Peripheral Nerve Diseases: Handbook of Clinical Neurophysiology, Volume 7

Handbook of Clinical Neurophysiology Series Editors

Jasper R. Daube Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA and

François Mauguière Functional Neurology and Epilepsy Department, Hôpital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, F-69394 Lyon Cedex 03, France

Volume 7 Peripheral Nerve Diseases Volume Editor

Jun Kimura Professor Emeritus, Department of Neurology, Kyoto University School of Medicine, Japan and Professor, Division of Clinical Electrophysiology, Department of of Neurology, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA

Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto 2006

Radarweg 29, 1043 NX, Amsterdam, The Netherlands © 2006, Elsevier B.V. All rights reserved. The right of Jun Kimura to be identified as editor of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without either the prior permission of the publishers or a licence permitting restricted copying in the United Kingdom issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1T 4LP. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, USA: phone: (+1) 215 238 3804, fax: (+1) 215 238 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’. This edition published 2006 ISBN 0 444 51358 2 ISSN 0 156 74 23 1 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Note 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 practitioner, 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 authors 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

Printed in the Netherlands

For Elsevier: Commissioning Editor: Michael Parkinson Project Development Editor: Lynn Watt Project Manager: Anne Dickie Design Director: George Ajayi

List of Contributors

James W. Albers

Department of Neurology, University of Michigan Health System, Ann Arbor, MI, USA.

Amer Al-Shekhlee

Case Western Reserve University, University Hospitals of Cleveland, OH, USA.

Michael J. Aminoff

Department of Neurology, School of Medicine, University of California, San Francisco, CA, USA.

Edward A. Aul

University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Department of Neurology, Iowa City, IA, USA.

Tulio E. Bertorini

University of Tennessee Health Science Center and Wesley Neurology Clinic, P.C., Memphis, TN, USA.

Juan M. Bilbao

Department of Neuropathology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Canada.

Hugh Bostock

Sobell Department, Institute of Neurology, University College London, Queen Square, London, UK.

Kevin B. Boylan

Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.

Mark B. Bromberg

Department of Neurology, University of Utah, Salt Lake City, UT, USA.

William F. Brown

McMaster University Medical Center, Hamilton, Ontario, Canada.

David Burke

Institute of Clinical Neurosciences, University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia.

William W. Campbell

Neurology Department, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Phillip F. Chance

Neurogenetics Laboratory, Chief, Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.

Vinay Chaudhry

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

David R. Cornblath

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Giorgio Cruccu

Dipartimento Scienze Neurologiche, Viale Università 30, Roma, Italy.

Elaine S. Date

Division of Physical Medicine & Rehabilitation, Department of Orthopedic Surgery, Stanford University Medical Center, Stanford, CA, USA.

J. Gert van Dijk

Department of Neurology and Clinical Neurophysiology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.

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LIST OF CONTRIBUTORS

Günther Deuschl

Department of Neurology, Christian-Albrechts-Universität Kiel, Niemannsweg 147, Kiel, Germany.

John England

Chairman of Neurology, Deaconess Billings Clinic, Neuroscience Department, Billings, MT, USA.

Roberto Guiloff

Neuromuscular Unit, West London Neurosciences Centre, Charing Cross Hospital, London, UK.

Chelsea Grow

George Washington University, Washington, DC, USA.

Mark C. Hannibal

Neurogenetics Laboratory, Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.

Richard A.C. Hughes

Department of Clinical Neurosciences, Guy’s, King’s and St Thomas’ School of Medicine, London, UK.

Ryuji Kaji

Department of Clinical Neuroscience, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.

Praful Kelkar

Department of Neurology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.

John J. Kelly

George Washington University, Washington, DC, USA.

Matthew C. Kiernan

Institute of Neurological Sciences, Prince of Wales Hospital, Prince of Wales Medical Research Institute and University of New South Wales, Sydney, Australia.

Byung - Jo Kim

Department of Neurology, Korea University Medical Center, Seoul, Korea.

Jun Kimura

Department of Neurology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.

Christian Krarup

Department of Clinical Neurophysiology NF3063, Rigshospitalet, Copenhagen, Denmark

Mark E. Landau

Clinical Neurophysiology, Walter Reed Army Medical Center, Washington DC, USA.

Daniel Larriviere

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Richard J. Lederman

Department of Neurology, S-91, Cleveland Clinic Foundation, Cleveland OH, USA.

Kerry H. Levin

Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, USA.

Cindy S.-Y. Lin

Sobell Department, Institute of Neurology, University College London, London, UK.

William J. Litchy

Consultant in Neurology, Department of Neurology, Mayo Clinic Rochester, MN, USA.

Janice M. Massey

Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, NC, USA.

Daniel L. Menkes

Department of Neurology, University of Tennessee Health Sciences Center at Memphis, Link Building, Memphis, TN, USA.

Gyl Midroni

Clinical Neurophysiology, St Michael’s Hospital, Toronto, Canada.

Suraj Muley

Department of Neurology, VAMC, University of Minnesota, Minneapolis, MN, USA.

LIST OF CONTRIBUTORS

xi

Nicholas M.F. Murray

The National Hospital for Neurology and Neurosurgery, London, UK.

Anh X. Nguyen

Neurology, CentraCare Clinic, Saint Cloud, MN, USA.

Hiroyuki Nodera

Department of Clinical Neuroscience, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.

J. Payan

D’ Aumale Cottages, Twickenham, Middlesex, UK.

Lawrence H. Phillips II

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

David C. Preston

Case Western Reserve University, University Hospitals of Cleveland, OH, USA.

Scott Riggins

Deaconess Billings Clinic, Neuroscience Department, Billings, MT, USA.

Lawrence R. Robinson

Department of Rehabilitation Medicine, University of Washington, Seattle, WA, USA.

Howard W. Sander

Weill Medical College, Cornell University, Peripheral Neuropathy Center, New York, NY, USA.

Barbara E. Shapiro

Neuromuscular Research, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Wilhelm J. Schulte-Mattler Neurologische Klinik und Poliklinik, Universität Regensburg, Regensburg, Germany. Benn E. Smith

Mayo Clinic College of Medicine, Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.

S Veronica Tan

The National Hospital for Neurology and Neurosurgery, London, UK.

James W. Teener

Department of Neurology, 1C325/0032 University Hospital, University of Michigan Health System, Ann Arbor, MI, USA.

W. Trojaborg

Helleruplund Alle 3, Hellerup, DK 2900, Denmark.

A. Truini

Department of Neurological Sciences, La Sapienza University, Rome, Italy.

Josep Valls-Solé

Unitat d’EMG,Servei de Neurologia, Hospital Clínic, Facultad de Medicina, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.

David B. Voduˇsek

Division of Neurology, University Medical Center, Zaloska Cesta 7, 1525 Ljubljana, Slovenia.

Francis O. Walker

Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Bradley V. Watson

London Health Sciences Centre, London, Ontario, Canada.

Asa J. Wilbourn

EMG Laboratory, S90, Cleveland Clinic Foundation, Cleveland, OH, USA.

Thoru Yamada

Department of Neurology, University of Iowa Hospital and Clinics, Iowa City, IA USA.

Malcolm Yeh

Department of Neurology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.

