakness.
The clinician should ask the child to circle the examiner, first in one direction and then in the other. If the child has hemispheric cerebellar disease, the child will tend to depart from the circular path toward the examiner or away from the examiner, depending on the side of the lesion.
It is advantageous to have the child climb steps to observe pelvic strength and stamina. Hip girdle strength can be assessed when the child is asked to squat and then stand rapidly. Evidence of hip girdle weakness may also be gained by asking the child to lie down in the supine position and sit up by flexing at the hip.
While the child walks and runs with shoes on, the examiner should listen and observe for evidence of scraping, scuffing, and slapping sounds. As described later, sensory ataxia and steppage gait are associated with “split” sounds.
More precise methods of gait analysis are available. Three-dimensional bilateral kinematic data can be obtained for analysis of the various facets of gait in children. The child is studied from several aspects: sagittal (i.e., the subject is viewed and monitored from the side), coronal (i.e., the subject is viewed and monitored from the front), and transverse (i.e., the subject is viewed and monitored from above). Data are generated from the changes in relationships as measured in angles (degrees) of various skeletal parts during the gait cycle [ Gage, 1991 ; Myers et al., 2004 ; Õunpuu et al., 1991 ; Schwartz et al., 2004 ].
Electromyographic patterns of extrinsic ankle muscles in healthy children between 4 and 11 years old demonstrate the significant effect of walking speed changes but are independent of growth over this age range. This information can also be reduced to and retrieved from a nomograph [ Detrembleur et al., 1997 ].

Differential Diagnosis

Spastic Hemiplegic Gait
Disruption of the corticospinal tract above the medulla results in contralateral abnormal tone, posture, and hemiplegic gait. The ipsilateral side is involved if the lesion occurs below the decussation of fibers in the medulla. Tone is often increased. Posture is characterized by leg extension or slight knee flexion. Hemiplegic gait includes impaired natural swing at the hip and knee with leg circumduction. The pelvis is often tilted upward on the involved side to permit adequate circumduction. With ambulation the leg moves forward and then swings back toward the midline in a circular movement. The heel-walking exercise is impaired as the patient scuffs the lateral sole and the toe of the shoe while dragging the foot. With more severe involvement, the movements are markedly slow and require great effort. Some children with modest spasticity of the knee may assume a position of mild flexion at the knee and hip, keep the foot held in the equinovarus position, and show reduced foot scuffing.
The affected leg bears weight for decidedly less time than the normal leg during ambulation. Involvement of the upper extremity leads to the arm being held in an awkward posture, usually close to the body, flexed at the elbow and wrist, and with a closed fist (i.e., cortical thumb). The expected rhythmic reciprocal swing of the arm with the stance phase of the opposite leg is absent. Dystonia rather than spasticity should be considered if the arm is held behind the plane of the body on a routine basis.
The etiology of hemiplegic gait cannot always be determined, but one should always look for focal brain lesions such as porencephalic cysts, subdural hematomas, cerebral masses, and cerebrovascular accidents.

Spastic Paraplegic Gait
Spastic paraplegia implies bilateral corticospinal tract dysfunction involving both legs out of proportion to upper extremity involvement. Patients with spastic paraplegia often have spasticity with flexion in the hips and knees, and weakness and limitation (or dorsiflexion) of both feet. The resultant posture resembles crouching. Occasionally, a child may manifest extreme spastic extension at the knees. The typical posture of the feet is equinovarus. Adduction of the thighs may cause the knees to brush one another during walking.
Infants may have a scissoring gait in which the legs cross; the highly increased adductor tone forces them into this position. Each step is deliberate, and the walking process painfully slow. Steps are short, and the toes are scuffed with each forward movement. Weight must be deliberately shifted from foot to foot, and the patient’s balance is unstable. This sequence is further complicated by the equinovarus position of the foot and the subsequent weight-bearing on the toes. Examination often reveals no cerebellar findings and no superficial or deep sensory impairment. The expected findings associated with corticospinal tract dysfunction include hyperactive deep tendon reflexes, ankle and knee clonus, extensor toe signs, and ankle contractures with resultant equinovarus positioning.
The most common cause of spastic paraplegia is prematurity with periventricular leukomalacia, but similar findings can result from hemispheric masses, porencephalic cysts, subdural hematomas, postmeningitic and postencephalitic states, and demyelinating diseases.
Toe walking may be the only indication of spastic paraplegia. However, isolated toe walking has a broad differential diagnosis, including spinal cord lesions (e.g., tethered cord syndrome), and can even be an early sign of autism. Sometimes, it is idiopathic, benign, or on a familial basis without relevance to future development. The clinician should establish the presence of other manifestations of upper motor neuron unit dysfunction before attributing pathologic significance to toe walking [ Kelly et al., 1997 ; Volpe, 1997 ].

Cerebellar Gait
The cerebellum serves as a coordinating motor center; optimal functioning requires reception and synthesis of sensory information from the peripheral nerves, posterior columns of the spinal cord, and cortex. An unsteady, wide-based, often lurching gait signifies cerebellar pathway dysfunction. Cerebellar hemispheric lesions result in veering to the ipsilateral side. For example, if a child with a right cerebellar lesion is asked to circle the examiner in a clockwise direction, he will collide with the examiner within a few circles. The cerebellar gait is sometimes similar to the walking pattern of individuals under the influence of drugs or alcohol. Titubation and sometimes truncal bobbing movements may occur in any direction but happen most frequently in the anteroposterior direction. Nystagmus is an inconstant feature.
In order for cerebellar impairment to be better observed, the child should be asked to rise from a chair, walk a straight line, and suddenly reverse direction while walking in a tight circle. The child should be asked to tandem-walk along a straight line to facilitate observation of ataxia. The child should be asked to stand with the feet close together, first with eyes open and then with eyes closed. This is the Romberg test, and the child with cerebellar difficulties will maintain a stable or mildly unsteady stance with eyes open, but sway or fall toward the involved cerebellar hemisphere with eyes closed. The Romberg test is most commonly caused by posterior column dysfunction. Occasionally, the same finding can be replicated by severe peripheral neuropathy.
Compromise of the cerebellar hemisphere is associated with abnormal movement of the ipsilateral limbs. If the anterior lobe of the cerebellum or midline cerebellar structures are compromised, only gait may be involved, without abnormalities of the upper extremities. These abnormalities usually include action tremor with resultant difficulties with fine coordination.
Conditions affecting the cerebellum range from congenital malformations to infections, acute and chronic metabolic diseases, and progressive degenerative disorders. Among these conditions are congenital malformations, inherited cerebellar atrophies, aminoacidurias, mitochondrial diseases, lipid storage diseases, anoxic episodes, demyelinating diseases, posterior fossa tumors, hydrocephalus, and intoxication. Many hereditary cerebellar diseases have been described; these conditions often affect only a small number of pedigrees [ Brown, 1980 ].

Acute Cerebellar Ataxia
The sudden, isolated appearance of ataxia without obvious cause requires systematic evaluation. Although the process is most often benign and self-limiting, the differential diagnosis is broad and includes some serious conditions [ Hayakawa and Katoh, 1995 ; Sunaga et al., 1995 ]. In many cases, the cause is postinfectious, often following an influenza-like syndrome within the preceding few weeks. The patient is usually between 1 and 4 years old with a peak in the second year of life [ Weiss and Carter, 1959 ]. The attacks may be so severe that the patient is bedridden, but more often present with unsteadiness and truncal ataxia. Nystagmus is present in one-half of these children [ Cotton, 1957 ]. Other inconstant features are hypotonia, tremor, and scanning speech. Noncerebellar symptoms may include headaches, photophobia, and lightheadedness.
Lumbar puncture usually includes normal opening pressure, mild pleocytosis and normal glucose and protein, although a slight increase in protein content may be evident after several weeks. Acute cerebellar ataxia has been linked with numerous bacterial and viral infections, including diphtheria, pertussis, typhoid fever, rubella, mumps, varicella, coxsackievirus A9, echovirus 9, and poliomyelitis [ King et al., 1958 ; Mendez-Cashion et al., 1962 ].
Full recovery, even with corticosteroid treatment, may require several months, but some children return to normal within 10 days, even without treatment. If no improvement in the ataxia occurs after several weeks, the clinician should be alert to the possible existence of a serious underlying cause. Approximately 30 percent of children retain a neurologic deficit, including ataxia and speech impairment [ Weiss and Carter, 1959 ]. The differential diagnosis of ataxia is found in Chapter 67 .
The diagnosis of a posterior fossa tumor should be excluded by neuroimaging with MRI. Papilledema is frequently associated with posterior fossa tumors that obstruct spinal fluid flow, but is often not present in intrinsic brainstem gliomas until much later in the disease course. The latter condition is usually associated with cranial nerve dysfunction, particularly the nerves that subserve eye and facial movements.
Ataxia associated with myoclonus may result from a neuroblastoma. The combination of myoclonus and neuroblastoma is known as the myoclonic encephalopathy syndrome, opsoclonus-myoclonus, or “dancing eyes, dancing feet.”
Acute trauma may induce cerebellar edema and subsequent hemorrhage with resultant ataxia. Hartnup’s disease and maple syrup urine disease may cause transient episodic ataxia. Children with absence seizures may appear to be ataxic and this may confound the diagnosis; their episodes of altered awareness, however brief, are a differentiating diagnostic feature.
The clinician must always keep in mind the possibility that ataxia was caused by unintentional poisoning in the young child or, especially in adolescents, the effects of illegal substances and diversion of drugs intended for medical use. Children who accidentally ingest a toxic or medicinal substance are usually too young to provide an accurate history of intake.

Sensory Ataxia
Ataxia results when the hemispheres and cerebellum are deprived of normal sensory input from various portions of the sensory system, including peripheral nerves, posterior roots, posterior columns, or connections leading from the posterior columns to the parietal lobes through the medial lemnisci. The patient experiences marked instability during standing and walking with a wide-based gait. Muscle power remains unaffected. The patient lacks position sense, and avoids obstacles by raising the legs inordinately and stepping sharply downward, the heel striking the ground first (“steppage gait”). A fraction of a second later the toe makes contact and produces the second part of a split sound. The child flexes the body slightly forward, and the gait is marked by variability of stride length. The child often compensates for loss of sensory awareness by looking at the ground during walking.
The child usually has no complaint of sensory abnormality unless ataxia is caused by a global peripheral neuropathy (i.e., one severely affecting all sensory modalities). However, examination will reveal abnormal position and vibratory sense primarily in the lower extremities. Romberg’s sign is positive. Causes for this gait in children include subacute combined degeneration, polyneuritis, demyelinating disease, and Friedreich’s ataxia.

Extrapyramidal Gait
Extrapyramidal gait disturbance is identified by decreased automatic movements, rigidity, and bradykinesia. The patient tilts the trunk and head forward. The arms are flexed at the elbows and wrists, and are held close to the body. The fingers are often extended, unlike the fisting in spastic quadriplegia. Shuffling gait is produced by the inability to lift the feet sufficiently. Steps are short and slow. The patient often leans forward, with a subsequent anterior shift of the center of gravity; this results in propulsion or festinating gait. The child may lose control and fall if the steps become more rapid and the center of gravity shifts unduly forward. This abnormal gait pattern may also be seen when the patient walks backward (retropulsion).
Characteristically, the affected child may have difficulty with the initial step and may take a few short steps or actually hop and shuffle forward before the walking sequence is established. In addition to the gait difficulties, children with extrapyramidal involvement have reduced blinking, are virtually devoid of facial expression (“mask facies”), and seldom fold their arms or cross their legs.
Patients with extrapyramidal gait usually have abnormalities of the structure and/or function of the basal ganglia, such as those seen in Parkinson’s disease, pantothenate kinase 2 deficiency (formerly known as Hallervorden–Spatz) disease, Wilson’s disease, postencephalitic syndromes, and drug toxicity.

Other Dyskinetic Gaits
A number of other movement disorders cause unusual gait patterns. Athetosis, when profound, may be associated with overall stiffness and bizarre body postures. With this condition, the feet may be positioned in plantar flexion, requiring the patient to bear weight on the toes. Inversion and dorsiflexion of the foot occur. After a stride is initiated, the flexed hip is externally rotated, the knee is flexed, and the foot remains in the plantar flexed position. The walk may have an associated dancelike or prancing appearance and may be incorrectly diagnosed as a form of conversion reaction.
This gait pattern is often associated with dystonia, particularly idiopathic torsion dystonia. The arms, hands, wrists, and fingers frequently move in deliberate, writhing movements about the long axis of the limb and then slowly reverse the rotational movement with irregular pace.
Other uncommon gait manifestations may accompany torsion dystonia. The foot may be held in plantar flexion or inversion. During the stationary phase, the leg may be rigid and a shoulder elevated. During the stride, the patient may have lordosis of the trunk, and the pelvis may be tilted forward with resultant partial hip flexion. Flexion of the knees may accompany the dystonia and may intensify as the patient develops dromedary gait. Because this manifestation may fluctuate in intensity, the clinician should be careful not to diagnose a conversion reaction. Children with this condition walk better backward than forward, including during the tandem-walk examination. This pattern of walking better backward than forward also may be found in patients who have quadriceps muscle weakness.
Chorea may also impair proximal hip muscle and trunk muscle action. The result is a rapidly shifting positioning of the trunk and body. The head may also move quickly along, with associated grimacing of the facial muscles, choreiform movements of the trunk and limbs, and irregular breathing patterns and sounds.

Steppage Gait
Weakness of dorsiflexion of the feet and toes, and fixed contracture in plantar flexion result in a steppage gait. The contracture most often accompanies weakness of the peroneal and anterior tibial muscles. To avoid stumbling, the child lifts the foot disproportionately high at the start of each stride. Flexion at the hip and knee is exaggerated, followed by a forward flinging of the foot. The toe precedes the heel or ball of the foot in hitting the ground, emitting the first portion of a split sound. This pattern of ground contact wears away the tips of shoes. The steps are similar to one another and rhythmic. This unusual gait may be isolated to one leg but is more often bilateral.
This condition is most often associated with anterior horn cell disease or peripheral neuropathic involvement in disease processes such as progressive muscular atrophy, poliomyelitis, Charcot–Marie–Tooth disease, and Guillain–Barré syndrome, or with distal myopathy.

Hip Weakness Gait
Severe weakness of the abductors and extensors of the hip leads to a pathologic “waddling” gait caused when the child walks with a marked lordosis of the thoracolumbar spine with a forward center of gravity to compensate for pelvic instability and wide-based gait. The pelvis markedly pivots and rotates sharply from side to side as weight shifts. This unusual movement pattern allows balance to be maintained despite hip muscle weakness. Stability may be further compromised by accompanying equinovarus deformities. These deformities are frequently present in various muscular dystrophies, inflammatory myositis, and childhood-onset spinal muscular atrophy (Kugelberg–Welander disease).

Gait Apraxia
Severe frontal lobe disease can result in gait disturbance despite absence of any direct motor or sensory impairment. Although the child may successfully complete certain simple and automatic movements with the legs, he or she is unable to implement more complex activities, such as tracing a circle with the feet, kicking an object, or attempting to walk in a prescribed pattern. The gait is deliberate. The patient may have difficulty initiating the walking process when already standing, and have further problems with execution of the serial acts of rising, standing, or walking. Other characteristics, such as perseveration of leg movements and rigidity, are often present. A curious phenomenon in which a leg becomes rigid when the limbs are passively manipulated occurs during fluctuating resistance (i.e., gegenhalten). Other frontal lobe manifestations, such as dementia and reappearance of primitive grasp reflexes, rooting, and palmomental reflexes, may be present.

Antalgic Gait (Painful Gait)
Pain can arise from any leg and foot structure, including nails, skin, joints, bone, and muscles. The associated limp is caused by a decreased weight support on the painful leg and increased duration of weight support on the unaffected leg [ Chung, 1974 ]. The examiner may require prolonged observation to determine the precise nature of the limp. The exact limp pattern is determined by the location of the pain [ Hensinger, 1977 ]. Bilateral antalgic gait can be the result of rickets.

Conversion Reaction Gait
Conversion disorders can simulate all types of gait abnormalities from ataxia, hemiplegia, and monoplegia to paraplegia. Children between 10 and 16 years old are most commonly affected. The gait pattern may vary from one moment to the next; this phenomenon should alert the examiner to the possible diagnosis of conversion reaction. Often the clinician will find no associated abnormalities of coordination, tone, or strength when the patient is sitting or lying down.
The gait of a child with conversion reaction may be outrageously intricate and may vary during the course of the examination. Slowness of gait is common in psychogenic gait disorders [ Baik and Lang, 2007 ]. Short periods of normal walking activity may occur at times. Tremulousness of the fingers and hands during standing or walking may be associated findings. Patients with conversion reactions resembling hemiplegia or monoplegia usually drag the foot along the floor or push it ahead, in contradistinction to patients with corticospinal tract difficulty who elevate and circumduct the leg during each step. When both legs are involved, the patient may be bedridden or use crutches. On occasion, the child lurches out of control but does not fall, demonstrating remarkable coordination and strength (astasia-abasia). In patients with a positive Romberg sign, the swaying is often at the hips with a tendency to separate the legs despite instructions to stand with feet together. Patients with conversion reactions usually do not separate their feet. They may have associated rapid random movements of the head, hands, and hips. If the patient falls, there may be a dramatic aspect to the mishap. Despite dramatic unsteadiness, the patient may be able to run or walk backward without difficulty. One caveat: patients with dystonia musculorum deformans may walk backward smoothly, although they have problems with forward ambulation.
Pediatric patients with conversion reaction gait difficulties are almost never malingerers. Rather, they have physical manifestation of underlying psychological disorder and require supportive and empathetic intervention. Reassurance that they will get rapidly better with a very brief course of physical therapy can often allow them to return to a normal gait; this is more effective than confronting the patient and family with a diagnosis that appears to trivialize their pain and fear. Even if the gait abnormalities resolve completely, patients and parents must receive experienced and measured professional therapy and counseling.

References
The complete list of references for this chapter is available online at www.expertconsult.com .
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Chapter 6 Vision Loss

Douglas R. Fredrick
In children, the complaint of blurred vision or vision loss is often nonspecific and may be difficult to elicit. Although most causes of vision loss in children result from ocular problems, neurologic disorders may have vision loss as a characteristic and early-manifesting feature [ Thompson and Kaufman, 2003 ]. The ability to determine the cause of vision loss frequently aids in the diagnosis of the underlying neurologic disorder, may help determine prognosis, and can be used to monitor treatment efficacy. A thorough understanding of the anatomy of the visual system, the normal stages of visual development in children, and the signs and symptoms of visual dysfunction in children can greatly aid clinicians in evaluating children with vision loss.

Visual Development
Of all the sensory systems, the visual system is perhaps the most immature at birth. It is structurally incapable of processing sensory stimuli to yield maximum visual acuity, and structural changes must occur in the first months of life if normal vision is to be achieved. Postnatal developmental reorganization of the retina takes place during the first several months of life, with intercellular connections forming between the photoreceptors and inner retinal cells [ Daw, 1994 ; Dubowitz et al., 1983 , 1986 ]. Myelination of the optic radiations through the temporal, parietal, and occipital lobes occurs in the first year of life [ Barkovich et al., 1992 ]. The most dramatic structural reorganization occurs in the striate cortex, where cortical cells responsible for the first stages of visual processing require normal focused visual input to develop in the correct orientation and to achieve maximum visual acuity. As described by Hubel and Wiesel [1962] , visual deprivation causes abnormal formation of the striate cortical cells and leads to amblyopia. For vision to develop normally, all of the anatomic components of the visual system must be properly formed during development. The sensory neurologic end organ for processing vision is the eye itself. The focusing components of the eye must be developing normally, with clear corneas, crystalline lenses, and optically transparent vitreous media. Properly focused light energy is converted to electrical signals in the photoreceptors that transmit this electrical information through a complex series of interactions through multiple layers of the retina to the ganglion cells, which send projections through the superficial layers of the retina to the optic nerve, finally synapsing in the lateral geniculate nucleus. At the level of the lateral geniculate nucleus, the first levels of cortical processing and organization take place. From the lateral geniculate nucleus, axons project along the optic radiations through the parietal and temporal lobes to synapse in the striate cortex of the occipital lobe. Visual processing occurs in multiple locations in the occipital and temporal lobes in areas labeled V1–V5 [ Amedi et al., 2003 ]. Processing of information from these centers occurs in visual association cortical centers, linking vision with speech, cognition, and more complex, higher cortical functions. A structurally intact neurologic substrate must receive properly focused visual information consistently over the first several years of life if normal, maximal visual acuity is to be achieved [ Boothe et al., 1985 ].

Assessment and Quantification of Visual Acuity

Vision Assessment in Infancy
At term, healthy infants display a wide range of visual behaviors, with some infants lying awake and alert and tracking faces from the first day of life, whereas others are seemingly disinterested in their visual world for the first several weeks. Several diagnostic methods can be used to determine whether an infant can see. Most infants can visually fix on a face and follow by 2 months of age. It is possible to assess vision before this time in the office with no special tools or techniques. The most important requisite for assessing visual acuity is that the infant is fully awake. A sleepy infant or one who has just eaten often cannot easily be aroused, no matter what maneuver the clinician undertakes.
For infants, light is usually an aversive stimulus, and turning on the lights or shining a light in the eye causes the infant to wince. This response is an indication that the child is experiencing some light stimuli. When infants have their eyes closed in a lighted room, they often open the eyes widely when the lights are turned off, almost in a startled fashion. This action allows the clinician to know that the infant at least can perceive light. The best stimulus to elicit visual behavior is the face of a parent or caretaker. Positional changes can also be used to the examiner’s advantage, because an infant who keeps his or her eyes closed often opens the eyes when held in the supine position and rotated gently about the observer. Another method is to grasp the infant under the arms and lift her or him above the observer’s head. The infant reflexively opens the eyes, allowing the observer to attract the infant’s attention. A third method is to start with an auditory cue to get the infant’s attention. The infant is held still while the face is moved backward and forward with the auditory cue. Once the infant attends to the observer’s face, the observer becomes silent but continues to move the face to see if the infant fixes and follows. Brightly colored toys that also have an auditory cue are helpful in determining fixation behavior. Mylar materials are especially attractive to infants and are easily transportable. As most infants fix and follow by 2 months of age, those who do not should be referred to an ophthalmologist.
Although fixation behavior allows the clinician to determine whether the infant can see, it does not quantify visual acuity. Two techniques have been devised for this purpose. They are used clinically and for research purposes, and have allowed estimation of visual acuity in visually immature infants [ Droste et al., 1991 ; Fulton et al., 1981 ]. The visual-evoked potential is an electrophysiologic test in which visual stimuli are presented to an alert and focused infant, and the cortical response to the visual stimulus is measured in a repeatable and quantifiable fashion [ Iinuma et al., 1997 ] (see Chapter 12 ). Typically, the infant is placed in front of a computer monitor at a close distance and presented with a visually interesting pattern. The pattern may be an alternating checkerboard, or horizontally or vertically aligned black and white stripes [ McCulloch and Taylor, 1992 ; Sokol et al., 1983 ]. The size of the stripes or checkerboard is described as cycles per degree or cycles per centimeter, which can be correlated to standard methods of visual or decimal visual acuity. Large targets are initially used to confirm that a cortical signal is recorded by occipitally placed scalp electrodes. The stimulus pattern is then slowly decreased in size until a recordable response can no longer be elicited. The limit of visual acuity is estimated when there is no longer a recordable electrical response to a viewed visual stimulus. The prerequisite for successfully completing this test is a child who is awake and paying attention to the monitor. As a child who looks elsewhere will not give an appropriate response, the examination must be performed quickly by a trained tester who is skilled at attracting the attention of young infants and maintaining their fixation [ Good, 2001 ; Iinuma et al., 1997 ].
A second test used to quantify visual acuity is the forced-choice preferential looking test (PLT) [ Mayer and Fulton, 1985 ]. Instead of using a cortically recorded electrical response, visual stimuli are presented and the child’s ability to see is determined by the ability to move the eyes toward the visual stimulus. Vertically or horizontally aligned black and white stripes are presented to the child on a test card. One side of the card has the stimulus; the other side of the card has a homogeneous gray background ( Figure 6-1A ). The infant is directed toward the test card in an apparatus where other visual stimuli are blocked from the infant’s view. When given a choice between a pattern background and a homogeneous background, infants instinctively are interested in the pattern background and make an eye movement or saccade toward the black and white stripes. An observer who is watching through a peephole in the middle of the card records in a masked fashion whether he or she sees the infant make the saccade. When the observer reliably identifies the eye movements, the card is removed, and the procedure repeated with test cards using smaller stimuli to quantify visual acuity. Limitations of this test include the need for an infant who is not irritable, a trained observer, and the appropriate apparatus (see Figure 6-1B ) [ Lewis and Maurer, 1986 ].

Fig. 6-1 Vision assessment in infancy.
A, Forced-choice preferential looking test (PLT) card. One side of the card contains high-contrast black and white stripes of specific spatial frequency, and the other side has a homogeneous gray background. B, Apparatus for PLT vision assessment. The examiner sits on one side of the screen, presents the test card to the child, and observes to see if the child makes a saccadic eye movement toward the stripes.
Both techniques have been validated in older children and are reliable and accurate methods to assess visual acuity. Using these techniques, it can be estimated that a neonate’s visual acuity is approximately 20/2000. By 2 months of age, acuity has improved to 20/200, and by 1 year of age, it is approximately 20/60. By 4 years of age, infants should see 20/25. At this age, more reliable tests of visual acuity can be used.

Vision Assessment in Children
Once a child becomes verbal but is still preliterate, matching tests can be used to quantify visual acuity ( Figure 6-2 ). In the past, the tumbling E has been used; the examiner asks the child to show the direction of the letter E as it is presented in numerous different positions. This test requires some visual spatial integration and visual spatial perception, which some children find difficult, and so may give falsely low estimates of visual acuity. These tests have been replaced by matching games such as HOTV cards and child recognition symbols or Lea symbols that ask a child to match test optotypes that are presented in progressively smaller sizes (see Figure 6-2 ). These tests have been validated and are consistent with Snellen visual acuity, which is the gold standard for measurement of visual acuity in children and adults. Snellen visual acuity can be recorded in numerous forms using notations such as 20/20, decimal notation, or “logmar” notation, a method of quantification that allows more useful statistical analysis when conducting studies of visual acuity in children and adults.

Fig. 6-2 Vision assessment in children.
A, The tumbling E test card requires the child to be able to point the hand in same direction as the bars of the E. B, The HOTV test card requires the child to point to the appropriate letter on a response card placed on the child’s lap. C, The Allen figures test requires the child to verbalize the name of the object.

Assessment of Color Vision
Assessment of color vision can be useful in determining the cause of vision loss. Optic nerve injury often causes decreased color vision as its first presenting sign, even before distance visual acuity or the size of the visual field has been affected. The most useful tests for this purpose are the Harley–Rand–Ritter (HRR) test plates and the Ishihara color plates. The HRR plates are patterns of colored dots that create shapes that can be identified by preliterate children. The Ishihara color plates use numbers as well as trails of colored dots to assess whether or not a child can detect color. The combination of these techniques can separate those children who simply have red–green color deficiency from those with impaired color vision caused by optic nerve injury.

Assessment of Visual Fields
It is not possible to quantify small visual-field deficits in young children. It is possible to diagnose significant hemianopias in small infants using a two-person examination technique. With this technique, one examiner sits in front of the child, maintaining fixation through use of a toy or verbal stimulus. A second tester stands behind the child and introduces a toy or colored object silently in the periphery of the child’s vision. When the child sees the toy, he or she generates a saccade or a head movement toward the toy. In this fashion, hemianopias can be detected, aiding in the diagnosis of underlying neurologic problems and determining rehabilitation strategies for children with vision impairment associated with neurologic disease. Older patients can be tested with kinetic perimetry using the Goldmann perimeter or tangent screen testing. Using the Goldmann perimeter, the examiner can assure fixation as a test object is brought in from the peripheral visual field. This test is particularly useful for patients who are being monitored for visual-field changes associated with benign intracranial hypertension, low-grade gliomas, or midline tumors that, before treatment, may induce ocular or central nervous system (CNS) injury.

Assessment of Ocular Motility
Assessment of ocular motility allows the examiner to assess function of cranial nerves III, IV, and VI (see Chapters 2 – 4 ). Ductions and versions can be tested using brightly colored toys and objects. It is important to check the child binocularly first before patching the infant’s eye because patching may be distracting and preclude acquiring useful information. Alignment should be checked using the alternate cover test where fixation is maintained and the visual axis of each eye is occluded alternately. Refixation of the eyes during alternate occlusion may indicate the presence of strabismus such as esotropia, exotropia, or hypertropia ( Figure 6-3 ).

Fig. 6-3 Assessment of ocular motility.
A, Esotropia of the left eye causes the corneal light reflex to be temporally displaced. B, Exotropia of the right eye causes the corneal light reflex to be nasally displaced.

Clinical Features Associated with Vision Loss
The three features that must be characterized in assessing vision loss are laterality of vision impairment, temporal nature of vision loss, and associated ocular and neurologic abnormalities. Children with unilateral vision loss are frequently asymptomatic. It is rare for a child to complain of blurred vision in one eye. When a child does realize that there is unilateral decreased visual acuity, it is usually because of the sudden discovery of this problem rather than its sudden onset. A child may develop conjunctivitis or get a foreign body in the “good” eye and only then notice the decreased visual acuity in the affected eye. Mild degrees of vision loss are not usually recognized by the child but are detected by a teacher or health-care provider at the time of a vision-screening examination. The rapidity of onset of the vision loss also depends on whether the loss is unilateral or bilateral; long-standing unilateral vision loss may not be noticed until the unaffected eye is covered. In contrast, bilateral sudden vision impairment, as can occur with compressive or rapidly demyelinating lesions, may be noticed by the child or caretaker immediately. Associated neurologic signs and symptoms often allow the clinician to localize the disease process before neuroimaging and help the neuroradiologist determine the best type of study to perform.
Because symptoms are inconsistently reported, clinicians must be familiar with the physical signs of unilateral vision loss. During the newborn’s physical examination, pediatricians must look for the presence of a red pupillary reflex in each eye. The presence of a white pupil is called leukocoria (i.e., white body), and it is associated with poorly developed vision in one or both affected eyes in the infant ( Figure 6-4 ). The causes of leukocoria are variable, and at a minimum, the condition can cause loss of vision; in more serious situations, leukocoria can be associated with life-threatening conditions such as retinoblastoma. Poor vision in one eye from birth often leads to strabismus that is noticed by the caretaker. Nystagmus is common when there is decreased visual acuity in one or both eyes resulting from a structural anomaly or to a functional deficit preventing visual information from being transmitted from the eye to the cortex [ Good, 2001 ; Hoyt and Fredrick, 1998 ; Jan and Freeman, 1998 ]. A vision screening examination failed because of decreased visual acuity in one eye is one of the most common reasons why children are referred to their pediatrician and ophthalmologist. In an infant, bilateral vision loss is manifested by strabismus or nystagmus and visual inattention with poor fixation after 2 months of age. Older children with mild vision loss are usually asymptomatic and their problems are not detected until vision is screened by their pediatrician or family practitioner. Children who have progressive loss of visual acuity exhibit behaviors such as sitting extremely close to the television, being disinterested in distant objects or activities, and having difficulty with tasks that require fine visual acuity.

Fig. 6-4 Leukocoria in a patient with retinoblastoma.
Attempts should be made to assess the temporal course of the vision loss. When there is unilateral sudden vision loss, it is usually accompanied by a sudden discovery. Bilateral sudden onset of vision loss is usually noticed by the parents when marked behavioral changes occur in their infant or child. Most causes of chronic vision loss are slowly progressive and often noticed, sometimes suddenly, in retrospect. Attempts should be made to elicit the history of the vision loss from parents and siblings, and from other caretakers and teachers who may provide insight as to the course of the vision loss.
Associated ocular features of vision loss are important to confirm. Infants with poor vision often develop nystagmus by 2 months of age. They are visually inattentive and do not fix and follow well by this age, and they frequently manifest strabismus or a “wandering eye.” Older children usually do not complain of vision problems but have strabismus. They often close one eye or squint the eye in different lighting conditions, rub their eyes frequently, and occasionally complain of double vision when strabismus occurs suddenly. Children with significant vision loss have disrupted circadian rhythms and disturbed sleep–wake cycles [ Leger et al., 1999 , 2002 ; Okawa et al., 1987 ; Palm et al., 1997 ]. Other associated neurologic symptoms include headache, nausea, and vomiting. Children with profound vision loss demonstrate stereotyped behaviors such as body rocking, rhythmic head movement, and gazing at their fingers or hands as they are moved rapidly in front of their eyes and face [ Fazzi et al., 1999 ].

Examination of Children with Vision Loss
It is the role of the neurologist or the primary care physician to document decreased visual acuity in children who are suspected of having vision loss or found to have vision loss during a screening examination. Infants should have their visual acuity assessed by their fixation behavior. Extraocular movements should be tested to evaluate cranial nerve function, and pupils should be tested to determine the response to light and presence or absence of an afferent pupillary defect. A direct ophthalmoscope should be used to check for a red reflex, because absence of the red reflex indicates a corneal or lenticular opacity or an intraocular tumor such as retinoblastoma. If the patient has any of these abnormalities, she or he should be seen by an ophthalmologist to assess for structural abnormalities and to recommend additional diagnostic tests. Older children can have their acuity assessed as described earlier. They should have a full motility examination, and an attempt should be made to examine the fundus. The neurologist should feel comfortable using dilating eye drops such as tropicamide (1 percent solution). This procedure facilitates examination of the optic nerve head and macula. Generally, both eyes should be dilated and a detailed note made of the date, time, dose and concentration of dilating agent, and whether one or both eyes were dilated. Parents should be explicitly told that this was done and what to expect regarding the time course of return of the pupillary size and near vision to baseline. Any child with abnormal visual acuity, motility, pupillary reflexes, or retinal examination should be referred to an ophthalmologist for further examination.

Vision Loss in Infants

Clinical Manifestations
Whereas most adults and older children with neurologic disease involving the visual pathways present with alterations in visual acuity or visual function, infants usually have problems resulting from failure of vision to develop normally after birth. Parents are concerned that their children fail to use their vision appropriately or never develop normal visual fixation behaviors. These children have no symptoms because they cannot articulate their complaints, but they manifest many signs that can be useful in diagnosing and localizing the cause of the decreased visual acuity. Signs of decreased visual acuity in an infant include failure to fix and follow an object by 2 months of age or visual inattention manifested by the complaint that the infant looks through the caretaker or indirectly at the caretaker’s face. The infant appears to be more interested in looking at windows or bright lights rather than objects or the caretaker.
Strabismus is another common complaint in children and infants who have poor visual acuity. Strabismus early in life is not rare. Up to 30 percent of infants manifest intermittent deviations in the first 2 months of life, with exotropia occurring more commonly than esotropia [ Nixon et al., 1985 ]. The deviation is usually intermittent and decreases in frequency over the first few months of life. Any child who has a strabismus lasting longer than a few months should be assessed for an underlying ocular anomaly. Constant deviations require close follow-up and early evaluation, particularly when there is constant exodeviation. Whereas infantile esotropia is readily apparent to the parents and quite frightening for them, this condition usually is not associated with an underlying neurologic abnormality. In contrast, constant exotropia should alert the practitioner that an underlying neurologic abnormality exists. If a constant esotropia is not associated with a sixth nerve palsy, it is usually not associated with neurologic problems.
Nystagmus is commonly seen in children who have bilateral structural anomalies, leading to abnormal visual development. Nystagmus rarely exists at birth. At birth, there may be other movements such as ocular flutter, square wave jerks, or saccadic intrusions that are short-lived and become infrequent over time. In contrast, when a child has a structural anomaly such as bilateral optic nerve hypoplasia, lack of visual stimulation of the striate cortex leads to a sensory nystagmus. The amplitude of the nystagmus can be quite large between the ages of 2 and 6 months, with the amplitude decreasing and the frequency increasing with time.
Infants with visual problems also often demonstrate behavioral mannerisms that help suggest the cause of the vision loss [ Brown et al., 1997b ; Good and Hoyt, 1989 ]. Children with retinal dysfunction from congenital dysfunction of the photoreceptors or from retinopathy of prematurity often press their eyes to generate some sort of photic stimulation [ Sonksen and Dale, 2002 ]. Children with cortical visual impairment may demonstrate overlooking behavior, an eccentric fixation, to maximize visual function in the visual fields that are least damaged from the underlying cortical injury. Patients with achromatopsia or congenital glaucoma may be quite photosensitive and demonstrate behaviors to shield their eyes from the light to minimize the dysphoric sensation they receive from visual stimulation.

Differential Diagnosis of Vision Loss in Infants
As with every physical sign and symptom, the history and general physical examination often determine the diagnosis, even before ophthalmologic and neurologic examination. For example, a child who had a traumatic birth with significant hypoxia is at high risk for cortical visual impairment. A child whose parents and grandparents had cataracts at birth must be evaluated for vision loss caused by congenital cataracts. If vision loss is suspected by the pediatrician or family practitioner, the child should be seen by an ophthalmologist before being referred to a neurologist. Most infants with vision loss have underlying ocular anomalies that can be diagnosed and obviate the need for expensive neuroimaging or genetic and metabolic testing. The ophthalmologist can direct the neurologist and geneticist toward the most likely diagnosis to minimize the inconvenience, cost, and morbidity associated with diagnostic evaluation in children with vision loss resulting from neurologic disease.

Structural Anomalies

Retinopathy of prematurity
Retinopathy of prematurity remains a common cause of vision impairment in infants, causing blindness in more than 500 infants each year in the United States. Despite intensive efforts by neonatologists and ophthalmologists to screen and treat the early stages of retinopathy, the disease progresses in some children. These patients develop cicatricial changes in the retina leading to vision impairment [ Pierce and Mukai, 1994 ]. Premature infants who do not develop retinopathy of prematurity are still at risk for cerebral vision impairment due to periventricular leukomalacia [ Jacobson et al., 2009 ].

Congenital cataracts
All infants should be screened for cataracts at birth by their pediatrician or family practitioner. The presence of a clear red reflex makes it unlikely that cataracts are present. An abnormal red reflex should prompt ophthalmologic evaluation to determine the location of the optical opacity.
The causes of congenital cataracts vary throughout the world [ Merin and Crawford, 1971 ]. In developed countries, the most common cause is autosomal-dominant cataracts, for which there is a clear history of congenital cataracts affecting multiple generations. These cataracts usually involve both eyes, with characteristic morphologic features. Infectious cataracts are uncommon in developed countries but are a leading cause of blindness in developing nations [ Bale and Murph, 1992 ]. Immunizations are effective in reducing the incidence of infectious cataracts, but other viral illnesses can cause cataracts, as can other malformations. Metabolic causes of cataracts include galactosemia, with which infants present with poor feeding and failure to thrive, and galactokinase deficiency, with which infants may be quite healthy. These two metabolic disorders can be distinguished by performing enzymatic assays of erythrocytes. Early detection and dietary treatment may prevent the neurologic sequelae of these disorders.
Most developed countries have programs to identify children at risk for cataracts, but screening occasionally fails, and the clinician should be aware of the oil droplet morphology of these refractive types of cataracts. Early recognition and treatment can prevent loss of vision and may result in reversal of early cataracts in patients with galactosemia. Often, cataracts are idiopathic, with no previous family history of cataracts. Other neurometabolic conditions, such as mitochondrial disorders, can be associated with cataracts. Frequently, these are not present at birth but evolve in the first few years [ Marcel, 1998 ; Sher et al., 1979 ]. For this reason, children with a suspected neurometabolic disorder should be followed to determine whether cataracts develop.
Treatment involves prompt recognition, removal of visually significant cataracts, and visual rehabilitation with intraocular lens implantation, extended-wear soft contact lenses, or aphakic spectacles [ Basti et al., 1996 ].

Corneal opacity
Corneal opacities usually are easily detected by pediatricians or parents at birth when a white spot, or leukoma, is detected within the cornea. These opacities are associated with other structural anomalies, such as microphthalmos, or small eye, and anterior segment dysgenesis, which may also be associated with glaucoma or birth trauma ( Figure 6-5 ). These corneal opacities can cause significant vision impairment and are difficult to correct, because the success rate of corneal transplantation is poor in infants.

