Clinical Neurophysiology of Infancy, Childhood, and Adolescence

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 CLINICAL NEUROPHYSIOLOGY OF INFANCY, CHILDHOOD, AND AD...

Author: Gregory Holmes | Solomon Moshe | H. Royden Jones

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1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

CLINICAL NEUROPHYSIOLOGY OF INFANCY, CHILDHOOD, AND ADOLESCENCE Copyright © 2006, Elsevier Inc. ISBN 0-7506-7251-X All rights reserved. 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. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions.’

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. 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 the practitioners, relying on their own experience and knowledge of the patient, 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 Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

Library of Congress Cataloging-in-Publication Data Clinical neurophysiology of infancy, childhood, and adolescence/Gregory L. Holmes, Solomon L. Moshé, H. Royden Jones, Jr.—1st ed. p. cm. ISBN 0-7506-7251-X 1. Pediatric neurology. 2. Neurophysiology. 3. Electroencephalography. 4. Evoked potentials (Electrophysiology) I. Holmes, Gregory L. II. Moshé, Solomon L. III. Jones, Jr., H. Royden RJ488.C56 2006 618.92′8—dc22 2005042084

Acquisitions Editor: Susan Pioli Developmental Editor: Kim J. Davis Publishing Services Manager: Frank Polizzano Senior Project Manager: Peter Faber Design Direction: Steven Stave Printed in the United States of America Last digit is the print number: 9

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Dedicated to the many children who have passed through our neurophysiology labs. To my wife Colleen, for her enthusiasm and perseverance. GLH To my mentor and father-in-law Dr. Marvin Cornblath (1925–2005), my wife Nancy, my son Jared, and all the children. SLM To my mom, a wonderful and vigorous, now 99-year-old, retired school teacher who loves children dearly, our own kids Roy, Kate, Fred and David, and to my wife Mary who is a terrific grandmother for Erik, Kristin, Kendall, Sam, and Natalie. HRJ

Contributors

P. IAN ANDREWS, MBBS, FRACP Senior Lecturer, School of Women’s and Children’s Health, University of New South Wales; Paediatric Neurologist, Division of Neurology, Sydney Children’s Hospital, Sydney, Australia Neuromuscular Transmission Defects

WARREN T. BLUME, MD, FRCPC Professor of Neurology and Paediatrics, Department of Clinical Neurosciences, University of Western Ontario; Neurologist, Department of Clinical Neurosciences, University Hospital, London, Ontario, Canada Normal Development of the Electroencephalogram: Infancy Through Adolescence

CHARLES F. BOLTON, MD Adjunct Professor, Department of Medicine, Division of Neurology, Queen’s University, Kingston, Ontario, Canada Neuromuscular Problems of the Critically Ill Neonate, Child, and Adolescent

ALEXIS D. BORO, MD Assistant Professor, Department of Neurology, Albert Einstein College of Medicine; Attending Physician, Department of Neurology, Montefiore Medical Center, Bronx, New York Basic Principles of Electroencephalography The Diagnosis of Brain Death

DEBORAH Y. BRADSHAW, MD Clinical Associate Professor, Department of Neurology, Upstate Medical University, Syracuse, New York Clinical Neurophysiology of Pediatric Polyneuropathies

SAMUEL L. BRIDGERS, MD Assistant Clinical Professor, Department of Neurology, Yale University School of Medicine; Director, EEG Laboratory, Hospital of St. Raphael, New Haven, Connecticut Ambulatory Electroencephalography

PHILIP J. BRUNQUELL, MD Associate Professor of Pediatrics and Neurology, University of Connecticut School of Medicine, Farmington, Connecticut; Medical Director, Clinical Neurophysiology Laboratories, Connecticut Children’s Medical Center, Hartford, Connecticut Head Trauma

TED M. BURNS, MD Assistant Professor, Department of Neurology, University of Virginia, Charlottesville, Virginia Clinical Neurophysiology of Pediatric Polyneuropathies Autonomic Testing in Childhood Clinical Neurophysiology of Pediatric Polyneuropathies

EDUARDO M. CASTILLO, PHD Assistant Professor, Department of Neurosurgery, University of Texas at Houston Medical School; Faculty, MEG Laboratory, Hermann Hospital, Houston, Texas Magnetoencephalography

THOMAS O. CRAWFORD, MD Associate Professor of Neurology and Pediatrics, Departments of Neurology and Pediatrics, Johns Hopkins University; Associate Professor of Neurology and Pediatrics, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland Spinal Muscular Atrophies and Other Disorders of the Anterior Horn Cell

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Contributors

BASIL T. DARRAS, MD Professor of Neurology, Department of Neurology, Harvard Medical School; Director, Neuromuscular Program, Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts Neuromuscular Problems of the Critically Ill Neonate, Child, and Adolescent The Interrelation of DNA Analysis with Clinical Neurophysiology in the Diagnosis of Chronic Neuromuscular Disorder of Childhood

MICHAEL DUCHOWNY, MD Professor of Clinical Neurology, University of Miami School of Medicine; Director, Comprehensive Epilepsy Program, Miami Children’s Hospital, Miami, Florida Long-Term Electroencephalogram and Video Monitoring

KARIN EDEBOL EEG-OLOFSSON, MD Associate Professor, University of Uppsala, Institute of Neuroscience; Assistant Professor, Department of Clinical Neurophysiology, Neurocentre, University Hospital, Uppsala, Sweden Transcranial Magnetic Stimulation: An Overview Sphincter Dysfunction

ALAN B. ETTINGER, MD Director, Comprehensive Epilepsy Center and Chief of EEG, Department of Neurology, Long Island Jewish Medical Center, New Hyde Park, New York; Chief of EEG, Department of Neurology, North Shore University Hospital, Manhasset, New York; Chief of EEG and Epilepsy, Department of Neurology, Huntington Hospital, Huntington, New York Basic Principles of Electroencephalography

KEVIN J. FELICE, DO Professor of Neurology and Director, Neuromuscular Program and EMG Laboratory, Department of Neurology, University of Connecticut School of Medicine, Farmington, Connecticut Focal Neuropathies in Children

ROBIN L. GILMORE, MD Staff Neurologist, Department of Neurology, Neurology Center of Middle Tennessee; Staff Neurologist, Department of Medicine, Maury Regional Hospital, Columbia, Tennessee Somatosensory Evoked Potentials in Pediatrics—Normal Somatosensory Evoked Potentials in Pediatrics—Abnormal

WILLIAM D. GOLDIE, MD Associate Clinical Professor, Departments of Pediatrics and Neurology, University of California—Los Angeles; Associate Clinical Professor, Division of Child Neurology, Children’s Hospital—Los Angeles, Los Angeles, California; Director, Child Neurology, and Director, Clinical Neurophysiology, Ventura County Medical Center, Ventura, California Visual Evoked Potentials in Pediatrics—Normal Visual Evoked Potentials in Pediatrics—Abnormal

SANDRA L. HELMERS, MD Associate Professor, Department of Neurology, Emory University School of Medicine; Associate Professor, Department of Neurology, Grady Health System, Atlanta; Associate Professor, Department of Neurology, Children’s Healthcare of Atlanta, Atlanta, Georgia Brainstem Auditory Evoked Potentials in Pediatrics—Normal Intraoperative Neurophysiologic Monitoring Using Evoked Potentials Brainstem Auditory Evoked Potentials in Pediatrics— Abnormal

GREGORY L. HOLMES, MD Professor of Medicine (Neurology) and Pediatrics, Dartmouth Medical School; Chief, Section of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Basic Principles of Electroencephalography Visual Analysis of the Neonatal Electroencephalogram Age-Specific Seizure Disorders Drug Effects on the Human Electroencephalogram

PAUL A. L. S. HWANG, MDCM, MSC, FRCPC Associate Professor of Neurology, University of Toronto Epilepsy Program; Head of Paediatric Neurology, North York General Hospital, Toronto, Ontario, Canada Age-Specific Seizure Disorders

PRASANNA JAYAKAR, MD, PHD Director, Neuroscience Center, Children’s Brain Institute, Miami Children’s Hospital, Miami, Florida Long-Term Electroencephalogram and Video Monitoring

H. ROYDEN JONES, JR., MD Jaime Ortiz-Patiño Chair in Neurology, Lahey Clinic, Burlington, Massachusetts; Clinical Professor of Neurology, Harvard Medical School; Director, Electromyography Laboratory, Children’s Hospital Boston, Boston, Massachusetts The Floppy Infant Plexopathies and Nerve Root Lesions Focal Neuropathies in Children

Contributors Clinical Neurophysiology of Pediatric Polyneuropathies Neuromuscular Problems of the Critically Ill Neonate, Child, and Adolescent The Interrelation of DNA Analysis with Clinical Neurophysiology in the Diagnosis of Chronic Neuromuscular Disorder of Childhood

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WILLIAM N. MAY, MD, MBA Associate Professor, Department of Pediatrics and Neurology, University of Tennessee; Chief Medical Officer, Administration Department, Le Bonheur Children’s Medical Center, Methodist Healthcare— Memphis Hospitals, Memphis, Tennessee Electroencephalography and Structural Disease of the Brain

SUSAN K. KLEIN, MD, PHD Assistant Professor, Department of Pediatrics, Case Western Reserve University; Child Neurologist, Department of Pediatrics, University Hospitals of Cleveland—Rainbow Babies and Children’s Hospital, Cleveland, Ohio Neurophysiology of Language and Behavioral Disorders in Children

SAMUEL E. KOSZER, MD Associate Professor of Neurology, Section Head, Epilepsy and Neurophysiology, Department of Neurology, Albany Medical College Hospital, Albany, New York Visual Analysis of the Neonatal Electroencephalogram Visual Analysis of the Pediatric Electroencephalogram

FAYE MCNALL, MED, REEG T Director of Education, American Society of Electroneurodiagnostic Technologists, Kansas City, Missouri Drug Effects on the Human Electroencephalogram

THOMAS A. MILLER, MD, FRCPC Associate Professor, Department of Physical Medicine and Rehabilitation, Schulich School of Medicine; Faculty of Medicine and Dentistry, University of Western Ontario; Director, Electrodiagnostic Laboratory, Co-Director, Peripheral Nerve Clinic, Consultant Physiatrist, Hand and Upper Limb Centre, St. Josephs Health Care, London, Ontario, Canada Plexopathies and Nerve Root Lesions

SURESH KOTAGAL, MD Professor, Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota Childhood Sleep-Wake Disorders

EDWARD H. KOVNAR, MD Attending Physician, Department of Pediatric Neurology, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Drug Effects on the Human Electroencephalogram Manifestations of Metabolic, Toxic, and Degenerative Diseases Infectious Diseases

NANCY L. KUNTZ, MD Assistant Professor of Neurology and Pediatrics, Department of Neurology, Mayo College of Medicine; Consultant in Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, Minnesota Clinical Neurophysiology of the Motor Unit in Infants and Children Clinical Neurophysiology of Pediatric Polyneuropathies Autonomic Testing in Childhood Muscle Disorders in Children: Neurophysiologic Contributions to Diagnosis and Management

SOLOMON L. MOSHÉ, MD Professor of Neurology, Neuroscience and Pediatrics, Vice Chair, Department of Neurology, Albert Einstein College of Medicine of Yeshiva University; Director, Child Neurology and Clinical Neurophysiology at Montefiore, The University Hospital of Albert Einstein College of Medicine and Jacobi Medical Center, Bronx, New York Basic Principles of Electroencephalography Visual Analysis of the Neonatal Electroencephalogram Visual Analysis of the Pediatric Electroencephalogram The Diagnosis of Brain Death

HIROSHI OTSUBO, MD Assistant Professor, Department of Paediatrics, University of Toronto; Director of Operations, Department of Clinical Neurophysiology and Epilepsy Monitoring, Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada Age-Specific Seizure Disorders

ANDREW C. PAPANICOLAOU, PHD Professor and Director, Division of Clinical Neurosciences, Department of Neurosurgery, University of Texas—Houston Medical School; Director, MEG Center, Memorial-Hermann Hospital; Director, Institute of Rehabilitation and Research; Adjunct Professor, Department of Psychology, University of Houston; Adjunct Professor, Department of Linguistics, Rice University, Houston, Texas Magnetoencephalography

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Contributors

MATTHEW PITT, MD, FRCP Attending Physician, Clinical Neurophysiology, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom Maturational Changes vis-à-vis Neurophysiology Markers and the Development of Peripheral Nerves

SUSANA QUIJANO-ROY, MD, PhD Assistant, Faculty of Medicine, Université de Versailles Saint-Quentin-en-Yvelines; Pediatric Neurologist, Department of Pediatrics, Intensive Care and Neurorespiratory Rehabilitation Department, Hôpital Universitaire Raymond Poncaré, Garches, France; Assistant, Pediatric Neurophysiology Unit, Hôpital d’Enfants Armand-Trousseau, Paris, France Facial and Bulbar Weakness

FRANCIS RENAULT, MD Associate Professor, Université Pierre et Marie Curie; Head, Pediatric Neurophysiology Unit, Hôpital d’Enfants Armand-Trousseau, Paris, France Facial and Bulbar Weakness

TREVOR J. RESNICK, MD Associate Professor and Director, Division of Pediatric Neurology, University of Miami School of Medicine; Chief, Department of Neurology, Miami Children’s Hospital, Miami, Florida Long-Term Electroencephalogram and Video Monitoring

JAMES J. RIVIELLO, JR., MD Professor of Neurology, Department of Neurology, Harvard Medical School; Director, Epilepsy Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts Age-Specific Seizure Disorders Drug Effects on the Human Electroencephalogram Infectious Diseases

MONIQUE M. RYAN, MBBS, M MED, FRACP Senior Lecturer, Discipline of Paediatrics and Child Health, University of Sydney; Paediatric Neurologist, T. Y. Nelson Department of Neurology and Neurosurgery, Children’s Hospital at Westmead, Sydney, Australia Autonomic Testing in Childhood

MARK S. SCHER, MD Professor of Pediatrics and Neurology, Department of Pediatrics, Case School of Medicine; Division Chief, Pediatric Neurology, Director, Pediatric/Epilepsy and Fetal/Neonatal Neurology and Programs, Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, Cleveland, Ohio Electroencephalography of the Newborn: Normal Features Neonatal Electroencephalography: Abnormal Features

KATHRYN J. SWOBODA, MD Associate Professor, Department of Neurology, University of Utah School of Medicine; Adjunct Associate Professor, Department of Pediatrics, Primary Children’s Medical Center, Salt Lake City, Utah The Floppy Infant

ROBERTO TUCHMAN, MD Associate Professor, Department of Neurology, University of Miami, Florida; Director, Autism Program, Department of Neurology, Miami Children’s Hospital Dan Marino Center, Weston, Florida Neurophysiology of Language and Behavioral Disorders in Children

JAMES W. WHELESS, MD Professor and Chief of Pediatric Neurology, Le Bonheur Chair in Pediatric Neurology, University of Tennessee Health Science Center; Director, Pediatric Neuroscience Center; Director, Le Bonheur Comprehensive Epilepsy Center, Le Bonheur Children’s Medical Center; Clinical Director and Chief of Pediatric Neurology, St. Jude Children’s Research Hospital, Memphis, Tennessee Magnetoencephalography (MEG)

ELAINE WYLLIE, MD Head, Section of Pediatric Neurology and Pediatric Epilepsy, Department of Neurology, Cleveland Clinic Foundation, Cleveland, Ohio Electroencephalography in the Evaluation for Epilepsy Surgery in Children

LEON ZACHAROWICZ, MD, MA Neurologist, Department of Psychiatry, North Shore Child and Family Guidance Center, Roslyn Heights, New York Visual Analysis of the Pediatric Electroencephalogram

DONALD B. SANDERS, MD Professor, Division of Neurology, Duke University Medical Center, Durham, North Carolina Neuromuscular Transmission Defects

Preface

Neurophysiologic testing is an important component of the clinical assessment of children with neurologic disorders. Early in the history of clinical neurophysiology, testing primarily involved electroencephalography (EEG), and later on measuring the speed of conduction along peripheral nerves became available. This field has dramatically expanded during the past decades and now additionally includes evoked potentials, electromyography (EMG), magnetoencephalography, and magnetic stimulation. The physiologic parameters measured in the child’s nervous system change rapidly from birth to the teenage years, with age-specific patterns expressed during discrete developmental periods. Clinical neurophysiologists must be aware of the challenges in testing and interpreting neurophysiologic studies in a continuously evolving system. Although many of the clinical neurophysiology techniques in adults can be extrapolated to children, there is a need to have a textbook dedicated solely to the performance and interpretation of these various neurophysiologic testing modalities in infancy and childhood. The wide diversity of clinical neurophysiologic studies has made it impossible for a single physician to review this entire field in detail. We have been successful in obtaining contributions from a wonderful group of authors with expertise in all aspects of pediatric neurophysiology. All of our contributors have graciously accepted the difficult task of providing a state-of-the-art perspective of the key elements appropriate to the performance and interpretation of clinical neurophysiologic studies in children of all ages. Neurophysiologic studies provide an important extension to the clinical evaluation and are predicated on a careful neurologic history and examination. These various parameters should never be interpreted in isolation from the neurologic condition for which testing was obtained.

Rather one should strive to make a “clinical correlation” of the neurophysiologic data vis-à-vis the history and examination findings. To this end, we have asked our contributors to provide succinct descriptions of clinical disorders where neurophysiologic testing is a valuable adjunct. Our authors have accepted this challenge and have provided beautiful summaries of clinical features and neurophysiologic findings for both common and rare neurologic disorders. We made every effort to blend the details important to classic electrophysiologic techniques of EEG and EMG studies with the newest techniques such as magnetic stimulation and magnetoencephalography. Since the era of Hans Berger, who made the first EEG recording at Jena, Germany, in 1924, and Edward Lambert, in Rochester, Minnesota, who brought clinical EMG to the fore in the early 1950s and later became the teacher of more than 50% of North American electromyographers, clinical neurophysiology has attracted talented and prolific investigators. The early contributions in the field remain important and are frequently cited in these chapters. We asked our contributing authors to balance the “classic, old,” but pertinent literature with more recent studies. Although it is not possible to cite every paper dealing with childhood clinical neurophysiology, our authors have succeeded in accurately and concisely surveying the neurophysiology literature. This textbook was designed to be of value to both trainees and established clinicians. While we hope some readers, particularly those in fellowships, will read the book cover to cover, it is likely that other colleagues will find specific chapters of primary interest. By providing a systematic and critical approach to childhood clinical neurophysiologic studies, this volume should serve as a stand-alone reference source of clinical neurophysiology xi

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Preface

information for professionals working with children who have one of the many neurologic disorders that can be better defined with neurophysiologic testing. We extend our heartfelt thanks to all of the authors who contributed to this volume. Because of each person’s welldeserved reputation in his or her respective fields of expertise, their contributions provide a special strength to this first monograph dedicated to the principles of pediatric clinical neurophysiology. Each clinical neurophysiologist has provided a special dedication to this project, and for this the editors are most grateful. We know that no first effort is perfect, and we hope our readers will feel free to advise us of any areas of confusion or mistakes that we have inadvertently overlooked. We very much appreciate the alacrity that our authors applied to our ministrations as well as their good humor when we occasionally applied pressure to come to closure. At times one has to state there is enough paint on the canvas and move forward in hopes the next round will provide opportunity to enhance the color. That is often difficult to achieve with such dedicated and conscientious colleagues, who seek perfection in their given fields as they have with their participation in this venture.

We greatly appreciated the efforts of Mr. Dennis Druin for his expertise in producing many of the illustrations in this volume and the wonderful assistance provided by our support staff: Emily R. Clough at Dartmouth Medical School; Ms. Pat Clements, the supervisor of the EEG laboratory at Montefiore Medical Center; and Mrs. Mary Kreconus of the Lahey Clinic. No project of this sort can come to fruition without the dedication of a top-notch executive publisher. Each of the editors is particularly indebted to Susan Pioli for her faith in this project and her unceasing urging, cajoling, and good humor while asking us to bring this project to conclusion. We also thank her colleague at Elsevier, Kim Davis, a developmental editor who was most helpful as we entered the gun lap for this project. Lastly, we thank our many neurologic colleagues in our respective institutions who have provided us support and constructive critique over the years. We are proud to have worked with each and every one of you! Gregory L. Holmes H. Royden Jones, Jr. Solomon L. Moshé

1 Basic Principles of Electroencephalography ALAN B. ETTINGER, ALEXIS D. BORO, GREGORY L. HOLMES AND SOLOMON L. MOSHÉ

Successful electroencephalograph (EEG) interpretation and analysis are predicated on a thorough understanding of the basic concepts of electrical neurophysiology. This chapter discusses the physiologic basis of the EEG, the fundamental principles of the electrical circuit, filters, the EEG apparatus, electrodes and their application to the scalp, special electrodes, digital technology, the EEG penwriting apparatus, frequency and voltage considerations, testing the recording system, sources of the EEG, localization of activity, artifacts, electrical safety, and special considerations in performing the EEG in children. Definitions of terms used in the chapter are presented in Appendix I.

PHYSIOLOGIC BASIS OF THE EEG The human brain contains more than 1012 neurons interconnected and communicating with each other via 1015 synaptic connections. It is through this communication process, termed signaling, that electrical activity is generated, resulting in the human EEG. The cells of the nervous system can be divided into two major categories: neurons and neuroglial cells. Although neurons come in many shapes and sizes, the major components of most neurons consist of the dendrites (which receive information), the cell body (which processes and integrates the information), and the axon (which conducts signals to other brain regions). Neuroglial cells, often referred to as glia, may also be involved. The three major categories of glial cells are (1) the astrocytes (which

maintain the correct metabolic milieu for neuronal signaling); (2) the oligodendrocytes (which myelinate neurons); and (3) the microglia (which serve as the brain’s macrophages and assist in brain recovery from injury). Neurons are classified into three broad types on the basis of the shape of the cell body and the patterns of the dendrites and axons. These types are the multipolar, pseudounipolar, and bipolar cells. Multipolar neurons are characterized by multiple dendrites that emerge from the cell body, resulting in a polygonal shape. The cell body of a pseudounipolar neuron is round and gives rise to a single dendritic process that divides close to the cell body into a peripheral and central branch. The peripheral branch transmits incoming sensory information while the central branch relays information onward to its target in the central nervous system. The two processes therefore act as a combined axon and dendrite. An example of a pseudounipolar neuron is the cell that relays information from the periphery into the central nervous system in the dorsal root ganglion. Bipolar neurons have a round or ovalshaped cell body with a large process emanating from each end of the cell body. Bipolar cells occur in the retinal and olfactory epithelium, vestibular ganglion, and auditory ganglion. Neurons are organized into neuronal ensembles of circuits that process specific kinds of information. Neurons that carry information into the circuit are termed afferent neurons, whereas neurons signaling information away from the circuit are referred to as efferent neurons. Nerve cells that participate only in the local aspects of a circuit 3

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Basic Principles and Maturational Change

are called interneurons. Processing circuits are combined to form systems that serve broader functions such as memory, vision, and hearing. Clinical neurophysiologic studies are based on the recording of both spontaneous electrical activity, as with the EEG, and stimulated response, such as evoked potentials. It is through the electrical signaling of information within these neuronal circuits that both spontaneous and evoked electrical activity can be measured. This chapter reviews some of the basic concepts of neuronal signaling that are important to the understanding of clinical neurophysiology.

Basis of Brain Electrical Activity Membrane Polarity The atom is composed of three basic particles: neutrons, electrons, and protons. The net charge of the three particles is zero. Neutrons are neutral, electrons carry a negative charge, and protons carry a positive charge. Upsetting this electrical balance by separating positive and negatively charged ions results in forces aimed at reinstitution of the electrical equilibrium and thereby a flow of charged ions. Ions may be separated by the application of energy of variable types such as mechanical, electrical, magnetic, or chemical. Electrical or chemical energy can separate charges in nerve cell membranes.1 All neurons and glia have lipid bilayer membranes separating the delicate internal machinery of the cell from the external environment. The neuronal membrane is an excellent insulator and separates different concentrations of ions inside the cell from those outside the cell. The activity of ion channels is fundamental to signaling in the nervous system. The movement of ions that carry electrical charge through ion channels results in voltage changes across the membrane. Electrical potentials are generated across the membranes of neurons because there are differences in the concentration of specific ions across the membrane and the membrane is selectively permeable to ion flow. Movement of ions across the membrane occurs through ion channels that consist of proteins that transverse the neuronal membrane and allow certain ions to cross in the direction of their concentration gradient. Na+ and Cl– are more concentrated outside the cell, but K+ and organic anions (consisting of amino acids and proteins) are more concentrated inside the cell. Na+ and Cl– therefore tend to flow into the cell, whereas K+ tends to flow outward. Because of the large size of the organic anions, flow through ion channels is not possible. However, ion flow is not strictly related to concentration gradients. Because of the selective permeability of ion channels, anions

(negatively charged ions) and cations (positively charged ions) inside the cell are not equal; therefore, there is a potential difference between the inside and outside of the cell—the membrane potential. In most neurons at rest the inside of the membrane is –70 mV compared with the outside (resting membrane potential). Ions are therefore subjected to two forces driving them across the membrane: (1) a chemical driving force that depends on the concentration gradient across the membrane and (2) an electrical driving force that depends on the electrical potential across the membrane. Ions flow from highconcentration areas to low-concentration areas (chemical driving force), and they flow to areas of opposite charge, where like charges repel and unlike charges attract (electrical driving force). The flux of ions through ion channels is passive and requires no metabolic energy. The kinetic properties of ion permeation are described by the channel’s conductance, which is determined by measuring the current (ion flux) that flows through the open channel in response to a given electrochemical driving force. The net electrochemical driving force is determined by the electrical potential difference across the membrane and the concentration gradient of the ions selective for the channel. To illustrate these physiologic features, the flow of K+ ions is considered (Fig. 1-1). Because K+ ions are present at a high concentration inside the cell, they tend to diffuse from inside to outside the cell down their chemical concentration gradient. As a result, the outside of the membrane becomes positively charged compared with the inside of the membrane. Once K+ diffusion has proceeded to a certain point, a potential develops across the membrane at which the electrical force driving K+ into the cell exactly balances the chemical force driving K+ out of the cell; that is, the outward movement of K+ (driven by its concentration gradient) is equal to the inward movement of K+ (driven by the electrical potential difference across the membrane). This potential is called the potassium equilibrium potential (EK). The equilibrium potential for any ion X can be calculated from the Nernst equation, Ex = (RT/zF) ln ([X]o/[X]i) where R is the gas constant, T is the temperature, z is the valence of the ion, F is the Faraday constant, and X is the concentration of the ion inside (i) and outside (o) the cell. Since RT/F is 25 mV at 25°C and the constant for converting from natural logarithms to base 10 logarithms is 2.3, z is +1 for K+, and the concentration of free K+ inside and outside the typical mammalian neuron is around 100 mmol and 3 mmol, respectively, the Nernst equation can be rewritten as

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Basic Principles of Electroencephalography

B

A

FIGURE 1–1 Passive K+ channel. In neurons, K+ has a higher concentration inside than outside (A). Because of the concentration differences, K+ diffuses from inside the cell to the outside. With K+ outflow, the inside of the cell becomes even more negative since the K+ ion is carrying a positive charge (B). At some point, an equilibrium is reached in which the electrical and chemical driving forces are equal and opposite and there is a balance between K+ entering and leaving the cell.

Ex = (58 mV/1) log ([3]/[100]) = –90 mV Na+ is more common outside the cell than inside; therefore, it tends to flow into the cell down its chemical concentration gradient. The equilibrium potential for Na+ is around +60 mV. Therefore, there is also an electrical driving force that drives Na+ into the cell by virtue of the negative electrical potential difference across the membrane. However, Na+ conductance of membrane at rest is very small (about 10 times smaller) compared with K+ conductance, and the influx of Na+ depolarizes the cell only slightly from the K+ equilibrium potential (–90 mV). Eventually, the resting membrane potential is established at the level at which the outward movement of K+ just balances the inward movement of Na+. This balance point (–70 mV) is only slightly more positive than the equilibrium potential for K+ (–90 mV) since neurons have relatively few Na+ channels open at rest and the conductance to Na+ is therefore low. The resting membrane potential (Vm) is not equal to either EK or ENa but lies between them. As a general rule, when Vm is determined by two or more ions, the influence

of each ion is determined not only by the concentration of the ion inside and outside the cell but also by the relative permeability of the membrane to each ion. The Goldman equation was developed to determine the membrane potential by taking into account the concentrations and permeability for the “big three” ions (in terms of concentration): Na+, K+, and Cl–. Vm = 58 log

Pk[K]i + PNa[Na]i + PCl[Cl]i Pk[K]o + PNa[Na]o + PCl[Cl]o

where P is the permeability of the membrane to each ion. The Goldman equation is an extension of the Nernst equation that considers the relative permeabilities of the ions involved. Table 1-1 provides the extracellular and intracellular free ion concentrations that can be used in the formula. Since ion leaks would eventually result in a rundown of Na+ and K+ gradients, the resting membrane potential would eventually be altered. The Na+-K+ pump, which moves Na+ and K+ ions against their net electrochemical gradients, extrudes Na+ from the cell while bringing K+

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TABLE 1–1 Extracellular and Intracellular Ion Concentrations Ion

Intracellular, mmol

Extracellular, mmol

Potassium Sodium Chloride Calcium

100 10 4-30 0.00001

3 110 110 2

into the cell. The energy to run this pump comes from the hydrolysis of adenosine triphosphate. At the resting membrane potential, the cell is not in equilibrium but rather in a steady state. The continuous passive influx of Na+ and efflux of K+ ions is counterbalanced by the Na+-K+ pump. At rest, the total electrical current flow through the membrane is null; therefore, no signal is recorded by an extracellular field potential electrode. Channel Gating Thus far we have discussed ion channels that are open in the resting state and are selectively permeable to ions. Resting channels normally are open and are not influenced significantly by extrinsic factors, such as the potential across the membrane. Resting channels are therefore critically important in maintaining the resting potential. There are also gated channels that can exist in several configuration states. The term gating is used to describe the transition of a channel between these different states. Most gated channels are closed when the membrane is at rest. Each ion channel has at least one open state and one or two closed states (Fig. 1-2). The two categories of gated channels are characterized by having an appropriate sensor—either a voltage type or a ligand type (i.e., the ligand receptor site). In voltagegated channel function the voltage across the membrane determines whether a conformational change in the channel occurs. In ligand-mediated channels the ligand binds to the channel, either at an extracellular site, as with neurotransmitters such as glutamate or γ-aminobutyric acid (GABA), or at an intracellular site, as in the case of certain cytoplasmic compounds such as Ca2+ and nucleotides. Ligands can also activate cellular signaling cascades that can covalently modify a channel through phosphorylation. Action Potential For a neuron to transmit information it must generate an electrical signal termed an action potential. Development of the action potential requires an electrical or chemical stimulus that alters ion flow into the cell. The electrical current that flows into and out of the cell is carried by ions, both positively charged (cations) and negatively charged (anions). The direction of current flow is conventionally defined as the direction of net movement

of positive charge. Cations move in the direction of the electrical current while anions move in the opposite direction. Whether or not there is a net flow of cations or anions into or out of the cell, the charge separation across the resting membrane is disturbed, altering the polarity of the membrane. A reduction of charge separation resulting in a less negative membrane potential is termed depolarization, and an increase in charge separation leading to a more negative membrane potential is called hyperpolarization. When the membrane potential depolarizes to a threshold (which is around –55 to –60 mV), the voltage-gated Na+ channels open rapidly. The influx of Na+ inward makes the interior of the cell more positive than before. The increase in depolarization causes still more voltage-gated Na+ channels to open, resulting in further acceleration of the depolarization. The positive feedback cycle initiates the action potential and is responsible for its all-or-none character. Once initiated, the action potential is independent of the stimulus. The membrane potential approaches, but never reaches, the equilibrium potential for Na+ (+60 mV) because K+ efflux continues during the depolarization and there is influx of Cl–. Depolarization during the action potential is very large but also very brief, lasting only 1 millisecond. These features of the action potential allow neuronal signaling with high fidelity at a very high rate (up to hundreds of action potentials per second). Termination of the action potential is due to rapid inactivation of Na+ channels and delayed (compared to Na+ channels) opening of voltage-gated K+ channels. The delayed increase in K+ efflux combines with a decrease in Na+ influx to produce a net efflux of positive charge from the cell, which continues until the cell has repolarized to its resting membrane potential. Figure 1-3 demonstrates the sequential opening of voltage-gated Na+ and K+ channels during the action potential. Thus, during the action potential, Na+ channels undergo transitions among three different states: resting, activated, or inactivated. On depolarization, the channel goes from the resting (closed) state to the activated (open) state. If the depolarization is brief, the channels go directly back to the resting state on repolarization. If the depolarization is maintained, the channels go from the open to the inactivated closed state. Once the channel is inactivated, it cannot be opened by further depolarization. The inactivation can be reversed only by repolarization of the membrane to its negative resting potential, which allows the channel to switch from the inactivated to the resting state. Each Na+ channel has two kinds of gates that must be opened simultaneously for the channel to conduct Na+ ions. An activation gate is closed when the membrane is at its negative resting potential and is rapidly opened by depolarization; an inactivation gate is open at the resting potential and closes slowly in response to depolarization.


A

7

B

C FIGURE 1–2 Voltage-gated Na+ channel. In the resting condition (A) the activation gate (black bar) is closed and the inactivation gate (ball and chain) is open. No Na+ flows because of the closed activation gate. With depolarization there is a conformational change of the channel and the activation gate opens (B). Na+ flow then occurs. This is followed by inactivation by the inactivation gate, prohibiting the further flow of Na+ ions (C). With repolarization of the membrane, the inactivation gate opens and the activation gate closes and the channel is ready for another cycle.

The channel conducts only for the brief period during a depolarization when both gates are open. Repolarization reverses the two processes, closing the activation gate rapidly and opening the inactivation gate more slowly. After the channel has returned to the resting state, it can again be activated by depolarization. Following an action potential the Na+ channels are inactivated and the K+ channels are activated. These transitory events make it more difficult for another action potential to be generated quickly. This refractory period limits the number of action potentials that a given nerve cell can produce per unit time. This phenomenon also explains why

action potentials do not reverberate up and down the neuronal membrane. Extracellular field potential electrodes can detect the action potentials from the individual neurons only if the size of electrode is comparable to the size of the cell (tens of microns) and if the electrode is very close to the cell soma, where the action potential is generated. The amplitude of the extracellularly recorded action potential is small, in the order of tens of microvolts, and the duration is less than a millisecond. With conventional EEG electrodes, the action potentials from individual neurons are too small to be detected. However, when many neurons

8


chemical synapses, there is a change in membrane potential. The change in membrane potential is typically not instantaneous because the membrane has both a resistive and a capacitive component. Neurons have three passive electrical properties that are important to electrical signaling: the resting membrane resistance, the membrane capacitance, and the intracellular axial resistance along the axons and dendrites. These membrane properties are important in determining whether an action potential will be generated. Current is defined as the amount of charge that flows through a conductor over a given set of time. Current is either direct or alternating in that

FIGURE 1–3 Generation of the action potential. The sequential opening of voltage-gated Na+ and K+ generates the action potential. Note that the Na+ conductances begin before the K+ conductances. The influx of Na+ makes the interior of the cell more positive than before, increasing the degree of depolarization, which causes still more voltage-gated Na+ channels to open, resulting in further acceleration of the depolarization. With the depolarization there is a greater electrical driving force on the K+ ions and K+ ions flow outward. The increase in K+ efflux combined with a decrease in Na+ influx results in an efflux of positive charge from the cell, which continues until the cell has repolarized.

fire action potentials simultaneously, which can occur, for instance, in patients with epilepsy, their summated action potentials can be detected in EEG recordings as a “population spike.” Transmission of Action Potentials The action potential can transverse long axonal distances without loss of amplitude despite the fact that neuronal membranes have relatively poor conducting properties. During the generation of the action potential there is some passive flow of current downstream from the action potential. The passive current flow depolarizes the membrane potential in adjacent regions of the axon, opening Na+ channels. The local depolarization results in another action potential that then spreads again in a continuing cycle until the end of the axon is reached. Signaling Changes When the postsynaptic membrane is stimulated through either electrical stimulation through gap junctions or at

1. Direct current represents electricity that flows in one direction only and is exemplified by the electrical current supplied by a routine battery used in common mechanical devices. 2. Alternating current repetitively changes direction between two opposite directions within the same circuit. This source of electricity is used to power mechanical devices that are plugged into home, office, and hospital wall outlets. In the United States, the frequency of alternation is 60 Hz (cycles/sec). Current is described in units called amperes, commonly abbreviated amps (A). Units of charge have been named coulombs (Q). By convention, when 1 Q of charge (6 × 1018 electrons) has traveled through a conductor over a period of 1 second, a current of 1 A has been observed. Conversely, a coulomb of charge represents the charge caused by a current of 1 A flowing for 1 second. One coulomb is approximately equal to the charge of 6 × 1018 electrons. This is expressed mathematically as I = Q/T where I is the current, Q is the charge, and T is time. All cell membranes have a resistance. Resistance is the part of the circuit that “resists” the flow of charges by converting the electrical flow of energy into heat. Energy is defined in the term of joules (J). One joule of energy is expended when 1 Q is moved across a potential difference of 1 V. The term impedance is used to describe the resistance in a circuit that is powered by an alternating current source and includes a device known as a capacitor. Quantified units of resistance or impedance have been termed ohms (Ω). All circuits always have some degree of resistance. The input resistance (Rin) of the cell determines how much the cell depolarizes in response to a steady current. The magnitude of the depolarization, that is, the change in membrane voltage (ΔV), is given by Ohm’s law:

9


ΔV = I × Rin Of two neurons receiving identical synaptic current inputs, the cell with the higher input resistance will have a greater change in membrane voltage. Input resistance depends on both the density of resting ion channels in the membrane and the size of the cell. The larger the neuron, the greater is its membrane surface area and the lower the input resistance, since there will be more resting channels to conduct. Membranes also act as capacitors. A capacitor consists of two conducting plates separated by an insulating layer. The fundamental property of a capacitor is its ability to store charges of opposite sign: positive charge on one plate, negative on the other. Voltage across a capacitor is proportional to the charge stored on the capacitor. Capacitors store electrical charge by maintaining a separation between positive and negative electrical charges.2 Although the plates are relatively close to each other, charges cannot traverse the insulating material to reach the opposite plate when direct current is applied. Ions of similar charge but on opposite plates repel each other, resulting in a further establishment of separated charges. On connecting a capacitor to an energy (voltage) source, the capacitor finally attains a separation in charges (or voltage) equal to that of the voltage source. When connected to a source of voltage where one side remains positive and the other negative as in “direct current,” one plate remains positive and the other negative. When alternating current is applied, the voltage source repetitively alternates from positive to negative and therefore the associated connected capacitor plates alternate from positive to negative charge. This, in effect, is comparable to a traversing of the insulating substances by charged ions.1 V = Q/C

FIGURE 1–4 An example of a circuit that includes a capacitor. R, resister; C, capacitor

ΔV = Ic × Δt/C The magnitude of the change in voltage across a capacitor in response to a current pulse depends on the duration of the current, because time is required to deposit and remove charge on the plates of the capacitor. Capacitance is directly proportional to the area of the plates of the capacitor. The larger the area of a capacitor, the more charge it will store for a given potential difference. Since all biologic membranes are composed of lipid bilayers with similar insulating properties that provide a similar separation between the two plates (4 nm), the specific capacitance per unit area of all biologic membranes has the same value. The total input capacitance of a spherical cell, Cin, is therefore given by the capacitance per unit area multiplied by the area of the cell, Cin = Cm(4πr2)

ΔV = ΔQ/C

where r is the radius of the cell. Since capacitance increases with the size of the cell, more charge, and therefore current, is required to produce the same change in membrane potential in a larger neuron than in a smaller one. The capacitance of the membrane has the effect of reducing the rate at which the membrane potential changes in response to a current pulse. If the membrane had only resistive properties, a step pulse of outward current passed across it would change the membrane potential instantaneously. Biologic membranes have both capacitive and resistive properties in parallel.

The change in charge ΔQ is the result of the flow of current across the capacitor (Ic). Since current is the flow of charge per unit time (Ic = ΔQ/Δt), the change in voltage across a capacitor can be calculated as a function of current and the time that the current flows.

Cell-to-Cell Communication The EEG represents a set of field potentials as recorded by multiple electrodes on the surface of the scalp. The electrical activity of the EEG is an attenuated measure of potentials alter the probability that an action potential

where Q is the charge in coulombs and C is the capacitance in farads (F). To alter the voltage, charge must either be added or removed from the capacitor. Capacitance is a term indicating the amount of current a capacitor can store. When capacitance is small, it takes very little current to fully charge the capacitor. Figure 1-4 is an example of a circuit that includes a capacitor.