Foreword

Clinical neurophysiology encompasses the application of a wide variety of electrophysiologic methods in the analysis of normal function and in the diagnosis and treatment of diseases involving the central nervous system, peripheral nervous system, autonomic nervous system and muscles. The steady increase in growth of subspecialty knowledge and skill in neurology has led to a need for the compilation of the whole range of physiologic methods applied in each of the major categories of neurologic disease. While some of these methods are applied to a single category of disease, most are useful in multiple clinical settings. Each volume has been designed to serve as the ultimate reference source for academic clinical neurophysiologists and subspecialists involved in neurology. It will provide information needed to fully understand the physiology and pathophysiology of disorders in their patients. As such, these volumes will also serve as a major teaching aid for trainees in each of the subspecialties. The Handbook volumes cover all the clinical disorders served by clinical neurophysiology, including the muscle and neuromuscular junction diseases, epilepsy, surgical epilepsy, motor system disorders, peripheral nerve disease, autonomic dysfunction, sleep disorders, oculomotor/balance disorders, somatosensory system disorders, behavioral disorders, visual and auditory system disorders, and the monitoring of neural function. Each volume will focus on the advances in one of these major areas of clinical neurophysiology. Each volume will include critical discussions of fresh ideas in basic neurophysiology, approaches to characterization of disease type, localization, severity and prognosis with detailed discussion of advances in techniques to accomplish these. It is recognized that some techniques will be discussed in more than one volume, but with different focuses in each of them. Each volume will also include an overview of the field; followed by a section that includes a detailed description of each of the CNP techniques used in the disorders, and a third section discussing electrophysiologic findings in specific diseases. The latter will include how to evaluate each along with a comparison of the relative contribution of each of the methods. A final section will discuss ongoing research studies, and anticipated future advances. Our increasing understanding of peripheral nerve diseases and their presentations as large fiber, small fiber, peripheral neuropathy, polyradiculopathy and mononeuropathy makes them a particularly appropriate volume in this series. We are privileged to have Jun Kimura, one of the world’s leaders in the clinical neurophysiology of peripheral nerve diseases as the volume editor. He has done a superb job of assembling the other world leaders in the description of the methods and in their application to individual categories of motor neuron disease. The volume covers diseases from the spinal anterior horn cell to the neuromuscular junction. Special emphasis is on clinical disorders, and the advances in techniques for diagnosing and understanding their pathophysiology. Wherever possibly applicable, the information presented focuses on evidence based medicine; the specificity and sensitivity of each test is provided when known, along with comparison of their relative values. Jasper R. Daube François Mauguière Series Editors

Preface

The International Federation of Clinical Neurophysiology (IFCN) has recognized the unmet need of neurologists who must practice electrodiagnostic medicine without specialized training. This discipline covers important areas of neurological diagnosis as the only technique currently available to document abnormalities of function rather than structure. Yet, there is no textbook that addresses all the issues faced by physicians who must deliver electrodiagnostic service. We have thus undertaken the task of creating a series of volumes on neurophysiological subspecialty topics utilizing the very latest information on various aspects of technology. This series constitutes one of the most ambitious projects of the IFCN attempting to review all the neurophysiologic disciplines of clinical interest. As part of this effort, our volume provides readers with a comprehensive source of reference for electrophysiologic investigations in the evaluation of peripheral nerve disorders. This volume consists of three parts: Section I Anatomy and Histology, Section II Methodology and Technique in Assessing the Peripheral Nerve, and Section III Clinical Application. The authors assigned to the first section wrote an overview on histological and physiological properties of the peripheral nervous system. This basic information should prepare readers for the subsequent presentations on techniques and the interpretation of findings. The chapters in the second section deal with general technical principles followed by detailed methods to test individual nerves, providing step-by-step instructions. Solely based on the information given herein, readers should be able to select the most appropriate technique to study the patient under consideration and interpret the data within the clinical context. The third section primarily relates to electrophysiologic abnormalities expected in each disease process, summarizing important findings for each of the techniques described earlier. This portion includes little methodological description to avoid overlap with technical chapters, and only an abbreviated clinical note pertinent to electrophysiologic findings without a full description of disease entities per se, which is outside the scope of this book. Although I have practiced only at the University of Iowa in the US and at Kyoto University in Japan, I am well acquainted with the variety of techniques widely used in European countries from my experience gained while serving on the Executive Committee of the IFCN. I have, therefore, tried to assemble an international slate of authors from different corners of the world to contribute to this volume. All of them are neurologists, physiatrists, or neurophysiologists practicing the art of clinical electrophysiology as it pertains to the assessment of the peripheral nerve. It has been my pleasure to work with so many distinguished experts in this endeavor, which will help improve the practice of clinical electrophysiology globally. I hope the perusal of this text will make the study of the next patient easier every step of the way. In electrodiagnostic assessments, we always consider nerve conduction and various other studies within the context of clinical signs and symptoms. Thus, most authors initially found it difficult to restrict the writing either to the technical domain without mentioning clinical features or to electrophysiologic abnormalities without stating the details of the methodology. Consequently, most chapters had to undergo one or two revisions after careful review. Fortunately, the authors graciously agreed to do the necessary extra work to tailor the contents to suit our needs, and to avoid major redundancy among the chapters dealing with technical and clinical aspects. Needless-to-say, certain aspects of information are repeated to make the discussion cohesive, but otherwise each chapter, standing on its own, delivers a focused description of the intended objectives.

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PREFACE

For those authors who completed the final version more than a year ago according to the original schedule, I thank you for your timely submission. For those who just recently finished the task for a number of justifiable reasons, I apologize for my constant reminders despite your effort, and thank you for your patience and hard work. A few authors dropped out after the initial agreement to participate in the project. When we did lose contact, despite our best efforts either by mail, telephone, or through mutual friends, we recruited other colleagues to step in and finish the task in the interest of time. It was my intention not to hold up publication of the volume beyond the reasonable deadline for missing chapters. Despite short notice, substitute authors were able to meet the deadline in an excellent form to bail us out. Thus, all chapters were written in a satisfactory manner, ranging over one and half years from the original target date of September 2003 to the actual date of culmination in February 2005. I wish to take this opportunity to thank all the contributors for their willingness to write and rewrite their chapters and their patience and constructive effort to achieve our goal. Jasper Daube, the Series Editor in charge of this volume, reviewed all the chapters, providing useful suggestions. I am also indebted to Sheila Mennen who coordinated our effort from the Iowa Office with the help of Leigha Rios and Wendy Sebteka to maintain a steady progress even when I worked in Kyoto or elsewhere. Regardless of my whereabouts, we were able to maintain uninterrupted correspondence by mail, which helped move the project forward in a steady, albeit slow, pace. I have used up all the favors that I could possibly ask of my friends. In fact, I am now so deeply in debt that I will be unable to edit another multi-author book for a while. But, on this sunny winter day, when we celebrate the conclusion of the project, the future can wait. Jun Kimura Volume Editor

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 1

Anatomy and histology of peripheral nerve Benn E. Smith* Mayo Clinic College of Medicine, Department of Neurology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA

1.1. Introduction Over the last 100 years the emphasis of human and mammalian neuroanatomy has traditionally been the central nervous system (CNS). The topic of this chapter is an introduction to the structure of “the other nervous system,” which is composed of delicate cables forming a dense tapestry of fibers coursing through every corner of the body, some axons destined to communicate with muscle fibers, others projecting to the vast cutaneous network of skin terminals, and the small diameter myelinated and unmyelinated fibers that comprise the peripheral autonomic nervous system. Neurons in the peripheral nervous system (PNS), like some cells that reside entirely within the brain and spinal cord, often traverse great distances. In the typical adult human a single dorsal root ganglion cell extends from its pacinian corpuscle in the hallux, past the cell body in the vicinity of the fifth lumbar intervertebral foramen, and up the fasciculus gracilis to its synapse with the second order neuron in the medulla. It can span 1.5 m or more, and have a diameter of only 10 to 20 microns. To illustrate these proportions on a somewhat larger scale, if the axon was 1 m in diameter, its extent from sensory nerve ending to rostral end would be approximately 100 km or more. While the cellular inhabitants of the cerebral cortex consist of as many as 1010 neurons of several different varieties, by comparison the cast of cellular characters in the PNS is relatively small. These include: (1) neurons (the anterior horn cell, dorsal root ganglion cell, and autonomic ganglion cell) and their axons; (2) the Schwann