Fig. 6-5 Corneal edema caused by a forceps injury at the time of delivery.
Embryologically, the cornea and crystalline lens originate from surface ectoderm, and the iris, uvea, and ciliary body arise from neural crest and mesenchymal cells, with all of the structures forming the anterior segment of the eye. When development is abnormal, the condition is called anterior segment dysgenesis, which can be associated with congenital corneal and lens opacities and with glaucoma, all of which can lead to permanent vision impairment in infants. Patients with anterior segment dysgenesis often have other associated dysmorphic features that indicate the presence of a syndrome or sequence that, if unrecognized, can lead to profound morbidity of the affected child. One example of a form of abnormal anterior segment development is the absence or profound hypoplasia of the iris, a condition known as aniridia. Aniridia is associated with abnormal retinal development leading to nystagmus and vision impairment. It may occur in isolation, or it may occur as a feature of a syndrome characterized by Wilms’ tumor, genitourinary abnormalities, and mental retardation (WAGR) that is associated with deletion on the short arm of chromosome 11 (11p13). Anterior segment anomalies involving the cornea, lens, and iris are known as Peters’ anomaly, and if the child also has mental retardation, the diagnosis of Peters’ syndrome is made. Dysgenesis of the iris and peripheral cornea causing glaucoma is called Rieger’s anomaly, and if associated dental, cardiac, and cerebellar abnormalities are present, the term Rieger’s syndrome is used. Collaboration with a medical geneticist is helpful in identifying other dysmorphic features and determining appropriate genetic testing. In developing countries, leading causes of blindness associated with corneal opacities are vitamin A deficiency and measles [ Semba and Bloem, 2004 ].

Ocular coloboma
Coloboma, or absence of tissue, can affect vision profoundly. If the coloboma involves the iris but not deeper tissues, visual acuity can be normal ( Figure 6-6 ). However, when the coloboma involves the central retina, macula, or the optic nerve, vision can be severely impaired [ Apple et al., 1982 ]. Children with bilateral colobomata are at high risk for underlying neurologic problems [ Chestler and France, 1988 ; Russell-Eggitt et al., 1990 ]. Any child with bilateral colobomata should be evaluated for chromosomal trisomies and the CHARGE association (i.e., coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies). Aicardi’s syndrome should be considered in any female with a seizure disorder and ocular colobomata ( Figure 6-7 ). Patients with Aicardi’s syndrome have ectopic gray matter and other CNS malformations; the disorder is X-linked and lethal for males [ Carney et al., 1993 ; Gloor et al., 1989 ]. Coloboma of the optic nerve can also be associated with underlying renal disease, known as the papillorenal syndrome; this diagnosis is made by genetic testing for mutations in the PAX6 gene [ Alur et al., 2010 ].

Fig. 6-6 Ocular coloboma.
A, Coloboma of the iris due to developmental anomalies is usually located inferonasally. B, Coloboma of the choroid and sensory retina can be seen in isolation or as part of a syndrome such as the CHARGE association (i.e., coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies). Vision may be normal if the macula is not involved.

Fig. 6-7 Optic nerve hypoplasia and chorioretinal lacunas seen in patients with Aicardi’s syndrome.

Congenital glaucoma
Congenital glaucoma occurs when the aqueous drainage pathways of the iris form abnormally, leading to increasing intraocular pressure, corneal edema, and optic nerve injury. Most cases of congenital glaucoma are not associated with specific syndromes or underlying neurologic disorders. The exception is Sturge–Weber syndrome, in which vascular anomalies involving the eye lead to increased episcleral venous pressure and glaucoma (see Chapter 40 ). These patients typically have cerebrovascular malformations, epilepsy, and contralateral hemiplegia.

Retinal dysplasia
Structural anomalies of the retina not associated with retinopathy of prematurity can lead to significant vision impairment. These forms of retinal dysplasia are frequently associated with a variety of neurologic malformations. An example is Walker–Warburg syndrome, in which congenital retinal dysplasia is associated with cerebral structural abnormalities such as hydrocephalus, agyria, and occasionally encephalocele (see Chapters 22 – 27 ). Muscle–eye–brain disease is another example of neurologic and retinal dysplasia resulting from abnormal glial development due to defective glycosylation of α-dystroglycan. This results in profound CNS involvement and significant vision loss [ Shenoy et al., 2010 ]. Norrie’s disease is an X-linked condition in which retinal dysplasia is associated with mental retardation and deafness. In this condition, a genetic defect in the gene product norrin leads to abnormal endothelial cell migration and proliferation [ Mintz-Hittner et al., 1996 ].

Optic nerve hypoplasia
Failure of the optic nerves to form properly leads to a small dysfunctional optic nerve [ Siatkowski et al., 1997 ]. In optic nerve hypoplasia, the nerve is small and its morphology abnormal ( Figure 6-8 ). Frequently, there is a double-ring sign; the scleral canal of the optic nerve is present, but the optic nerve tissues comprise only a small portion of the canal, leading to two distinct rings. Children with optic nerve hypoplasia frequently present with nystagmus. Children with optic nerve hypoplasia may have de Morsier’s syndrome, or septo-optic dysplasia, characterized by midline structural defects of the CNS (e.g., absence of the septum pellucidum, agenesis of the corpus callosum) in addition to neuroendocrine dysfunction (see Chapter 97 ). All children with optic nerve hypoplasia should undergo neuroimaging, with particular attention to the septum pellucidum, corpus callosum, and pituitary body [ Brodsky et al., 1990 ]. The presence of an ectopic bright spot places the child at higher risk for neuroendocrine dysfunction. Patients suspected of having septo-optic dysplasia should have their growth and endocrine status monitored closely [ Siatkowski et al., 1997 ; Skarf and Hoyt, 1984 ]. The absence of cerebral developmental anomalies does not mean that endocrine abnormalities will not occur, and children require continued endocrinologic follow-up [ Garcia-Filion, 2008a & b ]. A child may have normal endocrine function early in life and later develop panhypopituitarism. There have been numerous cases of sudden death associated with septo-optic dysplasia, in which affected children develop a febrile illness that leads to rapid decompensation and death due to adrenal insufficiency [ Brodsky et al., 1997 ]. This complication may occur in children who have or have not received corticosteroid therapy. Parents should be advised concerning these potential risks and treat all illnesses seriously.

Fig. 6-8 Optic nerve hypoplasia can be diagnosed by comparing the size of the nerve head with the caliber of the retinal vessels.
The cause of optic nerve hypoplasia is unknown, although there have been numerous case reports of optic nerve hypoplasia occurring in infants exposed prenatally to quinine, LSD, alcohol, and antiepileptic drugs [ Lambert et al., 1987 ]. The condition is usually seen in young mothers and first-born children. Some infants with optic nerve hypoplasia develop moderate visual function, and the clinician should be careful in prognosticating long-term visual function based on the appearance and size of the optic nerve.

Aniridia
Aniridia is a condition in which the iris fails to form completely. There is often a small rim of iris tissue, and children present with large pupils and nystagmus. Aniridia is associated with abnormal formation of the photoreceptors and foveal structure, creating the condition of foveal hypoplasia. Visual acuity is usually in the range of 20/200. Up to 20 percent of patients with aniridia develop glaucoma within the first decade, as well as the early onset of cataracts. A subset of patients with aniridia has an associated 11p13 chromosomal deletion, placing the child at risk for Wilms’ tumor. Patients with aniridia require evaluation by a geneticist and periodic renal ultrasounds to determine whether Wilms’ tumor is present.

Ocular or oculocutaneous albinism
Normal pigment formation is essential for normal ocular development and normal function of the retinal pigment epithelium [ Brodsky et al., 1993 ]. Albinism may involve the eye and skin (oculocutaneous albinism), or only the eye (ocular albinism); both forms are associated with decreased visual acuity. Patients with oculocutaneous albinism are more severely affected, with visual acuity in the 20/200 range, whereas those with ocular albinism have acuity in the range of 20/60 to 20/80. Both conditions manifest with nystagmus early in life. The diagnosis of ocular albinism is made by documenting transillumination defects in the iris during slit-lamp examination. This test can be performed in infants, and it obviates the need for further evaluation. Patients with oculocutaneous albinism should be assessed for systemic disease such as Chediak–Higashi syndrome, which is associated with white blood cell dysfunction and recurrent infections, and Hermansky–Pudlak syndrome, which increases the risk for rheologic abnormalities and clotting disorders [ Carden et al., 1998 ].

Leber’s congenital amaurosis
Leber’s congenital amaurosis is a disorder of the photoreceptors and the retinal pigment epithelium in which photoreceptor function is extinguished [ Babel et al., 1989 ; Brecelj and Steirn-Kranjc, 1999 ; Fulton et al., 1981 ]. Infants present with large-amplitude, slow-frequency, roving nystagmus. They frequently begin to press on their eyes by 2–3 months of age [ Lambert et al., 1997 ; Sullivan et al., 1994 ], and they may have a completely normal ophthalmoscopic examination with normal-appearing optic nerve and retina. The diagnosis is established by electroretinography [ Weleber, 2002 ]. In this test, the electrical amplitude of the retina is measured using a contact lens placed on the eye that is stimulated by bright lights to elicit a cone response and dim lights to stimulate a rod response ( Figure 6-9 ). In congenital amaurosis, both rod and cone responses are extinguished [ al-Salem, 1997 ; Heher et al., 1992 ].

Fig. 6-9 Electroretinogram for a normal child (left) and a child with Leber’s congenital amaurosis (right).
Different light stimuli can be used to localize abnormal function to rods or cones, or both.

Vision Loss Due to Cortical Visual Impairment
In developed countries, decreased vision caused by cortical or cerebral visual impairment is the leading cause of vision impairment in infants [ Blohme and Tornquist, 2000; Gilbert and Awan, 2003 ; Gilbert et al., 1999 ; Huo et al., 1999 ; Mervis et al., 2000 ]. Damage to the visually immature brain impedes normal visual development and leads to lifelong subnormal vision [ Brodsky et al., 2002 ; Hoyt, 2003 ]. The most common causes of cortical visual impairment in developed countries are neonatal encephalopathies [ Casteels et al., 1997 ; Flanagan et al., 2003 ; Lanzi et al., 1998 ] (see Chapter 17 ). The second most common cause of cortical visual impairment is periventricular leukomalacia [ Afshari et al., 2001 ; Hoyt and Fredrick, 1998 ; Huo et al., 1999 ] (see Chapter 19 ). Injury and ischemia lead to damage in the periventricular white matter and frequently affect visual development. The location of periventricular leukomalacia determines the form of cortical visual impairment. Lesions involving the anterior visual pathways (e.g., anterior corpus callosum) frequently result in oculomotor anomalies such as apraxia, saccadic paresis, and strabismus. These infants often have difficulty generating saccades and have poor visual fixation. Visual acuity in affected infants may be good but not useful because of the patient’s inability to move the eyes. Damage to the posterior visual pathways (e.g., parieto-occipital white matter, striate cortex) is usually associated with more severe vision loss, poor acuity, and a poor prognosis for recovery [ Dutton and Jacobson, 2001 ; Hoyt and Fredrick, 1998 ; Jacobson et al., 1998 ; Sonksen and Dale, 2002 ].
Clinical features of cortical visual impairment are those of an infant who fails to develop visual fixation behavior after 2–3 months of age [ Afshari et al., 2001 ]. These children are often neurologically impaired and have delayed motor milestones and abnormal findings for the neurologic examination [ Levtzion-Korach et al., 2000 ; Whiting et al., 1985 ]. Magnetic resonance imaging (MRI) in affected children usually provides evidence of leukoencephalopathy [ Casteels et al., 1997 ]. Infants with cortical visual impairment do not fix or follow, and appear to be visually disinterested in the environment [ Dutton and Jacobson, 2001 ; Good et al., 1994 ]. Often, the first stimulus of interest to the infant is a bright light or shiny object. Patients often keep their eyes elevated, looking upward to see the light in an overhanging light fixture or a window near the infant’s crib. Infants commonly demonstrate off and on visual behavior, during which there are moments of what appears to be normal visual fixation interspersed with longer periods of visual inattention. Infants respond well to high-contrast targets such as black and white toys and large pattern images. Children with profound cortical visual impairment early in infancy can demonstrate a progressive increase in visual function over several years and may become quite visually proficient [ Marcel, 1998 ]. It is important to refer children with cortical visual impairment for low-vision services that can provide sensory stimulation exercises, which improve the visual performance of infants and provide emotional, social, and educational support for parents [ Amedi et al., 2003 ; Ashmead et al., 1998 ; Levtzion-Korach et al., 2000 ; Zihl, 1980 ].

Structural Cerebral Anomalies Causing Cortical Visual Impairment

Hydrocephalus
Ophthalmic signs of hydrocephalus and increased intracranial pressure include the setting sun sign, which describes the infant’s gaze held in a downward fixed position, with the eyelids retracted and the infant unable to elevate the eyes willfully. Because the cranial sutures are not closed, papilledema usually does not occur early in infancy. After the cranial vault is closed, papilledema can occur as with any child with increased intracranial pressure (see Chapter 77 ). Children with hydrocephalus require surgical relief of their obstruction by ventriculostomy or ventriculoperitoneal shunt placement. An ophthalmologic examination should be obtained to document the presence of normal optic nerves or the absence of optic atrophy. Many older children with chronic hydrocephalus present with optic atrophy that precludes future useful information about the presence of intracranial pressure because atrophic optic nerves do not swell and cannot reflect increased intracranial pressure. Other ocular signs of increased intracranial pressure include cranial nerve VI paresis, often manifesting as new-onset esotropia. Some children with hydrocephalus are at risk for superior oblique muscle dysfunction (cranial nerve IV) leading to strabismus, in which the esotropia is worse in upward gaze.

Structural brain anomalies
Children with schizencephaly frequently have decreased visual acuity due to damage to the optic radiations and pathways. Contralateral hemianopias and epilepsy are common clinical manifestations. Visual function in children with large schizencephalic clefts, as well as those with porencephaly or hydrocephalus, may improve despite a very abnormal appearance on neuroimaging once the patient is shunted and the cortex re-expands [ Summers and MacDonald, 1990 ].
There are numerous congenital disorders associated with brain malformations, such as the Walker–Warburg syndrome, Dandy–Walker syndrome, and muscle–eye–brain disease, in which structural brain anomalies (see Chapters 22 – 27 ) are accompanied by decreased visual function due to striate cortex involvement or associated ocular anomalies such as retinal dysplasia [ Liu et al., 2000 ; Yamamoto et al., 2004 ].

Vision loss due to epilepsy
Children with epilepsy frequently have poor visual function. When the seizure disorder results from a structural abnormality, there is often concomitant strabismus, nystagmus, and developmental delay. Patients with seizures may develop visual auras before the seizure (see Chapter 54 ), and functional blindness during the postictal period [ Bauer et al., 1991 ]. Children with frequent seizures throughout the day often have poor visual fixation development. Abnormal electrical activity can interfere with the development of useful vision [ Trevathan et al., 1997 ]. The use of antiepileptic drugs may sedate the child to the point where general development is delayed, and this can affect development of visual acuity [ Remler et al., 1990 ]. Optimizing antiepileptic drug therapy should be encouraged, because visual acuity can markedly improve when seizures are well controlled [ Shahar and Barak, 2003 ]. Certain antiepileptic drugs such as vigabatrin may be associated with specific retinal or ophthalmic abnormalities (see Chapter 59 ).

Delayed visual maturation
Occasionally, a healthy infant older than 2 months is referred because of failure of development of visual fixation behaviors. Results of ophthalmologic and neurologic examinations may be completely normal. Such infants may have the condition of delayed visual maturation, a diagnosis of exclusion in which visual development is delayed but eventually becomes normal. Often, the onset of visual fixation is dramatic and usually occurs by 6 months of age. Three types of delayed visual maturation have been described [ Fielder et al., 1991 ]. In type I, the child is healthy and has normal vision by 1 year of age. In type II, the child has associated neurologic or systemic disease, and in type III, ocular anomalies occur. Most ophthalmologists reserve the diagnosis of delayed visual maturation for children who have the type I form [ Hoyt et al., 1983 ].

Diagnostic Evaluation of Infants with Poor Vision
An infant who fails to develop visual fixation should first be referred to an ophthalmologist [ Kivlin et al., 1990 ]. Examination by an ophthalmologist most often uncovers the causes of decreased vision, which may be due to any of the congenital structural anomalies described previously. If examination findings are completely normal, the next considerations are a neurologic examination and possibly neuroimaging. Certain neurologic signs and symptoms may suggest a specific neurologic diagnosis [ Backhouse et al., 1999 ]. MRI is preferred to computed tomography (CT) for evaluating structural anomalies. Neurometabolic testing should be performed to exclude reversible and potentially treatable inborn errors of metabolism involving carbohydrate or urea cycle metabolism or mitochondrial disorders [ Cooper et al., 2002 ; Goebel, 1995 ; Hansen et al., 1979 ; Santavuori et al., 1993 ]. These conditions are described in detail in various chapters in this textbook.
In an infant with poor visual function but normal neurologic examination results and normal neuroimaging findings, electroretinography may be used to determine the presence of photoreceptor dysfunction. Such patients usually demonstrate signs of retinal disease, including nystagmus and eye-pressing behavior. An electroretinogram is obtained by placement of a contact lens attached to electrodes on the surface of the cornea. Lights are used to stimulate the retina and the electrical responses are recorded. Depending on the light stimulus, determination can be made whether there is rod-related (affecting night vision) or cone-related dysfunction that affects central vision or color, or both (see Figure 6-9 ).
Assessing prognosis of central visual acuity should be done with caution in children. Normative values for electroretinographic latencies in infants vary but changes in the electroretinogram can be recorded serially as children mature.

Vision Loss in Children
The disease processes leading to vision loss in children are quite different from those affecting infants. Children often demonstrate different signs of vision loss and are frequently able to complain of symptoms associated with vision loss, thus aiding in the evaluation and guiding diagnostic strategies.

Symptoms and Signs of Vision Loss
Children with vision loss frequently do not complain about vision loss unless it is bilateral. Children often do not use the term blurred vision, but may say “I can’t see,” “things are fuzzy,” or “things are double.” Signs of vision loss are much more helpful. The first sign of vision loss is squinting behavior. When the child squints and closes the eyelids, the pinhole effect helps focus out-of-focus light. This behavior is common in children with refractive errors. Children also rub their eyes in attempt to clear their vision. Those with acute bilateral loss of vision will sit close to the television or become disinterested in activities occurring at a distance. They may hold objects very close to their faces to see them clearly. Children with new-onset strabismus associated with vision loss frequently close one eye to avoid diplopia. They may be sensitive to sunlight and shield their eyes because bright light may markedly decrease their visual acuity, especially when there is associated retinal dysfunction. Children may also tilt their heads when vision is reduced in one eye [ Nucci and Rosenbaum, 2002 ].

Differential Diagnosis of Vision Loss in Children
Refractive errors are the most common cause of vision loss in children. This form of vision loss is usually detected by a pediatrician who does a vision screening examination in the office, or by the school district that mandates vision checks in kindergarten or first grade. Vision loss may be unilateral or bilateral. Three types of refractive errors can occur. In myopia or nearsightedness, distant images are out of focus, and diverging lenses placed over the eyes allow the patient to see clearly at a distance and at a close range. Hyperopia, or farsightedness, is associated with an optical system that requires constant accommodation, which requires distant and near sight. Hyperopic children frequently complain of fatigue and strain when reading, as their hyperopia requires extra effort for near activities. These children often are prescribed glasses to be used when reading or doing other activities that require near vision. In astigmatism, irregular curvature of the cornea can lead to a decrease in distant and near visual acuity, and spectacles can be helpful for both distances. When vision loss is caused by refractive error, correcting the refractive error yields 20/20 vision in each eye.

Amblyopia
Amblyopia is decreased visual acuity caused by abnormal cortical stimulation of the developing visual system. There are three causes of amblyopia in children. Deprivation amblyopia occurs when an optical visual impediment in the eye prevents focused light from being received on the retina and transmitted to the developing occipital striate cortex. Conditions such as congenital cataract, infantile vitreous hemorrhage, or complete ptosis can lead to deprivation amblyopia. To treat this form of amblyopia, the visual impediment needs to be removed (e.g., cataract surgery in infants), and focused vision is restored. In strabismic amblyopia, a misalignment to the visual axis does not lead to diplopia in young children because the child quickly develops a fixation preference in one eye over the other, leading to amblyopia in the deviated eye. In anisometropia, unequal refractive errors between the two eyes leads to unequal, unfocused visual stimuli from one eye compared with the other, resulting in decreased visual acuity.
Amblyopia is a functional and structural condition wherein an abnormal visual stimulus leads to abnormal development of cortical visual processing cells with smaller cell size and abnormal intercellular connections [ Hubel and Wiesel, 1962 ]. These structural changes are reversible if detected early in life and treated with occlusion therapy. By removing the visual impairment, straightening the eye, or focusing the vision through spectacles, and then patching the unaffected eye to stimulate the immature visual system, amblyopia can be reversed. Whether or not vision can be restored depends on the age of detection. Success in reversing amblyopia lies in the underlying causative factor and the amount of compliance with occlusion therapy. Visual deprivation amblyopia is the most profound and must be reversed within the first few months of age, whereas anisometropic amblyopia can be reversed, even in the second decade of life, with aggressive patching therapy. As a rule, most children with amblyopia should be detected and treated by the age of 6 months for the best visual prognosis.

Ocular Anomalies Causing Vision Loss
In an infant with vision loss, it is helpful to approach the eye systematically from an external to an internal point to evaluate for causes of vision impairment.

Eyelid abnormalities: ptosis
Ptosis can be a cause of vision loss and a localizing sign of underlying impairment. It most commonly occurs as a congenital anomaly of the development of the levator muscle of the upper eyelid. During development, fatty infiltration may occur with abnormal muscle formation. Ptosis may be unilateral or bilateral. It may be so profound that it occludes the visual axis, leading to deprivation amblyopia. The eyelid may rest over the cornea and be associated with significant astigmatism that can lead to anisometropic amblyopia. Other forms of congenital ptosis include congenital third nerve palsy and the congenital fibrosis syndrome, which are associated with abnormalities of all extraocular muscles with very abnormal eye movements. Neurologic causes of ptosis in children include infant botulism, congenital Horner’s syndrome (associated with congenital neuroblastoma), or Marcus Gunn jaw wink syndrome, a synkinesis with eyelid bobbing occurring during masseter muscle function and chewing due to synkinesis of cranial nerves V and III.

Corneal anomalies
Although most corneal anomalies are structural anomalies seen in infants, such as Peters’ syndrome or scleralization of the cornea, acquired corneal dystrophies and degenerations can lead to vision loss. Keratoconus is a condition in which the cornea achieves extreme corneal curvature associated with peripheral corneal thinning. This anomaly is detectable by refractive changes and with slit-lamp examination. Some metabolic diseases manifest with corneal changes leading to vision loss. These include the mucopolysaccharidoses such as Hurler’s syndrome, which is associated with corneal clouding, and Fabry’s disease, which can lead to deposition of material in the cornea, decreasing visual acuity.

Anomalies of the iris
Inflammation of the pigmented tissues of the eyes constitutes a condition called uveitis. The most common cause of uveitis in children is found in conjunction with juvenile rheumatoid arthritis, especially in girls with pauciarticular, antinuclear antibody-positive juvenile rheumatoid arthritis. Up to 70 percent of these children may develop recurring iritis during the course of their disease. This form of iritis usually is not related to visual or ocular symptoms, because inflammation may not cause decreased visual acuity, pain, or redness, signs that are usually present in association with iritis when it occurs in adults. Iritis can cause decreased vision because it may develop in association with glaucoma or cataracts.

Anomalies of the retina
Degenerative diseases of the retina can cause gradual loss of visual acuity and may be extremely difficult to diagnose in young children ( Table 6-1 ). Unlike congenital retinal dysfunction that leads to large-amplitude nystagmus, marked vision impairment, and clear-cut electroretinographic findings, retinal degeneration in older children may be insidious in onset, unaccompanied by significant visual symptoms and with equivocal findings on electroretinography.

Table 6-1 Neurologic Disease Associated with Vision Loss and Retinal Abnormalities
One of the most common causes of visual dysfunction due to retinal dysfunction is Stargardt’s disease [ Weleber et al., 1984 ; Weleber, 2002 ], also known as fundus flavimaculatus. This disease is a degenerative condition of the retinal pigment epithelium leading to photoreceptor dysfunction [Szlyk et al., 1998 ]. There is a defect in flipase (ABCA4), with different mutations causing different presentations [ Weber, 2003 ]. Children present with slowly decreasing visual acuity. There are characteristic changes on funduscopic examination, and diagnostic tests such as fluorescein angiography, visual-field testing, and electroretinography can help confirm the diagnosis ( Figure 6-10 ). Mutations of the gene involved in phototransduction have been identified and characterized in some families with this condition [ Zack et al., 1999 ].

Fig. 6-10 Degenerative retinal disease.
Children with degenerative retinal disease often present with pigmentary changes in the retinal pigment epithelium, such as this granular- and mottled-appearing peripheral retina.

Retinitis pigmentosa
In retinitis pigmentosa, abnormalities of the retinal pigment epithelium can lead to photoreceptor dysfunction and death. Retinitis pigmentosa typically affects rods before affecting cones [ Foxman et al., 1985 ; Heidemann and Beck, 1987 ]. This process leads to initial symptoms of night blindness and constriction of the peripheral visual field, eventually affecting cones and central visual acuity. A typical “bone spicule” pattern of the retinal pigment epithelium is diagnostic. Electrodiagnostic tests, such as electroretinography, may be helpful. Retinitis pigmentosa has been characterized as involving rods or cones, or both. All modes of inheritance patterns have been described, and there may be variations of phenotypic expression within families. Although some investigators feel that vitamin supplementation may delay disease progression, there have been no studies proving any benefit with any treatment intervention for retinitis pigmentosa in children [ Szlyk et al., 1998 ].

Neurometabolic retinal dysfunction
Several neurometabolic disorders have been associated with retinal dysfunction and secondary vision loss [ Collins et al., 1990 ]. In neuronal ceroid lipofuscinosis, abnormal accumulation of neurotoxic products within the retina leads to cell dysfunction and death [ Backhouse et al., 1999 ; Bohra et al., 2000 ; Brown et al., 1993 ; Fulton et al., 1985 ; Spalton et al., 1980 ] (see Chapter 41 ). There are multiple forms of neuronal ceroid lipofuscinosis occurring in different age groups. Characteristic of all forms of neuronal ceroid lipofuscinosis is the development of decreased visual acuity resulting from poor retinal function [ Bohra et al., 2000 ]. Degeneration of the ganglion cell layer results in a typical funduscopic appearance, and ophthalmoscopic examination coupled with electrophysiologic testing can help diagnose these children who present with seizures and progressive dementia [ Cotlier, 1971 ]. Retinal dysfunction occurs in inherited mitochondrial cytopathies such as Kearns–Sayre syndrome, in which a pigmentary retinopathy is associated with decreased visual acuity, external ophthalmoplegia, and cardiac conduction defects. Retinitis is an unusual cause of vision loss in children, but it can occur in patients with cytomegalovirus infection, herpes simplex or zoster infection, cat-scratch disease, and Lyme disease [ Clarke et al., 2001 ; Dreyer et al., 1984 ; Purdy et al., 2003 ]. A history of immune suppression or recent systemic illness also can suggest the appropriate diagnosis.

Optic Nerve Disorders

Papilledema
The presence of increased intracranial pressure leads to edema of the optic nerve (i.e., papilledema). The borders of the optic nerve are indistinct and the vessels are swollen; the nerve itself is elevated, with surrounding hemorrhage or exudates ( Figure 6-11 ). Papilledema in children can be caused by obstruction of the ventricular system, craniosynostosis [ Fishman et al., 1971 ; Stavrou et al., 1997 ], or communicating hydrocephalus. Whereas early papilledema in adults rarely causes visual symptoms, papilledema can be chronic in children, with slow onset and relatively late discovery of disease, and decreased visual acuity can be a presenting complaint. Usually, this does not occur unless the increase in intracranial pressure is rapid and significant in onset or has been of long duration, leading to chronic axonal compression and edema formation in the retina and causing decreased visual acuity or cell death and incipient optic atrophy. For papilledema in children, mandatory neuroimaging should be followed by lumbar puncture [ Brodsky and Glasier, 1995 ]. Papilledema also occurs in children with malignant hypertension, leading to permanent vision loss if not corrected [ Browning et al., 2001 ]. Pseudotumor cerebri or benign intracranial hypertension is not an infrequent cause of papilledema in overweight children [ Baker et al., 1985 , 1989 ]. The diagnosis is made after neuroimaging excludes an obstructive lesion and lumbar puncture reveals increased intracranial pressure and no abnormal cytology. Occasionally, pseudotumor cerebri may be associated with sinovenous thrombosis that can be detected with magnetic resonance venography (MRV). Because many drugs can cause benign intracranial hypertension, the treatment is withdrawal of inciting agents such as tetracycline and its derivatives, and vitamin A analogs. Improvement is also seen with substantial weight loss. Visual dysfunction associated with possible secondary ischemic optic neuropathic changes should prompt consideration for optic nerve sheath fenestration or lumbar or ventriculoperitoneal shunting to relieve pressure to prevent permanent loss of visual acuity [ Brodsky and Rettele, 1998 ].

Fig. 6-11 Severe papilledema in a patient with idiopathic intracranial hypertension.
Notice the swollen and elevated nerve, peripapillary hemorrhage and engorged retinal veins, and blurring of the disc margins.

Pseudopapilledema
In pseudopapilledema, the optic nerve appears to be elevated, but there is a lack of edema surrounding the nerve, which is seen with true papilledema ( Figure 6-12 ). Pseudopapilledema can be seen with optic nerve head drusen. Optic nerve drusen are extracellular deposits of material within the nerve fiber layer that cause a lumpy elevation of the optic nerve. Later in childhood, the material develops a glistening calcific appearance and can be easily detected by autofluorescence angiography or by ultrasonography [ Bec et al., 1984 ; Friedman et al., 1977 ]. In earlier stages of the disease, the bright signal intensity and reflective characteristics are not as evident, making the diagnosis one of exclusion considered only after lumbar puncture and neuroimaging have eliminated more dangerous conditions [ Savage et al., 1985 ]. Pseudopapilledema can also be seen in hyperopia, in which the nerve head may look elevated. The absence of hemorrhages and of blurred disc margins suggests that pseudopapilledema is more likely to be present. Serial examinations and documentation by photography can help differentiate true papilledema from pseudopapilledema [ Mustonen, 1983 ].

Fig. 6-12 Optic disc drusen cause elevation of the optic nerve without obscuration of capillaries at the disc margin.
The circumpapillary light reflex is intact, and there is no venous congestion.

Optic neuritis
Whereas adults with optic neuritis usually present with unilateral disease, bilateral presentation is more common in children [ Kennedy and Carroll, 1960 ]. Children rarely complain of decreased vision in one eye. This phenomenon of failure to detect the unilateral disease may lead to the higher reported incidence of bilaterality and may be artifactual. Optic neuritis in children frequently follows viral illnesses; it is most commonly associated with inflammation and swelling of the optic nerve head, and may be accompanied by vasculitis ( Figure 6-13 ) [ Bar et al., 1990 ; Chrousos et al., 1990 ; Winterkorn, 1990 ]. In children, there is usually edema of the optic nerve associated with loss of vision and an afferent pupillary defect, whereas in adults, most cases of optic neuropathy are retrobulbar with no visible changes on ophthalmoscopy [ Sato et al., 1998 ]. Any demyelinating episode may be the first sign of multiple sclerosis, and the risk of a pediatric patient eventually developing multiple sclerosis varies from 7 to 56 percent [ Bye et al., 1985 ]. Children who have white matter changes on neuroimaging have a higher risk of developing multiple sclerosis and require close observation so that use of interferons may be considered [ Bonhomme et al., 2009 ]. A particular form of optic neuritis that occurs more frequently in children than adults is acute disseminated encephalomyelitis (ADEM), as described in Chapter 72 [ Brodsky and Beck, 1994 ]. This can lead to peripheral neurologic changes, central visual loss, and decreased visual acuity. ADEM is usually responsive to corticosteroid or interferon treatment, but relapses can occur, and patients may be followed with MRI and careful observation of vision, assessment of color vision, and examination of the pupils [ Sato et al., 1998 ]. Neuromyelitis optica, or Devic’s disease, is a rare, but debilitating form of optic neuritis that occurs in association with transverse myelitis; diagnosis is made by serologic detection of aquaporin-4 autoimmunity (NMO-IgG), a test which should be performed on all children with optic neuritis [ McKeon et al., 2008 ].

Fig. 6-13 Frosted angiitis in an immunosuppressed patient with cytomegalovirus retinitis and neuritis.

Optic atrophy
In children, optic atrophy is often not diagnosed until both eyes are affected ( Table 6-2 ). The most worrisome cause of optic atrophy is compressive disease of the optic nerve [ Liu, 2001 ; Varma et al., 2003 ]. Atrophy may occur from increased intracranial pressure due to obstructive intracranial lesions, or from compression of the optic nerve from orbital processes or intrinsic tumors of the optic nerve (e.g., optic nerve gliomas) [ Belgaumi et al., 1997 ; Fletcher et al., 1986 ]. Children with optic atrophy should undergo neuroimaging to establish a specific diagnosis. Neuroimaging will detect sellar lesions, such as pituitary adenoma or histiocytosis, suprasellar masses such as geminoma, and infiltrative hypothalamic/chiasmal gliomas. It is most difficult to formulate therapeutic approaches for this last condition, as treatment – whether by surgery, radiation, or chemotherapy – is unpredictable in outcome and may be associated with significant morbidity [ Opocher et al., 2006 ]. Children with neurofibromatosis type 1 and optic gliomas require close ophthalmic monitoring, as these tumors may demonstrate spontaneous regression, and treatment should only be considered if there is documented progressive loss of visual acuity or peripheral visual field.
Table 6-2 Neurologic Disease Associated with Vision Loss and Optic Atrophy Category Disease or Syndrome Developmental anomalies Optic nerve hypoplasia Septo-optic dysplasia or de Morsier’s syndrome   Prenatal or perinatal ischemia   Infarction   Periventricular leukomalacia   White matter disease of prematurity   Cerebral structural anomalies   Hydrocephalus   Schizencephaly   Walker–Warburg syndrome   Encephalocele   Holoprosencephaly Degenerative disease Leukodystrophies Adrenoleukodystrophy   Krabbe’s leukodystrophy   Pelizaeus–Merzbacher disease   Alexander’s disease   Canavan’s disease   Leigh’s syndrome   Lysosomal disorders   Gangliosidoses GM 1 and GM 2   Mucopolysaccharidoses   Niemann–Pick disease   Ataxias   Friedreich’s ataxia   Charcot–Marie–Tooth disease   Miscellaneous conditions   Neuronal ceroid lipofuscinosis   Wolfram’s syndrome   Zellweger’s syndrome Inflammatory conditions Infectious diseases Collagen–vascular disease   Autoimmune disorders Ischemic conditions Renal disease Sickle cell disease   Moyamoya disease Trauma Direct   Indirect Demyelinating conditions Optic neuritis Acute disseminated encephalomyelopathy   Multiple sclerosis   Leigh’s disease Compressive conditions Pituitary tumor Hypothalamic tumor   Craniopharyngioma   Optic nerve glioma   Optic nerve meningioma   Rhabdomyosarcoma   Papilledema   Idiopathic intracranial hypertension   Craniosynostosis or craniofacial dysostosis Hereditary conditions Kjer’s optic atrophy Leber’s congenital amaurosis   Mitochondrial cytopathy Toxicities Lead   Copper   Streptomycin   Hydroxyquinolones   Methanol   Ethambutol
When neuroimaging fails to demonstrate compressive lesions, hereditary optic atrophy should be considered [ Brown,1990 ; Eliott et al., 1993 ; Vinkler et al., 2003 ]. Kjer’s optic atrophy is transmitted in an autosomal-dominant pattern; it presents with slow onset of visual acuity loss, first in a 20/80 to 20/100 range and then stabilizing in the 20/400 range. Kjer’s optic atrophy has been mapped to OPA1 on chromosome 3 [ Egan and Kerrison, 2003 ]. Wolfram’s disease includes optic atrophy as one of its clinical features (i.e., diabetes insipidus, diabetes mellitus, optic atrophy deafness [DIDMOAD]), and this autosomal-recessive condition maps to WFS1 on chromosome 4p ( Egan and Kerrison, 2003 ). Examination of parents, siblings, and other relatives can be helpful in the diagnosis of hereditary optic neuropathies [ Brown et al., 1997a ; Kline and Glasier, 1979 ]. Neurometabolic diseases may cause optic atrophy and are usually diagnosed by the constellation of neurologic and physical findings associated with the disease [ Huber, 1994 ]. Ischemic optic neuropathy has been described in children with underlying renal insufficiency in which the patient develops sudden changes in blood pressure because of illness or blood loss [ Bates et al., 1999 ; Browning et al., 2001 ; Thomas et al., 2003 ].
When children sustain damage to the CNS prenatally or perinatally, damage to the occipital cortex and radiations can lead to death of the ganglion cells by trans-synaptic degeneration across the lateral geniculate nucleus [ Miller and Newman, 1981 ]. This damage is most commonly seen in preterm infants with periventricular leukomalacia, in which optic atrophy may be accompanied by extensive optic cupping due to death of the ganglion cell. Neuroimaging demonstrates periventricular leukomalacia or other white matter injury, and it can help confirm the diagnosis when suspected because of premature birth or birth accompanied by hypoxic-ischemic encephalopathy [ Uggetti et al., 1997 ].
Toxic optic neuropathies can occur with exposure or ingestion of heavy metals, disorders of mineral metabolism, and poisoning from methanol or medications such as ethambutol (see Chapter 100 ). Another group of disorders that can lead to optic atrophy are the mitochondrial encephalopathies (see Chapter 37 ). Patients with maternally transmitted Leber’s hereditary optic neuropathy present with loss of visual acuity in the second decade of life [ Acaroglu et al., 2001 ; Newman, 1993 ]. This is associated with characteristic unilateral changes in the optic nerve head and telangiectatic changes in the optic nerve head vessels. Bilateral involvement frequently develops within months. There have been numerous genetic polymorphisms described in patients with Leber’s optic atrophy, and molecular DNA testing is available [ Johns et al., 1992 , 1993 ]. Included in this group of disorders is Kearns–Sayre syndrome, mitochondrial encephalomyopathy with lactic acidosis and strokelike syndrome (MELAS) [ Rummelt et al., 1993 ], and myoclonic epilepsy with ragged red fiber disease (MERRF) (see Chapter 37 ).

Cerebral Vision Impairment
Whereas cerebral vision impairment in infants results from ischemic encephalopathy or white matter disease, impairment in older children usually is traumatic in nature [ Billingsley et al., 2002 ]. An ischemic episode such as a near-drowning, meningitis, or stroke can also cause cortical vision impairment. Toxic cortical blindness can be caused by vincristine, cyclosporine, and tacrolimus. Therapy should be discontinued in children receiving these agents to reverse the symptoms [ Jarosz et al., 1997 ; Schouten et al., 2003 ]. Visual acuity can be profoundly affected and show slow, progressive improvement over 1–2 years. The diagnosis is made by a combination of history, neuroimaging, and normal ocular examination findings.

Nystagmus in Infancy
Like the visual system, the ocular motor system is immature at birth. Abnormal eye movement such as ocular flutter, bobbing, saccadic intrusions, or saccadic paresis may be transient in the first few weeks of life, but they usually resolve completely. Nystagmus, or oscillation of the eyes in a stereotypic fashion, is rarely seen at birth but usually develops by 2 months of age. There are three primary causes of nystagmus in infancy, each having different visual consequences and health considerations [ Lambert et al., 1989 ].

Nystagmus Caused by Visual Deprivation
Any condition that causes failure of a formed visual image to be perceived by the striate cortex can lead to bilateral nystagmus ( Table 6-3 ). The most common causes are bilateral congenital cataracts, bilateral optic nerve hypoplasia, aniridia, albinism, and retinal anomalies. When the visual acuity is less than 20/200, nystagmus can be large in amplitude and slow in frequency at birth, but it usually becomes more rapid with a lower amplitude later in life. Depending on interventions to clear the visual axis and improve visual acuity, nystagmus may decrease, and visual acuity may be quite good if the condition is detected and treated early [ Jan et al., 1990 ]. If the structural anomaly is in the optic nerve or in the retina, surgical or optical interventions are usually not helpful in significantly improving visual acuity. The presence of an ocular anomaly usually obviates the need for additional neuroimaging and assessment.
Table 6-3 Causes of Bilateral Infantile Vision Impairment Manifesting with Nystagmus by Age 2 Months Category Cause of Impairment Disorders of corneal clarity Developmental anomalies Peters’ syndrome   Rieger’s syndrome   Sclerocornea   Congenital glaucoma   Forceps birth trauma Crystalline lens opacity Congenital cataract Uveal anomalies Aniridia   Oculocutaneous or ocular albinism Vitreous anomalies Vitreous hemorrhage   Persistent hyperplastic primary vitreous Retinal anomalies Leber’s congenital amaurosis   Achromatopsia or monochromatopsia   Retinopathy of prematurity   Retinal dysplasia   Chorioretinal scarring   Congenital toxoplasmosis   Chorioretinal coloboma Optic nerve anomalies Optic nerve hypoplasia   Optic nerve atrophy   Optic nerve coloboma   Morning glory disc

Nystagmus Due to Cerebral Disease
Brain tumors can cause nystagmus. The nystagmus may be monocular or binocular, and can occur in any pattern. Intracranial lesions can cause abnormal eye movements but are usually accompanied by other neurologic signs and symptoms associated with obstructive hydrocephalus or developmental anomalies. Differentiating children with intracranial pathologies from those with ocular anomalies usually is based on results of the ophthalmic and neurologic examinations. Neuroimaging may be needed to determine whether an underlying neurologic process is causing the patient’s abnormal eye movements.