10


will be produced in the postsynaptic cell. If there is depolarization of the membrane, the potential is termed an excitatory postsynaptic potential (EPSP), whereas if there is hyperpolarization the change in membrane potentials is referred to as an inhibitory postsynaptic potential (IPSP). EPSPs bring the membrane potential closer to threshold for action potential generation, whereas IPSPs keep the membrane potential more negative than the threshold potential. In the chemical synapses, whether the event is an EPSP or IPSP is dependent on the neurotransmitter released from the presynaptic neuron and the type or receptor activated in the postsynaptic neuron. In the cerebral cortex, about 90% of neurons (called the principal neurons) synthesize and release on their postsynaptic targets neurotransmitter glutamate, which is the principal neurotransmitter of excitation in the cortex. The remaining 10% of neurons (interneurons) synthesize and release the neurotransmitter GABA, which is the principal neurotransmitter of inhibition in the cortex. Electrical signal transmission from one cell to another occurs through the gap junctions. Gap junctions consist of hexameric complexes formed by the close juxtaposition of pores consisting of proteins called connexons, which span the neuronal membrane. The pore of a gap junction is larger than the pores of the voltage-gated ion channel and can therefore transfer much larger substances such as intracellular metabolites between cells. Electrical transmission across gap junctions occurs rapidly since passive current flow across the gap junction is virtually instantaneous. Gap junctions appear to have an important role in the synchronization of neuron firing, in particular in the interneuron networks. Chemical synapses have a wider spacing between cells, termed the synaptic cleft, and operate through release of neurotransmitter stored in vesicles. The neurotransmitter diffuses from the presynaptic membrane to the postsynaptic membrane. Neurotransmitter release occurs when an action potential reaches the terminals and initiates the opening of voltage-gated Ca2+ channels. The openings of these channels causes a rapid influx of Ca2+ into the presynaptic terminal. Elevation of the intracellular Ca2+ permits synaptic vesicles to fuse with the plasma membrane of the presynaptic neuron. Precisely how Ca2+ triggers the fusion and release of neurotransmitters is not clear. There are a number of proteins that bind with Ca2+ to elicit the cascade of events that lead to release of the transmitter. The fusion of the vesicular and neuronal membranes allows release of the neurotransmitter. Figure 1-5 is a drawing that illustrates the process of neurotransmitter release. Glutamate is the primary excitatory neurotransmitter in the brain. It has been estimated that more than half of the brain synapses release glutamate. Synaptic transmission

is mediated by glutamate, which is released from the principal (granular cells also release glutamate) neurons and depolarizes and excites the target neurons via three types of ionotropic receptors, named after their selective agonists (α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid [AMPA], kainate [KA], and N-methyl-Daspartate [NMDA]). Although all types of the glutamate receptors respond to glutamate, they have individual characteristics. The AMPA receptor rapidly responds to glutamate with opening of the short-living channel equally permeable to Na+ and K+ (the reversal potential ~ 0 mV), and current through the AMPA receptors results in neuronal depolarization. One synapse contains tens of AMPA receptors on the postsynaptic membrane, and summation of the currents through the AMPA receptors results in an EPSP of 0.1 mV. Therefore, to depolarize the postsynaptic neuron to the action potential threshold, simultaneous activation of several excitatory synapses is necessary. KA receptors are similar to AMPA receptors in the ionic selectivity but have slower kinetics. The third type of glutamate ionotropic receptors—NMDA receptor—does not directly participate in the information processing, but it plays the critical role in the synaptic plasticity. The NMDA channel has characteristics of both a neurotransmitter or ligandactivated and voltage-sensitive channel. At resting membrane potential, Mg2+ sits in the channel blocking the flow of ions. Only with depolarization of the membrane is Mg2+ displaced and Na+ and Ca2+ ions able to cross the channel. The high permeability of NMDA receptor to Ca2+ underlies its role in the synaptic plasticity, such as long-term potentiation of the strength of the synaptic transmission, which presumably participates in learning and memory. GABA is the principal inhibitory transmitter of the brain. Inhibitory synapses made by interneurons and employing GABA as their transmitter use two types of receptors: GABAA and GABAB. GABAA receptors are ligand-gated ion channels while GABAB receptors are metabotropic receptors (see later). GABAA receptors are inhibitory because their associated channels are permeable to Cl–. Since the reversal potential for Cl– is more negative than the threshold for neuronal firing, Cl– flow prevents action potential generation. Activation of GABAB receptors results in opening of K+ channels that also inhibit the postsynaptic cell. In the spinal cord, GABA and glycine act as neuroinhibitors by activating presynaptic autoreceptors. Physiologic Basis of the EEG Through either neurotransmitter release at chemical synapses or current flow through gap junctions, the postsynaptic membrane opens ligand-gated or voltage-gated channels and elicits postsynaptic potentials. Postsynaptic


A

11

B

FIGURE 1–5 Synaptic neurotransmission. An action potential travels down the axon until it reaches the synapse. The depolarization causes voltagegated Ca2+ channels to open. The influx of Ca2+ results in high concentrations of Ca2+ near the active zone. This triggers fusion of vesicles with neurotransmitter to the presynaptic cell membrane and emptying of the vesicles into the synaptic cleft. The neurotransmitter crosses to the postsynaptic membrane and results in depolarization of the membrane if it is an excitatory neurotransmitter. With glutamate release there is binding of the ligand to postsynaptic receptors (AMPA, NMDA, or KA) with subsequent inflow of Na+ ions.

the extracellular current flow from the summed activity of many neurons. The surface EEG predominately reflects the activity of cortical neurons close to the EEG electrode. The depth structures such as the hippocampus, thalamus, or brain stem do not contribute directly to the surface EEG. However, transmission of electrical impulses from distant sites has substantial effects on the surface EEG. For example, thalamocortical connections are critical in the synchronization of electrical activity such as sleep spindles. Oscillatory EEG patterns occur because of pacemaker cells where membrane voltage fluctuates spontaneously or because of the reciprocal interaction of excitatory and inhibitory neurons in circuit loops. The human EEG shows activity over the range of 1 to 150 Hz with amplitudes in the range of 20 to 100 μV. Until recently

electroencephalographers have concentrated on activity between 1 and 30 Hz. However, it is now recognized that frequencies in the gamma range are clinically relevant in normal3,4 and abnormal states.5 The waveforms recorded by the surface electrodes depend on the orientation and distance of the electrical source with respect to the recording electrode. To understand how the EEG is recorded it is helpful to use a diagram with a single neuron, although it is recognized that EEG activity is the result of thousands of neurons functioning within neuronal networks. Figure 1-6 shows a single neuron with current flowing into the dendrite at the site of generation of the excitatory postsynaptic potential creating a current sink. Current must complete a loop and therefore creates a source somewhere along the dendrites

12


located at the soma. Surface EEG electrodes detect the electrical field generated at the surface, and there is little influence from activity occurring at the cell body. Therefore, the deflection of the pen is opposite in the two conditions.

FIGURE 1–6 Current flow in a cortical neuron. See text for discussion.

or cell body. The size of the voltage created by the synaptic current is predicted by Ohm’s law (V = I × R). The Rm (membrane resistance) is much larger than the extracellular fluid, and the corresponding voltage recorded by an intracellular electrode is larger and of opposite polarity to an extracellular electrode positioned near the current sink. At the site of generation of an EPSP the extracellular electrode detects current (positive ions) flowing away from the electrode into the cytoplasm as a downward deflection, whereas the intracellular electrode detects a positive signal owing to the influx of Na+ ions. An extracellular electrode near the source has an opposite deflection. The direction of pen deflection is determined by location in regard to the sink and source. Note the differences in pen deflection depending on whether the extracellular electrode is near the source or sink. Now consider pen deflection as a function of location of the afferent signal in cortical neurons. In Figure 1-7 there are afferent inputs into either the apical dendrites (Fig. 1-7A) or cell body (Fig. 1-7B). In both cases the afferent stimuli lead to depolarization (sink) with current flow into the cell body. This results in an extracellular negativity. The current flow in Figure 1-7A results in a source in the apical dendrites, whereas in Figure 1-7B the source is

Origin of EEG Rhythms Despite numerous advances in the recording of the EEG and its usage in clinical neurology, the origin of the fundamental frequencies of the normal EEG remains surprisingly poorly understood. Even 75 years after Hans Berger’s initial characterization of the alpha rhythm,6 it is only recently that the basic cellular and synaptic mechanisms underlying the EEG have begun to be uncovered. A detailed analysis of the studies (predominantly animal experiments) concerned with generation of EEG rhythms is beyond the scope of this chapter, but the reader is referred to a number of excellent references on this subject.7-10 Such studies have led to the speculation that sleep spindles may originate from repetitive burst depolarizations from neurons in the reticular nucleus of the thalamus, which in turn has extensive thalamocortical connections with networks of cortical pyramidal cells. Delta activity associated with deep levels of sleep is also believed to be driven by the thalamus. Focal pathologic irregular delta (and theta) activity has been rigorously correlated with an assortment of deep white matter structural abnormalities11 and may result in part from loss of synaptic inputs toward cortical neurons, although specific mechanisms of this waveform generation remains unclear. Extensive work by Andersen and Andersson12 suggested that the thalamus was also responsible for the alpha rhythm, but more recent work suggests that islands of pyramidal neurons in the occipital cortex may be a more likely source and that large neuronal networks in the cortex have an intrinsic capacity for rhythmicity.13 The origins of beta activity associated with arousal and theta frequencies of drowsiness remain more obscure. Large EPSPs involving dendritic connections in more superficial cortical layers may produce major sustained depolarizations with a resultant negativity in extracellular regions. This major depolarization has been termed the paroxysmal depolarization shift (PDS)14 and may explain negative spikes, the hallmark of focal interictal epileptiform activity. It is a relatively slow depolarization that correlates in time and duration with spikes or sharp waves seen in the EEG. PDSs have been demonstrated in many animal models of epilepsy. The hyperpolarization following this PDS may explain the slow wave that often follows spikes or sharp waves seen on the EEG.15


A

13

B

FIGURE 1–7 A and B, Polarity of the surface EEG depends on the location of the synaptic activity within the cortex. See text for discussion.

FUNDAMENTAL PRINCIPLES OF THE ELECTRICAL CIRCUIT An electrical circuit comprises a conductor through which current flows, a power source that leads to the flow of charges, and a resistor. The power source produces energy that separates charges and thereby leads to the flow of charges in the attempt to re-establish electrical equilibrium. Nerve cell membranes separate charges through chemical diffusion gradients and active transport systems. Principles known as Kirchoff’s laws govern the properties of linked electrical circuits. Kirchoff’s Law No. 1 states that the voltages around a closed path in a circuit must sum to zero. It can be demonstrated by using Kirchoff’s Law No. 1 together with Ohm’s law that the total resistance in a circuit is equal to the sum of all component resistances. Kirchoff’s Law No. 2 states that the voltage between any two points in a circuit is the same, regardless of the path taken between those points. A transformer is a device designed to transfer increased or decreased voltages and currents. It is produced by wrapping a wire that is conducting current into a coil formation,

which sets up a magnetic field around it. When a second coil of conducting material is placed nearby, the second wire acquires some amount of the voltage and current from the first coil. This is achieved without directly connecting the conducting wires. The number of turns of the coil determines the strength of the voltage and current produced and provided to the second coil. Altering this variable determines whether increased or decreased current is lent to the second coil. Transformers are used to step down the major voltage produced by electrical generators of alternating current to the much reduced voltage levels used for delivery to buildings, allowing the use of common electrical appliances. Amplifiers are devices that increase, or “amplify,” the input signal produced by a voltage source. Amplifiers are designed to leave the input signal (voltage or current) unaltered except for multiplying the signal in magnitude. They use an external power supply to achieve the amplification. The degree of amplification is the ratio of input to output voltage.1 The EEG machine can be considered as a series of circuits, including amplifiers. Brain-generated electrical signals are small and are further attenuated by the

14


impedances of brain, skull, and skin. Production of the EEG requires the use of several amplifier circuits. Electrical signals generated by the brain are magnified by a preamplifier. Following this, the signal is modified by additional circuits known as filters (explained later), which select out undesired signal information. This final product is magnified once more by another group of amplifiers that produce a signal large enough to drive the pen-writing apparatus of the EEG machine. The EEG machine uses amplifiers known as differential, or “push-pull,” type, as opposed to single-ended amplifiers. The single-ended amplifier magnifies the signal of an input compared to a ground reference potential. For EEG recordings, a single-ended amplifier is problematic, since we are interested in voltage differences between electrode pairs. If two electrodes, each connected to ground, were connected together to compose one channel of EEG recording, a short circuit would occur that would in effect connect the voltages at the first and second electrode, producing no net differential signal. Differential amplifiers, in contrast, amplify only the potential difference between two inputs. A common signal to both electrodes is not amplified. Thus, a “common mode rejection” is achieved (Fig. 1-8). The 60-Hz interference arising from electrostatic effects of wires conducting alternating current as well as from electromagnetic effects of nearby appliances affects two inputs equally and is abolished by common mode rejection. With differential amplifiers, cerebral activity of large magnitude received at similar voltages at two electrodes is not easily seen.

FILTERS EEG circuitry incorporates devices known as filters that attenuate frequencies of little relevance to the interpretation of brain wave activity. The high-frequency filter (HFF) attenuates high frequencies, and the low-frequency filter (LFF) attenuates low-frequency activities. Cerebral generators of EEG activity can be considered as a battery producing varying voltages at different frequencies, connected to a circuit that includes a capacitor and a resistor. This simple model is displayed in Figure 1-9A. Using a switch, the resistor can be connected to the battery in such a way that three possibilities can be

+

R

2

1.5V

1

–

3 1␮f

Output C

A

Pos.2

Pos.1

Pos.3

Input voltage

B

Electrode 1 RA1 ( Ground )

RA2

63% Out

37% Output voltage

Electrode 2 T.C Charge

C

RB1 RB2

T.C discharge

Out

Electrode 3

FIGURE 1–8 Use of differential amplifiers to record from a common electrode (electrode 2). (From Tyner F, Knott J, et al. Fundamentals of EEG technology. Basic concepts and methods. New York, Raven Press, p. 58.)

FIGURE 1–9 A, EEG rhythms are composed of rising and falling voltages at a given frequency and are comparable to a battery supplying input voltages that run on and off repetitively, as measured at the site of the capacitor. Diagrammatically this is comparable to the rapid connection and disconnection of a battery from its circuit. B, The actual input voltages produced by the battery. C, Voltages seen at the capacitor. T.C., time constant. (From Tyner F, Knott J, Mayer W. Fundamentals of EEG technology. Basic concepts and methods. New York: Raven Press, 1983, p. 48.)

15


attained depending on the final connection. One possibility would be to complete the circuit and charge the capacitor. A second option would be to leave the circuit disconnected, thereby keeping the capacitor at whatever charge it has acquired. A third possibility would be to connect the resistor to a part of the circuit that does not include the battery. In this case, the capacitor discharges any voltage it has acquired.16 EEG rhythms are composed of rising and falling voltages at a given frequency and are comparable to a battery supplying input voltages that run on and off repetitively, as measured at the site of the capacitor. Diagrammatically this is comparable to the rapid connection and disconnection of a battery from its circuit. The EEG signal seen on paper depicts what a voltmeter would detect as changes in the voltage at the capacitor at specific point in time. There is an inherent difference between the actual input voltages produced by the battery and the voltages seen at the capacitor, because it takes time for the capacitor to charge, and because of such factors as impedance in the circuit and properties of the capacitor itself. For example, when the battery is at maximal voltage at a specific point in time, the capacitor has not yet achieved the same voltage as the source. Displayed graphically (Fig. 1-9B, part 2), a line representing the rise of the battery’s voltage would be vertical, whereas the capacitor’s voltage curve would have a substantial slope, implying that the battery had not achieved its maximal voltage at that point but would theoretically achieve it at a later point in time. Analog filters can be characterized in terms of the time constant, which is the time required to charge or discharge a capacitor to a specified degree. Since the time constant is subject to the properties of capacitance and resistance, the relationship between these variables may be expressed as TC = C × R where TC is the time constant, R is resistance, and C is capacitance. Based on exponential properties related to the rate of charge or discharge of a capacitor, the time constant is defined as the amount of time for a 1 μF capacitor to either charge or discharge 63% of maximum charge. For example, if the capacitance is 1 μF and the resistance is 1 megaohm (MΩ), the time constant will equal 1 second, indicating that it requires 1 second for the capacitor to charge or discharge 63% of its initial charge. In the example provided earlier (Fig. 1-10B), the time required for 63% charge of the capacitor is comparable to the time required for voltage decline across the resistor to 37% of the original voltage. This is applicable to both HFFs and LFFs. In EEG terms, however, the time constant usually refers to voltage activity at the resistor and is used synonymously with the LFF (see later).

C +

R Output –

A 10 5 1

Input voltage

0 10

63%

5 0

– Voltage across C

10 5 0

= Voltage across R

+37%

37%

2

3 –37%

TC = R ´ C

B FIGURE 1–10 Voltage drops in an RC circuit. A, In contrast to Figure 1-9, the low-frequency filter (LFF) is achieved by monitoring the voltage across the resistor rather than across the capacitor. See text. B, (1) Input voltage; (2) Voltage across the capacitor, reflecting the function of the high-frequency filter; (3) Voltage across the resistor, reflecting the function of the LFF. (From Tyner F, Knott J, Mayer W. Fundamentals of EEG technology. Basic concepts and methods. New York: Raven Press, 1983, p. 51.)

High-Frequency Filter The HFF attenuates waveforms of high frequencies. Moving the switch rapidly between positions 2 and 3 simulates a high-frequency input. As shown in Figure 1-9, with this configuration there is a gradual increase of the recorded voltage. The resultant wave has the appearance of being shifted in time, as if its maximum would be achieved at a later point in time. When there is insufficient time for each wave to reach its maximum, such as when a wave is part of a rapid frequency, the amplitude of the wave experiences a relative attenuation.16 The HFF does not abruptly attenuate frequencies at any given setting but rather affects all high-frequency rhythms to varying degrees along a spectrum, with the fastest frequencies most affected and the slower frequencies least affected. The slowest frequencies are unaffected. For example, a 70-Hz filter attenuates frequencies near 70 Hz or higher, and a 35Hz filter attenuates frequencies near 35 Hz and higher. The principles of the analog HFF are presented in Appendix II.

Low-Frequency Filter The LFF attenuates low frequencies and can be represented diagrammatically by switching the location of the

16


f = 1/2πTC where f is the frequency selected for the filter and TC is the time constant. The ratio 1/2π = 0.16, so the formula can be easily remembered as f = 0.16/TC For example, if the time constant was set at 0.1 second, the LLF would equal 1.6 Hz. If the time constant was increased to 0.3 second, the filter frequency would equal 0.53 Hz. More details regarding the theory of the LFF are given in Appendix II. During the performance of an EEG, one of several LFF (or time constant) settings may be selected at a given time. The switch on the EEG panel selects a different capacitive resistance configuration. These configurations may be designed with the same value for resistance but a different capacitance. Alternatively, each configuration may have the same value for capacitance but a different resistance. As the value of the LFF setting goes up (i.e., from 1 to 5 Hz), attenuation of low-frequency rhythms increases. As higher values for LFF are set, individual slow waves of interest experience decrements in amplitude and phase shifts. The peak appears earlier in time. Using measurements of sine waves of different frequencies against different LFF settings, one can determine the output amplitudes at each LFF setting per given frequency. The amplitudes become progressively smaller at frequencies increasingly below the filter setting. In a similar fashion to that of the LFF, several different resistance-capacitance configurations may be selected for the input circuit to travel through in the HFF setting. The system may be designed to select circuits with varying capacitors with resistance held constant or varying resistors with the capacitance held constant. A larger capacitance results in an increased attenuation of high frequencies. Just as in the case of the LFF, sine waves can be used to see the effects of the HFF on different frequencies. As

opposed to the LFF where there is no attenuation when a pure direct current signal without a filter is used, some attenuation of signal occurs with the pen-writing apparatus when increasingly high-frequency sine waves are applied purely because of electromechanical forces that prevent the pen from writing so quickly. This is not an issue with digital EEG, in which the limiting factors for recording fast frequencies are the sample rates and the filters installed by the manufacturers.

Determining the Effect of Filters on the Input Signal By comparing the absolute amplitude to the output attained, the percentage of output attenuation can be determined. A frequency response curve can be drawn by plotting the percentage of attenuation of the absolute amplitude on the y axis with 0 at the top and 100 at the bottom against input frequency on the x axis (Fig. 1-11). For any LFF frequency, a curve emerges with a line arising from the lower left corner of the graph and reaching a plateau at the 0% attenuation mark. The LFF not only attenuates frequencies below the filter setting but also attenuates frequencies slightly above the LFF setting. However, most of the attenuation involves frequencies below the LFF setting. On the frequency response curve, the given number for a filter is called the cutoff frequency. At this setting the predetermined frequency is attenuated by 20% to 30% depending on the particular instrument. The cutoff frequency distinguishes between significant and insignificant attenuation, since one might consider attenuation greater than 20% or 30% to be a “significant” attenuation. At frequencies higher than the cutoff frequency, an essentially linear relationship exists between input and output voltage. When the HFF is applied, attenuation involves frequencies not just at or above the frequency setting value but also to some extent frequencies near but below that

% Attenuation

battery and resistor seen in Figure 1-9 and connecting the circuit at point 2 (Fig. 1-10A). Another term for LFF is high-pass filter because it allows high frequencies to pass through. The LFF is often used synonymously with the time constant. This is because the time constant can be easily measured with a calibration signal, and since there is an inverse relationship between time and frequency, the setting of the LFF can be alternatively expressed as a setting for the time constant. One can select filter frequencies for attenuation of undesired rhythms and signify this in terms of an alteration in the time constant. The relationship is expressed mathematically as

0 10 20 30

3 dB

50

6 dB

75

100 .05

.1 .2 .3 .5

1 2 5 10 20 Input frequency, Hz

FIGURE 1–11 Frequency response curve with low-frequency filter of 0.3 Hz.

17

Basic Principles of Electroencephalography TABLE 1–2 Output Amplitude (mm) at Twelve Input Frequencies at Three HF Filter Settings* Input Frequency (Hz) HF Filter, Hz

5

10

15

20

25

35

40

50

55

60

70

100

None 70 35 15

10 10 10 10

10 10 10 9

10 10 10 8

10 10 9.5 7

10 10 9 6

10 10 8 4.5

10 10 7.5 3

10 10 7 2.5

10 10 6 2

9.5 9.5 5 1.5

8 8 3 1

3.5 3.5 2 1

* LF = 0.1 Hz; S = 10 μV/mm; input = 100 μV. † No LF in this channel. HF, high-frequency; LF, low-frequency; S, sensitivity. From Tyner F, Knott J, Mayer W: Fundamentals of EEG Technology: Basic Concepts and Methods. New York, Raven Press, 1983.

% Attenuation

0 20 30

3 dB

50

6 dB

75 100

3

5

10

20 30 50 70100

Hz

FIGURE 1–12 Frequency response curve with high-frequency filter of 35 Hz.

0 % Attenuation

frequency setting. A comparison between HFF values against amplitudes produced at different frequencies is shown in Table 1-2. Alternatively, a table comparing HFF values against percentages of amplitude attenuation at different frequencies can be generated.16 Graphs can also be generated by placing percent attenuation with 0 on top and 100% on bottom of the y axis and input frequencies on the x axis. Frequency response curves can be generated for each filter setting (Fig. 1-12). The curve typically arises from the top approximately mid-graph and descends toward the right lower hand corner, reaching a frequency of 100 Hz and 100% attenuation. These curves are also influenced by the electromechanical effects of the inkwriting apparatus on analog machines. Similar to that of the LFF, the cutoff frequency for the HFF is that frequency which is attenuated 20% or 30%. Joining the frequency response curves for a given LFF (or time constant) and HFF over a range of low to high frequencies results in bell-shaped curves. An example is shown in Figure 1-13.16 The currently recorded EEG consists of frequencies between 0.1 and 100 Hz. The most commonly used filters are 1 Hz (LFF) and 70 Hz (HFF). Frequencies greater than 70 Hz are not considered clinically significant, whereas the percentage of slow frequencies may increase with brain insults. Filters can be considered windows, allowing for better depiction of certain frequencies and

20 30 50 75 100

.05 .1

.5

1

5

10 20

50 100 200

Hz

FIGURE 1–13 Joining of the frequency response curves for a low-frequency filter of 0.3 Hz and high-frequency filter of 70 Hz.

attenuation of others. For example, to see slow waves, one method is to change the LFF from 1 Hz to 0.3 Hz. Another strategy would be to reduce the HFF to a lower setting, such as a reduction to 35 Hz, which attenuates faster frequencies that may obscure slower electrographic activity of interest. Frequencies of interest can also be viewed by changing the “paper” speed, which traditionally was 30 mm/sec. For example, changing the paper speed to 15 or 10 mm/sec allows slower rhythms to be readily identified. Digital EEGs have the advantage of changing the paper speed after the test has been performed in contrast with paper EEGs, in which changes must be performed during the data acquisition. The LFF and HFF are filters that attenuate rhythms at the low or high ends of the EEG spectrum. The “notch” filter attenuates a narrow band of frequencies with a maximum at 60 Hz.6 This is necessary because the EEG apparatus is in an environment leaving it susceptible to a 60-Hz interference pattern resulting from the commonly used 60-Hz alternating electrical current. Since the filter cannot distinguish between frequencies of cerebral and extracerebral origin, the filter also attenuates cerebral frequencies in the selected range (Fig. 1-14). The use of the 60-Hz filter can be avoided if all electrode impedances are

18

Basic Principles and Maturational Change Input ⫽ 50 uV HFF ⫽ 35 Hz S ⫽ 7 uV/mm

0

% Response

80 3 50

6

dB

TC ⫽ 0.3 LFF ⫽ 5.3 Hz

12

25

15

5

10

60 100

200

Hz

FIGURE 1–14 Frequency response curve of a 60-Hz notch filter.

equal. In this case, 60 Hz will be rejected by the common mode arrangement. At the beginning of the EEG recording, a process of calibration is performed involving the display of uniform square wave pulses that allows each channel of recording to be compared for uniformity. Calibration also shows the effects of different filters on such uniform waves. A square wave can be thought of as a complex combination of multiple sine wave components of different frequencies. The use of filters changes the morphology of square waves (Fig. 1-15). Based on the morphology of the altered square waves, the electroencephalographer can deduce an alteration in filter frequency.16 As the time constant is progressively decreased (LFF is increased), square wave pulses assume a more narrow morphology, since the fast phase of waves decays more rapidly (see Fig. 1-15). Additionally, square wave amplitudes are also diminished since the square wave is also composed of low-frequency sine wave components attenuated by the increased LFF setting. The effect of HFF on the square wave calibration pulse can also be demonstrated since the square wave also has high-frequency sine wave components. As the HFF gets a lower value (setting a lower limit for more attenuation), the high-frequency components of the square wave are more affected and contribute a more rounded-off appearance on the square wave. For example, one might see a progression from a narrow peak to a rounded-off upphase. Figure 1-16 demonstrates the combined effects of different HFFs and LFFs on the square pulse.

THE EEG APPARATUS The complete EEG apparatus is composed of several major components. These include electrodes placed on

TC ⫽ 0.1 LFF ⫽ 1.6 Hz

TC ⫽ 0.01 LFF ⫽ 53 Hz

1 sec

FIGURE 1–15 Changing the morphology of square waves with the use of different low-frequency filters. TC, time constant; HFF, highfrequency filter; S, sensitivity.

the head as well as a wire emanating from each electrode that has a terminal pin. Each pin goes into a receptacle known as a “jack” located on an electrode board jackbox. A cable connects the jackbox to the EEG machine. The EEG machine includes master control switches for all amplifiers as well as individual switches for each amplifier. These can select the sensitivity of the recording and the LFF and HFFs. There are also other components including the notch filter, pen-writing devices with paper


A

B

C

D

LF=0.1Hz

LF=0.3 Hz

LF=1 Hz

LF=5 Hz

19

tages among the different patients recorded. A discussion of the referential and bipolar montages is included later in the chapter.

HF=70

ELECTRODES AND THEIR APPLICATION TO THE SCALP

HF=35

HF=15

100␮v 1sec

FIGURE 1–16 A-D, Changing the morphology of squares with the use of different low-frequency (LF) and high-frequency (HF) filters. (From Tyner F, Knott J, Mayer W. Fundamentals of EEG technology. Basic concepts and methods. New York: Raven Press, 1983, p. 115.)

recordings, a device to control paper speed, a calibration device, a device to gauge electrode impedance, and a power supply and cord.16 Each electrode is connected to a specific point on the electrode selector. The electrode selector connects any pair of electrodes to a single amplifier and the resulting signal is displayed on the corresponding channel on the EEG. The first channel may represent the voltage at a frontal electrode compared with that at the vertex. A second channel could hypothetically compare voltage at the vertex with that at an occipital electrode. The typical routine EEG comprises multiple channels varying from as few as 8 to as many as 21. The specific order and arrangement of these pairs of electrodes are known as a montage. Multiple montages are used sequentially during each recording to attempt to study activity from all major portions of the cortex. EEG laboratories tend to use uniform mon-

Resistance and impedance are important considerations in the EEG since the electrical changes comprising EEG signals are affected at multiple sites and are subject to many potential alterations before their final appearance on paper. Sites of resistance include resistance in the brain, skull, and skin-electrode interface; in the conducting wires from the head of the patient to the EEG apparatus; and in the EEG apparatus, including the pen-writing device. Before electrodes are placed, a process of lightly abrading the skin is performed to remove superficial layers of oils and dead skin that may have some degree of conductivity and could thereby alter the signal delivered to the EEG apparatus. After the electrodes are applied, impedances should be checked, and if they are persistently high, the abrasion process should be repeated as necessary. Subsequently, an electrolyte gel is applied to the electrode as the latter is placed on the scalp. This gel facilitates the direct connection between the electrode and the skin and lowers the impedance at the electrode-skin interface.16 Electrodes should be well applied to avoid movement artifact, shown in the EEG as an electrode “pop” (Fig. 1-17), which is a change in electrostatic potential due to movement and loss of common mode rejection. The conductive solution collodion, which requires more time and effort to apply, has the advantage of providing a more secure contact between the electrode and the scalp. This reduces movement artifact and is particularly useful for prolonged recordings. The typical electrode is a silver chloride (AgCl) electrode. The electrode provides acceptable conductivity and does not irritate the skin of the scalp; it may be immersed

Fp2–F4

F4–C4

C4–P4

P4–02

FIGURE 1–17 Electrode pop artifact (between arrows).

20


in an electrolyte gel such as sodium chloride (NaCl). This chemical combination promotes a flow of charges that is ultimately received at the amplifier. When a negative charge arises from cortical generators, it causes negative chloride ions to leave the gel immersing the skin. The Cl– ion combines with the positive silver (Ag2+) ion to yield the product of AgCl and a residual free electron ion that is recorded at the amplifier. The process of ion exchange lends the name reversible to this type of electrode. Nonreversible electrodes are considered to be less optimal for EEG use because they are more prone to modifying incoming signals.1 A systematic and generally accepted convention for electrode placement over the scalp was developed by Jasper to avoid a haphazard application of electrodes. This convention, known as the International 10-20 System,17 was designed to avoid the errors inherent in a mere visual approximation for the site of electrode placement and to encourage replicability in EEG results among different EEG laboratories and different patients. The International 10-20 System is based on anatomic landmarks and percentages of the distances between them instead of absolute interelectrode distance values. The latter would be problematic since the same absolute distances over a small head would produce a very different localization over a large head. The convention recommends the use of 21 electrodes for standard conditions of recording and assigns odd numbers to the electrodes on the left and even ones to those on the right. Letters linked to these numbers refer to regions of the head and are shown in Table 1-3. The system also allows for the use of additional electrodes, at intermediate points beyond or between the above mentioned electrodes. For example, Fpz would represent a mid-prefrontal region and Oz a mid-occipital area. The specific locations of these electrodes are based on four landmarks on the head: the nasion, the inion, and the TABLE 1–3 Electrode Positions Electrodes

Approximate Region of Brain Coverage

Fp1, Fp2 F3, F4 F7, F8 C3, C4 T3, T4 T5, T6 A1, A2 P3, P4 O1, O2 Fz Cz Pz

Anterior frontal Frontal Anterior temporal Posterior frontal (overlying central sulcus) Mid-temporal Posterior temporal Ear Parietal Occipital Frontal midline Posterior frontal midline Parietal midline

left and right preauricular areas. The following is a summary of the locations16: • A mark placed midway between the nasion and inion localizes Cz. • Points representing 10%, 20%, 20%, 20%, 20%, and 10% of the total distance along the line linking the nasion and inion over the vertex of the head represent the locations of Fpz, Fz, Cz, Pz, and Oz, respectively. • Points representing 10%, 20%, 20%, 20%, 20%, and 10% of the total distance along the line linking the two preauricular points assign the locations of T3, C3, Cz, C4, and T4, respectively. • Points representing 10%, 20%, 20%, 20%, 20%, and 10% of the total distance along the line linking Fpz and Oz going through T3 represent the locations of Fp1, F7, T3, T5, and O1, respectively. • Points representing 10%, 20%, 20%, 20%, 20%, and 10% of the total distance along the line linking Fpz and Oz going through T4 represent the locations of Fp2, F8, T4, T6, and O2, respectively. • A position midway between Fpl and C3 represents F3, and a position midway between Fp2 and C4 represents C4. • A position midway between Fp2 and C4 represents the location of F4. • A position midway between C3 and O1 localizes P3, and a position midway between C4 and O2 localizes P4. In 1991 the American Electroencephalographic Society (now called the American Clinical Neurophysiology Society) added nomenclature guidelines that designated specific identifications and locations of 75 electrode positions along 10 anteroposterior planes and 4 coronal chains (Fig. 1-18).18 Several electrodes have different names in the 10-20 system and the extended nomenclature: The electrodes T3 and T4 in the 10-20 system are referred to as T7 and T8 in the expanded system, and T5 and T6 are referred to as P7 and P8 under the new nomenclature. Although there is uniformity with localization and naming of electrodes, there is still variation among centers in the type of montages used, that is, the specific configurations of electrode comparisons in a set of channels. Some laboratories employ additional electrodes at intermediate distances between the 21 electrodes already mentioned, with the hope of enhancing the yield and localization of specific EEG activity of interest such as epileptiform abnormalities. Examples of montages are shown in Figures 1-19 to 1-21.

SPECIAL ELECTRODES Specific clinical situations may warrant the use of special electrodes. However, because of patient comfort and

21

Basic Principles of Electroencephalography Modified combinatorial nomenclature NZ FPZ

FP1 AF7 F9 F7 FT9

A1

FT7

T9

TP7

TP9

F5

FC5

AF3 F3

FP2

AFZ F1

FZ

AF8

AF4

F6

F4

F2

FC3

FC1

FCZ

FC2

FC4

FC6

C5

C3

C1

CZ

C2

C4

C6

CP5

CP3

CP1

CPZ

CP2

CP4

CP6

P5 P9 PO7

P1

P3 PO3 O1

PZ POZ OZ

P2

P4 PO4

F10

F8

FT10

FT8

T10

TP8

A2

L

R

TP10

P6 P10 PO8

O2

IZ

FIGURE 1–18 Modified International 10-20 System nomenclature.

FIGURE 1–20 Transverse montage.

L

R

FIGURE 1–19 Bipolar montage (double banana).

reliability, these special electrodes are now rarely used, particularly in children. Nasopharyngeal electrodes are made of small silver spheres attached to long wires. These

are inserted though the nares to lie in the nasopharynx. They are designed to record electrical activity from the anteromesial surfaces of the temporal lobes, regions that are thought to be somewhat less accessible to scalp electrodes. They are usually employed to increase the yield on mesial temporal ictal and interictal epileptiform abnormalities. Nasopharyngeal electrodes are uncomfortable and often are contaminated by artifact. Infrequently used nasoethmoidal electrodes inserted into the nose and through the floor of the ethmoid sinus may be used to better sample EEG activity of the basal frontal lobe.19 Sphenoidal electrodes are more invasive electrodes used for even better recording of the mesial temporal area.10-12 These wires are inserted through a cannula into the inferotemporal fossae with their tips lying in the vicinity of the foramen ovale on each side. Although they sample the same area as nasopharyngeal electrodes, they can be left in place for prolonged recordings (several days to more than a week), are better tolerated by patients after insertion, and provide a recording less compromised by artifacts.20 Anterotemporal electrodes (T1/T2) that are placed 1 cm above a point one third of the distance from the external auditory meatus to the outer tragus of the eye may delineate anterior temporal lobe discharges more than conventional electrode placement. There is controversy whether T1/T2 electrodes provide as much information as sphenoidal electrodes. Sphenoidal electrodes can be safely placed in children.20-22

22


To vertex

To ipsilateral ear

L

R

FIGURE 1–21 Reference montage.

DIGITAL TECHNOLOGY Digital EEG machines record, amplify, and filter the electrical activity generated by the brain in much the same way as the analog machines described earlier in this chapter. In an analog machine, the resulting signal is used to drive a pen-writer. Digital processing, however, begins with conversion of this continuous signal into a series of discreet, regularly spaced data points. The key component of the digital EEG machine is the analog-to-digital converter (ADC).23 The signal from a single EEG channel is delivered to the converter, its voltage is measured at regular intervals, and this numerical value is stored in memory. The precision with which the ADC digitizes the input voltage depends on the voltage range of the ADC and the number of “bits” with which it represents the measured voltage, where each bit corresponds to a digit in a binary number. An n-digit binary number can represent 2n different states. A two-digit binary number, for example, has four possible values: 00, 01, 10, and 11. A 2-bit ADC with an input range of ±100 μV would assign voltages of –75, –25, 25, or 75 μV to each measurement. More generally, if Vr is the voltage range of the ADC and n is the number of bits, the input signal can be resolved in steps of Vr/2n volts. At a resolution of 2 bits,

digitization would unacceptably distort the original signal. The resolution could be improved by limiting the input range of the ADC, but this would come at the expense of the ADC’s dynamic range. Not surprisingly, digital EEG did not gain wide acceptance until 12- and 16-bit ADCs became widely available.23 A typical ADC on the market today has an input range of ±10 mV and a 22-bit sampling resolution and can resolve voltage differences of 20 mV/222 = 4.8 nV. For most applications, increasing precision beyond this increases storage requirements without improving clinical utility. The fidelity with which the analog signal is replicated also depends on the frequency with which it is sampled. The Nyquist theorem states that to unambiguously characterize a signal of a given frequency F, the signal must be sampled at a rate of more than two times F.23 For example, a 50-Hz signal must be sampled at 100 Hz or more. This procedure prevents “aliasing,” the phenomenon in which a signal of a certain frequency is sampled too slowly so that the resulting samples represent a signal with a frequency that is lower than that of the original analog signal. Figure 1-22 illustrates this phenomenon. The EEG frequencies of clinical interest lie between 0.1 and 70 Hz. This necessitates a sampling rate of at least 140 Hz. To prevent the aliased representation of the higher


23

Visualizing the Digital EEG

FIGURE 1–22 Digitizing an EEG signal at a frequency that is too low (i.e., using time intervals that are too long). Sampling of a 20-Hz waveform and an 80-Hz waveform end up looking the same.

frequency components of the analog EEG signal from contaminating the digitized signal, the signal is filtered with analog “antialiasing” filters prior to digitization. These are HFFs whose cutoff frequencies are one half or less of the sampling rate. In practice, most EEG machines sample at 200 Hz or more. First, this oversampling permits a smoother representation of the analog waveform. Second, this allows for the fact that the antialiasing filters do not block all the signal energy above their cutoff frequency— by choosing a sampling rate that is greater than twice the highest EEG frequency of interest, one can then choose an antialiasing filter with a cutoff frequency that is significantly less than one half of the sampling rate to prevent aliasing without filtering EEG frequencies of clinical interest. Unfortunately, increasing the sampling rate comes at the cost of increased storage requirements.

Digital Filters Digital filters offer several advantages over the analog filters discussed earlier. First, analog filters operate on the signal as it is being acquired, prior to its representation on paper or digitization and storage. The information removed by analog filtering is irrevocably lost. By contrast, digital filters operate on the digitized signal. As is the case with other aspects of the visualization of the digitized EEG, post hoc digital filtering does not alter the stored signal and so refiltering with any combination of filters is possible. Second, digital filters can be designed so as not to introduce the phase delay inevitably associated with analog filters. Third, unlike analog filters, which are realized in relatively inflexible circuits of resistors and capacitors, digital filters exist in a program stored in the processor’s memory and can therefore be modified without changing the hardware. Finally, analog filters can be sensitive to temperature changes and are subject to drift over time. Digital filters are stable in these respects. A brief introduction to the theory of digital filters is presented in Appendix III.