* Correspondence to: Benn E. Smith, Assistant Professor in Neurology, Mayo Clinic College of Medicine, Consultant, Department of Neurology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. E-mail address: [email protected] Tel.: +480-301-8100; fax: +480-301-8451.

cell (which together with the axon constitutes the nerve fiber, some myelinated, others still ensheathed by Schwann cells but without myelin, being therefore unmyelinated); (3) connective tissue elements (including cells and cytoskeletal scaffolding forming the endoneurium, perineurium, and epineurium), and (4) cells that comprise and travel through blood vessels. Each of these components will be described in the following pages. The unusual architecture of nerve fibers is well suited to their primary function of relaying information from one part of the body to another. Neural signals may be propagated slowly or very rapidly, with conduction velocities ranging from less than 1 to greater than 100 m/s, the peripheral axon also serves the organism by transporting small molecules, vesicles, and larger organelles both away from and toward the cell body (Brown, 2003). Multiple systems exist within the nerve fiber to mediate axonal transport (Chao, 2003). A variety of substances and cellular commodities are translocated in the slow systems (moving at 1–2 mm daily, while others are conveyed via the fast systems with velocities exceeding 400 mm per day. The functions of these transport systems are thought to include: (1) maintenance of the metabolic integrity of long cellular processes far removed from the protein synthetic machinery of the nucleus; (2) ferrying of substances to the nerve terminal to be used in synaptic functions and functions such as neuromuscular transmission; and (3) mediating so-called “trophic influences” on postsynaptic neurons or other cells with which neural contact is maintained. The neurotrophins, reviewed by Kernie and Parada, are important in peripheral development, critical to the reparative process after nerve trauma, and play a sustentacular role on postsynaptic cells (Kernie and Parada, 2000). In contrast, in unmyelinated nerve fibers, conduction velocities of propagated nerve impulses are very slow, in the range of 1 m/s. There are examples of rapidly conducting unmyelinated fibers, but upper end velocities

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can only be achieved when the diameter of the axon is substantially increased, as in the case of the invertebrate giant squid axon. In order to achieve faster conduction velocities without resorting to massively enlarged axon diameters, the mammalian solution is myelination. While the myelinated fiber may be studied readily by light microscopy, the size of the unmyelinated fiber has made the details of its morphology inaccessible until the advent of electron microscopy (Fig. 1.1). Similarly, until recent times, clinical neurophysiologic methods have largely focused on functions mediated by myelinated fibers. Advances in sensory and autonomic physiology have witnessed the development of clinically informative techniques which interrogate functions mediated by unmyelinated fibers (Low et al., 2003). In addition, immunohistochemical analyses of skin nerves have opened a new avenue to the morphologic study of small myelinated and unmyelinated fibers in health and disease (Polydefkis et al., 2003). Although it is a simple matter to distinguish myelinated fibers from unmyelinated fibers on histologic grounds at the electron micro-

BENN E. SMITH

scopic level, it is not yet possible to categorize an individual myelinated fiber as motor or sensory by morphology alone. The same is true of unmyelinated fibers. One cannot distinguish afferents from efferents by inspecting their single profiles on electron micrographs. Different classes of myelinated and unmyelinated fibers have different conduction velocities, which allow them to be classified roughly into functional groups (see below, Section 5.). 1.2. Myelinated nerve fiber anatomy Myelinated axons in the PNS are lengthy thin cytoplasmic processes that extend from parent nerve cell bodies residing either in the central nervous system, as in the case of motor neurons in the spinal cord and brain stem, or in peripheral sensory and autonomic ganglia. Many of these cells, therefore, extend from the CNS into the periphery, or, like the dorsal root ganglion cell, send long axons both centrally (dorsal column sensory axons) and peripherally (primary sensory

Fig. 1.1 A region of myelinated fibers and unmyelinated fibers from a transverse section of the tibial nerve of a normal baboon. Osmium tetroxide fixation × 7200. LMF = large myelinated fiber; SMF = small myelinated fiber; UMF = unmyelinated fiber (Thomas et al., 1993 with permission from Elsevier).

ANATOMY AND HISTOLOGY OF PERIPHERAL NERVE

afferent nerve fibers). The only peripheral nerve cells that can truly be said to reside entirely outside the CNS are the postganglionic autonomic neurons. As large myelinated nerve fibers are most accessible to morphologic, electrophysiologic, and molecular biologic study, they will be the main emphasis for the remainder of this chapter. As mentioned previously, the myelinated peripheral nerve fiber consists of the axon and multiple Schwann cells, the latter forming a series of internodes like elongated beads on a string (the axon), interrupted by narrow gaps between beads, the nodes of Ranvier. This cylindrical myelin sheath typically invests the axon from a point near the cell body, extending peripherally to within a few microns of the nerve terminals of the axon. The cytoplasm of each myelin-forming Schwann cell–other Schwann cells invest but do not form myelin around unmyelinated peripheral axons, with cytoplasmic profiles being stained histochemically by glial fibrillary acid protein (Cheng and Zochodne, 2002) – forms a narrow band outside of the myelin sheath referred to as the abaxonal cytoplasm. The outermost turn of the abaxonal cytoplasm forms the outer mesaxon (Fig. 1.2). This abaxonal compartment is home to a number of organelles and cytoskeletal ele-

Fig. 1.2 Transmission electron micrograph of a transverse section of a small myelinated fiber from 5 day postnatal mouse sciatic nerve. aSc = adaxonal Schwann cell cytoplasm; im = inner mesaxon; ml = myelin lamellae; om = outer mesaxon; sm = Schwann cell surface membrane (Reproduced from Thomas, Ochoa,1984 with permission from Elsevier).

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ments, which are excluded from the region of compact myelin, including an elongated cigar-shaped Schwann cell nucleus, often located approximately midway between the nodes that define the borders of a given internode. Another layer of Schwann cell cytoplasm, the adaxonal compartment, can be found juxtaposed between the innermost myelin turn and the underlying axolemma. The tongue of Schwann cell cytoplasm which envelopes the axon most closely is the inner mesaxon (Fig. 1.2). The thin gap (usually 15–20 nm) between the axonal membrane and the adaxonal Schwann cell layer is the periaxonal space. Other interruptions in the compact spiral structure of the myelin sheath include pockets of cytoplasm form microvilli and terminal loops in the nodal and paranodal regions as well as usually diagonally-oriented SchmidtLanterman incisures which form irregularly occurring periodic conical gaps in the myelin along most internodes. A number of detailed and more lengthy reviews of the morphology of the myelinated axon and Schwann cell may provide additional useful information (Thomas and Ochoa, 1984; Williams et al., 1989; Peters et al., 1991; Thomas et al., 1993; Midroni and Bilbao, 1995). 1.2.1. Axonal anatomy The mammalian axon is clothed within an asymmetric trilaminar plasma membrane known as the axolemma, which ultrastructural studies have shown to be approximately 7–9 nm thick. Both the inner and outer leaflets are osmiophilic, the inner being more dense. An electron lucent clear zone separates the two. Numerous rounded 7–12 nm particles are evident, particularly on the inner surface of the axolemma by freeze-fracture studies particularly in and around the nodes of Ranvier (Thomas and Ochoa, 1984). These are thought to represent transmembrane proteins such as ion channels. The axonal cytoplasm, also called axoplasm, is rich with cytoskeletal elements, membrane bound organelles, and other structures of varying electron density. Organelles seen by ultrastructural investigations have included mitochondria, smooth endoplasmic reticulum, rare ribosomes, multivesicular bodies, dense core vesicles, glycogen particles, and polyglucosan bodies. Transmission electron microscopy has demonstrated microfilaments, microtubules, and intermediate filaments—also called neurofilaments (Thomas and Ochoa, 1984). The cross-sectional area of an axon is