Congenital Motor Nystagmus
Congenital motor nystagmus is a diagnosis of exclusion. If ocular examination has revealed no abnormality, electroretinography has found normal retinal function, and neuroimaging has demonstrated no abnormal structural or functional anomalies of the brain, the diagnosis of congenital motor nystagmus can be considered. Often, the diagnosis can be made without electrophysiologic testing or neuroimaging. There is frequently a family history of nystagmus occurring in siblings, parents, or grandparents. The nystagmus often is similar to that observed in other family members. It is coarse at onset, with a slow frequency and high amplitude, and becomes more rapid but smaller in magnitude with maturation. Between the ages of 2 and 4 years, children develop good head and neck control that allows the individual to move in certain positions to dampen the frequency and the amplitude of the nystagmus. This condition is called the null point; patients gaze or hold their heads in positions so that the eyes demonstrate minimal movement, which affords them the best visual acuity possible. It is important to explain to parents that children with nystagmus do not experience oscillopsia and that their visual acuity is decreased because they do not process the visual information when the eyes are not aligned toward the object of regard. By placing the eyes in the null point, the amount of time spent not looking at the object of regard decreases, and visual acuity increases. When testing children with nystagmus, it is important to test monocularly and binocularly because occlusion of one eye can greatly increase the amplitude and frequency of nystagmus and result in decreased visual acuity measurements.
Although congenital motor nystagmus is presumed to arise from a neurologic abnormality of fixation, it is not known whether the molecular defect is located in the eye or in the brain. It may be inherited as an autosomal-dominant, autosomal-recessive, or X-linked disease. Congenital motor nystagmus has been linked to Xq26–q27 [ Kerrison et al., 1999 ].

Transient Episodic Vision Loss in Children
To hear a child complain about occasional abnormal vision is not a rare phenomenon. School-age children frequently complain about blurred vision after prolonged distance or near-visual tasks such as reading, taking tests, or taking notes from the white board. These symptoms are usually brief and resolve after a short period of rest. Complaints of more profound transient and episodic visual loss or blindness should make the clinician consider three causes: intracranial hypertension, migraine, and functional vision loss. Increased intracranial pressure can cause transient obscuration of vision, especially when children change position from supine to standing. They may also complain of positive scotoma and “black-out spells.” Migraines in children do not usually manifest as classic migraines but frequently have an atypical presentation with vision loss, frequent episodes of abdominal pain, and absence of headache [ Barlow, 1994 ; Ehyai and Fenichel, 1978 ]. Obtaining a family history of migraines and excluding intracranial pathology are important in establishing this frequently missed diagnosis [ Hockaday, 1979 ; Tomsak and Jergens, 1987 ]. A child may complain about decreased visual acuity but have normal vision without ocular pathology. This form of functional visual loss has a variety of causes and may be difficult to diagnose and detect [ Schwartz and Vahgei, 1998 ]. Children most often complain about bilateral vision loss and initially report visual acuity in the 20/400 range. Their symptoms may be exaggerated, but the children rarely bump into objects when entering a room despite reports of markedly diminished visual acuity. This is a diagnosis of exclusion, and children should be carefully examined, perhaps on repeated occasions, before the diagnosis is made.
The ophthalmologist can use certain techniques to uncover functional visual loss, including placing the child behind the phoropter, and surreptitiously and purposefully blurring the vision using high plus lenses, and then uncovering one eye or the other and monitoring visual acuity as the vision is being cleared. Often, patients with functional vision loss have miraculous improvement of vision when given a pair of glasses with very low refractive power. These children simply want a pair of glasses and are pretending to have poor visual acuity. Other children who are feigning vision loss to seek attention may be more difficult to diagnosis. An inconsistency between near visual acuity and distance visual acuity, the presence of stereovision when tested with polarized lenses, and nonphysiologic visual fields should cause the examiner to suspect functional visual loss [ Mewasingh et al., 2002 ]. Functional visual loss is a diagnosis of exclusion only after the patient has had a thorough ophthalmic examination and more than one measurement of visual acuity. Occasionally, the practitioner must resort to neuroimaging and/or electrophysiologic retinal testing before becoming confident in diagnosing functional vision loss. After the diagnosis is made, supportive reassurance for the child and the family that vision will return and that the child will be able to see usually leads to rapid clearing of the visual “impairment.” Special consideration should be given to children, because there have been numerous cases of sexual abuse occurring in children who present with decreased visual acuity [ Kathol et al., 1983 ].
The vast majority of children with complaints of vision loss have benign refractive conditions that are easily corrected, but the complaint of blurred vision should always be taken seriously by pediatricians and primary care providers, as it can be a harbinger of more serious conditions. In the absence of focal or specific neurologic findings, an examination by an ophthalmologist can often determine the diagnosis and spare the child unnecessary and costly diagnostic interventions, and reserve neurologic consultation for appropriate patients. Knowledge of the common causes of vision loss in children ( Table 6-4 ) will help the neurologist work in a multidisciplinary fashion to assure prompt diagnosis and institution of vision-saving therapies.
Table 6-4 Causes of Vision Loss, Associated Findings, and Diagnostic Recommendations Cause of Vision Loss Associated Findings/Syndrome * Diagnostic Evaluation Leber’s congenital amaurosis Large-amplitude, slow-frequency, roving nystagmus at 2 months of age; eye pressing (oculodigital sign) Electroretinogram for photoreceptor function; renal consultation to rule out Senior’s syndrome Ocular albinism/oculocutaneous albinism Moderate-amplitude nystagmus by 2 months, fair skin, X-linked inheritence; rule out Chediak–Higashi and Hermansky–Pudlak syndromes Slit-lamp examination for iris transillumination defects; examine mother for signs of retinal hypopigmentation Aniridia Nystagmus at 2 months; consider WAGR syndrome Slit-lamp examination shows lack of iris development; obtain genetic consult and urologic consultation to rule out and follow for Wilms’ tumor Achromatopsia High-frequency, low-amplitude nystagmus due to lack of cone photoreceptor development; photophobia Electroretinogram for photoreceptor function Optic nerve coloboma Nystagmus if severe and bilateral, strabismus if unilateral; CHARGE sequence, papillorenal syndrome MRI of brain to rule out encephalocele and other structural anomalies; genetic and renal consultation to rule out other syndromes Optic nerve hypoplasia Nystagmus by 2 months if bilateral, strabismus if unilateral; septo-optic dysplasia/Aicardi’s syndrome; hypoglycemic at birth, signs of panhypopituitarism MRI of brain – look for agenesis of corpus callosum, absence of septum pellucidum, absence or ectopy of pituitary bright spot, gray matter heterotopia in Aicardi’s syndrome Retinopathy of prematurity History of prematurity, oculodigital sign Ophthalmic examination Norrie’s syndrome Nystagmus at 2 months, X-linked, bilateral retinal detachment with cataract Ophthalmic examination; genetic consultation Congenital cataract Nystagmus at 2 months if complete cataract, strabismus if unilateral; stigmata of trisomies; metabolic signs if enzymatic or mitochondrial Ophthalmic examination; if bilateral, consider galatosemia screen, urine amino acids (Lowe’s syndrome), urine for reducing substances, genetic consultation; examine parents to rule out autosomal-dominant cataract; TORCH evaluation Optic neuritis Vision loss, possible pain with eye movements, afferent pupil defect, focal neurologic findings; ADEM, neuromyelitis optica (Devic’s disease), multiple sclerosis, syphilis, Lyme disease, cat-scratch disease, toxin (nutritional, ethambutol, methanol), Leber’s hereditary optic neuropathy Ophthalmic examination, MRI, lumbar puncture with opening pressure, serology and monoclonal bands, infectious disease consultation, genetic evaluation if positive family history; test for Leber’s hereditary optic neuropathy Optic atrophy Vision loss, strabismus, associated focal neurologic findings, endocrine signs/symptoms, deafness, loss of milestones in NCL/neurometabolic disorders/Leigh’s disease; family history Attention to pre- and perinatal history, neuroimaging, genetic consultation, endocrinologic consultation, assess for mitochondrial dysfunction Cerebral visual impairment Vision loss, sterotypic features: off/on, saccadic paresis; history of pre-/perinatal ischemia, intraventricular hemorrhage/prematurity, meningitis, cerebral developmental anomaly, cerebral palsy, seizure disorder Neuroimaging; genetics if no known etiology Refractive errors/amblyopia Often sudden discovery or during screening examination; family history common; nonfocal neurologic examination; refractive errors correct with pinhole Ophthalmic examination Papilledema Vision loss only if chronic or rapid onset, scotoma on change in position, constricted fields, esotropia with abducens paresis, headache, nausea; risk factors for idiopathic intracranial hypertension – obese, female, estrogen use, tetracycline, vitamin A, steroids, growth hormone, cerebral venous thrombosis Ophthalmic examination – loss of spontaneous venous pulsations and edema of optic nerve, MRI and MRV, lumbar puncture with opening pressure
* ADEM, acute disseminated encephalomyelitis; CHARGE, coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies; NCL, neuronal ceroid lipafuscinosis; TORCH, toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus; WAGR, Wilms’ tumor, genitourinary abnormalities, and mental retardation.

References
The complete list of references for this chapter is available online at www.expertconsult.com .
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Chapter 7 Hearing Impairment

Isabelle Rapin, Oranee Sanmaneechai
Hearing problems, frequent in childhood, often go unrecognized. Physicians may not inquire about hearing or routinely screen for hearing impairment. Perhaps they rely on newborn screening, overlooking the fact that it may not have been done; or perhaps a single newborn screening study was done, but progressive hearing loss was missed. Overlooking the significant hearing loss of a young child may result in a lifetime of deleterious consequences [ Furth, 1966 ; Rapin, 1979 ]. The prevalence of conductive impairment resulting from chronic middle ear effusion is high among preschoolers. Its effect on language acquisition and later academic achievement is controversial, but may not be negligible in the face of another medical or social handicap [ Wallace et al., 1996 ; Roberts and Wallace, 1997 ]. Universal neonatal auditory screening places the prevalence of hearing loss at 1.1 (confidence interval [CI] 0.22–3.61) per 1000 [ Mehra et al., 2009 ], with severe to profound loss in at least 1 per 1000 children [ Krahl and O’Donoghue, 2010 ; Fortnum et al., 2001 ]. The prevalence of mild hearing impairment (threshold worse than 20 decibels, the internationally accepted upper limit of normal hearing) in childhood and adolescence is 3.1 percent based on audiometric screening studies, but only 1.9 percent by self-report [ Mehra et al., 2009 ]. Severe hearing loss in infants or toddlers precludes language learning without highly specialized and intensive habilitation and special education, unless the child happens to be the child of deaf parents whose language is sign language. Even today, most severely hearing-impaired children learn the oral and written language of their culture inadequately. The severe informational deprivation these children suffer because of inadequate language skills prevents many from achieving their cognitive and vocational potential. Early cochlear implants, which require intensive training, especially if provided later than toddlerhood, have brightened the picture, but they are not universally available or effective.

Anatomy and Physiology of the Ear and Auditory System
Except for the pinna, the entire ear is encased in the temporal bone. The ear and cranial nerve VIII provide information about two sensory modalities, sound, and the angular acceleration of the head and its position with respect to the vertical plane. Although audition and vestibular function are distinct, the inner ear contains the sensory receptor organs for both of these systems, which share a common blood supply and fluid milieu. Therefore vascular and inflammatory diseases and trauma are likely to be unselective and to affect both systems. Some genetic and biochemical defects affect audition and vestibular function selectively, others not, but the proportion of cases of vestibular impairment associated with hearing loss will remain unknown as long as vestibular function is not tested routinely in children with impaired hearing. The clinical consequences of damage to the vestibule are discussed in Chapter 8 . Many excellent reviews of the anatomy and physiology of the ear are available (e.g., Brodal, 1981 ; Pickles, 1997 ; Alberti and Ruben, 1988 ; Wright, 1997 ).

Embryology and Anatomy

The external ear
The external ear consists of the pinna, external ear canal, and outer surface of the tympanic membrane. Their embryologic origins are the first and second branchial arches and first branchial groove. The external ear begins to develop at about 40 days’ gestation and is completed by the fourth month.

The middle ear
The middle ear or tympanic cavity derives from the first pharyngeal pouch at about the same time. It communicates with the mastoid air cells and, through the eustachian tube, with the nasopharynx. Pressure in the middle ear is equalized with atmospheric pressure whenever the eustachian tube opens during swallowing or yawning. The air-filled middle ear contains the ossicular chain. The eardrum, ossicular chain, and stapes footplate form a complex impedance-matching transformer that amplifies sound energy approximately 22-fold in transferring sound pressure in air from the outer surface of the tympanic membrane to the perilymphatic fluid of the cochlea. Contraction of the tensor tympani muscle, innervated by a branch of the masticator root of cranial nerve V, and especially of the stapedius muscle, innervated by cranial nerve VII, damp loud sound transmission. These muscles contract just before the start of phonation and attenuate the perceived loudness of one’s own voice. The middle ear also contains the chorda tympani, which carries taste and salivary fibers, and travels along the inner surface of the tympanic membrane, the geniculate ganglion, and the facial nerve, which are encased in a bony canal in the wall of the middle ear.

The inner ear
The inner ear comprises two sensory organs encased in a common fluid-filled membranous sac: the 2½ turn coiled cochlea (ventral), and the vestibule (dorsal), made up of the three semicircular canals, utricle, and saccule ( Figure 7-1 ). The inner ear arises from the otic vesicle, the development of which begins at the end of the first month of gestation and is essentially complete in 50 days. It is encased in the otic capsule or bony labyrinth, which is adult-size at birth, lest growth alter frequency tuning of the cochlear basilar membrane. The bony labyrinth contains two separate fluid-filled compartments. The bony outer perilymphatic compartment completely surrounds the inner membranous endolymphatic compartment. The perilymph is a high-sodium plasma ultrafiltrate which, at least in infancy, communicates with the cerebrospinal fluid (CSF) through the cochlear aqueduct (see below). The auditory and vestibular receptors and first-order afferent neurons are located within the endolymphatic compartment. The endolymph is a high-potassium fluid which is maintained at +80 mV relative to the perilymph. Maintenance of this and other cellular ionic gradients is an energy-consuming process dependent on mitochondria, in particular in the highly vascularized, metabolically active stria vascularis of the scala media. These gradients are essential for generating the electrical currents that arise from the bending of the stereocilia on the endolabyrinthine vestibular and cochlear hair cells, and for reversing the ionic fluxes that bending generates. Hearing and vestibular function are dependent on the function of multiple intercellular ionic gap and tight junctions, pumps, and transporters, and on multiple neurotransmitters’ synaptic release, transporters, and receptors. Mouse models of genetic hearing losses are enormously accelerating progress in understanding the cellular and molecular biology and physiology of hearing and hearing loss [ Friedman and Griffith, 2003 ; Frolenkov et al., 2004 ; Belyantseva et al., 2003 ; Petersen et al., 2008 ; Petersen and Willems, 2006 ; Petersen, 2002 ; Dror and Avraham, 2009 ].

Fig. 7-1 The intricate relationship of the semicircular canals, vestibule, and cochlea.
The membranous labyrinth contains endolymph and is separated from the bony labyrinth by perilymph. The ampullae at the terminus of each semicircular canal open into the vestibule. A crista is contained within each ampulla. The superior portion of the vestibule is the utricle. The inferior portion is the saccule. The stapes footplate fits in the oval window of the scala vestibuli. Direction of flow of perilymph is indicated by the arrows.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
In the cochlea, the perilymph-filled scala vestibuli and scala tympani, which communicate at the apex of the cochlea through the helicotrema, surround the scala media, which contains the organ of Corti bathed in the endolymph. The footplate of the stapes is encased in the oval window of the scala vestibuli. The round window of the scala tympani is covered by a compliant membrane that bulges outward into the middle ear cavity whenever the stapes footplate compresses the perilymph. The resultant traveling wave in the perilymph sets off a radial movement of the basilar membrane, starting at the base of the cochlea and ending at the apex. The frequency and intensity of the sound determine which areas of the basilar membrane sustain maximum displacement. High-pitched sounds produce maximum displacement of the basilar membrane near the base of the cochlea, whereas low-pitched sounds do so near the apex.
Both the perilymphatic and endolymphatic compartments have clinically significant intracranial extensions. The perilymphatic space close to the base of the scala tympani is continuous with the subarachnoid space of the posterior fossa through the cochlear aqueduct, patent in neonates but barely detected or obliterated in adults. Patency of the cochlear aqueduct in early life may be a factor in the higher prevalence of purulent endolabyrinthitis – which often results in profound deafness with vestibular impairment [ Merchant and Gopen, 1996 ] – among young children than among adults. In children (and adults) fistulas around or through the stapes footplate may result in gushing of perilymph or even CSF into the middle ear, fluctuating, often progressive hearing loss, or episodic vertigo, and require surgical repair to prevent potential bacterial meningitis [ Reilly, 1989 ; Weber et al., 2003 ]. The endolymphatic space of the vestibule, via the endolymphatic duct encased in the bony vestibular aqueduct of the otic capsule, opens into the endolymphatic sac located within the dura on the dorsal surface of the petrous bone, close to the internal acoustic meatus. Two disorders characterized by an excess of endolymphatic fluid production/pressure result in enlargement of these structures. The better-known is Ménière’s syndrome, notorious in adults but uncommon in children, which is characterized by episodes of severe vertigo and tinnitus and by a fluctuating, later progressive, sensorineural hearing loss. It may respond to diuretics, but if it does not, it may require drainage of the endolabyrinthine sac or other surgical approaches to decompress the endolabyrinthine compartment [ Huang, 2002 ]. The second is Pendred’s syndrome, characterized by deficient transmembrane transport of chloride and iodide anions, causing a severe prelingual hearing loss and adolescent or adult euthyroid goiter. Knockout mice deficient in pendrin have a decreased endolymphatic potential, the pH is lowered, and Ca ++ is increased [ Nakaya et al., 2007 ]. Fetal enlargement of the endolabyrinthic duct and sac can be presumed to be the reason for congenital enlargement of the vestibular aqueduct (EVA) or other malformations of the otic capsule (Mondini malformation) frequent in Pendred syndrome but also seen in other syndromes [ Petersen and Willems, 2006 ; Gonzalez-Garcia et al., 2006 ].
The scala media, in which the organ of Corti resides, is triangular in cross-section, with its apex directed medially toward the modiolus (axis) of the cochlea, to which it is anchored. Its vertical side, mostly lined by the stria vascularis, is apposed to the osseous outer wall of the cochlea ( Figure 7-2 ). The floor of the scala media is formed by the basilar membrane and osseous spiral lamina, which separate the scala media from the scala tympani. The roof of the scala media is formed by Reissner’s membrane, partitioning it from the scala vestibuli. The organ of Corti sits on the basilar membrane, a coiled, mobile, truncated triangular membrane whose stiffer, narrower end is located at the base of the cochlea and whose wider, more pliable end is located at the apex. The organ of Corti consists of a long, orderly, longitudinal file of radial (transverse) rows. Each row is made up of four hair cells surrounded by specialized supporting cells located on either side of the hollow tunnel of Corti. Adjacent rows are stimulated by maxima of the traveling wave and are thus narrowly tuned to particular sound frequencies. Two pillar cells meeting at the apex of the triangular tunnel make up its lateral walls and the basilar membrane its floor; the tunnel is filled by the cortilymph, which has its own ionic composition. Each radial row comprises a single inner hair cell situated on the modiolar side of the tunnel and three efferent outer hair cells. The inner hair cell is the auditory afferent receptor, of which there are about 3500 [ Spoendlin, 1988 ].

Fig. 7-2 Structural components of the organ of Corti.
The flow of the perilymph results in movement of the scala media (cochlear partition), which vibrates around its attachment to the modiolus and osseous spiral lamina. The complex traveling wave in the basilar membrane produces unequal shearing forces on the stereocilia of groups of hair cells, which are the transducers of sound.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)
There are about 12,000 efferent outer hair cells, which receive their inputs from the olivocochlear bundle. Their role is to modulate acoustic reception by the inner hair cells and spiral ganglion cells [ Hunter-Duvar and Harrison, 1988 ]. On its apical surface, each inner hair cell has a straight palissade of some 60 stereocilia, whereas the palissade is arranged in a V shape on each outer hair cell. Three stereocilia of graded length, linked at their tips, make up each “stick” of the palissades, an arrangement that ensures that only the longest cilium of the outer hair cells reaches the gelatinous tectorial membrane attached to the modiolus. Stereocilia contain actin filaments and myosins and other motor molecules [ Dror and Avraham, 2009 ]. The hair cells and supporting cells thus tightly couple movements of the basilar and tectorial membranes, ensuring synchronized bending of the stereocilia in response to the traveling waves induced by sound along the basilar membrane [ Frolenkov et al., 2004 ]. Cell adhesion proteins (cadherins) keep hair cells, cilia, and supporting cells tightly packed, and ionic channels provide fast communication among them. The base of each inner hair cell synapses with the dendrites of about 20 type I spiral ganglion neurons, which number about 30,000, whereas the dendrites of a single smaller type II spiral ganglion neuron contact about 10 outer hair cells. Axons of the efferent olivocochlear bundle divide widely, each synapsing on many outer hair cells; in contrast, they terminate sparingly on the inner hair cells and dendrites of the type I spiral ganglion neurons [ Hunter-Duvar and Harrison, 1988 ]. Glutamate is the main excitatory neurotransmitter between the inner hair cells and ionotropic receptors on the dendrites of type I spiral auditory neurons [ Oestreicher et al., 2002 ]. Olivocochlear synapses of the efferent pathway with the outer hair cells and type II spiral ganglion neurons are mainly inhibitory through the release of gamma-aminobutyric acid (GABA) and dopamine, although its modulation also involves release of acetylcholine and other excitatory neurotransmitters.
The afferent first-order type I auditory neurons constitute the spiral ganglion of Corti located in the modiolus of the cochlea. Both their dendrites and their axons are myelinated. As discussed later, documenting their preserved function and that of their processes is crucial when evaluating a hearing-impaired individual for a cochlear implant because the prosthesis stimulates these neurons, not the hair cells. First-order vestibular neurons form the ganglion of Scarpa, which is located at the base of the internal auditory meatus. The meatus contains the cochlear and vestibular divisions of cranial nerve VIII, the efferent fibers of the inhibitory olivocochlear bundle, the facial nerve VII, chorda tympani, and internal auditory artery and vein.

Central auditory pathway
The axons of the spiral ganglion neurons project to the cochlear nuclei of the medulla. They are of quite uniform caliber, which means that their conduction velocities are uniform, crucial for sound transmission. Axons from the base of the cochlea, which carry high-frequency sounds, project to the ventral cochlear nucleus and ventral portion of the dorsal cochlear nucleus; those from the apex of the cochlea, which carry low-frequency sounds, project to the dorsal portion of the dorsal cochlear nucleus ( Figure 7-3 ). Each spiral ganglion neuron is connected to five different types of neurons in the cochlear nuclei. Most axons of the cochlear nuclei cross the midline, forming the acoustic striae on the floor of the fourth ventricle as they course through the trapezoid body to form the ascending lateral lemniscus. Relays in the central auditory pathway include the cochlear nuclei, superior olivary complex, nucleus of the lateral lemniscus, inferior colliculus, and medial geniculate body of the thalamus where all fibers synapse before reaching the primary and secondary auditory cortices of the superior temporal gyrus. Tremendous multiplication characterizes the auditory pathway of the rhesus monkey, which goes from the 3,500 inner hair cells to 30,000 spiral ganglion neurons and to about 10 million neurons in the medial geniculate body, which projects to both primary (area 41) and secondary (area 42) auditory cortices in the superior temporal gyrus. Neurons of area 41 project to area 42 situated behind it. The secondary auditory areas of the two hemispheres are connected through fibers traveling in the body of the corpus callosum. They are also widely connected to other cortical areas, including frontal and temporoparietal language areas, the cingulate gyrus, and frontolateral cortices.

Fig. 7-3 Peripheral and central auditory pathway, which is both crossed and uncrossed, and projects to the horizontally oriented auditory cortex of the planum temporale.
There are about 300 times more fibers in the central auditory pathway than in cranial nerve VIII, and there are extensive connections between the left and right brainstem relays.
(Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Physiology
The relevant dimensions of sound are intensity, which is expressed in decibels (dB), and frequency, which is measured in cycles per second or Hertz (Hz) [ Katz, 2002 ]. Units of intensity and frequency are logarithmic. The decibel scale displayed on audiograms appears to be linear, but the units themselves are logarithmic. An increase of about 10 dB results approximately in doubling of subjective loudness. Audiometers are calibrated so that audiometric 0 (i.e., normal auditory sensitivity or hearing level, or 0 dB of hearing loss) corresponds to the internationally accepted average threshold of normal hearing at each frequency. The lower limit of normal hearing has been set at 20 dB below audiometric 0 across the frequency range. The ear is most sensitive at about 2000 Hz and very sensitive between 1000 and 4000 Hz, with sensitivity decreasing rapidly below 500 Hz (low frequencies/pitches) and above 4000 Hz (high frequencies/pitches). At the extremes of the audible frequency band, more sound pressure is required to reach threshold than in the middle of the band. Therefore, the sensitivity curve across frequencies of the human ear is U-shaped; for the sake of convenience, this was transformed to a straight line representing mean normal hearing (sound pressure associated with 0 dB of hearing loss). Localization of sound in space is in part mediated by differences in intensity and lag in phase of sounds reaching each of the ears. Processing of sound frequency, intensity, location, onset, and cessation takes place largely in brainstem auditory relays.
The primary role of the pinna is in sound localization. The middle ear acts as a sound amplifier that compensates for loss of sound energy as it is transmitted from air to fluid because of the much greater area of the tympanic membrane compared to that of the oval window, the vibration pattern of the eardrum, and the leverage of the ossicular chain. Sound in air is also transmitted to the cochlea through the skull, but it occurs at threshold intensities that exceed air conduction by 40–60 dB. Bone conduction is important in children with prolonged or frequent middle ear effusions, whose thresholds may be raised up to 40–60 dB at times. Middle ear effusion may be detrimental for language acquisition if associated with other social or medical handicaps [ Wallace et al., 1996 ], but it never renders children profoundly deaf. Bone conduction prostheses are critical for children with anotia, canal atresia, and other malformations of the external and middle ear who may have normally functioning cochleas and can therefore acquire language competently if provided promptly with appropriate bone conduction hearing aids or other prostheses.
The hair cells are the transducers from mechanical energy to sensory stimulation; their action depends on radial and longitudinal displacements of the basilar membrane by sound and on the ionic gradients of the various compartments and cells of the cochlea. The afferent inner hair cells are the sensory receptors for sound. The role of the efferent outer hair cells, which are contractile and tightly coupled to the basilar and tectorial membranes, is to modulate the activity of the inner hair cells and type I spiral ganglion neurons. These receive both excitatory and inhibitory inputs from the olivocochlear bundle. The roles of the outer hair cells are enhancement of sensitivity and frequency selectivity, but also overall damping, depending on olivocochlear inputs. Together with contraction of the middle ear muscles mentioned earlier, the olivocochlear/outer hair cells damp the speaker’s perception of what he/she is saying.
The auditory system is tonotopically selective throughout. The basilar membrane is a highly sensitive and very sharply tuned resonator. Also narrowly tuned, cells in the cochlea and higher relays of the auditory system, including the auditory cortex, respond selectively to certain frequencies and only at much higher intensities or not at all to others. At low sound intensity, each spiral ganglion neuron near the apex of the cochlea follows the periodicity of a particular low-pitched tone, whereas at frequencies greater than 1000 Hz, it is groups of neurons which follow the periodicity of particular high-pitched tones. Tuning is less selective at high sound intensities.
Physiologic tests of hearing, including acoustic immittance and middle ear reflexes, otoacoustic emissions (OAEs), electrocochleography, brainstem auditory-evoked responses/auditory brainstem responses (BAER/ABR), are discussed later in the section on testing.

Classification of Hearing Losses
Multiple overlapping, non-mutually exclusive clinical dimensions are required to define and classify hearing losses. Each clinically derived subtype encompasses multiple etiologies ( Box 7-1 ).

Box 7-1 Likely Causes of Chronic Hearing Loss Classified by Type of Hearing Loss

Conductive Hearing Loss

Acute or chronic otitis media or mastoiditis
Chronic middle ear effusion
Malformation of the external or middle ear
Ossicular ankylosis, necrosis, traumatic disruption
Cholesteatoma or other middle ear mass

Sensorineural (Endocochlear) Hearing Loss

Sensory hearing loss: inner hair cell pathology

Genetic (many types, e.g., connexin 26, Usher’s syndrome)
Cochlear malformation (e.g., Mondini malformation)
Perinatal problems (e.g., anoxia, ototoxicity)
Congenital infection (e.g., rubella, cytomegalovirus)
Endolabyrinthitis, purulent (e.g., meningitis, mastoiditis) or viral
Ototoxic (prenatal or postnatal)
Temporal bone fracture
Sound trauma

Auditory neuropathy: spiral ganglion cell pathology with acoustic nerve degeneration, or primary neuropathy

Genetic (many types, e.g., GJB2 , OPA1 , otoferlin)
Hereditary sensorimotor neuropathies (some subtypes)
Friedreich’s ataxia
Cockayne’s syndrome
Tumor (e.g., acoustic neurinoma in neurofibromatosis type 2, cerebropontine angle tumor)
Kernicterus (neonatal hyperbilirubinemia)

Central Auditory (Retrocochlear) Hearing Loss

Brainstem hearing loss
Kernicterus (neonatal hyperbilirubinemia)
Brainstem glioma, malformation, demyelination
Leukodystrophy (e.g., mitochondrial cytopathy, adrenoleukodystrophy)
Cortical deafness, verbal auditory agnosia
Landau–Kleffner syndrome
Bilateral auditory cortex lesion

Classification of Hearing Loss by Clinical Features

Unilateral Hearing Loss
Most hearing loss is bilateral, although not necessarily equally severe in each ear. Most unilateral loss is conductive. Unilateral loss without anomalies of the pinna or external ear canal may be caused by prenatal viral infections such as rubella and cytomegalovirus, by acquired viral infections like mumps, by complications of mastoiditis or other bacterial infections of the middle ear, or as the result of trauma or neoplasia. Unilateral or asymmetrical malformations, many detectable by imaging, may consist of abnormalities of the ossicular chain or otic capsule, such as Mondini malformations, EVA, and others. They may or may not be associated with vestibular pathology or malformations. Unilateral or grossly asymmetrical hearing loss is rarely genetic.

Conductive Hearing Loss
Conductive hearing loss results from pathologic conditions of the external ear canal, tympanic membrane, or middle ear. As stressed earlier, a purely conductive hearing loss does not exceed 60 dB because the skull conducts sound to the cochlea above that intensity. The most common causes of conductive hearing losses in young children are acute (infectious) and chronic (secretory) otitis media resulting from eustachian tube dysfunction. Chronic middle ear effusion is particularly common in infants with cleft or submucosal cleft palate or midfacial malformations, like that seen in children with Down syndrome. It rarely produces hearing loss in excess of 40 dB. Congenital anomalies of the ear canal and middle ear and trauma account for most other cases of conductive loss.

Sensorineural (Endocochlear) Hearing Loss
Contemporary research has made great progress toward pinning down the biology of hearing loss, but it is also revealing the enormous complexities of the underlying molecular and cellular mechanisms, complexities that jeopardize neat classification based on anatomical criteria. Sensory hearing loss denotes pathology limited to the hair cells without involvement of the spiral ganglion cells. Here we use sensorineural loss synonymously with endocochlear hearing loss to refer to all nonconductive peripheral hearing loss arising from pathology in the organ of Corti, i.e., the hair cells or spiral ganglion cells and their processes. As will be seen, the term “auditory neuropathy” is particularly confusing for neurologists. We use retrocochlear, neural, or central hearing loss for pathology in the central auditory pathway from the brainstem relays to the cortex.
Sensorineural hearing loss may or may not be associated with vestibular dysfunction. Vestibular dysfunction was present in 41 percent of pupils at a Dutch school for the deaf, and was most prevalent in children with thresholds above 90 dB and those with exogenous hearing losses [ Huyghen et al., 1993 ]. It is characteristic of Usher’s syndrome [ Petersen and Willems, 2006 ; Ahmed et al., 2009 ] and of many children deafened by purulent meningitis [ Merchant and Gopen, 1996 ]. It is not clear how much an awareness of the presence or absence of a vestibular deficit would help in the differential diagnosis of congenital hearing loss because vestibular testing is not performed routinely in deaf children.

Sensory hearing loss
This term refers to selective pathology of the inner hair cells, such as their inadequate development, dysfunction, degeneration, or death. Some pathologies may preclude hearing from the start, while others may be progressive; the speed of progression will determine the age at which hearing will become functionally compromised. Many of the consequences of genetic hearing loss (discussed later) are very specific. Some are selective for the cilia, which can be malformed, have impaired motility, be disorganized rather than neatly bundled, or have faulty intercommunication or connections with the tectorial membrane. Ciliated receptor cells of the labyrinth and retinal rods and cones may also be involved by the same mutations, resulting in the three subtypes of Usher’s syndrome [ Friedman and Griffith, 2003 ; Petersen and Willems, 2006 ; Dror and Avraham, 2009 ]. Although most pathologies involve both inner and outer hair cells, a few are selective for the inner hair cells, so that OAE testing of the outer hair cells as the sole screening surrogate for inner hair function can be severely misleading, as was the case in a few premature infants whose temporal bones were examined postmortem [ Amatuzzi et al., 2001 ]. One of many mutations of the GJB2 gene results in lack of the connexin 26 K + gap-junction protein, and is responsible for almost half the cases of profound nonsyndromic recessive prelingual hearing loss. Depending on the amount of connexin 26 protein synthesized, however, some GBJ2 mutations may be selective for the inner hair cells, with resultant absent ABRs but misleadingly preserved OAEs, the pattern audiologists label “auditory neuropathy” (see below). Inadequate synthesis of claudin, an adhesion molecule of intercellular tight junctions, results in a rare recessive deafness due to selective degeneration of the outer hair cells. Some other hearing loss is associated with initially nonlethal malfunction of ionic pumps and channels or neurotransmitter release, or with faulty transporters, receptors, or reuptake at synapses between the hair cells and dendrites of the spiral ganglion cells. For example, there are mutations of genes for collagen which affect the tectorial membrane. In short, as more and more different mutations are being identified that involve not only the hair cells but also other cells and tissues in the organ of Corti, endocochlear hearing loss may be a more accurate term than sensory hearing loss. To complicate matters further, what starts out as a sensory (hair cell) deficit may not remain “pure”. Deafferentation of the spiral ganglion cells may eventually lead to their apoptic death, and vice versa [ Sobkowicz et al., 1999 ]; spiral ganglion neurons receive both afferent (hair cell) and efferent (olivary, outer hair cell) innervation [ Sobkowicz et al., 2004 ]. Trans-synaptic degeneration may not be inevitable in humans [ Teufert et al., 2006 ], although the endstage of long-standing hearing loss is often collapse of the entire organ of Corti and depletion of neuronal cell bodies in the modiolus, including their axons in the eighth nerve, with trans-synaptic degeneration in higher auditory relays [ Rapin et al., 2006 ; Gandolfi et al., 1984 ].

Hearing loss due to pathology in spiral ganglion neurons: “auditory neuropathy”
Dysfunction at the synapse between the inner hair cells and type I spiral ganglion cells may arise from problems with the inner hair cells’ release or reuptake of neurotransmitter, with transporters, or with the glutamate receptors or ion-gated channels of the myelinated dendrites of the spiral ganglion cells. For example, otoferlin deficiency causes profound deafness because of impaired vesicle exocytosis specific to these synapses [ Santarelli et al., 2008 ]. It fulfills audiologic criteria for an audiologic diagnosis of “auditory neuropathy”, i.e., absent ABRs and preserved OAEs, about which two points need to be made. First, this test result alone does not allow a distinction to be made between malfunction of the inner hair cells, type I spiral ganglion neurons, or the synapses between them. Second, hearing loss may be missed if one relies on OAEs without ABRs because OAEs reflect only outer hair cell function. Pathology of spiral ganglion cell soma results in degeneration of both their dendrites and axons, a classic afferent axonal auditory neuropathy with an inexcitable eighth nerve. Compression of the eighth nerve, or a biochemical or autoimmune disorder of myelin affecting both dendrites and axons, will slow and dys-synchronize conduction, with a resultant demyelinating auditory neuropathy. Long-standing axonal and demyelinating neuropathies ultimately become mixed and the nerve becomes inexcitable.
Some axonal and demyelinating auditory neuropathies occur as part of a systemic neuropathy, most often genetic, as hearing loss in acute or chronic autoimmune polyradiculoneuropathy is exceptionally rare. “True” auditory neuropathy may be a feature of some hereditary sensorimotor neuropathies (e.g., Charcot–Marie–Tooth disease) [ Ouvrier et al., 2007 ]; Friedreich’s ataxia, where the neuropathy is the consequence of ganglion cell degeneration [ Lopez-Diaz-de-Leon et al., 2003 ; Spoendlin, 1974 ]; or brain diseases with both a leukodystrophy and demyelinating neuropathy, like Cockayne’s syndrome [ Rapin et al., 2006 ]. “True” auditory neuropathy as an entity with the particular audiologic characteristics described earlier did not come to widespread attention until it was studied systematically in a genetic isolate with a variant of hereditary sensorimotor neuropathy [ Starr et al., 1996 ]. It may be associated with vestibular impairment [ Kaga et al., 1996 ]. Compression of the nerve by a mass in the cerebellopontine angle or internal auditory canal is a well-known and more common cause of conduction block in the auditory nerve in adults; in children, acoustic tumors virtually always signal neurofibromatosis type 2 [ Martuza and Eldridge, 1988 ]. As is well known, acoustic tumors start in the vestibular division of cranial nerve VIII and compress the cochlear division.
Demyelinating auditory neuropathy slows conduction; both axonal and demyelinating neuropathies desynchronize volleys. The result is delay, decreased amplitude, distortion, or abolition of the ABR, and worse speech discrimination than expected from the pure tone threshold, although, admittedly, that threshold can vary widely [ Starr et al., 2004 ]. Auditory neuropathy can lead to deafness when severe. This has led to audiologists using “auditory dys-synchrony” as synonymous with “auditory neuropathy” [ Berlin et al., 2003 ; Hood and Berlin, 2009 ], taken to mean pathology limited to the inner hair cells, their synapses with type I spiral ganglion neurons, or any part of that cell, with preservation of outer hair cell function. Audiologists’ main concern is to differentiate between inner hair cell and spiral ganglion cell pathologies, which necessitates other tests, as viable ganglion cells, but not neurons, determine eligibility for a cochlear implant. Although this generic use of the term “auditory neuropathy” may be acceptable, even in nonsyndromic cases without evidence of eighth nerve involvement, we stress that it is clearly unacceptable for cases where the pathology is in the brainstem. There are mixed auditory neuropathies and central auditory disorders, like neonatal hyperbilirubinemia, recently shown in the Gunn rat to involve not only kernicterus of the auditory and vestibular brainstem nuclei and basal ganglia, but also of the auditory nerve and spiral ganglia neurons, sparing the hair cells [ Shaia et al., 2005 ].

Central Auditory (Retrocochlear) Hearing Loss

Brainstem hearing loss
Hearing loss attributable to dysfunction or damage to the central auditory pathway is infrequent in children and rarely gives rise to total hearing loss because of the bilaterality of central acoustic projections. Adrenoleukodystrophy may impair hearing because of demyelination of the brainstem or acoustic radiations [ Grimes et al., 1983 ; Kaga et al., 1980 ]. An occasional brainstem glioma and other brainstem pathologies, such as disseminated encephalomyelitis, may impair hearing [ Yagi et al., 1980 ]. As mentioned above, mixed loss due to involvement of peripheral and brainstem pathology includes kernicterus, neonatal hyperbilirubinemia, and compression of the acoustic nerve and brainstem by a neoplasm.

Cortical deafness
This rare cause of hearing loss implies bilateral pathology in the acoustic radiations or in the auditory cortex. Auditory sensitivity may be preserved, but recognition of the source of sounds and decoding of the acoustic code of language (phonology) are impaired. The best-documented example is acquired epileptic aphasia (Landau–Kleffner syndrome), the rare insidious loss of language in children with temporoparietal epileptiform electroencephalogram (EEG) activity with or without clinical seizures. It usually reflects verbal auditory agnosia, or, in severe cases, auditory agnosia or cortical deafness [ Kaga, 1999b ; Klein et al., 1995 ; Lewine et al., 1999 ].