The digitally recorded EEG is typically displayed on a computer monitor.23 Important determinants of how a digital signal will look on a monitor are monitor size and the number of pixels used to demonstrate the EEG signal. Increasing the number of the pixels increases the accuracy and crispness of the visual display. Larger monitors may improve the visualization of tracings and allow space for each channel.

Advantages of Digital EEG In contrast with analog machines, which record the EEG in the same montage in which it is displayed, digital EEG machines normally record the signal in a fixed referential montage. A common reference electrode or combination of electrodes serves as the second input into the differential amplifier for each channel. Recording the data in this way facilitates its display in any conceivable montage: Fp1-F3 can be obtained by simply subtracting Fp1-reference from F3-reference. Digital EEG therefore allows for both on-line and post hoc reformatting of an EEG segment in different montages. The ability to view a particular discharge or sequence in a variety of montages is one of the key advantages of the digital EEG. This is useful in addressing a host of localization problems. Similarly, the digitized EEG can be reviewed using a variety of different filters. The EEG signal is normally acquired with “wide-open” analog filters prior to digitization that prevent aliasing and eliminate low-frequency artifact but permit the frequencies of clinical interest to be recorded without attenuation. Specific combinations of digital HFFs and LFFs and notch filters are then applied during review as needed. For example, filtering muscle artifact by reducing the cutoff frequency of the HFF often makes it possible to analyze portions of a record that would otherwise be uninterpretable. The filtered muscle artifact, however, can resemble spikes. By momentarily changing the cutoff frequency of the HFF, this issue can usually be resolved without difficulty. To better appreciate slow waves, one can increase the cutoff frequency of the low filter. Conversely, another strategy would be to reduce the cutoff frequency of the HFF to attenuate faster frequencies that may obscure underlying slow activity. The voltage and time scales of the displayed EEG can also be changed during review. Compressing the time scale is another strategy to appreciate subtle background slowing that complements the adjustment of the filter parameters. Expanding the time scale can be helpful in determining phase relationships of transients across channels. This can be useful to resolve localization problems and to identify secondary bilateral synchrony. The ability

24


to change the voltage scale during review is often helpful when, for example, the record contains occasional highvoltage discharges. Most of the record can be viewed at a scale appropriate to analyze background abnormalities, while the scale can be compressed (i.e., the sensitivity increased) to evaluate the lateralizing and localizing features of the high-voltage transients. The ease with which the digital EEG can be reformatted has changed the way it is recorded and interpreted. Prior to the digital era, EEG technicians recorded the EEG in a sequence of montages and carefully monitored the sensitivity at which the signal was displayed. Because post hoc reformatting was impossible, the burden of selecting a nonstandard montage to resolve interpretive questions usually fell to the technician. In many institutions the technician still cycles the default montage in which the EEG appears through the routine montages and monitors the default sensitivity. These decisions are often less crucial than they were in the past because reformatting does not alter the stored data. Digital EEG does not, however, reduce the burden on the technician. No amount of manipulation allows the reader to compensate for a poorly recorded EEG. In particular, a poorly applied reference electrode can render the entire record uninterpretable.

registration of spike and seizure foci with imaging studies is emerging as a particularly promising technique. Finally, since the inception of electroencephalography, clinical attention has focused on a fairly narrow frequency band. The upper end of this band reflects both an inherent limitation of the surface EEG—both lipid membranes and the skull act as HFFs and higher frequency activity overlaps with the scalp EMG—as well as the electromechanical limitations of a pen-writing apparatus. Baseline drift at the scalp-electrode interface and the characteristics of conventional amplifiers and filters have limited recording at very low frequencies. With the advent of intracranial recording with microelectrodes, it is now possible to record fast-field oscillations of 500 Hz and higher. It is now recognized that frequencies in the gamma range are clinically relevant in normal3,4 and abnormal states.5 Direct current–stable electrodes and direct current–coupled amplifiers have become increasingly available, which, in combination with digital technology, has greatly simplified the recording and analysis of very low-frequency EEG activity. The exploration of the full bandwidth of the EEG is one of the frontiers of encephalography.

THE EEG PEN-WRITING APPARATUS New Applications of Digital EEG The data-handling capabilities and flexibility of digital EEG have facilitated the development of long-term monitoring. This has revolutionized the use of the EEG for the classification of seizures and the presurgical evaluation in the epilepsy monitoring unit. Correlation of the digitized EEG with digital video is routine. Storing an EEG on a compact disk requires approximately 1000 times less physical space than on paper. Digital technology has also increased the role of the EEG in the neurointensive care unit (NICU), where it is used to detect subclinical seizures and to titrate antiepileptic therapy in status epilepticus. Digital EEG can also be used in the NICU to screen for the development of focal cerebral ischemia and increased intracranial pressure.24 Ambulatory EEG monitoring, which was difficult to realize in the era of bulky analog machines, is now an expanding application of digital EEG. Digital technology has also permitted the development of computer-aided quantitative techniques for analyzing the EEG. Spectral analysis and spike and seizure detection algorithms are available and may be useful to prioritize portions of records obtained during long-term EEG monitoring for visual analysis. Automated scoring of sleep studies is approaching clinical utility. Spike modeling and localization techniques are fertile areas of research, and a variety of clinical applications are under development;

Analog EEG machines have a pen-writer that uses simple electromagnetic forces.17 The pen-writer produces deflections that represent the rhythms and patterns seen on the EEG. A conducting coil is used for receiving the amplified EEG signal, and an electromagnetic field develops around it. In one type of design, the coil is attached on one end to a pivot point, which allows it to rotate. Each coil is placed between the poles of a stable magnet, creating forces of action and repulsion between the coil and the magnetic poles that are constantly changing in accordance with the changing EEG signal. Forces of attraction or repulsion cause the coil to experience a deflection in upward and downward directions corresponding to the alternating voltages of the EEG signal. A pen attached to each coil transcribes the EEG signal onto paper (Fig. 1-23). An oscillating pen-coil device is susceptible to the problem of extending beyond the intended range of motion (overshooting). Mechanical properties such as inertia and friction can lead to overshooting.25 Although the initial tendency to begin movement is much less than that of a body already in motion, the weight of the pen contributes to inertia, causing a pen in motion to continue moving and therefore overshoot. An electrical or mechanical system of “damping” is employed to avoid these excessive oscillations. Electrical damping systems work by electrically adjusting the pen positions when they stray from normal positions. Mechanical systems alter the pressure exerted

Basic Principles of Electroencephalography Stylus

Amplifier output

Magnet

FIGURE 1–23 A pen attached to each coil in an analog EEG, which transcribes the EEG signal onto paper.

by the pen on the paper. However, both damping systems may result in some degree of modification of the frequency response to the EEG signal, especially at the highfrequency end. The pen actually writes the form of an arc instead of a perfectly vertical deflection. This results from the pivot point attachment of the pen. A signal of high amplitude assumes an arc form in a more obvious fashion than does a signal of lower amplitude. In the interpretation of the EEG, this may produce subtle timing errors, with higher amplitude waveforms most affected. The distance between EEG channels is designed to avoid pens hitting each other.16 With digital technology the EEG is typically displayed on a computer monitor.23 Important determinants of how a digital signal will look on a monitor are monitor size and the number of pixels used to demonstrate the EEG signal. The fewer the pixels, the less crisp, the less accurate, and the less detailed will be the visual display. Larger monitors may help better visualize tracings and allow space for each channel.

25

paper and easier recognition of slow-frequency waveforms. In some centers, 15 mm/sec is the standard paper speed used in neonatal recordings. With digital technology, paper speed can be altered as desired and is not restricted to the speed at which the technician recorded. Gain refers to the ratio of output to input at the amplifier. The sensitivity of the recording is the amount of millimeters of pen deflection assigned to each microvolt of output signal amplitude and is expressed as microvolt per millimeter. The sensitivity can be changed during the recording to enhance or diminish the representation of voltages on paper. EEGs often begin with a sensitivity of 7 μV/mm, since most voltages of cerebral origin and of interest to the electroencephalographer are reasonably displayed with this sensitivity. Since each channel displayed on the EEG represents the comparison of two inputs, a convention has been established for the direction of the pen deflection. When the voltage in the first input is positive (less negative) with respect to the second input, the pen is deflected downward. When the first input is negative (less positive) with respect to the second input, the pen is deflected upward. Alternatively, when the second input is more negative (less positive) with respect to the first input, the pen moves downward. When the second input is more positive (less negative) with respect to the first input, the pen moves upward.23,26 These variations are displayed in Figure 1-24.

TESTING THE RECORDING SYSTEM To ensure that the EEG faithfully represents the voltages it receives, the recording system is tested by delivering external cerebral signals of uniform voltage to each

FREQUENCY AND VOLTAGE CONSIDERATIONS The EEG paper commonly used in the United States is designed to have each 1-second interval correspond to a 30-mm distance between any two repeating adjacent bold vertical lines, as that paper speed is set at 30 mm/sec. Most recordings use 30 mm/sec as a standard rate. However, many laboratories use a recording speed of 15 mm/sec for neonatal EEGs. When the intention is to better identify rhythms composed of waves of longer duration, slowing down the paper speed to 15 mm/sec results in the consolidation of EEG activities over a smaller amount of

FIGURE 1–24 Established convention for the direction of the pen deflection in response to polarity of the first and second electrode composing the input signal. (From Tyner F, Knott J, Mayer W. Fundamentals of EEG technology. Basic concepts and methods. New York: Raven Press, 1983, p. 146.)

26


FIGURE 1–25 Biocalibration that uses a frontal-to-occipital derivation.

amplifier and assessing the produced EEG pattern or aberrations in wave morphology. During this calibration process,25 a consistent current input signal is applied to produce square waves or sinusoidal waves that can be compared among the different channels of recording. It is easier to understand calibration using a square wave, although sinusoidal waves or even brain waves can be used as the calibration signal. The use of brain waves derived from the front and back of the head in the contralateral hemispheres (Fpl-O2) is a longstanding ritual called biocalibration and is performed just prior to the actual recordings. This is an opportunity to detect subtle differences in the display of uniform signals of cerebral origin and to correct them before the actual recording of the routine EEG (Fig. 1-25). At arbitrarily selected sensitivity and filter settings,16 a calibration button that applies the input signal is pressed. As described in the section explaining filters, the calibration pulse seen on the EEG represents the voltage at the

resistor. With a slope of decline governed by the value setting of the LFF (or time constant), the signal undergoes a decay in voltage, ultimately reaching a 0 baseline (see Fig. 1-10B). When a manual setting is used, continuing to press the calibration button preserves the input voltage but the voltage across the resistor remains at 0. Immediately on release of the calibration button, the pen deflects in an opposite direction. At the end of the test recording, filter settings and sensitivity changes used during the actual recording of the patient are applied to the calibration signal to demonstrate proper response by the EEG apparatus.

LOCALIZATION OF ACTIVITY In the interpretation of the EEG, pattern recognition alone is insufficient for the accurate assessment of normal and abnormal rhythms. Tables 1-4 and 1-5 summarize the Text continued on p. 31


27

TABLE 1–4 EEG Abnormalities and Their Clinical Significance EEG CHARACTERISTICS

SIGNIFICANCE

Background Abnormalities

Posterior dominant rhythm < 8 Hz (subject ≥ 3 yr of age) Generalized background slowing, including or excluding slowing of the posterior rhythm

Disorganization Excessive or distorted sleep patterns

Diffuse disturbance. Nonspecific, but may occur in toxic-metabolic disorders (electrolyte abnormalities, medication effects) and degenerative disorders, including dementia Diffuse, bilateral polymorphic delta activity and loss of reactivity indicate more severe cerebral dysfunction. Usually reflects a global process such as drug intoxication, uremia, hepatic disease, hypoxia, degenerative disorders, encephalitis, or meningitis. Can be seen with thalamic or midbrain dysfunction on the basis of bilateral structural lesions or herniation Absence of the anteroposterior frequency and amplitude gradients appropriate for the patient’s age and state of arousal. Implies a significant, diffuse disturbance of cerebral function In the absence of other findings, suggests a mild, diffuse abnormality of cerebral function

Abnormal Slow Waves Focal or lateralized slowing

Intermittent rhythmic delta activity (IRDA), generalized

Frontally predominant intermittent rhythmic delta activity (FIRDA) Occipitally predominant intermittent rhythmic delta activity (OIRDA)

Can represent a transient focal disturbance (consider the postictal state, complicated migraine, or head trauma) or a structural lesion, characteristically involving white matter (consider tumor, vascular, infectious, traumatic, local developmental, and degenerative diseases). A demonstrable structural lesion is more likely if the slowing is continuous, polymorphic, and of delta rather than theta frequency. Structural lesions are often associated with a focal loss of faster frequencies or in some cases with a focal attenuation of all EEG activities Bisynchronous rhythmic slow waves with a wide distribution. Usually associated with a diffuse encephalopathy. Occasionally occurs in the setting of widespread structural damage involving subcortical and cortical gray matter to a greater extent than white matter and in the setting of circumscribed structural lesions involving mesial frontal, diencephalic, or brain stem structures Common presentation of bisynchronous rhythmic slow waves in adults. Significance similar to that of IRDA. Occasionally seen with increased intracranial pressure, deep midline or subcortical lesions More common in children. Significance similar to that of IRDA. Must be differentiated from posterior slow waves of youth and other normal presentations of occipital slow waves

Abnormal Fast Activity Generalized excessive fast activity Focal excessive fast activity

Most often represents a medication effect (barbiturates or benzodiazepines). Also can occur in hyperthyroidism, acute or chronic anxiety, and as a normal variant Suggests a dysplastic cortical lesion

Periodic Patterns Periodic generalized complexes

Triphasic waves

May be seen in Creutzfeldt-Jacob disease (CJD), subacute sclerosing panencephalitis (SSPE), and phencyclidine intoxication. In both CJD and SSPE, the discharges may be associated with myoclonus. In CJD, the complexes are often stereotyped diphasic or triphasic transients occurring at intervals on the order 1 sec. Also are often triggered by sudden, loud noises. In SSPE, the complexes consist of high-voltage polyspikes, sharp waves, and slow components occurring at intervals of 3-20 sec. The complexes are usually not provoked by stimulation Consist of three phases, each longer than the one before. The second phase is positive in polarity and has the greatest amplitude. Voltage is usually maximal over the anterior head regions. There is often an anterior-to-posterior phase delay. May appear at 0.5- to 1-sec intervals or sporadically. Reflect a metabolic derangement. Classically associated with hepatic encephalopathy but also occur in other conditions such as uremia, hyponatremia, and lithium intoxication. Usually seen in patients with a mild alteration of consciousness rather than stupor or coma

28


TABLE 1–4 Continued EEG CHARACTERISTICS

SIGNIFICANCE

Pseudoperiodic lateralized epileptiform discharges (PLEDs)

Pseudoperiodic, sharply contoured waveforms with lateralized fields. Typically involve large areas of one hemisphere and may involve the homologous regions of the other. Bilaterally independent discharges (BiPLEDs) occur. If the pseudoperiodic discharges are localized to a region, e.g., anterior temporal lobe (as with herpes encephalitis), the term pseudoperiodic focal epileptiform discharges (PFEDs) may be more appropriate. PLEDs are associated with relatively acute structural lesions including those caused by encephalitis, infarction, hemorrhage, tumor, or abscess. Sometimes appear in the setting of an acute toxic or metabolic insult in a patient with a preexisting lesion. Can also represent an ictal or postictal pattern and a consequence of anoxia Pseudoperiodic complexes variably composed of polyspikes, sharp waves, and slow components separated by periods of background attenuation. Seen with severe diffuse disturbances such as anoxia, hypothermia, and high doses of central nervous system depressant medications

Burst-suppression pattern

Coma Patterns Beta, alpha, and theta coma patterns

Spindle coma pattern Voltage suppression, generalized

Electrocerebral inactivity

Generalized, invariant, monorhythmic activity in the beta, alpha, or theta frequency ranges. In beta coma, the activities are widespread and are usually of high amplitude. In alpha and theta coma, the expected anterior-toposterior amplitude and frequency gradients are absent. The beta coma pattern often occurs in coma caused or complicated by benzodiazepines or barbiturates and in this setting is associated with a good outcome. The alpha and theta coma patterns are of less prognostic significance than the presence or absence of reactivity and spontaneous variability Repetitive sleep spindles and sometimes vertex waves resembling stage II sleep in a comatose patient. Depending on the underlying etiology, this pattern is often associated with a good prognosis Defined as the absence of electrical brain activity > 10 μV. Consistent with severe encephalopathy. This pattern should be considered abnormal only in the setting of impaired consciousness because some normal individuals have brain activity that does not exceed this threshold Defined as the absence of electrical brain activity > 3 μV. In the appropriate clinical scenario, a technically adequate EEG demonstrating this pattern supports the diagnosis of brain death. This pattern can be seen in potentially reversible conditions such as benzodiazepine overdose

Epileptiform Abnormalities Spike

Sharp wave Polyspikes Centrotemporal spikes

Spike-wave complex

Sharply contoured waveform standing out from the background with a duration of 20-70 msec. The major deflection is most often surface negative. Indicates a focal area of epileptogenic potential. Rarely seen in individuals who have no history of seizures Sharply contoured waveform standing out from the background with a duration of 70-200 msec. Similar significance to that of spikes Repetitive spikes without intervening background. Rarely seen in individuals who have no history of seizures. Their detailed interpretation depends on their distribution and other features of the EEG Stereotyped spikes located in the central and temporal regions. May have a slightly shifting distribution. Unilateral in about 70% of routine records. Individual spikes characteristically have the field distribution of horizontal dipoles, such that a positive phase reversal over the anterior head regions and a negative phase reversal over the central and temporal regions is seen in longitudinal bipolar recordings. These spikes often dramatically increase in frequency. In the appropriate clinical setting, these discharges support the diagnosis of childhood epilepsy with centrotemporal spikes A spike followed by a slow wave. Most often the major deflections have the same polarity

29

Basic Principles of Electroencephalography TABLE 1–4 Continued EEG CHARACTERISTICS

SIGNIFICANCE

Rapid spike-wave complexes

Rhythmic runs of bisynchronous spike-wave complexes with a repetition rate > 3 Hz. Indicative of generalized seizure disorder, usually of the genetically determined type Indicative of generalized seizure disorder. Classically seen in absence seizures, although this pattern also occurs in other genetically determined epilepsy syndromes Rhythmic runs of bisynchronous spike-wave complexes with a repetition rate < 3 Hz. Indicative of a generalized seizure disorder. Often seen in the symptomatic and cryptogenic epileptic syndromes such as Lennox-Gastaut syndrome. Prolonged runs of these complexes, in the absence of evolution of their frequency or morphology and clinical manifestations, often represent an interictal phenomenon Two or more spikes occurring in sequence followed by a slow wave. The major deflections of each component usually have the same polarity. These are indicative of a generalized seizure disorder. Their detailed interpretation depends on their repetition rate Bisynchronous polyspike or polyspike-wave discharges appearing during photic stimulation that are not synchronized with the flash rate. Indicative of a predisposition to photogenic seizures. Seen in a subset of patients with genetically determined generalized and occipital epilepsies and rarely in patients with other epilepsy syndromes High-amplitude (>200 μV), disorganized and slow background with multifocal spikes. This pattern is usually present interictally in patients with infantile spasms Repetitive, rhythmic waveforms evolving in frequency and morphology that usually begin abruptly and interrupt the patient’s background activities. These sequences may consist of waveforms similar to the patient’s interictal epileptiform abnormalities or entirely distinct patterns Sudden attenuation of amplitude preceded by a frontally maximal or generalized paroxysmal complex composed of a high-amplitude slow wave with or without superimposed sharp components. The most common ictal pattern associated with infantile spasms. Also seen with atonic seizures

3-Hz spike-wave complexes Slow spike-wave complexes

Polyspike-wave complex

Photoparoxysmal response

Hypsarrhythmia EEG seizure patterns

Data from References 32-38.

TABLE 1–5 Pseudoepileptiform Patterns (benign EEG variants) Pattern

Morphology

Distribution

Context

Comment

14- and 6-Hz positive bursts

Negative arciform deflection alternates with sharply contoured positive component. Discharges occur in 4000 gm) who has had a vertex delivery with an associated shoulder dystocia presents the most common setting for a BPPN.47,49 Other major risk factors are summarized in Box 31-5. These are detailed earlier.36,43,44,49-53 Less commonly a BPPN occurs in some low-birthweight babies born in a breech position.47,54,55 The knowledge of risk factors would be most useful if it were to provide a means to prevent a BPPN. To date prenatal prediction of the risk of shoulder dystocia in largebirthweight fetuses is difficult and imprecise. Kay stated that “it seems unlikely that we are any nearer preventative strategies for this rare complication.”44,55,57,58 Although a 52-fold increased rate of BPPN occurs in macrosomic newborns of diabetic mothers, delivered by instrumentation, 92% of these babies were delivered vaginally without complications.59 Furthermore, and possibly paradoxically, a BPPN occasionally occurs after caesarean section.60 Rarely, fetal positioning and intrauterine amniotic bands may contribute to the presence of a BPPN.9,61 Engineering force analysis demonstrates that, in the presence of a shoulder dystocia, endogenous forces (i.e., uterine and maternal expulsive efforts) are four to nine times greater when contrasted with exogenous forces such as clinically applied traction to the fetal head.62 Clinical Examination The evaluation of a baby with a BPPN is often difficult and imprecise. A baby with classic Erb’s palsy lies with the affected arm limp at her or his side with the shoulder adducted, internally rotated, elbow extended, forearm pronated, fingers and wrists flexed—a characteristic posture referred to as “porter’s tip.” The shoulder is adducted secondary to paralysis of the deltoid, teres minor, infraspinatus, and supraspinatus muscles. Shoulder internal rotation occurs due to the unopposed contraction of the pectoralis, latissimus dorsi as well as the subscapularis muscles. Elbow extension results from the effect of gravity as well as paralysis of the elbow flexors (biceps, brachialis, and brachioradialis [C5-C6]). Paralysis of the supinator and biceps leads to forearm pronation (C5-C6). The flexed wrist and fingers occur because the wrist extensors are weakened also (C5-C6) (Fig. 31-9). A number of authors have suggested a more global assessment of upper limb function, allowing a predictive as well as prognostic clinical tool. One refinement designed to study recovery com-

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Plexopathies and Nerve Root Lesions

A

B

C

FIGURE 31–8 A, Brachial plexus anatomy after a severe stretch injury, with major roots being avulsed from the spinal cord. Note that the anterior primary ramus of each nerve root receives a contribution from the corresponding sympathetic trunk ganglion, the gray ramus communicans. In addition, the first thoracic anterior primary ramus contributes preganglionic sympathetic fibers to the inferior cervical (stellate) ganglion via a white ramus communicans. B, Classic “waiter’s tip” posture of an infant with neonatal brachial plexopathy. C, An older child with associated Horner’s syndrome. (A to C, Copyright ©1987, Icon Learning Systems, LLC. A subsidiary of MediMedia, USA, Inc. All rights reserved.)

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Neuromuscular Disorders

BOX 31-4 CLASSIFICATION OF OBSTETRIC BRACHIAL PLEXUS PALSY Group I (C5-C6): paralysis of the shoulder and biceps Group II (C5-C7): paralysis of the shoulder biceps and forearm extensors Group III (C5-T1): complete paralysis of the limb Group IV (C5-T1): complete paralysis of the limb with Horner’s syndrome From Brown WF, Bolton CF, Aminoff MJ (eds): Neuromuscular Function and Disease. Philadelphia, WB Saunders, 2002, p 1606.

BOX 31-5 BPPN RISK FACTORS Shoulder dystocia Large birthweight (>4 kg) Maternal diabetes Multiparity Second-stage labor > 60 min Assisted delivery (e.g., use of forceps, vacuum extraction) Previous child with BPPN Intrauterine torticollis BPPN, brachial plexus palsy of the newborn.

FIGURE 31–9 The classic posture of an infant with Erb’s palsy (upper trunk C5-C6). A large macrosomic baby (>4200 gm) at 6 weeks of age. The extremity is held adducted, in internal rotation and pronated, and extended at the elbow. The wrist, fingers, and thumb are flexed. (From Brown WF, Bolton CF, Aminoff MJ [eds]: Neuromuscular Function and Disease. Philadelphia, WB Saunders, 2002, p 1607.)

TABLE 31–1. PROGNOSTIC FACTORS: NEONATAL BRACHIAL PLEXOPATHIES Prognosis

Factors

Poor

Completely flail upper limb with Horner’s syndrome (Narakas46 group IV) Horner’s syndrome Phrenic nerve paralysis No recovery of biceps function (elbow flexion) by 3-4 mo Score of < 3.5 at 3 mo (HSCT scale) Root avulsion; pseudomeningocele (nerve rootlets absent) Recovery of elbow flexion by 2 mo Antigravity strength of elbow flexion by 3 mo No EMG evidence of axonal loss Scores of > 3.5 at 3 mo (HSCT scale) No root avulsion; no pseudomeningoceles with MRI imaging Motor unit recovery MUAPs volitional in biceps at 4/12 but not antigravity elbow flexion Clavicular fracture Narakas group II (C5-C7) Early recovery of elbow flexion but less than antigravity (by age 4 mo) and then plateau

bines a measurement of active limb movements and compares them with the normal side.63 Prognostic Factors Significant recovery is usually seen with an Erb’s BPPN, excluding the relatively rare, unfortunate infant with rupture and avulsion of each affected nerve root (Table 31-1 and Box 31-6). However, there is extensive debate vis-à-vis the timing and degree of effective reinnervation. The incidence of complete recovery varies enormously because of differing populations selected at different stages of reinnervation with varied criteria for the diagnosis of full or complete recovery. A pan-plexus injury with either a Horner’s sign or an associated phrenic nerve palsy has an especially poor prognosis with greater than 50% developing little or no clinical function.46,54,56,64-66 Although a concurrent

Good

Unknown/ indeterminate

HSCT, Hospital for Sick Children Toronto; MUAP, motor unit action potential.

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BOX 31-6 UNFAVORABLE PROGNOSTIC SIGNS OF BPPN Lower plexus lesions Erb-Klumpke lesion lacking some improvement within 1st wk No appreciable recovery by age 6 mo Nature of injury (avulsion or rupture) Horner’s syndrome Associated fracture of ribs, clavicle, and humerus BPPN, brachial plexus palsy of the newborn.

clavicular fracture in a newborn supports a traumatic process, when this is associated with a BPPN, it surprisingly holds no prognostic value in predicting spontaneous recovery.64,67 Natural History Prognosis is clearly the best for infants with BP lesions confined to the upper trunk and lateral cord. Overall, 70% to 92% of infants with neonatal brachial plexopathy have a good to excellent result when followed over a long-term period.42,68,69 Close to 15% of infants with BPPN experience significant permanent disability.56,69-71 In contradistinction other clinical researchers are somewhat less optimistic. A Swedish study showed that complete recovery occurred in only 49% and severe impairment in 22%.40

Neurophysiologic Prediction of Outcome Most centers today combine clinical assessment and neurophysiology to improve accuracy in evaluating the severity. In general, the items in Table 31-2 provide a good guideline vis-à-vis the neural lesion. The extent of the lesion is evaluated by the features at presentation, whereas the type of nerve injury is determined by the clinical improvement over time. Neurophysiologic findings enhance their predictive value.10,11 The predictive outcome was particularly good for nerves innervated by the C6-C7 roots. The lower predictive value for C5 likely reflects the fact that it is not possible to record CMAPs from C5-innervated muscles. Because of some of the EMG limitations in the newborn population as described earlier in this chapter, at times there is significant difficulty attempting to define the presence of root avulsion utilizing this methodology. This highlights the need for appropriate complementary imaging of the plexus, particularly MRI, or computed tomographic (CT) myelography for evaluation of BPPN. The Role of Neuroimaging Avulsion of ventral or dorsal nerve rootlets from the spinal cord results in preganglionic nerve root injury with no potential for nerve regeneration (see Fig. 31-5D-F). The diagnosis of nerve root avulsion is based on showing deformity of the subarachnoid space or a pseudomeningocele. Unfortunately this is not a precise technique because a significant percentage of avulsions show no evidence of pseudomeningocele, and pseudomeningoceles do occur without root avulsion.72-74 Root avulsions are best defined by identifying the absence of rootlets in the pseudomeningocele.49,75 This absence on

TABLE 31–2. THE NEUROPHYSIOLOGIC GRADING SYSTEM Type

CMAP

EMG

Lesion*

A: Generally quite good

Normal

Conduction block Neurapraxia (Sunderland 1)

B: Favorable

Normal or >50% of uninjured side

B: Unfavorable

Absent or age 6 mo Total plexus (Erb-Klumpke) lesion, particularly with Horner’s syndrome* Avulsion suggested by an Erb’s palsy with no change > 3 mo† Upper trunk lesion with phrenic nerve lesion† *The Swedish study93 found no value for surgery here. †Indication has been advocated by surgeons and it is primarily based on clinical and not EMG findings. BPPN, brachial plexus palsy of the newborn.

Furthermore, surgical colleagues believe that an upper BP lesion combined with a phrenic nerve palsy represents an indication for early exploration, as does the presence of a phrenic nerve palsy following breech delivery.56 This continues to be a controversial area, with still no welldefined, absolutely agreed on indications. This was reviewed in detail by Jones and associates in 2003.92 Certain favorable neurophysiologic findings, particularly ones including demonstration of neurapraxia, often lessen the urgency to explore the plexus. Even when EMG findings suggest an unfavorable prognosis, it is wise to delay exploration of the plexus for 2 to 6 months while clinical evolution is monitored. If clinical features still do not improve and continue to be concordant with the neurophysiologic findings, surgical exploration is indicated, ideally at about 6 months of age.10 A detailed report from the Karolinska Institute in Stockholm merits careful consideration for those committed to a better understanding of BPPN.93 A nonoperative approach was compared to microneurosurgical sural or nerve root graft. This study is unique in that it studied the children’s “functional outcome.” (A detailed analysis of these data is provided in Reference 94.) In summary, all children who achieved complete recovery by 5 years of age had already gained some recovery by 2 months of age, and all children with Erb-type lesions achieved normal hand and wrist movement. However, functional outcome monitored by the “pick-up” test was somewhat limited (among those operated on, 50% of 8 performed well; among those not operated on, 77% of 15 performed well; and in the early recovery group, 91% of 32 performed well). Note, however, that our Swedish colleagues’ analyses do not include the abilities of the 67 of 135 children who had

595

complete resolution at age 6 months. Retrospectively, most of these infants were recovered at age 6 months. Nonoperated children who experienced a late recovery had higher grip strength and bimanual activity than those who were operated among the Erb-plus (C5-C7) group. In those infants with a BPPN who had early intervention and were operated before 6 months, such an approach was no more effective than those who later had surgery. Surgery provided no advantage in those with ErbKlumpke type lesions, even though this has been listed as a standard indication for intervention.94 The finding that 67 of 135 children who had the most common Erb-type BPPN lesion, who achieved full recovery by age 6 months, were not included in this evaluation, as well as relatively small operative numbers (32 of 214 of C5-C6 or C5-C7 lesions), significantly biases their study’s opening discussion comment that “a better shoulder movement is apparent in C5-C6 palsies that have been operated on.”93,95 It is clear that new approaches are needed to both treat and analyze the value of various therapeutic interventions for BPPN that occurs in about 2 of 1000 births, or 40 times annually, in Sweden.93 Newer Therapies What with the relatively poor results to date of various therapeutic approaches, it is apparent that new clinical and research approaches are indicated if there is going to be any type of reasonable progress in the care of these infants. The reader is referred to the thoughtful papers of Korak and coworkers22 in 2004 and Strombeck and Fernell in 2003.95 These consider the role of central nervous system plasticity after injury and the eventual outcome. If progress is to be made, these authors and their colleagues may be leading us into a more fruitful albeit extremely challenging pathway for success.

POSTNEONATAL BRACHIAL PLEXOPATHIES With the exception of BPPN, these are generally uncommon occurrences among neonates and infants with the one exception of a rare form of occult osteomyelitis affecting the humeral head and extending to the adjacent plexus.96-98 This pathologic process contrasts with the precipitous onset of root avulsion and plexus injury at birth.16 Beyond the immediate perinatal period there are various hereditary, postinflammatory, and traumatic mechanisms, particularly including child abuse, that require diagnostic consideration. The differential diagnosis of BP palsy also includes rare other congenital motor unit lesions such as segmental anterior horn cell processes at the cervical spinal cord, amyoplasia, and a pseudoparesis.99

596


Osteomyelitis-related brachial plexopathy is an unusual BP with an acute onset in the immediate postneonatal period. Failure to consider this lesion in the differential diagnosis of an acutely acquired infantile BP in a previously healthy baby may lead to a serious plexus insult because of a delay in instituting appropriate antibiotic therapy. Criteria for differentiating this idiopathic BP are summarized in Box 31-9.34,100

We have recognized one instance in a 19-day-old girl with a 5-day history of fever and rhinorrhea with diminished movement in one arm over the prior 24 hours. An EMG performed at Children’s Hospital Boston (CHB) 3 weeks after onset of arm weakness demonstrated normal motor and sensory conduction studies.98 However, there was a markedly diminished number of MUAPs with many fibrillation potentials confined to the affected deltoid and biceps muscles. This was compatible with an upper cord BP lesion. She was successfully treated with penicillin G. Repeat bone scan on the 5th day of admission demonstrated a proximal right humerus osteomyelitis near the shoulder (Fig. 31-10). Later Clay reported a similar illness in a 9-week-old infant with 2-week history of an occult osteomyelitis. Initial EMG at 14 days was unremarkable; however, EMG findings demonstrated active denervation at 6 days later.34 Full recovery did not occur for 8 months. Both children had very elevated erythrocyte sedimentation rates (ESRs) of 90 and 81 mm/hr; modest leukocytosis; and positive cultures for group B beta-hemolytic streptococci, one from blood culture and the other on shoulder tap after blood culture was negative. Bone scan may be diagnostic for a proximal humeral osteomyelitis; however, a delay in onset of a specific change should not dissuade one from making the clinical diagnosis. The pathophysiology of this relationship awaits elucidation. An

A

B

BOX 31-9 CLINICAL SIGNS OF INFANTILE OSTEOMYELITIS BRACHIAL PLEXOPATHY Acute to subacute onset Fever ESR elevated Streptococcal infection Abnormality of humerus Bone scan focal ESR, erythrocyte sedimentation rate.

Osteomyelitis-Related Brachial Plexopathy

FIGURE 31–10 Osteomyelitis of the proximal humerus as a cause of brachial plexus neuropathy. Routine radiograph of the humerus (A) and bone scan (B) both demonstrate osteomyelitis (arrows). (A and B, From Clay SA: Osteomyelitis as a cause of brachial plexus neuropathy. Am J Dis Child 1982;136:1054-1056.)


597

unusual case of pyogenic Staphylococcus aureus cervical osteomyelitis with paraspinal abscess and resulting. Erb’s palsy is reported from Oman.101

Hereditary Brachial Plexus Neuropathies Hereditary Neuralgic Amyotrophy Hereditary BP neuropathy (HBPN) is also known as hereditary neuralgic amyotrophy. Typically these children have intermittent episodes of shoulder and arm pain, weakness, and atrophy initially presenting before age 5 years. One of three children also experienced an isolated phrenic nerve paralysis at age 7 weeks.96 A characteristic Modigliani physiognomy of slender-faced youth characterized by closeset eyes (hypotelorism), long nasal bridge, and facial asymmetry is characteristic (Figs. 31-11 and 31-12).96,102 Except for their recurrent nature, these painful BPs mimic idiopathic BP neuropathy (IBPN), that is, neuralgic amyotrophy. This contrasts with the exclusively painless presentation of another hereditary neuropathic process sometimes hav-

FIGURE 31–12 Child with heredofamilial brachial plexopathy. (From Dunn HG, Daube JR, Gomez MR: Heredofamilial brachial plexus neuropathy [hereditary neuralgic amyotrophy with brachial predilection] in childhood. Dev Med Child Neurol 1978;20:28-46.)

FIGURE 31–11 Modigliani portrait with hypotelorism and a slender facies. (From Dunn HG, Daube JR, Gomez MR: Heredofamilial brachial plexus neuropathy [hereditary neuralgic amyotrophy with brachial predilection] in childhood. Dev Med Child Neurol 1978;20:28-46.)

ing a recurrent course. It is known as hereditary neuropathy with liability to pressure palsy (HNPP). Recovery was often incomplete.97,103,104 This must also be differentiated from both HBPN and IBPN.96,97,103,105,106 Children with HBPN have an autosomal dominant inheritance pattern. The primary genetic site involved is non-neuronal, perhaps related to connective tissue.102 Thus genes coding for connective tissue could lead to a BP neuropathy due to direct pressure, diminished blood supply, or an immune mechanism.104 The tissue inhibitor of metalloproteinase 2 (TIMP2) is another intriguing gene on chromosome 17. Matrix metalloproteinases are involved in the pathogenesis of experimental autoimmune neuritis (an animal model of immune mediated neuropathies).104 Certain characteristics may guide one in ordering DNA testing when seeing children with their first BP (Box 31-10). There are just a few reports of NCS in HBPN, not enough to establish a specific pattern. A predominant median and radial sensory fiber involvement with low-amplitude SNAPs was noted.96 Motor conduction velocity was usually normal or only mildly slowed. Fibrillation potentials in the affected

598


BOX 31-10 FACTORS FAVORING A FAMILIAL MECHANISM FOR NONTRAUMATIC CHILDHOOD BP There is an equal appearance in boys and girls. Neuralgic amyotrophy (IBPN) occurs more commonly with boys. Mothers with HBPN report pregnancy-related exacerbations.97 HBPN has a broader distribution of plexus involvement that contrasts with the predominant upper trunk, lateral cord damage seen with IBPN.106 BP, brachial plexus; IBPN, idiopathic BP neuropathy; HBPN, hereditary BP neuropathy.

muscles are compatible with an axonal process in some children with HBPN. Hereditary Neuropathy with Liability to Pressure Palsy About 10% of patients with HNPP have BP involvement.107 This often can be differentiated from HBPN, usually associated with pain similar to IBPN, by the fact that HNPP is usually painless. The generic locus for HNPP is located on 17p11.2 differing from HBPN at 17q25.102 This locus is similar to Charcot-Marie Tooth (type 1A) hereditary motor sensory neuropathy. The genetic abnormality is a duplication at 17p11.2 with HNPP in contrast to the deletion located at 17p11.2. with Charcot-Marie Tooth.108 This interstitial deletion causes the complete loss of one allele of the peripheral myelin protein 22 (PMP22 gene). Current molecular genetic tests and clinical guidelines provide for improved diagnosis and counseling for patients with HNPP. In general, these families experience isolated mononeuropathies, particularly to nerves sensitive to compression (i.e., median, radial, and peroneal). Occasionally, some HNPP children have a painless brachial plexopathy or even a monomelic mononeuritis multiplex picture. One 16-year-old child developed a paresis of the posterior and lateral portions of the BP after sleeping with his arm tucked under his head.109

Idiopathic Brachial Plexus Neuropathy (Neuralgic Amyotrophy) Idiopathic, likely autoimmune, acute BP neuropathy has multiple terminologies, including Parsonage-Turner

syndrome, neuralgic amyotrophy, and idiopathic brachial neuritis. The nonspecific term IBPN is most appropriate because no etiologic or pathophysiologic implications are inherent in this designation. Others suggest that neuralgic amyotrophy is the most appropriate name because pain is often the first symptom subsequently followed by shoulder girdle weakness.33,110-112 This is much more commonly recognized in the adult. However, the Mayo Clinic experience included 7 of 99 patients younger than 20 years of age, the youngest presenting at age 3 months.33 Typically IBPN affects nerves innervating the shoulder girdle muscles; however, some other portions of this plexus and its terminal branches, such as the anterior interosseous nerve, are occasionally involved.113 Bilateral but asymmetric involvement is noted in about one third of patients.5,33 IBPN is a diagnosis of exclusion; therefore, one needs to search for other pathophysiologic mechanisms. Two reports of childhood IBPN include at least three nonfamilial instances, with onset between the ages of 16 months and 9 years. The youngest child had a painless, diffuse brachial plexitis with flaccid weakness of the entire arm and weak grasp 4 days after a febrile illness.114 Eight months later this infant had a poor recovery in comparison with the excellent recovery at 6 months in the 3.5-year-old child whose IBPN was confined to the proximal arm.114

Brachial Plexus Pressure Palsies Two areas of potential compressive injuries to the BP are defined in children. They are relatively uncommon.115,116 With the wise introduction of mandatory automobile infant safety seats to prevent free-flight injuries of the unrestrained baby, one might consider that the potential for a compressive injury to the BP may be more frequent. However, to date, that has not been our experience. There is one interesting notation of a previously healthy 9-month-old infant who was confined in a rear-facing infant restraint seat with a self-retracting shoulder harness during a 7-day, 2500-mile journey. This baby was never confined to the seat for more than 4 hours. On the last leg of the trip, the infant lost function in the left arm. Neurologic examination documented weakness in the distribution of the BP lateral and posterior cords. There were no other possible etiologic mechanisms. Unfortunately DNA testing for HNPP was not yet available; one would wonder whether the infant or parents had the same findings. No EMG was performed. This baby had a full recovery, suggesting neurapraxic injury secondary to the harness.117 Despite the increasing use of backpacks by school-aged children, an increased incidence of previously described rucksack palsies, initially noted in children participating in scouting,118 has yet to be experienced. In Japan, 15 of 16


sports-related BPs were secondary to mountain climbing with packs as heavy as 40 kg. It is suggested that these lesions occurred secondary to axillary nerve compression. None of these injuries was further defined by EMG.119 However, again the possibility of HNPP and/or HBPN would deserve consideration today.