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one of the main characteristics by which it is identified and classified. The caliber of axons in peripheral nerve fibers follows specific patterns and allows functional categorization of axons. In adult mammalian nerve, the normal range of axon caliber varies by a factor of 10 000, ranging from the most miniscule unmyelinated axon to the largest myelinated axon (Hoffman and Griffin, 1993). Axon diameter has physiologic and structural implications for the peripheral nervous system. The caliber of the axon influences myelin thickness and perhaps myelinogenesis in the developing nerve. The link between axon diameter and nerve conduction velocity in meters per second is equivalent to six times the diameter in μm (CV = 6 D) (Hursh, 1939). For smaller myelinated nerve fibers, the factor is less (CV = 3.5 D to 4.5 D) (Bessou and Perl, 1969; Boyd and Davey, 1968) and for unmyelinated fibers the factor is still lower (CV = 1.7 D) (Gasser, 1955). A reflection of this diameter dependency of CV is the latency of the monosynaptic reflex arc, which is increased when axon caliber is diminished (Farel, 1978). Recruitment order of myelinated nerve fibers also relates to axonal diameter (Henneman, 1965). In addition, changes in axonal cross-sectional area are frequently encountered in peripheral nervous system disorders where they may be a product of secondary demyelination. 1.2.2. Schwann cell anatomy Proceeding from the outer aspect of the Schwann cell inward, the first structure encountered is the basal lamina. The entire Schwann cell is surrounded by a basement membrane, which is continuous across the node of Ranvier, forming an elongated tube the length of the nerve fiber, thought to be important in guiding regenerating nerve fibers following injury to the axon. Like the axolemma, the plasma membrane of the Schwann cell is trilaminar, but unlike the membrane delimiting the axon, its inner and outer layers are of similar electron density. The Schwann cell which invests myelinated nerve fibers is perhaps best considered unfurled from its spiraled grasp on the axon. As Thomas and Ochoa point out, in this configuration it is a flattened, trapezoid-shaped cell that consists of three different zones (Thomas and Ochoa, 1984). The innermost or smallest dimension is the adaxonal cytoplasmic region. The outmost, somewhat wider segment is the abaxonal cytoplasm that invests the compact myelin sheath and extends the nodal microvilli from its distal and proximal margins. The intermediate portion contains compact myelin, with a lateral rim

BENN E. SMITH

of cytoplasm helically attached to the axolemma in the vicinity of the paranode. Schmidt-Lanterman incisures criss-cross the compact myelin, sometimes forming cytoplasmic conduits between the adaxonal and abaxonal cytoplasm (Fig. 1.3). The most conspicuous occupant of the outer region of the Schwann cell is it nucleus. Almost invariably oriented along the axis of its axon, it is often surrounded by a pocket of cytoplasm containing a variety of organelles such as mitochondria, endoplasmic reticulum, Golgi apparatus, centrioles, and π (pi) granules. In addition to functioning as the myelin forming cells of the PNS, Schwann cells appear to play a significant role in peripheral neural development (Mirsky et al., 2002). 1.2.2.1. Myelin sheath The characteristic ultrastructural feature of myelinated nerve fibers in transverse sections is a very regular compact spiral of alternating dark and light lamellae. On closer inspection, aldehyde fixed osmicated preparations demonstrate a radial periodicity of 12 to 17 nm, while the periodicity is somewhat greater (16 to 19 nm) by x-ray diffraction in unfixed nerve tissue (Finean, 1958). The chemical explanation for the alternating dark and light bands of peripheral myelin developed slowly over the last century. Once the main components of brain myelin were found to be protein and lipid, x-ray diffraction analysis led to the concept that myelin might consist of alternating layers of protein and lipid. The model of the plasma membrane as a lipid bilayer with hydrophobic lipid moieties directed inward and hydrophobic protein components directed outward has prepared the way for an understanding of images seen on high-resolution electron microscopy. Fixation by osmium tetroxide for electron microscopy resulted in the osmium becoming attached to the polar groups, with dark electron-dense regions interpreted as indicating polar regions in myelin where lipid and protein interact, while the light electron-lucent region was thought to represent the hydrophobic fatty acid chains of the lipid bilayer (Bischoff, 1967). Further studies have confirmed this model (Napolitano, 1969). 1.2.2.2. Schmidt-Lanterman incisures Although originally described in living nerve fibers (Schmidt, 1874; Lanterman, 1877; Nageotte, 1910), many early researchers thought these structures to be artifacts of preparation. Schmidt-Lanterman incisures are now recognized as being normal elements of myelinated nerve. Being more numerous in fibers with thick myelin, they are often not present in paranodal

ANATOMY AND HISTOLOGY OF PERIPHERAL NERVE

7

Fig. 1.3 Diagram of a Schwann cell unfurled. The white regions are those containing cytoplasm while the stippled areas semicompact myelin and the black territories compact myelin. Note the cytoplasmic channels (“incisures”) some of which are complete and others of which are blind ends (Mugnaini et al., 1977).

and perinuclear regions of compact myelin (Fig. 1.4). A number of investigators have found that incisures are more frequent in developing or remyelinating nerve (Hiscoe, 1947; Ghabriel and Allt, 1981). Although the function of Schmidt-Lanterman incisures has not been established, including the contention that they are involved in peristaltic movement of axoplasm or transport of metabolites from the Schwann cell to the axon, some experiments have demonstrated the translocation of tracers such as ruthenium red first in the cytoplasmic spiral, then in the adaxonal Schwann cell cytoplasm, and finally in the axon itself (Thomas and Ochoa, 1984). 1.2.2.3. Node of Ranvier In 1871, Ranvier described regular indentations in peripheral nerve fibers as an “annular constriction of the nerve tube, of an elegant form.” It was not until well into the following century that the nature of the nodes was

determined to be a segmental interruption in the myelin sheath (Ranvier, 1871) (Fig. 1.5). Berthold has reviewed the ultrastructural maturation of nodes of Ranvier in the developing cat (Berthold, 1996). 1.2.2.3.1. The nodal axon. On approaching the node of Ranvier the axon narrows in caliber to somewhere between 1/3 and 1/6 of the internodal axonal cross sectional area. The effect seems to be more pronounced for larger axons. A particularly unusual finding at the node is the high density of particles on the outer cytoplasmic leaflet by freeze-fracture, as great as 1200/μm2 (Schnapp and Mugnaini, 1978). It has been suggested that these particles may correspond to voltage-gated sodium channels. As to the mechanism of clustering the particles in this particular site, Rosenbluth has suggested that protein synthesis occurs in the cell body, with mature proteins being transported in the

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BENN E. SMITH

Fig. 1.4 Transmission electron micrograph of a Schmidt-Lanterman incisure. ax = axon; ml = myelin lamellae; mt = microtubule; pv = pinocytotic vesicle; Sc = Schwann cell cytoplasm (Reproduced from Thomas, Ochoa, 1984 with permission from Elsevier).

anterograde direction floating in the axolemma, and being sequestered in the nodal region, trapped by the myelin attachment on either side of the node (Rosenbluth, 1976). The inner cytoplasmic leaflet of the nodal axolemma (P face) also demonstrates a high density of particles. Whether these may be associated with ATPase activity or other ion channels has not yet been established. It is

known that the nodal axon has few mitochondria, leading to the concept that some of the energy for nerve conduction may arise from the adjacent Schwann cell (Williams and Landon, 1964). 1.2.2.3.2. The paranodal region. The morphology of the myelin sheath and its associated myelin is nothing short of spectacular in the paranodal region. The first

Fig. 1.5 Transmission electron micrograph of an osmicated mouse nerve, longitudinal section, illustrating a node of Ranvier. ax = axon; m = mitochondrion; mvb = multivesicular body; tl = terminal loops of Schwann cell cytoplasm (Reproduced from Thomas, Ochoa, 1984 with permission from Elsevier).