Classification by Severity and Shape of Hearing Loss
The lower limit of normal hearing has been set at 20 dB. Hearing loss can be classified by its severity ( Table 7-1 ). Mild flat losses of up to 40 dB do not preclude the acquisition of speech but may significantly impoverish it, the degree of language handicap depending on the age of the child and the severity and configuration of the hearing loss. If the loss is present from early infancy, it is likely to delay speech [ Abraham et al., 1996 ; Gravel et al., 1996 ], especially if the child is socially deprived or otherwise handicapped [ Wallace et al., 1996 ]. Middle ear effusion in an older child with well-established verbal skills constitutes a minor handicap. Children with even mild losses who are having academic difficulty may benefit from amplification and preferential seating in school and from a mild-gain individual or classroom FM system.
Table 7-1 Severity of Hearing Loss Severity * Consequences † Management None: 0–20 Normal speech and language None Mild: 25–40 Speech and language normal, mildly delayed, or slightly impaired in normal children, detrimental in multiply handicapped or socially deprived children Repeated testing Preferential seating May need speech therapy and FM loop in school Moderate: 45–60 Speech and language usually delayed and defective, especially consonants; significant impairment in most children Hearing aid; FM loop in school Auditory training; speech and language therapy Normal school and resource room with teacher of the hard of hearing Severe: 65–80 Speech and language usually severely defective; require intensive specialized training Hearing aid, FM loop, cochlear implant? Auditory training, sign language desirable; focus on written language Unimplanted: most do best in special school or class for the deaf, at least initially Profound: 85+ Most develop poor or no speech, even with early specialized training; language severely defective in most, who sign much better Hearing aid, cochlear implant Intensive auditory training Sign language critically important (total communication or, better, American Sign Language); focus on written language Unimplanted or unsuccessfully implanted: most do best in specialized programs for the deaf
* Severity is measured in decibels of hearing loss (dB HL)/pure tone average. Each category of severity is recorded in dB HL or decibels above the average normal hearing threshold. Pure tone average refers to the mean of thresholds at 500, 1000, and 2000 Hz.
† Not all consequences of hearing loss of designated severities are listed. These characteristics vary among individual children within a category.
In most children, moderate loss of 45–60 dB interferes severely with, but does not preclude altogether, the acquisition of speech. Children with moderate and severe (65–80 dB) hearing loss gain the most from hearing aids [ Nozza, 1996 ; Roeser et al., 1995 ]. Virtually all children with severe hearing loss require some type of special education to learn language adequately. Profound loss (>85 dB) and total loss preclude the acquisition of language without intensive specialized education. Strictly speaking, the term deafness applies only to these last two groups, but it is often used loosely in referring to all children who cannot learn language without special assistance.
Children with very limited or no hearing benefit little from hearing aids, except, perhaps, for the awareness that a sound has occurred. Most profoundly deaf adolescents and adults do not wear hearing aids, although, as children, they should be encouraged to wear aids because it is difficult to predict who will benefit from them. Children with profound but incomplete hearing losses gain more from their cochlear implants than those with pure tone average thresholds exceeding 100 dB [ Pulsifer et al., 2003 ], and toddlers implanted early (from 6 months to 2 years) benefit much more from their implants than children implanted in middle childhood [ Govaerts et al., 2002 ], [ Sharma et al., 2009 ]. As stressed earlier, functional spiral ganglion cells are required for cochlear implantation.
The shape of the audiometric threshold provides another classification criterion for hearing loss and, with the severity of impairment, determines its effects on language acquisition. The two most common types of auditory threshold pattern in hearing loss are the flat and the sloping high-tone loss threshold curves, with U (dish)-shaped and inverted U (dome)-shaped and rising thresholds being less frequent. Sloping high-tone losses are particularly treacherous clinically. They are common and often overlooked unless systematic testing across the entire frequency range is performed; this is because children may respond normally to environmental sounds and voices that contain energy in the low frequencies, which the children can hear, but not in the mid- and high frequencies critical for consonant discrimination.

Classification by Age at Onset of the Hearing Loss
Age at deafening has a profound effect on its consequences. Schein and Delk, in their outstanding sociologic study of the deaf in the United States [ Schein and Delk, 1974 ], list three main types of age-related childhood hearing loss: congenital or prelingual, perilingual, and postlingual. Prelingual means prenatal or infantile onset. Perilingual means onset during the acquisition of language and its grammatical rules, arbitrarily set by age 3 years. Most preschoolers who lose their hearing soon after age 3, i.e., technically postlingually, retain little expressive speech or language comprehension, even if great effort is made to preserve it, although they may have somewhat less difficulty reacquiring speech than children who never had hearing. Thus, age 3 years seems too young to mark the division between the prelingually/perilingually and the postlingually deaf. Children who do the worst are those who are essentially totally deaf – for example, from purulent meningitis – in whom pathology reveals total collapse of the entire endolymphatic organs, both vestibular and cochlear. Very young children need to hear to continue speaking. Prompt loss of speech is also typical of children with acquired epileptic aphasia with word deafness. Even if they are 5 years or older, they are likely to be mute and to start communicating with gestures or writing, not speech.
Pediatric deafness is mostly infantile. Schein and Delk found that the great majority of the prevocationally deaf – those whose deafness began before the age of 19 years, before they started working in a job or profession – are prelingually or perilingually deaf, proof that severe hearing loss acquired after infancy is uncommon. Any young child with severe loss of hearing from an ostensibly irreversible acquired cause like purulent meningitis (not epilepsy!), who shows no sign of improvement after several weeks, needs urgent electrophysiologic testing to find out whether at least some of the spiral ganglion cells have survived so the child can undergo prompt cochlear implantation in order to spare as much speech as possible. Another reason for early implantation is that ossification of the cochlea [ Isaacson et al., 2009 ] and at least some trans-synaptic degeneration of the spiral ganglion neurons are long-term sequelae of purulent endolabyrinthitis which jeopardize successful implantation [ Papsin and Gordon, 2007 ].

Classification by the Course of the Hearing Loss
Most severe sensorineural hearing loss is static, but about 10 percent, notably that caused by cytomegalovirus infection [ Fowler et al., 1997 ] or a neurologic disease such as an acoustic tumor, and a significant proportion of genetic hearing loss ( Table 7-2 ), is progressive [ Davis et al., 1995 ]. Hearing loss that worsens rapidly during infancy is unlikely to be recognized as progressive, but it probably accounts for some of the children who pass neonatal screening and later turn out to be deaf. Genetic hearing loss that does not become apparent until later childhood or adult life is progressive by definition. It is now clear that both genetics and deleterious environmental influences, including acoustic trauma, contribute to the ubiquitous presbyacusis of old age. Genetic information about progressive hearing loss is generally insufficient to predict the course of a child’s hearing loss because different mutations of a given gene can result in disparate phenotypes, depending on the amount of protein synthesized. Unless the child belongs to a large family with many affected members with similar courses, who inherited an identical mutation from a distant founder, early prediction of outcome is not fully reliable. Slowly progressive hearing loss tends to denote less detrimental molecular effects or, perhaps, greater susceptibility to environmental influences than those causing early deafness. Other hearing loss, such as that due to middle ear effusion, episodic acoustic trauma, salicylate intoxication, and Ménière’s disease, fluctuates. Reasons for fluctuation are not always apparent.

Table 7-2 Selected Syndromic Genetic Hearing Loss (Ordered by Prevalence Among Children with Severe/Profound Loss)*

Syndromic Versus Nonsyndromic Hearing Loss
This classification would seem straightforward; nonsyndromic implies an isolated hearing loss with or without vestibular impairment, whereas syndromic means that it is associated with involvement of other organ systems. Classification is not always straightforward, however, because systemic manifestations associated with early-onset, apparently nonsyndromic hearing losses may be quite delayed. For example, in classic Usher’s syndrome, retinitis pigmentosa worsens slowly during childhood and total blindness may be delayed until young adulthood, whereas deafness and vestibular impairment are typically prenatal; in Pendred’s syndrome, goiter, and in Alport’s syndrome, progressive renal disease may lag for several years; and in the Jervell and Lange–Nielsen syndrome (prolonged Q–T interval), the first occurrence of fainting is quite unpredictable. Thus the syndromic vs. nonsyndromic classification does not have strict etiologic implications. Genetic or nongenetic hearing loss with overt malformations or obvious systemic manifestations or cognitive deficits is that most likely to be considered syndromic. Two of the most easily recognizable types are Treacher–Collins and Waardenburg’s syndromes, but there are many dozens of others, and the list keeps growing (see later).

Pathology
Conductive hearing loss may result from atresia of the external canal, usually associated with gross malformation or absence of the pinna; malformation, dislocation, or destruction of the ossicular chain; fluid or a mass in the tympanic cavity; fixation of the stapes footplate; tympanosclerosis (i.e., fibrosis, scarring, or calcification of the tympanic membrane); destruction of the tympanic membrane; or a combination of these conditions. In young children, by far the most common cause of conductive hearing loss is middle ear effusion attributable to an incompetent eustachian tube, a condition that improves as the base of the skull grows. Remember that even complete canal atresia or severe abnormality of the middle ear produces a hearing loss of at most 60 dB because the skull transmits sound above this intensity directly to the inner ear.
Malformations may be part of a branchial arch malformation syndrome, which may or may not be genetic, which also involves the face and, in some children, is associated with anomalies in other organ systems such as the spine, limbs, gastrointestinal tract, or genitourinary system [ Toriello et al., 2004 ]. These associated anomalies tend to arise at the same time during gestation as the ear anomalies. Because the neural crest contributes to the formation of the ear and these other systems, the entire malformation complex may be regarded as a cristopathy. Ear anomalies may also be associated with anomalies of the posterior fossa, brainstem, other cranial nerves, eyes, and brain [ Wiznitzer et al., 1987 ].
To recapitulate, sensorineural hearing loss often results from hair-cell or synaptic dysfunction or hair-cell loss, with or without associated damage to the neurons of the spiral ganglion [ Merchant et al., 2005 ; Dublin, 1976 ] and stria vascularis. The cells of the organ of Corti and spiral ganglion are end-state cells incapable of cell division [ Ruben, 1967 ], which explains the irreversibility of most sensorineural hearing loss. Spiral ganglion neuronal pathology leads to Wallerian degeneration in the acoustic nerve and may result in delayed transneuronal degeneration in the central auditory pathway [ Ruben and Rapin, 1980 ; Gandolfi et al., 1984 ]. Primary nerve deafness or auditory neuropathy may be axonal, demyelinating, or mixed, the latter inevitable with long-standing demyelination or axonapathy; it may even be potentially reversible in compression by a tumor or an infiltrative process of the meninges.
Infections, including bacterial meningitis, congenital rubella, and cytomegalovirus; trauma; and vascular disease are unselective and are likely to damage all elements of the cochlea and vestibule; they may even result in cochlear ossification [ Douglas et al., 2008 ]. Bacterial meningitis may deafen because of purulent endolabyrinthitis, or by lymphocytic infiltration of the vestibule and cochlea and cellular apoptosis, which suggest an immune pathophysiology [ Nadol, Jr., 1997 ]. Some viral infections are surprisingly selective, producing only a high-tone loss rather than total destruction of the cochlea. Pathologic study of the ears of 66 patients who were profoundly deaf revealed that those with presumptive postnatal viral and bacterial labyrinthitis or with malformative and genetic causes were less likely to have residual spiral ganglion cells than those in whom deafness resulted from aminoglycoside toxicity or sudden idiopathic hearing loss [ Nadol et al., 1989 ]. Ototoxic drugs [ Stavroulaki et al., 2002 ; Stavroulaki et al., 2001 ], some other toxins, and sound trauma [ Salvi et al., 1986 ] are highly selective as to the cell type they destroy. Also highly selective are the genetic hearing loss syndromes, which molecular biology and neuropathology are rapidly elucidating in animal models (see below).
Genetic sensorineural hearing loss is more often the result of malfunction or early death of cells in the cochlea than of their failure to form, although some of those that appear non-syndromic are associated with a variety of malformations of the bony labyrinth [ Westerhof et al., 2001 ]. As previously stressed, which cell type is affected by genetic hearing loss varies [ Bahmad et al., 2008 ; Cremers et al., 1998 ; Sampaio et al., 2004 ]. In the Mondini malformation, the cochlea is incompletely developed and involvement of the semicircular canals varies [ Sennaroglu and Saatci, 2002 ]. Enlargement of the vestibular aqueduct and endolymphatic sac may be isolated or occur with other inner ear anomalies [ Yang et al., 2009 ], and be accompanied by a variably severe or fluctuating hearing loss and, occasionally, by paroxysmal vertigo. Patency of the cochlear aqueduct may be associated with a perilymphatic or even CSF fistula into the middle ear, usually around the stapes footplate [ Liu et al., 2008 ; Reilly and Weber, 1996 ], which, in some children, can cause incapacitating episodes of vertigo.
The pathology of deafness in humans lags behind its rapid progress in animal models. Examination of the ear requires sawing into the petrous bone, lengthy decalcification of the specimen, and serial sectioning. Because of the long interval between the diagnosis of hearing loss and the death of patients, physicians are unlikely to remember the details of the hearing impairment. The ear is rarely removed at postmortem examination, even though there are a number of specialized laboratories and temporal bone banks willing to study specimens, provided they are accompanied by adequate information regarding the patient’s hearing and clinical status. The National Institute of Deafness and Other Communication Disorders of the National Institutes of Health provides a listing of these laboratories, which may be obtained from < nidcdinfo@nidcd.nih.gov >.

Etiology
There are three etiologic categories of hearing loss: genetic, acquired, and unknown. Genetic hearing loss accounts for some 50–65 percent of children who fail newborn screening, and known acquired loss causes some 25–30 percent [ Morton and Nance, 2006 ], [ Wang et al., 2011 ], while the remainder are of unknown etiology, a proportion bound to shrink as more individuals undergo genetic and immunologic testing. An unknown number of cases may be multifactorial and account for some of the delayed or progressive apparently nongenetic cases (for example, some subclinical infections, others with mitochondrial inheritance of susceptibility to aminoglycoside antibiotics, and other toxins) [ Kokotas et al., 2007 ].

Genetic Causes
A number of useful reviews [ Petersen et al., 2008 ; Petersen and Willems, 2006 ; Petersen, 2002 ; Kokotas et al., 2007 ; Friedman and Griffith, 2003 ; Dror and Avraham, 2009 ] discuss the cell biology and pathophysiology of known genetic hearing loss, although they cannot keep up with progress in the field. Two indispensable regularly updated web resources are Online Mendelian Inheritance in Man (OMIM) ( http://www.ncbi.nlm.nih.gov/omim/ ) and Hereditary Hearing Loss Homepage ( http://hereditaryhearingloss.org ). The following abbreviated review, which is limited to a few hearing loss types that child neurologists may encounter, depends heavily on these sources. The somewhat outdated book by Toriello and colleagues [ Toriello et al., 2004 ] remains useful because of the clinical details and pictures it provides.
Genetic hearing loss is generally bilateral but may be asymmetric, and may be static or progressive. The most salient asymmetric dominant hearing loss is neurofibromatosis type 2 (NF2) [ Asthagiri et al., 2009 ]. Mendelian gene defects can be autosomal-recessive or autosomal-dominant, X-linked recessive – even, exceptionally, Y-linked – or mitochondrial. Compound heterozygous mutations of recessive genes are generally more prevalent than homozygous mutations. Sporadic deafness may be due to unrecognized recessive disease, to new dominant mutation, cytogenetic anomaly, or single-stranded copy number variation (CNV). When insertions, deletions, translocations, or other chromosomal rearrangements are large, they may affect two or more adjacent genes, and many are detectable by high-resolution chromosome banding studies. As modern genetics keeps demonstrating, what was thought clinically to be a single disease regularly turns out to be several, resulting from mutations of distinct genes that affect a common pathophysiologic or metabolic pathway. Further, clinically distinct syndromes often arise from allelic or nonallelic mutations in different parts of the same gene, with more or less severe consequences for protein synthesis. For example, the amount of the protein pendrin determines in large measure the severity of the phenotype in Pendred’s syndrome, and in some cases whether the trait is inherited in dominant or recessive fashion. Because of these complexities, we are not giving the names of most genes we mention in the text or tables; nor do we try to mention all of the phenotypes resulting from the mutations of a particular gene. OMIM is more up to date and should be consulted for details because only super-specialists can hope to dominate the genetics of hearing loss.

Syndromic Genetic Hearing Loss
Several hundred syndromic forms account for some 30 percent of all genetic deafness [ Toriello et al., 2004 ]. We list only a few of the more prevalent or salient ones in Table 7-2 . Sex-linked disorders, both syndromic and nonsyndromic, are rare [ Petersen et al., 2008 ]. Some syndromic losses are easy to spot because of their characteristic features, notably Treacher–Collins [ Marres, 2002 ] and Waardenburg’s syndrome [ Nance, 2003 ]. Deafness is not the most prominent aspect of the disorder in others, and it only becomes symptomatic later in life in still others [e.g., the “auditory neuropathy” of Friedreich’s ataxia [ Lopez-Diaz-de-Leon et al., 2003 ], some hereditary sensorimotor neuropathies [ Starr et al., 1996 ; Nicholson et al., 2008 ], and dominant optic atrophy (OPA1) [ Huang et al., 2009 ]. Table 7-3 lists a few pediatric neurologic disorders associated with hearing loss. Among the polysaccharidoses, the loss is generally mixed, i.e., conductive and sensorineural; it is most consistent and severe in Hunter’s syndrome but is reported in the others as well [ Cho et al., 2008 ; Riedner and Levin, 1977 ; Simmons et al., 2005 ]. Hearing loss in the leukodystrophies may be due to involvement of the central white matter – as in adrenoleukodystrophy [ Pillion et al., 2006 ], or of both peripheral and central myelin – as in Cockayne’s syndrome [ Rapin et al., 2006 ]. Hearing loss is a feature of a significant proportion of mitochondrial diseases [ DiMauro and Schon, 2003 ; Finsterer et al., 2009 ]. As is well known, if the mutation affects the mitochondrial DNA, all the children of an affected mother are at risk for hearing loss, although not necessarily of equal severity, whereas mitochondrial deafness arising from nuclear DNA mutations follow Mendelian inheritance patterns.

Table 7-3 Selected Neurologic, Neuromuscular, and Mitochondrial Disorders Associated with Sensorineural Hearing Loss*

Nonsyndromic Genetic Hearing Loss
Nonsyndromic cases account for approximately 70 percent of genetic hearing loss. Close to 80 percent of prelingual nonsyndromic deafness is autosomal-recessive, 20 percent dominant, 1 percent X-linked, and less than 1 percent mitochondrial [ Morton and Nance, 2006 ; Petersen et al., 2008 ; Petersen and Willems, 2006 ; Petersen, 2002 ; Kokotas et al., 2007 ]. Since nonsyndromic loss shares phenotypes, genetic testing is required to identify its numerous underlying genotypes. Genetic testing in the clinic tends to focus on identifying the more prevalent mutated genes, not on identifying the many specific mutations of any given one, although current technology may change this. Laboratories specialized in this work have made breathtaking progress toward understanding the function of the genes for syndromic and nonsyndromic hearing loss. The Friedman and Griffith review [ Friedman and Griffith, 2003 ] is particularly helpful because it groups disorders by the roles of the involved genes according to the function of individual cochlear cells.
Cochlear channelopathies are responsible for a major category of nonsyndromic hearing loss. The GJB2 gene is the most common recessive gene for profound prelingual nonsyndromic deafness. It codes for connexin 26, a gap-junction protein of the many cells of the inner ear that participate in recycling K + to the endolymph after sound excitation. Mutations for connexin 30 are rarer causes of hearing loss [ Liu et al., 2009 ]. Connexin 31 mutations are associated with some of the hereditary sensorimotor neuropathies (HSMN), a few of which also involve hearing. Some of the other genes responsible for axonal or demyelinating HSMN and the trinucleotide repeat (GAA) gene of Friedreich’s ataxia are responsible for occasional childhood-onset progressive hearing loss [ Ouvrier et al., 2007 ]. Another gene, KCNQ4 , also involved in K + recycling, produces a dominant progressive high-tone hearing loss in the second and third decades [ Petersen, 2002 ]. Lack of the protein pendrin results in Pendred’s syndrome, a severe recessive prelingual hearing loss which can be syndromic or nonsyndromic, and is often associated with EVA or a Mondini malformation. EVA suggests a direct or indirect influence of impaired anionic transport of iodide and chloride on the fetal endolymph, whereas development of a euthyroid goiter is delayed until the second decade [ Petersen and Willems, 2006 ]. The sodium/potassium ATPases play a major role in transmembrane ionic transport essential for maintaining ionic gradients in a number of cell types of the cochlea [ Carelli et al., 2009 ]; in rats they are also involved calcium signaling [ Meyer et al., 2009 ] and in glutamate transport at the synapses between inner hair cells and spiral ganglion type I neurons [ McLean et al., 2009 ; Santarelli et al., 2009 ]. Specificity of otoferlin for release at excitatory glutamatergic inner hair-cell synapses means that this cause of profound prelingual deafness is of the “auditory neuropathy” type, because the outer hair cells and their OAEs are preserved. In contrast, mutations affecting claudin, a major structural protein of intercellular tight junctions, produce deafness by rapid selective degeneration of the outer hair cells, with only later degeneration of the inner hair cells [ Petersen and Willems, 2006 ].
Among the many other causes of sensorineural hearing losses, there are mutations of structural genes for the tectorial membrane, genes specific to cilia, and mutations of a number of the myosin cellular motors. These motors affect bending of the hair cells in response to movement of the basilar membrane and are responsible for some subtypes of Usher’s syndrome, other subtypes of which are due to inadequate adhesion molecules (cadherins). Cellular motors require energy provided by the adenosine triphosphate (ATP) generated by the mitochondrial electron transport chain [ Kokotas et al., 2007 ]. The high prevalence of hearing loss in mitochondrial diseases is most likely linked to inadequate generation of the energy required not only for the motors but also to maintain ionic gradients for continuous fast neurotransmission of sound. Mitochondrial function plays a role in ototoxicity, acoustic trauma, and the effects of anoxia. Mutation of the dominant nuclear mitochondrial gene OPA1 causes early optic atrophy with later progressive hearing loss and ataxia of variable severity. Other mitochondrial diseases associated with hearing loss are listed in Table 7-3 . This short list is but an illustration of the complexities of the ever-growing number of potential molecular mechanisms responsible for hearing loss.
Genetic testing and counseling of affected children and their families are discussed in later sections.

Malformations
Ear malformations may be sporadic or genetic, and involve one or several parts of the ear, some isolated, some part of complex malformation syndromes. Bilateral anomalies are more likely than unilateral ones to involve the brain and other organ systems. Some, but by no means all, are associated with intellectual deficits or autism [ Wiznitzer et al., 1987 ]. The severity of malformations of the external ear and face does not predict outcome reliably unless associated with a major brain abnormality, so that a reliable prognosis cannot be provided in infancy.
Stenosis or atresia of the external ear canal may occur in isolation or be associated with malformation of the pinna and middle ear, and, in some children, the inner ear [ Toriello et al., 2004 ]. Atresia produces a severe conductive loss and requires neonatal referral for bone conduction aids. The pinna may be absent, reduced to a small remnant (microtia), associated with one or more preauricular tags, or be present but malformed. The pinna with its lower half missing or deformed strongly suggests the CHARGE association (i.e., coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies) [ Stromland et al., 2005 ]. Malformations of the ossicular chain and cochlea, and those of the central auditory canal containing cranial nerves VII and VIII are best visualized with ultra-thin, high-resolution computed tomography (CT) of the temporal bones. Patency of the cochlear scala tympani is critical for implantation candidacy. Microtia is frequently associated with ipsilateral facial palsy or deficient growth of the face (hemifacial microsomia), and conductive or mixed hearing loss [ Carvalho et al., 1999 ]. In Möbius’ syndrome sensorineural hearing loss and involvement of other cranial nerves besides VI and VII may occur [ Griz et al., 2007 ]. As previously mentioned, some cochlear anomalies are associated with perilymphatic/CSF fistulas into the middle ear, usually through the stapes footplate; they may produce fluctuating or progressive hearing loss and severe intermittent labyrinthine dysfunction with vertigo, nausea, or vomiting, and they may provide a path for a purulent endolabyrinthitis or meningitis [ Reilly and Weber, 1996 ].

Acquired Causes
See Box 7-2 .

Box 7-2 Main Causes of Acquired Hearing Loss

Infection

Congenital infections
Cytomegalovirus, rubella
Syphilis (childhood-onset), toxoplasmosis
Acquired infections
Chronic purulent otitis media, mastoiditis
Middle ear effusion due to repeated upper respiratory infection
Mumps, measles, scarlet fever *
Endolabyrinthitis from bacterial meningitis
Others

Perinatal insults

Hyperbilirubinemia (especially in premature infants)
Prematurity †
Severe anoxia
Ototoxic drugs

Ototoxic drugs

Aminoglycosides (e.g., streptomycin, dihydrostreptomycin, kanamycin, neomycin)
Furosemide, ethacrynic acid
Cisplatin
Thalidomide (prenatal exposure)
Aspirin (transient)

Trauma

Temporal bone fracture
Hemorrhage into the middle ear or cochlea
Ossicular dislocation
Sound trauma

Neoplasms

Bilateral acoustic neurinoma (neurofibromatosis type 2)
Other cerebellopontine angle tumor
Tumor of the middle ear (e.g., rhabdomyosarcoma, glomus)

* These are rare causes of deafness and their etiologic importance has been exaggerated.
† Perinatal insults and prematurity have additive effects; if hearing loss occurs, it is generally multifactorial. Selective IHC loss in some.

Middle Ear Effusion
The major cause of middle ear effusion is eustachian tube dysfunction, often resulting from repeated upper respiratory infection or allergic rhinitis with adenoid hypertrophy, by malformation or immaturity of the eustachian tube, or anomalies of the palate or skull base. Most middle ear effusions are transient and produce a fluctuating hearing loss of variable duration and rarely of more than mild severity. Chronic middle ear effusion (“glue ear”) often goes undetected and may be responsible for moderate conductive loss or, occasionally, mixed loss when granulation tissue involves the inner ear. Although the long-term consequences of middle ear effusion for language skills depend on whether there are associated handicaps, including low socioeconomic status [ Roberts et al., 2004 ], otolaryngologists recommend its prompt detection, treatment with decongestants – not necessarily antibiotics, and insertion of ventilating tubes if indicated [ Rosenfeld et al., 2004 ]. This is especially important in children who have sensorineural hearing loss because an additional 30 or 40 dB of conductive loss can transform a hard-of-hearing child into a deaf one. Ventilating tubes do not preclude the wearing of hearing aids.

Congenital Infections
Congenital cytomegalovirus (CMV) infection accounts for some 20 percent of hearing loss detected by neonatal screening [ Morton and Nance, 2006 ]. It can be progressive or may fluctuate in infants with prolonged viral shedding [ Roizen, 2003 ]. Twenty-two (7 percent) of 307 children with asymptomatic CMV at birth had hearing loss, which deteriorated further in 11. It fluctuated in 5 of the 11 and was progressive in 4 of the 11; age at deterioration ranged from age 2 to 5 years [ Fowler et al., 1997 ]. Among infants infected early in pregnancy, whether the mother’s infection was primary or a reinfection, those symptomatic at birth and those with a higher viral load had a higher risk of neurologic sequelae and hearing loss [ Pass et al., 2006 ; Lanari et al., 2006 ; Rosenthal et al., 2009 ]. Neonatal thrombocytopenia and intracranial calcification are harbingers of intellectual impairment, occasionally with autistic features and hearing or visual impairment [ Boppana et al., 1997 ; Ogawa et al., 2006 ]. Reports of attempts to treat CMV postnatally or in utero are anecdotal. Because postnatal infection is ubiquitous, availability of cord blood or neonatal isolation of CMV from the urine is needed to document the fact that CMV is responsible for a sporadic hearing loss.
Of other TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus) infections, toxoplasmosis is a rare cause of congenital hearing loss with vestibular impairment. Congenital syphilis does not cause hearing loss until later in childhood, but it needs to be treated to reverse or arrest its progress. Besides retinopathy, hearing loss is the most common manifestation of congenital rubella [ Chess et al., 1971 ], now rare because of immunization. As with CMV, the severity of the hearing loss varies. It may progress because of viral persistence, and may be associated with vestibular impairment and with signs of CNS damage, such as microcephaly, motor deficits, mental deficiency, autism, and learning disability. The most severely handicapped children are those in whom deafness is associated with marked visual impairment due to cataract and other eye pathologies or with autism. However, physicians should be conservative in predicting outcome in infants with congenital rubella because it can be more favorable than expected [ Chess, 1977 ].

Prematurity
Longitudinal studies of premature infants and other graduates of neonatal intensive care units reveal a significant number of children with impaired hearing [ Amatuzzi et al., 2001 ; Amatuzzi, et al., 2011 ; Valkama et al., 2000 ; Robertson et al., 2009 ]. Percentages vary around 3–5 percent, compared to 1 in 1000 in the general population. Prematurity per se is rarely responsible for hearing loss because the ear is fully developed at the end of the second trimester. Hearing loss in graduates of the neonatal intensive care unit results from some or all of the many complications and the treatments necessary for survival [ Roizen, 2003 ]. Therefore, it is rarely possible to attribute a hearing loss to any one of these factors, which may have cumulative effects.

Neonatal Hyperbilirubinemia
Hyperbilirubinemia of the newborn has become infrequent in Europe and the US because of preventive measures, such as the routine use of RhoGAM after the birth of a Rhesus-positive infant to a Rhesus-negative mother, phototherapy in all neonates whose bilirubin exceeds safe levels, intrauterine transfusion, and exchange transfusion in the few with high levels likely to cause kernicterus. Kernicterus may occur when levels of unconjugated bilirubin are low in asphyxiated, acidotic, and premature infants, or in those who receive various drugs competing with bilirubin for albumin binding sites [ Ostrow et al., 2003 ]. There was no correlation, however, between bilirubin levels and IQ or hearing loss in the Perinatal Collaborative Study [ Newman and Klebanoff, 1993 ], and later studies in very low birth weight infants stress that multiple variables besides peak bilirubin modulate outcome [ Oh et al., 2003 ].
Kernicterus is named for bilirubin staining and damage to the nuclei of the central auditory and vestibular pathways, cerebellar nuclei, and basal ganglia. Evidence in animals appears to have resolved the controversy of whether kernicterus-associated hearing loss involves the cochlea or only the central pathway; in Gunn rats the hair cells are unaffected but the spiral ganglion cells and their axons are damaged [ Shaia et al., 2005 ], i.e., there is an “auditory neuropathy”. Audiologic testing of hyperbilirubinemic infants confirms this conclusion in at least some of them [ Nickisch et al., 2009 ; Xoinis et al., 2007 ]. Hyperbilirubinemia typically causes a high-tone loss but may produce profound hearing loss in some infants. When severe hyperbilirubinemia also causes athetosis and a severe dysarthria, affected children unable to communicate through gestures or speech may be misdiagnosed as intellectually deficient. Unlike children whose athetosis is caused by severe ischemic/hypoxic encephalopathy, many kernicteric children without other complications are intelligent because pure hyperbilirubinemia does not affect the cerebral cortex.

Acquired Infections
Otitis media, measles, scarlet fever, mumps (which may produce unilateral hearing loss), and other childhood illnesses can be responsible for prelingual deafness, but they are probably blamed more often than warranted. Although herpes zoster causes Ramsay Hunt syndrome, which may be associated with unilateral hearing loss later in life, the varicella and herpes simplex viruses do not seem to cause deafness in early life.
Purulent meningitis is the acquired infection most likely by far to deafen children [ Dodge et al., 1984 ). Temporal bone pathology revealed purulent endolabyrinthitis in 20 of 41 ears examined; it involved the cochlea in all 20, and the vestibule as well in 10 [ Merchant and Gopen, 1996 ]. The other 21 ears had histologically intact sensory organs without inflammatory cells, although eosinophilic staining of the inner ear fluids in 14 suggested the possibility of serous labyrinthitis. An audiologic study carried out in 124 children during the meningitis detected hearing loss within 6 hours of diagnosis in 13 percent, and it was permanent in less than 3 percent. In 10 percent the hearing loss reversed within 48 hours, giving some credence to the serous labyrinthitis theory [ Richardson et al., 1997 ]. Although Haemophilus influenzae is the most common cause of meningitis in non-immunized children, S treptococcus pneumoniae is the organism most frequently responsible for permanent deafness and a later ossified cochlea [ Douglas et al., 2008 ]. All children with meningitis must have a formal hearing test before they leave the hospital because undetected hearing and vestibular losses are often misinterpreted as brain damage in a child who is mute and temporarily unable to sit, stand, or walk. If deafness is documented, candidacy for prompt cochlear implantation needs to be determined with physiologic tests to forestall regression of what oral language had already developed, degeneration of denervated surviving spiral ganglion cells, and ossification of the cochlea [ Isaacson et al., 2009 ; Douglas et al., 2008 ; Nadol, Jr., 1997 ].
Meningitis is a rare complication of cochlear implants [ Reefhuis et al., 2003 ]. Recurrent meningitis suggests a possible communication between the subarachnoid space and middle ear, a rare consequence of a fracture or malformations of the otic capsule [ Liu et al., 2008 ] or of a perilymphatic fistula [ Mostafa et al., 2005 ].

Ototoxicity
Pediatric ototoxic drugs include aminoglycosides in infants who inherited from their mothers a mitochondrial mutation responsible for some nonsyndromic hearing loss and drug sensitivity [ Van Camp and Smith, 2000 ]. Other ototoxic drugs include macrolide antibiotics, loop diuretics, platinum-based antineoplastic agents, some antimalarials, salicylates, and nonsteroidal anti-inflammatory drugs [ Yorgason et al., 2006 ]. Unlike the other drugs, salicylate produces a transient hearing loss.

Trauma
Trauma can induce bleeding into the middle ear and dislocate the ossicular chain. The resultant conductive loss may be mixed if it is associated with trauma to the cochlea. Fractures through the otic capsule often produce severe unilateral hearing loss associated with signs of acute labyrinthine dysfunction. As just noted, they may occasionally create a communication between the middle ear and intracranial spaces, and result in delayed meningitis. High-resolution CT detects petrous fractures much more reliably than do plain radiographs of the skull.
Trauma by high-intensity sound produces temporary loss of hearing (temporary threshold shift), which can become irreversible if prolonged or repeated. Even if brief, an explosively loud noise can result in permanent hearing loss. Acoustic trauma can damage the hair cells and their synapses with the spiral ganglion cells [ Pujol and Puel, 1999 ]. There is increasing concern about sound trauma, for example, from exposure to noise in the newborn intensive care unit, the very loud music that some adolescents are addicted to, and even very high-gain auditory prostheses.

Neoplasms
Brainstem gliomas are exceptional causes of retrocochlear hearing loss in childhood. The bilateral vestibular schwannomas of neurofibromatosis type 2 result from a dominant mutation in the tumor suppressor NF2 gene on chromosome 22. If untreated, they eventually result in deafness. They typically become symptomatic in adolescence or adulthood, although childhood cases involving cranial nerve VIII, other cranial nerves, and other neoplasms are well documented [ Nunes and MacCollin, 2003 ].
Tumors of the ear include glomus tumors and other rare neoplasms. Cholesteatomas of the middle ear and mastoid often arise in the presence of chronic middle ear disease associated with perforation of the drum at its limbus. Intracranial cholesteatomas are idiopathic and may compromise hearing when located in the cerebellopontine angle.

Clinical Evaluation and Laboratory Tests

Patient and Family Histories
A detailed family history and pedigree are an integral part of the evaluation of every newly identified hearing-impaired child. Parents must be questioned closely about consanguinity, infections during pregnancy, prematurity, perinatal insults, exposure to ototoxic drugs, prior meningitis, and any other event that might have resulted in hearing loss in the child. It is better to obtain birth records of mother and child, and records from any other hospital where the child might have been admitted for a serious illness, than to rely on the parents’ collective memory, because parents are prone to blame deafness on some trauma, episode of transient anoxia, or bad ear infection that had nothing to do with the hearing loss. Most parents are unaware that unexplained sporadic hearing loss is more likely to be genetic and recessive than the sole consequence of a perinatal incident.

Physical, Developmental, and Otolaryngologic Evaluations
In addition to examining the child for pathologic conditions of the external ear and tympanic membrane, such as a malformed pinna, middle ear effusion, tympanic perforation, fistula, or palatal or submucosal cleft likely responsible for eustachian tube dysfunction, it is essential to look for evidence of associated anomalies in other organ systems. Pigmentation disorders of the skin and iris, unusual facial features, preauricular tags, anhidrosis, hyperkeratosis, and anomalies of the fingers or nails can suggest a specific diagnosis. Syndromic hearing loss may be associated with retinal pathology, congenital heart disease, spinal anomalies, and genitourinary or gastrointestinal malformations or diseases. The many genetic and nongenetic syndromes associated with hearing loss are detailed, usually with pictures, in other sources [ Cohen, 1997 ; Toriello et al., 2004 ] and websites ( http://www.ncbi.nlm.nih.gov/omim/ Online Mendelian Inheritance in Man [OMIM] and http://hereditaryhearingloss.org Hereditary Hearing Loss Homepage).
A neurologic evaluation is indicated whenever there are associated problems. Malformations of the ear are quite often associated with malformations of some of the structures of the posterior fossa, notably nuclear agenesis [ Wiznitzer et al., 1987 ]. Hypotonic hearing-impaired children with or without delayed motor milestones require neurologic assessment to decide whether vestibular impairment contributes to the hypotonicity or whether the child has cerebellar, lower motor neuron, or muscle involvement, or one of many conditions affecting both the brain and the ear. As mentioned, detection of a neuropathy is particularly important in children with “auditory neuropathy.”
Assessment of the child’s developmental level and mental status is essential, but keep in mind that few evaluators are qualified to disentangle the consequences of language and information deprivation from independent cognitive deficit; in addition, the evaluators may not share a common language with a deaf child. Most states mandate triennial formal psychological testing of children with severe hearing loss, but neurologists need to be aware that few competent psychologists have adequate experience of evaluating the deaf. A significant proportion of deaf children are truly intellectually deficient or autistic as well as hearing-impaired, and it is critical to provide habilitation for both deficits [ Jure et al., 1991 ]. In older deaf children, whether or not they have an implanted cochlear prosthesis, a review of academic skills is required because hearing-impaired children are no less prone to developmental problems, including intellectual deficiency, attention-deficit hyperactivity disorder, and learning disabilities, than children with normal hearing. Children with severe hearing loss, especially those whose families do not share an adequate common language with them, are at high risk for behavioral and psychiatric problems. There are small numbers of psychiatrists, social workers, and psychologists who have adequate experience and communication skills to evaluate and provide counseling for deaf children. Primary care providers and other professionals who evaluate these children need to be alert to these problems and refer children having difficulties promptly for adequate help. No meaningful long-term prognosis can be offered without knowledge of the child’s neurologic, psychiatric, and developmental status.

Screening in Neonates and Infants
Universal screening of neonates and graduates of neonatal intensive care units before they leave the hospital is now mandated in most states and many countries. This requires availability and efficient administration of electrophysiologic testing 7 days a week, now that early discharge is the rule. As an occasional inborn infant and those home-delivered will be missed, it is essential that pediatricians check results and inform parents at the first well-baby visit. In order not to misdiagnose children with “auditory neuropathy,” it is recommended that both ABR and OAE, described below, be used in the nursery [ Cone-Wesson et al., 2000 ; Norton et al., 2000 ; Robertson et al., 2009 ]. Prompt referral and follow-up testing within a month is crucial for all neonates who fail the neonatal screen. Referral for definitive hearing testing is also required for any neonate who passed but has an immediate family member with a significant hearing impairment; who has a malformed pinna, face, or palate; who has Down syndrome or some other syndromic condition known to be associated with hearing loss; or who manifests any condition listed in the position paper of the American Academy of Pediatrics, Joint Committee on Infant Hearing [ American Academy of Pediatrics, 2007 ] ( Box 7-3 ). No child, including a neonate, is too young or too handicapped to undergo quantitative assessment of the functional state of the middle ear and sensitivity of the cochlea and auditory pathway. The mere suspicion of inadequate hearing, language or other developmental delay at any age, regardless of any other plausible cause for inadequate or unintelligible speech, mandates prompt, definitive assessment of hearing and middle-ear function with physiologic testing, without wasting time on repeated and often unreliable behavioral tests. Hearing loss is a hidden handicap in infancy. Even today, there are still infants who do not receive adequate follow-up after identification, especially among immigrant and indigent families.