Traumatic Brachial Plexopathies The older child and adolescent, in particular, are exposed to a number of potential traumatic mechanisms. These include motorcycle injuries, other accidental sports trauma, various war wounds, hunting injuries, other gunshot wounds, and surgery.119-128 Sports injuries frequently cause BP injuries among adolescents.129-138 Typically these occur in football, lacrosse, and/or rugby where these are referred to as a “burner” or “stinger.” Their exact pathophysiology is unclear. There are two major proposed etiologies: (1) traction of the C5-C6 cervical nerve roots and/or (2) a mild stretch injury to the upper trunk of the BP. Anatomically, based on the location of the “weak link” at the root level (because of the lack of supporting connective tissue structures), a number of authors suggest that the nerve root is a prime consideration for the lesion.121 Neither injury has any longterm sequela. Only a few nondefinitive EMG studies are available.5,121,133,134 Needle EMG was the most sensitive, sometimes noting neurogenic changes in the upper trunk muscles, although in most cases the EMG was normal or only suggestive of a decreased recruitment and interference pattern compatible with neuropraxia. EMG is primarily valuable for individuals who sustain more than a period of episodic pain and weakness or are unable to “shake it off.”129 A normal NEE, particularly in supraspinatus and infraspinatus muscles, when the patient reports feelings of weakness in the shoulder girdle alerts the clinician to consider certain musculoskeletal causes. These include a rotator cuff tear and/or fracture.

Neoplasms It is extremely rare for a child to have a brachial plexopathy as the presentation of a tumor. This contrasts with the adult experience. Important features that distinguish these children with a tumor from idiopathic BP are outlined in Box 31-11.100

Thoracic Outlet Syndrome Thoracic outlet syndrome (TOS) is a rare condition, in our experience, if one follows the strict electrodiagnostic criteria for a neurologic TOS as defined by Gilliatt and

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BOX 31-11 FEATURES OF A CHILDHOOD BP SUGGESTING A TUMOR History of normal delivery and birthweight Onset after the neonatal period Progressive course Scratch marks on a weak arm Supraclavicular mass in area with no radiographic clavicular fracture BP, brachial plexus. Adapted from Alfonso I, Alfonso DT, Papazian O: Focal upper extremity neuropathy in neonates. Semin Pediatr Neurol 2000;7:4-14.

BOX 31-12 MODIFIED GILLIATT139,141,144 NCS EMG CRITERIA FOR THORACIC OUTLET SYNDROME Ulnar SNAP 5th finger low amplitude to absent* Medial antebrachial cutaneous SNAP absent* Median innervated thenar CMAP low amplitude* Median II digit SNAP normal Ulnar-innervated hypothenar CMAP normal to low amplitude Motor NCV, DL preserved F waves slight to moderately prolonged, median more than ulnar Active and chronic denervation in ulnar and median intrinsics, flexor carpi ulnaris, and extensor indicis proprius *Essential for diagnosis. NCS, nerve conduction study; SNAP, sensory nerve action potential; CMAP, compound motor action potential; NCV, nerve conduction velocity; DL, distal latency.

associates139 (Box 31-12). The incidence of this condition has been estimated to be 1 in 1 million.140 However, it is important to recognize because its sequelae can become quite disabling.141 In general TOS primarily occurs in young women who undergo strenuous activities of the upper extremities or have bad working postures.141 Most of Gilliatt’s patients presented with hand weakness and/or atrophy affecting median more than the ulnar intrinsics. Pain and paresthesia, primarily on the medial aspect of

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the arm, forearm, and occasionally the hand, was present in 12 of 14 patients; however, it was usually mild and the primary complaint in only 5 patients. The cause was either a cervical rib or increased length of the C7 transverse process.139 Usually these patients have sharp fibrous bands extending from the rudimentary rib or the tip of the C7 transverse process. The C8 and T1 anterior primary rami or the lower trunk of the BP become stretched and compressed while passing over these bands.5,142,143 This is almost always a unilateral process clinically, although there is a recent well-documented instance of a bilaterally significant TOS beginning at age 17 years in a girl shortly after she commenced work as a hairdresser.141 This teenager had profound atrophy of both hands. Axial CT confirmed the chest radiograph presence of rudimentary C7 cervical ribs. There are multiple reports of bilateral cervical ribs, but this was the first one found to have clinically significant findings on examination and EMG. At surgery the cervical ribs and thick fibrous bands were removed by a transaxillary approach. Within a short time her pain and paresthesia disappeared. There was no followup after 1 month when repeat EMG was unchanged. Gilliatt and associates in 1978139 proposed the major EMG criteria for diagnosis of TOS, and in general these have been reliable. They have since been modified somewhat by Wilbourn and coworkers144 in 1999 and Tilki in 2004.141 (See the items identified as “essential for diagnosis” in Box 31-12.) The absent ulnar and medial antebrachial cutaneous SNAP, in keeping with the low-amplitude median CMAP, primarily T1 fibers, is classic for a medial plexus/lower trunk lesion. This is the only area where these respective fibers are contiguous. Wilbourn144 advised utilizing the medial antebrachial cutaneous nerve of the forearm in patients with “true” or neurogenic TOS. He provided an excellent discussion of TOS, including its controversial nature and clinical findings. Ouvrier and associates145 reported a 4-year-old child with thenar atrophy and weakness who, on cervical spine radiography, demonstrated a congenital Klippel-Feil anomaly associated with small cervical ribs. The ipsilateral median SNAP amplitude was low to normal, but still only 50% of the opposite unaffected side. The ipsilateral ulnar SNAPs from the nerve were of low amplitude. Needle EMG demonstrated chronic denervation in thenar muscles. An elongated C7 transverse process articulating with the first rib was found at surgery. There was only a little improvement over the next 5 years. One of us (H.R.J.), in 26 years at CHB, has also seen just one TOS case. He refused surgery and was lost to follow-up after 1 year.

Rare Brachial Plexopathies There are a few other unusual causes for a pediatric BP. These include neonatal hemangiomatosis,146,147 neck

compression,112 and an exostosis of the first rib.100 A brachial plexopathy is also described following therapy for childhood acute lymphoblastic leukemia.148-150

Pseudoparesis It is sometimes a diagnostic challenge when dealing with a youngster who complains of limb pain or deformity and feels the arm is weak or numb. Often the neurologic examination as well as EMG are normal. Many of these individuals are splinting their extremities because the pain is exacerbated by movement and they thus interpret this as “weakness.” Conditions such as complex regional pain syndrome, also known as reflex sympathies dystrophy or causalgia, are a significant consideration, particularly if there has been a history of minor trauma. In this setting the EMG is always normal. To better understand this condition, the reader is referred to a recent excellent review.151 It is always wise to follow such patients longitudinally rather than to suggest at first pass that the normal evaluation must thus suggest a diagnosis of a somatoform disorder. At times the subtle early signs of a peripheral motor unit lesion, at most any level, will declare themselves later on as new clinical findings evolve to point to the correct diagnosis. Repeat EMG may be helpful in this regard. On other occasions conditions such as juvenile rheumatoid arthritis and soft tissue, bony, or spinal cord tumors may emerge as the clinical course evolves.

LUMBOSACRAL PLEXOPATHIES Lesions of the LSP are the most uncommon peripheral nerve problems seen in our pediatric EMG laboratories. Most occur secondary to trauma including motor vehicle accidents, pelvic fracture, and gunshot wounds.122,152-163 LSPs are also linked to more subtle trauma associated with an underlying predisposing factor including hereditary liability to pressure palsy and Ehlers-Danlos syndrome.164,165 Some LSPs are most probably related to an immunerelated postviral plexitis.153,166,167 Tumors are another rare cause and can be a malignant one such as a lymphoma (H.R.J., personal experience at CHB) or benign (lipoma).168 Additionally, and rarely, iatrogenic etiologies occur.168-172

General Principles of EMG Evaluation for Pediatric Lumbosacral Plexopathies With the exception of the femoral nerve, none of the other nerves originating in the lumbar plexus lend themselves to direct stimulation for conventional NCS. This is especially true in children; in fact, for emotional sensitivities we do not even attempt to stimulate the femoral


nerve in any child. Therefore, one is dependent on the results of needle EMG to assess function of the femoral and obturator nerves. In contrast, the sacral sciatic-derived peroneal and tibial nerve components are available for routine NCS. Occasionally, a child does not tolerate stimulation in the popliteal fossa, and we are often content to study only the distal component. In the infant, sural stimulation is sometimes technically difficult.173 As in the cervical spine, a normal SNAP amplitude in an area of abnormal sensation (peripheral nerve and/or dermatome) may suggest a preganglionic lesion and help differentiate a root or intraspinal (i.e., preganglionic) lesion from a plexus abnormality (see Fig. 31-5). To further differentiate a plexus lesion, especially from the more common proximal sciatic nerve defect, multiple muscles require examination, occasionally including the gluteae medius and maximus. Additionally, one must exclude an intraspinal or nerve root process by examining the paraspinal muscles. These investigations are demanding in children. It is also difficult to obtain appropriate relaxation here, especially with infants and young children. Therefore, when there is a possible LSP diagnosis (see Fig. 31-6), one may best perform the EMG with anesthetic help in the outpatient surgical center.

Neuroimaging MRI provides excellent detail. When there is a reasonable clinical suspicion of a plexopathy, an MRI is the study of choice. The new 3.0 Tesla MRIs will be particularly helpful.

Lumbosacral Plexus Lesions Neonatal Lumbosacral Plexopathies Trauma to the LSP is rare in newborns.174,175 Eng176 summarized her experience with three neonates during a 7-year period. These babies sustained lumbosacral “traction” injuries after breech delivery. She emphasized the importance of differentiating these lesions from an asymmetric myelomeningocele, infantile poliomyelitis, parenteral injection injury, or a central nervous system process. Unfortunately no precise details of the clinical or EMG findings were described. None of these three infants had a complete recovery; however, the length of follow-up time is not reported.176 Another infant is reported who had a precise EMG performed after a precipitous double-footed breech delivery.175 At birth, this infant was unable to extend the knee or to rotate it internally. A follow-up evaluation at 4 months of age demonstrated inability to extend the knee or internally rotate the leg, atrophy and hypotonia of the quadriceps muscle, mild flexion contracture at the knee, and an absent quadriceps muscle stretch reflex. Radi-

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ographic examination of the lumbar spine and hip were normal. No pelvic or paravertebral masses were found on ultrasonography of the pelvis and spine. An EMG demonstrated denervation confined to the quadriceps and adductor magnus muscles. Excessive birth traction was suggested as a possible cause for the injury to the lumbar plexus; however, an isolated injury to the L2-L4 nerve roots was not excluded. Volpe described one similar infant who had a good recovery.177 Idiopathic Lumbosacral Plexopathy Primary LSP rarely occurs, particularly in children. It has been reported in six children from ages 2 to 16 years. It presents with a rapid onset of pain, weakness, and muscle atrophy. A viral illness preceded the LSP onset by 3 to 10 days in five of these six children. The lumbar plexus was predominantly involved. The LSP diagnosis was confirmed by EMG; however, details of these studies were not reported. Four children recovered within 3 months, and two had mild residual weakness.153,178,179 Evans166 reported a 15-year-old girl who presented with sudden, sharp inguinal pain associated with mid-thigh paresthesias. Weakness of the iliopsoas, quadriceps, and adductor muscles occurred 1 day later. EMG demonstrated denervation in both the femoral and obturator innervated muscles with a normal paraspinal evaluation. Significant recovery occurred in 3 months. They likened this condition to the well-described counterpart of IBPN known as neuralgic amyotrophy.166 Traumatic Lumbosacral Plexopathies Infants are susceptible to stretch injuries at the LSP similar to the BP. Traumatic lumbosacral nerve root avulsion rarely occurs.177,180 It is variously associated with flexion-abduction injury to the hip, hyperextension of the thigh with pelvic fracture,181 posterior dislocation of the hip, and sacral fractures.182,183 According to pathologic studies at a postmortem study,184 the L3-S3 roots rupture proximal to the spinal ganglion but distal to their origin at the cord. This contrasts with the more common root avulsion that occurs directly from the spinal cord in the cervical spine.181 However, both have the same effects on the outcome of an EMG with preservation of SNAPs because the dorsal root ganglia remain intact. Stretch injuries to the LSP are more common than root avulsion but are still relatively rare.152,155,185 The sciatic is the predominant nerve involved. This is reported subsequent to pelvic-sacral fractures and hip dislocations.158,186,187 Potentially serious lumbosacral plexopathies may result from unusual, seemingly innocent activities of children, particularly babies, as illustrated by one Raggedy Ann-like case seen at CHB.17 There, a 4-month-old infant’s sister playfully

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but vigorously pulled him across the floor by his leg. Later that day, his leg was limp, lacked spontaneous motion, and was cool. Examination demonstrated a flaccid leg with no muscle stretch reflexes. Orthopedic evaluation, including appropriate radiographs, was normal. NCS demonstrated a low-amplitude posterior tibial CMAP but normal tibial NCV and distal latencies with normal peroneal nerve function. The EMG study demonstrated fibrillation potentials in the tibialis anterior and medial gastrocnemius, with diminished number of MUAP in these muscles and the vastus lateralis. Seven months later, proximal strength was normal; however, there was some residual distal weakness. Lumbosacral Injuries Related to Abdominal Trauma Infants rarely sustain crush injuries that result in pressure-induced lumbosacral plexopathies. One 13-monthold developed a flaccid leg, with the exception of preserved iliopsoas function. This was secondary to an acute abdominal crush injury.156 During the next few days, loss of function ensued in the opposite leg with iliopsoas and quadriceps being the only muscles with preserved strength. Muscle stretch reflexes were absent bilaterally. An MRI of the lumbosacral spine was normal. EMG performed 72 hours after injury demonstrated bilaterally absent peroneal F waves and tibial H-reflexes but otherwise normal peroneal motor NCS. No MUAP were activated; however, no signs of denervation were demonstrated in the leg and the lumbosacral paraspinal muscles. Within 1 month the child had clinically recovered. Repeat EMG demonstrated normal MUPs in the previously silent muscles. The only signs of axonal damage were noted in the tibialis anterior muscles. F waves returned 3 months after injury. The clinical and EMG courses were thought to be primarily compatible with a neurapraxic injury.156 Other traumatic mechanisms include knife injuries, gunshot wounds, and motor vehicle accidents.122,154

HEMORRHAGIC COMPLICATIONS Iliopsoas hemorrhage can result in a femoral neuropathy, especially in the context of a bleeding diathesis. This occurred in a 15-year-old boy with hemophilia.188 Similar to that in adults receiving anticoagulant medication, the lesion is related to hemorrhage within the iliopsoas muscle. Neoplasms When the onset of weakness is more insidious, the possibility of a retroperitoneal mass also needs consideration. Imaging (MRI) and EMG are helpful in localizing the

lesion. Cancer, metastatic disease, and primary tumor affecting the LSP are rare conditions in children.148 Pyriformis Syndrome It has been suggested that the pyriformis muscle entraps the sciatic nerve as it passes through this muscle palsy. This is an often disputed entity, and if it does occur it must be an exceedingly rare condition. We have never seen such. However, this was postulated to have occurred as a complication of posterior fossa surgery performed in the seated position in a 10-year-old boy.189 The most common differential is a sciatic nerve palsy (see discussion of mononeuropathies in Chapter 30). Miscellaneous Lumbosacral Plexopathy There are a few other rare etiologies to consider in the differential diagnosis of sudden leg weakness in children. Fortunately, poliomyelitis is no longer a problem in North America. In the mid 1990s when the live vaccine was the primary form of immunization, there were at least three cases of postimmunization infantile poliomyelitis for which one of our authors (H.R.J.) was consulted.190-192 However, one must still keep the possibility of poliomyelitis in the differential diagnosis of any child with acute leg weakness, usually with pain and fever just before embarkation from their native land and who has recently arrived from endemic areas of the world particularly Africa, Egypt, and India. The EMG demonstrates a primary motor lesion with acute denervation and preserved sensory function.

PEDIATRIC NERVE ROOT LESIONS: OVERVIEW OF NEUROPHYSIOLOGIC AND MRI TESTING MODALITIES Cervical or lumbosacral radiculopathies or LSRs caused by disorders of bones and/or supporting structures (intervertebral disks) surrounding the spinal cord and cauda equina are rare disorders in children, although such has been documented in the lumbosacral region as early as age 27 months.193 It is occasionally difficult to make a differential diagnosis between the more common mononeuropathies, or brachial plexopathies, and the rare case of cervical root damage while performing a pediatric EMG. As nerve root avulsions and BP injury often occur concomitantly particularly in children, the presence of EMG findings compatible with a primary plexus lesion does not exclude damage at the nerve root level. Because it is much more difficult to obtain cervical paraspinal muscle relaxation in kids, this essential EMG differential diagnostic technique is usually a problem in the unrelaxed child. Most children do not require operative intervention. From a structural (anatomic) standpoint, an MRI is the


study of choice for any child with a suspected nerve root lesion. The question of a radiculopathy is an unusual reason for referral to a pediatric EMG laboratory. Nevertheless, it is important to consider the rare possibility of a nerve root process in the differential diagnosis of any child with cervical or lumbosacral pain, especially those with a radicular component.

EMG General Principles of EMG Diagnosis in Nerve Root Disorders In the uncommon instance of a child presenting with a radiculopathy, the MRI is the study of choice. If the MRI is diagnostic, there is absolutely no need to proceed with an EMG. The nerve root responds to a focal lesion by undergoing axonal loss, focal demyelination, or both. There are no reports of EMG findings in asymptomatic healthy children. In adults these also are limited except with regard to paraspinal muscles. Haig has found a false-positive rate in the order of 5% in adults.194 The understanding of the difference between a preganglionic injury and a postganglionic lesion is crucial in the electrodiagnostic assessment of neck and arm or back and leg pain (see Fig. 31-2). Compressive radiculopathies occur so proximally that a potential conduction block in a preganglionic locus cannot be evaluated by routine NCSs. Given that the dorsal root ganglion is outside (distal to the intervertebral foramen), the corresponding SNAP will not be impaired. However, the corresponding motor component measured by CMAP amplitude can be affected if the lesion produces axonal loss. Thus CMAP amplitude will be reduced. Recent adult studies demonstrate that EMG and MRI findings agree in the majority (60%) of patients with a clinical history compatible with cervical or lumbosacral radiculopathy (LSR). EMG provides the best information in those instances when the MRI is normal and there is need to establish a diagnosis, particularly when the clinical picture strongly suggests a radiculopathy. Sensitivity, Specificity, and Limitation of EMG Before commencing the EMG study, it is important to appreciate the limiting factors of EMG in the assessment and diagnosis of radiculopathies. These are mainly related to the location and nature of the lesion as just noted. Furthermore, there is an important dependence on the timing of the original lesion and thereby the duration of the pathology. Even when all “new” techniques are included, electrodiagnosis does not detect “all” compressive radiculopathies. EMG findings can therefore never be used to exclude a radiculopathy. In the context of the clini-

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cal presentation and findings, one of the most important values of EMG testing is that it can help distinguish other causes of pain, numbness, and/or neurogenic phenomena in the affected extremity. Nerve Conduction Studies The presence of normal SNAPs when the patient has clinically verified sensory loss is one of the essential criteria for a diagnosis of a nerve root lesion. The finding of normal median and ulnar SNAPs lends support to the diagnosis of a C7-C8 intraspinal lesion. When one attempts to differentiate lesions at C6 from those involving the BP, normal median SNAPs recorded from the thumb or lateral antebrachial cutaneous SNAPs provide a useful means to localize lesions to the C6 roots especially when paraspinal muscle EMG is unreliable.5,195 The converse does not apply, that is, the absence of SNAPS, implying a postganglionic plexus lesion does not exclude a concomitant nerve root lesion.16 In most radiculopathies, because of dual root innervation to most muscles, there is little significant effect on CMAP amplitude. However, the L5 root primarily innervates the extensor digitorum brevis, and it may atrophy quite rapidly with an acute root lesion. Thus the peroneal CMAP may be diminished in this setting. Such is a nonspecific finding until the electromyographer also finds a retained superficial peroneal SNAP compatible with a preganglionic nerve root lesion (see Fig. 31-1). Although both types of late responses (F waves and H reflexes) may be abnormal when there is a nerve root lesion, these are relatively nonspecific findings. The value of H reflexes in the assessment of children with radiculopathies has not been studied. From the practical viewpoint, stimulation in the popliteal fossa is relatively uncomfortable and the tolerance of children is quite limited when one has to perform the repetitive testing necessary to confirm the true absence of this response if indeed there is a pathology present impacting on the H reflex. Thus, at CHB we rarely use this study. Needle EMG Examination Needle EMG is the most important and useful procedure of the various electrodiagnostic methods available to assess patients with a suspected radiculopathy.196 The presence of fibrillation potentials and neurogenic MUPs within specific myotomes, primarily the C5-C8 or L4-S1 distribution, are dependent on the severity of the lesion. Although needle EMG is essential, it requires fairly extensive assessment. Unfortunately, many children are unable to tolerate the careful evaluation that adult electromyographers typically pursue in search of a subtle nerve root lesion. Furthermore, needle EMG assesses only motor fibers and can only primarily detect the effects of motor axonal loss. If the clinical

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BOX 31-13 CLASSIC NEEDLE EMG NEUROPATHIC CHANGES Membrane instability, positive sharp waves and fibrillation potentials Other signs of membrane instability and ectopic motor discharge, including CRDs, fasciculations Large MUAP amplitude, increased percentage of polyphasic MUAP potentials Decreased MUAP recruitment and interference pattern MUAP, motor unit potential; CRD, complex repetitive discharge.

picture is primarily one of a sensory radiculopathy, without damage to the ventral or dorsal primary motor rami, needle EMG, is by definition, going to be normal. However, when the motor nerve root does sustain axonal damage, one can often find fibrillation potentials and other insertional abnormalities as well as neurogenic MUPs of large size that fire rapidly (Box 31-13). This offers confirmation of a chronic radiculopathy if the findings are confined to the distribution of a single root. Generally abnormalities within the myotome in question need to be demonstrated in at least two or more muscles receiving innervation from the same root and preferably via different peripheral nerves and/or the paraspinal muscles (see Chapter 6 for myotome charts appendix). The sensitivity of needle EMG is dependent on the severity of the axonal loss and the duration of symptoms. Studies may be falsely negative if they are performed either too early or too late in the course of a radiculopathy. One cannot exclude a radiculopathy with a normal EMG.

MRI and CT in the Diagnosis of Radiculopathies Clinical correlation with MRI and/or CT myelography and surgery has been demonstrated (sensitivity and correlation coefficients of 70% to 95%) in adults.196 However, no similar studies are known in children. Nevertheless an MRI is the study of choice for children with possible radiculopathies. At times one will initially be evaluating a child with an EMG for a possible mononeuropathy or plexus lesion when the findings do not support such a diagnosis, and one should move on to exclude the unusual childhood radiculopathy. It is here where a combined utilization of EMG and MRI may provide the diagnosis.

Somatosensory Evoked Potentials Somatosensory evoked potentials (SSEPs) theoretically should help in the evaluation of patients with suspected root lesions. However, extensive evaluation has shown that they are not helpful in the assessment of patients with radicular pathology.197 Furthermore, recent studies in children with brachial plexopathies show extensive somatosensory innervation, further limiting their clinical applicability.198 In summary, somatosensory potentials evoked by nerve trunk stimulation are diagnostically unhelpful, whereas both cutaneous and dermatomal SSEPs are insensitive in patients with chronically unequivocal root lesions, making it unlikely that they will be of any clinical use when the diagnosis is less clear.197 These are primarily of value in the assessment of spinal cord involvement.

Magnetic Stimulation The spinal roots and the proximal portions of peripheral nerves can be stimulated by a rapidly changing magnetic field. However, from a practical clinical viewpoint it is not clear whether magnetic stimulation has any advantage over electrical stimulation and their clinical applicability requires further research.199

PEDIATRIC ROOT DISORDERS It is often difficult to make a differential diagnosis between the more common mononeuropathies, or brachial plexopathies, and the rare case of cervical root damage while performing a pediatric EMG. As nerve root avulsions and BP injury often occur concomitantly, particularly in children, the presence of EMG findings compatible with a primary plexus lesion does not exclude damage at the nerve root level. Because it is much more difficult to obtain cervical paraspinal muscle relaxation in kids, this EMG differential diagnosis is sometimes a problem in the setting of a possible traumatic mechanism. The finding of normal median and ulnar SNAPs lends support to the diagnosis of a C7-C8 intraspinal lesion. When one attempts to differentiate lesions at C6 from those involving the BP, normal median SNAPs recorded from the thumb or lateral antebrachial cutaneous SNAPs provide a useful means to localize lesions to the C6 roots especially when paraspinal muscle EMG is unreliable.5,192 The converse does not apply, that is, the absence of SNAPS, implying a postganglionic plexus lesion does not exclude a concomitant nerve root lesion.15


CERVICAL RADICULOPATHY Children rarely have primary cervical nerve root lesions. In a review of 561 Mayo Clinic patients with a cervical radiculopathy, only 41 individuals (7%) were 15 to 29 years old.200 No more specific breakdown of the adolescents included in this report is available. The study excluded one 13-year-old girl with a cervical radiculopathy. This exclusion further supports the rarity of this lesion in children and adolescents.200

Clinical Profile Cervical radiculopathies do occur in adolescents but are exceedingly rare in younger children. We are unaware of any instance in a preschool-aged child in contrast with one instance of LSR.193 In general we have not seen the typical case of a classic C6 or C7 radiculopathy among children or adolescents as is so common in adults. Although uncommon, this most likely relates to the excellent diagnostic accuracy of MRI for these lesions. However, occasionally one performs an EMG on a teenager who is referred with a query of a cervical radiculopathy who primarily has painless arm weakness and not any symptoms of pain or paresthesia. This should raise a question of other disorders, including congenital spinal stenosis, or some primary intramedullary lesions, including Hirayama’s disorder, or, rarely, early motor neuron disease. EMG testing in both congenital spinal stenosis and Hirayama flexion myelopathy demonstrates a primary active neurogenic process in the affected extremity. In addition, each of these entities has modest chronic neurogenic changes in the clinically silent, or less affected, contralateral extremity. HNPP is another rare entity that also requires consideration in the presentation of painless arm weakness (see Chapter 32).201 There is a similar, also genetically linked, process of an acute, recurrent, painful brachial plexopathy that may also mimic a nerve root lesion, as noted earlier in this chapter.202

Differential Diagnosis of Pediatric Cervical Root Lesions Congenital Cervical Stenosis Although our experience has not included any typical cervical radiculopathies secondary to disk or uncovertebral (osteophyte-induced foraminal stenosis) mechanisms,200 two children with congenital cervical spine lesions have been studied at CHB. One was a 13-year-old child with a short history of pain in the right shoulder and arm exacerbated by swimming. EMG demonstrated C7-T1 denervation. Cervical spine radiography demonstrated anomalous

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hypoplastic vertebral bodies with incompletely developed interspaces. Another case, a 16-year-old boy with a 3-month history of progressive painless arm weakness first apparent when he played basketball, had not had any paresthesias or other sensory symptoms to suggest spinal root involvement. Prior to his EMG the clinical diagnosis had been a possible BP lesion. Weakness predominantly affected the infraspinatus, supraspinatus, serratus anterior, deltoid, and possibly the opposite deltoid muscles. Muscle stretch reflexes were normal, and no sensory loss was detected. Motor and sensory NCSs were normal. Needle EMG demonstrated active denervation in C5 to C8 dermatomes; contralateral changes were confined to C5. We were unable to obtain total relaxation of the cervical paraspinal muscles. Cervical spine radiography demonstrated en bloc C2-C3 vertebrae with diminished diameter of the spinal canal from C4 to C7. Myelography demonstrated spinal stenosis from C2 to C7. Decompressive cervical laminectomy was performed. His outcome was unknown, because he was lost to follow-up review shortly after the operation. Juvenile Muscular Atrophy of Distal Upper Extremity; Hirayama Flexion Myelopathy Juvenile muscular atrophy of distal upper extremity is another rare cause for painless arm weakness in an adolescent.203 Initially this affects hand function and is confused with a C8 radiculopathy, medial brachial plexopathy, or an ulnar neuropathy. However, these patients have no pain or paresthesia making these more common mechanisms unlikely. Initially this is reminiscent of amyotrophic lateral sclerosis, something even more rare in this age group. Fortunately, amyotrophic lateral sclerosis has been seen just once in a teenager during one of our authors’ career (H.R.J.). Hirayama’s disease generally affects adolescent boys of eastern Pacific rim heritage. However, we have seen a total of four similar cases among caucasians at CHB and Lahey. Typically this insidiously progressive disorder has a selflimiting course usually not progressing for more than 5 years. It predominantly affects just one upper extremity and to a much lesser extent its contralateral homologue.204 The cervical spinal cord is the primary site of pathology. It is now thought that this is related to a flexion myelopathy.205 Grisel’s Syndrome Grisel’s syndrome is an uncommon infectious process that primarily produces subluxation of the atlantoaxial joint. It is found in both children and adults.206,207 Typically these patients present with unrelenting neck and/or throat pain. This is often followed by torticollis and sometimes subluxation at this spinal joint. Typically there is a preceding

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history of a flulike illness, otitis, tonsillitis, or pharyngitis. Subsequently an insidious onset of a progressively severe and localized unremitting spinal pain develops. About 15% of patients develop a cervical radiculopathy radiating into the shoulder. Some have a relatively precipitous onset of a torticollis and/or greater occipital nerve paresthesia. A myelopathy may follow characterized by transient or fixed quadriparesis and rarely death.206,207 Despite the infectious nature of this illness, it is uncommon for these children to appear highly septic. Spinal percussion tenderness and restriction of neck movement, including torticollis are the primary findings with physical examination. No EMG studies are mentioned in this review. However, their report points to the importance of considering this potentially serious illness in the rare instance of a child referred to the EMG laboratory with severe neck pain and symptoms of a cervical radiculopathy.

LUMBOSACRAL ROOT (LSR) DISEASE On the rare occasions that herniation of the nucleus pulposus occurs in children, it usually occurs in the lumbosacral area. At the Mayo Clinic an orthopedic report evaluated 1368 pediatric cases 16 years or younger for back, disk, or sciatic pain between 1950 and 1975.208 In many patients, a diagnosis of lumbar disk herniation was considered a possibility, and most of these responded well to conservative, nonoperative forms of therapy. However, 50 (3.7%) required surgical removal of one or more disks. These children with lumbar disk procedures represented 0.5% of lumbar laminectomies performed at the Mayo Clinic during that time span.208 In a later surgically proven series of LSRs seen at Mayo Clinic, the estimated pediatric prevalence was 0.8% and 3.2%.209 Another U.S. university hospital experience reported 10 adolescents with LSR seen during a 30-year epoch.210 Thus they saw one instance every 3 years! There may be a significantly higher incidence of juvenile disk LSR in Japan. One Japanese study reported 70 patients, age 9 to 19 years. This represented 15.4% of 456 patients having LSR surgery from 1951 to 1977.211 Fifty-five of 70 were boys; 21 were younger than 15 years of age. The youngest reported case is a 27-month-old child who fell from his cradle and over 2 weeks developed back pain, irritability, and gait difficulty. MRI demonstrated the LSR abnormality, and surgery was successful.188

Clinical Presentation Back pain or sciatica, or both, is the typical clinical presentation. Although all children had sciatica, 12 (17%) in Japan211 and 17 (34%) at Mayo Clinic had sciatica without back pain.208 Trauma related to athletic injuries, lifting,

falls, or back injury occurring at work accounted for at least half of the cases in two series.210,211 In the Mayo study where there was a 36% incidence of trauma, the athletic injuries occurred in a variety of sports, including football, basketball, baseball, soccer, cheerleading, tennis, and running.208 Clinical examination demonstrated relatively subtle neurologic deficits. Although focal weakness primarily involving the tibialis anterior and/or toe extensors was detected in some, in one series no footdrop was noted in any child. Recognizable sensory loss was identifiable in 10% (lateral foot 8% and medial foot 2%) to 58% of these adolescents. Severe paravertebral muscle spasm was also present along with limited spinal motion, cough-sneeze exacerbation in many (76%), or a positive Lasègue sign in up to 86% of children.208 Bowel and urinary tract disturbance occurred just once among the 155 children reported in four studies of adolescent LSRs. This was a 14-year-old boy with a cauda equina syndrome secondary to lumbar disk disease that required surgical repair.208-211

Imaging Studies MRI is the diagnostic study of choice. Eleven of 20 patients in a 37-year retrospective study at CHB had an MRI performed for disk disease. In 1996 this senior neurosurgeon still believed that CT imaging was the best modality because it was simple, briefer, and kinder to the child. It gave a clear differentiation between bone, disk, ligaments, and ossified ligament.212 Myelography was the primary means of diagnosis in the earlier studies. Standard spinal radiography demonstrated a 30% incidence of congenital bony abnormalities.208 These included spina bifida occulta in 16%, sacralization of the last lumbar vertebra in 14%, and an extra lumbar vertebra in 10%. In another study routine spine radiographs were diagnostic in 18 (58%) of the 32 children with a specific final diagnosis.213 The value of a combined diagnostic approach including lumbosacral radiographs, CT, or MRI, along with EMG, is suggested for LSRs in teenage children.214

EMG It is now unusual to evaluate children with back and/or sciatic pain in our CHB EMG laboratory. When we do, these are atypical clinical circumstances not infrequently having a significant suggestion of a complex regional pain syndrome such as reflex sympathetic dystrophy and causalgia after a relatively minor injury. There are few data on this subject from other institutions. EMGs were positive in five instances, including one child with normal results on myelography.214 In this one instance with


TABLE 31–4. DIFFERENTIAL DIAGNOSIS OF BACK PAIN IN CHILDREN Age < 10 Years

Age ≥ 10 Years

Infectious Vertebral osteomyelitis Diskitis Tumor

Infectious Spondylolysis, spondylolisthesis Scheuermann’s disease Herniated nucleus pulposus Tumors

negative myelography, CT suggested superior facet entrapment. This was confirmed surgically. No data are included as to whether more than 5 EMGs were performed and, if so, what the false-negative rate was with this procedure.

Differential Diagnosis Because pediatric lumbosacral disk disease is uncommon, unusual mechanisms need to be considered in children with lumbar nerve root symptoms (Table 31-4). One 6-year Orthopaedic Surgery Department review from Royal Manchester Children’s Hospital in the United Kingdom evaluated their low back pain experience in children 15 years of age or younger. This represented 2% of nontrauma referrals to this clinic.213 They were able to define a specific diagnosis in 32 of these 61 children. The variety of pathologic mechanisms included various infections (n = 5); tumors (n = 4); spondylosis, including spondylolisthesis (n = 8); Scheuermann’s disease (n = 9); and miscellaneous processes (n = 2). Inflammatory Diskitis. Disk protrusion may sometimes be secondary to diskitis.211 This same diagnosis was also considered in one 3-year-old boy who was seen because of acute severe low back pain, fever, and refusal to walk, sit, or stand.215 The neurologic examination was difficult to perform because he kept his legs tightly flexed on his abdomen. Straight-leg testing was markedly positive bilaterally. The right patellar muscle stretch reflex was absent. No other focal signs were detected. He was managed conservatively, but no improvement occurred. Myelography demonstrated a protruded L4-L5 disk. Surgery failed to identify any unusual mechanism for the nerve root lesion. He had an excellent surgical result. The fever subsided spontaneously, and no cause for it was identified. Today, MRI helps exclude spontaneous disk space infections because these lesions have a presentation similar to that of classic disk disease.216,217 Ankylosing Spondylitis. In older children, especially adolescents, the possibility of early ankylosing spondylitis always deserves consideration in the differential diagnosis

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of sciatica particularly with adolescent boys who present with classic sciatica. Routine radiographs and/or bony CT of the sacroiliac joints is often the diagnostic tool of choice in these young men, especially one with a positive human leukocyte antigen (HLA) B27 study. The electromyographer needs to be alert to this possibility in any adolescent male presenting to the laboratory with sciatica because ankylosing spondylitis is eventually crippling if not recognized early on. Often these patients have a concomitant history of early morning stiffness and “jelling” associated with diminished chest excursion on examination. Neoplasms Schwannoma. Nerve root tumors, although quite uncommon, always require consideration in the differential diagnosis of lumbosacral disk disease. A 16-year-old high school wrestler experienced 1 year of pain in the left buttock radiating into the thigh and calf. CT of the lumbosacral spine demonstrated a mass at L5-S1; at laminectomy this was an S1 schwannoma.218 EMG was not performed. Osteoblastoma. In another instance, a 13-year-old girl presented with a 6-month history of vague low back pain precipitated in gymnasium class. She had hypoesthesia in the L3 dermatome, weakness of the quadriceps, and absent knee jerk. EMG demonstrated an L3 radiculopathy. Simple palpation detected a paravertebral mass that proved to be an osteoblastoma.219 Congenital Spinal Tumors. Occasionally lipomas, often associated with a tethered cord, need to be considered in the differential diagnosis of lumbar radiculopathies presenting with footdrop or foot deformities. In the two instances we evaluated (one at Lahey and the other at CHB), there was no associated back pain. One was a 13-year-old boy with 2 years of progressive footdrop. He had 3/5 weakness of the tibialis anterior, 0.5-cm calf atrophy, and pes cavus. Peroneal and tibial NCS and sural SNAPs were normal. EMG demonstrated findings of S1 > L5 nerve root involvement including abnormal insertional activity in the lumbar paraspinal muscles. The normal SNAPs suggested a preganglionic lesion excluding a much more common evolving peroneal or peroneal division sciatic nerve lesion in this youngster with no back pain. This case emphasizes the need for a thorough EMG especially when the findings do not fit the usual pattern. Spinal MRI demonstrated a tethered cord and congenital tumor. MRI is the diagnostic study of choice. Sacral Bone Tumors. Primary sacral bone tumors may present with radicular pain, paresthesias, progressive weakness, and later paresis of the extremity.220 MRI and CT are the best diagnostic studies. Standard spinal radiographs often demonstrate normal results in the early stages of these lesions. In Kozlowski and coworkers’

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review220 of 16 children, 13 had Ewing’s sarcoma, and the other 3 each had an osteoblastoma, hemangiopericytoma, and a chordoma, respectively.

surgery in children and adolescents were good, a reoperation was required in 10% to 25% of cases.208,211

Scoliosis Primary spinal scoliosis surgery also predisposes to the occurrence of pediatric LSRs. A 29% incidence of postoperative LSRs was reported.221 EMG signs of myotomal weakness (not otherwise defined) were found in 4 of 14 children (mean age, 16 years). Fifty percent of these lesions were related to direct surgical trauma. The remaining LSRs occurred secondary to traction within the lumbosacral area.