ANATOMY AND HISTOLOGY OF PERIPHERAL NERVE

departure from the compacted myelin in the internode is a series of broad large folds, typically three to six in number, which extend for a distance of approximately 40 μm from the node on large myelinated fibers. The axon within the region of myelin expansion conforms to the shape of the myelin folding. The valleys between the myelin folds on the outer aspect of the myelin layer contain Schwann cell cytoplasm packed with large numbers of mitochondria (Berthold, 1967). Of note, the large myelin expansions on either side of the node are not symmetrical. The expansion on the proximal side, closer to the cell body, is larger. It is apparent from the nerve compression experiments of Ochoa and colleagues and the morphologic research on inherited tendency to pressure palsies by Dyck and co-workers that the terminal rim of cytoplasm of the myelin lamellae is firmly attached to the axolemma on both sides of the node (Ochoa et al., 1972; Yoshikawa and Dyck, 1991). 1.2.2.3.3. The nodal gap. As the myelin tapers toward the node, the lamellae separate, forming multiple small rounded bulbs of Schwann cell cytoplasm, like a collar of clusters of grapes applied to the axon. These nodal processes are 70–100 nm in diameter. Histochemical studies have shown that the node is bathed in polyanionic materials which might form a cation reservoir at the node. This could be important in buffering the ionic currents that accompany saltatory conduction. 1.2.3. Molecular biology 1.2.3.1. Structural proteins of peripheral nerve The major peripheral nerve structural proteins occur in high concentrations. These molecules have no known enzymatic properties, but do possess the capacity to polymerize into filamentous structures (Pleasure, 1984). Interstitial collagen fibrils, that abound in nerves, are composed entirely of tropocollagen. The main function of collagen that constitutes 25 to 50% of total peripheral nerve protein, is to enable nerve trunks to resist stretch and mechanical forces. Tissue culture studies have shown that interstitial collagen is also important for normal myelin development. Type IV collagen is a major constituent of the basal lamina, which invests perineurial cells, Schwann cells, and axons. At least four different varieties of intermediate filaments (IF) have been found in peripheral nerve. Ten nanometer (nm) neurofilaments, identified only in

9

nerve cell bodies and axons, are polymers of peptides with a range of molecular weights between 68 and 210 kD. There are two types of IF in Schwann cells. One consists of polymers of vimentin, while another is likely related to desmin, a component of IF more often associated with muscle. Myelinating Schwann cells control the number and phosphorylation of axonal neurofilaments, which are direct determinants of axonal caliber (Martini, 2001). Some satellite cells in peripheral autonomic ganglia may contain IF composed of peptides antigenically similar to glial fibrillary acid protein (GFAP), and therefore bear a similarity to IF of CNS astrocytes. The role each of these intermediate filament subtypes plays is unknown. As a cytoskeletal-associated protein, periaxin may function by regulating the shape of the Schwann cell and by mitigating gene expression during formation of the myelin sheath by facilitating integration of extracellular signalling through the cytoskeleton (Takashima et al., 2002). Microfilaments of 6 nm diameter are characteristically detected in large numbers in the growth cones of advancing axons. Sensitive immunohistochemical techniques also demonstrate these actin microfilaments to be widely distributed in most cell types, including mature neurons and Schwann cells. Actin microfilaments play an essential role in cell motility and have been implicated in axonal transport. Microtubules consist of 25 nm cylinders formed by polymerization of tubulin dimers. These structures are abundant in axons and also present in Schwann cells, fibroblasts, and other cells in peripheral nerve. Microtubules play a major cytoskeletal function as well as participating heavily in axoplasmic transport. In recent years, a number of neuropeptides have been demonstrated in association with cutaneous peripheral nerve terminals in the epidermis, dermis, and specialized sensory end organs (Scholzen et al., 1998). These neuropeptides include calcitonin gene-related polypeptide (CGRP), neurokinin A (NKA), neuropeptide Y (NPY), substance P (SP), and vasoactive intestinal polypeptide (VIP) among others. Connexin 32 (CX32) is a gap junction protein present in uncompacted myelin which in Schwann cells is used to join adjacent membranes in paranodal loops and Schmidt-Lanterman incisures. CX32 forms tiny conduits that facilitate transfer of ions and other small molecules between Schwann cells and axons. When the

10

gene for CX32 is defective, X-linked Charcot– Marie–Tooth (CMTX) results (Bergoffen et al., 1993). 1.2.3.2. Glycoproteins of peripheral nerve myelin Most of the studies of glycoproteins in peripheral nerve have focused on peripheral nerve myelin, as these have significance to a number of peripheral neuropathies. Preparations of isolated myelin from peripheral nerve have been found to contain a prominent glycoprotein, P0 (“P zero”), a homophilic adhesion molecule with a molecular weight of 28 to 30 kD. This protein represents 50 to 60% of the total myelin protein in the peripheral nervous system and is thought to be the major protein mediating myelin compaction. Myelin P0 undergoes post-translational fucosylation, phosphorylation, and sulfation. Its carbohydrate content constitutes 6.3% by weight and exists as a monosaccharide having one sialic acid, one galactose, one fucose, three mannose, and three N-acetylglucosamine residues per mole of protein (Poduslo, 1984). The P0 gene is encoded by chromosome 1q21-23. Different mutations in the P0 gene may result in divergent morphologic and physiologic effects on the myelin sheath. Depending on where the point mutation occurs, the result can be Charcot–Marie–Tooth 1B, Dejerine-Sottas syndrome, congenital hypomyelination, or CMT2 (Zhou and Griffin, 2003). Peripheral myelin protein 22 (PMP22) is a transmembrane glycoprotein found in compact myelin, which appears to function in the formation and maintenance of myelin, but which may also be involved with Schwann cell proliferation, differentiation, and apoptosis (Fabbretti et al., 1995; Zoidl et al., 1995; Jetten and Suter, 2000). While abnormal duplication of a 1.5 megabase domain of chromosome 17p11.2 that contains the PMP22 gene leads to Charcot–Marie–Tooth 1A (CMT1A), point mutations in the PMP22 have been associated with a variety of other inherited neuropathies including CMT1 phenotype, hereditary neuropathy with liability to pressure palsies (HNPP), and rarely Charcot–Marie–Tooth 2 (Zhou and Griffin, 2003). A deletion of the 1.5 megabase stretch of 17p11.2 is the most common cause of HNPP. Two basic proteins have been found in peripheral nerve myelin. The first, called P1, has a molecular weight of 18.5 kD and is similar if not the same as myelin basic protein in the CNS. It induces experimental allergic encephalomyelitis (EAE) when injected into experimental animals. The second is P2, which is found in very low concentrations in adult Schwann cells