Box 7-3 Indications for Hearing Screening Tests (OAE, BAER) in High-Risk Newborns, Infants, and Children * , †

A Birth to 1 month

Family history of hereditary childhood sensorineural hearing loss
Congenital perinatal TORCH infection (i.e., cytomegalovirus, rubella, toxoplasmosis)
Craniofacial anomalies: malformation of the pinna, ear canal, face, palate, other syndromic or nonsyndromic dysmorphology; Down syndrome
Stigmata or other findings associated with syndromic hearing loss
Neonatal intensive care unit admission, or on mechanical ventilation >5 days, or received ECMO
Hyperbilirubinemia: untreated or required exchange transfusion
Exposed to ototoxic drugs: aminoglycosides, loop diuretics
Bacterial meningitis (e.g., group B streptococcus, Escherichia coli , Listeria monocytogenes , etc.)
Low birth weight (<1500 g or 3.3 lb)

B One month through 3 years: conditions requiring rescreening

Parent or caregiver concern regarding hearing, speech, language, or developmental delay
Confirmed postnatal bacterial and viral infections associated with sensorineural hearing loss
Significant head trauma, especially basal skull/temporal bone fracture
Recurrent or persistent otitis media with effusion lasting at least 3 months
Chemotherapy, ototoxic drugs, loop diuretics
Syndromes associated with progressive or late-onset syndromic hearing loss (e.g., osteopetrosis, Usher’s, Waardenburg’s, Alport’s, Pendred’s, Jervell and Lange–Nielsen syndromes)
Conditions previously listed in section A, rescreening at 24–30 months of age

C Throughout infancy and childhood: conditions requiring periodic monitoring

Parent, caregiver, or teacher concern regarding hearing, speech, language, or developmental delay
Family history of hereditary childhood-onset deafness, or earlier diagnosed genetic hearing loss
All children with new-onset, progressive, severe, or profound hearing loss
TORCH infections (except herpes simplex)
Neurofibromatosis type 2
Genetic neurodegenerative disorder (e.g., Hunter’s syndrome, sensorimotor neuropathies such as Friedreich’s ataxia and Charcot–Marie–Tooth syndrome, mitochondrial disease, leukodystrophy, etc.)

* This list of indicators is meant to be used when universal hearing screening at birth is not available and to identify children in need of further audiometric testing beyond infancy.
† BAER/ABR, brainstem auditory-evoked responses/auditory brainstem responses; ECMO, extracorporeal membrane oxygenation; OAE, otoacoustic emissions; TORCH, toxoplasmosis, rubella, cytomegalovirus, herpes simplex, syphilis.
(Adapted from American Acadamy of Pediatrics, Joint Committee on Infant Hearing. Most recent: Year 2007 position statement: Principles and guidelines for early hearing detection and intervention programs. Pediatrics 2007:120:898.)

Assessments of Vestibular Function and Vision
Ideally, children with sensorineural hearing loss should undergo vestibular testing, described in Chapter 8 , to detect Usher’s, Pendred’s, and other deafness syndromes affecting both the vestibule and the cochlea. Lack of vestibular function may explain delayed gross motor milestones and stumbling in dim light [ Kaga, 1999a ]. Lack of vestibular function puts children at risk for drowning because, in the absence of gravity, they may become disoriented under water.
Detection of suboptimal vision is crucial because hearing-impaired children are exceptionally dependent on their eyes. Yearly refraction of young deaf children is recommended, inasmuch as children who require glasses rarely complain of poor vision and since most refractive errors arise in childhood. Examination of the retina by an ophthalmologist is essential because it may yield crucial etiologic evidence, like the chorioretinitis associated with an intrauterine infection or the retinitis pigmentosa of Usher’s syndrome. Children with vestibular dysfunction must be referred immediately to an ophthalmologist who is aware that Usher’s syndrome (see Table 7-2 for subtypes) is being considered. These children are prime candidates for early cochlear implantation, as their deafness is due to abnormality of the cochlear (and vestibular) cilia of the hair cells. Electroretinography is more sensitive than ophthalmoscopy in the early stages of retinitis pigmentosa [ Young et al., 1996 ].

Types of Hearing Tests
There are two broad categories of hearing tests: behavioral tests that assess perception and behavioral verbal or nonverbal response to calibrated auditory stimuli, and physiologic tests of the sensitivity of the auditory system.

Behavioral hearing tests

Behavioral Tests of Conductive Hearing
Because sound is conducted through bone as well as through air, albeit with a threshold some 60 dB higher, presenting sound to the skull makes it possible to differentiate conductive from sensorineural hearing losses. Bone conduction is part of formal audiometry, with a vibrator placed on the mastoid of the ear being tested. Bone conduction audiometry is crucial in children with anotia (absent pinna and ear canal) or atresia of the external ear, or other middle-ear malformations, and is required in children with abnormal immittance tests and absent acoustic reflexes. Neurologists will occasionally screen older children for unilateral conductive hearing loss with the Weber test. This consists of placing a vibrating tuning fork on top of the head; the sound is heard better in the ear with a conductive loss than in the opposite ear. In the Rinne test the sound of a vibrating tuning fork is heard better and longer when it is placed on the mastoid process of an ear with a conductive hearing loss than when it is held in front of that ear.

Office Behavioral Screening Tests
In a pediatric office setting, testing is limited to behavioral screening and perhaps to tympanometry, which assesses the mechanical properties of the middle ear (see below). At best, infant screening is reassuring in normally developing children in whom there is no suspicion of auditory impairment. Lack of behavioral response to sound may not signal a peripheral hearing loss in uncooperative, autistic, or severely retarded children. Because of their pitfalls, behavioral screening tests are insufficient and they are inappropriate in multiply handicapped children, children with risk factors for deafness, or a clinical suspicion of hearing loss, all of whom must be referred promptly for formal quantitative testing.
Speaking softly to a child without risk factors, even if the response is appropriate, may be misleading if it provides nonverbal tactile or visual cues, or if speaking is louder than intended. Crumpling paper or ringing a small bell out of the child’s sight and observing whether the child turns the head and eyes promptly in the direction of the sound may exclude profound hearing loss but not a milder or high-tone loss. Consistent head turning in the horizontal plane does not occur before 6 months of age and in the vertical plane until almost 1 year, and young blind children do not turn toward a sound source. It is dangerous to rely on such subtle responses as eye widening and cessation of activity as indicators of hearing because they are subject to observer bias. In a toddler aged 1 year or older who is not suspected of deficient hearing, lack of turning toward the speaker or failure to respond verbally should also lead to suspicion of autism or attention deficit disorder, but it mandates immediate referral for audiometry because interpreting lack of response as unwillingness to cooperate rather than failure to hear or comprehend is a major error. Producing a loud sound out of an infant’s or toddler’s field of vision is uninformative because hand claps and dropped metal basins are likely to provide a falsely reassuring somatosensory cue. As with all biologic measurements, a single observation does not suffice; a reproducible one is required, with the caveat that habituation occurs after a few presentations, as soon as the stimulus has lost its novelty and alerting properties. These characteristics are exploited in the research laboratory to study speech sound discrimination in infancy [ Kuhl et al., 1997 ]. There are screening instruments available, such as a 3000-Hz warbler of variable and calibrated intensity, but they are subject to some of the caveats just discussed.

Formal behavioral audiometry
Behavioral audiometry in a soundproof room, presenting calibrated pure tones and other acoustic stimuli though air and bone to each ear through earphones, is the gold standard against which all other tests of hearing are gauged. Behavioral audiometry is quantitative and efficient in experienced hands. It ensures that sound has been perceived and processed because it has elicited a specific response, but it does necessitate cooperation on the child’s part and adequate motivation and attention. Pure-tone behavioral audiometry yields sensitive, reliable, and reproducible threshold curves. It may be applicable to some young and handicapped infants with such refinements as visually reinforced and play audiometry. Conditioned behavioral techniques are not clinically reliable in infants whose developmental age is less than 6 months [ Gravel and Traquina, 1992 ], despite the fact that it may be measurable in the research laboratory with experimental behavioral methods.
In older children, standard audiometry enables the comparison of air with bone thresholds in the same way as in adults. In sensorineural hearing losses, air and bone thresholds are identical, whereas in conductive hearing losses, bone thresholds are better than air-conduction thresholds. Many children have mixed hearing losses, in which bone threshold is better than air threshold, but both are elevated. Middle-ear fluid is a common cause of fluctuating hearing loss. Especially if associated with signs of vestibular dysfunction, sensorineural fluctuating loss may suggest cytomegalovirus infection, labyrinthine fistula, endolymphatic hydrops, and other disorders, some of which may require surgical intervention.
Many kinds of sensorineural hearing loss and most kinds of conductive hearing loss produce flat threshold curves (i.e., they impair hearing for sounds at all frequencies to more or less the same degree) ( Figure 7-4 ). The average profoundly deaf child has minimal or no functionally useful hearing ( Figure 7-5 ), despite responses to low frequencies that may represent awareness of vibration rather than hearing. Sloping hearing losses ( Figure 7-6 ) are common and affect higher frequencies to a much greater degree than lower frequencies. This type of hearing loss is notoriously easy to overlook clinically. Such children are not deaf because they may respond to voices, especially male voices and broadband environmental noises which always contain some energy at the low end of the frequency spectrum, at nearly the same intensities as hearing children. Lack of hearing in the high frequencies has particularly deleterious consequences for language learning because consonant sounds differ in their high-pitched components. Because consonants carry most of the linguistic message, children with sharply sloping hearing losses are more handicapped than hearing-impaired children with the same mean pure tone average but a flat audiogram. Children with sloping hearing losses and other irregular thresholds may benefit from, and better tolerate, newer hearing aids that amplify certain frequencies selectively. Some hearing aids transpose frequencies into a range where the child has better preserved hearing [ Auriemmo et al., 2009 ; Gravel and Chute, 1996 ]. Rarer types of audiometric threshold curves, some of them associated with particular causes of hearing losses, are U-shaped, in that they involve the middle frequencies more than the high and low, and inverted U-shaped or dome-shaped losses which involve the high and low frequencies more than the middle frequencies. Occasionally, patients have preserved hearing in the so-called ultra-high frequencies, those above 8000 Hz [ Feghali et al., 1985 ]. Poor correlation between language ability and audiometric threshold is especially common in patients with “auditory neuropathy” and those with pathology of the central auditory pathway rather than hair cell pathology [ Sininger and Starr, 2001 ].

Fig. 7-4 Pure tone air-conduction audiogram for moderate binaural flat hearing loss.
If it had been a mixed hearing loss, the level of bone conduction would have been indicated in brackets. O, right ear; X, left ear.

Fig. 7-5 Pure tone air-conduction audiogram for profound binaural loss at all frequencies, with slight residual hearing at 250, 500, and 1000 Hz.
No response (arrows) occurs at 2000 and 4000 Hz in the left ear. O, right ear, X, left ear.

Fig. 7-6 Pure tone air-conduction audiogram for severe binaural sloping hearing loss.
An acoustic reflex (Z) was present at 500–1000 Hz but absent (arrows) at 2000–4000 Hz, confirming the shape of the hearing loss. O, right ear; X, left ear.

Behavioral Tests of Central Auditory Function
Large batteries of tests requiring responses to auditory stimuli more complex than pure tone detection are often administered to children with learning disabilities and language disorders in an effort to understand the source of their problem [ Hood and Berlin, 2003 ]. Speech audiometry measures the ability to discriminate speech sounds and to repeat phonetically balanced sounds. The ability to comprehend words that are distorted or presented against a noisy background is often impaired in children with high-tone losses. Competing words or sounds may be presented simultaneously to both ears (dichotic test) to assess cerebral dominance for the processing of language. In virtually everyone, including most left-handed people, language is processed preferentially in the left hemisphere, whereas the right hemisphere is dominant for musical melody, the intonation of speech (prosody), and environmental sounds. In dichotic testing, words presented to the right ear of left hemisphere-dominant individuals are somewhat more likely to be reported than those presented to the left ear. Dichotic testing is helpful for detecting pathologic lateralization of the auditory brain because stimuli presented to the ear contralateral to a damaged hemisphere may be not be reported [ Hugdahl and Carlsson, 1994 ; Nass et al., 1992 ].

Electrophysiologic hearing tests
The advent of electrophysiologic hearing tests has revolutionized pediatric audiometry and enabled universal neonatal screening, as well as definitive assessment, without the need for a behavioral response, even in uncooperative, multiply handicapped youngsters. Some tests necessitate sedation or general anesthesia. Most physiologic tests do not ensure that sound has been “heard” – that is, processed – to elicit a response.

Acoustic Immittance and Middle Ear Reflexes
Acoustic immittance quantifies the compliance of the eardrum and middle-ear transducer (ossicular chain, stapes footplate). It is widely used to screen for middle-ear effusions and other hearing anomalies [ Katz, 2002 ; Nozza, 1996 ]. Tympanometry consists of introducing air under measured pressure into the occluded external canal and aspirating it to assess the compliance and mobility of the eardrum. Eustachian tube occlusion results in negative middle-ear pressure, which stiffens (decreases the compliance of) the tympanic membrane. Negative middle-ear pressure causes secretion of incompressible fluid (serous otitis media, glue ear if the effusion is chronic and inspissated), which immobilizes the tympanic membrane.
An immobile or perforated drum, or an open ventilating tube precludes recording of the acoustic reflex. This reflex is caused by contraction of the stapedius muscle in response to a loud sound (at least 40 dB, usually 70–90 dB above normal hearing threshold). Its presence indicates that the middle-ear transducer is intact, the middle ear is aerated, and the acoustic (cranial nerve VIII) to facial (cranial nerve VII) reflex arc is intact, including its relays in the brainstem. It is abolished in auditory and facial neuropathies and in brainstem pathologies that interrupt their connection. The acoustic reflex is not a test of auditory sensitivity. It is useful for localizing the site of pathology in patients with Bell’s palsies: present when the pathologic process responsible for the facial palsy is distal to the middle ear, absent when the process is proximal to the nerve to the stapedius muscle. It is abolished or its threshold elevated in cochlear deafness and “auditory neuropathies,” brainstem tumors, leukemic meningeal infiltration, and other more central processes.

Otoacoustic Emissions (OAEs)
Bending of the stereocilia of the outer hair cells in response to clicks or tones generates transient narrowband sounds (OAEs) detectable above background emissions. These OAEs can be measured if highly amplified with a probe in the external ear canal, provided the middle-ear transducer and outer hair cells are functional ( Figure 7-7 ). Recording of OAEs is now automated, easy, and quick, and the results are reliable over a wide range of frequencies. OAE testing only exceptionally requires sedation; it is noninvasive and much cheaper than electrocochleography in the operating room, and faster than BAER or ABR. These qualities make OAE a suitable relatively inexpensive test for universal neonatal screening [ Norton et al., 2000 ; Morton and Nance, 2006 ]. The recommendation is to test, twice within a few weeks, those infants who fail the neonatal screen because about 10 percent of results are false-positives generally caused by amniotic fluid in the middle ear. If the infant fails again, brainstem-evoked responses are needed to corroborate the result; in fact, some audiologists recommend using ABR in the neonatal nursery if no OAEs are detected. OAEs are especially useful for detecting mild-to-moderate hearing loss, such as that caused by middle or inner ear pathology, or for monitoring early signs of antibiotic or antineoplastic ototoxicity [ Stavroulaki et al., 2001 , 2002 ]. As stressed several times earlier, the presence of OAEs is deceptive when pathology is selective for the inner hair cell or type I spiral ganglion neurons: e.g., in occasional carriers of the GBJ2 gene, which codes for the gap junction connexin 26 [ Santarelli et al., 2008 ], those with OPA1 mutations, who lack otoferlin at the mutation between inner hair cells and type I spiral ganglion cell dendrites, and others with “acoustic neuropathy,” as seems to be the case in some sick newborns with some auditory pathologies, including hyperbilirubinemia [ Amatuzzi et al., 2001 , 2011 ].

Fig. 7-7 Averaged transient evoked otoacoustic emission recording in an ear of a 7.5-year-old girl with normal hearing.
A, Amplitude scale to permit examination of the input (click) stimulus. The stimulus was an 83-dB sound pressure level and was presented repeatedly. B, Amplified view of the time course of the evoked otoacoustic emission recorded from the external ear canal, with the first 4 milliseconds of the trace blanking out the stimulus artifact. Two separate averages are superimposed to show the high level of reproducibility. C, Frequency spectrum of the response versus background noise in the ear canal (shaded blue), demonstrating an excellent signal-to-noise ratio and therefore unequivocal outer hair cell function across all the frequencies up to 6 kHz. The output displays provided by clinical instruments include the number of stimuli that entered into the average, the number and percentage of stimuli automatically rejected because of excessive noise, the reproducibility of the two recorded waves, and the elapsed test time.
(From Durant JD. Physical and physiologic bases of hearing. In: Bluestone CD, Stool SE, Kenna MA, eds. Pediatric otolaryngology, 3rd edn. Philadelphia: WB Saunders, 1996.)
Transient suppression of the OAEs by presenting a loud stimulus to the contralateral ear and recording OAEs (and compound action potential) with measurably damped amplitude denotes an intact bilateral brainstem reflex which stimulates the olivocochlear bundle, thus inhibiting the outer hair cells. Like the acoustic stapedius reflex, its input depends on functioning ipsilateral inner hair cells, type I spiral ganglion cells, eighth nerve, and brainstem cochlear nucleus, but its output, measured contralaterally, signals integrity of the superior olivary complex, olivocochlear bundle, and outer hair cells [ Hood and Berlin, 2009 ].

Electrocochleography and Cochlear Potentials
A number of electric potentials are generated in the cochlea in response to sounds of various frequencies. They are recorded optimally with a transtympanic electrode at the round window, which requires anesthesia in children [ Pickles, 1997 ; McMahon et al., 2009 ]. Electrocochleography has become increasingly important for deciding about the eligibility of hearing-impaired individuals for a cochlear implantat. It provides reasonably reliable data on the selective function of the outer hair cells (cochlear microphonic function), dendrites of the type I spiral ganglion neurons (dendritic potential), the activation of these neurons (summating potential), and the compound action potential generated in their synchronously discharging axons (auditory nerve).

Brainstem Auditory-Evoked Responses/Auditory Brainstem Responses (BAER/ABR)
ABR testing does not require cooperation from the subject; it can be performed reliably at any age, whether the child is awake, asleep, or anesthetized. It is an ideal technique to supplement behavioral audiometry in hard-to-test infants and children. Its disadvantage is that it often requires sedation. As just stated, ABR testing is widely used in neonatal screening, often in conjunction with OAEs. Presence of an ABR does not rule out pathology above the level of the superior colliculus, thus “hearing.” This limitation does not detract from ABR’s usefulness because these higher deficits are much less prevalent than more peripheral pathologies. ABRs to clicks provide data on the collective response to sounds containing energy at frequencies of 100–8000 Hz and on the function of each of the relays of the auditory pathway. For audiometric applications where frequency-specific threshold estimates are required, it is important also to obtain ABRs to either brief tone bursts or notched white noise [ Stapells et al., 1995 ]. For example, reproducible responses to 500 and 2000 Hz at intensities of 30 and 20 dB above normal hearing level for these stimuli almost certainly indicate normal peripheral sensitivity. In infants with microtia or an extremely narrow canal, or when it is crucial to determine that hearing loss is conductive rather than sensorineural, the stimuli can be presented through a bone oscillator.
The five waves of the ABR reflect activation of each of the relays of the auditory pathway: the auditory nerve, cochlear nucleus, superior olivary complex, nucleus of the lateral lemniscus, and inferior colliculus or structures in their vicinities. Averaging techniques enable the recording from the scalp of the tiny negative compound action potential of the auditory nerve, called wave I of the ABR ( Figure 7-8 ). In normally hearing adolescents and adults, the average latency of wave I to clicks is 1.5 msec (maximum 1.9 msec) at high intensity, and the average latency of wave V, the largest, is 5.5 msec (maximum 5.9 msec). Latency is longer at low intensities and in infants [ Stapells and Oates, 1997 ]. Absence of the ABR may indicate peripheral sensorineural hearing loss, or dys-synchronous conduction due to an axonopathy in either the auditory nerve or the brainstem [ Sininger and Starr, 2001 ]. Alone, absence of wave I does not discriminate between pathologies in the inner hair cells, their synapses with the spiral ganglion cells, or spiral ganglion cell/auditory nerve pathology. Absence of wave I (and later waves) with absent OAE signifies peripheral hearing loss; absence of wave I with recordable OAE (and cochlear microphonic function) suggests either selective damage to the spiral ganglion cells or a true auditory neuropathy with preservation of the hair cells, or at least of the inner hair cells. Sparing of wave I with absent later waves or prolonged interwave interval suggests intrinsic brainstem pathology such as by demyelination or a neoplasm. Increased interpeak latency between waves I and III points to a demyelinating auditory neuropathy, and between waves III and V, to a pathologic process in the brainstem. Compression of the acoustic nerve by an acoustic tumor may prolong or suppress waves I–III and affect later waves.

Fig. 7-8 Components of the scalp-recorded averaged auditory-evoked responses to 1000 clicks presented at 60 dB above the subject’s threshold.
Each panel contains four different trials superimposed to show the reliability of the responses. Notice the different time scales on the abscissas and different amplitude scales on the ordinates. The top panel shows the seven waves of the brainstem response, the middle panel shows the middle components, and the lower panel shows the early obligatory cortical waves. Negativity at the vertex electrode produces an upward deflection.
(From Durant JD. Physical and physiologic bases of hearing. In: Bluestone CD, Stool SE, Kenna MA, eds. Pediatric otolaryngology, 3rd edn. Philadelphia: WB Saunders, 1996.)
Transmission time is prolonged in premature infants and newborns, and decreases with maturity as myelination advances. It is often prolonged transiently in stressed neonates and some young children, but prolonged transmission time alone is rarely predictive of future neurologic, auditory, or cognitive deficits. To reiterate for neurologists, the audiologists’ definition of “auditory neuropathy” does not necessarily imply a neuropathy of the eighth nerve [ Marsh and Kazahaya, 2009 ]; rather, it means absent ABR or distorted ABR with prolonged latency, preserved OAE, and more severely impaired speech discrimination and production than predictable from the behavioral audiogram, which may reveal anything from normal to severely impaired hearing threshold.

Subcortical and Cortical Tests
For clinical purposes, later cortical potentials are less useful gauges of hearing sensitivity than brainstem potentials, primarily because they are altered by changes in alertness and sleep phase. Some of their components provide physiologic correlates of the later stages of auditory perception and discrimination [ Hood and Berlin, 2003 ]. They are therefore very useful for research into the brain basis of auditory processing and language disorders because they supplement functional imaging by providing data about hearing in the msec time domain.
Physiologic activation of higher relays of the central auditory pathway can be recorded with averaging (see Figure 7-8 ) [ Steinschneider and Dunn, 2002 ]. The somewhat inconsistently recordable waves VI and VII of the brainstem response are believed to reflect activity in the vicinity of the medial geniculate body and auditory radiations. So-called middle latency potentials [ Kraus and McGee, 1990 ], which have a latency of about 15–80 msec, may reflect activation of the acoustic radiations and initial activation of the auditory cortex. Later obligatory potentials originate in the primary and secondary auditory cortices and are recorded with maximum amplitude at the vertex of the scalp because of the geometry of the primary auditory cortex, which lies horizontally in the planum temporale of the Sylvian fissure. The mismatch negativity, a frontocentral potential with a latency range of 60–120 msec, is recorded when the response to infrequent auditory stimuli, interspersed unpredictably among frequent stimuli, is subtracted from the response to the frequent stimuli. As the mismatch negativity does not require attention or the generation of a behavioral response, it may be suitable to test auditory discrimination in infants or uncooperative children [ Steinschneider and Dunn, 2002 ].
Later components of auditory event-related potentials (ERPs) differ by their latencies and topographies, and they are contingent on the cognitive processing of various aspects of the signal. These later components depend on what parts of the language-processing cortical areas are activated when subjects are required to respond to various phonologic, syntactic, or semantic aspects of language. For example, Steinschneider and Dunn [ Steinschneider and Dunn, 2002 ] recorded differences in evoked responses to voiced consonants such as d, compared with unvoiced consonants such as t, generated in auditory cortex in monkeys and humans. Neville and Mills [ Neville and Mills, 1997 ; Mills and Neville, 1997 ] have studied electrophysiologic correlates of grammatical maturation by examining changes in a negative complex recorded over the anterior temporal or frontal cortex of the left hemisphere (including Broca’s area) in response to closed class words such as articles, prepositions, and conjunctions. They further studied correlates of semantic maturation by examining changes in a negative complex recorded from temporoparietal loci (including Wernicke’s area) in response to open class words such as nouns, verbs, and adjectives. They also used evoked responses to study the emergence of word comprehension in normal and language-delayed toddlers. Dunn and colleagues [ Dunn and Bates, 2005 ] were able to characterize differences in semantic processing (i.e., organization of the lexicon or repository of word meanings) in verbal children with autism compared to normal subjects. Together with imaging, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT), these electrophysiologic techniques make it possible to identify the cortical and subcortical circuitry that participates in the various stages of auditory and language processing.

Imaging of the Ear
In neonates, the bony labyrinth is seen on transorbital view of a plain skull radiograph because the otic capsule is fully grown at birth and proportionately larger and better calcified than the remainder of the skull. High-resolution, thin-cut, and tridimensional CT and MRI have added an entirely new dimension to the imaging of the ear [ Westerhof et al., 2001 ; King et al., 2002 ]. Every structure from the external canal to the internal auditory meatus, and the many pathologies and malformations that can affect them, are depicted clearly, but interpretation requires expertise. The yield of radiologic examination of the temporal bones is much higher when the hearing loss is mixed, conductive, or fluctuating, and when there are malformations in other organ systems than in nonsyndromic hearing loss. Imaging, together with sophisticated electrophysiology, is critical in children who are being considered for cochlear implants because a patent scala tympani and viable spiral ganglion cells are prerequisites. Prostheses applied to the brainstem may be effective when the cochlea is unsuitable for an implant [ Grayeli et al., 2003 ].

Miscellaneous Blood, Urine, and Other Tests
By far the most prevalent viral infection causing hearing loss today is congenital CMV, which can be recovered from the urine, in some infants for months, and be responsible for progressive or fluctuating loss [ Fowler et al., 1997 ; Rosenthal et al., 2009 ]. High levels of immunoglobulin M suggest an active infection in the neonate, whereas high immunoglobulin G levels are acquired passively from the mother. Many neonates are not visibly infected and later antibody titers are of limited value because most young children acquire CMV asymptomatically. A deaf child born with a cataract or chorioretinitis almost certainly was infected with rubella or CMV because, among the other TORCH infections, toxoplasmosis rarely causes deafness, herpes simplex probably does not, and syphilis does but in later childhood [ Boppana et al., 1997 ; Chess et al., 1971 ]. Further epidemiologic studies are needed to assess the relative importance of CMV infection as a cause of sporadic hearing loss.
Congenital hypothyroidism with goiter (e.g., cretinism) due to iodine deficiency used to be a prominent cause of hearing loss but only remains so in small pockets of the world [ Squatrito et al., 1981 ]. Individuals with Pendred’s syndrome are euthyroid despite progressive or fluctuating goiters in adolescence. Diagnosis based on the perchorate discharge test is less reliable and informative than genetic testing [ Campbell et al., 2001 ).
Children with genetic hearing losses must, at a minimum, have a urinalysis, perhaps on a yearly basis, because a literature search reveals many dozens of syndromes in which hearing loss may be associated with renal or genitourinary anomalies. The yield is highest in, but by no means limited to, those with syndromic hearing loss. Hearing loss with anomalies of the external and middle ear, including tags and fistulas, requires kidney imaging because as many as 10 percent may have serious genitourinary anomalies [ Senel et al., 2009 ; Kochhar et al., 2007 ). Alport’s syndrome, with dominant, recessive, or X-linked inheritance, associates progressive life-threatening nephritis with hematuria and progressive hearing loss [ Hertz, 2009 ]. Waardenburg’s syndrome is occasionally associated with renal anomalies [ Ekinci et al., 2005 ].
All deaf children must have an electrocardiogram to exclude the rare but life-threatening long Q–T syndrome (Jervell and Lange–Nielsen syndrome), a potassium channelopathy responsible for both the heart dysrhythmia and the deafness with vestibular impairment [ Crotti et al., 2008 ]. The syncopal attacks may be mistaken for seizures, a major error because many of these children have died suddenly and unexpectedly, but might otherwise have been treated effectively with a noradrenergic beta-blocker or a pacemaker. Other tests for heart disease need to be considered in congenital rubella and a number of hearing loss syndromes.

Genetic Testing and Counseling
Children suspected of having a genetic disease known to be associated with hearing loss – like Hunter-type mucopolysaccharidosis [ Cho et al., 2008 ], for example – require genetic confirmation. How far to pursue a specific diagnosis in undiagnosed children with suspected genetic disease or sporadic hearing loss is currently in flux. The number of “deafness genes” for which there is now a definitive genetic test stands at well over 100. Gene microarrays provide the opportunity to test for hundreds of genes simultaneously, without the need for a candidate gene, but they remain expensive. Genetic testing has led to stunning progress toward clarifying the pathophysiology of deafness, but it rarely has an impact on the proband. Many centers test sporadic nonsyndromic profound congenital hearing loss for connexin 26 because it accounts for some half of the cases [ Petersen and Willems, 2006 ]. A major reason to pursue a specific genetic diagnosis, besides pointing to potential associated problems, is genetic counseling.
Several hundred mutations are estimated to be responsible for genetic hearing losses. Carrier frequency in the general hearing population for the connexin 26 mutations, the most prevalent cause of recessive nonsyndromic hearing loss, is more than 1 in 100 and as high as 1 in 30 in some regions, with strong evidence of founder effects [ Mercier et al., 2005 ; Gasparini et al., 2000 ]. There are no figures for overall carrier frequency for deafness, but given the very large number of recessive genes discovered so far, an estimate of 1 in 4 may not be unreasonable. The probability of unrelated hearing parents having a second hearing-impaired child if the cause of deafness in the older child is unknown is at least 1 in 10, a composite of the general population risk for deafness of 1 in 1000 and of 1 in 4 when the deafness is genetic and recessive, plus 1 in 2 when it is dominant but not expressed (or unrecognized) in one of the parents. The empirically derived recurrence risk of 1 in 10, applicable with minor deviations worldwide, indicates that sporadic deafness is much more likely to be genetic than acquired. An earlier survey in 1969–70 suggested that 62.8 percent of deafness was genetically caused (47.1 percent of cases recessive, 15.7 percent dominant), and the sporadic 37.2 percent remainder mainly acquired [ Marazita et al., 1993 ]. More recent estimates are quite similar: approximately 30 percent acquired [ Morton and Nance, 2006 ]. An unknown proportion of the sporadic cases may be isolated autosomal-recessive cases, an assumption supported by the report that, in Jerusalem, the prevalence of childhood deafness decreased in parallel with the diminishing rate of consanguinity [ Feinmesser et al., 1990 ]. Parents must be told that autosomal-recessive inheritance cannot be excluded when the cause of their child’s hearing loss is unknown.
There are two reasons, besides research, to offer genetic testing: first, for the benefit of probands, and second, for providing interested parents, families, and, in the future, probands with genetic counseling . Clinical benefits for probands lie mainly in discovering the likelihood of involvement of other tissues, such as the retina, heart, kidney, or inner ear malformations, with potentially deleterious consequences; as pointed out above, other recommended and less expensive screening tests can identify most such involvement. Testing for specific mutations is indicated in what were previously viewed as single-gene deafness diseases, which we now know can arise from separate genes with quite different prognoses: e.g., Usher’s syndrome [ Ouyang et al., 2005 ], Alport’s disease [ Hertz, 2009 ], the long Q–T interval [ Crotti et al., 2008 ], Pendred’s syndrome [ Pera et al., 2008 ], and others. Genetic counseling regarding the risk for future pregnancies is a major reason for offering genetic testing. Prenatal diagnosis is desired by many parents of children with hearing loss [ Brunger et al., 2000 ], especially when hearing loss is part of a major systemic illness or multiorgan malformation syndrome like the CHARGE association [ Jyonouchi et al., 2009 ] and arguably Usher’s syndrome type I. Prenatal genetic diagnosis for the consideration of selective abortion in isolated nonsyndromic hearing loss is quite another matter, hotly debated, not only in the deafness community but by ethicists as well. How individuals in the current generation who have benefited from cochlear implants will feel about genetic counseling in the future is an open question. The number of genetic causes of hearing loss, which now include mitochondrial genetics, microRNAs, and epigenetic influences, is so large and growing so rapidly that even recent reviews are out of date. Sophisticated genetic counseling is time-consuming and requires consulting up-to-date electronic resources such as Online Mendelian Inheritance in Man (OMIM) ( http://www.ncbi.nlm.nih.gov/omim/ ), Hereditary Hearing Loss Homepage (HHH) ( http://hereditaryhearingloss.org ) and syndrome-specific Connexin Deafness Homepage ( http://davinci.crg.es/deafness ).
Testing for research is crucial, as it has reaped countless benefits for understanding the cellular pathophysiology of deafness, but it needs to be clearly labeled as such and the way it is paid for discussed openly. Public or private research funds, not out-of-pocket expense or charges to public or private medical insurance, are the legitimate sources of support for genetic testing for research. Genetic testing and the development of animal models based on it are responsible for spectacular progress in understanding the workings of the cochlea [ Dror and Avraham, 2009 ]. They have also revealed how much more complicated than anticipated hearing is at the molecular and cellular level. Genetic results have spilled over into the understanding of parallel pathways in other organs like the heart, muscle, and eye. The deaf community is very interested in this research, but understandably wants transparency in its purposes and manner of funding.

Psychologic Evaluation
Hearing speech is a major vehicle for incidental learning that is unavailable to deaf children. Television has little meaning without sound, and signed captions are available for only a few selected programs. With the exception of the most proficient implanted or amplified children, most deaf children lag behind hearing children by several years in learning to read fluently enough to read printed captions on TV, or read for pleasure or as an efficient means for gaining information. Even today, most of the unimplanted (and an unknown fraction of the implanted) do not achieve this level of proficiency [ Conrad, 1979 ; DiFrancesca, 1972 ]. Their school experience is likely to be less enriching than that of their hearing peers, especially as much time is consumed, at least in the early grades, by learning language and, later, by attempting academic catch-up. Even normally intelligent deaf children are likely to suffer severe experiential and cultural deprivation. A study performed by Furth (1966) found that they knew and experienced less than their hearing peers, and impoverished language for thought altered their cognitive experience. This is still the case for many children who risk being marginalized in the adult workplace.
Not surprisingly, unimplanted deaf children tend to do dramatically less well than hearing children on verbal portions of intelligence test batteries; however, some of them inexplicably also do less well on nonverbal tests, perhaps because they have an unrelated learning disability or are penalized by their meager language because verbal ability for many people is advantageous for carrying out ostensibly nonverbal memory or picture arrangement tasks. A few psychologic test batteries have been developed and standardized for deaf populations such as the Wechsler Scales, Central Institute for the Deaf Preschool Performance Scale [ Geers and Lane, 1984 ], Snijders–Oomen Non-Verbal Intelligence Scale [ Snijders et al., 1988 ], and Leiter International Performance Scale [ Roid and Miller, 1997 ]. Others can be administered verbally or nonverbally; these include the Hiskey–Nebraska Test of Learning Aptitude [ Hiskey, 1966 ], which has lower norms for deaf than hearing children, and the Raven Matrices [ Raven, 2003 ]. Although there are encouraging reports on the achievements of implanted children, it is still too early to determine how many of them will match their hearing peers. While there have always been some exceptional deaf individuals who have performed at the highest level of intellectual and professional ability, as a result of frequently associated brain anomalies, the difficulty of acquiring language skills in a hearing world, and the inadequacy of conventional IQ testing in atypical populations [ Lane, 1992 ], they represent a small minority of the congenitally deaf. It is still too early to evaluate to what extent cochlear implants will reverse this disparity in adults fortunate enough to have been implanted early and to have received the intensive training required to profit optimally from these prostheses.

Brain, Language, and Intellectual Consequences of Auditory Deprivation
It might be assumed that deafness, which affects a peripheral receptor and not the brain, should have no effect on cognitive competence, especially during development; however, deprivation of input through one of the major sensory channels changes brain structure and function profoundly [ Sharma et al., 2009 ]. It also drastically changes the environment that shapes development. Abundant anatomic and physiologic evidence testifies to alteration of cortico-cortical and cortico-subcortical connectivity of the brain in sensory deprivation. Laboratory evidence in a number of species, as well as human electrophysiologic, functional imaging, and neuropsychologic studies, documents deviations from expectation [ Proksch and Bavelier, 2002 ]. Cross-modal plasticity reflects alteration in multimodal cortical areas and, due to pruning of fibers receiving no inputs from the missing modality, those from other sensory modalities occupy receptor sites in sensory cortex deprived of what should have been its dominant input [ Roeder and Neville, 2003 ]. There is no increase in auditory sensitivity or somatosensory threshold in the congenitally blind, yet there is enhanced function in these modalities, especially with training, enabling efficient Braille reading, remarkable auditory memory, and, in more than a few blind individuals, exceptional talent for music. The reciprocal situation exists in congenital or early childhood deafness, which results in enhanced perception of movement in the peripheral visual fields [ Bavelier et al., 2000 ].
In normal 6-month-old infants followed for the next 2 years, the extent of cortical activity elicited by auditory stimuli over visual brain regions shrink, illustrating a decrease with maturation of cross-modal electrophysiologic function [ Neville and Bavelier, 2002 ]. Such observations suggest that there is a limited time frame, up to age 7 years, for an auditory prosthesis to foster optimal development of auditory cortex [ Sharma et al., 2009 ]. Better acquisition of speech after cochlear implantation in young versus older congenitally deaf children supports this contention [ Govaerts et al., 2002 ], although some degree of plasticity remains even in adults, as demonstrated by reorganization of tonotopic projections to auditory cortex in acquired high-tone loss [ Dietrich et al., 2001 ]. At a minimum, deafness affects the life experience of the child (and family) profoundly, which has consequences for brain organization, intelligence, and personality [ Mayberry, 2003 ; Rapin, 1979 ].
The most serious consequence of lack of hearing is information deprivation. Deaf children of hearing parents, who represent more than 90 percent of severely hearing-impaired children, are much more seriously deprived than deaf children of deaf parents who use American Sign Language (ASL) as their primary language [ Schlesinger and Meadow, 1972 ]. Deaf children of deaf parents learn ASL at the language-learning age and communicate normally with their parents. There are several reasons why normal communication with parents is unlikely to develop in the deaf child of hearing parents: diagnosis of hearing loss may be delayed and speech (lip) reading is a grossly inefficient way to learn language. At best, early intervention provides hearing aids and a few hours a day of exposure to fluent signers, while many hearing parents of deaf children are reluctant to learn sign language; even if they do eventually learn it, few achieve fluency. The false expectation that a cochlear implant will restore normal hearing and that language will soon follow has resurrected antagonism against Sign in hearing parents and some professionals. If early cochlear implantation is not available, many deaf children of hearing parents are likely to develop with only the gestures (“home sign”) they and their parents have devised as their means of communication until they enter a school for the deaf. The situation is aggravated for immigrant families who speak a different language at home than the one taught in school. Language development is innate in the young child; this was documented by the observation that unrelated deaf children brought together rapidly created, without any adult intervention, what became a fully functional new sign language, with not only its own shared vocabulary but also its own grammar – in other words, a complete language [ Senghas et al., 2004 ].
Early cochlear implants are enabling normally intelligent deaf children provided with intensive habilitation to become surprisingly proficient in oral language, so that even their signing deaf parents, some of whom were previously opposed to implantation, are seeing the advantage for their children of bilingualism in oral language and Sign [ Christiansen and Leigh, 2004 ]. With the exception of children with severely compromised cognition, some children with moderate retardation profit from implants, so that most are provided with implants in affluent countries, albeit not always as early as would be desirable. But to reiterate, this expensive technology is out of reach for most children with hearing loss in the world, at least today, because it requires a surgical procedure, electronic instrumentation, meticulous technical servicing and recalibration of the device, and on-going, intensive anditory/language training for a number of years. Consequently, emphasis on early exposure to fluent signers remains desirable to promote bilingualism at the language-learning age, a fact that is widely misunderstood and rejected.