SUMMARY AND OVERVIEW

Pediatric Gynecologic Lesion Mimicking an LSR A 12-year-old girl who had not begun to menstruate presented with symptoms mimicking an LSR characterized by 8 months of intermittent, low back and right sacroiliac pain. She then had 6- to 8-week symptom-free intervals only to once again have a recurrence. This interfered with sleeping and sitting but was relieved by bending forward or lying on the side. Examination demonstrated typical findings of an L5 radiculopathy. Additionally, a gynecologic evaluation demonstrated no vaginal opening. Pelvic ultrasonography showed a 13 × 10 cm mid-pelvic mass. At surgery this proved to be a congenital absence of the lower one third of the vagina. A vaginoplasty released 750 mL of menstrual fluids. Her low back pain was relieved immediately. Six months later, all signs of an L5 radiculopathy disappeared.222 The dilated imperforate vagina with the hematometra was thought to have compressed the LSP, mimicking a nerve root lesion. Noting that only about half of the referrals to an orthopedic children’s hospital outpatient clinic proved to have spinal disease and that no diagnosis was reached in the other children, Deathe222 suggested that pelvic ultrasonography needs to be part of the evaluation of indeterminate back pain and lumbar radiculopathy, especially in adolescent girls. This is especially pertinent noting that the incidence of this type of congenital anomaly is about 1 in 5000 phenotype females.

Therapy Conservative management is usually quite successful for the treatment of adolescents and children with LSRs. At Mayo fewer than 1 in 25 children who had lumbar disk disease required surgery.208 In contrast, a significantly higher percentage of Australian adolescents with disk disease (30 [35%] of 87) required surgery.223 Only 40% of Japanese children initially improved with conservative therapy; however, even then their symptoms tended to recur on return to school.211 Although results of LSR disk

In the adolescent population lumbosacral disk disorders are relatively uncommon.212 The presentation in children is often different from that in the adult. It is important for the clinician to always add this diagnosis to the differential and to consider the possibility of LSR and/or one of the more unusual conditions that may mimic a radiculopathy. Summary points include the following: • MRI provides an excellent anatomic correlation. • EMG cannot exclude a radiculopathy. • Back and leg pain in children and adolescents is most likely related to an LSR. However, one must always exclude a primary vertebral or disk space infection, spinal or nerve root tumor, other intraspinal pathology, or, in adolescent girls, an imperforate vagina.

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142. Roos DB: Thoracic outlet syndrome is underdiagnosed. Muscle Nerve 1999;22:126-129. 143. Wilbourn AJ: The thoracic outlet syndrome is overdiagnosed. Arch Neurol 1990;47:328-330. 144. Wilbourn AJ: Thoracic outlet syndrome is overdiagnosed. Muscle Nerve 1999;22:130-136. 145. Ouvrier RA, McLeod JG, Pollard JD: Peripheral Neuropathy in Childhood. New York, Mac Keith, 1990. 146. Lucas JW, Holden KR, Purohit DM, Cure JK: Neonatal hemangiomatosis associated with brachial plexus palsy. J Child Neurol 1995;10:411-413. 147. Sadleir LG, Connolly MB: Acquired brachial plexus neuropathy in the neonate: A rare presentation of late-onset group-B streptococcal osteomyelitis. Dev Med Child Neurol 1998;40:496-499. 148. Harila-Saari AH, Vainionpaa LK, Kovala TT, et al: Nerve lesions after therapy for childhood acute lymphoblastic leukemia. Cancer 1998;82:200-207. 149. Alessandri AJ, Pritchard SL, Massing BG, et al: Misleading leads: Bone pain caused by isolated paraspinal extramedullary relapse of childhood acute lymphoblastic leukemia. Med Pediatr Oncol 1999;33:113-115. 150. Inoue M, Kawano T, Matsumura H, et al: Solitary benign schwannoma of the brachial plexus. Surg Neurol 1983;20:103-108. 151. Sethna NF: Complex regional pain syndromes I and II (reflex sympathetic dystrophy). In Jones HR, De Vivo D, Darras B (eds): Neuromuscular Disorders of Infancy, Childhood, and Adolescence. Philadelphia, Butterworth Heinemann Health, 2003, pp 1185-1197. 152. Barquet A: Traumatic anterior dislocation of the hip in childhood. Injury 1982;13:435-440. 153. Chad DA, Bradley WG: Lumbosacral plexopathy. Semin Neurol 1987;7:97-107. 154. Chiou-Tan FY, Kemp K, Elfenbaum M, et al: Lumbosacral plexopathy in gunshot wounds and motor vehicle accidents: Comparison of electrophysiologic findings. Am J Phys Med Rehabil 2001;80:280-285. 155. Christie J, Jamieson EW: Traction lesion of the lumbosacral plexus. J R Coll Surg Edinb 1974;19:384-385. 156. Egel RT, Cueva JP, Adair RL: Posttraumatic childhood lumbosacral plexus neuropathy. Pediatr Neurol 1995;12:62-64. 157. Jellis JE, Helal B: Childhood sciatic palsies: Congenital and traumatic. Proc R Soc Med 1970;63:655-656. 158. Kline DG, Kim D, Midha R, et al: Management and results of sciatic nerve injuries: A 24-year experience. J Neurosurg 1998;89:13-23. 159. Kim DH, Murovic JA, Tiel R, Kline DG: Management and outcomes in 353 surgically treated sciatic nerve lesions. J Neurosurg 2004;101(1):8-17. 160. Marra TA: Recurrent lumbosacral and brachial plexopathy associated with schistosomiasis. Arch Neurol 1983;40:586-587. 161. Rai SK, Far RF, Ghovanlou B: Neurologic deficits associated with sacral wing fractures. Orthopedics 1990;13:1363-1366.

Plexopathies and Nerve Root Lesions 162. Switzer JA, Nork SE, Routt ML: Comminuted fractures of the iliac wing. J Orthop Trauma 2000;14:270-276. 163. Stoehr M: Traumatic and postoperative lesions of the lumbosacral plexus. Arch Neurol 1978;35:757-760. 164. Gabreels-Festen AA, Gabreels FJ, Joosten EM, et al: Hereditary neuropathy with liability to pressure palsies in childhood. Neuropediatrics 1992;23:138-143. 165. Galan E, Kousseff BG: Peripheral neuropathy in EhlersDanlos syndrome. Pediatr Neurol 1995;12:242-245. 166. Evans BA, Stevens JC, Dyck PJ: Lumbosacral plexus neuropathy. Neurology 1981;31:1327-1330. 167. Thomson AJ: Idiopathic lumbosacral plexus neuropathy in two children. Dev Med Child Neurol 1993;35:258-261. 168. Pasternak JF, Volpe JJ: Lumbosacral lipoma with acute deterioration during infancy. Pediatrics 1980;66:125-128. 169. MacDonald NE, Marcuse EK: Neurologic injury after vaccination: Buttocks as injection site. Can Med Assoc J 1994;150:326. 170. MacDonald NE: Does immunization in the buttocks cause sciatic nerve injury? Pediatrics 1994;93:351. 171. Marin R, Bryant PR, Eng GD: Lumbosacral plexopathy temporally related to vaccination. Clin Pediatr 1994;33:175-177. 172. Villarejo FJ, Pascual AM: Injection injury of the sciatic nerve (370 cases). Childs Nerv Syst 1993;9:229-232. 173. Bye A, Fagan E: Nerve conduction studies of the sural nerve in childhood. J Child Neurol 1988;3:94-99. 174. Dumitru D: Lumbosacral Plexopathies and Proximal Mononeuropathies: Electrodiagnostic Medicine. Philadelphia, Hanley & Belfus, 1995, pp 643-688. 175. Hope EE, Bodensteiner JB, Thong N: Neonatal lumbar plexus injury. Arch Neurol 1985;42:94-95. 176. Eng GD: Neuromuscular disease. In Avery GB, Fletcher MA, Macdonald MG (eds): Neonatology: Pathophysiology and Management of the Newborn. Philadelphia, WB Saunders, 1981, pp 989-992. 177. Volpe JJ: Injuries of extracranial, cranial, intracranial, spinal cord, and peripheral nervous system structures. In Neurology of the Newborn. Philadelphia, JB Lippincott, 1987, pp 638-658. 178. Awerbuch G, Levin GR, Dabrowski E: Lumbosacral plexus neuropathy of children. Ann Neurol 1989;26:452. 179. Awerbuch GI, Nigro MA, Dabrowski E, Levin JR: Childhood lumbosacral plexus neuropathy. Pediatr Neurol 1989;5:314-316. 180. Chin CH, Chew KC: Lumbosacral nerve root avulsion. Injury 1997;28:674-678. 181. Verstraete KL, Martens F, Smeets P, et al: Traumatic lumbosacral nerve root meningoceles: The value of myelography in the assessment of nerve root. Neuroradiology 1989;31:425-429. 182. Barnett HG, Connolly ES: Lumbosacral nerve root avulsion: Report of a case and review of the literature. J Trauma 1975;15:532-535. 183. Kolawole TM, Hawass ND, Shaheen MA, et al: Lumbosacral plexus avulsion injury: Clinical, myelographic, and computerized features. J Trauma 1988;28:861-865.

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184. Huittinen VM: Lumbosacral nerve injury in fracture of the pelvis: A postmortem radiographic and patho-anatomical study. Acta Chir Scand Suppl 1972;429:3-43. 185. Young NL, Davis RJ, Bell DF, Redmond DM: Electromyographic and nerve conduction changes after tibial lengthening by the Ilizarov method. J Pediatr Orthop 1993;13:473-477. 186. Jones HR, Gianturco LE, Gross PT, Buchhalter J: Sciatic neuropathies in childhood: A report of ten cases and review of the literature. J Child Neurol 1988;3:193-199. 187. Yuen EC, Olney RK, So YT: Sciatic neuropathy: Clinical and prognostic features in 73 patients. Neurology 1994;44:1669-1674. 188. Gertzbein SD, Evans DC: Femoral nerve neuropathy complicating iliopsoas haemorrhage in patients. J Bone Joint Surg Br 1972;54-B:149-151. 189. Brown JA, Braun MA, Namey TC: Pyriformis syndrome in a 10-year-old boy as a complication of operation with the patient in the sitting position. Neurosurgery 1988;23:117-119. 190. Beausoleil JL, Nordgren RE, Modlin JF: Vaccine-associated paralytic poliomyelitis. J Child Neurol 1994;9:334-335. 191. David W, Doyle J: Acute Infantile Weakness: A case of vaccine associated poliomyelitis. Muscle Nerve 1997;20:747-749. 192. Goldstein J: Infantile poliomyelitis in a recently immunized baby seen at Yale. Personal Communication, 1995. 193. Revuelta R, De Juambelz PP, Fernandez B, Flores JA: Lumbar disc herniation in a 27-month-old child: Case report. J Neurosurg 2000;92:98-100. 194. Haig AJ: The prevalence of lumbar paraspinal spontaneous activity in asymptomatic subjects. Muscle Nerve 1996;19:1503-1504. 195. Wilbourn AJ: Electrodiagnosis of plexopathies. Neurol Clin 1985;3:511-529. 196. Wilbourn AJ, Aminoff MJ: AAEM minimonograph 32: The electrodiagnostic examination in patients with radiculopathies. American Association of Electrodiagnostic Medicine. Muscle Nerve 1998;21:1612-1631. 197. Eisen A: The utility of proximal nerve conduction in radiculopathies: The cons. Electroencephalogr Clin Neurophysiol 1991;78:171-172. 198. Colon AJ, Vredeveld JW, Blaauw G, et al: Extensive somatosensory innervation in infants with obstetric brachial palsy. Clin Anat 2003;16:25-29. 199. Burke D, Adams RW, Skuse NF: The effects of voluntary contraction on the H reflex of human limb muscles. Brain 1989;112:417-433. 200. Radhakrishnan K, Litchy WJ, O’Fallon WM, Kurland LT: Epidemiology of cervical radiculopathy: A populationbased study from Rochester, Minnesota, 1976 through 1990. Brain 1994;117:325-335. 201. Infante J, Garcia A, Combarros O, et al: Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion. Muscle Nerve 2001;24:1149-1155. 202. Stogbauer F, Young P, Kerschensteiner M, et al: Recurrent brachial plexus palsies as the only clinical expression of

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32 Focal Neuropathies in Children KEVIN J. FELICE AND H. ROYDEN JONES, JR.

Mononeuropathies in children are uncommon, accounting for less than 10% of pediatric referrals for electroneuromyography testing.1-3 This is in contrast to mononeuropathies in adults, which account for about 30% of electromyogram (EMG) referrals. The particular nerve involvement also distinguishes focal neuropathies in children from those in adults. In children, nerve involvement is nearly equal in distribution among the median, ulnar, radial, peroneal, and sciatic nerves, whereas in adults, median mononeuropathies, mainly due to carpal tunnel syndrome (CTS), account for 65% of focal neuropathies (Fig 32-1). The major reason for this is the much lower incidence of CTS in children. The mechanisms of nerve injury are another major difference between focal neuropathies in children and adults. Trauma is the most common injury type in children, accounting for 37% to 76% of cases. Traumatic injuries due to fractures and lacerations are a major cause of mononeuropathies in children, and many are related to sports injuries. Compression injuries are the second most common cause of pediatric mononeuropathies, whereas nerve entrapment injuries are relatively uncommon. In distinction, entrapment and compression injuries account for the majority of injuries in adults. The following sections discuss the diagnosis and management of focal neuropathies in children. The reader should also supplement this material by referring to larger texts dedicated to the topics of pediatric EMG and focal neuropathies.3,4

MEDIAN NERVE Anatomy The median nerve is formed in the axilla by branches of the lateral and medial cords of the brachial plexus (Fig. 32-2).4 In the forearm, the median nerve innervates the pronator teres (C6-7), flexor carpi radialis (C6-7), palmaris longus (C7-T1) and flexor digitorum superficialis (C7-8). The anterior interosseous nerve, a primarily motor nerve, separates from the main trunk of the median nerve in the upper forearm and travels distally to innervate the lateral head of the flexor digitorum profundus (C7-8), flexor pollicis longus (C7-8), and pronator quadratus (C7-8). In the lower forearm, the median nerve gives off the palmar cutaneous branch. The main trunk then enters the wrist and travels through the carpal tunnel. Distal to the carpal tunnel, the median nerve divides into sensory and motor terminal branches. The motor branch supplies the first and second lumbricals (C8-T1) in the palm; in addition, a recurrent thenar motor branch supplies the abductor pollicis brevis (C8-T1), opponens pollicis (C8-T1), and superficial head of the flexor pollicis brevis (C8-T1). The terminal sensory branches supply sensation to the thumb, index and middle fingers, and the lateral aspect of the ring finger. Proximal median nerve injuries are associated with weakness and sensory loss in the entire distribution of the nerve, whereas distal injuries (e.g., CTS) usually cause restricted

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70 60 50 40 % 30 20 10 0 Median

Ulnar

Radial

Sciatic

Peroneal

Other

FIGURE 32–1 Distribution of mononeuropathies in 113 pediatric and 712 adult patients. The solid bar represents pediatric patients.

involvement in the distribution of the terminal motor and sensory nerves.

Etiology Distal Median Mononeuropathies Carpal Tunnel Syndrome. The causes of distal median mononeuropathies are shown in Box 32-1. In young children, CTS is uncommon and, when present, is usually associated with an underlying disorder. In a recent large epidemiologic study of CTS in the general population over a 2-year period in Marshfield, Wisconsin, the diagnosis of probable or definite CTS was made in 309 patients.5 Of these, seven (2.3%) were children, younger than 17 years of age, establishing an incidence rate of 0.26 per 1000 personyears. The specific pediatric ages in this large study were not reported. However, case reports have documented CTS in infants with a positive family history of the disorder6 and in children as young as age 2 years with mucopolysaccharidosis type IV.7 Idiopathic CTS is more common in older children and teens.3,8 The symptoms of CTS in older children are similar to those of adults and include bilateral hand pain and numbness, occasional radiating pain into the upper arm and shoulder, nocturnal tingling in the fingers, morning hand paresthesia, and worsening of symptoms with certain activities (e.g., skiing, computer games).3 Clinical signs may be absent or range in severity from mild sensory loss in the distribution of the median nerve (usually sparing the palm) to thenar muscle weakness and atrophy. In infants and small children with CTS, the signs may include reduced movements of the fingers and insensitivity to pain.3,6

FIGURE 32–2 Diagram of the median nerve and the muscles that it supplies. (Courtesy of Lahey Clinic, Burlington, MA.)

Predisposing factors in pediatric CTS include congenital canal stenosis (e.g., familial CTS),6,9-12 wrist trauma or injuries,3,13,14 thickening of the flexor retinaculum (e.g., mucopolysaccharidoses, mucolipidoses, trigger finger),7,15-19 repetitive hand and wrist movements (e.g., sports related, work related, cerebral palsy with dystonic hand movements),3,13,15,20,21 tenosynovitis (e.g., scleroderma, rubella),3,22 Schwartz-Jampel syndrome,23 hereditary neuropathy with liability to pressure palsies (HNPP),24 pyogenic infections,25 and juvenile chronic arthritis.26 CTS has also been associated with Poland’s syndrome.27 In addition to CTS, distal median mononeuropathies may result from congenital constriction bands,28 hematoma from blood gas determination,29 compression from a cast,13 compression from a calcified flexor digitorum tendon,30 and secondary to burns at the wrist.31

Focal Neuropathies in Children

BOX 32-1 CAUSES OF DISTAL MEDIAN MONONEUROPATHIES Carpal tunnel syndrome Idiopathic Activity related (e.g., skiing, bicycling, golfing, computer games) Trauma Inborn errors of metabolism (e.g., mucopolysaccharidoses, mucolipidoses) Scleroderma Poland’s syndrome Cerebral palsy with dystonic hand movements Schwartz-Jampel syndrome Trigger finger Lipofibromatous hamartoma Rubella Hereditary neuropathy with liability to pressure palsies Familial carpal tunnel syndrome Other distal median mononeuropathies Hematoma (e.g., radial artery puncture) Constriction bands Compression from cast

Thenar Atrophy. Thenar atrophy is an unusual manifestation of CTS in children. Rare cases of thenar atrophy have been associated with inborn errors of metabolism, pseudoneuroma of the median nerve, congenital constriction bands, foreshortened index finger, and trigger finger.3 In the latter two conditions, the median nerve appears to be compressed by idiopathic thickening of the flexor retinaculum. These conditions are usually associated with concomitant involvement of the median sensory fibers. In distinction, Cavanaugh’s syndrome, a hypoplastic disorder of the thenar muscles and hand bones, is not associated with median nerve compression or sensory fiber involvement.32 Proximal Median Mononeuropathies Overview. The causes of proximal median mononeuropathies are shown in Box 32-2. Trauma is the most common cause of proximal median nerve injuries in children. In the Children’s Hospital Boston (CHB) series of 17 patients, 10 (59%) developed median mononeuropathies as a direct result of limb trauma.13 Bone fractures seem to be the most common cause of nerve trauma. Median nerve compression, entrapment, or laceration injuries have resulted from traumatic fractures of the supracondylar humerus, midradius, and radioulnar joint. Most of these injuries involve

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BOX 32-2 CAUSES OF PROXIMAL MEDIAN MONONEUROPATHIES Trauma Fractures Blunt nerve trauma Lacerations Trauma following arterial or venous puncture Entrapment Ligament of Struthers Fibromuscular bands Pronator syndrome Bicipital aponeurosis Tumors Lipofibromas Hamartomas Neurofibromas Hemangiomas Other Osteoid osteoma Juvenile cutaneous mucinosis Abscess Idiopathic Calcified flexor digitorum superficialis tendon

the main trunk of the median nerve; however, the anterior interosseous nerve may also be traumatized in isolation as the result of a supracondylar fracture.33 Traumatic median nerve injuries have also resulted from elbow dislocations, lacerations, blunt nerve trauma from athletic activities, and trauma inflicted by arterial or venous puncture.3,29,34,35 Entrapment. Rarely, the median nerve may be entrapped by an osteoid osteoma,13 the ligament of Struthers,16 congenital fibromuscular bands,27,35-37 pronator teres,38,39 and bicipital aponeurosis.40 The ligament of Struthers, a fibrous band extending from a small supracondylar spur to the medial epicondyle of the humerus, forms the roof of a tunnel through which the median nerve and brachial artery pass. Despite the common occurrence of the spur, visible on plain radiograph in about 2% of the population, the ligament of Struthers is a rare cause of median nerve entrapment.4 In pronator syndrome, the median nerve is entrapped by the hypertrophied heads or thickened tendinous bands of the pronator teres muscle. Given that involvement is distal to the motor branch innervating the pronator teres, this muscle is usually not involved; this is in distinction to more proximal median lesions (e.g., ligament of Struthers entrapment). Congenital constriction bands may cause proximal

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median nerve entrapment injuries, occasionally with concurrent involvement of the radial and ulnar nerves.28 Miscellaneous Median Nerve Lesions The proximal and distal segments of the median nerve have also been damaged secondary to contiguous lipofibromas,41,42 hamartomas,43 neurofibromas,44 and hemangiomas.45 Other causes of median nerve pediatric median mononeuropathy include juvenile cutaneous mucinosis,3 calcified flexor digitorum superficialis tendon,30 and abscess.25 Anterior interosseous neuropathy has been reported in several children, either of spontaneous onset due to probable brachial neuritis33,46 or associated with supracondylar fractures of the humerus.46,47

Evaluation EMG Our EMG evaluation of the median nerve in infants and small children includes a sensory nerve action potential (SNAP) from either the index or middle finger, compound muscle action potential (CMAP) from the thenar muscles, median motor conduction velocity across the forearm segment, comparative ulnar sensory and motor conduction studies, and needle examination of the minimal number of necessary muscles. In older children with mild symptoms, the examination should also include median and ulnar mixed nerve action potentials (MNAPs), or “palmar” studies. Distal Median Nerve Lesions. In cases of mild CTS, one may expect to find prolonged peak latencies of the median MNAP and SNAP. Prolongation of the median CMAP distal latency and attenuation of the SNAP amplitude indicate more moderate disease. Severe CTS is associated with an absent or attenuated thenar CMAP and needle examination abnormalities indicating both active (e.g., fibrillations, positive sharp waves) and chronic (e.g., large and polyphasic motor unit action potentials) changes of denervation and reinnervation in the abductor pollicis brevis. Proximal Median Nerve Lesions. The distal latencies are usually normal although mild prolongation of the median SNAP latency is occasionally reported in some of these lesions.13 In contrast, conduction velocities across the forearm segment may be reduced with demyelinating injuries. Needle examination abnormalities often extend into median-innervated forearm muscles with axonal or mixed injuries. Congenital Thenar Hypoplasia (Cavanaugh’s Syndrome). The CMAP is of low amplitude or absent, whereas the median SNAP amplitude and peak latency are normal. Thenar motor unit action potentials are reduced in number without associated denervation potentials.

Other Studies The clinical findings and EMG results may dictate the need for additional studies in the evaluation of median mononeuropathies. Magnetic resonance imaging (MRI) may offer more precise anatomic assessment of suspected soft tissue infiltrative or compressive lesions, especially with symptoms of slowly progressive dysfunction or with signs of palpable focal tenderness or fullness.3,4 Plain roentgenograms of the hand may be indicated in suspected cases of congenital thenar hypotrophy to assess for hypoplastic changes of hand bones.32 In suspected cases of ligament of Struthers entrapment, radiographs of the distal humerus are useful to identify the bony spur often seen in that disorder. Metabolic studies for the mucopolysaccharidoses and mucolipidoses are indicated in suspected cases of CTS associated with dysmorphic features, organomegaly, and other system disease.

Treatment and Prognosis Traumatic mononeuropathies require prompt attention. EMG studies are usually employed initially following trauma to assess for nerve continuity, characterize the injury type (e.g., axonal, demyelinating, or mixed), and predict a prognosis for recovery. Within 9 to 11 days following acute axonal injury, wallerian degeneration is complete,48 and EMG studies are recommended at this point in cases with severe dysfunction or when nerve function cannot be assessed clinically due to other factors related to the trauma (e.g., immobilization, casting).49 In neuropraxia (focal demyelinating injury), the distal median SNAP and CMAP are preserved; however, stimulation proximal to the site of injury evokes an attenuated or absent response, that is, a partial or complete conduction block. With mild or moderate axonotmesis (axonal injury), the distal SNAP and CMAP are attenuated or absent. Two to 3 weeks following an axonal injury, the needle examination reveals fibrillations and positive sharp waves in medianinnervated muscles distal to the site of injury. In severe axonotmesis or when there is total lack of continuity of the peripheral nerve, neurotmesis occurs. In this setting the distal median SNAP and CMAP are absent. Because nerve continuity may be uncertain in some of these cases, early surgical exploration and, if necessary, repair is usually recommended. Quite often, EMG findings indicate both demyelinating and axonal features (mixed nerve injury) in traumatic nerve injuries. In cases with preserved continuity and slow return of function, periodic EMG evaluation may be helpful in understanding the dynamics of nerve regeneration, collateral sprouting, and muscle reinnervation.

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Treatment in mild idiopathic and activity-related CTS should be focused on conservative measures and avoidance of compromising hand positions and activities such as occurred with a high school ski racer whose symptoms cleared by changing the manner in which he held his ski poles. Median nerve decompression surgery should be reserved for patients with continued or progressive symptoms refractory to conservative measures or when the EMG study indicates axon–loss. Surgical decompression is indicated in distal median mononeuropathies associated with the inborn errors of metabolism, pseudoneuroma, trigger finger, and congenital constriction bands. Distal mononeuropathies related to trauma or activity may improve with conservative therapy only. Surgical decompression usually affords some improvement in symptoms and function, with ultimate recovery related to the degree of axonal loss. In general, children with median mononeuropathies tend to have a good prognosis. Of 17 CHB patients with various types of pediatric median mononeuropathies, 12 (70%) had documented improvement at follow-up.13 Improvement was noted with traumatic, compressive, and entrapment injuries. Poor prognosis was documented in 4 children, 2 with entrapment due to supracondylar fractures and 2 with CTS.13

CASE STUDY 1. A 6-year-old boy with Hunter’s syndrome (mucopolysaccharidosis type II) was noted to have weak thumb opposition and hand weakness. The neurologic examination was remarkable for reduced thumb movements and generalized hyporeflexia. Nerve conduction studies were remarkable for absent median SNAPs, low-amplitude median CMAPs, and prolonged median CMAP distal latencies on both sides (Fig. 32-3). The ulnar and sural sensory and ulnar and peroneal motor nerve conduction studies were normal. Needle EMG of the abductor pollicis brevis showed reduced insertional activity, no fibrillations or positive sharp waves, and absent recruitment of motor unit action potentials. It was unclear whether the absence of motor unit recruitment was due to poor recruitment from chronic denervation or poor activation due to discomfort. Comments The EMG findings showed evidence of severe bilateral median mononeuropathies, localized at the wrist/palm segments, and were consistent CTS. The association between CTS and the mucopolysaccharidoses is well known. Thickening of the flexor retinaculum causes compression of the median nerve within the narrow confines of the

carpal tunnel. Such cases should be considered for surgical treatment.

CASE STUDY 2. A 12-year-old girl developed left hand weakness and numbness following a left supracondylar elbow fracture 2 months prior to the EMG study. The neurologic examination revealed marked weakness and atrophy of the thenar muscles; weakness of the flexor digitorum profundus of digit 2 and flexor pollicis longus; and light touch sensory loss along the palmar aspect of the lateral hand, thumb, and index and middle fingers. Nerve conduction studies revealed an absent left median SNAP and low-amplitude median CMAP (i.e., 0.6 mV) from the thenar muscles. The median motor conduction velocity across the forearm segment was preserved at 50 m/sec. Other nerve conduction studies including left ulnar and radial sensory, and right median and left ulnar motor were normal. Needle examination showed increased insertional activity, sustained fibrillations and positive sharp waves, and absent recruitment of motor unit action potentials from the left abductor pollicis brevis and flexor pollicis longus. Needle examination of the left pronator teres, first dorsal interosseous, and extensor indicis was normal. Comments The EMG findings showed evidence of a severe axon-loss median mononeuropathy, localized proximal to the innervation of the flexor pollicis longus (forearm segment), consistent with a traumatic nerve injury. The preserved, albeit low-amplitude, median CMAP was evidence for nerve continuity. Based on these findings, the referring physician opted for conservative therapy and follow-up clinical assessments.

ULNAR NERVE Anatomy The ulnar nerve is derived from the medial cord of the brachial plexus (C8-T1) (Fig. 32-4).4 In the forearm, the ulnar nerve innervates the flexor carpi ulnaris (C8-T1) and the medial head of flexor digitorum profundus (C8-T1). Prior to reaching the hand, the ulnar nerve gives off the palmar and dorsal cutaneous branches in the lower forearm. At the wrist, the nerve enters Guyon canal and then bifurcates into the superficial and deep branches. The superficial branch innervates the palmaris brevis muscle (C8-T1) and then becomes the terminal sensory nerves, which supply

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A

B

FIGURE 32–3 Nerve conduction studies for Case Study 1. A, The median motor nerve conduction study with stimulation at the wrist (waveform 1) and elbow (waveform 2) is compared to the ulnar study with stimulation at the wrist (waveform 3) and below elbow segment (waveform 4). Note the low-amplitude median compound muscle action potentials and prolonged median distal latency. B, The median to second lumbrical motor nerve conduction study is compared to the ulnar to interosseous study. For both, stimulation is at the wrist at a fixed distance of 70 mm. Note the comparative distal latency difference of 0.8 mm (normal, < 0.5 mm). DL, distal latency; CV, conduction velocity.

sensation to the fifth digit and medial aspect of the ring finger. The deep branch supplies the hypothenar muscles (C8-T1), including the abductor digiti minimi, opponens digiti minimi, and flexor digiti minimi, then curves along the palm providing motor branches to the third and fourth lumbricals (C8-T1), the four dorsal and three palmar interossei (C8-T1), adductor pollicis (C8-T1), and the deep head of the flexor pollicis brevis (C8-T1).

Etiology Trauma The most common cause of ulnar mononeuropathy in children is trauma (Box 32-3). Of the 21 CHB pediatric ulnar mononeuropathy cases described in 1996, 11 (52%) resulted directly from nerve trauma.50 Proximal ulnar mononeuropathies due to trauma resulted from supracondylar fracture, medial epicondylar fracture, forearm

fracture, elbow laceration, stab wound, and an elbow puncture wound. Distal radial fractures are a cause of ulnar mononeuropathies at the wrist. Fractures and dislocations may cause nerve damage via blunt injury, entrapment, compression, or laceration.51 The ulnar nerve may also be damaged as the result of surgery to repair an elbow or forearm fracture. Delayed or “tardy” ulnar nerve palsy is described in children following elbow trauma, presumably due to post-traumatic bony changes and fibrosis.8 Entrapment The cubital tunnel syndrome was a surgically documented cause of entrapment in two children in our series.50 A third case of presumed cubital tunnel syndrome occurred in an 18-year-old hockey goalie during one season when he carried heavy goalie pads with his arm in flexion; the symptoms improved at the end of the season. Other causes of ulnar nerve entrapment include a persist-

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BOX 32-3 CAUSES OF ULNAR MONONEUROPATHIES

FIGURE 32–4 Diagram of the ulnar nerve and the muscles that it supplies. (Courtesy of Lahey Clinic, Burlington, MA.)

ent epitrochleoanconeus muscle52 and congenital constriction bands.28 Compression Five children at CHB suffered from compressive ulnar mononeuropathies.50 Of these, two had compressive mononeuropathies at the elbow during surgical procedures, one developed a transient sleep palsy restricted to the dorsal cutaneous branch, one had bilateral compressive mononeuropathies at the forearm or elbow due to wheelchair rests, and one had compression at the wrist from bicycle hand rests. The ulnar nerve may be compressed from a weightlifting bar53 and bicycle hand rests.54 Miscellaneous Mechanisms Other causes of ulnar mononeuropathies include leprosy,55 hemorrhage in hemophilia,56 extravasation of intra-

Trauma Fractures—supracondylar, medial epicondylar, forearm, distal radial Lacerations, puncture and stab wounds Blunt trauma Superficial burns Repetitive throwing movements Nerve ischemia Entrapment Cubital tunnel syndrome Persistent epitrochleoanconeus muscle Congenital constriction bands Compression Surgical compression Wheelchair arm rests Bicycle hand rests Weightlifting bar Hemorrhage related to hemophilia Infiltration of intravenous fluids Compartment syndrome Following fracture or dislocation Tumors Hamartomas Neurofibromas Neurilemomas Other Leprosy Focal hypertrophic neuropathy Recurrent dislocation Hereditary neuropathy with liability to pressure palsies

venous fluids with subsequent compartment syndrome,57 focal hypertrophic neuropathy,58 burns,59 repetitive throwing injuries in baseball pitchers,60 tumors,61 and hamartomas.62

EMG Evaluation Our EMG evaluation of the ulnar nerve includes an ulnar SNAP from the small finger; ulnar motor nerve conduction studies from the hypothenar muscles; motor conduction velocities across the forearm and elbow segments; comparative median sensory and motor nerve conduction studies; and needle examination of the first dorsal interosseous, abductor digiti minimi, and flexor carpi ulnaris muscles. Occasionally, ulnar motor nerve conduction studies recorded from the first dorsal interosseous provide additional information as to the degree of conduction abnormalities at

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the wrist or elbow segments.63 The addition of the dorsal ulnar cutaneous SNAP may help in differentiating between ulnar lesions at the wrist and elbow. Also, the medial antebrachial cutaneous SNAP may help exclude brachial plexus involvement in selected cases. Ulnar mononeuropathies localized at the wrist or hand may involve the terminal motor branch, proximal or distal to the innervation of the hypothenar muscles, the terminal sensory branch, or both. These lesions spare the dorsal ulnar cutaneous SNAP and are associated with preserved motor conduction velocities across the elbow segment. Demyelinating ulnar mononeuropathies at the elbow segment are associated with focal motor conduction block or conduction slowing; axonal mononeuropathies with absent or attenuated distal SNAP and CMAP amplitudes, and evidence of variable changes of denervation and reinnervation on needle examination of ulnar hand and forearm muscles; and mixed injuries with combination of demyelinating and axonal features.

EMG study, following weightlifting exercises. The exercises consisted of several sets of bench presses with a heavy bar held in the palms. There was no pain or sensory loss. The neurologic examination was remarkable for moderate weakness without atrophy of the right palmar and dorsal interossei, lumbrical of fingers 4 and 5, and adductor pollicis; mild weakness of right hypothenar muscles; normal thenar, forearm, and upper arm muscle strength; normal and symmetric reflexes; and a normal sensory examination. The right median, ulnar, and medial antebrachial cutaneous SNAPs were normal. The right median motor nerve conduction studies were normal. The right ulnar CMAPs from the hypothenar and first dorsal interosseous muscles showed prolonged distal latencies and reduced amplitudes. Ulnar motor conduction velocities across the elbow segment were normal. Stimulation of the right ulnar nerve at the palm and wrist sites, distal and proximal to the suspected injury, revealed severe partial conduction block of 85% and conduction velocity slowing across the wrist/ palm segment (Fig. 32-5). Needle EMG of the abductor

Treatment and Prognosis EMG is useful for deciding on the appropriate management of pediatric ulnar mononeuropathies. This includes nerve decompression and repair of fractures following trauma, surgical nerve repair and grafting following nerve lacerations and severe traumatic injuries, resection of compressive masses and tumors, nerve decompression in cubital tunnel syndrome, and nerve transposition and decompression with progressive lesions localized at the elbow segment. Twelve surgical procedures were performed at CHB among 21 children with ulnar mononeuropathy: five to repair acute fractures and lacerations, two to decompress the nerve in cubital tunnel, one to decompress the nerve following a medial epicondylar fracture, one transposition surgery, two resections of neuromas, and one nerve graft procedure following a laceration.50 In the CHB series of 21 children with pediatric ulnar mononeuropathy, 15 (71%) were seen in follow-up (range 2 months to 6 years) after the initial evaluation.50 Followup examinations found that only 56% of children with traumatic versus 83% with nontraumatic ulnar mononeuropathies had a favorable outcome. Two children with cubital tunnel syndrome improved following ulnar nerve decompression and anterior transposition surgeries.

CASE STUDY 3. An 18-year-old high school senior complained of painless right hand weakness (i.e., inability to spread or fan his fingers).53 The symptoms began abruptly 2 weeks prior to the

FIGURE 32–5 Nerve conduction studies for Case Study 3. The right ulnar nerve is stimulated at the palm (waveform 1) and wrist (waveform 2) sites, distal and proximal to the suspected injury, with a recording electrode on the first dorsal interosseous muscle. Note the severe partial conduction block of 85% and conduction velocity slowing of 33 m/sec across the wrist/palm segment. Amp, amplitude; CV, conduction velocity.


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digiti minimi and first dorsal interosseous revealed markedly reduced recruitment of normal-appearing and faster-frequency motor unit action potentials. Fibrillations and positive sharp waves were not present. Comments The EMG findings were consistent with a severe demyelinating injury to the terminal motor branch of the right ulnar nerve, proximal to the innervation of the hypothenar muscles. We recommended that the patient discontinue weightlifting, and within 3 months his right hand strength returned to normal and the motor conduction block had completely resolved.53 This is the typical response to removal of an acute or recurrent source of nerve compression. This type of injury has been previously described with other types of activities, including long distance bicycling.

CASE STUDY 4. A 17-year-old girl complained of right hand numbness for the 2 months prior to the EMG study. The symptoms began soon after starting a part-time telemarketing job. During her work, she would lean on her right elbow for prolonged periods. She denied weakness or pain. The neurologic examination was remarkable for reduced light touch sensation along the medial right hand (dorsal and palmar surfaces), and fourth and fifth fingers. Muscle bulk, strength, and reflexes were normal. Bilateral ulnar and right median SNAPs and motor nerve conduction studies were normal. Right ulnar sensory nerve conduction studies showed conduction slowing and probable partial sensory conduction block across the elbow segment (Fig. 32-6). Needle examination of right ulnar-innervated hand muscles was normal. Comments The EMG findings showed evidence of an ulnar mononeuropathy at the elbow segment due to a mild demyelinating injury to sensory fibers. The clinical and EMG findings suggested mild recurrent nerve compression from poor elbow positioning during her work. The symptoms completely resolved over the next several weeks following adjustments to her arm and elbow during subsequent telemarketing work.

RADIAL NERVE Anatomy The radial nerve is derived from the posterior cord of the brachial plexus (C5-8) (Fig. 32-7).4 It descends in the

FIGURE 32–6 Nerve conduction studies for Case Study 4. Right median (waveform 1), right ulnar (waveforms 2 to 4), and left ulnar (waveforms 5 to 7) sensory nerve action potentials (SNAPs) are shown. The ulnar SNAPs are recorded from the small finger with stimulation at the wrist (waveforms 2 and 5), below-elbow (waveforms 3 and 6), and above-elbow (waveforms 4 and 7) sites. Note the low-amplitude ulnar SNAP (arrow) with stimulation above the right elbow (waveform 4) as compared to the contralateral SNAP (waveform 7). The sensory conduction velocity across the right elbow segment is 47 m/sec (normal, > 53 m/sec).

upper arm between the long and medial heads of the triceps, posterior to the axillary artery. Proximal to the spiral groove, the radial nerve gives off the posterior cutaneous nerve of the arm, motor branches to the triceps (C6-8) and anconeus (C6-8), and posterior cutaneous nerve of the forearm. At the spiral groove, the nerve travels from the medial to the posterolateral aspect of the lower arm. Distal to the groove, the radial nerve innervates the brachioradialis (C5-6) and extensor carpi radialis longus (C5-6). Here this nerve bifurcates into superficial and deep branches. The superficial branch descends in the forearm under the brachioradialis prior to emerging in the distal forearm as the superficial sensory branch, supplying sensation to the posteromedial hand and first web space. The deep branch continues as the posterior interosseous nerve and enters the supinator muscle through an opening termed the arcade of Fröhse. Within the extensor compartment of the forearm, the posterior interosseous nerve innervates the supinator (C6-7), extensor carpi radialis

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BOX 32-4 CAUSES OF RADIAL MONONEUROPATHIES Trauma Fractures—Monteggia, supracondylar, lateral condylar Lacerations Injection injuries Arthroscopic elbow surgery Compression Neonatal Perioperative Compartment syndrome Sleep palsy Crutch palsy Tumors Lipomas Ganglia Fibromas Neuromas Hemangiomas Other Multiple septal entrapment Hereditary neuropathy with liability to pressure palsies FIGURE 32–7 Diagram of the radial and axillary nerves and the muscles that they supply. (Courtesy of Lahey Clinic, Burlington, MA.)

brevis (C5-7), extensor digitorum (C7-8), extensor digiti minimi (C7-8), extensor carpi ulnaris (C7-8), abductor pollicis longus (C7-8), extensor pollicis longus (C7-8), extensor pollicis brevis (C7-8), and extensor indicis (C7-8).