BENN E. SMITH

(Webster, 1993). P2 injected experimentally results in experimental allergic neuritis (EAN). Myelin-associated glycoprotein (MAG) is a high molecular weight glycoprotein and a member of the immunoglobulin superfamily. One function of MAG is to serve as a signal to modulate the caliber of myelinated axons (Yin et al., 1998). This glycoprotein localizes to Schmidt-Lanterman incisures, paranodal regions, and periaxonal Schwann cell regions, and has been implicated in some autoimmune neuropathies. 1.2.3.3. Lipids of peripheral nerve myelin Although there are some differences that appear to correspond to age, studies of peripheral nerve myelin lipids, endoneurium, or whole nerve from several mammalian species reveal many similarities. The major lipids of the membranes are cholesterol, cerebroside, ethanolamine plasmalogen, sphingomyelin, phosphatidylcholine, and phosphatidylserine, the most abundant being cholesterol (Yao, 1984). The class of lipids of greatest clinical interest to physicians involved with neuromuscular disease, the glycolipids (or gangliosides), has been the subject of a recent review (Willison and Yuki, 2002). Advancing knowledge of these molecules is improving the localization of specific glycolipids to peripheral nerve with increasing precision (Gong et al., 2002). Patients with Guillain–Barré syndrome associated with preceding Campylobacter jejuni infection have been found to have high titers of IgG antibodies to GM1, GD1b, GD1a, and GalNAc-GD1a. Elevated anti-GQ1b antibodies are consistently associated with the Miller Fisher syndrome. 1.3. Development and aging: fiber diameter composition of peripheral nerve The fetal human sural nerve has been studied extensively and is useful for comparison with adult nerve fibers because this nerve is sometimes biopsied in children and adults for diagnostic purposes (Ochoa, 1971; Shield et al., 1986). In the 9-week old human foetus the sural nerve has small fascicles containing large bundles of axons surrounded by Schwann cell processes. A basal lamina surrounds these processes with narrow clefts containing collagen fibrils. By week 16, the axon bundle size diminishes and the number of bundles increases as does the Schwann cell number. The unimodal fiber diameter histogram peak has increased to 2.4 μm. Studies of the developing trochlear nerve showed that the axonal outgrowth occurs at different times, with some fibers undergoing

ANATOMY AND HISTOLOGY OF PERIPHERAL NERVE

degeneration before and others after myelination (Mustafa and Gamble, 1978). Myelination appears to have begun in human sural nerve by week 18 (Ochoa, 1971). At this stage, a number of axons between 1.0 and 3.2 μm in diameter had paired 1:1 with Schwann cells and had formed small spirals of cytoplasm. During the postnatal period the number of myelinated fibers rises from nearly 4000 to about 12000 by age 5 years (Gutrecht and Dyck, 1970). Sural nerve conduction velocities increase from 35 m/s during months 1–6 to 40 m/s between months 7–12 and further to between 48 and 62 m/s from age 25–60 months, the normal range being 43 to 65 m/s between ages 121 and 180 months (Kuntz NL [1983] Childhood sensory nerve conductions studies [unpublished data]). The adult normal value range is 43 to 59 m/s (age 20–40). Conduction velocity slows progressively beginning at 20–30 years of age, by age 80 having slowed by approximately 10 m/s (Daube, 1996). In normal peripheral nerve, the contour of the compound action potential (the waveform recorded from a nerve following application of an external electrical impulse of sufficient energy to depolarize the vast majority of myelinated fibers in that nerve) is determined by the relative numbers of excitable and conducting nerve fibers demonstrating various conduction velocities. Because conduction velocity and response amplitude are proportional to diameter of the fiber, by using appropriate proportionality factors, one can make a reasonable prediction of the fiber diameter spectrum in normal nerve from the contour

11

of the compound action potential. This principle was first applied by Gasser and Erlanger (1927), and more recently further explored by Lambert and Dyck (1984). The diameter histogram plotted per mm2 of fascicular area of normal sural nerve tissue of infants or small children show a unimodal histogram with a peak in the 3 to 5 μm range. Similar plots made from normal adult human sural nerve demonstrates a bimodal histogram with peaks at 2.5 and 8.0 μm. (Fig. 1.6), the normal distribution of myelinated fibers in the adult being from 2 to 22 μm (O’Sullivan, 1968). 1.4. Fascicular anatomy of peripheral nerve trunks Peripheral nerve trunks contain multiple fascicles (Fig. 1.7). While there appears to be a high degree of somatotopy in peripheral nerves, because of the exchange between fibers between fascicles as they course from proximal to distal, partial nerve lesions may produce restricted deficits that might confuse the clinician attempting to localize the lesion (Stewart, 2003). The same is true of the sympathetic trunk (Aguayo et al., 1976). 1.5. Nerve terminal anatomy 1.5.1. At the neuromuscular junction Each motor unit is composed of one anterior horn cell, its single axon, the terminal branches which fan

Number of axons

Child

Adult

100

100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10 0.4 0.8 1.2 1.6 2.0 2.4 2.8 3.2 μm diameter

0.4 0.8 1.2 1.6 2.0 2.4 2.8 3.2 μm diameter

Fig. 1.6 Frequency distribution of unmyelinated fibers from a boy aged 15 years (left) and an adult patient with isoniazid neuropathy (Ochoa, 1970 with permission from Elsevier).

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BENN E. SMITH

Fig. 1.7 Transverse section of mammalian peripheral nerve consisting of ten fascicles fixed with osmium tetroxide. The myelinated fibers stand out as dark rings (Stewart, 1987).

Synapsin-I,II Rab 3a Rabphilin 3a Cysteine string protein SV2 Synaptobrevin Synaptotagmin Synaptophysin Vesicular ACh transporter

S-100 N-CAM

Choline acetyltransferase

nn Schwa Cell

Nerve Terminal

a CGRP

from the axon near or in the muscle it innervates, the neuromuscular junctions formed by those terminal branches, and the postsynaptic skeletal muscle fibers supplied by the anterior horn cell. Although the vast majority of muscle fibers in normal individuals are innervated by a single anterior horn cell, in extraocular muscles some muscle fibers may receive synaptic input from multiple anterior horn cells (Meiggioli et al., 2004). As a myelinated fiber approaches its muscle, the myelin sheath is lost and the terminal branches, invested by Schwann cell cytoplasm, near the muscle membrane. Each fine terminal branch expands into a terminal bouton or swelling, which comes to rest in a small depression in the muscle membrane. The basal lamina of the Schwann cell is continuous with that of the sarcolemma. The highly intricate subcellular design of the presynaptic nerve terminal, the synapse, the postsynaptic nerve terminal, the muscle cell, and the organelles that populate these structures are well beyond the focus of this chapter. The reader is encouraged to peruse Engel and Frazini-Armstrong’s authoritative text which describes muscle development, muscle contraction, neuromuscular transmission, and structural details of the neuromuscular junction in a well-illustrated and comprehensive review (Engel and FranziniArmstrong, 2004). A number of proteins at the neuromuscular junction have both physiologic and pathophysiologic significance for clinical neuromuscular disorders (Fig. 1.8).