Management

Amplification and Hearing Aids
As some genetic and nongenetic hearing loss, notably that due to congenital CMV infection, is progressive, audiograms must be obtained regularly throughout childhood. Hearing aids are variable gain amplifiers inserted into the external ear canal. They must be evaluated at regular intervals so that they continue to fit snugly in the growing ear canal. Behind-the-ear miniaturized hearing aids yield as much amplification as the body-worn aids of the past. Their smallness does have disadvantages: easier loss and damage.
All infants and children with a significant hearing loss must be fitted forthwith with hearing aids by trained pediatric audiologists who select optimal amplification devices to fit each child’s particular needs so as to maximize the development of residual auditory function [ Chase and Gravel, 1996 ; Roeser et al., 1995 ]. Cochlear implantation should be considered promptly as early as the age of 6 months if the loss is severe or profound (see below). Amplification is especially effective for children with conductive loss, who derive more benefit from amplification than children with sensorineural hearing loss because their inner ears are normal and the aid bypasses their defective mechanical sound transducers. Children with atresia can be fitted with bone oscillators. Some hard-of-hearing children have difficulty accepting a hearing aid inasmuch as amplification may make them perceive moderately intense sounds and ambient noise as intolerably loud (i.e., recruitment). Advanced prescriptive fitting techniques and wide dynamic range compression circuitry allow output-limiting characteristics to be determined and verified instrumentally, even in very young children. Children with high-tone and other nonflat hearing loss require hearing aids with selective frequency amplification fitted to the shape of their individual thresholds. Even profoundly deaf children may gain awareness of sound despite their having little discrimination.
It is essential to explain to parents that hearing aids do not restore hearing and only bring within the child’s narrow hearing window sounds that would otherwise be below hearing threshold. The aids do so at the expense of distortion of amplitude (and often frequency) and loss of signal-to-noise ratio. Sound cannot be amplified to the point of acoustic trauma, which occurs at equal intensity in normal and impaired ears.
Radio-frequency FM closed-loop listening systems are widely used in schools for the deaf, in some mainstream educational settings, and by some parents. The advantage of such a system is that each child receives the amplified speech signal from the speaker in his or her hearing aids, with much less amplification of background noise than with standard hearing aids which amplify unselectively. The teacher or parent can wear a transmitter and the child the FM receiver, enabling some severely hearing-impaired children to be mainstreamed into normal classrooms. Schools for the deaf insist that all children wear hearing aids in school, at least during the elementary years. Many of the profoundly deaf adolescents and adults who derive little or no benefit from aids choose not to wear them. Usually binaural aids are prescribed so that children have access to cues for sound localization and can benefit from better hearing in noisy backgrounds [ Chase and Gravel, 1996 ].
Surprisingly, it turns out that some children with severe unilateral hearing loss are at somewhat of a disadvantage for language development and academic achievement [ Lieu, 2004 ]. Children with unilateral (or bilateral) anotia, microtia, or canal atresia need to be fitted with a bone conduction hearing aid soon after birth; after age 4 years, when skull growth is essentially complete, they can be fitted with an implanted bone conduction hearing aid [ Snik et al., 2008 ]. It is generally recommended that children with unilateral losses be provided with an aid, despite normal hearing contralaterally, because a significant proportion of them experience academic difficulties [ Lieu, 2004 ]. A variety of approaches have been recommended to improve sound localization, including provision of an FM system in their classrooms [ Updike, 1994 ].

Cochlear Implants
In developed countries, cochlear implants now dominate management of severe to profound hearing loss in children [ Papsin and Gordon, 2007 ]. A cochlear implant is a complex electronic prosthesis with five main parts: three external and two implanted. The external components are (1) a microphone that picks up sound signals and sends them to (2) a speech processor that selects the sounds to be passed on to (3) a transmitter worn on the scalp. The transmitter transfers the signals through the scalp to (4) an implanted receiver/stimulator anchored to the skull under the scalp, sitting opposite to the external transmitter. This computerized device digitizes sound signals into electronic pulses of graded frequencies that it transmits to (5) stimulating electrodes on very thin wires of variable calibrated lengths bearing stimulating electrodes. The wires are bundled and inserted into the scala tympani under the basilar membrane, enabling the electrodes to stimulate the spiral ganglion neurons’ dendrites tonotopically, according to their positions along the basilar membrane [ Wilson and Dorman, 2008 ]. Implant technology keeps improving and recent cochlear prostheses, which enable superior speech discrimination, are multichannel and programmable. A cochlear implant costs $40,000–$60,000, and to be optimally effective has on-going costs; the unit requires close follow-up to monitor its calibration and performance, and children require intensive long-term speech and language training if they are to achieve good speech comprehension and adequate intelligibility, given the coarseness of the device’s input compared to ear’s ability to code the richness of natural speech signals. Its cost puts it out of reach of all but a small minority of children in developing countries, although considerably cheaper instrumentation is under development [ An et al., 2008 ].
Observations over more than a dozen years indicate that cochlear implants are reassuringly safe and maintain their effectiveness in the long term. Originally – and some still hold this view – unilateral implantation was recommended in order to reserve the other ear in case of a major complication in the implanted side, or in case of a future major technologic breakthrough. A new trend is bilateral simultaneous implantation so as to enhance sound localization and mitigate interfering ambient noise effects [ Eapen and Buchman, 2009 ; Papsin and Gordon, 2007 ]. Follow-up studies indicate that bilateral implantation is superior to unilateral in that it optimizes language learning and speech intelligibility because it increases discrimination. Unilateral insertion remains widely used and quite effective.
Most complications occurred within 5 years among 500 consecutive implants at all ages in one center. The overall rate was 16 percent, minor in 5.6 percent, major in 3.2 percent, and reimplantation, usually successful, had to be done in 7.2 percent [ Venail et al., 2008 ]. Only a handful of postmortem evaluations of long-term effects of prostheses on the cochlea have appeared so far [ Kawano et al., 1998 ]. Granuloma in the cochlea [ Nadol et al., 2008 ], and new bone formation and fibrosis along the electrode [ Somdas et al., 2007 ] were described, but their prevalence awaits study of a larger number of specimens. There are very rare reports of damage upon insertion [ Verbist et al., 2009 ] and of delayed meningitis because of the artificial communication between the middle ear and scala tympani created by the implant [ Reefhuis et al., 2003 ; Papsin and Gordon, 2007 ]. This risk mandates routine immunization against Streptococcus pneumoniae for all implanted children [ Wilson-Clark et al., 2006 ].
The etiology of the severe or profound hearing loss being considered for implantation is marginally relevant. As already stated, the prosthesis requires a patent scala tympani and a sufficient contingent of functional spiral ganglion neurons. Therefore CT and detailed electrophysiologic testing to establish neuronal viability are mandatory. Development of a prosthesis directly stimulating the brainstem auditory pathway for persons in whom cochlear implantation is impossible is at an early stage of development [ Colletti et al., 2007 ].
Age at implantation is important [ Amatuzzi et al., 2011 ]. As discussed earlier, neonatal screening yields an occasional false diagnosis of deafness, presumably due to a potentially reversible neonatal insult like hyperbilirubinemia or hypoxia [ Attias and Raveh, 2007 ; Amatuzzi et al., 2001 ], or perhaps amniotic fluid in the middle ear, or conversely a false diagnosis of adequate hearing if only OAEs without ABRs were used for screening. Therefore, implantation is not recommended until after age 6 months, when a definitive audiometric curve will have been established, the scalp will be thicker, the skull and mastoid will have grown substantially, and the risks of anesthesia are lower. Infancy, between 6 and at most 24 months, the language-learning age, is the optimal age for implantation [ Cheng et al., 1999 ], although later implantation still provides substantial though shrinking benefit [ Beadle et al., 2005 ]. Superiority of the prosthesis over hearing aid amplification is especially marked for speech articulation [ Flipsen, Jr., 2008 ; Artieres et al., 2009 ].
By now, several thousand prelingually deaf children have been implanted worldwide, and age at implantation and intensity of postimplantation habilitation are shown to be major factors for enabling profoundly deaf children to be mainstreamed [ Geers et al., 2003 ]. Speech production and especially intelligibility remain low for many months after implantation, and comprehension is limited, except for words that have been taught specifically. With intensive intervention, young children eventually reach the stage of “picking up” oral language. This considerable delay after implantation has raised the issue of whether to continue the use of sign language to assist communication. Most oralist educators are vehemently opposed to Sign. Others point out that continued exposure to Sign is helpful to prelingually deaf children while intensive therapy is teaching them what hearing and speech are all about because it provides them with an effective means for communication and explanation. Deaf children at the language-learning age can “pick up” Sign without instruction if exposed to fluent signers for an adequate number of waking hours. In Sweden, commitment of the parents to becoming proficient in Sign and continuing to use it is the norm for implanted children. Follow-up several years after implantation found that good speakers were also good signers; in fact, they had become bilingual [ Preisler et al., 2002 ]. Some members of the deaf community, especially deaf parents of deaf children, have mixed feelings about cochlear implants, fearing that the children will distance themselves and give up the rich cultural heritage of that community. Understandably, they want their children to be fluent signers as well as speakers. Some are justifiably anxious about the short- and long-term demands and potential complications of implants [ Christiansen and Leigh, 2004 ].

Reconstructive Surgery
Reconstructive surgery for external and middle ear malformations is contraindicated in very young children because they are at high risk for middle-ear infections. Even in older children, middle-ear reconstruction carries with it the small danger of adding a sensorineural component to the conductive loss. Unilateral surgery is usually recommended. Bone oscillation hearing aids, particularly those anchored internally to the mastoid, invariably give good results, whereas the outcome of reconstructive surgery is somewhat problematic [ Raveh et al., 2002 ; Siegert, 2003 ]. In severe microtia or anotia, exploration of the middle ear, and creation of an ear canal, tympanic membrane, and an acceptable pinna, entail several stages of plastic and otologic procedures carried out in middle childhood or the teenage years, when important cosmetic and functional benefits balance out their burden [ Siegert, 2003 ].

Education
Since the enactment of U.S. Public Law 94-142 in 1975, a variety of infant auditory training programs have become available to any infant or preschooler younger than 3 years who is identified as hearing-impaired, and most states provide full-day, 11 months per year special education for deaf children, starting at age 3. Programs in different localities differ in detail. Most infant programs are at least partially home-based, provided by an itinerant teacher of the deaf working with parents and child and providing auditory, speech, and language training, including Sign if desired.
Most hard-of-hearing children and those with unilateral hearing loss can be mainstreamed into normal classes from the start, provided they have hearing aids and an FM system, and speak reasonably intelligibly. They need to have access to a part-time special teacher for the hearing-impaired to give them individual academic assistance and to receive on-going speech and language therapy. To attend at least some mainstream classes, those more severely impaired who have inadequate English may require a deaf interpreter and also access to notes and help with reading assignments. Many children with implants are able to function in mainstream classes, although most require on-going individual speech training [ Bosco et al., 2005 ; Geers et al., 2008 ].
A much smaller proportion of the deaf than the hearing population is able to acquire a college education or enter a profession, even though there are specialized universities for the deaf, such as Gallaudet University in Washington, DC; the National Technical Institute for the Deaf at the Rochester Institute of Technology in Rochester, New York; and other smaller programs. What proportion of deaf adolescents who have been implanted early will be able to attend college or technical schools without special help remains to be seen.
How best to educate deaf children who do not have cochlear implants has, for more than a century, been the subject of raging controversy between the proponents of oralism and those who champion the use of sign language plus, at a minimum, competent literacy. One problem is that, starting in the late 19th century, the hearing have prescribed how the deaf should be educated [ Lane, 1984 , 1992 ]. Inevitably, hearing parents would like their deaf children to speak and be educated well enough to blend into the normal population. This aspiration has become much more realistic with the advent of implants. Bilingualism in Sign is highly desirable for the implanted deaf and required for the hearing children of deaf parents who are members of the signing community.
Not all parents and teachers of the deaf understand that implants are doomed to failure when there are no spiral ganglion cells or the eighth nerve is affected by a severe true auditory neuropathy. Persisting with a purely oralist approach in such children is to repeat what was a dismal failure for the majority of the prelingually deaf, and lasted a century, until the resurgence of ASL in the 1980s. Many parents overestimate the efficiency of lip reading, not realizing that many speech sounds are not visible on the lips. Fortunately, TV and education have lessened the stigma of Sign, but by no means does the public truly believe that speaking is but one form of language, and that Sign is just as rich and viable a language as English, Arabic, or Chinese [ Klima and Bellugi, 1979 ; Lane and Philip, 1984 ]. Few people understand the importance of children acquiring language on their own, without instruction, at the normal language-learning-age, i.e., during infancy and the early preschool years, by being exposed to fluent users of a language. Later, languages have to be taught by a much less efficient process; taught languages, especially their phonology, are almost never acquired as well as a person’s native tongue, and taught languages can be shown to occupy cortical areas that differ, with overlaps, from those of the native language [ Neville and Mills, 1997 ]. Because most deaf children without implants who are taught with the oralist approach do not become fully proficient in English, including written English, it is unfair to delay exposing them to Sign until they have failed oralism. We and others strongly believe this also applies to implanted children, not all of whom will profit as much as hoped from the implant.
Deaf and hearing children of deaf parents, who are exposed to the native language of their deaf community, i.e., ASL in the United States, French Sign Language in France, and other sign languages in other countries, begin to express themselves in Sign at an earlier age than hearing children start to speak. Presumably this is because gestures develop earlier than speech, and because producing signs requires less refined motor coordination than producing intelligible words [ Mayberry, 2003 ; Schlesinger and Meadow, 1972 ]. Children whose native language is some form of Sign acquire at the expected age syntactic devices such as the question forms, pronouns, prepositions, etc., of Sign, and they understand that each person, thing, feeling, and action has a name; thus, from the start, they possess a rich and fully adequate vehicle for self-expression.
Like simultaneous translation between any two languages, simultaneous expression in ASL and spoken English is not literal because Sign’s syntax is encoded entirely differently from that of English. Starting in the early 1970s, many deaf educators recommended the use of Signed Exact English for deaf education. Signed Exact English is a contrived language that transliterates English word for word into signs borrowed from ASL; words are produced in their order of appearance in English, and there are signs for English grammatical markers like plurals or tense indicators. It enables speaking and signing to proceed simultaneously (i.e., total communication). It was hoped that this approach would provide deaf children with a channel to express themselves, simultaneously facilitating their learning of English. Although it was a step in the right direction, Signed Exact English is not well suited for a visually coded language; consequently, there is strong movement, that started in the 1980s, toward a return to ASL, which had been banished from many schools for the deaf by well-meaning hearing teachers [ Lane, 1984 ; Sacks, 1989 ].
There is no convincing evidence that learning Sign delays the acquisition of written English. Lane [ Lane, 1992 ], writing before the advent of implants, strongly urged the use of Sign with deaf children, to provide them with a language to serve as a foundation for learning English as a second language. In native signers, learning English at school age can begin by concentrating on proficiency in written language and the alphabetical code. Currently, unimplanted deaf children, even in schools or classes that use Sign, spend much time in speech training, yet most children are grossly deficient in their knowledge of written and spoken English, to the detriment of their educational achievement and general cognitive proficiency [ Conrad, 1979 ; DiFrancesca, 1972 ; Lane, 1992 ]. Happily, cochlear implants are changing this state of affairs, as stressed repeatedly [ Geers et al., 2008 ]. A consequence of this success story is that, as children sufficiently proficient in English and other subjects are increasingly mainstreamed into regular classrooms with appropriate assistance, the population in the shrinking number of schools and classes for the deaf has changed. It now includes a higher proportion of hearing-impaired, multiply handicapped children than in the past, in addition to nonimplanted children by parental choice and those whom the prosthesis did not help.
It is still debatable whether deaf children with minimal knowledge of spoken English perform better in mainstream schools with deaf interpreters and individual tutoring, or in schools for the deaf where everyone uses Sign. It is also uncertain which approach provides “the least restrictive environment” prescribed by U.S. Public Law 94-142. The small number of boarding schools for the deaf remain practical for children who live in small, isolated communities unable to provide special services for one deaf child, especially if the child has multiple needs. Residential placement is much more acceptable than in the past, because it is possible to have children go home for some or all weekends. Residential school placement offers the advantage of deaf peers, the consistent use of Sign by most teachers and caretakers, and the loss of the stigma of being considered handicapped. It may be the least restrictive environment for children from deprived backgrounds whose families are not motivated to learn Sign, cannot provide extensive auditory language training, and may not even speak English, the only language besides ASL used in deaf education in the United States. In day schools for the deaf, such children may have no opportunity to communicate with anyone except during the 6 hours of the 180 school days. Some deaf children have serious behavior problems because their parents may feel guilty over their child’s handicap and are reluctant to discipline him or her, or may not be able to communicate adequately enough with their child to impose parental control. Yet most deaf children do not have severe behavior problems, and deafness alone is not an adequate explanation for autistic behaviors.

Genetic Counseling in Hearing Loss
Providing parents with up-to-date genetic counseling, which was discussed earlier, is an important aspect of management. To reiterate, the following points should be conveyed:
1. Seemingly sporadic hearing loss may well be genetic because many cases are recessive. The most advanced testing, including microarray, can miss very rare or yet to be described genetic causes.
2. Each pregnancy is a new event independent of the previous one. In the case of an identified genetic defect, only risk can be predicted unless the new pregnancy is tested by amniocentesis or chorionic villus sampling.
3. Different mutations of any given gene can result in very different phenotypes. Even sibling carriers of the same mutation can differ clinically because the phenotype may depend in part on the individual’s genetic background, which varies in all but monozygotic twins. In addition, epigenetic effects vary individually, even in monozygotic twins, which contributes to possible phenotypic discrepancies between them.
4. There are acquired causes of hearing loss, such as infection, ototoxicity, etc. Some syndromic malformatons are genetic, others not.
5. Late-appearing hearing loss may be slowly progressive genetic hearing loss, or may be acquired, or both, as in the case of a genetic susceptibility to some environmental factor.
Even well-educated parents are unlikely to be familiar with straightforward Mendelian genetics, let alone mitochondrial genetics, or modern genetic concepts like single-strand microdeletions or other rearrangements. Genetic counseling requires time, expertise, and the services of a professional genetic counselor to provide in-depth information.

Outcome

Consequences of Hearing Loss for Overall Development
Intelligent deaf children who have a supportive family, whose hearing loss was diagnosed early, and who had the benefit of optimal habilitation, including an implant and vigorous language training, do well cognitively, socially, emotionally, and educationally, no matter their proficiency in oral language. Even today, with rare exceptions, the less privileged and those implanted late still remain significantly or severely deficient in language and overall academic proficiency. Their reading ability and other educational accomplishments are likely to lag and fall further behind those of their hearing peers [ Conrad, 1979 ; Schein and Delk, 1974 ; Geers et al., 2008 ]. At a minimum, deafness affects the life experience of the child (and family) profoundly, with secondary consequences for “smarts”, education, and personality [ Mayberry, 2003 ; Rapin, 1979 ]. Yet many deaf people do find a niche in the workplace and are able to function reasonably independently, albeit often supported in part by Social Security Disability Income (SSI).
The deaf are at risk for significant medical and emotional problems because there are few members of their families, neighbors, physicians, nurses, social workers, job counselors and coaches, psychiatrists, psychologists, and other health-care workers with whom they can communicate adequately. The profound jeopardy of even intelligent deaf-autistic, deaf-blind, and otherwise multiply handicapped deaf children is not being addressed adequately. There is a need for medical and other professionals who understand the particular problems of deaf individuals and who can communicate with them to evaluate and treat them competently.
Despite these obstacles, many nonimplanted deaf adults are independent and self-supporting [ Greenberg, 1970 ]. Deaf communities exist in most large cities and provide informal networks of social and practical assistance to their members [ Schein and Delk, 1974 ]. Many deaf children are not diagnosed as early as would be desirable, and grow up without the benefits of optimal habilitation. They may experience severe social deprivation and may have parents who are not able to communicate with them, except through a primitive gesture system, a few spoken nouns and verbs, and words such as “no.” However, even totally deprived deaf adults are capable of learning a language, provided they are intelligent, highly motivated, and lucky enough to meet a truly dedicated teacher [ Schaller, 1991 ].
The great majority of the prevocationally deaf – i.e., those whose deafness began before the age of 19 years, before they started working in a job or profession – are prelingually or perilingually deaf. The impact of cochlear implants and more active efforts to accommodate hearing-impaired students into grade school and mainstream higher education will no doubt change the conclusions of the 1974 Schein and Delk study, but it remains to be seen by how much. Schein and Delk discuss the jobs the prevocationally deaf were able to secure, and their family and social circumstances. In general, because of their curtailed verbal skills, including those in written language, these deaf adults encountered severe limitations to their vocational options. Most married deaf partners, and the community of deaf persons that exists in every sizable city helped them find suitable employment and navigate the complexities of mainstream society. It remains to be seen what proportion of the severely or profoundly prelingually or perilingually deaf cochlear implants will allow to be integrated seamlessly into the society of the hearing.

Acknowledgments
The helpful suggestions of the late Judith S. Gravel, Michelle Dunn, and Robert J. Ruben are gratefully acknowledged. Dr. Rapin is also grateful to the principals and many teachers at St. Joseph’s School for the Deaf in the Bronx and at the Florida School for the Deaf and the Blind, who discussed issues of deaf education with her over a span of more than four decades.

Conflicts of Interest
Neither author has any to declare.

References
The complete list of references for this chapter is available online at www.expertconsult.com .
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Chapter 8 Vertigo

Joseph M. Furman, Margaretha L. Casselbrant

Introduction
Vertigo in children may escape recognition because of the child’s inability to describe the symptoms, the short duration of most vertiginous episodes, the presence of overwhelming autonomic symptoms, or the mistaken idea that an episode of vertigo may be a manifestation of a behavioral disorder.
Vertigo is defined in clinical practice as a subjective sensation of movement, such as spinning, turning, or whirling, of the patient or the surroundings. Dizziness is a nonspecific term used by patients to describe sensations of altered orientation to the environment that may or may not include vertigo.
While vertigo may be a symptom of a vestibular disorder in the pediatric population, patients react to and describe dizziness in different ways in relation to their age. For instance, young children cannot accurately relate symptoms of dizziness. Preschool children rarely complain of vertigo or dizziness but may feel clumsy or be perceived as such by family or teachers. Older children and adolescents are usually able to explain their symptoms well, with their explanations differing little from the explanations of adults.
In any case, a vestibular abnormality should be suspected in a child who is observed to be clumsy, displays unprovoked fright, or who spontaneously clings to a parent. Sudden and recurrent bouts of unexplained nausea and vomiting also are suggestive of a vestibular abnormality.
In children, as well as in adults, a careful history, physical examination, and laboratory testing can establish the cause of dizziness in most patients.

Physiologic Basis of Balance
When a hair cell is stimulated by rotation, translation, or change in orientation with respect to gravity, the firing rate in the eighth nerve fiber innervating that particular hair cell either increases or decreases. Movements that cause the stereocilia to bend toward the kinocilium result in a depolarization of the hair cell and cause the eighth nerve fiber to increase its firing rate, while movements that bend the stereocilia away from the kinocilium decrease the neural firing in the eighth nerve. The eighth nerve synapses in the vestibular nuclei, which consist of superior, medial, lateral, and inferior divisions. In addition to the input from the labyrinth, the vestibular nuclei receive input from other sensory systems, such as vision, somatic sensation, and audition. The sensory information is integrated and the output from the vestibular nuclei influence eye movements, truncal stability, and spatial orientation.
The oculovestibular reflex is a mechanism by which a head movement automatically results in an eye movement that is equal and opposite to the head movement so that the visual axis of the eye stays on target: that is, a leftward head movement is associated with a rightward eye movement and vice versa. Another feature of the oculovestibular reflex is that the two vestibular nuclear complexes on either side of the brainstem cooperate with one another in such a way that, for the horizontal system, when one nucleus is excited, the other is inhibited. The central nervous system responds to differences in neural activity between the two vestibular complexes. When there is no head movement, the neural activity, i.e., the resting discharge, is symmetrical in the two vestibular nuclei. The brain detects no differences in neural activity and concludes that the head is not moving ( Figure 8-1A ). When the head moves, e.g., to the left, endolymph flow produces an excitatory response in the labyrinth on the side toward which the head moves, e.g., on the left, and an inhibitory response on the opposite side, e.g., on the right. Thus, neural activity in the vestibular nerve and nuclei, e.g., on the left and right, increases and decreases, respectively ( Figure 8-1B ). The brain interprets this difference in neural activity between the two vestibular complexes as a head movement and generates appropriate oculovestibular and postural responses. This reciprocal push-pull balance between the two labyrinths is disrupted following labyrinthine injury.

Fig. 8-1 Schematic illustrations of the “push-pull” effect of the oculovestibular reflex.
A, No head movement in healthy subject. B, Head movement to the left in healthy subject. C, Right acute peripheral vestibular injury.
An acute loss of peripheral vestibular function unilaterally, e.g., on the right, causes a loss of resting neural discharge activity in that vestibular nerve and the ipsilateral nucleus ( Figure 8-1C ). Since the brain responds to differences between the two labyrinths, this will be interpreted by the brain as a rapid head movement toward the healthy labyrinth, i.e. vertigo. “Corrective” eye movements are produced toward the opposite side, resulting in nystagmus, with the slow component moving toward the abnormal side, e.g., the right, and the quick components of nystagmus moving toward the healthy labyrinth, e.g., the left.

Evaluation of Patients with Dizziness
At the initial visit, in addition to the chief complaint, a complete medical history that includes associated symptoms, past medical history, family history, and medication use is mandatory.
After the interview, a complete physical examination should be performed, with particular emphasis on the cranial nerves, including an examination of eye movements.

History

Chief Complaint
It is important that the child explain the symptoms in his or her own vocabulary and describe associated sensations, such as headache, nausea, vomiting, or motion sickness. It might be helpful to relate the patient’s symptoms to experiences, such as being on a merry-go-round. It is important to establish the onset, duration, and frequency of dizziness episodes and to associate the episodes with certain activities.
The clinician should inquire about the presence of hearing loss, its onset, evolution or progression, fluctuation and worsening, and improving or stable status. Does the patient have tinnitus or a feeling of fullness? Is the hearing loss bilateral or unilateral? To establish the presence of neurologic symptoms, the clinician should determine whether there have been instances of convulsions, altered mental status, weakness, numbness, disturbances of swallowing or taste, coughing, facial paralysis, or blurring and loss of vision.

Physical Examination
In addition to a complete neurologic examination, the child should also be observed when walking or running for incoordination of movements, i.e., ataxia. Also, an assessment of nystagmus is especially important. Spontaneous nystagmus is an involuntary, rhythmic movement of the eyes not induced by any external stimulation. Spontaneous nystagmus has two components: slow and fast. Nystagmus is named by the fast component, which is easily identified. Spontaneous nystagmus is tested by having the patient look straight ahead with and without fixation. Gaze-evoked nystagmus is assessed by having the patient deviate the eyes laterally (no greater than 30 degrees) with fixation. Positional testing is performed with the use of maneuvers that may produce nystagmus or vertigo. Static positional nystagmus is assessed by placing the patient in each of the following six positions: sitting, supine, supine with the head turned to the right, supine with the head turned to the left, and right and left lateral positions. Positional nystagmus presents as soon as the patient assumes the position and persists for as long as the patient remains in the provocative position. Assessment of vestibulospinal function with a foam pad ( Figure 8-2 ) should be performed with or without a visual conflict dome.

Fig. 8-2 The Pediatric Clinical Test of Sensory Organization and Balance.
A, A child standing on the medium-density foam with her eyes open. B, The same child standing on the foam with the visual conflict dome.
In addition to a history and physical examination, an assessment may include vestibular testing. Vestibular laboratory testing is recommended in any child with a history of vertigo in whom a thorough history and physical examination have not established a diagnosis, in order to differentiate between a peripheral or central vestibular lesion, and to identify the side of the lesion in a peripheral abnormality. In addition, vestibular laboratory testing provides permanent documentation, and changes can be followed by repeat testing. Vestibular laboratory testing includes oculovestibular and vestibulospinal tests. Both types of tests provide only an indirect measure of the function of the vestibular end organs, in that they rely on measures of motor response, e.g., eye movements or postural sway, resulting from vestibular sensory input.

Videonystagmography
Videonystagmography (VNG) is currently the most widely used method of recording eye movements; it uses infrared light. Ocular motor testing, positional testing, and caloric testing constitute a common test battery that requires about 1 hour. Sedatives and vestibular suppressant medications should be discontinued for 2 days prior to testing. Ocular motor testing evaluates neural motor output independent of the vestibular system ( Figure 8-3 ). Abnormalities in the ocular motor system may cause misleading conclusions from vestibular testing that relies on eye movements. Testing saccades uses a computer-controlled sequence of target jumps. Saccade abnormalities are defined as overshooting the target (hypermetric saccades) and undershooting the target (hypometric saccades). Disorders in the saccadic system suggest a central nervous system abnormality. Spontaneous nystagmus and gaze-evoked nystagmus are recorded with and without fixation (closing the eyes or darkness) ( Figure 8-4 ), and by asking the patient to look 30 degrees to the right and left. Spontaneous nystagmus present in darkness without fixation, which decreases or resolves with visual fixation, suggests a peripheral vestibular disorder. However, spontaneous nystagmus that is present with fixation and does not significantly decrease with loss of fixation is most likely a central nervous system abnormality. Ocular pursuit involves asking the patient to follow a moving target back and forth along a slow pendular path. Normal subjects can follow a target smoothly without interruption. Abnormalities of pursuit tracking are caused by lesions in the central nervous system. Laboratory testing of optokinetic nystagmus uses black-and-white stripes moving left and right. Abnormalities include asymmetries or absence of responses, which suggest a central nervous system abnormality.

Fig. 8-3 Examples of normal responses and abnormalities of the saccadic eye movement system, the pursuit system, and optokinetic nystagmus.
(From Baloh RW. The Essentials of Neurotology. Philadelphia: Oxford University Press, Inc, 1984.)

Fig. 8-4 Recording of spontaneous nystagmus.
Note that during eyes open (with fixation) the patient had almost no nystagmus, but during eyes open in the dark (without fixation) a latent vestibular nystagmus became manifest. Upward deflections denote rightward movement.
(From Furman JM, Cass SP. Evaluation of dizzy patients. Slide lecture series. American Academy of Otolaryngology-Head and Neck Surgery Inc., Alexandria, VA 1994.)
Positional testing includes both static and paroxysmal (dynamic) testing. As in the clinical assessment, during static positional testing the patient is placed in the sitting, supine, head left, head right, left lateral, and right lateral positions in darkness. Static positional nystagmus, contrary to paroxysmal nystagmus, presents as soon as the patient assumes the provocative position and persists for as long as the patient stays in that position. Static positional nystagmus is a nonspecific, nonlocalizing vestibular sign. Paroxysmal positional testing employs the Dix–Hallpike maneuver, a maneuver that involves bringing the patient from sitting with the head straight to sitting with the head turned 45 degrees to one side to lying down with the head still turned and the neck extended 20 degrees below the horizontal. The patient is then sat up again and the maneuver is repeated with the head turning to the opposite side. Upon attainment and maintenance of each head-back stance, the eye movements are noted. Latency to onset of nystagmus, a rotational component to the nystagmus, and attenuation of the nystagmus with maintenance of the position all suggest the diagnosis of benign paroxysmal positional vertigo, especially if this maneuver reproduces the patient’s symptoms. This condition is rare in children.

Caloric Testing
Caloric testing aims to assess each labyrinth separately by producing nystagmus via thermal stimulation of the vestibular system. The patient is placed in a position in which the horizontal semicircular canals lie in the vertical plane (head elevated 30 degrees). Caloric stimulation causes a convection current in the horizontal semicircular canal that causes a deflection of the cupula (into which the hairs of the hair cells are embedded) and a change in activity of the vestibular nerve. Cold irrigation produces a fast nystagmus component away from the irrigated ear; warm irrigation produces a fast nystagmus component toward the irrigated ear ( Figure 8-5 ). Binaural bithermal caloric testing uses stimuli of 30°C and 44°C, and each canal is irrigated for 30 seconds with 250 mL of water. There is a rest period of 5 minutes between irrigations. The most common method of measuring the caloric response is to compute the peak slow-component velocity of the nystagmus induced by the thermal stimulus, which reflects the intensity of the vestibular response. To compare the responsiveness of one ear to the other ear, it is established practice to use Jongkees’ formula to compute a percentage of “reduced vestibular response”:

Fig. 8-5 Mechanism of caloric stimulation of the horizontal semicircular canal (see text for details).
(From Baloh RW, Hornbill V. Clinical Neurophysiology of the Vestibular System, 2nd edn. Philadelphia, Oxford University Press, Inc, 1990.)

For many laboratories, normal limits are considered to be a reduced vestibular response of more than 24 percent. A reduced vestibular response suggests a peripheral vestibular lesion.

Rotational Testing
Rotation is the natural stimulus to the semicircular canals. Rotational testing causes minimal discomfort, and is precise and well tolerated, even by infants and young children. Rotation stimulates both labyrinths at the same time and thus does not provide lateralizing information. Caloric response and rotational testing are complementary. The most common type of rotational testing uses sinusoidal harmonic acceleration. The eye velocity produced by the rotation is compared with stimulus velocity.
Three parameters are derived from rotational testing: gain, phase, and symmetry. Gain is a measure of the size of the response. Reduced gain indicates decreased vestibular sensitivity. Unilateral vestibular loss may or may not reduce gain. Thus, reduced gain usually indicates bilateral vestibular loss. Phase describes the timing relationship between the rotational chair velocity and the eye velocity. Ideal eye movements have zero phase lead whereas large phase leads are usually abnormal. Phase is a highly sensitive but nonspecific measure of vestibular system abnormalities. The directional preponderance (i.e., deviation from symmetry) of the eye movements is derived by comparing the velocity of the eye movement to right and left. Directional preponderance is a nonspecific sign. Note that gain, phase, and degree of symmetry do not indicate the site or the side of the lesion. However, rotational testing measures change in response to vestibular disease and can be used to monitor a child’s progress.

Computerized Dynamic Platform Posturography
Computerized dynamic posturography, known commercially as EquiTest™ (NeuroCom International, Inc.), consists of a floor and a visual scene that can move ( Figure 8-6A ). By combining visual and floor conditions, six different sensory conditions can be used to assess the patient’s ability to use combinations of sensory inputs ( Figure 8-6B ). Conditions 5 and 6 assess how patients use vestibular information when it is the only available sense providing reliable information; reduced or distorted sensory information from the visual system and somatosensory system forces patients to rely on their vestibular sensations to maintain upright balance.

Fig. 8-6 The EquiTest system.
A, EquiTest system (NeuroCom International, Inc.) shows the child standing on the platform surrounded by a visual scene. A safety harness is attached to the child in case loss of balance should occur. The platform surface and visual surround are capable of moving independently or simultaneously. Pressure-sensing strain gauges beneath the platform surface detect the patient’s sway by measuring vertical and horizontal forces applied to the surface. B, The six sensory testing conditions of the EquiTest posturography platform.
(From NeuroCom International, Inc., Clackman, Ore.)

Posturography and Vestibular Disorders – Results from the Medical Literature
Several studies have suggested that, after successful vestibular compensation, posturography test results normalize and patients lose their “5,6 pattern” (i.e., their abnormal response to conditions 5 and 6 on posturography testing) and may, in fact, have normal postural sway [ Furman, 1995 ]. Thus, posturography may provide valuable information regarding the status of compensation for a peripheral vestibular deficit.

Vestibular-Evoked Myogenic Potentials
Vestibular-evoked myogenic potentials (VEMPs) refer to electrical activity recorded from neck muscles in response to intense auditory clicks [ Colebatch and Halmagyi, 1992 ; Murofushi et al., 1998 ]. VEMPs provide information about the status of the sacculus and inferior vestibular nerve. A limitation of VEMPs is that it requires normal middle ear function when performed using air-conducted stimuli. VEMPs have been performed successfully in children [ Kelsch et al., 2006 ; Brantberg et al., 2007 ; Valente, 2007 ]. Children as young as age 3 can tolerate testing [ Kelsch et al., 2006 ].

Disorders Producing Vertigo
Vertigo in children can be divided into three broad categories:
1. acute nonrecurring spontaneous vertigo
2. recurrent vertigo
3. nonvertiginous dizziness, dysequilibrium, and ataxia ( Table 8-1 ).

Table 8-1 Comparison of Disorders Causing Childhood Dizziness
A recent study of 2000 children found that vertigo in children was caused by: a migrainous equivalent, 25 percent; paroxysmal benign vertigo of childhood, 20 percent; head trauma, 10 percent; ocular disorders, 10 percent; inner ear malformations, 10 percent; vestibular neuronitis, 5 percent; labyrinthitis, 5 percent; and posterior fossa tumors, less than 1 percent [ Wiener-Vacher, 2008 ].

Acute Nonrecurring Spontaneous Vertigo
Acute nonrecurring spontaneous vertigo is unusual in children. In an acute vestibular syndrome, the vertigo that is experienced results in a reduction in the normal baseline activity in the ipsilateral vestibular nerve. Since the brain responds to differences in activity between the two vestibular nuclear complexes, the patient experiences vertigo. Additionally, the child may experience autonomic symptoms, including nausea and vomiting. Typically, children adapt to an acute loss of unilateral peripheral vestibular function within several days.

Head Trauma
Head trauma can cause an acute episode of vertigo via a labyrinthine concussion . The mechanism of injury in labyrinthine concussion is poorly understood but may relate to pressure waves transmitted to the labyrinth. Other mechanisms of vertigo after head trauma include injury of the CNS, specifically, a brainstem or cerebellar contusion, or a temporal bone fracture. Another diagnostic consideration for a patient with head trauma followed by vertigo or nonspecific dizziness is that of perilymphatic fistula, i.e., an anomalous connection between the inner ear and middle ear spaces that has been well documented in children [ Supance and Bluestone, 1983 ].

Vestibular Neuritis
Vestibular neuritis is rarely seen in children younger than 10 years old. It should be considered when a viral syndrome is followed by symptoms suggestive of an acute unilateral peripheral vestibular loss [ Sekitani et al., 1993 ]. It presents with acute severe vertigo, nystagmus, nausea, and vomiting. The vertigo is worsened by head movements, and patients often prefer to lie down, usually with the affected ear up. There is no hearing loss or tinnitus. Management is supportive and symptomatic, with early ambulation. Vestibular suppressants such as meclizine may be given, but only for a short course, as they may delay long-term recovery.

Recurrent Vertigo
Recurrent vertigo in children can be a result of disease of the peripheral or central vestibular system. However, most recurrent vertigo in children is due to a central nervous system disorder rather than a peripheral vestibular disorder.

Migraine-Related Dizziness
Migraine is probably the most common cause of recurrent vertigo in children. Whereas migraine typically presents as headache in adults, other manifestations of migraine, including recurrent vertigo and dysequilibrium, are more common in children. Benign paroxysmal vertigo of childhood, which is likely to be of migrainous origin, as well as paroxysmal torticollis of infancy, can present with recurrent vertigo in children. Nonvertiginous symptoms of vestibular dysfunction can also be related to migraine. The manifestations of migraine in childhood are quite varied [ Balkany and Finkel, 1986 ].
Benign paroxysmal vertigo of childhood was first described by Basser [ Basser, 1964 ]. Vertigo occurs in isolation, without tinnitus and hearing loss. The age of onset is usually by 4 years, but can be as late as 12 years [ Blayney and Colman, 1984 ]. Vertigo usually lasts less than 1 minute but may last only seconds. Vertigo may occur while sitting, standing, or lying. Pallor, nausea, sweating, and occasionally vomiting occur. Consciousness is not impaired and the child can recall the episode. There may be no pain or headache associated with the attacks. Immediately after the attack, the child resumes normal activities. The interval between the attacks varies from weekly to every 6 months. Vertigo attacks usually cease spontaneously after a few years. Physical examination, including a neurologic evaluation, is normal, as is imaging of the skull and temporal bones. Basser reported a moderate or complete canal paresis on caloric testing [ Basser, 1964 ]. However, the response to bithermal caloric testing has been found to be highly variable [ Dunn and Snyder, 1976 ; Finkelhor and Harker, 1987 ; Mira et al., 1984 ]. Other testing is normal. Children with benign paroxysmal vertigo of childhood often have a positive family history of migraine, and migraine headaches may develop in later years [ Koehler, 1980 ; Lanzi et al., 1994 ] and may respond positively to antimigraine treatment. The initial treatment of migrainous vertigo in children is dietary restrictions of foods known to provoke migraine [ Constantine and Scott, 1994 ]. If this is unsuccessful, the next step is symptomatic treatment with a vestibular suppressant, such as meclizine, during episodes. However, the episodes are usually very brief. If the spells are frequent and especially if they impair school performance, use of a prophylactic antimigraine agent, such as propranolol, should strongly be considered [ Cass et al., 1997 ].

Ménière’s Disease
Ménière’s disease, a syndrome presumably caused by endolymphatic hydrops, can occur spontaneously or as a delayed sequela of a previous insult from trauma or viral infection. The disorder rarely occurs in children [ Filipo and Barbara, 1985 ; Hausler et al., 1987 ; Meyerhoff et al., 1978 ]. Ménière’s disease is characterized by a combination of dizziness, unilateral hearing loss, and unilateral tinnitus, which are usually preceded by a feeling of fullness in the affected ear. Following episodes, children are more likely to recover auditory function than are adults. Ménière’s disease can be bilateral. Also, with time, a reduction in the responsiveness of the involved peripheral vestibular system occurs. Management of endolymphatic hydrops in children includes reassurance and explanation of the condition to the parents, in addition to salt restriction and a diuretic [ Cyr et al., 1985 ].