Etiology (Box 32-4) At CHB 8 (53%) of 15 children with radial mononeuropathies had traumatic injuries, 5 due to fractures and 3 due to lacerations.64 All of these were axon-loss injuries, 4 involving the main trunk of the radial nerve distal to the spiral groove and 1 involving the posterior interosseous nerve fibers only due to a supracondylar fracture. Of the lacerations, 2 involved the upper arm and the other involved the forearm. All were axon-loss injuries, including isolated posterior interosseous neuropathies in 2 cases and a distal radial neuropathy in the other. Others report radial nerve trauma due to injection injuries and arthroscopic elbow surgery.65 Compression Injuries In children the radial nerve is most susceptible to compression injury at the spiral groove segment. Compression

injuries of the radial nerve were documented in 6 (40%) of 15 children, including 2 neonatal and 4 postnatal injuries.64 Two of the 4 postnatal injuries were localized at the spiral groove segment, one a conduction block injury due to nerve compression sustained during surgery, and the other a mixed injury due to a sleep palsy. The other 2 postnatal compression injuries included a demyelinating posterior interosseous injury due to an acute compartment syndrome from infiltration of intravenously administered chemotherapy in a child with Hodgkin’s disease and bilateral axon-loss proximal trunk radial mononeuropathies due to improper use of crutches. Neonatal Radial Mononeuropathy Neonatal radial mononeuropathies occur with intrauterine compression by uterine contraction rings,66,67 prolonged labor,3 subcutaneous fat necrosis,68 and subcutaneous abscess or hematoma.69 At birth, the radial nerve may be injured by a humeral fracture, hematoma, blood pressure monitoring,70 and prolonged birth-related external compression.71 In HNPP, radial mononeuropathies may be the presenting feature. Up to 3% of HNPP patients younger than 10 years of age, including infants, have radial nerve involvement in the spiral groove of the humerus.72

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Entrapment One of our 15 children with radial nerve palsy, a 3-yearold girl, developed a progressive radial distribution weakness over the first 3 years of life.64 At surgical exploration the nerve resembled a string of sausages with multiple areas of tight compression. However, the microscopic specimen consisted of scar tissue related to entrapment within the interfascial septum and did not represent a tomaculous neuropathy. Entrapment of the radial nerve within the triceps muscle has also been reported.73,74 Miscellaneous The radial nerve may also be affected by benign tumors and other compressive lesions. These have included lipomas, ganglia, fibromas, neuromas, and hemangiomas.3

Evaluation Our EMG evaluation of the radial nerve includes a radial SNAP from the affected limb, comparative radial SNAP from the unaffected limb (or ipsilateral median SNAP if both limbs are affected), and needle EMG of upper arm (e.g., triceps) and forearm (e.g., brachioradialis) radialinnervated muscles, and a muscle innervated by the posterior interosseous nerve (e.g., extensor indicis). Radial motor nerve conduction studies are technically difficult in neonates and small children. In older children, we find the radial motor study, recorded from the extensor indicis and stimulated at three sites (forearm, below and above spiral groove), to be relatively easy to perform and reliable in demonstrating conduction abnormalities across the spiral groove segment. Pure demyelinating injuries at the spiral groove segment are associated with motor conduction block, slowing or both; normal distal radial SNAPs and CMAPs; and reduced recruitment of motor unit action potentials without abnormal spontaneous activity in affected muscles. Axonal injuries are associated with absent or attenuated radial SNAPs and CMAPs and reduced recruitment of motor unit action potentials with fibrillations and positive sharp waves in affected muscles. Posterior interosseous neuropathies are associated with a normal radial SNAP, a low-amplitude or absent CMAP from the extensor indicis, and needle examination abnormalities limited to radial-innervated muscles distal to the supinator.

Treatment and Prognosis Traumatic Injuries Traumatic injuries related to fractures require prompt surgical repair. Early EMG studies are indicated with lacerations and fractures to assess for nerve continuity. An absent radial SNAP and CMAP distal to the site of injury at 9 to 11 days post-trauma indicates severe axonotmesis or neu-

rotmesis, raises the possibility of a radial nerve laceration or severe disruption, and warrants surgical exploration and, if necessary, nerve repair. Seven (88%) of the eight children with traumatic radial mononeuropathies at CHB improved or completely recovered within 7 to 17 months.64 A 6-yearold boy with a severe axon-loss posterior interosseous nerve injury following a supracondylar fracture showed no clinical improvement after 4 years. Compression Injuries Acute compression injuries at the spiral groove segment, usually associated with demyelinating or mixed nerve injuries, afford a more favorable prognosis for full recovery. All six cases of neonatal and postnatal radial mononeuropathies due to nerve compression injuries had complete recoveries at follow-up. Slowly progressive radial or posterior interosseous nerve dysfunction may require MRI studies and surgical exploration to search for possible tumors, fascial bands, or other sources of nerve compression or entrapment.

CASE STUDY 5. A 17-year-old boy awakened with a right wrist drop about 1 month prior to the EMG study. He denied prior medical or neurologic problems, neck or arm injuries, or pain. The neurologic examination revealed severe weakness without atrophy of the right brachioradialis, wrist extensors, and finger extensors. Triceps muscle bulk and strength were normal. There was reduced light touch and pinprick sensation along the dorsal aspect of the first web space between the right thumb and index finger. Nerve conduction studies revealed symmetrically normal radial SNAP amplitudes in the 24 to 28 μV range. The right radial to extensor indicis motor nerve conduction study showed partial conduction block and conduction velocity slowing across the upper arm (spiral groove) segment (Fig. 32-8). The right median, right ulnar, and left radial motor nerve conduction studies were normal. Needle examination was remarkable for slightly increased insertional activity, rare fibrillations and positive sharp waves, and markedly reduced recruitment of normal-appearing and faster frequency motor unit action potentials restricted to the right extensor indicis, extensor digitorum communis, and brachioradialis muscles. Needle examination of the triceps was normal. Comments The EMG findings were consistent with a right radial mononeuropathy, localized at the spiral groove segment, due to a demyelinating nerve injury. Despite the severity of the clinical findings, the EMG results predicted a complete recovery of function and, in fact, the follow-up examination

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BOX 32-5 CAUSES OF OTHER UPPER EXTREMITY MONONEUROPATHIES

FIGURE 32–8 Nerve conduction studies for Case Study 5. With a recording electrode over the extensor indicis muscle, the right radial nerve is stimulated at the forearm (waveform 1), below-spiral groove (waveform 2), and above-spiral groove (waveform 3) sites. Note the partial conduction block and conduction velocity slowing across the spiral groove segment. Amp, amplitude; CV, conduction velocity.

3 months later was normal. The cause of the injury was presumed to be nerve compression during sleep (sleep palsy).

OTHER UPPER EXTREMITY NERVES Axillary Nerve Along with the radial nerve, the axillary nerve is the other major derivation of the posterior cord of the brachial plexus and lies in close proximity to the surgical neck of the humerus (see Fig. 32-7).4 The major branches of the axillary nerve include motor branches to the deltoid and teres minor muscles (C5-6) and the lateral cutaneous nerve of the arm. Axillary nerve injuries cause weakness of arm abduction, deltoid muscle atrophy with severe axonal injuries, and sensory loss along the upper lateral arm. In children, axillary mononeuropathies are reported in sports-related shoulder trauma and exostosis of the humerus (Box 32-5).3,75 EMG evaluation of axillary mononeuropathies in children is usually limited to the needle examination of the deltoid muscle.

Axillary nerve Exostosis of the humerus Sports-related injuries Trauma Long thoracic nerve Milwaukee brace Trauma Sports-related injuries Idiopathic Musculocutaneous nerve Body cast Hereditary neuropathy with liability to pressure palsies Idiopathic Suprascapular nerve Entrapment within transverse ligament at suprascapular notch Compression by ganglion Trauma Thoracodorsal nerve Thoracotomy and chest tube insertion Spinal accessory nerve Surgical injury Hereditary neuropathy with liability to pressure palsies Idiopathic

Long Thoracic Nerve The long thoracic nerve originates from the C5-7 roots and descends in the axilla, posterior to the brachial plexus, to innervate the serratus anterior muscle, which anchors the scapula to the chest wall.4 Injuries to the long thoracic nerve cause winging of the scapula, especially with the arms in anterior abduction. Reported causes of long thoracic mononeuropathies (see Box 32-5) in children include sports-related injuries (e.g., tennis, weightlifting), shoulder trauma, compression from a Milwaukee brace, and idiopathic lesions.3,76,77 EMG evaluation is usually limited to the needle examination of the serratus anterior at its digitations over the ribs at the mid-axillary line.

Musculocutaneous Nerve The musculocutaneous nerve is derived from the lateral cord of the brachial plexus; innervates the biceps brachii,

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FIGURE 32–10 Diagram of the suprascapular nerve and the muscles that it supplies. (Courtesy of Lahey Clinic, Burlington, MA.)

locutaneous mononeuropathy was not previously identified since no known injury could be identified. The EMG evaluation of the musculocutaneous nerve may include the lateral antebrachial cutaneous SNAP, a biceps brachii CMAP, and needle examination of the biceps brachii and coracobrachialis.

Suprascapular Nerve

FIGURE 32–9 Diagram of the musculocutaneous nerve and the muscles that it supplies. (Courtesy of Lahey Clinic, Burlington, MA.)

brachialis, and coracobrachialis muscles (C5-6); and terminates as the lateral cutaneous nerve of the forearm (Fig. 32-9).4 Injuries to the musculocutaneous nerve are associated with weakness of arm flexion and sensory loss along the lateral forearm. Three cases reported in 1986 included a child with compression of the nerve by a body cast, another child with an idiopathic lesion causing biceps muscle atrophy, and a third child with isolated involvement of lateral antebrachial cutaneous nerve (see Box 32-5).71 One 16-year-old boy with painless right biceps weakness and atrophy was found to have a musculocutaneous mononeuropathy superimposed on a diffuse demyelinating sensorimotor polyneuropathy.24 The diagnosis of HNPP was later confirmed with DNA studies. The cause of the muscu-

The suprascapular nerve originates from the upper trunk of the brachial plexus and innervates the supraspinatus and infraspinatus (C5-6) muscles (Fig. 32-10).4 Injuries to this nerve cause shoulder abduction and external rotation weakness. Lesions to this nerve usually result from entrapment injuries or trauma (see Box 32-5). A 14-year-old girl sustained a blow to her shoulder as she stumbled in gymnastics and was later found to have entrapment of the nerve by the transverse ligament in the suprascapular notch.78 Other identified mechanisms of pediatric suprascapular mononeuropathies include sportsrelated injuries and compression by a ganglion cyst.79,80 The EMG evaluation includes needle EMG of the supraspinatus and infraspinatus muscles. In a cooperative child, one may consider obtaining CMAPs from both muscles with needle recording electrodes.

Thoracodorsal Nerve The thoracodorsal nerve is derived from the posterior cord of the brachial plexus and innervates the latissimus dorsi (C6-8).4 One of us (K.J.F.) recently evaluated an 8-year-old girl who developed right latissimus dorsi

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atrophy following insertion of a chest tube with subsequent development of a chest wall empyema (see Case Study 7). The authors have not seen other reported cases of thoracodorsal mononeuropathy in children.

Spinal Accessory Nerve The spinal accessory nerve is derived from two populations of motor neurons: cranial fibers from the nucleus ambiguus and spinal fibers from upper cervical motor neurons. The nerve exits the skull via the jugular foramen. The cranial fibers are destined to innervate the laryngeal muscles while the spinal fibers innervate the sternocleidomastoid and trapezius muscles. Injury to the spinal accessory nerve occurs rarely and usually results as a complication of surgical procedures involving the posterior triangle of the neck (see Box 32-5).3 One of us (K.J.F.) has evaluated two children with isolated spinal accessory mononeuropathy. One was a 16-year-old girl with an idiopathic spinal accessory mononeuropathy. The other was a 13-year-old girl who was found to have a droopy left shoulder during a school scoliosis screening evaluation.24 The examination was remarkable for left trapezius weakness and atrophy, mild left scapular winging, diffusely hypoactive reflexes, and pes cavus foot deformities. The EMG study documented a left spinal accessory mononeuropathy superimposed on a diffuse sensorimotor polyneuropathy. Subsequent DNA studies confirmed the diagnosis of HNPP. The EMG evaluation of spinal accessory mononeuropathies includes obtaining a CMAP from the trapezius, and needle examination of the trapezius and sternocleidomastoid.

CASE STUDY 6. A 17-year-old boy noted right arm weakness following right shoulder surgery 3 weeks prior to the EMG study. The surgery was indicated to repair a torn labrum. The neurologic examination was remarkable for marked weakness of right arm flexion, an absent right biceps brachii reflex, and reduced light touch sensation along the lateral aspect of the right forearm. Nerve conduction studies showed an absent right musculocutaneous SNAP. The right median, right radial, and left musculocutaneous SNAPs were normal. The right musculocutaneous CMAP amplitude was markedly reduced at 0.2 mV as compared to the left response of 4.2 mV. The right median motor nerve conduction study and F-wave latency were normal. Needle examination revealed increased insertional activity, sustained fibrillations and positive sharp waves, and absent recruitment of motor unit action potentials from the right

biceps brachii and coracobrachialis muscles. Needle examination of the right deltoid and triceps was normal. Comments The EMG findings were consistent with a severe axon-loss right musculocutaneous mononeuropathy, probably resulting from compression or trauma of the nerve incurred during the shoulder surgery. The preservation of the right musculocutaneous CMAP suggested some degree of nerve continuity. Given the absence of clinical and EMG improvement 3 months later, the patient underwent nerve grafting microsurgery. Two years following surgery, he reported partial improvement in arm flexion strength.

CASE STUDY 7. A 15-month-old girl was referred to the EMG laboratory to assess for left shoulder weakness and mild scapular winging. The weakness was noted soon after a complicated birth that resulted in a left thoracotomy and chest tube insertion for a chest wall empyema. The neurologic examination revealed atrophy of the left latissimus dorsi and mild left scapular winging. The left median sensory and motor nerve conduction studies were normal. Needle examination revealed reduced recruitment of motor unit action potentials from the left latissimus dorsi. The motor unit action potentials from this muscle were of increased amplitude and duration, showed increased phases and turns, and fired at faster than normal frequencies. No fibrillations or positive sharp waves were observed. Needle examination of the left trapezius, serratus anterior, and rhomboids was normal. Comments The EMG findings were consistent with a chronic axonloss injury to the left thoracodorsal nerve or motor branch innervating the latissimus dorsi muscle. The injury probably resulted from the thoracotomy, chest tube insertion, or both.

CASE STUDY 8. A 16-year-old girl was referred to the EMG laboratory to assess her left shoulder weakness. The weakness was first noticed during a routine physical examination by her pediatrician 3 years earlier. There was no known injury, and she denied neck, shoulder, or arm pain. The neurologic examination was remarkable for atrophy and weakness of the upper left trapezius muscle and mild scapular winging, especially prominent with the arm in lateral abduction.

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A

B FIGURE 32–11 Nerve conduction studies and needle electromyography for Case Study 8. A, Comparative studies of the right (waveform 1) and left (waveform 2) spinal accessory compound muscle action potentials (CMAPs). The spinal accessory nerve is stimulated just posterior to the sternocleidomastoid muscle with recording electrodes over the upper trapezius. Note the low-amplitude CMAP on the left side. B, Example of complex repetitive discharge recorded from the left trapezius muscle. Amp, amplitude.

Otherwise, left shoulder and limb muscles were of normal bulk and strength. The left sternocleidomastoid muscle was also of normal bulk and strength. Nerve conduction studies were remarkable for a markedly reduced left spinal accessory CMAP, recorded from the upper trapezius (Fig. 32-11). The left upper extremity SNAPs, left median and ulnar motor nerve conduction studies, and right spinal accessory CMAP were normal. Needle examination was remarkable for reduced insertional activity, abundant complex repetitive discharges, and markedly reduced recruitment of motor unit action potentials from the left trapezius muscle (see Fig. 32-11). Motor unit action potentials were of increased amplitude and duration and fired at faster than normal frequencies. Needle examination of selected left arm muscles, left serratus anterior, left sternocleidomastoid, and right trapezius was normal. Comments The EMG findings were consistent with a chronic axonloss left spinal accessory mononeuropathy, localized distal to the branch innervating the sternocleidomastoid muscle. This was called an idiopathic spinal accessory mononeuropathy; however, it is possible that the neuropathy was due to a prior nerve injury in the neck (e.g., compression from backpack) or partial form of brachial neuritis.

FIGURE 32–12 Diagram of the sciatic nerve and the muscles that it supplies. (Courtesy of Lahey Clinic, Burlington, MA.)

SCIATIC NERVE Anatomy The sciatic nerve is derived from the lower lumbar (L4-5) and upper sacral (S1-2) roots, emerges from the lumbosacral plexus, exits the pelvis through the infrapiriform foramen, and descends in the posterior thigh to innervate the semitendinosus (L4-S2), semimembranosus (L4-S2), biceps femoris (L4-S2), and distal part of the adductor magnus (Fig. 32-12).4 The sciatic nerve consists of two welldefined nerve bundles including the lateral or peroneal division and medial or tibial division. The lateral division innervates the short head of biceps femoris while the medial division supplies the other hamstring muscles. At the apex of the popliteal fossa, the sciatic nerve bifurcates into its two terminal branches: the common peroneal and tibial nerves.

Etiology (Box 32-6) Sciatic mononeuropathies account for more than 20% of pediatric mononeuropathies.2 Pediatric sciatic mononeuropathies can affect all age groups, from neonates to

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BOX 32-6 CAUSES OF SCIATIC MONONEUROPATHIES Neonatal trauma Breech deliveries Intragluteal injections Umbilical artery injections and catheterizations Other trauma Lacerations Crush injuries Hip dislocations Surgery Compression Hard surfaces Orthopedic appliances Entrapment Myofascial bands Iliac bony exostoses Systemic disease Vasculitis Purpura fulminans Tumors Lymphoma Chloroma Neurofibromas Localized hypertrophic neuropathy Idiopathic progressive mononeuropathy

adolescents, and the location of nerve injuries is similar to those occurring in adults. The nerve can be injured in the pelvis, the sciatic notch, or in the thigh with an acute, subacute, or chronic clinical course. Sciatic mononeuropathies manifest with weakness of knee flexion and weakness and sensory loss in the distributions of the common peroneal and tibial nerves. Sciatic Compression Neuropathies Compression is one of the primary causes for a child’s sciatic mononeuropathy. In a retrospective review of sciatic mononeuropathies seen at CHB, 21 cases were diagnosed in a 14-year period.81 A nontraumatic mechanism was present in 85% and, of these, 33% were due to compressive injuries. At CHB sciatic compression neuropathies have included multiple mechanisms such as long leg and body casts, prolonged pressure on the nerve in a newborn, and heel compression in a child who slept with the leg tucked under his buttock.81 Other causes of sciatic mononeuropathy include external compression by sitting on hard surfaces,82 nerve injury in the setting of severe weight loss,83 after a prolonged sitting position during surgery,84-87 and prolonged pressure

in critically ill patients in the intensive care unit.87-89 A lithotomy position is frequently reported as a cause of adult sciatic mononeuropathies, and we have also seen this in children.81,90,91 Sitting in the lotus position has also caused compressive sciatic mononeuropathy.92 The mechanism of injury is unclear and is postulated to be due to ischemia, stretch, or external compression.93,94 Endometriosis95 and persistent sciatic artery at the pelvic notch may predispose to sciatic nerve compression mononeuropathy.96 Hematomas Six of 36 sciatic nerve injuries described in one report were due to compression by hematomas in patients with hemophilia.97 Sciatic mononeuropathy due to an occult hematocolpos was reported in an adolescent girl who had longstanding back pain and leg weakness.98 Tumors Benign and malignant tumors should be considered in any child with a progressive sciatic mononeuropathy. A Mayo Clinic review identified 35 cases of sciatic mononeuropathies in patients ranging in age from 5 to 72 years, with various tumors including neurilemomas, neurofibromas, and neurofibrosarcomas.99 Most of these patients present with pain and progressive weakness in the affected limb. Painless footdrop or progressive foot deformities are other presenting features of sciatic nerve tumors.99,100 Tumor compression of the sciatic nerve is reported with neurofibromas,101 primary lymphomas,3,81,102 pelvic neuroblastomas,81,103 and chloromas.104 Trauma Traumatic injuries to the sciatic nerve occur less commonly than traumatic injuries to other lower and upper extremity nerves.1-3,81 At the CHB traumatic sciatic mononeuropathies resulted from laceration, crush injury, and a hip dislocation.81 Other traumatic sciatic mononeuropathies include fracture-dislocation of the hip,105 stretch injuries,106 and crush injuries during natural catastrophies.107 The nerve can be acutely lacerated, stretched, or compressed or later entrapped in heterotopic ossification. This is the mechanism involved in sciatic mononeuropathies in athletes108 and during hip surgery in children with juvenile rheumatoid arthritis.105 Infants. Babies are also subject to experiencing a traumatic sciatic mononeuropathy. Mechanisms include breech deliveries,3,109 intragluteal injections,110-112 toxic injuries during umbilical vessel injections,113-115 and idiopathic neonatal sciatic mononeuropathy.116,117 Prenatal compression of the sciatic and other nerves has been documented clinically and electromyographically.81,118,119 Prenatal injuries are usually secondary to external compression due to reduced fetal activity, especially with decreased amniotic

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fluid, abnormal uterine contractions during prolonged labor, amniotic fluid bands, or uterine abnormalities.119 Such an infant may have a necrotic ischemic lesion (eschar) at the site of compression as evidence of intrauterine onset.119 EMG performed in the first days of life becomes important to document the prenatal onset of the nerve injury.118 Miscellaneous Other causes of sciatic mononeuropathies include nerve entrapment by myofascial bands or congenital iliac anomalies,120-123 nerve ischemia from hypereosinophilic vasculitis,124 and idiopathic injuries.125,126

Evaluation Our EMG evaluation of the sciatic nerve includes the sural and superficial peroneal SNAPs, peroneal and tibial motor nerve conduction studies, F-wave and H-reflex studies, and needle examination of selected muscles innervated by the medial and lateral division of the sciatic nerve (e.g., short and long head of biceps femoris, medial gastrocnemius, anterior tibialis). Needle examination of gluteal muscles may be necessary for differentiation between sciatic and lumbosacral plexus injuries. Lumbosacral root lesions can usually be differentiated from sciatic mononeuropathies by the preservation of the sural and superficial peroneal SNAPs in the former; however, these are rare in children. Nerve imaging studies including MRI and magnetic resonance neurography may be helpful in disclosing nerve enlargement or compression by a mass or tumor.127-134 The large size of the sciatic nerve is conducive to imaging study diagnosis; however, some lesions including myofascial bands and perineuromas are not yet readily visible by MRI and may require magnetic resonance neurography, ultrasonography, or surgical exploration.135-137 Surgical Exploration Surgery proved to be diagnostic and curable in one instance when a fibrous band was identified entrapping the sciatic nerve in the posterior thigh.125 At CHB we had a negative exploration but were disappointed with the limited degree of exploration.

Treatment and Prognosis At CHB the degree of recovery for sciatic mononeuropathies could not necessarily be predicted by the EMG findings or mechanism of nerve injury.81 Seven (44%) of 16 children with long-term follow up did not improve, including those who underwent exploratory surgery and nerve repair.81 In a much larger series of sciatic mononeuropathies, including both adults as well as children, surgical repair was performed only in those individuals with

persistent deficits in the peroneal or tibial distribution.137 Management was guided by nerve action potential recordings, which indicated whether neurolysis or resection of the lesion was required. Useful peroneal function was achieved when the nerve action potential was recorded distal to the lesion, but overall improvement was only 36%. The tibial division had a much better recovery, regardless of the level or mechanism of injury.137

CASE STUDY 9. A 2-year-old boy developed a right leg limp soon after receiving a right intragluteal injection of an antipyretic medication while visiting his African home 3 months prior to the EMG study. The past medical history was otherwise unremarkable. The examination was remarkable for weakness of right foot plantar flexion while ambulant, weakness of toe flexion and extension, atrophy of right intrinsic foot muscles, and absent right ankle jerk. The nerve conduction studies showed absent right sural and superficial peroneal SNAPs, absent right tibial CMAP from the adductor hallucis muscle, and markedly attenuated right peroneal CMAP from the extensor digitorum brevis muscle. The left sural SNAP and left peroneal motor nerve conduction studies were normal. The needle examination showed increased insertional activity; sustained fibrillations and positive sharp waves; and reduced recruitment of motor unit action potentials from the right medial gastrocnemius, biceps femoris, and anterior tibialis. No motor unit action potentials were recorded from the medial gastrocnemius. Motor unit action potential were of slightly increased amplitude and duration and fired at faster than normal frequencies from the biceps femoris and anterior tibialis. Needle examination of the vastus lateralis and gluteus maximus was normal. Comments The EMG findings were consistent with a subacute to early chronic axon-loss right sciatic mononeuropathy. Fortunately, intragluteal injection injuries are no longer a commonly reported cause of sciatic mononeuropathies in children. Education and proper knowledge of how to perform intramuscular injections by health care providers have undoubtedly reduced the incidence of this type of nerve injury.

PERONEAL NERVE Anatomy The common peroneal or lateral popliteal nerve derives from the sciatic nerve in the popliteal fossa (Fig. 32-13).4

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nerve, a motor branch of the superficial peroneal nerve, which provides partial innervation of the extensor digitorum brevis muscle.

Etiology Children with peroneal mononeuropathies typically present with a footdrop and, less commonly, with pain and paresthesia on the dorsum of the foot. The site of involvement in pediatric peroneal mononeuropathies is similar to that of adults,138 being at the fibular head in 94% and at the ankle in 6% at CHB.139 The common peroneal nerve was affected in 59% of the cases, deep peroneal nerve in 12%, and superficial peroneal nerve in 6%. In the remaining 23%, a precise localization was limited by technical factors.139 Causes of peroneal mononeuropathy are shown in Box 32-7.

FIGURE 32–13 Diagram of the peroneal nerve and the muscles that it supplies. (Courtesy of Lahey Clinic, Burlington, MA.)

In the popliteal fossa, the common peroneal nerve gives off two sensory branches, the lateral sural cutaneous nerve, and the lateral cutaneous nerve of the calf. After rounding the head of the fibula, the common peroneal nerve bifurcates into its two terminal branches: the deep and superficial peroneal nerves. The deep peroneal nerve innervates the tibialis anterior (L4-5), extensor hallucis longus (L5-S1), extensor digitorum longus and brevis (L5-S1), and the peroneus tertius (L5-S1) muscles. After supplying the extensor digitorum brevis on the dorsum of the foot, the deep peroneal nerve terminates as a small sensory branch, innervating the dorsal skin between the first and second toes. The superficial peroneal nerve innervates the peroneus longus and brevis (L5-S1) muscles and then terminates as a sensory branch that innervates the skin of the lateral lower foreleg and dorsum of the foot and toes. An important anomaly in up to 20% of subjects is the accessory peroneal

Compression Compression was the primary mechanism for pediatric peroneal mononeuropathies, 10 (59%) of 17, in our experience.138 The mode of onset was acute in 4 patients and indeterminate in the other 6. Half of the compressive peroneal mononeuropathies were iatrogenic, caused by casts, Buck’s traction, Velcro straps, and intravenous footboard tape in a newborn. Three girls with anorexia nervosa had compression at the fibular head due to severe weight loss and chronic leg crossing.139 This is similar to “slimmer’s palsy” seen in adolescents, as well as adults.140-143 There are other rather unique causes of peroneal nerve compression in children. These include prolonged compression during water skiing on a knee board,144,145 with anterior tibial compartment syndrome,146 and from complications of anaphylactoid purpura147 and critical illness.148 Newborns are also subject to iatrogenic compression injuries to the peroneal nerve. Mechanisms include intravenous fluid infiltration149 and compression by tape used to secure a footboard.139,150 Entrapment Less commonly, common or deep peroneal mononeuropathies present with a chronic progressive footdrop, repeated ankle sprains secondary to peroneal muscle weakness, or a cavus foot deformity due to entrapment of the peroneal nerve. Childhood causes of entrapment include at the division of the common peroneal nerve near the tendinous origin of the peroneus longus muscle at the fibula head.139,151 Bony exostoses at the fibular head or talotibial exostosis deriving from osteochondromas have provided another proximal entrapment site.152,153 Isolated superficial peroneal mononeuropathy can result from entrapment by scarring due to repetitive ankle sprain.154 MRI can assist in the diagnosis, and limited fasciec-

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BOX 32-7 CAUSES OF PERONEAL MONONEUROPATHIES Newborn Intrauterine Idiopathic Intravenous fluid infiltration Footboards Birth trauma with popliteal fossa hematomas Compression Orthopedic appliance Anorexia and chronic leg crossing Weight reduction Anaphylactoid purpura Entrapment Bony exostoses Fibrotendinous bands Hemangioma Synovial cyst Ganglia Trauma Lacerations Martial arts injuries Blunt trauma Traction stretch injury Burns Tumors Schwannoma Hemangioma Osteochondroma Systemic Diabetes mellitus Hereditary neuropathy with liability to pressure palsies

tomy often helps alleviate the symptoms.154,155 This nerve may also be entrapped where it exits the lateral compartment.156 Mass Lesions: Cysts, Schwannomas, and Hemangiomas Various cystic lesions can affect the peroneal nerve in children including synovial cysts, intraneural ganglion cysts, and a ganglion in the anterior compartment.133,157-162 Occult nerve tumors can involve either the common, superficial, or deep peroneal nerves and often present with protracted symptoms. A child with a schwannoma of the superficial peroneal nerve presented with chronic paresthesia of the calf and toes for 1 year; the diagnosis was established dur-

ing surgical exploration.139 Hemangioma is another rare cause of peroneal mononeuropathy.163 Localized hypertrophic neuropathy or intraneural perineuromas also lead to pediatric peroneal mononeuropathy.135,164 This benign condition was difficult to diagnose in the past, usually requiring surgical exploration.139 However, magnetic resonance neurography has improved the diagnosis of nerve tumors and has allowed for preoperative localization.134,135,137,165 Trauma Trauma to the peroneal nerve occurs relatively infrequently, accounting for just 17% of our CHB experience.139 Laceration of the deep peroneal nerve at the fibula head occurred in one child,139 and a similar injury in an adolescent who lacerated the nerve with a skate blade.166 Another child suffered a traumatic peroneal mononeuropathy during a motor vehicle accident, and a third child during repetitive blunt trauma in martial arts.139 Surfing trauma is also reported in adolescents.167 Newborn Newborns may also develop peroneal mononeuropathies; one had an antenatal onset.118,168-170 The etiology in these is unclear, but the rapid and complete recovery in most cases points to a neuropraxic lesion. Two of the infants had abnormal intrauterine positions with a breech presentation and a stretching mechanism was postulated.168-170 In others, uterine contraction rings might have caused a compressive lesion with axonal injury. One infant had fibrillation potentials present just 18 hours after delivery.118 Miscellaneous Diffuse polyneuropathies may rarely underlie some childhood peroneal mononeuropathy including diabetes mellitus,171-173 leprosy,174 and HNPP.175-178 In some children, the etiology of a progressive peroneal mononeuropathy remains elusive despite surgical exploration and pathologic analysis of the nerve.125

Evaluation EMG evaluation of the peroneal nerve includes the superficial peroneal SNAP, peroneal motor nerve conduction studies from the extensor digitorum brevis and the tibialis anterior muscles, and needle examination of peroneal-innervated muscles.179 The sural SNAP, tibial motor nerve conduction studies, and contralateral peroneal nerve studies may be indicated sometimes in children when isolated primary etiology is not apparent. Motor conduction studies below and above the fibular head are required to assess for conduction block or slowing across this segment. Occasionally, peroneal motor nerve

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conduction studies with recording electrodes on the tibialis anterior or peroneus longus may be required. The preservation of the superficial peroneal SNAP in a child with footdrop usually points to either a pure conduction block injury at the fibular head or to another process (i.e., L5 radiculopathy). Nerve conduction studies in most instances of peroneal compression show conduction block at the fibular head; the degree of conduction block correlates with clinical weakness.139,141 Sciatic mononeuropathies presenting with footdrop usually show EMG evidence of more diffuse and proximal abnormalities, including absent or attenuated sural and tibial motor responses, and needle examination abnormalities of the short head of biceps femoris. Needle examination of the lumbosacral paraspinal muscles can assist in differentiating peroneal mononeuropathies from the uncommon L5 root lesions leading to pediatric footdrop. Imaging studies, particularly MRI or computed tomography (CT), may be helpful in localization and diagnosis, especially in patients presenting with a slowing progressive deficit that warrants consideration of chronic nerve compression or focal entrapment from a synovial cyst nerve tumor or osteochondromas.152 DNA Testing The presence of conduction block superimposed on a diffuse polyneuropathy with pronounced segmental demyelinating features at common sites of compression and entrapment should also raise the question of HNPP. Specific DNA testing for the deletion on chromosome 17 can be diagnostic in this instance. If the parents have normal nerve conduction studies, this suggests a de novo mutation in the PMP22 gene. Surgical Exploration On occasion, surgical exploration may be indicated with progressive lesions. In our CHB experience this approach defined a peroneal nerve entrapment at the knee from the peroneus longus tendon. In another instance a schwannoma at the fibular head was demonstrated.139

Treatment and Prognosis Childhood peroneal mononeuropathies have a variable but often good prognosis. EMG results might provide useful prognostic information, since an absent or low-amplitude CMAP has been related to an unfavorable outcome.139 At CHB 13 (76%) of 17 patients had complete or significant improvement.139 The 4 patients with a poor recovery included 2 with blunt trauma, 1 a perioperative lesion, and 1 an entrapment lesion where surgical release was delayed.139 The best prognosis was for children with demonstrable conduction block at the fibular head.139

Skillful primary repair of peripheral nerves in children is often followed by significant recovery.180 Near nerve intraoperative recordings can help detect early nerve injury and avoid more severe damage during surgery.181 If a childhood peroneal mononeuropathy fails to improve within 3 to 4 months, it is best to perform reparative surgery early on.182,183 When improvement is not achieved despite surgical release or decompression of the nerve, tendon transfer operation can re-establish functional foot dorsiflexion and improve ambulation.184

CASE STUDY 10. A 5-year-old girl developed insidiously progressive right footdrop over a 3-month period. There was no known antecedent injury, and she denied back or leg pain. The neurologic examination was remarkable for severe weakness of the right foot and toe extensors, moderate weakness of right foot evertors, atrophy of the right anterolateral foreleg muscles and extensor digitorum brevis, and reduced light touch sensation along the dorsum of the right foot. The ankle jerks were symmetrically normal. Nerve conduction studies revealed an absent right superficial peroneal SNAP and absent peroneal CMAPs recorded from the extensor digitorum brevis, tibialis anterior, and peroneus longus. The right sural SNAP, right tibial motor nerve conduction study, left superficial peroneal SNAP, and left peroneal motor nerve conduction study were normal. Needle examination revealed slightly increased insertional activity and reduced recruitment of motor unit action potentials from the right peroneus longus and anterior tibialis. The motor unit action potentials were of increased amplitude and duration and fired at faster than normal frequencies. No sustained fibrillations or positive sharp waves were observed. Needle examination of the right posterior tibialis and short head of biceps femoris was normal. Plain radiographs of the right leg revealed a large mass in the area of the proximal fibula. Surgical resection and biopsy disclosed a benign osteochondroma. Follow-up clinical and EMG examinations 1 year later showed no improvement. Comments The EMG findings were consistent with a chronic axon-loss right common peroneal mononeuropathy, localized distal to the innervation of the short head of biceps femoris. The insidiously progressive clinical course and EMG findings prompted imaging studies of the right knee and proximal foreleg. Benign tumors including osteochondromas should be considered in such cases of slowly progressive footdrop in an otherwise healthy child.

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nerve conduction abnormalities were also present and included low-amplitude SNAPs, prolonged median SNAP peak latency, prolonged peroneal and median CMAP distal latencies, and reduced motor conduction velocities across the fibular head for the right peroneal nerve and across the elbow segment for the left ulnar nerve. Needle examination of the left anterior tibialis revealed increased insertional activity, sustained fibrillations and positive sharp waves, and absent recruitment of motor unit action potentials. The results of nerve conduction studies prompted clinical and EMG evaluations of her parents and DNA testing for HNPP. Nerve conduction studies on her parents were normal. DNA studies on the patient were positive for the 1.5 Mb deletion mutation of the peripheral myelin protein 22 (PMP22) gene on 17p11.2.

FIGURE 32–14 Motor nerve conduction studies for Case Study 11. The left peroneal to the extensor digitorum brevis (EDB) (waveforms 1 to 3), peroneal to the tibialis anterior (TA) (waveforms 4 and 5), peroneal to peroneus longus (PL) (waveforms 6 and 7), and tibial to adductor hallucis (AH) (waveforms 8 and 9) compound muscle action potentials are shown. For the peroneal motor nerves, stimulation is at the ankle (waveform 1), below-fibular head (waveforms 2, 4, and 6), and above-fibular head (waveforms 3, 5, and 7) sites. Note the complete motor conduction block (waveforms 3, 5, and 7). Also of note is the prolonged peroneal to extensor digitorum brevis distal latency of 7.5 milliseconds (normal, < 6.1 milliseconds), a common finding in hereditary neuropathy with liability to pressure palsies.

Comments The EMG findings were consistent with a left common peroneal mononeuropathy due to a severe conduction block injury (mild concurrent axonal injury as well) at the fibular head, superimposed on a diffuse polyneuropathy with pronounced, segmentally demyelinating features at common sites of compression and entrapment. The features of the polyneuropathy strongly raised the possibility of HNPP; subsequent DNA testing in this patient confirmed this diagnosis. The normal nerve conduction studies in her parents suggested a de novo mutation in the PMP22 gene; however, this was not confirmed with DNA testing of her parents. HNPPs should be considered in any child with recurrent mononeuropathies or diffuse sensorimotor polyneuropathy with segmentally demyelinating features at common sites of nerve compression and entrapment.

FEMORAL NERVE Anatomy

CASE STUDY 11. A 12-year-old girl awoke with left footdrop about 5 weeks prior to the EMG study. She complained of severe weakness and sensory symptoms but denied back or limb pain. There was no personal or family history of neurologic or medical problems. The neurologic examination revealed complete weakness of the left foot and toe extensors and left foot evertors. Light touch sensation was reduced along the lateral foreleg and dorsum of the foot on the left side. The ankle jerks were symmetrically normal. Nerve conduction studies showed a low-amplitude left superficial peroneal SNAP and complete left peroneal motor conduction block across the fibular head (Fig. 32-14). Diffuse

The femoral nerve derives from the posterior rami of the L2-4 segments and roots, innervates and passes through the psoas muscle (L2-3), runs along the iliacus muscle (L2-3) that it also innervates, descends beneath the inguinal ligament to enter the thigh, and then bifurcates into the anterior and posterior divisions (Fig. 32-15).4 The anterior division divides into a muscular branch to the sartorius (L2-3) and a sensory branch, the medial cutaneous nerve of the thigh. The posterior division divides into the muscular branches that innervate the pectineus (L2-3) and quadriceps (L2-4) muscles, and the saphenous nerve that provides sensation to the skin over the medial aspect of the foreleg. Femoral nerve lesions proximal to the innervation of the psoas and iliacus are associated with weakness of hip flexion

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BOX 32-8 CAUSES OF OTHER LOWER EXTREMITY MONONEUROPATHIES Femoral nerve Postsurgical Perineuromas Intraneural and iliopsoas hematomas in hemophilia Neurofibromas Idiopathic Lateral femoral cutaneous nerve Orthopedic appliance Blunt trauma Idiopathic (meralgia paresthetica) Sural nerve Ankle jewelry Tibial nerve Trauma in popliteal fossa Tarsal tunnel syndrome Obturator nerve Birth-related trauma

FIGURE 32–15 Diagram of the femoral and obturator nerves and the muscles that they supply. (Courtesy of Lahey Clinic, Burlington, MA.)

and knee extension and sensory loss along anteromedial thigh and medial foreleg. Lesions localized distal to this site but proximal to the femoral triangle cause similar clinical findings, with the exception that hip flexion is preserved.

Etiology Femoral mononeuropathies are extremely rare in children (Box 32-8). One of us (K.J.F.) has evaluated three children with femoral mononeuropathies over a 10-year period. The first child developed a severe femoral mononeuropathy with involvement of hip flexors following renal transplant surgery. Follow-up evaluation 1 year later showed minimal improvement in function. The second child developed thigh weakness and numbness following a spontaneous iliacus hematoma resulting from hemophilia. In our third child, the cause of the mild femoral mononeuropathy was not determined. Other reported causes of femoral mononeuropathy include surgical injury, stretch injuries, perineuromas, intraneural hemorrhage or iliopsoas hematomas, neurofibromas, and idiopathic injuries.2,3,97,125,135,185-187

Evaluation The EMG evaluation of a femoral mononeuropathy in a child does not routinely include femoral motor nerve conduction studies because these studies are uncomfortable, somewhat emotionally disconcerting to the natural shyness in children, and do not seem to add much to the overall EMG evaluation per se. However, we do obtain a saphenous SNAP. Needle examination of muscles innervated by the femoral nerve generally includes the iliacus and vastus lateralis, and on occasion the vastus medialis, rectus femoris, and sartorius muscles. Needle examination of the adductor longus and lumbar paraspinal muscles is usually performed as well to differentiate between isolated femoral mononeuropathies and more proximal lesions. Imaging studies including MRI and CT scans are recommended in cases with slowly progressive symptoms or when a nerve tumor is suspected.