Acetylcholine

1.5.2. In the skin Liminin-a2,a4,a5,b2,g1 Collagen IV-a3,a4,a5 AChE-T, Q Agrin Neuregulin GalNAcβ-X N-CAM Na channels Ankyrin Dystrophin aDystrobrevin-2 Syntrophin-α1,β1

Rim K+ channels Ca++ channels Syntaxin SNAP 25

Muscle Fiber

Rapsyn Utrophin aDystrobrevin-1 β2-Syntrophin

AChR-α,β,δ,e Intergrin a7A,B,b1 Dystroglycan a,b Sarcoglycan-a,β,g,δ MuSK ErbB2,3,4 GalNAc transferase

Fig. 1.8 Molecular components of the neuromuscular junction of functional, structural, and pathophysiologic significance. The elements for which knockout mice have been generated are indicated in boldface type (Sanes et al., 1998).

Primary afferent nerve fibers in mammals range in axon diameter from 0.2 to 20 μm. Some of the smallest fibers are unmyelinated. There is an uneven distribution of peripheral nerve fiber diameters (Fig. 1.9) and their corresponding conduction velocities (Table 1.1). When a single afferent nerve is supramaximally stimulated, the compound nerve action potential recorded at a distance of several centimeters shows a response consisting of multiple peaks (Fig. 1.10). These peaks are designated with uncial Roman letters for their major components and minuscule Greek letters for their subgroups (Gasser and Erlanger, 1927; Gasser, 1941). In muscle nerves, the peaks are often labelled by Roman numerals (Table 1.1). Although the peaks were originally associated with specific sensory modalities (Aαβ with tactile sensation and Aδ with sharp or stinging pain), more recently it has been established that primary sensory

ANATOMY AND HISTOLOGY OF PERIPHERAL NERVE

Aδ

13

Aαβ

60

Number of fibers

50 40 30 20 10

0 0.8

2.4 4.0

5.5 7.1 8.7 10.3 11.8 13.4 15.0 16.5 diameter (in μm)

afferents may better be categorized by the type of environmental stimulus that excite the cell preferentially, that is, at the lowest threshold, the so-called adequate stimulus (Light and Perl, 1993). In this paradigm, three categories of cutaneous sensory units emerge, low threshold mechanoreceptors, thermoreceptors, and nociceptors, which are described in greater detail elsewhere (Light and Perl, 1993). Quantitative immunohistochemical pathology has recently been used to study human myelinated and unmyelinated nerve terminals as well as sensory receptors in health and disease (Fig. 1.11). 1.6. Connective tissue elements While the electrically excitable tissues within peripheral nerve, that is the axon and myelin sheath, have been the focus of academic study and clinical interest for many years, perhaps chiefly among those with an inclination toward physiology, the interstitial eleTable 1.1

Fig. 1.9 Primary afferent nerve fiber diameter histogram of 294 randomly selected fibers from two feline sural nerves as assessed by electron microscopy (Burgess et al., 1968).

ments, that is connective tissues, have been relatively neglected. Peripheral neuropathologists have emphasized that information gleaned from surveying interstitial abnormalities in nerve is often hidden from the techniques employed by the neurophysiologist. In addition, investigations in recent years have emphasized the considerable importance of connective tissue structures in the normal function of peripheral nerves. These have been reviewed in detail by Thomas and Olsson (Thomas and Olsson, 1984). The original observations of Key and Retzius and also by Ranvier (Ranvier, 1878) formed the basis for all that has followed. Key and Retzius were the first to suggest that the peripheral connective tissues be subdivided into epineurium, perineurium, and endoneurium. This terminology still remains the most satisfactory (Key and Retzius, 1876). Some hold that, for morphologic reasons, the perineurium should not be considered as a connective tissue, but rather as part of the membranous covering of the whole of the entire nervous system, both centrally and peripherally. 1.6.1. Epineurium

Primary afferent nerve fibers classified by conduction velocity and fiber diameter. (Reproduced from Light, Perl, 1993 with permission from Elsevier).

Cutaneous nerve

Muscle nerve

Aαβ

Group I

Aδ C

Group II Group III Group IV

Conduction velocity in cat (m/s)

Diameter (mm)

72–130 35–108 36–72 3–30 0.2–2

12–22 6–18 6–12 3–7 0.25–1.35

The epineurium is thought of as a condensation of loose connective tissues that surround the perineurial ensheathment of the fascicles of uni- and multifascicular nerves. Despite being continuous with the surrounding connective tissues, the physical attachment is fairly loose, so that the nerve trunks maintain mobility except where tethered by large blood vessels or exiting branches. Where nerves cross joints greater proportions of epineurial connective tissue are present. In human nerve trunks, Sunderland and Bradley found that the epineurium usually constitutes anything from 30 to 75% of the cross-sectional

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BENN E. SMITH

Fig. 1.10 Drawing of the compound nerve action potential recorded from a mammalian saphenous sensory nerve with the Aαβ, Aδ, and C fiber components labeled (Gasser, 1941).

area, although extremes of 22 and 88% were documented (Sunderland, Bradley, 1949). As a general trend, the more fascicles a nerve trunk carries, the greater the contribution of epineurium to its crosssectional area. The collagen bundles are scattered throughout the epineurium. These fibers are primarily oriented along the axis of the nerve trunk. Elastic fibers, also mainly oriented longitudinally, have been identified

by light and electron microscopy, particularly in proximity to the perineurium. Apart from fibroblasts, which comprise the main cells constituting epineurial structures, the epineurium may contain mast cells, and even the occasional single immune system representative such as a lymphocyte or macrophage. Variable quantities of epineurial fat may be present, particularly in the larger proximal nerve trunks (Fig. 1.12).

Fig. 1.11 Confocal microscope images of cutaneous nerves stained with protein gene product (PGP) (green) and myelin basic protein (MBP) (red). The box in panel B encloses a single internode bordered on each side by a node of Ranvier (Nolano et al., 2003).

ANATOMY AND HISTOLOGY OF PERIPHERAL NERVE

The vasa nervorum enter the epineurium at various levels. On entering the nerve, these vessels communicate with a complex longitudinal anastomotic network of arterioles and venules. The epineurium also contains lymphatic vessels, which are not thought to be present within the fascicles. Sunderland surveyed the literature on the lymph drainage of nerves and concluded that an epineurial lymphatic capillary network is drained by lymphatic channels that accompany the arteries of the nerve trunk, which coalesce to form larger channels, and ultimately drain into regional lymph nodes (Sunderland, 1965). 1.6.2. Perineurium Although Key and Retzius recognized that the essential component of perineurium is a lamellated arrangement of flattened cells (Fig. 1.13), a disagreement arose concerning the embryological origin of these cells and whether there may be a separate connective tissue layer external to the lamellated cellular layer that can be distinguished from the epineurium. There is a general agreement that the perineurium provides a covering for both the somatic and peripheral autonomic nerves and their ganglia (Shantha, 1968). The perineurial lamellae are composed of concentric layers of flattened polygonal cells, the morphology of which was skillfully illustrated by Key and Retzius in their original descriptions, and subsequently confirmed

Fig. 1.12 Drawing of a transverse section through the edge of the rabbit brachial plexus showing the arrangement of epineurium, perineurium, and endoneurium (Key and Retzius, 1876).