Seizure Disorders
Seizure disorders are often accompanied by some sense of dizziness and dysequilibrium, although seizures are not frequently associated with true vertigo. However, the term “tornado epilepsy” has been used to describe seizures that are associated with a sense of spinning that can mimic the symptoms of a peripheral vestibular ailment [ Eviatar and Eviatar, 1977 ].

Familial Periodic Ataxia
Familial periodic ataxia is a rare syndrome with autosomal-dominant inheritance, and is characterized by episodes of dizziness, dysequilibrium, and gait instability that may last for several hours. At least two types of the syndrome have been identified [ Farmer and Mustian, 1963 ; Parker, 1946 ], and genetic testing is available. These syndromes differ in the duration of the paroxysms of ataxia.

Nonvertiginous Dysequilibrium
Patients with both peripheral and central vestibular disorders can have nonvertiginous dysequilibrium, imbalance, and ataxia. Indeed, many disorders affecting the central nervous system are symptomatic in this way. Bilateral peripheral vestibular disorders typically occur without vertigo and thus may mimic a central disorder. Numerous central nervous system abnormalities can be associated with nonvertiginous dizziness. Many of these abnormalities involve the cerebellum and include cerebellar hypoplasia, posterior fossa tumors, and Chiari malformations. Also, medication side effects should not be overlooked when evaluating a child with dizziness and dysequilibrium.

Bilateral Peripheral Vestibular Loss
Bilateral peripheral vestibular loss can be either congenital and due to inner ear malformations, or acquired from meningitis, ototoxicity, and autoimmune disease of the inner ear. Regardless of etiology, bilateral vestibular loss, if severe, is called Dandy’s syndrome. Dandy’s syndrome is characterized by two specific symptoms: namely, oscillopsia (i.e., jumbling of the visual surround during head motion) and severe gait instability in darkness [ Dandy, 1941 ]. Children with bilateral vestibular loss often learn to use alternative sensory inputs, such as vision and proprioception. Also, they modify strategies of eye movements. Environments and tasks that require vestibular function, such as ambulating in dimly lit spaces or trying to maintain stable vision during walking, are extremely challenging for individuals with bilateral vestibular loss.

Central Nervous System Disorders
Numerous central nervous system disorders cause dizziness, dysequilibrium, imbalance, and ataxia. In childhood, cerebellar abnormalities, such as cerebellar vermian hypoplasia, posterior fossa tumors, and Chiari malformation, are the most common disorders encountered. The clinical presentation of such patients may be confusing, because they are unlikely to have vertigo and may not display evidence of limb ataxia if their abnormalities affect solely midline cerebellar structures.

Drug-Induced Dizziness
Many drugs can cause nonvertiginous dizziness. For example, the aminoglycosides, especially gentamicin, can cause ototoxicity, which may result in bilateral peripheral vestibular loss. In the pediatric age group, phenytoin is used in the treatment of epilepsy and may produce dizziness and nystagmus as signs of intoxication. With this in mind, any child in whom dizziness develops while on a regular medication should be viewed as a possible case of iatrogenic dizziness.

Non-Neurotologic Disorders
Another cause of dizziness in children is psychiatric dizziness, which usually occurs in children of school age. It may be associated with depression, adjustment reaction of adolescence, and behavior problems. Such children usually have normal vestibular and auditory testing, normal electroencephalograms, and normal imaging studies. When evaluating a child with dizziness, it is essential to determine whether the patient has an associated anxiety disorder, either as the sole cause of their vertiginous complaints, as an accompaniment to an underlying balance system abnormality, or indirectly related to the dizziness, e.g., through a common brainstem ailment causing both dysequilibrium and an anxiety disorder. Treating anxiety disorders in children is challenging because of medication side effects. If the anxiety symptoms are severe, patients should be referred to a child psychiatrist.

References
The complete list of references for this chapter is available online at www.expertconsult.com .
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Sekitani T., et al. Vestibular neuronitis: epidemiological survey by questionnaire in Japan. Acta Otolaryngol Suppl . 1993;503:9-12.
Supance J.S., Bluestone C.D. Perilymph fistulas in infants and children. Otolaryngol Head Neck Surg . 1983;91(6):663-671.
Valente M. Maturational effects of the vestibular system: a study of rotary chair, computerized dynamic posturography, and vestibular evoked myogenic potentials with children. J Am Acad Audiol . 2007;18(6):461-481.
Wiener-Vacher S.R. Vestibular disorders in children. Int J Audiol . 2008;47(9):578-583.
Chapter 9 Taste and Smell

Julie A. Mennella

Chemical Senses
The chemical senses of taste, smell, and chemical irritation convey a range of information, warning us of environmental hazards and determining the flavor of ingested foods and liquids, whether the flavor of a food is good or bad. The pleasure experienced upon ingestion is a complex process mediated by the chemical senses (taste, smell, and irritant properties of foods) in the periphery and then multiple brain substrates, which are remarkably well conserved phylogenetically [ Berridge and Kringelbach, 2008 ]. The degree to which the chemicals that stimulate these flavor senses are liked or disliked is determined by innate or inborn factors, learning and experience, and the interactions among these. In essence, these senses function as gatekeepers throughout the life span. They control one of the most important decisions an animal is required to make – whether to reject a foreign substance or to take it into the body, and if the substance is ingested, to inform the gastrointestinal system about the quality and quantity of the impending rush of nutrients.
The literature reviewed in this chapter suggests that human infants have functioning gustatory and olfactory systems that modulate their feeding and expressive behaviors [ Ganchrow and Mennella, 2003 ; Mennella and Beauchamp, 2008 ]. Although responsiveness is evident early in development, infants are not merely miniature adults, because these chemosensory systems mature postnatally and are influenced by experiences in ways we are just beginning to understand. Because little is known about the infant’s perception of chemical irritation (e.g., sensations of burn, viscosity, and temperature resulting from stimulation of nerve endings in the soft membranes of the buccal and nasal cavities), the discussion focuses on the senses of taste and smell, but acknowledges that this other chemical sense may play an important role in the behavior of infants.

Taste, Smell, and Flavor
Taste or gustation refers to the sensation that occurs when chemicals stimulate taste receptors located on a large portion of the tongue’s dorsum and other parts of the oropharynx, such as the larynx, pharynx, and epiglottis [ Doty, 2003 ]. The taste system is attuned to a small number of perceptual classes of experience, the so-called basic tastes, each of which specifies crucial information about nutrients or dangerous substances. These basic tastes either stimulate intake (sweet, salty, and savory) or inhibit it (bitter and perhaps sour) when ingested within a generally restricted range of concentrations.
From an evolutionary perspective, these taste qualities likely evolved to detect and reject that which is harmful and to seek out and ingest that which is beneficial. It has been hypothesized that the small number of taste qualities evolved because of the functional importance of the primary stimuli (e.g., sugars, salts, amino acids and proteins, organic acids, bitter toxins) in nutrient selection, especially during childhood. Preference for salty and sweet tastes is thought to have evolved to attract us respectively to minerals and energy-producing sugars and vitamins. Rejection of bitter-tasting and irritating substances evolved to protect the animal from being poisoned and the plant producing these chemicals from being eaten [ Jacobs et al., 1978 ; Glendinning, 1994 ]. This rejection is commonly observed when children reject the bitter taste of green vegetables or many liquid formulations of drugs. Rejecting the bitter taste of medicine can, however, thwart the benefits of even the most powerful drugs. Many active pharmaceutical ingredients taste bitter or irritate the mouth and throat. Effective methods of avoiding unpleasant tastes for adults, encapsulating the medicine in pill or tablet form, are problematic since many children cannot or will not swallow either preparation. However, while bitter tastes are innately disliked, with experience people may come to like certain foods that are bitter, particularly some vegetables, and foods and beverages with pharmacologically active bitter compounds, such as caffeine or ethanol.
By being intimately connected to the ingestion or rejection of foods via hedonics, taste and olfaction can contribute to weight loss or gain, and when healthful foods are avoided, can pose a nutritional risk [ Mattes and Cowart 1994 ; Doty, 2009 ]. Further, excessive intake of foods containing highly preferred tastes (sweet, salty) because of their strong hedonic component may cause or exacerbate a number of illnesses, including hypertension and diabetes. Beyond nutrition, sweet taste is linked to brain pathways involved in reward processing and learning. Many drugs of abuse, which give pleasure, exert their influence through some of these same pathways, and consequently there are many biological commonalities between overconsumption of sweets and drug addiction [ Pepino and Mennella 2007 ; Berridge and Kringelbach 2008 ; Levine et al., 2003 ].
The chemicals that elicit taste qualities are detected not only by specialized receptors on the tongue and other parts of the oral cavity, but by the gastrointestinal system as well [ Egan and Margolskee, 2008 ]. The taste receptors in the oral cavity are localized in taste buds and are innervated by branches of three cranial nerves: the facial (VII), glossopharyngeal (IX), and vagal (X) nerves ( Figure 9-1 and Figure 9-2 ). During the past decade, major progress has been made in identifying the initial events in taste recognition [ Bachmanov and Beauchamp, 2007 ; Chandrashekar et al., 2006 ; Katz et al., 2008 ; Kim et al., 2006 ]. It appears that two different strategies have evolved to detect taste molecules. For salty and sour tastes, it is widely believed that ion channels serve as receptors. Here H + (sour) and Na + (salty) ions are thought to flow through the channels into the cell. The cell is then activated and sends an electrical message to the brain. However, for both of these taste qualities, the molecular identity of the receptors and their exact mechanisms are still unknown. For sweet, umami, and bitter tastes, G-protein coupled receptors (GPCRs) appear to play the most prominent roles. These GPCRs bind taste molecules in a sort of lock-and-key mechanism, thereby activating the taste cell to send an electrical message to the brain. For sweet and umami, a family of three GPCRs, named T1R1, T1R2, and T1R3, act in pairs (T1R1+T1R3 for umami, and T1R2+T1R3 for sweet) to detect molecules imparting these taste qualities. A substantially larger family of GPCRs, the T2Rs (around 25), constitutes the bitter receptors.

Fig. 9-1 Taste innervation is supplied by cranial nerves VII, IX, and X.
Filiform, fungiform, and circumvallate papillae are present, with most taste sensation originating from the fungiform and circumvallate papillae. The anterior two-thirds of the tongue are innervated by the chorda tympani, a branch of cranial nerve VII, whereas the posterior one-third of the tongue and palate is innervated by cranial nerves IX and X. Central connections of the pathways of the cranial nerves in the nucleus solitarius ascend through the thalamus to the parietal operculum. S.S.P.N., small superficial petrosal nerve.

Fig. 9-2 Lateral depiction of the innervation of cranial nerves VII, IX, and X in the tongue and their relation to major vascular and other soft tissue structures.
Smell or olfaction occurs when chemicals stimulate olfactory receptors located on a relatively small patch of tissue high in the nasal cavity ( Figure 9-3 ) [ Doty, 2003 , 2009 ]. The organization of the olfactory system reflects the need to recognize a wide range of odors and to discriminate one odor from another. There are several noteworthy differences between the taste and smell system. First, unlike the gustatory receptors, the olfactory neurons are the actual receptor cells and are uniquely exposed to the external environment. Second, they can regenerate from basal cells after being damaged. Third, the olfactory receptors are served by only a single cranial nerve (I). Fourth, there is a much larger number of odor qualities, as suggested by the identification of a large family of genes that apparently code for a large number of receptor proteins located on membranes of the cilia of olfactory neurons [ Buck and Axel, 1991 ]. In fact, the olfactory receptor genes are encoded by the largest mammalian gene superfamily of more than 1000 genes [ Buck and Axel, 1991 ]; however, more than half of this receptor gene family are pseudogenes in humans [ Gilad et al., 2003 ]. Fifth, odor stimuli can reach the olfactory receptors in two ways. Odor molecules can reach the olfactory receptors by entering the nostrils during inhalation (orthonasal route) or by travelling from the back of the oral cavity toward the roof of the nasal pharynx (retronasal route). It is this retronasal stimulation arising from the molecules of foodstuffs that leads to many of the flavor sensations we experience during eating.

Fig. 9-3 The sagittal section demonstrates the major structures involved in olfaction.
The olfactory cells lie within the olfactory epithelium and mucosa, where they are stimulated by different odors. The cells give rise to filaments that traverse the cribriform plate of the ethmoid bone and synapse in the olfactory bulb. Each cell synapses with a number of glomeruli within the bulb, which are composed of dendrites from other cells within the bulb and the mitral and tufted cells. Axons from these cells form the olfactory tract, which projects into five regions: the anterior olfactory nucleus, the piriform cortex, the olfactory tubercle, the corticomedial amygdala, and the entorhinal cortex.
Although there is some evidence that some odors may be innately biased in a positive or negative direction [ Khan et al., 2007 ], individual experiences largely determine how much a person likes or dislikes the odor component of a food or beverage flavor. Through experiences, odors acquire personal significance [ Forestell and Mennella, 2005 ; Mennella and Forestell, 2008 ; Mennella and Garcia, 2000 ]. Memories evoked by odors are more emotionally charged and resistant to change than those evoked by other sensory stimuli [ Herz and Cupchik, 1995 ]. The unique processing of olfactory information [ Cahill et al., 1995 ], and the olfactory system’s immediate access to the neurological substrates underlying nonverbal aspects of emotion and memory [ Royet and Plailly, 2004 ], help explain the large emotional component of food aromas. This, coupled with the recent finding that the most salient memories formed during the first decade of life will likely be olfactory in nature [ Willander and Larsson, 2006 ], explains how food aromas can trigger memories of childhood and why flavors and food aromas experienced during childhood remain preferred, and to some extent, can provide comfort.
Flavor, as an attribute of foods and beverages, is defined as the integration of multiple sensory inputs of the taste, retronasal olfaction, and irritation of a substance in the oral and nasal cavities. However, the perceptions arising from the taste and smell senses are often confused and misappropriated [ Rozin, 1982 ], with sensations such as vanilla, fish, chocolate, and coffee being erroneously attributed only to the taste system, although much of the sensory input results from retronasal olfaction. Holding the nose while eating interrupts retronasal olfaction and thereby eliminates many of the subtleties of food or medicines, leaving the taste components remaining. Another example of the importance of olfaction in flavor perception is the inability to discriminate common foods when olfactory receptors are blocked by an upper respiratory infection.

Clinical Disorders of Taste and Smell
The common confusion between taste and retronasal olfaction is highlighted because many patients, young and old, report they cannot taste when they suffer only from olfactory loss [ Cowart et al., 1997 ; Pribitkin et al., 2003 ]. The sense of smell appears to be more vulnerable than that of taste, in part because of the differences described earlier. Approximately two-thirds of patients who present to specialized chemosensory clinics complained of taste loss, but most patients were diagnosed with a measurable smell rather than gustatory dysfunction, as the basis of their “taste” complaint [ Cowart et al., 1997 ]. A retrospective review of the 1176 patients evaluated for chemosensory dysfunction complaints at the Monell–Jefferson Chemosensory Clinical Research Center in Philadelphia revealed that severe, generalized taste deficits (i.e., complete or nearly complete taste loss) do occur but are extremely rare (<1 percent of patients), whereas profound olfactory deficits are more common (32 percent of patients) [ Pribitkin et al., 2003 ]. A complete listing of the taste and smell centers that specialize in the assessment and treatment of chemosensory problems, along with information about the National Institute on Deafness and Other Communication Disorders (NIDCD) clearinghouse, a national resource center for information about hearing, balance, smell, taste, voice, speech, and language for health professionals, patients, industry, and the public, can be found in Box 9-1 .

Box 9-1 Clinics Specializing in Disorders of Taste and Smell

Connecticut Chemosensory Clinical Research Center
University of Connecticut Health Center
Farmington, CT 06032
(860) 679-2459

Monell–Jefferson Chemosensory Clinical Research Center *
Monell Chemical Senses Center
3500 Market St.
Philadelphia, PA 19104
(267) 519-4755

Rocky Mountain Taste and Smell Center*
University of Colorado Hospital
1635 Aurora Court
Aurora, CO 80045
(303) 828-2820

San Diego Nasal Dysfunction Clinic
UCSD Medical Center
9350 Campus Point Drive
La Jolla, CA 92037
(619) 543-3893 or (619) 657-8594

University of Florida McKnight Brain Institute’s Center for Smell and Taste
100 S Newell Drive, Room L1-100J
PO Box 100127
Gainesville, FLA 32610-0127
(352) 294-0199

University of Pennsylvania Smell and Taste Center
Hospital of the University of Pennsylvania
3400 Spruce St., G1
Philadelphia, PA 19104
(215) 662-6580

* Indicates centers that are supported by the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health. The NIDCD supports and conducts research and research training on the normal and disordered processes of hearing, balance, smell, taste, voice, speech, and language, and provides health information, based upon scientific discovery, to the public. The NIDCD Information Clearinghouse can be reached by calling (800) 241-1044 (voice) or (800) 241-1055 (TTY), 8:30 am to 5:00 pm (ET), or by sending an e-mail to nidcdinfo@nidcd.nih.gov. For more information about NIDCD programs, visit the website at www.nidcd.nih.gov .
Although complete taste loss is rare, clinical disorders that influence taste and smell perception are more common. The confusion between taste and retronasal olfaction underscores the need for careful sensory evaluation of these causes and helps explain why patients’ description of the complaint are often inaccurate. Moreover, clinical disorders that influence taste perception involve multiple organ systems and require a multidisciplinary approach for appropriate diagnosis and management [ Bromley and Doty, 2003 ; Hoffman et al., 2009 ]. Particular attention should be paid to the history of problems with speech articulation, salivation, chewing, swallowing, oral pain or burn, otitis media, mouth dryness, periodontal disease, foul breath odor, recent dental procedures and surgeries, recent radiation exposure, medications, bruxism, and dietary changes. Questions about hearing, tinnitus, and balance may reveal useful information because the vestibulocochlear nerve travels near the facial nerve and is susceptible to similar conditions [ Bromley and Doty, 2003 ].
The neurologic examination should pay particular attention to the first (olfactory), fifth (trigeminal), seventh (facial), ninth (glossopharyngeal), and tenth (vagus) cranial nerves and their central connections. Frontal lobe function and signs of increased intracranial pressure, such as papilledema and abducens nerve palsies, should be assessed [ Barwick, 1989 ]. The oral cavity should be checked for dryness, inflammation, infections, and suspicious lesions. The tongue should be palpated to detect masses, neoplastic lesions, or collections in the tongue’s musculature, and its color, presence of plaque, and degree of salivation should be evaluated. Of particular importance are the appearance of teeth, gums, and taste papillae, and the color of the dorsal surface of the tongue (i.e., white, brown, or red [atrophic]) [ Spielman, 1998 ]. For some gustatory disorders, a detailed dental history may be helpful. The nasal cavity and sinuses should be checked because the color of the mucosa, presence of a purulent discharge, edema, and atrophy may indicate a condition that can affect olfactory functioning [ Snow et al., 1991 ]. Newer endoscopes (e.g., Storz) may assist in visualizing the olfactory epithelium. Sinus radiographs may be useful when evaluating ethmoid or diffuse sinus disease, whereas computed tomographic (CT) scans may be indicated if intracranial or sinus disease is suspected. However, no significant relation has been found between the size of the nasal and sinus structures as assessed by CT scans and smell ability in adults [ Hong et al., 1998 ]. Magnetic resonance imaging (MRI), the method of choice for soft-tissue anatomy and central nervous system (CNS) structures, has been used to evaluate sites of injury in patients with post-traumatic olfactory deficits [ Yousem et al., 1996 ]. MRI of the oropharynx and neck should be conducted for patients presenting with ageusia (complete loss of taste), to exclude hematoma or abscess of the tongue and surrounding tissues [ Pribitkin et al., 2003 ]. Gustatory dysfunction has been related to MRI-established ischemia, hemorrhage, or demyelination plaques in the brainstem and higher cortical areas in some patients with chronic dysgeusia [ Bromley and Doty, 2003 ].
In addition to a careful medical history and otolaryngologic examination, assessment of a smell or taste complaint should involve standardized testing using a variety of psychophysical techniques (e.g., detection thresholds, magnitude estimates, quality identification) in a clinical setting [ Cowart et al., 1997 ; Frank et al., 2003 ; Pribitkin et al., 2003 ; Snyder et al., 2006 ]. For example, patients are often asked to identify the taste quality (i.e., sweet, sour, bitter, salty) of a solution that is sipped or to identify an odor that is smelled. Retronasal olfactory function also should be assessed [ Heilmann et al., 2002 ; Pierce and Halpern, 1996 ]. For younger pediatric populations, age-appropriate odorants (i.e., baby powder, bubble gum, candy cane, licorice, and peach) are recommended [ Richman et al., 1995 ]. A commercially available scratch-and-smell test, the University of Pennsylvania Smell Identification Test (Sensonics, Inc., Haddon Heights, NJ; www.sensonics.com ), has found widespread acceptance because of its relative ease of administration. In addition to identification, detection thresholds and intensity functions can be determined by having patients signify, usually verbally, the presence, absence, or intensity of a taste or smell stimulus presented at various concentrations [ Bartoshuk et al., 1987 ; Frank et al., 2003 ].
The lack of standardized methodology and the need for testing methods suitable for clinical and field assessment [ Snyder and Bartoshuk, 2009 ; Hoffman et al., 2009 ] is magnified when the clinician or researcher needs to evaluate olfactory and taste functioning in young children. First, because young children are more prone to attention lapses and have shorter memory spans, any method relying on sustained attention that places demands on memory could yield spurious findings. Second, because young children tend to answer questions in the affirmative, a forced-choice categorization procedure is generally preferred. Age-appropriate tasks, embedded in the context of a game that is fun for children and minimizes the impact of language and cognitive development, are particularly effective [ Schmidt and Beauchamp, 1988 ; Forestell and Mennella, 2005 ; Mennella et al., 2005 , 2011 ]. Third, children are likely to be unfamiliar with many of the odor stimuli used in adult tests and have limited ability to read and identify labels to select from alternative choices, which is the typical adult response option [ Dalton et al., 2009 ]. To address this gap in appropriate methodology, the National Institutes of Health (NIH) Blueprint for Neuroscience Research was established and then funded the Toolbox Initiative (see www.nihtoolbox.org ) to assemble brief, comprehensive assessment tools that can be used by clinicians and researchers in a variety of settings in four domains: cognition, emotion, sensation, and motor. Included in sensation domain is the development and validation of a specialized battery of tests to assess both taste [Mennella et al., 2011] and smell sensitivity (the analytic precision of the sensory system) and hedonics (pleasantness, liking, or preference) for diverse populations from 3 to 85 years of age (visit www.nihtoolbox.org for updates).
As shown in Box 9-2 and Box 9-3 , disorders of taste and smell in adults (and presumably in younger patients) can arise from a variety of sources, including medications, radiation therapy, nutritional deficiencies, metabolic changes, head trauma, otitis media, tonsillectomy, chronic disorders of the nasal epithelia, neurologic disorders such as tumors, viral infections, endocrine imbalances, aging, and environmental exposure [ Cowart et al., 1997 ; Doty, 2003 , 2009 ; Doty et al., 2003 ; Mott and Leopold, 1991 ; Murphy et al., 2003 ; Schiffman, 1983 ; Spielman, 1998 ]. However, many of the conditions listed are based on adult patients’ reports and not on standardized test assessments of chemosensory functioning or controlled clinical trials.

Box 9-2 Conditions Associated with Disturbances of Taste

Congenital conditions
Familial dysautonomia
Turner’s syndrome
Endocrine, metabolic, and autoimmune conditions
Adrenal insufficiency
Cronkhite–Canada syndrome
Diabetes mellitus
Gastrointestinal and liver diseases: acute hepatitis, chronic liver disease, obstructive jaundice
Hypothyroidism, pseudohypoparathyroidism
Hyperthyroidism
Lupus erythematosus
Primary amyloidosis (affecting tongue)
Reiter’s syndrome
Scleroderma
Sjögren’s syndrome
Hypertension
Iatrogenic conditions
Acoustic tumor removal
After hypophysectomy
After laryngectomy
After tonsillectomy
Cerebellopontine angle meningioma removal
Chorda tympani injury or stretching
Radiation or chemotherapy
Temporal lobectomy
Infectious conditions
After upper respiratory tract infection
Candidiasis
Ulcerative lesions (e.g., gonorrhea, herpes simplex virus infection, mycoses, syphilis, varicella zoster infection)
Local processes
Glossitis
Hansen’s disease
Oral mycosis
Otitis media
Parotid infection or tumor
Sjögren’s syndrome
Submandibular gland carcinoma
Neurologic conditions
Bell’s palsy
Brain tumor
Guillain–Barré syndrome
Head trauma
High-altitude syndrome
Migraine
Multiple sclerosis
Seizure disorders
Psychiatric conditions
Bulimia
Uremia or dialysis
Miscellaneous conditions
Acquired immunodeficiency syndrome (AIDS)-related periodontitis
Cancer
Dental caries
Gastric reflux disease
Gingivitis (acute and chronic)
Occupational exposure
(Data from Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am 1991;75:1321 and from Bromley SM, Dory RL. Clinical disorders affecting taste: Evaluation and management. In: Dory RL, ed. Handbook of olfaction and gustation, 2nd edn. New York: Marcel Dekker, 2003:935.)

Box 9-3 Conditions Associated with Disturbances of Olfaction

Congenital conditions
Cleft palate (males)
Down syndrome
Familial dysautonomia
Kallmann’s syndrome
Turner’s syndrome
Endocrine or metabolic conditions
Adrenal insufficiency
Diabetes mellitus
Hypothyroidism
Pseudohypoparathyroidism
Iatrogenic conditions
After laryngectomy
Ethmoidectomy
Hypertelorism procedures
Orbitofrontal lobectomy
Radiotherapy
Rhinoplasty
Submucous resection, nasal septum
Temporal lobectomy
Infectious conditions
Herpes simplex meningoencephalitis
Human immunodeficiency virus (HIV) infection
Upper respiratory tract, viral
Liver disease
Acute viral hepatitis
Cirrhosis
Local processes
Hansen’s disease
Nasal obstruction (adenoid hypertrophy, large inferior turbinates)
Polyposis
Sjögren’s syndrome
Tumors
Neurologic conditions
Alzheimer’s disease
Head trauma
Huntington’s disease
Korsakoff’s syndrome
Multiple sclerosis
Meningiomas
Migraines
Parkinson’s disease
Seizure disorders
Temporal lobe tumors
Psychiatric conditions
Hypochondriasis
Major depression
Post-traumatic stress disorder
Schizophrenia
Uremia or dialysis
Miscellaneous conditions
Cystic fibrosis
Giant cell arteritis
Occupational exposure
Sarcoidosis
(Adapted from Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am 1991;75:1321.)
Despite advances in our understanding of the mechanisms and functions of the chemical senses, there are no internationally accepted standards of impairment for the chemical senses [ Hoffman et al., 2009 ], and the treatment options for taste and smell disorders remain limited. Olfactory dysfunctions resulting from impairment of odor access to the olfactory receptors may be treated. For example, patients may experience improvements in olfactory ability after adenoidectomy [ Ghorbanian et al., 1983 ] or surgical management of nasal polyps because of the re-establishment of nasal airflow [but see Doty and Mishra, 2001 ]. However, those individuals whose source of deficit lies within the olfactory neuroepithelium or central olfactory or cortical pathways typically have no treatment options available other than time and possible spontaneous recovery. Similarly, the prognosis for severe taste loss is mixed, and delayed, gradual recovery was the most common pattern observed in such patients [ Pribitkin et al., 2003 ]. Although zinc supplementation has received considerable attention as a treatment for taste loss, two double-blind studies failed to determine a benefit compared with placebo [ Henkin et al., 1976 ; Yoshida et al., 1991 ].

The Ontogeny of Taste Perception and Preferences
The following sections focus on research in infants, children, and adolescents. The study of the chemical senses is possible throughout the life span and includes many variables, such as age, genetics, and feeding history, that can influence their responses. Conditions associated with disturbances of taste or smell, or both, in pediatric populations are also discussed.

Fetus and Preterm Infants
Although amniotic fluid and embryonic membranes provide a series of barriers that protect the fetus from outside world disturbances, the fetus is nevertheless exposed to a variety of chemosensory stimuli in utero. The composition of amniotic fluid varies over the course of gestation, particularly as the fetus begins to urinate, so that by term, the human fetus is actively swallowing almost a liter per day and has been exposed to a variety of substances, including glucose, fructose, lactic acid, pyruvic acid, fatty acids, phospholipids, creatinine, urea, uric acid, amino acids, proteins, and salts [ Liley, 1972 ].
The taste system is well developed before birth. The apparatus needed to detect taste stimuli, the taste buds, makes its first appearance around 7 or 8 weeks’ gestation, and by 13–15 weeks, the taste bud begins to resemble the adult bud morphologically, except for the cornification overlying the papilla [ Bradley, 1972 ]. Taste pores, which provide the access for taste stimuli to interact with taste receptor cells, are present in fetal fungiform papillae before the end of the fourth month [ Bradley, 1972 ; Hersch and Ganchrow, 1980 ; Witt and Reutter, 1997 ]. There is some evidence, albeit weak and indirect, for preferential responding to taste stimuli in the human fetus. Clinical observations of differential fetal swallowing after the injection of sweet or bitter substances into the amniotic fluid suggest that the fetus prefers sweet and rejects bitter, but these observations are inconclusive because of the methodologic limitations in measuring fetal responses [ DeSnoo, 1937 ; Liley, 1972 ].
Another approach used in determining whether taste perception and preferences are present before birth is to study preterm infants. Such studies reported increased salivation in response to oral presentations of a drop of pure lemon juice, diminished suckling in response to quinine solutions, and enhanced suckling in response to glucose compared with water [ Tatzer et al., 1985 ]. Because premature infants are at risk for aspirating fluids because of immature suck–swallow coordination, a method was developed that did not necessitate the delivery of any fluids while administering a taste. The taste substance was embedded in a nipple-shaped gelatin medium that released small amounts of the substance when it was mouthed or sucked. Infants, born preterm and tested between 33 and 40 weeks after conception, produced more frequent, stronger sucking responses when offered a sucrose-sweetened nipple compared with a nonsweet latex nipple [ Maone et al., 1990 ].
In conclusion, studies on premature infants support the hypothesis that preference for sweet taste is evidenced before birth. These data also suggest that taste buds are capable of conveying gustatory information to the CNS by the third trimester of pregnancy, and this information is available to systems organizing changes in sucking, facial expressions, and other affective behaviors [ Ganchrow and Mennella, 2003 ].

Newborns, Infants, and Young Children
In some of the earliest investigations of human taste development, facial expressions suggestive of contentment and liking or discomfort and rejection were used to assess the newborn’s responsiveness to taste stimuli. This testing revealed that, during the first few hours of life, infants display relatively consistent, quality-specific facial expressions when the sweet taste of sugars, the sour taste of concentrated citric acid, and the bitter taste of concentrated quinine and urea are presented into the oral cavity [ Ganchrow et al., 1983 ; Rosenstein and Oster, 1990 ; Steiner, 1977 ]. No distinct facial response has been reported for stimulation with salt taste [ Rosenstein and Oster, 1990 ; Steiner, 1977 ]. Although infants beyond the neonatal period (1–24 months) have been most neglected in studies of taste development, the findings gleaned from basic research suggest that changes in responses to each of the five basic tastes – sweet, umami, sour, bitter, and salty – occur during development ( Table 9-1 ).

Table 9-1 Developmental Changes in Response to Tastes

Sweet Taste
Children’s liking for all that is sweet, which is universal and evident worldwide, reflects their basic biology [ Mennella, 2008 ]. Consistent with the findings on premature infants’ response to sweets, newborns exhibit a strong acceptance of sweet-tasting sugars. Infants can detect even dilute sweet solutions, and they differentiate various degrees of sweetness and different kinds of sugars [ Desor et al., 1977 ]. The preference for sweet taste remains heightened during childhood and adolescence, and declines during late adolescence to the level observed in adulthood [ Desor et al., 1977 ]. With regard to sweets, infants, children, and teenagers are truly living in their own sensory worlds, preferring more intense sensations of sweetness than adults.
Heightened preferences for sweet tastes may have an ecologic basis. At birth, the innate preference for sweet tastes evolved to help us solve the basic nutritional problem of attracting us to mothers’ milk, and then to sweet-tasting foods, such as fruits, which contain energy-producing sugars, minerals, and vitamins. But sugars are more than a highly preferred taste and the liking for sweets displayed by infants may also reflect the physiologic effects of sugars. A small amount of a sweet-tasting liquid placed on the tongue of a crying newborn exerts a rapid, calming effect that persists for several minutes [ Barr et al., 1994 ; Blass and Hoffmeyer, 1991 ]. The rapid onset of analgesia, which has been observed during painful procedures such as blood sampling and circumcision, suggests that afferent signals from the mouth are responsible for such effects. Because noncaloric sweet substances (e.g., aspartame) mimic the analgesic effects produced by sucrose [ Barr et al., 1999 ], and because the administration of sucrose by nasogastric tube is not effective in reducing crying in newborns [ Ramenghi et al., 1999 ], afferent signals from the mouth, rather than gastric or metabolic changes, appear to be responsible for the analgesic properties of sweet tastes.
Sucrose continues to have analgesic properties in 8- to 11-year-old children undergoing a cold pressor test [ Miller et al., 1994 ; Pepino and Mennella, 2005 ]. The more children liked the sweet taste, the better sucrose worked as an analgesic [ Pepino and Mennella, 2005 ]. Whether the analgesic effect of sweet taste was induced by the sweetness per se or by the pleasantness or palatability of the stimulus remains unknown. The use of sucrose in mediating analgesia is intriguing because of its natural simplicity, viability, and efficacy. However, more research is needed to determine its efficacy in reducing pain after repeated administrations [ Barr et al., 1994 ; Johnston et al., 1999 ; Masters-Harte and Abdel-Rahman, 2001 ]. Randomized controlled studies reveal benefit of sucrose analgesia during simple procedures in newborns [ Codipietro et al., 2008 ].

Umami Taste
Although there is no English word for it, umami (a Japanese term) is a savory taste exemplified by glutamate and 5′ nucleotides that occurs naturally in many foods such as tomatoes, parmesan cheese, cured ham, sun-dried tomatoes, seaweed, fish, and meats. Although the taste of umami itself is subtle, it blends well with other tastes to expand and round out flavors. Developmental research has revealed that infants display distinct positive facial expressions similar to those observed with sweetness (i.e., facial relaxation, followed by positive mouth gaping) when tasting soup to which monosodium glutamate (MSG) has been added compared with the soup diluent alone [ Beauchamp and Pearson, 1991 ; Steiner, 1987 ; Vazquez et al., 1982 ]. MSG alone does not appear to elicit those facial responses, however, raising the question of exactly what it is about the MSG-flavored soup that is preferred.
Early in life, infants are exposed to pronounced differences in levels and patterns of umami taste experiences because different types of milk contain variable amounts of compounds having specific taste qualities [ Mennella et al., 2009 ]. Perhaps the most striking, from a sensory perspective, is the difference in the taste-active amino acid, glutamate. Glutamate is the most abundant free amino acid in human milk; it is 40-fold higher in milk relative to plasma [ Ramirez et al., 2001 ], and accounts for more than 50 percent of the total free amino acid content [ Rassin et al., 1978 ]. Although glutamate levels in human milk [ Mehaia and Al-Kanhal, 1992 ; Sarwar et al., 1998 ] are several times greater than that found in cows’ milk [ Sarwar et al., 1998 ] and bovine milk-based formulas, levels in hydrolysate formulas are more than 300 times greater [ Hernell and Lonnerdal, 2003 ; Harzer et al., 1984 ]. During infancy, those infants who are fed hydrolysate formulas or who are breastfed prefer savory-tasting foods more than those who are fed cow’s milk formula [ Mennella et al., 2009 ], providing further evidence that taste preferences can be modified early in life in response to the types of milks/formulas and solid foods eaten during infancy.

Sour Taste
In contrast to the innate preference for sweet and umami tastes, newborns reject the sour taste of citric acid, as evidenced by facial grimacing [ Steiner, 1977 ] and reduced intake [ Desor et al., 1975 ]. Little is known about the ontogeny of sour taste preferences because of the paucity of scientific research in this area. However, one study demonstrated that preference for sour tastes is heightened during childhood [ Liem and Mennella, 2003 ]. One-third of the 5- to 9-year-old children tested, but none of the adults, preferred extremely sour tastes in a food matrix. Moreover, the children’s preferences for sour tastes generalized to other foods, such as candies and lemons [see also Liem et al., 2006 ]. One explanation for such findings is that there are ontogenic changes in taste perception, independent of experiences, that underlie the heightened sour preferences in some children. Another explanation for individual difference in level of preferred sour taste lies in the child’s previous experiences [ Liem and Mennella, 2002 ; Mennella and Beauchamp, 2002 ; Liem and de Graaf, 2004 ]. For example, children who were fed a formula that has a sour and bitter flavor component (i.e., protein hydrolysate formulas) during their infancy preferred higher levels of citric acid in juice and were less likely to make negative facial expressions during the taste tests compared with children who were fed milk-based formulas.

Bitter Taste
Rejection of bitter tastes is evident early in life, although there seem to be differences based on the bitter compound tested. For example, while human infants respond with highly negative facial expressions to concentrated quinine [ Ganchrow et al., 1983 ], significant rejection of urea does not occur until a few weeks after birth [ Kajuira et al., 1992 ]. Although these data are consistent with the hypothesis that there is an early developmental change in the perception of this particular bitter taste, they could instead reflect changes in the ability of the infant to regulate the intake of bitter solutions. A different developmental timetable for rejecting different bitter compounds may reflect the multiple controls of bitterness sensation that develop at different rates [ Margolskee, 2002 ]. Moreover, the 25 different bitter receptors, each likely responsive to one or several structurally related bitter compounds, could be expressed at different times during development. Furthermore, there is some indication that there may be sensitive periods, such that early experiences with bitter tastes and other off flavors predispose individuals to be more accepting of these flavors later in life [ Mennella et al., 2005 ].
One of the predominant flavor characteristics of the prototypical healthy foods – vegetables – is their bitterness. Indeed, many of the apparent health-related benefits of consuming vegetables comes precisely from bitter ingredients such as glucosinolates, which at low levels are healthful but at higher levels can be harmful. However, there are individual differences in how sensitive people are to specific bitter compounds. The classic example of genetic differences in taste sensitivity is for phenylthiocarbamide (PTC) and the related chemical 6-n-propylthiouracil (PROP). Some people can detect these compounds at low concentrations, whereas others need much higher concentrations, or cannot detect them at all [ Bufe et al., 2005 ; Hayes et al., 2008 ; Kim et al., 2003 ]. The gene TAS2R38 , which accounts for this taste polymorphism, codes for one member of the family of taste receptors that respond to bitter stimuli. Recently, it was discovered that variation in this bitter receptor specifically regulates adults’ bitterness perception of cruciferous vegetables known to contain PTC-like glucosinolates (e.g., turnips, broccoli, mustard greens) [ Sandell and Breslin, 2006 ]. Children are not only more likely to experience a strong bitter taste from PTC and its chemical relative, PROP, but are also more sensitive to it, detecting it at lower concentrations than adults [ Anliker et al., 1991 ; Karam and Freire-Maia, 1967 ; Mennella et al., 2005 ]. This age-related change in sensitivity for PROP was recently shown to be affected by sequence diversity in the bitter taste receptor TAS2R38 gene. Children who were heterozygous for the common form of this receptor were more sensitive to the bitterness of PROP than were adults with this same form [ Mennella et al., 2005 ]. Like sweet and salt preference, the timing of the shift from childlike to adultlike PROP perception occurs during adolescence [ Mennella et al., 2010 ]. The age-related change in bitter perception is likely to have a broad impact because of the high allele frequencies of the taster and non-taster haplotypes in the human population.
A common culinary method to reduce the unpleasantness of bitter taste is the addition of salt. Sodium salts impart a desirable taste to foods, and they are effective in reducing the bitterness and increasing the acceptance of some bitter compounds by adults [ Breslin and Beauchamp, 1995 ] and children [ Mennella et al., 2003 ]. Although the mechanisms underlying the sodium’s effectiveness as a bitter blocker remain unknown, studies in adults revealed that sodium is the most effective cation at inhibiting bitterness of several oral pharmaceuticals (e.g., ranitidine, acetaminophen, pseudoephedrine, which presumably act at the peripheral taste level and not by cognitive effects) [ Keast and Breslin, 2002 ]. Since children prefer salted solutions even more than adults, the use of sodium salts may be an especially effective strategy for reducing the bitterness of pharmaceutical liquids designed for the pediatric population. Moreover, the intensity of the sweetness of a liquid formulation may be enhanced by the addition of a sodium salt, presumably by blocking bitterness and thereby releasing sweetness from cognitive suppression [ Breslin and Beauchamp, 1995 ]. Additional blockers of bitterness have been identified both in research publications and in the patent literature (e.g., phosphatidic acid β-lactoglobulin, glutamate, AMP adenosine monophosphate) [ Mennella and Beauchamp 2008 ]. With progress in understanding the molecular mechanisms underlying bitter taste perception and how bitter blockers function to suppress bitterness, it may be possible to predict the efficacy of these blockers for a drug of interest, with the ultimate goal of decreasing the bitterness, and hence increasing palatability and compliance when children need to take liquid drug formulations.