Treatment and Prognosis Femoral nerve lesions are too uncommon to make any form of generalization. However, as with the previously discussed mononeuropathies, the amount of axonal damage determines the timing to recovery and its eventual outcome. It is difficult to generalize with children because

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OTHER LOWER EXTREMITY NERVES Lateral Femoral Cutaneous Nerve

FIGURE 32–16 Needle electromyography for Case Study 12. Note the large motor unit action potentials from the left vastus lateralis, a finding consistent with chronic reinnervation via collateral sprouting.

they often have more potential for a more significant functional return than do adults with a “similar” lesion.

CASE STUDY 12. A 13-year-old boy developed left thigh weakness, atrophy, and sensory symptoms following a motor vehicle accident about 5 years prior to the EMG test. The injury involved some upper thigh and back trauma but no fractures or dislocations. There was no prior history of neurologic disease. The neurologic examination revealed moderate weakness and atrophy of the left quadriceps muscles, mild left hip flexor weakness, and an absent left ankle jerk. Nerve conduction studies showed an absent left saphenous SNAP. The right saphenous and left sural, superficial peroneal, and median SNAPs were normal. The left peroneal, tibial, and ulnar motor nerve conduction studies and F-wave latencies were normal. The left tibial H-reflex study was normal. Needle examination revealed reduced recruitment of motor unit action potentials from the left vastus lateralis and iliacus. Motor unit action potentials were of increased amplitude and duration, showed increased phases and turns, and fired at faster than normal frequencies (Fig. 32-16). No fibrillations or positive sharp waves were observed. Needle examination of other left leg muscles including the adductor longus, left lumbosacral paraspinal muscles, and right vastus lateralis muscle was normal. Comments The EMG findings were consistent with a chronic axonloss left femoral mononeuropathy, localized proximal to the innervation of the iliacus muscle. Although the cause of injury was not certain, it was suspected that the proximal femoral nerve was injured directly by trauma or from a compressive hematoma.

The lateral femoral cutaneous nerve is a pure sensory nerve that derives from the second and third lumbar segments and supplies sensation to the skin along the anterolateral thigh.4 Its clinical manifestations are similar to adults with numbness and pain along the lateral thigh. An extremely rare neuropathy in children, it has been observed as an idiopathic lesion,3 caused by compression with an orthopedic harness8 and by sport injuries, either by direct blunt trauma to the thigh in high-energy sports,108 or in girl gymnasts due to the repetitive impact on the thigh by the bars (see Box 32-8).188 Although, previously the lateral femoral cutaneous SNAP was thought to be difficult to obtain with routine nerve conduction study in normal subjects the technology has improved and we should consider using this study in the occasional child where there is clinical indication. In general the diagnosis of meralgia paresthetica is usually based on clinical findings.

Sural Nerve The sural nerve is another primary sensory nerve. It derives from the medial sural cutaneous (branch of tibial) and lateral sural cutaneous (branch of common peroneal) nerves in the distal popliteal fossa. It supplies sensation to the lateral ankle and foot.4 A compressive sural mononeuropathy caused by a tight ankle bracelet was reported in a young girl (see Box 32-8).189

Tibial Nerve The tibial nerve derives from the sciatic nerve in the popliteal fossa and courses down the back of the leg to the medial ankle (Fig. 32-17).4 In the popliteal fossa, it gives off the medial sural cutaneous nerve. In the back of the leg it gives off the motor branches to the medial and lateral gastrocnemius (S1-2), soleus (S1-2), tibialis posterior (L4-5), flexor digitorum longus (L5-S2), and flexor hallucis longus (S1-2). The nerve then passes along the medial malleolus, through the tarsal tunnel, and terminates into the medial plantar, lateral plantar, and calcaneal nerves (S1-2). Tibial mononeuropathies in children are extremely rare and often occur concomitantly with peroneal nerve injuries in the popliteal fossa (see Box 32-8).3 One report of “tarsal tunnel syndrome” in children noted improvement in symptoms following decompression surgery; however, none of the cases were confirmed by EMG studies.190

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REFERENCES

FIGURE 32–17 Diagram of the tibial nerve and the muscles that it supplies. (Courtesy of Lahey Clinic, Burlington, MA.)

Obturator Nerve The obturator nerve derives from the lumbar plexus and L2-4 roots, courses along the pelvis, and enters the obturator canal. It then descends into the medial thigh as the anterior and posterior branches (see Fig. 32-15).4 The anterior branch supplies the pectineus, adductor longus, adductor brevis, and gracilis muscles. It then terminates in a sensory branch that supplies the skin along the medial thigh. The posterior branch supplies the obturator externus, adductor magnus, and adductor brevis muscles. Two instances of “obturator mononeuropathy” due to birth-related injuries have been reported. However, neither was confirmed with EMG studies (see Box 32-8).191,192 Obturator mononeuropathies are exceedingly rare in children, and we have not documented such an injury in our EMG laboratories.

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158. Gayet LE, Morand F, Goujon JM, et al: Compression of the peroneal nerve by a cyst in a seven-year-old child. Eur J Pediatr Surg 1998;8:61-63. 159. Gurdjian ES, Larsen RD, Lindner DW: Intraneural cyst of the peroneal and ulnar nerves: Report of two cases. J Neurosurg 1965;23:76-78. 160. Martins RS, Martinez J, de Aguiar PH, et al: Intraneural synovial cyst of the peroneal nerve: Case report. Arq Neuropsiquiatr 1997;55:831-833. 161. Nucci F, Artico M, Santoro A, et al: Intraneural synovial cyst of the peroneal nerve: Report of two cases and review of the literature. Neurosurgery 1990;26:339-344. 162. Beck TD, Miller KE, Kruse RW: An unusual presentation of intoeing in a child. J Am Osteopath Assoc 1998;98:48-50. 163. Bilge T, Kaya A, Alatli M, et al: Hemangioma of the peroneal nerve: Case report and review of the literature. Neurosurgery 1989;25:649-652. 164. Johnson PC, Kline DG: Localized hypertrophic neuropathy: Possible focal perineurial barrier defect. Acta Neuropathol 1989;77:514-518. 165. Houshian S, Freund KG: Gigantic benign schwannoma in the lateral peroneal nerve. Am J Knee Surg 1999;12:41-42. 166. Shevell MI, Stewart JD: Laceration of the common peroneal nerve by a skate blade. Can Med Assoc J 1988;139:311-312. 167. Watemberg N, Amsel S, Sadeh M, Lerman-Sagie T: Common peroneal neuropathy due to surfing. J Child Neurol 2000;15:420-421. 168. Crumrine PK, Koenigsberger MR, Chutorian AM: Footdrop in the neonate with neurologic and electrophysiologic data. J Pediatr 1975;86:779-780. 169. Godley DR: Neonatal peroneal neurapraxia: A report of two cases and review of the literature. Am J Orthop 1998;27:803-804. 170. Yilmaz Y, Oge AE, Yilmaz-Degpirmenci S, Say A: Peroneal nerve palsy: The role of early electromyography. Europ J Paediatr Neurol 2000;4:239-242. 171. Barkai L, Kempler P, Vamosi I, et al: Peripheral sensory nerve dysfunction in children and adolescents with type 1 diabetes mellitus. Diabet Med 1998;15:228-233. 172. el Bahri-Ben M, Gouider FR, Fredj M, et al: Childhood diabetic neuropathy: A clinical and electrophysiological study. Funct Neurol 2000;15:35-40. 173. Lawrence D, Locke S: Neuropathy in children with diabetes mellitus. BMJ 1963;5333:784-785. 174. Choe W: Leprosy presenting as unilateral foot drop in an immigrant boy. Postgrad Med J 1994;70:111-112. 175. Cruz-Martinez A, Arpa J, Palau F: Peroneal neuropathy after weight loss. J Peripher Nerv Syst 2000;5:101-105. 176. Mouton P, Tardieu S, Gouider R, et al: Spectrum of clinical and electrophysiologic features in HNPP patients with the 17p11.2 deletion. Neurology 1999;52:1440-1446. 177. Gabreels-Festen AA, Gabreels FJ, Joosten EM, et al: Hereditary neuropathy with liability to pressure palsies in childhood. Neuropediatrics 1992;23:138-143.

Focal Neuropathies in Children 178. Pareyson D, Solari A, Taroni F, et al: Detection of hereditary neuropathy with liability to pressure palsies among patients with acute painless mononeuropathy or plexopathy. Muscle Nerve 1998;21:1686-1691. 179. Sourkes M, Stewart JD: Common peroneal neuropathy: A study of selective motor and sensory involvement. Neurology 1991;41:1029-1033. 180. Birch R, Achan P: Peripheral nerve repairs and their results in children. Hand Clin 2000;16:579-595. 181. Wexler I, Paley D, Herzenberg JE, Herbert A: Detection of nerve entrapment during limb lengthening by means of near-nerve recording. Electromyogr Clin Neurophysiol 1998;38:161-167. 182. Fabre T, Piton C, Andre D, et al: Peroneal nerve entrapment. J Bone Joint Surg Am 1998;80-A:47-53. 183. Piton C, Fabre T, Lasseur E, et al: Common fibular nerve lesions—etiology and treatment: Apropos of 146 cases with surgical treatment. Rev Chir Orthop Reparatrice Appar Mot 1997;83:515-521. 184. Breukink SO, Spronk CA, Dijkstra PU, et al: Transposition of the tendon of M. tibialis posterior an effective treatment of drop foot: Retrospective study with follow-up in 12 patients. Ned Tijdschr Geneeskd 2000;144:604-608.

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185. Carter GT, McDonald CM, Chan TT, Margherita AJ: Isolated femoral mononeuropathy to the vastus lateralis: EMG and MRI findings. Muscle Nerve 1995;18:341-344. 186. Takao M, Fukuuchi Y, Koto A, et al: Localized hypertrophic mononeuropathy involving the femoral nerve. Neurology 1999;52:389-392. 187. Sharma S, Ray R: Femoral pain of solitary neurofibromatous origin. Ind Pediatr 1988;25:1221-1223. 188. Macgregor J, Moncur JA: Meralgia paraesthetica: A sports lesion in girl gymnasts. Br J Sports Med 1977;11:16-19. 189. Reisin R, Pardal A, Ruggieri V, Gold L: Sural neuropathy due to external pressure: Report of three cases. Neurology 1994;44:2408-2409. 190. Albrektsson B, Rydholm A, Rydholm U: The tarsal tunnel syndrome in children. J Bone Joint Surg Br 1982;64-B:215-217. 191. Craig WS, Clark JMP: Obturator palsy in the newly born. Arch Dis Child 1962;37:661-662. 192. Craig WS, Clark JMP: Of peripheral nerve palsies in the newborn. J Obstet Gynecol Br Empire 1958;65:229-237.

33 Clinical Neurophysiology of Pediatric Polyneuropathies TED M. BURNS, DEBORAH Y. BRADSHAW, NANCY L. KUNTZ, AND H. ROYDEN JONES, JR.

OVERVIEW TO THE ELECTRODIAGNOSTIC EVALUATION OF PEDIATRIC POLYNEUROPATHIES Epidemiology The epidemiology of polyneuropathy in children differs significantly from that in adults. Awareness of these differences allows rational design, modification, and interpretation of the electrodiagnostic study in children. Four key principles should be kept in mind. First, genetically determined polyneuropathies are much more common than acquired neuropathies in children.1-5 It is estimated that two thirds to three quarters of pediatric neuropathies are inherited.4,6 Second, under the genetically determined rubric, all types of Charcot-Marie-Tooth (CMT) (hereditary motor and sensory neuropathy) predominate. The prevalence of CMT has been estimated at 1 per 2500 to 10,000, which makes it far and away the single most common cause of polyneuropathy in the pediatric population.7,8 Third, of acquired polyneuropathies, acute and chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs) make up the majority of cases. Guillain-Barré syndrome (GBS) has an estimated incidence of 1 per 100,000 in the pediatric population. The incidence of childhood CIDP is probably one tenth that of childhood GBS, whereas the prevalence of childhood CIDP, a chronic disorder, is estimated at less than 1 per 100,000.9-16 Fourth, a striking

difference between the adult and pediatric populations is that polyneuropathies associated with systemic diseases such as diabetes mellitus, malignancy, paraproteinemia, chronic alcohol use, collagen vascular disease, vitamin deficiencies, and chronic renal disease are rare in childhood. Large case series of pediatric polyneuropathy are limited by referral and selection bias, as well as by variable classification of the inherited neuropathies. Thus, they often do not mirror epidemiologic studies. Nonetheless, they provide insight into the etiologies and frequency of the pediatric polyneuropathies seen at neuromuscular clinics. A series of 61 children with polyneuropathy admitted to the Vanderbilt Medical Center from 1971 to 1977 included 17 cases of GBS (28%), 11 cases of CMT (18%), 5 cases of spinocerebellar degeneration (8%), 5 polyneuropathies associated with systemic disease (8%) and 16 idiopathic cases (26%).2 Hereditary motor and sensory neuropathies (CMT) made up only 42% of cases in a series of 249 pediatric polyneuropathies seen at Children’s Hospital of Philadelphia over a 12-year period.17 An inflammatory demyelinating polyradiculoneuropathy was diagnosed in 41% of children; a referral bias may have contributed to this higher frequency of acquired demyelinating polyneuropathies in this series. Polyneuropathies associated with collagen vascular disease, metabolic disorders, and toxins were much less common. An Australian series based on sural nerve analysis in children with subacute or chronic polyneuropathies found that at least 71% of cases were inherited.18 CMT-1 was the most 645

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common diagnosis, followed by CMT-2. CIDP was diagnosed in 11% of patients. Cases of GBS were excluded. Other studies confirm that CMT-1 is much more common than CMT-2, especially in the pediatric population.18-25 Of a pooled European pediatric series of 287 inherited peripheral neuropathies, 51% had CMT-1.23 CMT-2 was identified in 21% of children. CMT-3 (Dejerine-Sottas disease [DSD]), defined in this series as autosomal recessive congenital demyelinating neuropathy, was diagnosed in 12% of cases. Many DSD cases are now known to be due to de novo mutations in the same genes that cause CMT-1.22,25,26 The X-linked form of CMT (CMT-X), now identified as the second most common form of CMT, was not recognized at the time of this series. Hereditary sensory neuropathies were diagnosed in only 3% of cases.

Clinical History The clinical history is a most important guide for the child electrodiagnostician. The age of onset and temporal evolution of the polyneuropathy provide important clues that must influence the design of the electrodiagnostic study. Although inherited polyneuropathies are more common than acquired etiologies at all ages of the pediatric population, inherited polyneuropathies are increasingly likely the earlier the onset of polyneuropathy. Age of onset is also helpful because individual inherited polyneuropathies tend to present at ages typical for those disorders. For example, CMT is not usually clinically apparent until the 2nd decade, although if an EMG is performed early in the 1st decade it is usually abnormal27 but not invariably so.28 Age of onset may be difficult to determine in younger children. This is especially true of the inherited polyneuropathies in which clinical deficits manifest insidiously. In fact, patient or parent uncertainty about the time of onset suggests that the polyneuropathy has a genetic basis. Physicians should ask specific questions about the child’s present and past activities, milestones, and motor skills. A temporal profile characterized by an unequivocal loss of skills or milestones points away from a CMT diagnosis and is in keeping with an acquired etiology such as GBS or, in the chronic setting, CIDP. However, a loss of motor milestones per se does not exclude certain other inherited neuropathies, particularly those caused by inborn errors of metabolism. The loss of skills in GBS or CIDP is limited to motor functions, whereas inborn neurometabolic errors impact the child’s development globally (i.e., also includes cognition, personality, and so forth). Given the likelihood that a child presenting with polyneuropathy has a hereditary disorder, the family history should receive special attention. Parents should be questioned carefully about the family history. This may, by itself, reveal the diagnosis. In addition, parents and siblings should be examined. Any living family member with suspi-

cious symptoms should be interviewed and examined, if at all possible. In many instances, focused electrodiagnostic testing on family members should be considered.

Neurologic Examination Clues to etiology are often present in the general examination. Pes cavus and hammertoe deformities are complications of longstanding neuropathies such as CMT. Pes planus and valgus angulation of the forefoot are less common.19-21,29,30 Pes cavus is not, however, a sine qua non of a hereditary polyneuropathy. At the Children’s Hospital, Boston (CHB), only 50% of children seen in the electrodiagnostic laboratory for evaluation of such orthopedic abnormalities have had nerve conduction studies (NCSs) compatible with a hereditary polyneuropathy.31 Enlarged peripheral nerves may be present in longstanding hereditary or acquired demyelinating and remyelinating (hypertrophic) polyneuropathies, including CMT-1 and CIDP. The general physical examination may offer further diagnostic clues, particularly in the form of dermatologic and ophthalmologic abnormalities associated with specific childhood polyneuropathies. The examiner should assess whether the motor findings have a predominantly distal, generalized, or proximal distribution. Most polyneuropathies have a distal predominance. Predominantly proximal weakness is occasionally seen, usually in the lower extremities, and suggests an acquired inflammatory demyelinating polyradiculoneuropathy. Almost all childhood peripheral neuropathies are bilaterally symmetric. Rarely, asymmetric findings compatible with the diagnosis of mononeuritis multiplex are seen in adolescents with acquired neuropathies.32 When asymmetry or multifocality is suspected, bilateral electrodiagnostic testing should be performed. In general, a 50% or greater reduction in motor or sensory nerve action potential amplitude or area relative to the contralateral response is considered significant.

ELECTROMYOGRAPHY The role of electromyographic (EMG) testing is to confirm the presence of a polyneuropathy and to elucidate the underlying pathophysiology. NCSs provide the best noninvasive means of differentiating a demyelinating process from that with predominantly axonal pathology. Information on the distribution, severity, and temporal course of neuropathy can also be obtained from the electrodiagnostic assessment. Parents accompanying their child to the electrodiagnostic laboratory are often uninformed or misinformed about the purpose and clinical value of electrodiagnosis. It is helpful for the electromyographer to speak with parents at the time

Clinical Neurophysiology of Pediatric Polyneuropathies

the appointment is scheduled, if possible. If not, there should be a detailed discussion of the purpose and nature of the procedure when the child and parents arrive in the EMG laboratory. An understanding of the test alleviates any anxiety and guilt the parent may feel about putting their child through a painful procedure. Parents are more willing to assist in comforting the child during the study if they understand its aims and potential benefits. Various technical approaches are used by skillful pediatric electromyographers to obtain both competent and empathetically successful studies. Techniques of pediatric EMG are discussed in detail in dedicated texts.33,34 Dr. Kuntz’s approach at the Mayo Clinic is detailed in Chapter 6. All colleagues attempt to put the child and their parents at ease by finding a means to involve the patient in the procedure. At CHB the child is encouraged to watch the recording screen “building mountains” as the motor or sensory action potentials appear or by identifying the sound of the motor unit potentials as “rain” or a “motorcycle.”33 When the youngster does have difficulty tolerating the EMG, it is preferable to reschedule this procedure at a later date under sedation, with nitrous oxide or propofol anesthesia. The major disadvantage of this approach is the diminished opportunity to carefully examine motor unit potentials under voluntary control, but one can usually gain a reasonable sense of motor unit potential characteristics under light anesthesia by reflex stimulation of the extremity, such as by tickling the sole of the foot to observe activation of the tibialis anterior or iliopsoas. The appropriate interpretation of pediatric electrodiagnostic studies depends on appreciation of the normal neurophysiologic maturational changes of infancy and early childhood. Nerve conduction parameters and motor unit potentials evolve from less than 50% of adult values in neonates to reach adult values between ages 3 and 5 years in parallel with the maturation of peripheral nerve myelin.35-44 The normal range of nerve conduction parameters for infants and children is annotated in Chapter 7, Tables 7:1-16. Characterizing a polyneuropathy as demyelinating or axonal is helpful to the diagnostic process. With this in mind, this chapter categorizes the various polyneuropathies as either predominantly demyelinating or predominantly axonal. This dichotomous characterization is useful for polyneuropathies that clearly fit in one category, for example, the demyelinating CMT polyneuropathies. In many cases, however, there are electrodiagnostic featuresof a mixed demyelinating and axonal polyneuropathy. In fact, most polyneuropathies have neurophysiologic and histopathologic evidence of both myelin and axon pathology, although either myelin or axon pathology may predominate. This often means, however, that the polyneuropathies encountered in clinical practice do not conform perfectly to one category or the other. Nonetheless, because of the

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significant diagnostic value obtained by making the distinction when possible, this chapter considers predominantly demyelinating and predominantly axonal polyneuropathies separately. However, the reader should keep in mind the limitations of this paradigm.

PRIMARILY DEMYELINATING POLYNEUROPATHIES: ELECTRODIAGNOSTIC FEATURES Whenever possible, an EMG performed to evaluate polyneuropathies should characterize the polyneuropathy as either demyelinating or axonal. The identification of a primarily demyelinating polyneuropathy is critically important because the differential diagnosis for demyelinating polyneuropathies is much more limited than that of axonal polyneuropathies. The demyelinating polyneuropathies include CMT, GBS, CIDP, and, much less commonly, an inborn error of metabolism such as a leukodystrophy (e.g., globoid cell leukodystrophy, metachromatic leukodystrophy). An important physiologic consequence of demyelination is conduction slowing, whereby motor and sensory conduction velocities (CVs) are reduced and distal motor and Fwave minimal latencies are prolonged. It is important that a polyneuropathy be considered primarily demyelinating only when the conduction is sufficiently slow. It is generally accepted that to be deemed primarily demyelinating, CV of motor nerves must be less than 80% of the lower limit of normal (LLN) if the amplitude is greater than 80% LLN, or less than 70% LLN if amplitude is less than 80% LLN. Distal latencies must be greater than 125% of upper limit of normal (ULN) if amplitude is greater than 80% of LLN, or greater than 150% of ULN if amplitude is less than 80% of LLN. F-wave latencies must be greater than 120% of ULN if amplitude is greater than 80% of LLN, or greater than 150% of ULN if amplitude is less than 80% of LLN.45 These indices of demyelination are particularly useful for most forms of inherited demyelinating polyneuropathies where severe conduction slowing should be evident in all motor nerves and all nerve segments studied (see later). In contrast, acquired demyelinating polyneuropathies demonstrate multifocal, nonuniform slowing such that conduction slowing is not anticipated in every nerve but should be present in more than one nerve. Various research criteria for the diagnosis of CIDP reflect this fact.46-48 Criteria adapted from the recent European Neuromuscular Center consortium on CIDP International Workshop entitled “Childhood Chronic Inflammatory Demyelinating Polyneuropathy” are listed in Box 33-1.48 Electromyography can help distinguish between hereditary and acquired demyelinating polyneuropathies. Most hereditary demyelinating neuropathies demonstrate uniform

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BOX 33-1 CLINICAL AND ELECTROPHYSIOLOGIC CRITERIA FOR CHILDHOOD CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY (CIDP) Mandatory Clinical Criteria Progression of muscle weakness in proximal and distal muscles of upper and lower extremities over at least 4 wk or Rapid progression (Guillain-Barré-like presentation) followed by relapsing or protracted course (>1 yr) Areflexia or hyporeflexia Major Laboratory Features Electrophysiologic Criteria Must demonstrate at least three of the following four major abnormalities in motor nerves (or two of the major plus two of the supportive criteria) A. Major 1. Conduction block or abnormal temporal dispersion* in one or more motor nerves at sites not prone to compression a. Conduction block: at least 50% drop in negative peak area or peak-to-peak amplitude of proximal compound muscle action potential (CMAP) if duration of negative peak of proximal CMAP is < 130% of distal CMAP duration b. Temporal dispersion: abnormal if duration of negative peak of proximal CMAP is > 130% of distal CMAP duration* 2. Reduction in conduction velocity (CV) in two or more nerves: < 75% of mean CV value for age minus 2 SD 3. Prolonged distal latency (DL) in two or more nerves: >130% of mean DL value for age plus 2 SD 4. Absent F waves or prolonged F-wave minimal latency (ML) in two or more nerves: > 130% of mean F-wave ML for age plus 2 SD B. Supportive When conduction block is absent, the following abnormal electrophysiologic parameters are indicative of nonuniform slowing and thus of an acquired neuropathy: 1. Abnormal median sensory nerve action potential (SNAP) while the sural nerve SNAP is normal 2. Abnormally low terminal latency index94,97,99: distal conduction distance (mm)/(conduction velocity [m/sec]) ÷ distal motor latency [msec])

3. Side-to-side comparison of motor CVs showing a difference of > 10 m/sec between nerves Cerebrospinal Fluid (CSF) Criteria Protein > 45 mg/dL Cell count < 10 cells/mm3 Nerve Biopsy Features Predominant features of demyelination Exclusion Criteria A. Clinical features or history of a hereditary neuropathy, other disease, or exposure to drugs or toxins known to cause peripheral neuropathy B. Laboratory findings (including nerve biopsy or genetic testing) that show evidence of a cause other than CIDP C. Electrodiagnostic features of abnormal neuromuscular transmission, myopathy, or anterior horn cell disease Diagnostic Criteria (must meet all exclusion criteria) A. Confirmed CIDP 1. Mandatory clinical features 2. Electrodiagnostic and CSF features B. Possible CIDP 1. Mandatory clinical features 2. One of the three laboratory findings *Conduction block and temporal dispersion can be assessed only in nerves where the amplitude of the distal CMAP is > 1 mV. From Nevo Y, Topaloglu H: 88th ENMC International Workshop: Childhood chronic inflammatory demyelinating polyneuropathy (including revised diagnostic criteria), Naarden, The Netherlands, December 8-10, 2002. Neuromuscul Disord 12:195-200, 2002.

slowing along all segments of individual nerves and affect all nerves to the same degree. In contrast, acquired demyelinating neuropathies affect nerves in a multifocal or nonuniform fashion. This difference is readily explained by the fact that hereditary neuropathies are genetically determined disorders of myelin formation and thus all myelin is incorrectly formed. Acquired demyelinating disorders such as GBS or CIDP demonstrate nonuniformity of slowing because of the patchy nature of immune attack. Wilbourn, and later Lewis and Sumner, pointed out these important differences between acquired and inherited demyelinating neuropathies.49,50 Lewis and Sumner compared the electrophysiologic studies of nerves in the upper extremities of 40 patients with acquired demyelinating neuropathy to 18 patients with CMT-1. All but 4 of the 40 patients with acquired demyelinating neuropathy showed at least one feature of differential slowing. Significant differences in


slowing were observed between the ulnar and median motor nerves and between proximal and distal segments of the median motor nerve in the acquired demyelinating form, whereas slowing was uniform in CMT-1. Nineteen of 35 in the acquired neuropathy group had CVs of median motor nerves that differed from ulnar motor CVs by at least 5 m/sec; 8 of 35 had differences greater than 10 m/sec. This was not observed in CMT-1. A study of 127 CMT-1 patients found that motor CVs were almost identical when comparing ulnar nerve to median nerve, or when comparing median, ulnar, or peroneal nerves side to side. The same uniformity applied to proximal versus distal segments of the same nerve, to median versus ulnar F-wave minimal latencies, and even to median motor nerve versus peroneal motor nerve.51 However, some exceptions to this general rule of uniformity in genetically determined polyneuropathies are occasionally noted; such has been seen in both CMT-X28 and metrachromatic leukodystrophy.52 To establish whether nerve conduction is slowed uniformly or differentially, a number of motor nerves must be studied. Side-to-side comparisons of the same nerve are particularly helpful. Comparing motor nerve CVs (NCVs) of different nerves in the same limb is also useful. In general, the difference in CV between nerves does not exceed 10 m/sec in the inherited demyelinating polyneuropathies. If comparing CVs of upper to lower motor nerves, a difference up to 15 m/sec is allowable for “uniform” slowing. Analyzing the characteristics of conduction along a particular nerve also aids in the determination of uniformity or nonuniformity of conduction. For example, conduction slowing should be similar along the entire length of the nerve in an inherited demyelinating polyneuropathy, whereas in an acquired case differential slowing is common. Differential slowing may manifest as an unusually prolonged F wave or distal latency in the setting of a normal or near-normal forelimb CV.49,50,53,54 In acquired demyelinating polyneuropathies, demyelination may affect individual axons or groups of axons within a nerve to differing degrees, so that some fibers conduct much more slowly than others. This results in the electrophysiologic phenomenon of abnormal temporal dispersion (Fig. 33-1). Abnormal temporal dispersion at sites not prone to entrapment is a common feature of acquired demyelinating polyneuropathies and is not typically seen in inherited demyelinating polyneuropathies. Abnormal temporal dispersion can be defined as a prolongation of compound muscle action potential (CMAP) duration of greater than 20% for the peroneal, median, and ulnar motor nerves and a greater than 30% prolongation for the tibial nerve, when comparing distal stimulation to proximal stimulation of the nerve.55 Lewis and Sumner found that in patients with CMT-1, no patient had an increased CMAP duration of greater than 25% with proximal versus wrist

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stimulation. In contrast, two thirds of patients with acquired demyelinating neuropathies had an increased duration of greater than 40%, frequently with temporal dispersion of 100% or more.49 Another physiologic consequence of segmental demyelination is conduction block, defined as the failure of nerve fibers to transmit electrical impulses across a demyelinated segment. Thus, stimulation distal to a demyelinated segment elicits a larger CMAP amplitude than stimulation proximal to the area of demyelination (Fig. 33-2). Conduction block may be complete, in which case the impulse fails to conduct across any myelinated nerve fibers and results in an unelicitable CMAP. More commonly, partial conduction block is observed, manifested as a significant reduction in motor nerve action potential (CMAP) amplitude and area with proximal versus distal stimulation. Criteria for the diagnosis of conduction block include proper technique and the absence of significant temporal dispersion.56 To suggest an acquired demyelinating neuropathy, the conduction block must occur at anatomic sites not prone to entrapment. For example, the conduction block may be present in the peroneal nerve between the ankle and below the fibular head, median nerve between the wrist and elbow, and/or the ulnar nerve between the wrist and below the elbow. Proposed criteria for definite, partial, and probable partial conduction block for different motor nerves with different degrees of temporal dispersion have been published.57 In general, conduction block is defined as a reduction in CMAP amplitude or area of greater than 40% to 50% in the absence of significant temporal dispersion. Conduction block is less commonly observed in inherited demyelinating polyneuropathies.53 A series of 127 CMT-1 patients found that only 19 (5.3%) of 360 nerve segments studied showed a reduction of greater than 50% amplitude on proximal versus distal stimulation.51 It is noteworthy, however, that in 13 of these 19 cases, the distal CMAP amplitude was reduced (including 6 cases with CMAP amplitude less than 50% of LLN), suggesting that interphase cancellation may have contributed. This illustrates that caution must be used in interpreting conduction block when the distal CMAP is already low (Fig. 33-3). In the 6 cases in which the distal CMAP was not reduced, the apparent conduction block was observed at common sites of entrapment, such as the fibular head in 5 cases. However, other authors have reported the presence of conduction block on NCS of patients with CMT-1,58,59 but in one such case series the authors questioned whether supramaximal stimulation was attained. These authors found that when 3 patients were re-examined with higher stimulation, only one of three clearly displayed conduction block. This case series illustrates the importance of delivering supramaximal stimulation, especially since stronger stimuli are often required to obtain a response for some inherited demyelinating polyneuropathies.

650 MNC Record Switch: N-R Stim: 1

Neuromuscular Disorders #1 Data on Local Hard Disk Rate: Non-Recurrent

Level:

Peroneal.L 38.4 mA 5 ms

A

38.4mA

1

200 uV

A

73.7mA

2

200 uV

08:55:53

Dur: 0.3 ms Step: 3

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Rectify: Off 6.1.0

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: EDB

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Area mVms

Temp °C

A1: Knee

16.8

25.1

0.3

1.9

34.2

A2: Ankle

3.6

4.7

2.1

5.1

33.9

A3: Fibula

14.7

25.3

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0.6

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A4: Malleolus

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Knee-Ankle

262

13.2

20

Ankle-EDB

57

3.6

220

11.1

Fibula-Ankle

20

Malleolus-EDB TEMP: 34.4°C

FIGURE 33–1 Temporal dispersion of the peroneal motor nerve on nerve conduction study in a 3{1/2}-year-old girl with chronic inflammatory demyelinating polyradiculoneuropathy for 18 months. EDB, extensor digitorum brevis; CV, conduction velocity. (From Burns TM, Dyck PJ, Darras BT, Jones HR Jr: Chronic inflammatory demyelinating polyradiculoneuropathy. In Jones HR, De Vivo DC, Darras BT [eds]: Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia, Butterworth Heinemann Health, 2003, pp 445-468.)

Bolton characterized an unusual group of five children seen during a 15-year period with congenital or inherited polyneuropathies as having the high-low syndrome.60 Typically when performing NCSs on infants, one only needs an electrical stimulus of 0.05 or 0.1 millisecond duration to easily evoke a motor or sensory response. In contrast, rarely one finds a child requiring maximal voltage and a stimulus duration of 0.5 milliseconds (Fig. 33-4). Because such stimuli are inherently uncomfortable, one needs to perform this type of study under analgesic medication. Once a CMAP was obtained, each child had remarkably low CVs; thus high stimulus, low CV syndrome. Four of these children required stimuli of 0.2 millisecond and the last a 0.5 millisecond stimulus to obtain a motor CMAP; each was of very low amplitude 0.2 mV for the three

infants, and the other two ranged from 0.5 to 1.5 mV. The one floppy infant requiring 0.5 millisecond stimulus only demonstrated a CMAP on one of three motor nerves tested. CVs in all instances were 3 to 8 m/sec with the exception of 10 to 13 m/sec for metachromatic leukodystrophy. Distal latencies were similarly very prolonged, generally ranging from 10 to 33 milliseconds. These children had varied clinical presentations primarily as a floppy infant, or a persistent hypotonia in three, who later on evidenced developmental motor delay, gait ataxia, and clumsy limbs with relatively preserved muscle bulk. The peripheral nerves were normal to palpation in each child; none had palpably enlarged nerves. Each of these babies eventually were proved to have a variety of CMT, such as DSD (CMT-3). One of the other two chil-

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Clinical Neurophysiology of Pediatric Polyneuropathies MNC Record Switch: N-R Stim: 1

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FIGURE 33–2 Partial conduction block of the median motor nerve in a 3{1/2}-year-old girl with chronic inflammatory demyelinating polyradiculoneuropathy. APB, abductor pollicis brevis; CV, conduction velocity. (From Burns TM, Dyck PJ, Darras BT, Jones HR Jr: Chronic inflammatory demyelinating polyradiculoneuropathy. In Jones HR, De Vivo DC, Darras BT [eds]: Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia, Butterworth Heinemann Health, 2003, pp 445-468.)

dren had a progressive polyneuropathy later defined as a component of metachromatic leukodystrophy, whereas the other proved to have a remitting relapsing polyneuropathy of the CIDP type.60 There are exceptions to the general rule that inherited demyelinating polyneuropathies display uniform conduction slowing. CMT-X61 and hereditary neuropathy with liability to pressure palsies (HNPP) are two inherited polyneuropathies that often exhibit multifocality or nonuniformity of slowing on electrodiagnostic testing, and this may occasionally make it difficult to distinguish CIDP from these inherited disorders. HNPP and CMT-X, discussed in more detail later, more typically present in adults and less commonly in adolescents. Refsum’s disease and adrenomyeloneuropathy (AMN) are rare inherited disorders in which NCS may reveal multifocal demyelination. In Refsum’s disease, motor CVs usually are

markedly slow in the primarily demyelinating range and may show multifocal slowing. NCS in AMN are less abnormal and suggest a mixed neuropathic pattern of multifocal demyelination and axonal loss.62,63 We have also observed that CMAP dispersion is a common finding on electrodiagnostic testing of children with metachromatic leukodystrophy.52 The CVs of normal children increase during the first 3 to 5 years from values in the 20 to 30 m/sec range to normal adult values in the 40 to 50 m/sec range. In contrast, in children with CMT-1, CVs may begin in either a similar range but often decrease slightly during this period before leveling off.64,65 Thus, it may be difficult to conclusively determine slowing of CV during the first 2 or 3 years of life, and abnormal slowing may become much more evident in both inherited and acquired demyelinating neuropathy after the first few years. For example, in a child with

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FIGURE 33–3 Peroneal motor nerve conduction studies in a 12-year-old boy with a 1-year history of relapsing-remitting chronic inflammatory demyelinating polyradiculoneuropathy partially responsive to intravenous immunoglobulin, plasmapheresis, or prednisone. Distal latencies are prolonged, and conduction velocities (CVs) are low. The peroneal distal compound muscle action potential (CMAP) is less than 50% of the lower limit of normal for age. Clinicians must be cautious when interpreting conduction block if the distal CMAP is already low. The clinical history and response to immunotherapy were critical in making the diagnosis. (From Burns TM, Dyck PJ, Darras BT, Jones HR Jr: Chronic inflammatory demyelinating polyradiculoneuropathy. In Jones HR, De Vivo DC, Darras BT [eds]: Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia, Butterworth Heinemann Health, 2003, pp 445-468.)

CMT-1, motor NCVs may be in the mid-20s (m/sec) during the first year of life—therefore in the normal range for age—then remain in the mid-20s throughout childhood and adulthood—thereby falling below the ageadjusted normal range.

ACUTE DEMYELINATING POLYNEUROPATHIES The demyelinating form of GBS is the only acute demyelinating neuropathy seen with significant frequency. GBS is a clinical syndrome characterized by generalized weakness

FIGURE 33–4 Median nerve conduction study. Strong stimuli (maximum voltage, 0.2-millisecond duration) at the wrist (A) and elbow (B) evoked no sensory responses from the digital nerves (lower traces in A and B) and low-amplitude compound thenar muscle action potentials of greatly prolonged latencies (upper traces in A and B). Conduction velocity was 6 m/sec between elbow and wrist, and the distal latency was 15 milliseconds. Note the prominent shock artifact on wrist stimulation. (A and B, From Bolton CF: Polyneuropathies. In Jones HR Jr, Bolton CF, Harper CM Jr: Pediatric Clinical Electromyography. Philadelphia, Lippincott-Raven, 1996, pp 251-352.)

evolving over days to a maximum of 4 weeks. Weakness and depressed or absent muscle stretch reflexes are the two features required for diagnosis.66 Cytoalbuminologic dissociation in the cerebrospinal fluid (CSF) (elevated protein with normal cell count) also occurs in most patients. GBS has several pathophysiologic subtypes: acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN) and Miller-Fisher syndrome (MFS). AIDP, the demyelinating form of GBS, predominates in Western Europe, the United States, and Australia. All forms but MFS have a similar presentation. They can be readily differentiated only by electrodiagnosis, the axonal forms having a poorer prognosis than the demyelinating form. For a discussion of AMAN and AMSAN, see the section on acute axonal neuropathies. GBS (all types) affects patients of all ages, but incidence increases throughout life, so that children are affected


much less frequently than adults. Incidence in patients younger than 15 years of age is approximately 0.8 to 1.5 per 100,000.16,67-69 Detailed data on frequency at different ages during childhood are scarce. However, a study of more than 10,000 GBS-related hospital discharges in the United States conducted by the Centers for Disease Control and Prevention found similar incidences of GBS in children of all ages, except for a particularly low incidence during infancy (0.38 per 100,000).69 In Paraguay, GBS was more common in children aged 4 years or younger than in older children16 and Delanoe and associates found a predominance of cases younger than 3 years of age.70 A German study of 175 children found a bimodal age distribution with peaks at 4 and 12 years.71

Infantile Guillain-Barré Syndrome Although rare, GBS does occur in infancy. It presents with acute hypotonia and weakness, which may be associated with respiratory distress and feeding difficulties. Even less commonly, GBS develops in utero or in the neonatal period.72-75 Diagnosis is apparent when a diagnosis of acute inflammatory demyelinating polyneuropathy has already been made in the affected mother72,74 but is more difficult where there is no maternal history of weakness or sensory loss.73,75 Electrodiagnosis in such cases is suggestive of acquired demyelinating polyneuropathy. Findings include slowed nerve conduction, temporal dispersion, conduction block, and evidence on the needle examination of acute denervation.73,75 The electrodiagnostic examination is useful for differentiation of infantile GBS from other causes of acquired infantile hypotonia, such as poliomyelitis, infantile botulism, and myasthenia gravis.76 CSF protein is usually elevated; CSF cell count should be normal. In most cases recovery has been spontaneous and complete, although occasional infants subsequently developed CIDP.77,78 There is a single report of a rapid recovery after intravenous immunoglobulin therapy in a 2-week-old infant with GBS.72

Childhood Guillain-Barré Syndrome Clinical Features GBS is the most common cause of acute flaccid paralysis in childhood.2,79 A gastroenteritis or respiratory infection is often seen 2 to 4 weeks before the development of GBS.71,79-81 The primary features of GBS are rapidly progressive limb weakness with lost or diminished muscle stretch reflexes. Other findings such as distal paresthesia, facial weakness, and dysautonomia often prove helpful in the early diagnosis of individual cases.79-81 Weakness is usually symmetric in pediatric GBS and more marked in the lower extremities. Affected children have difficulty

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climbing stairs, squatting, and rising. Proximal weakness is not uncommon. By definition, GBS has a rapid course, reaching a maximal deficit usually within 10 to 14 days in 80% of children but occasionally not for 4 weeks.79 Pain is often prominent in childhood GBS70,82,83 and may confound the initial diagnosis, particularly in younger children. Pain was the presenting symptom in 47% of children with GBS in one large clinical series.70 The pain typically involves the back, neck, and legs. Children may refuse to bear weight and resist passive limb movement. It is commonly associated with marked irritability and may be accompanied by vomiting and headache.82 This “pseudomeningoencephalopathic” presentation may be associated with other signs of meningeal irritation including stiff neck and Kernig’s and Brudzinski’s signs. Creatine kinase may occasionally be elevated, causing confusion with an acute myopathy. Childhood GBS may also present with an acute sensory ataxia, especially in toddlers.84,85 The differential diagnosis of such cases also includes the Fisher variant of GBS (ophthalmoplegia, ataxia, and areflexia).85 Cranial nerve palsies, usually of the facial or oculomotor nerves, are an uncommon presenting sign of pediatric GBS.79,86 Respiratory insufficiency is a rare but important initial presentation of pediatric GBS.87 In one report the development of respiratory failure was associated with rapid evolution of complete flaccid paralysis and loss of all brainstem reflexes, including pupillary responses mimicking brain death.88 Internal ophthalmoplegia is rare in AIDP and should prompt consideration of diphtheria, tick paralysis, and botulism.88 Transient dysautonomia sometimes occurs and may be the major risk factor for the rare occurrence of a pediatric fatal outcome. Urinary sphincter dysfunction occurs concomitantly but almost always recedes within 24 hours. When it does not, a spinal cord lesion requires immediate consideration. Occasionally, GBS is accompanied by symptomatic central nervous system (CNS) demyelination.89-91 Children with GBS should be admitted to hospital for monitoring. Although weakness and hypotonia may be relatively mild at onset, the potential for sudden, sometimes fatal, respiratory or autonomic compromise should always be anticipated.79 The importance of zealous cardiovascular and autonomic monitoring in all cases of GBS must be emphasized.92 Mortality in children with GBS is fortunately a rare occurrence (< 1% in the United States69 and probably < 5% worldwide).16,93 Deaths are due to potentially preventable respiratory complications. Autonomic instability is a predictor of fatal cardiac arrhythmias in GBS.92 Children with mild GBS who are able to ambulate unassisted are usually monitored and given supportive care, such as physical therapy and analgesics. Those unable to walk unassisted or with respiratory compromise should be treated with either intravenous immunoglobulin, a more

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practical therapy for childhood GBS because of its ease of administration, or plasma exchange. Retrospective studies suggest that either treatment hastens recovery of independent ambulation in GBS.71,80,94-100 Clinical responses to intravenous immunoglobulin may be dramatic.101,102 A total dose of 2 gm/kg of intravenous immunoglobulin is given over 2 to 5 days and is generally well tolerated at all ages.84 Cerebrospinal Fluid Analysis CSF analysis usually demonstrates the classic albuminocytologic dissociation with protein values between 80 and 200 mg/dL. The presence of more than 50 leukocytes per milliliter is atypical of pediatric GBS and should prompt consideration of poliomyelitis,103,104 West Nile virus,105 CNS lymphoma,106 and Lyme infection. In contrast with adults, we are unaware of any cases of children developing GBS as the presenting sign of human immunodeficiency virus (HIV).107 Magnetic Resonance Imaging Magnetic resonance imaging (MRI) demonstrates hypertrophic and gadolinium-enhancing cauda equina, and lumbar roots have been demonstrated in children with GBS83,108 and the distribution of nerve root enhancement appears to correlate with the distribution of pain.83 Nerve root enhancement is nonspecific, however, and may also be seen in CIDP, sarcoidosis, lymphoma, and leptomeningeal carcinoma. Gullain-Barré Pathogenesis

Stage I. Lymphocytes migrates through endoneural vessels and surround nerve fiber, but myelin sheath and axon not yet damaged

Subtle nerve root enhancement has been reported in severe CMT-1; thus, enhancement per se cannot rule out inherited demyelinating radiculoneuropathies.109 MRI is an important testing modality to exclude cord lesions, including both mass lesions and transverse myelitis in those children in whom GBS is associated with sphincter dysfunction. Electrodiagnosis in Demyelinating GBS The typical EMG findings of childhood GBS include slowing of CVs to less than two thirds normal, prolongation of distal latencies, and loss or prolongation of F waves and H reflexes.79 Slowing of motor nerve conduction is more profound in younger children.79,86 However, this result does not correlate with the child’s clinical features or prognosis. In those rare instances where the only neurophysiologic abnormality is the loss of F waves from affected extremities, the alternative diagnosis of transverse myelitis also requires consideration (Fig. 33-5). Delanoe and associates, using established criteria for demyelination, examined the temporal evolution of nerve conduction abnormalities in 43 children with demyelinating GBS.70 During week 1 of illness, the most common abnormalities in descending order of frequency were a prolonged or absent F wave (88%), prolonged distal latency (75%), and conduction block (58%). Slowing of motor CV was noted in 50% of children during the first week. Sensory conduction abnormalities were infrequent. Syndrome Nerve conduction velocity Response of hypothenar muscles to ulnar nerve stimulation Response Response (Normal conduction velocity) to stimulus to stimulus at wrist at elbow

Stage II. More lymphocytes extruded and macrophages appear. Segmental demyelination begins; however, axon not yet affected

Stage III. Multifocal myelin sheath and axonal damage, Central chromatolysis of nerve cell body occurs and muscle begins to develop denervation atrophy Stage IV. Extensive axonal destruction. Some nerve cell bodies irreversibly damaged, but function may be preserved because of adjacent less-affected nerve fibers

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FIGURE 33–5 Pathogenesis and progression of Guillain-Barré syndrome. (Modified from Jones HR Jr: Collection of Medical Illustrations, Vol. I, part II. West Caldwell, NJ, Ciba, 1986, pp 218-219. Copyright©Ciba.)


During week 2, reduced CMAP amplitude was universal. Prolonged distal latency was present in 92% and slowed motor CV in 84%. Conduction block and/or temporal dispersion were observed in 61%. The frequency of conduction block and/or temporal dispersion declined thereafter. CMAP amplitude reduction was maximal during week 3, whereas abnormalities of CV (distal latencies, F waves) were maximally abnormal during week 5. Compared with similar data in adults,110 children showed slower evolution of conduction slowing and much more rapid recovery of CMAP amplitudes. This group proposed diagnostic criteria for demyelinating GBS in children, which they assert would permit a tentative diagnosis in 90% of children in the first week and a definite diagnosis during week 2. Sensory conduction abnormalities were less frequent than motor and the most common abnormality was the now classic feature of GBS, abnormal median sensory with sparing of the sural response. In adults with GBS, a mean CMAP amplitude of less than 20% of the LLN is predictive of slow and incomplete recovery.111 Pediatric GBS series comprising patients with the AIDP form have shown good recovery despite low mean CMAP amplitudes.79,112,113 Ammache and colleagues113 found that the only electrophysiologic predictor of outcome in a small group of children with GBS was the presence of conduction block. This correlated with a good outcome. Some children do have slow and incomplete recovery, however.114,115 These children probably have an axonal form of GBS, either AMAN or AMSAN (see section on acute axonal neuropathies for a full discussion). Differential Diagnosis of Childhood Gullain-Barré Syndrome. (Box 33-2) Both spinal cord tumors and transverse myelitis may produce a rapidly progressive paralysis, hyporeflexia or areflexia, back pain, and sphincter dysfunction.116 Sphincter dysfunction is common with spinal cord lesions but rare and usually quite transient in GBS.117 Transverse myelitis may be associated with marked elevation of the CSF protein and with significant CSF pleocytosis.116 Poliomyelitis and disorders of neuromuscular transmission such as infantile botulism also require careful consideration. West Nile virus infection occurs in the Western hemisphere. Neurologic complications are much more common in the elderly, but several cases of meningoencephalitis have been reported in children.105,118 Adults may manifest a poliomyelitis-like syndrome of limb pain, multifocal weakness, preserved sensation, and a CSF pleocytosis. Electrophysiology shows reduced CMAP amplitudes and fibrillations with normal sensory responses. Similar cases can be anticipated in children in the future, and this diagnosis should be considered in the febrile child with limb weakness. Asymmetry, absence of sensory involve-

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BOX 33-2 DIFFERENTIAL DIAGNOSIS IN GUILLAIN-BARRÉ SYNDROME Pseudoencephalopathy Meningitis Meningoencephalitis Cerebellar syndrome Postinfectious cerebellar ataxia Structural lesion Myelopathy Spinal cord compression Transverse myelitis Acute disseminated encephalomyelitis Anterior spinal artery distribution infarction Anterior horn cells Enteroviral infection Poliomyelitis Peripheral nerve Tick paralysis Diphtheria Lyme disease Toxins and drugs Porphyria Critical illness polyneuropathy Mitochondrial disease Neuromuscular junction Botulism Myasthenia gravis Neuromuscular blockade Pseudocholinesterase deficiency Muscle disorders Acute myositis Infectious Autoimmune Metabolic myopathy Glycogen metabolism disorders and others Periodic paralysis Critical care myopathy From Sladky JT: Guillain-Barré syndrome. In Jones HR, De Vivo DC, Darras BT (eds): Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia, Butterworth Heinemann Health, 2003, pp 407-424.

ment, CSF pleocytosis, and a motor axonal pattern distinguish it from demyelinating GBS. Moreover, weakness appears concurrent with fever in West Nile virus but occurs in the postinfectious period in GBS. HIV has occasionally been associated with GBS,107 although to our knowledge GBS has not been the presenting

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illness of pediatric HIV infection. Toxins, including heavy metals, glue sniffing, buckthorn wild cherry, and fish toxins may also warrant consideration in the diagnosis of GBS.117 Although uncommon, tick paralysis is potentially fatal without specific treatment and should be considered in all children with acute flaccid paralysis. Early pupillary involvement is common in tick paralysis but only rarely observed in GBS.119 Typical EMG findings in tick paralysis include markedly diminished CMAP amplitudes, with preserved motor CVs, motor distal latencies, and SNAPs.119-121 Tick paralysis can be difficult to distinguish from the axonal forms of GBS, but it does not demonstrate the multifocal demyelination characteristic of classic GBS. All children with acute generalized weakness should be examined carefully for ticks, with special attention to the scalp. Removal of ticks results in dramatic improvement.119,120 Diphtheria still needs consideration in children with recent pharyngitis, fever, and acute peripheral neuropathy with associated bulbar palsy. The immunization history is of importance in this clinical setting.122 One of the authors has seen seven instances of diphtheria during his career, all of whom had incomplete immunization, and two developed neurologic problems; one a generalized polyneuropathy and the other a severe bulbar palsy (Jones HR, personal communication, 2005.) Hepatic porphyria and hereditary tyrosinemia are discussed later and should be considered in the appropriate setting. Vincristine toxicity may present as an acute polyneuropathy in children with underlying CMT disease.123 Critical illness polyneuropathy should also be considered in the appropriate setting (Box 33-3).124 However, in our experience a critical illness myopathy is more common in children.125

BOX 33-3 DIFFERENTIAL DIAGNOSIS OF CRITICAL ILLNESS POLYNEUROPATHY Spinal cord lesions Prolonged neuromuscular blockade Steroid or relaxant-induced myopathy Acute necrotizing myopathy Hypophosphatemia Toxic and thiamine-deficiency neuropathies Asthma-amyotrophy (Hopkins) syndrome Guillain-Barré syndrome From Ouvrier RA: Neuropathies secondary to systemic disorders. In Jones HR, De Vivo DC, Darras BT (eds): Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia, Butterworth Heinemann Health, 2003, pp 493-503.

A few rare inborn metabolic errors, including tyrosinemia, porphyria, or Leigh’s disease,126 may also have a precipitous onset of symptoms resembling childhood GBS. Hypokalemic paralysis, presenting as a manifestation of proximal renal tubular acidosis, has mimicked GBS in a 14-year-old girl with paraplegia and areflexia.127 Barium carbonate poisoning, severe vomiting and diarrhea, and clay ingestions have also presented with a similar clinical picture. One 18-year-old boy presented with 5 hours of numbness and quadriplegia, with hypokalemia (K+ of 2.11 mEq/mL). In retrospect, he had consumed barium containing rat poison on a suicide attempt just an hour before the onset of his muscle weakness.128 Children with overwhelming sepsis or status asthmaticus may develop a critical illness neuromuscular syndrome, either a myopathy or a polyneuropathy, mimicking GBS.129 In the rare instance of a recurrence of GBS, before one assumes that an immunologically mediated CIDP is present,130 some of these metabolic, toxic, and possibly hereditary neuropathies also need consideration.131-133 With the frequency of severe pain in childhood GBS,134 the possible diagnosis of an inflammatory myopathy is sometimes the initial diagnostic consideration. Acute childhood myositis, in contrast with dermatomyositis, is the most likely diagnosis in this scenario. Most often these children have severe pain localized to the calves, preventing them from walking. Additionally, there is not a significant weakness. Dermatomyositis and periodic paralysis may also sometimes have subacute or acute onsets of paralysis mimicking GBS. The sometimes subtle rash distinguishes the former, whereas a careful family history may help differentiate the latter. Prognosis of Guillain-Barré Syndrome in Children Generally, the prognosis of GBS in childhood is good.70,79,80 Most children have minimal residual impairment by 1 to 4 months from onset.70,79,80,86,96,97,101,102 Children have a shorter clinical course and more complete recovery than is typical of adult GBS.71,79,80 Clinical predictors of slower recovery include severe weakness, rapid progression of weakness, cranial nerve deficits, and the need for assisted ventilation.71,113 Children with the axonal forms of GBS, AMAN, and AMSAN have slower and less complete recovery than children with AIDP. A small percentage of infants and children presenting with acute GBS later develop chronic inflammatory polyneuropathy.77,135,136 Guillain-Barré Variants AMAN, a variant of GBS, is predominantly seen in children and young adults in northern China but has also been noted in children in many other parts of the world (e.g.,


Argentina, Canada, Mexico, Spain, as well as the United States). AMAN occurs more commonly among younger children in rural environments with poor sanitation.137 CMAPs are reduced in amplitude; however, motor and sensory CVs are often normal and the EMG shows early denervation. In children with AMAN, weakness, along with EMG evidence of denervation, progressed more rapidly, evolved to a greater severity, resolved more slowly, and led to greater disability at 12-month follow-up, compared with children with AIDP.138,138a

CHRONIC GENETICALLY DETERMINED DEMYELINATING POLYNEUROPATHIES Most requests for neuromuscular evaluation of infants are prompted by the recognition of generalized hypotonia. Polyneuropathy is an uncommon cause of the “floppy infant” syndrome, which is due in approximately three quarters of cases to disorders of the CNS.139-141 In those children who ultimately prove to have neuromuscular disorders, infantile spinal muscular atrophy (SMA), congenital myopathies, and neuromuscular junction disorders are more common than polyneuropathy (Box 33-4).139-142 The absence of SNAPs, if not due to technical difficulties, is perhaps the most important electrodiagnostic clue to the diagnosis of neonatal polyneuropathies.

BOX 33-4 CONGENITAL AND EARLY INFANTILE NEUROPATHIES Peripheral neuropathies with no associated CNS component Hereditary motor and sensory neuropathies (Charcot-Marie-Tooth) Hereditary motor neuronopathies Hereditary sensory and autonomic neuropathies Peripheral neuropathies as part of metabolic or hereditary degenerative CNS disorders Immunologically mediated neuropathies CNS, central nervous system. From Gabreëls-Festen A, Gabreëls F: Congenital and early infantile neuropathies. In Jones HR, De Vivo DC, Darras BT (eds): Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia, Butterworth Heinemann Health, 2003, pp 361-388.

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Infantile-Onset Polyneuropathies Classically, these inherited demyelinating and hypomyelinating polyneuropathies have been typically known as either Dejerine-Sottas disease (DSD) or congenital hypomyelinating neuropathy (CHN).25,26,143,144 Both CHN and DSD were formerly believed to be of autosomal recessive inheritance, but today most instances are recognized to have new dominant point mutations of MPZ, EGR2, or PMP22.22,25,26,145,146 However, genetic analysis is still unrevealing in a significant proportion of infantile onset polyneuropathies (see Box 33-4).26 Affected infants have nonprogressive weakness, severe hypotonia, areflexia, and respiratory failure. At times some of these babies have the phenotypical appearance of WerdnigHoffmann disease (SMA-1) with the generalized hypotonia, a bell-shaped chest and abdomen, paradoxical respirations, and even tongue fasciculations. The pulmonary compromise may lead to a fatal outcome within the first few months. Sensory nerve action potentials are not elicitable. This finding per se is the primary distinguishing feature separating these neuropathies from SMA. Motor nerve conductions are extremely slow from birth, in the range of 3 to 10 m/sec, even more so than the axonal changes of SMA. Fibrillation potentials, positive waves, and reduced recruitment of motor unit potentials are seen on the needle examination. The CSF protein level is sometimes markedly elevated. Sural nerve biopsy generally demonstrates a severe hypomyelinating neuropathy, with or without onion bulb formation. Rarely, a primary axonal polyneuropathy is the underlying mechanism. When confronted with any floppy infant one always needs to consider a broad spectrum of motor unit disorders. In general 80% of these babies have a primary CNS mechanism and the remainder a lesion in the peripheral motor unit. This is summarized in Box 33-5. Autosomal recessive CMT (ARCMT, CMT-4) often presents during infancy. Mutations for demyelinating ARCMT have been identified in at least five genes: GDAP1, MTMR2, NDRG1, PRX, and EGR2 and additional loci are identified on chromosomes 5q and 11p15. ARCMT may present as a demyelinating or axonal polyneuropathy. An updated listing of mutations for CMT can be found at http://www.molgen.ua.ac.be/CMTMutations/default.cfm.

Charcot-Marie-Tooth (Hereditary Motor and Sensory Neuropathy) CMT disease, the most common inherited polyneuropathy, is a genetically heterogeneous group of sensorimotor polyneuropathies sharing a similar clinical phenotype.19-21,29,30 The frequency of CMT is estimated to be 1 per 2500 to 10,000, making it the most common inherited neuromuscular disorder.3,7,8 Characteristic find-

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BOX 33-5 DIFFERENTIAL DIAGNOSIS OF FLOPPY INFANT Peripheral Motor Unit Disorder Anterior horn cell Poliomyelitis Peripheral nerve Guillain-Barré syndrome Tick paralysis Neuromuscular junction Infantile botulism Myasthenia gravis Mg2+ intoxication Muscle Polymyositis

ings include weakness and wasting of the distal limb muscles (especially the peroneal compartments), skeletal deformities such as pes cavus, absent or decreased muscle stretch reflexes, and distal sensory loss.19-21,29,30 Classification systems for CMT have historically been based on clinical features, mode of inheritance, NCSs, and neuropathologic findings.19-21,29 Two major subgroups of autosomal dominant CMT were initially identified on the basis of electrophysiologic and neuropathologic criteria. Parenthetically one needs to note that for almost a quarter of a century these two common hereditary polyneuropathies were referred to as hereditary motor sensory neuropathies (HMSN), types I to IV. Recently, there has been a return to an acronym terminology historically recognizing CMT. Electrophysiologic criteria are still the practical key to making the major clinical differentiation. CMT-1 patients have uniform slowing of nerve conduction, with hypertrophic nerves related to the characteristic abnormal myelination. In contrast with CMT-2, NCVs are normal, CMAP amplitudes low, and the associated pathologic changes include neuronal degeneration and axon loss.19-21,29 CMT-2 is discussed further in the section “Genetically Determined Chronic Axonal Polyneuropathies of Infancy and Childhood.” CMT-1 usually manifests during the first or second decade of life.19-21,29,30 Many genetic mutations have been discovered for CMT, especially for the demyelinating forms. As mentioned earlier, an updated list of mutations can be found online at http://www.molgen.ua.ac.be/ CMTMutations/default.cfm. DNA testing is commercially available for a number of these mutations, most commonly for those causing CMT-1, DSD, and CMT-X. The demyelinating form of autosomal dominant CMT usually presents clinically in the very late first or second decade of life. Its most frequent initial signs include

difficulty walking, foot deformity (pes cavus or cavus varus, clawing of toes, atrophy of intrinsic foot muscles), lower limb areflexia, and palpable nerve enlargement (Fig. 33-6).147,148 NCSs reveal a uniform, demyelinating sensorimotor polyneuropathy (discussed in detail earlier in this chapter within the section discussing the electrodiagnostic features of demyelinating polyneuropathies). The recent, rapid evolution in the application of genetic DNA technology to the clinical arena is well illustrated by the study of hereditary polyneuropathies. PMP22 mutations characterize 60% to 80% of cases of CMT-1.5,30,145,149-156 In almost all cases of CMT-1A, duplication of the 1.5-megabase chromosomal region containing PMP22 results in overexpression of PMP22 protein.25,157 Only rarely (“1% of CMT-1 cases”), point mutations of the PMP22 gene cause CMT1A.24,25,158 In contrast, deletion of the same 1.5-megabase chromosomal region results in HNPP.159-163 HNPP is due most often to a deletion of the 17p11.2 region. This rare neuropathy characteristically results in nonuniform slowing, especially distally and at sites of compression.164-166 Entrapment neuropathies are common in HNPP; they clinically present as classic mononeuropathies at sites of entrapment. In addition, a “distally accentuated myelinopathy” is often observed in which conduction slowing of motor and sensory fibers is more pronounced distally.166-169 Nonuniform slowing may be seen in asymptomatic HNPP patients, including 5- and 6-year-old children.165,166 Conduction block also may be observed in HNPP. Uncini and coworkers reported that conduction block was found in 25% of HNPP patients using a greater than 20% drop in area or amplitude as criteria and in 6% of patients using a greater than 50% drop as criteria.165 CMT-X is the second most common cause of a hereditary demyelinating polyneuropathy. This is caused by mutations in the Connexin 32 gene, and more than 200 different genetic mutations are identified.54,170,171 Both males and females may be affected by this X-linked disorder. Males typically are more clinically affected and have slower NCVs than females.172-176 The presentation of CMT-X is one of a distal sensorimotor polyneuropathy, which may be primarily demyelinating or axonal. Occasionally with CMT-1, electrophysiologic findings of slowing are nonuniform and consequently can be suggestive of an acquired (i.e., CIDP) rather than inherited disorder.177 The nonuniformity may be more obvious in CMT-X females, but it is also observed in males.177

Metabolic Demyelinating Disorders See Tables 33-1 and 33-2. Lysosomal Storage Diseases: Sphingolipidoses Globoid Cell Leukodystrophy and Metachromatic Leukodystrophy. These are rare autosomal recessive lyso-


659

Hereditary Motor-Sensory Neuropathy Type I

Swelling of the auricular nerve, may be visible or palpable

Thin (storklike) legs with very high arch (pes cavus) and claw foot or hammertoes due to atrophy of peroneal, anterior tibial, and long extensor muscles of toes

FIGURE 33–6 Clinical presentations of Charcot-Marie-Tooth neuropathy type 1. (Copyright©1997, Icon Learning Systems, LLC. A subsidiary of MediMedia, USA, Inc. All rights reserved.)

somal storage disorders. Typically these disorders present during infancy or early childhood with features of both progressive central and peripheral demyelination.178,179 Both globoid cell leukodystrophy and metachromatic leukodystrophy have devastating consequences without treatment, and thus prompt diagnosis is becoming increasingly important as novel therapies are further refined. Concomitant CNS manifestations usually serve to alert the clinician that the infant’s polyneuropathy is due to a more systemic disorder (i.e., globoid cell leukodystrophy and metachromatic leukodystrophy) rather than one confined to the peripheral nervous system. However, the polyneuropathy may be the presenting manifestation of either disorder, particularly metachromatic leukodystrophy; the CNS manifestations

may be subtle or do not become evident for a few more months. Globoid cell leukodystrophy is caused by a deficiency of the enzyme galactosylceramidase present in its classic Krabbe form. The first symptoms usually become evident between 3 and 8 months of age with motor retardation, episodic tonic rigidity with opisthotic posturing, seizures, and extreme behavioral irritability.180 These clinical features usually overshadow the associated demyelinating polyneuropathy, although occasional instances with acute-onset or clinically prominent polyneuropathy are reported in infancy and childhood.180-182 Although nerve biopsy reveals segmental demyelination and cytoplasmic inclusions,183 this diagnostic modality is rarely necessary given the recent availability of

660


TABLE 33–1. PERIPHERAL NEUROPATHY IN INHERITED METABOLIC DISEASES Category

Disease

Lysosomal storage Krabbe’s disease diseases: Sphingolipidoses Metachromatic leukodystrophy Fabry’s disease Peroxisomal diseases

Lipids

Mitochondrial diseases

Amino acids

Stored Material

Biochemical Defect

Galactosylceramide Galactosylceramide β-galactosidase

Mechanical Defect

Chromosome

GLAC

14q25-31

ARSA Sulfatide sulfatase (arylsulfatase A) GLA Trihexosylceramide Trihexosylceramide α-galactosidase VLCFA CoA synthetase ALDP Adrenomyeloneuropathy VLCFA Sulfatide

Refsum’s disease Hyperoxaluria

Phytanic acid Calcium oxalates

Cerebrotendinous xanthomatosis Tangier’s disease Abetalipoproteinemia LCHAD

Cholestanol

Leigh’s disease

Phytanic acid oxidase Alanine-glyoxylate aminotransferase Cholesterol 27-hydroxylase Unknown Unknown Trifunctional protein and long-chain 3-hydroxy-acyl-CoA dehydrogenase

PHYH AGT

22q13.31-ter Xq22.1 X128 10p 2q36-37

CTX Unknown Unknown MTP/LCHAD

Unknown Unknown Unknown

Lactate/pyruvate

Multiple enzymes

Multiple nucleotide 8993 (mtDNA)

NARP

Lactate/pyruvate

Tyrosinemia type 1

Tyrosine/succinylacetone

ATP synthase subunit 6 FAH

Cholesterol esters 3-Hydroxy dicarboxylic aciduria

Fumarylacetoacetate hydrolase

15

CoA, coenzyme A; LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase; NARP, neuropathy, ataxia, retinitis pigmentosa; VLCFA, very long-chain fatty acid; ATP, adenosine triphosphate; mtDNA, mitochondrial DNA. From Moser HW, Percy AK: Peripheral neuropathy in inherited metabolic disease. In Jones HR, De Vivo DC, Darras BT (eds): Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia, Butterworth Heinemann Health, 2003, pp 469-492.

genetic testing. Bone marrow transplantation may be beneficial in the rare juvenile variant when performed early in the disease course. Unfortunately to date this modality has not been successful in the therapy of the more common (1 per 100,000) infantile form of globoid cell leukodystrophy.184,185 Metachromatic Leukodystrophy. This autosomal recessive disorder develops when there is a deficiency of arylsulfatase A or its activator protein.186 This sulfatide lipidosis usually presents in infancy with rapid motor regression and the development of spasticity, dysarthria, dementia, and ataxia.187,188 Peripheral neuropathy is invariable; occasionally this is the predominant presenting clinical feature.187,188 At times both the late infantile and juvenile variants may mimic CMT. In one of the infants evaluated at CHB and who had a prior CMT diagnosis, the presence of Babinski signs were an important clinical indicator of concomitant CNS dysfunction.189 On another instance a previously healthy child presented with a CIDP-like illness over a 4-week period. NCS demonstrated diffuse NCV slowing (30m/sec); the CSF had a protein 10 times the ULN. When the child only had a modest response to immunosuppressive therapy, biochemical analysis was carried out. This documented a partial arylsulfatase deficiency.190

NCVs in children with metachromatic leukodystrophy are in the primarily demyelinating range.181,191 Typically motor NCVs show uniform slowing without temporal dispersion or conduction block.54 Occasional cases are, however, associated with dispersed CMAPs that mimic CIDP.189 Although sural nerve biopsy is no longer necessary, given the availability of DNA testing, it demonstrates metachromatic deposits within peripheral nerves. Bone marrow transplantation should be considered for treatment of presymptomatic siblings of children having infantile or the early stages of juvenile metachromatic leukodystrophy. This modality can diminish or stabilize the CNS manifestations, although it has not been helpful for the peripheral components of this disorder.185,192 Peroxisomal Storage Disorders Refsum’s Disease Refsum’s disease is a rare autosomal recessive disorder of lipid metabolism caused by a deficiency of phytanoyl-CoA hydroxylase.193 Classic findings of Refsum’s disease include retinitis pigmentosa with impaired night vision, cerebellar ataxia, a demyelinating peripheral neuropathy, and elevated CSF protein by age 20 years.194 The peripheral neuropathy


661

TABLE 33–2. PERIPHERAL NEUROPATHIC FEATURES OF INHERITED METABOLIC DISEASES Category

Disease

Lysosomal storage diseases: Sphingolipidoses

Krabbe’s disease

Neuropathic and EMG Features

Metachromatic leukodystrophy Fabry’s disease Peroxisomal diseases

Adrenomyeloneuropathy Refsum’s disease Hyperoxaluria

Lipids

Cerebrotendinous xanthomatosis Tangier’s disease Abetalipoproteinemia

Mitochondrial diseases

LCHAD

Amino acids

Leigh’s disease NARP Tyrosinemia type 1

Other

Acute intermittent porphyria

Schwann cell inclusions Segmental demyelination Schwann cell sulfatide (metachromatic) accumulation Segmental demyelination Lamellar inclusions in perineurial cells Axonal loss Schwann cell inclusions Segmental demyelination Schwann cell inclusions Onion bulb formation Segmental demyelination Axonal degeneration Segmental demyelination Schwann cell vacuoles Axonal loss Schwann cell vacuoles Axonal loss Axonal degeneration Segmental demyelination Axonal loss Segmental demyelination Segmental demyelination Segmental demyelination Axonal loss Segmental demyelination Axonal degeneration Segmental demyelination

LCHAD, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase; NARP, neuropathy; ataxia, retinitis pigmentosa. From Moser HW, Percy AK: Peripheral neuropathy in inherited metabolic disease. In Jones HR, De Vivo DC, Darras BT (eds): Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia, Butterworth Heinemann Health, 2003, pp 469-492.

of Refsum’s disease may develop late in the disease course and is of variable severity. Motor NCVs are usually markedly reduced into the primarily demyelinating range. Diagnosis is by assay of serum levels of phytanic acid. Treatment is by avoidance of foods that contain phytanic acid, including dairy products and beef.195 Adrenoleukodystrophy and Adrenomyeloneuropathy The childhood cerebral form of adrenoleukodystrophy (CCALD) causes progressive cerebral white matter degeneration, leading to blindness, ataxia, quadriparesis, dementia, and death by the second decade of life. Peripheral nerve abnormalities are minimal relative to the CNS manifestations of CCALD. AMN is a phenotypic variant. It usually presents as a slowly progressive myelopathy beginning in the third or fourth decade for men and the fourth or fifth decade for women.62,196,197 However, it is occasionally seen in childhood.198 The typical EMG features of AMN are multifocal slowing of motor CVs, low-amplitude CMAPs, and low or

absent SNAPs. In a case series of 99 men with AMN and 38 heterozygous women, 26 patients had at least one nerve variable value in the demyelinating range.62 However, overall, NCSs in patients with AMN suggest a mixture of axonal loss and multifocal demyelination.62,63,197,198 Analysis of plasma saturated very long-chain fatty acids (VLCFA) is the most frequently used diagnostic assay.199 The principal biochemical abnormality is the accumulation of VLCFA in tissues and also in the plasma. The defective gene maps to Xq28. It codes for a peroxisomal membrane protein referred to as ALDP or ABCD1. More than 300 mutations have been identified and are updated in the website www.x-ald.nl. Hyperoxaluria Hyperoxaluria is an interesting, rare disorder that occurs either as a primary genetic metabolic mechanism or develops secondary to dietary factors or coincident renal disease.200 The inborn metabolic form of hyperoxaluria has its primary biochemical basis related to a deficiency of the liver peroxisomal enzyme, alanine glyoxylate aminotransferase (AGT), or the cytosolic enzyme, D-glycerate dehydrogenase/

662


glyoxylate reductase (DGDH/GR). These two disorders are classified as primary hyperoxaluria (PH)-1 due to AGT deficiency or PH-2 due to DGDH/GR deficiency. PH-1 becomes clinically apparent before 5 years of age, usually presenting with either hematuria or renal colic secondary to calcium oxalate urolithiasis whose accumulation leads to chronic renal insufficiency. A peripheral neuropathy is one feature of the PH-1 form of hyperoxaluria. Although painful paresthesia and muscle weakness do occur, clinical manifestations of peripheral neuropathy tend to be relatively minor. This neuropathy includes features of both axonal degeneration and segmental demyelination.201-204 Lipid Disorder Polyneuropathies Tangier’s disease, abetalipoproteinemia, and cerebrotendinous xanthomatosis (cholestanol lipidosis) are three of the most uncommon childhood polyneuropathies. Because of the predominance of axonal pathology in this subclass of pediatric neuropathies, the first two are detailed in a later section. Cholestanol Lipidosis (Cerebrotendinous Xanthomatosis) Cholestanol lipidosis is also an uncommon autosomal recessive disorder; although peripheral nerve pathology is common, clinical signs are mild. More typically, initial manifestations begin in late childhood or adolescence consisting of cataracts; xanthomas over extensor tendons, especially the Achilles tendon; and slowly progressive spasticity, cerebellar ataxia, and dementia.178 These xanthomas, containing cholesterol and cholestanol, also develop within brain white matter, particularly in the cerebellum. Psychiatric disturbance (hallucinations, delusions, or other manifestations of schizophrenia) may precede other neurologic features. NCVs are variably reduced often in the demyelinating range. In one instance motor NCVs of peroneal and tibial nerves were 12 to 34 m/sec and 38 to 40 m/sec in median nerves.205 The SNAPs were absent in the legs, were of low amplitude in the arms, whereas sensory NCVs were slow in the arms. Needle EMG was normal. Sural nerve biopsy demonstrated segmental demyelination, remyelination, and axonal degeneration. When this diagnosis is detected early on, and appropriate treatment modalities with cholic acid initiated, its morbidity appears relatively benign. Treatment normalizes MCVs as well as EEG and evoked response abnormalities. The biochemical abnormalities are characterized by defective cholesterol 27-hydroxylase activity.206 As a consequence, cholesterol is converted via a side reaction to cholestanol (dihydrocholesterol). MRI demonstrates dif-

fuse low-density white matter lesion.207 Serum cholesterol levels are normal, but cholestanol levels in serum, CSF, and red blood cells are increased.208 Cholesterol 27-hydroxylase activity is deficient. Several mutations have been identified in the gene for cerebrotendinous xanthomatosis.209 Xeroderma Pigmentosum Xeroderma pigmentosum is a rare autosomal recessive disorder that is associated with photosensitivity, telangiectasia, predisposition to cutaneous malignancies, and ataxia. NCSs and sural nerve biopsies demonstrate mixed demyelination and axon loss.210 Amino Acid Disorders Tyrosinemia is primarily discussed in the subsequent axonal polyneuropathy section, although there is a demyelinating component. Glycoproteinoses Sialidosis type 1 is a lysosomal storage disorder of neuraminidase function. It is characterized by myoclonus and development of nonpigmentary macular degeneration (a “cherry-red spot”). An associated demyelinating neuropathy has been rarely reported.211 Chediak-Higashi Syndrome Chediak-Higashi syndrome is an autosomal recessive disorder that is associated with defective pigmentation and susceptibility to infection and to lymphoreticular malignancies. Affected children may develop a demyelinating neuropathy with conduction block.212 Mitochondrial Polyneuropathies Mitochondrial polyneuropathies may be either demyelinating or axonal. Hence, they are also discussed in the chronic axonal polyneuropathy section of this chapter. The polyneuropathy is almost always chronic, although exceptions are recorded.213 For example, Leigh’s disease also presents with a pediatric Guillain-Barré-like syndrome. Leigh’s Disease (Subacute Necrotizing Encephalopathy) Leigh’s disease typically presents in early infancy or childhood. Because of its propensity for having multisystem neurologic manifestations, the clinician is continually challenged to consider a diagnosis of Leigh’s disease. Symptomatology may include an encephalopathic component with lethargy or coma, particularly during infancy. Other manifestations include a peripheral neuropathy, ataxia and intention tremor, involuntary movements, external ophthalmoplegia, loss of vision, impaired hearing, vascular-type headaches, seizures, swallowing-feeding difficulties, and hypotonia.214 Brainstem


dysfunction is virtually always present; the clinical picture is dominated by lethargy or coma, feeding and swallowing difficulties, and hypotonia. Lactic acidosis may be significant. Death occurs within 6 to 24 months of onset. Those children who initially become symptomatic during their preschool period evidence growth failure, external ophthalmoplegia, movement disorders (dystonia, choreoathetosis, or myoclonus)215; ataxia and intention tremor as well as vascular-type headaches are more prominent. Lactic acidosis may sometimes be documented. An older-age onset is associated with a 5- to 10-year survival. Because of the multisystem predominance, peripheral neuropathic signs may be obscured. NCVs are significantly reduced to the demyelinating range. Brainstem auditory evoked responses are affected.216 The typical enzyme deficiencies involve mutations of nuclear or mitochondrial DNA.178 The inheritance pattern of Leigh’s disease is heterogeneous, involving both X-linked and autosomal recessive mendelian as well as mitochondrial mechanisms.215–217 Brain MRI most frequently demonstrates abnormalities in the thalamus, basal ganglia, and brainstem.215 Involvement of the putamen is virtually uniform. There is no effective therapy; however, certain supportive modalities, including home ventilator programs, may be helpful. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder due to mutations in thymidine phosphorylase.218,219 Mutations in thymidine phosphorylase prevent normal catabolism of thymidine. The accumulation of thymidine likely impairs mitochondrial DNA replication and repair, leading to mitochondrial dysfunction. Clinical onset ranges from ages 5 months to adulthood, with an average of 18 years. Children with MNGIE develop a polyneuropathy associated with gastrointestinal dysfunction, ophthalmoparesis, ptosis, cachexia, and hearing loss. The polyneuropathy is demyelinating in approximately half of MNGIE patients and has mixed axonal and demyelinating electrodiagnostic features in the remainder.218 Brain MRI demonstrates evidence of a leukoencephalopathy.

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY It is estimated that childhood CIDP may account for up to 10% of cases of all childhood polyneuropathies.10,11,17,18

663

Rarely, CIDP presents during infancy.77,78 This neuropathy occurs more commonly during the preschool years136,220; however, an onset in later childhood is more typical. Generally childhood CIDP presents subacutely, although its onset may be relatively rapid and indistinguishable from GBS.135,136,221 The cardinal clinical features of CIDP include generalized weakness and reduced or absent muscle stretch reflexes, often associated with symmetric sensory symptoms or signs. Most children present because of gait abnormalities.11,135,136,220-224 Muscle weakness is often both proximal and distal due to patchy immune attack along the length of the peripheral nerves and nerve roots. The presence of proximal weakness serves to differentiate this disorder from the hereditary demyelinating neuropathies where distal weakness predominates. Less commonly the upper extremities are equally or more affected.136,220-222,224 Paresthesia and distal sensory loss are often difficult to identify in children.136,220-223 The cranial nerves are occasionally involved in CIDP. Facial weakness, dysarthria, and dysphagia may occur.136,220,221,223 Significant involvement of the respiratory muscles is rare but occasionally reported.225 Elevation of the CSF protein (>35 mg/dL) without pleocytosis (

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