Salty Taste
Infant response to salt taste provides the clearest example of a developmental change to a taste stimulus that occurs postnatally [ Beauchamp and Cowart, 1993 ]. Consistent with the absence of a facial response to salt taste in the newborn, preferential ingestion and differential sucking of salt water relative to plain water are absent in the very young infant and do not emerge until approximately 4–6 months of age [ Beauchamp et al., 1986 , 1994 ]. Experience with salty tastes does not appear to play a major role in this shift from indifference or rejection of salt at birth to acceptance in later infancy. This developmental change instead may reflect postnatal maturation of central or peripheral mechanisms underlying salt taste perception, as has been demonstrated in animal model studies [ Hill and Mistretta, 1990 ]. The preference that emerges at 4 months appears to be largely unlearned.
Research has revealed that young children undergo another developmental shift in their preference for salt taste. By 18 months of age, children begin rejecting salted water. Like adults, they do not choose to consume salt water, but they begin exhibiting robust preferences for salt in soup and other foods such as carrots or pretzels [ Beauchamp and Moran, 1984 ]. In other words, the same level of saltiness may elicit a positive or negative response, depending on the medium in which salt is presented to the child, underlying the importance of sensory context in its perceived pleasantness and preference. Similar to the heightened preferences observed for sweet taste, preschoolers and teenagers prefer greater saltiness than adults [ Beauchamp et al., 1986 ]. The adult pattern for salt taste preference does not emerge until late adolescence. Factors responsible for this age-related difference are not known. Nevertheless, as discussed in the next section, research findings suggest that salt liking and preferences in infants and young children are regulated to some extent by prior dietary exposure.

Early Experiences and Preferences for Salt Taste during Childhood and Adolescence
A series of animal-model experiments testing the development of salt (NaCl) sensitivity demonstrated that rat pups whose mothers were severely salt-restricted during an early period of gestation have altered sensitivity, behaviorally and electrophysiologically, when tested at various times after birth [ Stewart et al., 1997 ]. The mechanism by which the deprivation results in this reduced salt sensitivity remains elusive, but the fact that there is a sensitive period for this effect has been established. Similarly, variation in salt intake between conception and 30 days of age in rats led to persistent difference in preference in adulthood [ Contreras and Kosten, 1983 ]. These data are consistent with the hypothesis that high salt intake of the mother and young infant leads to high salt intake later in life. In other animal-model studies of salt preferences, it was found that rat pups given one or several experiences of sodium depletion exhibit heightened preference for salt as adults [ Frankmann et al., 1986 ]. Evidence suggests that early exposures are more effective than later ones in establishing this heightened preference, leading the investigators to propose that the hormonal changes consequent to sodium depletion (i.e., increases in angiotensin and aldosterone) permanently alter structures in the brain that are responsible for modulating salt intake.
A series of studies in humans have suggested a parallel phenomenon. The adult offspring (college students) of mothers who experienced considerable morning sickness during their pregnancies had greater salt preferences compared with students whose mothers suffered little or no morning sickness [ Crystal and Bernstein, 1995 ]. The proposed mechanism is that morning sickness leads to transient fluid and sodium depletion in a manner analogous to that reported in animal-model studies. Consistent with these findings, 12- to 14-year-old children who had been exposed to a chloride-deficient formula during early development had heightened preferences for salty (but not sweet) foods relative to their unexposed control siblings [ Stein et al., 1996 ]. Because chloride deficiency mimics sodium deficiency in some ways (e.g., altered hormonal profile), this finding is consistent with other rat and human studies.
That salt liking and preference in infants and young children are regulated to some extent by prior dietary exposure is suggested by the finding that bottle-fed infants exhibit higher salt preferences than do breastfed infants [ Beauchamp and Stein, 2008 ], perhaps due to the greater amounts of sodium in formula relative to breast milk. Other evidence indicates that infants who are fed starchy foods (that likely also contain substantial amounts of salt) early in life have elevated salt preferences compared to infants whose early supplemental feedings do not contain these high-salt foods [ Beauchamp and Stein, 2008 ].
The findings relating preference for salty taste to the amount of exposure are correlational and hence do not prove cause and effect. However, studies in adults revealed that the experimental manipulation of salt intake can alter salt taste perception and preference [ Beauchamp et al., 1990 ; Bertino et al., 1982 ]. When total salt intake is reduced over a substantial time period, adults prefer lower levels of salt and perceive a given level of salt as being more intense. This taste change, which takes 2–3 months, can be rapidly reversed when individuals are returned to their typical dietary salt level [ Beauchamp et al., 1990 ].
The taste world of the child is different from that of the adult because sensitivity to several different taste stimuli develops at different times postnatally (see Table 9-1 ). Specifically, responses to sweet tastes are evident prenatally, and major changes are not known to occur postnatally. The rejection of sour tastes is evidenced from birth onward. In contrast, salt and bitter sensitivities change postnatally, with salt sensitivity providing the clearest example.
Hard-wired from birth, the basic biology of humans steers us to seek out sweet foods dense with energy, salty foods dense with minerals, and savory foods rich in proteins, and to reject bitter-tasting toxins and unripe sour foods. The developmental changes in sweet and salt preferences and bitter rejection may reflect changes in sensitivity independent of experience, or may be a consequence of specific experiences, or both. Salty taste preferences are apparently more plastic than are sweet preferences, and childhood may represent a time of heightened bitter sensitivity for some children. Nevertheless, our knowledge of how early exposures impact later preferences and intake remains incomplete. It will be important to determine whether early exposure to lower-salt foods can help protect the developing child from excess intake later in life, and whether early exposure to bitter-tasting vegetables promotes vegetables acceptance during childhood.

Clinical Significance
Taste dysfunctions are described by several terms. Ageusia refers to a complete loss of gustatory function, whereas hypogeusia refers to diminished sensitivity to detect a specific taste quality or class of compounds (e.g., phenylthiocarbamide). Dysgeusia and phantogeusia respectively refer to distortion in the perceived qualities of a taste stimulus and the experience of a taste sensation in the apparent absence of a gustatory stimulus [ Cowart et al., 1997 ]. The study of clinical abnormalities in taste perception in pediatric populations has received little scientific attention, in part because the clinical assessment of taste is not well developed [ Cowart et al., 1997 ]. However, some reports in these age groups, although limited, are highlighted here. Box 9-2 lists conditions that sometimes are associated with taste disorders in adults.
A few disorders with neurologic symptoms have been associated with taste disturbances in infants and children. Familial dysautonomia, a hereditary autonomic and sensory neuropathy that affects almost exclusively Jewish children of Ashkenazi extraction, is caused by a defect localized to the chromosome 9q31–q33 [ Blumenfeld et al., 1993 ]. Features of this disorder include corneal abrasions, lack of tearing, erythematous blotching of the skin, paroxysmal hypertension, emotional lability, increased sweating, cold hands and feet, drooling, scoliosis, and the absence of fungiform papillae on the tongue. Patients with this disorder could detect but failed to label correctly salty, bitter, sweet, and water stimuli compared with control children and adults [ Gadoth et al., 1997 ]. Sour taste and the sense of smell were preserved in these dysautonomic patients.
Another congenital disorder that may affect taste perception but does not manifest until later childhood is Melkersson–Rosenthal syndrome. Features of this syndrome include chronic facial swelling, relapsing peripheral unilateral or bilateral facial palsy, and in some individuals, lingua plicata (i.e., “scrotal” tongue). A report of a patient with clinical features of this syndrome suggests that the gene is located at 9p11 [ Smeets et al., 1994 ]. Of interest is the report that this patient, who had no facial palsy, complained of taste loss in the anterior part of the tongue. Surgical procedures of the head or neck may sometimes result in taste loss or dysgeusia. For example, tonsillectomy has been associated with taste dysfunction, perhaps because of damage to the lingual branch of the glossopharyngeal nerve [ Reider, 1981 ], whereas surgical procedures that involve the middle ear may damage the chorda tympani nerve (branch of cranial nerve VII), which mediates taste perception on the anterior tongue [ Della Fera et al., 1995 ; Duffy et al., 2003 ]. Damage to or anesthesia of the chorda tympani nerve can increase taste sensations (particularly bitter) from the other taste nerves (i.e., glossopharyngeal branch of cranial nerve IX and cranial nerve X) and blunt retronasal olfactory sensations from cranial nerve I [ Duffy et al., 2003 ]. Likewise, middle-ear infections or oral infections that reach the middle ear through the eustachian tubes may affect the chorda tympani nerve as it passes between the malleus and incus, and affect taste perception. Insults to chorda tympani nerve function may explain some taste disruptions [ Duffy et al., 2003 ; Bartoshuk et al., 1996 ]. In particular, exposure to otitis media during childhood was associated with losses of bitter taste on the tip of the tongue and, when severe, reduction in the perception of sweetness throughout the mouth [ Duffy et al., 2003 ; Kim et al., 2007 ; Tanasescu et al., 2000 ], which was associated with a higher risk for obesity [ Snyder et al., 2003 ].
Endocrine, metabolic, and nutritional disorders causing loss of taste are rare in adults and presumably in pediatric populations. Children with chronic renal failure exhibited reduced preference for sweet-tasting foods, which was unrelated to plasma zinc levels [ Bellisle et al., 1995 ], whereas infants and children diagnosed as suffering from second- and third-degree protein-energy malnutrition preferred soup to which casein hydrolysate had been added over soup alone [ Beauchamp et al., 1987 ; Vazquez et al., 1982 ]. Well-nourished control infants and malnourished infants who had recovered exhibited the opposite response, suggesting that protein-energy status affects taste preferences [ Beauchamp et al., 1987 ; Vazquez et al., 1982 ]. Both the well-nourished and malnourished infants preferred the sweet-tasting liquids and rejected bitter-tasting (urea) and sour-tasting (citric acid) liquids. Such findings provide information that may be useful for clinicians in planning palatable diets for these patients. Although the most common etiologic factor contributing to taste disturbances in adults appears to be medication use, there are few reports regarding similar effects in pediatric populations [ Ahonen et al., 2004 ]. Not all individuals taking a particular drug are affected, and the mechanisms by which these medications alter chemosensory function are not well understood. Nevertheless, a variety of medications have been reported sometimes to cause taste (and smell) dysfunction in adults ( Table 9-2 ) [ Abdollahi and Radfar, 2003 ; Ackerman and Kasbekar, 1997 ; Mott et al., 1993 ; Murphy et al., 2003 ; Schiffman, 1983 ; Spielman, 1998 ].
Table 9-2 Drugs Associated with Taste and Smell Dysfunction Class of Medication Specific Drugs * Chemosensory Dysfunction Anesthetic Benzocaine Loss of taste   Lidocaine Loss of smell   Cocaine HCl Loss of smell   Tetracaine HCl Loss of taste Antibacterial Procaine penicillin Metallic dysgeusia   Metronidazole HCl Metallic dysgeusia   Tetracycline Metallic dysgeusia   Doxycycline Anosmia, parosmia Antiepileptic Carbamazepine Hypogeusia   Tegretol Hypogeusia Antidiabetic Biguanide Metallic dysgeusia Antifungal Amphotericin B Hypogeusia Anti-inflammatory Phenylbutazone Ageusia   Azelastine Bitter, metallic dysgeusia Immunosuppressive/antineoplastic 5-Fluorouracil Sour, bitter dysgeusia   Methotrexate Sour, metallic dysgeusia; ageusia   Cisplatin Ageusia Antirheumatic Allopurinol Metallic dysgeusia   Penicillamine Metallic dysgeusia Antithyroid Methylthiouracil Taste and smell loss Cardiovascular Captopril Increased taste thresholds   Diltiazem Hypogeusia, hyposomia   Nifedipine Taste and smell distortions Dental products Chlorhexidine Ageusia, loss of salty taste, persistent aftertaste   Hexidine Altered taste   Sodium lauryl sulfate Loss of sweet and salty taste; taste disturbance Muscle relaxant Baclofen Ageusia, hypogeusia Opiate Codeine Olfactory depression   Morphine Olfactory depression Sympathomimetic Amphetamines Bitter dysgeusia; olfactory dysfunction Tranquilizers Chlormezanone Ageusia; metallic and bitter dysgeusia
* This is a partial listing of the medications associated with taste and smell disturbances in adults. Not all individuals taking a particular drug are affected, and the mechanisms by which these medications alter chemosensory function are not well understood.
(Adapted from Ackerman and Kasbekar, 1997 ; Mott et al., 1993 ; Murphy et al., 2003 ; Schiffman, 1983 ; Spielman, 1998. )

The Ontogeny of Olfactory and Flavor Perception
Relative to studies on taste perception, less is known about the ontogeny of olfactory and flavor perception. However, the research discussed in the following sections demonstrates that infants are able to detect and discriminate between a wide variety of odors shortly after birth. They hedonically respond to differences in odor quality [ Mennella and Beauchamp, 1991a , 1998a ; Soussignan et al., 1997 ], appear to be as sensitive to odors as adults (if not more so), and are capable of retaining complex olfactory and flavor memories [ Mennella et al., 2001 ; Schaal et al., 2000 ; Sullivan et al., 1991 ).

Fetus
Although the olfactory system is well developed before birth, it is not known whether the human fetus responds to olfactory stimuli [ Arey, 1930 ; Bossey, 1980 ; Nakashima et al., 1984 ]. However, the environment in which the fetus lives – the amnion – can be odorous. In addition to certain disease states, such as maple syrup disease [ Menkes et al., 1954 ], phenylketonuria [ Partington, 1961 ], and trimethylaminuria [ Lee et al., 1976 ], the odor of amniotic fluid reflects the foods eaten by the pregnant mother [ Mace et al., 1976 ; Mennella et al., 1995 , 2001 ; Schaal et al., 2000 ]. That the amniotic fluid and the newborn’s body can acquire the odor of a spicy meal ingested by the mother before giving birth suggests that odorous compounds in the mother’s diet can be transferred to amniotic fluid and ingested by the fetus [ Hauser et al., 1985 ]. This phenomenon has been experimentally demonstrated in a study in which amniotic fluid samples were obtained from pregnant women who were undergoing routine amniocentesis and who ingested garlic or placebo capsules approximately 45 minutes before the procedure [ Mennella et al., 1995 ]. The odor of the amniotic fluid obtained from the women who ingested the garlic, as determined by adult human evaluators, was judged to be stronger or more like garlic than amniotic fluid from the control women who did not consume garlic.
Because the normal fetus has open airway passages that are bathed in amniotic fluid and swallows significant amounts of amniotic fluid during the latter stages of gestation, inhaling more than twice the volume it swallows, the fetus may be exposed to a unique olfactory environment before birth [ Pritchard, 1965 ; Schaffer, 1910 ]. As discussed later, this secretion represents the first exposure to flavors (odors and tastes) that will subsequently be provided by mother’s milk and then the foods of the table. Studies in other animals reveal that certain odors experienced in utero were preferred postnatally [ Hepper, 1988 ].

Newborn
Shortly after birth, human infants can detect a wide variety of volatile chemicals, and appear to be as sensitive to odors as adults, if not more so. Research has shown that they can detect and discriminate among many qualitatively distinct odorants, as evidenced by changes in their facial responses, body movements, and heart and respiratory rates, and anatomic studies on human fetuses suggest that their olfactory neuroepithelium has a higher ratio of olfactory to respiratory epithelium compared with normal adults with no history of infection or exposure to toxins [ Engen, 1982 ; Nakashima et al., 1984 ; Rovee, 1972 ].
Infants also display physiological and hedonic responses to salient odors. For example, newborns who were separated from their mothers cried significantly less when they were exposed to amniotic fluid [ Varendi et al., 1998 ]. This finding is consistent with previous reports stating that newborns can detect the odor of amniotic fluid and that they prefer the odor of their own amniotic fluid relative to a control stimulus or unfamiliar amniotic fluid for at least the first few days of life. This topic has been reviewed by Porter and Schaal [2003] . By the fourth day of life, those infants who are breastfed acquire preferences for the odor of breast milk relative to the odor of their own amniotic fluid [ Marlier et al., 1998 ]. Although amniotic fluid or its volatile components are initially particularly attractive to all newborns, this attraction appears to be relatively transient as infants gain experience with breastfeeding [ Varendi et al., 1997 ].
After birth, the most salient of odors for the newborn are those originating from the mother [ Macfarlane, 1975 ]. Within hours of birth, mothers and infants can recognize each other through the sense of smell alone [ Schaal, 1988 ]. The ability of breastfed infants to discriminate the odors of their mothers from those of other lactating women is not limited to odors emanating from the breast region because they can also discriminate odors originating from their mothers’ underarms and neck [ Cernoch and Porter, 1985 ; Schaal, 1986 ]. Like other mammalian young, this recognition of and preference for maternal odors may play a role in guiding the infant to the nipple area and facilitating early nipple attachment and suckling. This conclusion is supported by the finding that newborns preferred their mothers’ breasts unwashed compared with the same breasts that had been thoroughly washed and were therefore less odorous [ Varendi et al., 1994 ].

Infants and Retronasal Perception of Flavors
Considerable research indicates that the amniotic fluid and mother’s milk are rich in flavor and that the flavors directly reflect the foods and beverages eaten (e.g., carrot, garlic, mint, alcohol, vanilla, tobacco, anise) or substances inhaled (e.g., tobacco) by the mother [ Mennella and Beauchamp, 1991b , 1991c , 1993 , 1996 , 1998b ; Mennella et al., 2001 ; Schaal et al., 2000 ]. The retronasal perception of odors in mother’s milk provides the infant with the potential for a rich source of various chemosensory experiences and a possible route for the development of preference for a diet similar to the mother’s, because the context in which the flavor is experienced, with the mother and during feeding, consists of a variety of elements (e.g., tactile stimulation, warmth, milk, mother’s voice) that are reinforcers for early learning.
The transition from a diet consisting exclusively of human milk to a mixed diet may be facilitated by providing the infant with bridges of familiarity, such that the infant experiences a commonality of flavors in the two feeding situations. For example, breastfed infants who had been fed cereal mixed in water for approximately 2 weeks readily accepted the cereal when it was subsequently prepared with mother’s milk [ Mennella and Beauchamp, 1997 ]. They consumed more of the cereal, and displayed a series of behaviors signaling their preferences. Because the infant’s first flavor experiences occur before birth in amniotic fluid, breast milk bridges the experiences of flavors in utero to those in solid foods. Moreover, experience with a particular flavor in amniotic fluid or mother’s milk biases the infant’s preferences for that flavor during breastfeeding [ Mennella and Beauchamp, 1993 , 1996 ] and weaning [ Mennella et al., 2001 ]. The sweetness and textural properties of human milk, such as viscosity and mouth-coating, vary from mother to mother, suggesting that breastfeeding, unlike formula feeding, provides the infant with the potential for a rich source of other variations in chemosensory experiences. The types and intensity of flavors experienced in breast milk may be unique for each infant and serve to identify the culture to which the child is born and raised. In other words, the flavor principles of the child’s culture are experienced prior to their first taste of solid foods [ Mennella, 2007 ].
Because the chemical senses are functional during infancy and change during development, breastfed infants may have the opportunity to learn about the flavor of the foods of their culture long before solids are introduced. Unlike the bottle-fed infant, who experiences a constant set of flavors from standard formulas, the breastfed infant’s sensory world is extremely rich and varied. When an infant is exposed to a flavor in the amniotic fluid or breast milk and is tested sometime later, the exposed infants accept the flavor more than infants without such experience [ Mennella et al., 2001 ]. This pattern makes evolutionary sense since the foods that a woman eats when she is pregnant and nursing are precisely the ones that her infant should prefer. All else being equal, these are the flavors that are associated with nutritious foods, or at least, foods she has access to, and hence the foods to which the infant will have the earliest exposure. In a recent study, it was shown that breastfeeding conferred an advantage when infants first tasted a food but only if their mothers regularly eat similar-tasting foods [ Forestell and Mennella, 2007 ]. If their mothers eat fruits and vegetables, breastfed infants will learn about these dietary choices by experiencing the flavors in mother’s milk, thus highlighting the importance of a varied diet for both pregnant and lactating women [ Forestell and Mennella, 2007 ; Mennella et al., 2008 ]. These varied sensory experiences with food flavors may help explain why children who were breastfed were less picky [ Galloway et al., 2003 ] and more willing to try new foods [ Sullivan and Birch, 1994 ; Mennella and Beauchamp, 1996 ]; this, in turn, contributes to greater fruit and vegetable consumption in childhood.
There are indications that infants are also learning about the flavor profile of the formula, although monotonous, that they are consuming [ Mennella et al., 2006 , 2009 ], and that the effects of these early experiences may be long-lived. For example, some work demonstrated that experience with the sour and bitter flavors of protein hydrolysate formulas programmed later acceptance of these flavors during infancy [ Mennella et al., 2004 ] and elicited more positive responses to sensory attributes associated with formulas (e.g., sour taste, aroma) in 4- to 5-year-old children [ Mennella and Beauchamp, 2002 ].

Young Children
The few published studies that have focused on olfactory preferences in verbal children indicate that they have likes and dislikes for a range of odors but that their hedonic experience may be different from adults. Because children younger than 5 years old appear to respond positively to some odors, such as the odor of synthetic sweat and feces, some investigators have concluded that they do not have aversions to odors that adults and older children find offensive, and are generally more tolerant of odors than are adults [ Engen, 1982 ; Stein et al., 1958 ].
Some of the discrepancies as to when olfactory preferences and aversions arise can be traced to methodologic and technical difficulties in testing young children. For example, children younger than 6 years tend to answer a positively phrased question in the affirmative, and they have a shorter attention span than older children [ Engen, 1974 ]. Their responses may be biased and not reflect their actual reaction to the odor. By using methods that are sensitive to these behavioral limitations and that embed the olfactory task in the context of a game, research has demonstrated that olfactory preferences and aversions are evidenced in children as young as 3 years [ Schmidt and Beauchamp, 1988 ; Mennella and Garcia, 2000 ; Forestell and Mennella, 2005 ; Mennella and Forestell, 2008 ]. Like adults, children preferred the odor of C16 aldehyde (i.e., strawberry), phenylethyl-methylethyl carbinol (i.e., floral), l -carvone (i.e., spearmint), and methyl salicylate (i.e., wintergreen), but they disliked the odor of butyric acid (i.e., strong cheese or vomit) and pyridine (i.e., spoiled milk).
Of special interest was the reported difference between children and adults in their affective judgments of the odor of androstenone; 92 percent of the children and 59 percent of the adults rated this odor as bad. Androstenone is an interesting odor because it can be perceived as smelling urinous, sweaty, musky, like sandalwood, or having no smell; twin studies revealed that genetic differences between individuals contribute to these differences in the perception of androstenone [ Wysocki and Beauchamp, 1989 ]. Approximately one-half of the adult population has a specific anosmia to this odor. A high percentage of children rated this odor as bad, suggesting that most or perhaps all 3-year-old children can detect this odor. A developmental shift in the perception of androstenone occurs at or near adolescence, when approximately 50 percent of individuals lose the ability to smell this odor. The mechanisms underlying this change in perception remain unknown.
The early state of maturity and plasticity of the olfactory system favors its involvement in the adaptive responses to the challenges of normal or atypical development [ Sullivan et al., 1991 ]. Experience-induced plasticity in response to odors is a means by which the olfactory system can be tuned to emphasize transduction of stimuli deemed relevant within an individual’s environment. Second, salient memories formed during the first 10 years of life will likely be olfactory in nature. That is, autobiographical memories triggered by olfactory information mainly occurred during the first decade of life, whereas those associated with verbal and visual cues peaked later in adolescence and early adulthood [ Willander and Larsson, 2006 ]. In a set of studies, we found that children whose parents use alcohol to change their state of mind and reduce feelings of dysphoria were no better at identifying the odor than children of nonescape drinkers. However, they were more likely to dislike the odor of beer when compared to children whose parents did not drink to escape [ Mennella and Garcia, 2000 ; Mennella and Forestell, 2008 ). Similarly, children whose mothers smoked cigarettes to relieve tension disliked the odor of cigarette smoke more than children whose mothers smoked for reasons other than tension relief [ Forestell and Mennella, 2005 ].
These findings suggest that children’s hedonic judgment of odors can be shifted either upward or downward depending on the hedonic valence of the odor. When an odor, which is generally liked by most children (e.g., the odor of beer), is associated with negative consequences such as parental stress and tensions, their liking for this odor decreases. When an odor, which is generally disliked by most children (e.g., the cigarette odor), is associated with positive consequences (such as relaxed mothers, low mood disturbance), it becomes preferred by children. Furthermore, children’s learning about alcohol and tobacco is not just based on the frequency of exposure, but rather on the associations made between the sensory experience and the emotional context in which their parents drink or smoke. Whether such associations (either positive or negative) affect children’s risk for smoking or drinking initiation is not known. Assessment of the time course and the long-term effects of early hedonic judgments about alcohol and cigarette odor are important areas for future research.

Clinical Significance of Olfaction
The terminology used to describe olfactory dysfunction parallels that used for taste disorders. Anosmia refers to the complete absence of olfactory functioning, whereas hyposmia refers to diminished olfactory functioning. In some patients, there may be a deficit in the perception of only a specific odorous compound (e.g., androsterone) or a class of compound; this condition is commonly referred to as specific anosmia. Hyperosmia refers to an increased sensitivity to smell, dysosmia or parosmia refers to conditions in which there are distortions in the perceived qualities of the odor stimulus in the presence of an odor, and phantosmia often refers to the perception of an odor when there is no odor present [ Cowart et al., 1997 ; Doty, 2009 ].
Box 9-3 lists several conditions that are associated with olfactory disorders in adults. Paranasal sinus disease, prior upper respiratory tract infection, and head trauma account for the majority (i.e., more than two-thirds) of adult cases of olfactory dysfunction [ Mott and Leopold, 1991 ; Cowart et al., 1997 ; Doty, 2009 ]. Of particular relevance to the neurologist is the fact that a cardinal feature of several neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s) is an olfactory deficit. In children, the loss of smell (and hearing) is less common after head trauma compared with adults [ Jacobi et al., 1986 ]. Common causes associated with impaired olfactory sensitivity in children include nasal obstruction; allergic, chronic, or hypertrophic rhinitis; and nasal polyps (frequently seen in children suffering from cystic fibrosis) [ Ghorbanian et al., 1983 ]. Olfactory functioning improves after adenoidectomy in children with nasal obstruction caused by adenoid hypertrophy [ Ghorbanian et al., 1983 ]. Evaluation of a child with partial or complete loss of smell may require referral to an otorhinolaryngologist to determine whether there are any local pathologic findings (e.g., foreign body, nasal polyp). Shearing of the olfactory nerves, hemorrhage into the olfactory bulb, fractures of the cribriform plate, and frontal lobe contusions have all been reported in children, but their impact on chemosensory functions remains unknown.
Like the sense of taste, little is known about genetic and congenital disorders of smell perception in infants and children. The principal genetic syndrome associated with alterations in smell perception, Kallmann’s syndrome, is characterized by the coexistence of hypogonadotropic hypogonadism and permanent anosmia. MRI of the olfactory bulbs and sulcus revealed no evidence of morphologic changes in these areas [ Ghadami et al., 2004 ]. In part, these symptoms appear to be the result of the failure of neurons producing gonadotropin-releasing hormone to migrate from the olfactory placode to the brain during embryonic development, and the lack of synaptic connections between olfactory neurons and the olfactory bulbs [ Kallmann et al., 1944 ; Rawson et al., 1995 ]. Patients with this syndrome, which appears to be X-linked recessive (Xp22.3) in some families [ Meitinger et al., 1990 ] and autosomal-recessive in others, may also have renal agenesis, mirror movements of the hands, pes cavus, high-arched palate, and cerebellar ataxia [ Hardelin et al., 1992 ]. A number of genes have been identified recently that are associated with this syndrome ( Hardelin and Dode, 2008 ). Down syndrome is another congenital condition associated with decreased ability to smell in adult patients; however, olfactory dysfunction is not evident during young adolescence and presumably during childhood [ McKeown et al., 1996 ; Murphy and Jinich, 1996 ]. As with the sense of taste, a variety of medications can sometimes affect olfactory perception in adults (see Table 9-2 ). Moreover, certain metals (e.g., cadmium, zinc), tobacco products, and a variety of industrial substances cause olfactory loss or distortion [ Schiffman and Nagle, 1992 ].

Summary
The newborn infant and the fetus have functioning chemosensory systems, and their feeding and expressive behaviors are modulated by taste and smell stimuli. Although these sensory systems are operable early in ontogeny, the human fetus and newborn infant are not merely miniature adults, because their sensory systems mature postnatally and are influenced by experience in ways not yet fully understood. Hard-wired from birth, the basic biology of humans steers us to seek out sweet foods dense with energy, salty foods dense with minerals, and savory foods rich in proteins, and to reject bitter-tasting toxins and unripe sour foods. The sensory and biological considerations shed light on why it is difficult to make lifestyle changes in young children and why it is difficult for children to eat nutritious foods when these foods do not taste good to them. We cannot easily change the basic ingrained biology of liking sweets and avoiding bitterness. What we can do is modulate children’s flavor preferences by providing early exposure, starting in utero, to a wide variety of healthy flavors and moderating exposure to salt. The reward systems that encourage us to seek out pleasurable sensations and the emotional potency of food- and flavor-related memories initiated early in life together play a role in the strong emotional component of food habits. An appreciation of the complexity of early feeding, and a greater understanding of the cultural and biological mechanisms underlying the development of food preferences will aid in our development of evidence-based strategies and programs to improve the diets of our children.
The study of smell and taste perception in clinical populations of infants and children, and the impact of chemosensory dysfunction on nutritional status have received little scientific attention, and they remain important areas for future investigations. Also needed is more basic research on bitter taste-masking and blocking. Many parents are faced with the daily challenge of getting their children to take a medicine. The bad flavor of the medicine can thwart the benefits of even the most powerful drug, and failure to consume medication may do the child harm; in some cases, it is life-threatening. While there are no easy solutions to this dilemma, children’s acceptance of many medicines can be improved by applying the knowledge gleaned from basic research in the flavor senses. Better understanding of the scientific basis for distaste, and how to ameliorate it, is a public health priority for advancing availability of formulations of drug products that will be accepted by children.

Acknowledgments
Preparation of this manuscript was supported by grant DCø11287 from the National Institute for Deafness and other Communication Disorders and grant HD37119 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

References
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Part II
Neurodiagnostic Testing
Chapter 10 Spinal Fluid Examination

David J. Michelson
For more than a century, physicians have employed lumbar puncture (LP) and examination of the cerebrospinal fluid (CSF) in the diagnosis and management of neurologic diseases. CSF evaluation is contributing to our still-evolving understanding of the pathophysiology of central nervous system (CNS) disorders, while continuing to play an as yet indispensable role in the clinical management of many of those disorders. The particulars of how CSF analysis is used in specific areas of research and treatment are discussed in the chapters related to the particular CNS disorder. This chapter provides essential background for those discussions, reviewing normal CSF physiology, considerations in the performance of the LP, and the fundamentals of CSF analysis.

History
Although known since ancient times, presence of fluid within the cavities of the brain was for many millennia thought to be pathologic. The Edwin Smith Surgical Papyrus, written around the 17th century bc , is considered the earliest record of the existence of CSF. In the 4th century bc , the Hippocratic writings mention removing CSF from the ventricles of a patient with hydrocephalus. Even with the detailed descriptions of the cerebral ventricles provided by Galen in the 2nd century ad , the function of the CSF remained almost unknown until the advent of more modern scientific techniques. Richard Lower, an English physician, first suggested in 1669 that the “watery humor” could be reabsorbed by the venous system. In 1757, Pacchioni postulated that the CSF was secreted, rather than absorbed, by the arachnoid granulations that now bear his name. In 1764, Cotugno performed careful dissections of the brain and spinal cord before decapitation, allowing him to be the first to describe the presence of CSF within the subarachnoid space.
It was Magendie who, in 1825, provided the first comprehensive description of the CSF pathways. He detailed the communication between the ventricles and the subarachnoid spaces of the brain and spinal cord, and was the first to describe the fluid as cerebrospinal. Although this was correct, he mistakenly concluded that the CSF was secreted by the pia-arachnoid and flowed toward the ventricles. The observations of Monro in 1783 and those of Kellie in 1824 drew attention to the nearly fixed volume of the cranial contents, although it was Burton who reported in 1846 that the blood, brain, and CSF volumes could undergo reciprocal changes, a concept now referred to as the Monro–Kellie doctrine. Definitive anatomic studies of the CSF pathways by Weed in 1935 built on the influential work done by Key and Retzius in 1875, were the first to suggest that CSF was derived from the choroid plexus and the interstitial fluid of the brain.
In 1891, Wynter first reported the use of LP as a therapeutic measure after using the technique in a patient with tuberculous meningitis. The diagnostic value of LP was first recognized and described by Quincke in 1891. His innovations included using a percutaneous needle with a stylet, a manometer to record the opening pressure, and measurements of CSF cell counts, protein concentration, and sugar content. The technique quickly gained acceptance and had become a routine part of medical care by the turn of the 20th century. Several authors have summarized this early history [ Vandam, 1989 ]. Numerous subsequent investigators have contributed to an ever-expanding understanding of the value of CSF analysis in various neurologic diseases [ Fishman, 1992 ].

Cerebrospinal Fluid Formation, Flow, and Absorption
CSF is principally formed by secretion from the choroid plexus, villous invaginations of the walls of the lateral, third, and fourth ventricles which are richly vascularized and lined by a ciliated epithelium ( Figure 10-1 ). The choroid plexus of the lateral ventricles is continuous through the foramina of Monro with the choroid plexus of the roof of the third ventricle. The arterial supply to this portion of the choroid plexus originates from the anterior choroidal arteries, which branch off the internal carotid artery, and from the posterior choroidal arteries, which are branches of the posterior cerebral arteries. The choroid plexus within the fourth ventricle, which sends extensions through the lateral foramina of Luschka, is usually supplied by the posterior inferior cerebellar arteries. In studies of rats, blood flow to choroidal vessels is almost 10 times greater than that to the cerebral cortex [ Szmydynger-Chodobska et al., 1994] . Nerves derived from several sources, including the cervical sympathetic chain, the neural plexus of the internal carotid and posterior cerebral arteries, and the vagal nuclei, provide extensive adrenergic, cholinergic, and peptidergic innervation of the blood vessels and epithelial cells of the choroid plexus. These inputs have an influence on the rate of CSF production that is independent of vasomotor changes [ Lindvall and Owman, 1981 ].

Fig. 10-1 Structure of the choroid plexus.
A, Light microscopy of a section through the choroid plexus and ventricle from the brain of a dog (Luxol fast blue and hematoxylin stain, × 200). B, A similar view of the choroid plexus in diagrammatic form. BV, blood vessel; CT, connective tissue.
( A, Courtesy of Dr. Thomas Caceci, Virginia–Maryland College of Veterinary Medicine. B, Adapted from a drawing by Dr. Samir El-Shafey, Virginia–Maryland College of Veterinary Medicine.)
The capillaries of the choroid plexus, unlike those found in most other areas of the brain, have large fenestrations that offer little resistance to the passage of fluid, ions, and small macromolecules [ Segal, 1993 ]. Passage of blood past these capillaries creates an ultrafiltrate of plasma within the interstitial space at the basolateral surface of the epithelial cells. Analysis of the ionic composition of CSF relative to plasma ( Table 10-1 ) reveals that this interstitial fluid is modified considerably before it reaches the ventricular system, and strongly supports CSF formation being an active secretory process [ Davson et al., 1987 ].

Table 10-1 Solute Concentrations in Plasma and Lumbar Cerebrospinal Fluid
Additional studies have found that CSF secretion depends highly on active transport proteins that, as with other secretory epithelia, are differentially localized on the apical and basolateral membranes of the choroid plexus epithelial cells. Water follows the flow of sodium and chloride ions from the interstitial fluid into the CSF. Carbonic anhydrase within the epithelial cells catalyzes the formation of carbonic acid from water and carbon dioxide. Carbon dioxide diffuses freely, but the dissociation products of carbonic acid, bicarbonate and hydrogen, are transported across the basolateral membrane by specific proteins in exchange for sodium and chloride, favoring the passive diffusion of water into the cells [ Speake et al., 2001 ]. Sodium transport out of the cells is principally mediated by sodium–potassium ATPases on the apical membrane, with selectively permeable apical chloride and potassium channels rounding out the complement of transporters thought to be most important to creating a net flow of water into the CSF ( Figure 10-2 ). Water does flow passively along osmotic gradients through the choroid plexus, moving freely through the aquaporin-1 channels which are highly expressed on the apical surface of the epithelial cells [ Tait et al., 2008 ]. However, the contribution to CSF production from osmosis is minimal, as CSF production by experimental animals is unaltered even by instillation of high osmolar fluid into the ventricles [ Macaulay and Zeuthen, 2009 ].

Fig. 10-2 Major processes involved in cerebrospinal fluid (CSF) secretion.
1, Carbonic anhydrase catalyzes the production of bicarbonate ions and protons from carbon dioxide. 2, Bicarbonate is exchanged for chloride across the basolateral membrane. 3, Bicarbonate and chloride flow into the CSF through anion channels, down an electrochemical gradient, and through sodium–potassium–chloride cotransport. 4, Sodium is exchanged for protons across the basolateral membrane and for potassium across the apical membrane. 5, Water follows the osmotic gradient created by the combined secretion of sodium, chloride, and bicarbonate into the CSF.
(From Brown PD, Davies SL, Speake T, et al. Molecular mechanisms of cerebrospinal fluid production. Neuroscience 2004;129:957.)
Other specific active transport proteins present along the basolateral membrane allow transport into the CSF of essential hydrophilic micronutrients, including glucose, amino acids, purines, nucleosides, and vitamins. Transport proteins along the apical membrane work to clear the CSF of potentially toxic metabolites, such as organic acids and bases [ Spector and Johanson, 1989 ].
Tight junctions link the choroid plexus epithelial cells, limiting the free diffusion of ionic molecules and creating the blood–CSF barrier. Although protein diffusion is largely restricted, most of the small amount of protein found in the CSF is nevertheless of plasma origin. Maintenance of a relatively stable CSF composition, despite wide variation in the composition of the plasma, reflects the integrity of the blood–CSF barrier and the work of active transporters against concentration gradients [ Fishman, 1992 ].
The choroid plexus produces from 70 to 90 percent of the CSF, with the remainder deriving from movement of brain parenchymal interstitial fluid across the ependyma into the ventricles and across the meninges into the subarachnoid space [ Proescholdt, 2000 ]. The rate of CSF formation in healthy adults averages 0.35 mL per minute, or roughly 500 mL each day. Children produce proportionally less CSF, depending on their height and weight, with as little as 25 mL produced per day in newborns. Postmortem studies have provided estimates that total CSF volume ranges from 50 mL in term neonates to 150 mL in adults, with only a small percentage contained within normal-sized ventricles. The total volume of the CSF undergoes complete replacement 3–4 times each day.
Choroid plexus epithelial cells express a wide range of receptors for hormones and neurotransmitters [ Nilsson et al., 1992 ], but the rate of CSF formation appears to remain fairly constant under most conditions. Many factors have been found to influence the rate of CSF production in animal models, including cholera toxin, norepinephrine, hyperosmolality, hypothermia, atrial natriuretic hormone, vasopressin, serotonin, and dopamine [ Rosenberg, 1990 ]. Cholera toxin and norepinephrine increase CSF production through an increase in cyclic AMP formation, which has been linked to increased bicarbonate transport [ Saito and Wright, 1984 ].
Greatly reduced CSF production has been seen after experimental administration of the sodium–potassium ATPase inhibitor ouabain [ Vates et al., 1964] . Carbonic anhydrase inhibitors, such as acetazolamide, can reduce the choroidal production of CSF in rats by 50–100 percent [ Fishman, 1992 ]. Of the seven mammalian isoforms of carbonic anhydrase, however, the CAIII isoform that is most abundant in the human choroid plexus is insensitive to acetazolamide [ Nogradi et al., 1993 ], explaining the somewhat limited clinical effectiveness of this medication [ Cowan and Whitelaw, 1991 ]. Furosemide and other loop diuretics weakly inhibit carbonic anhydrase activity but are thought to reduce CSF production through inhibition of sodium, potassium, and chloride co-transporters [ Jo