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by electron microscopy. While the number of lamellae is generally proportional to the diameter of the fascicle, up to 15 layers may be present around the fascicles of large mammalian nerve trunks. Perineurial cells are bounded on both sides by basal lamina, although gaps in this membrane over short lengths are sometimes seen. The basal lamina is sometimes quite thick, sometimes as much 0.5 μm in human nerves. The cytoplasm is scant except in the perinuclear region. Organelles such as endoplasmic reticulum and mitochondria are predominantly found huddled near the nucleus, and glycogen particles often abound (Fig. 1.13). Thomas and Cravioto were among the first to observe that contiguous perineurial cells either overlapped or interdigitated with one another, but without interposition of basal lamina between adjacent membranes. At some sites, contiguous perineurial cells are linked by “tight junctions,” where the extracellular space appears to be obliterated (Thomas, 1963; Cravioto, 1966). Tight junctions are important in perineurial cells as evidenced by the abundant expression of claudin-1, a major structural protein of the tight junction, which interacts with occludin and ZO-1 (Folpe et al., 2002). Other markers expressed by perineurial cells include epithelial membrane antigen and glucose transporter 1 (Hirose et al., 2003). The existence of such cell relationships may be related to the diffusion barrier property of the perineurium. The finding of endocytotic vesicles,

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BENN E. SMITH

and neuromuscular junctions, however, the perineurial sleeve terminates with an open end. From detailed studies of the mouse neuromuscular junction, Saito and Zacks demonstrated that terminal perineurial cell processes form a bell-shaped cuff that does not directly contact the innervated muscle fiber (Saito and Zacks, 1969). Instead, between the termination of the perineurial sheath and the basal lamina covering the muscle fiber there is an open gap of 1 to 1.5 μm. The conclusion is that this arrangement provides a point of communication between the endoneurial space and the exterior. 1.6.3. Endoneurium

Fig. 1.13 Drawing of the surface perspective of the canine forelimb nerve demonstrating the mosaic pattern of polygonal perineurial cells (Key and Retzius, 1876).

particularly in the outer lamellae, may indicate a transport system across perineurial cells. Histochemical analysis suggests that perineurial cells contain a wide range of phosphorylating enzymes and high titers of both ATPase and creatine phosphatase activity (Shanthaveerappa and Bourne, 1962). On this basis, these cells could be considered well equipped to act as a metabolically active diffusion barrier. The nature of the junctional contacts between the perineurial cells have been further defined by the methodology of freeze-fracture. At the points of contact between adjacent perineurial cells extensive zonulae occludentes (tight junctions) are confirmed. The perineurium is penetrated by blood vessels, which link the longitudinal anastomotic network of arterioles and venules in the epineurium with the longitudinal intrafascicular capillary (microvessel) network. The consistently observed arrangement is that vessels carry in with them a perineurial “sleeve” for some distance, which does not come in close contact with the vascular wall, but rather terminates and provides a communication between the endoneurial and epineurial compartments. A perineurial investment follows the exiting terminal nerve branches into the periphery. Here the smallest nerve twigs may be ensheathed by a single layer of perineurial cells (the sheath of Henle). This layer then merges with the capsules of the muscle spindles and the encapsulated end organs. At unencapsulated endings

The endoneurium is the collective compartment within each fascicle of peripheral nerve, occupied by sparse connective tissue elements, nerve fibers, microvessels, and occasional single cells. Collagen fibrils in the endoneurium are similar in appearance and dimension to those of the perineurium, being oriented longitudinally, and demonstrating condensations in the proximity of nerve fibers and endoneurial microvessels. There are sizable spaces within nerve fascicles, which ultrastructural studies demonstrate to consist of a finely granular heterogeneous material without a specific identifiable profile, even by electron microscopy. A few morphologic patterns can, however, be discerned, including a space of variable thickness immediately subjacent to the perineurium. Nerve fibers tend to be grouped into small loose bundles. The cross-sectional area bordered by perineurium is termed the transverse endoneurial area. This has been estimated to range from 0.6 to 1.2 mm2 in distal human sural nerve. Of the total, the space taken up by dense collagen fibrils is 0.3 mm2. The remaining endoneurium populated by myelinated and unmyelinated nerve fibers is 0.2 to 0.4 mm2 (Thomas and Olsson, 1984). Each nerve fiber is clothed with a basal lamina that follows the contour of the nodes of Ranvier and is continuous across them, covering both the Schwann cell nodal and paranodal apparatus as well as the intervening extracellular space. Slightly external to this, a thin band of collagen fibrils surround the larger myelinated nerve fibers; these typically show a circular and oblique orientation. Still further from the nerve fiber are longitudinally oriented collagen fibrils comprising the outer endoneurial sheath. No clear demarcation between the inner and outer endoneurial sheaths is apparent around the smaller myelinated and unmyelinated nerve fibers, where collagen fibrils are less densely packed and oriented parallel to the nerve fiber axis.

ANATOMY AND HISTOLOGY OF PERIPHERAL NERVE

The most numerous cells inhabiting the endoneurium are endoneurial fibroblasts and Schwann cells. Occasional cells with the cytologic and histochemical features of macrophages and lymphocytes are also seen in normal mammalian and human nerve, often in a perivascular or subperineurial distribution. Mast cells may also occur in the endoneurium, being much more commonly encountered in rat nerve than in human, rabbit, or guinea pig nerve. 1.6.4. Blood vessels Not only does peripheral nerve cell architecture possess unique features distinct from that of the CNS, the PNS vascular supply demonstrates structural peculiarities providing advantages in supplying oxygen, nutrients, and waste removal for the structures they perfuse. The diffusion and transport properties of vasa nervorum endothelium appears to be of particular functional significance. There are two main structural characteristics that distinguish the peripheral nerve blood supply. These are: (1) the dense branching anastomotic network of vessels that weaves in and out of the epineurial and perineurial compartments; and (2) the system of endoneurial microvessels, which perfuses the endoneurial space. Large segmental vessels give off nutrient arteries, which, in turn, branch out to form multiple arteries that enter the epineurium. These arteries then contribute to the anastomotic epineurial/perineurial network, which ultimately is the source of the tiny terminal microvessel branches in the endoneurium. Although these vessels have the diameter of small arterioles and capillaries, they are referred to simply as “microvessels” (Olsson, 1984). Because small terminal nerve branches are devoid of endoneurial blood vessels but still often possess a perineurial sheath, they are thought to receive nutrients and other vital substances through diffusion. It may also be that very small caliber nerve trunks are partly supplied by this mechanism and therefore not completely dependent on endoneurial vessels. The arrangement of venous drainage of the nerve appears to mirror that of the arterial supply. The small and large vessels in the epineurium are invested with rather loose connective tissue. The vessel wall proper is indistinguishable from vessels in other organs, demonstrating endothelial cells, pericytes, basement membrane, and in the larger channels, circularlyoriented smooth muscle cells. Still larger vessels in the epineurium show longitudinally arrayed smooth muscle

17

elements. Transmission electron microscopy of endoneurial endothelial cells confirms the presence of numerous tight junctions between neighbouring cells. This arrangement is presumed to form an osmotic barrier which is relatively impermeable to protein and smaller molecules, which is referred to as the blood-nerve barrier (Allt and Lawrenson, 2000). When considered with the perineurium and the nerve-cerebrospinal fluid barrier, the blood-nerve barrier provides a relatively protected environment for the peripheral nerve (Olsson et al., 1971). In peripheral nerve, particularly in the course of certain inflammatory demyelinating neuropathies, a staggering array of proinflammatory cytokines are elaborated or stimulated by resident and recruited immunoreactive cells such as macrophages, lymphocytes, mast cells, and perhaps Schwann cells and neurons. These substances include tumour necrosis factor alpha and beta, interleukin 1, 2, and 6, leukemia inhibitory factor, vascular endothelial growth factor, interferon gamma, and transforming growth factor beta (Creange et al., 1997) 1.6.5. Central-peripheral transition The cells and sparse connective tissue of spinal root endoneurium are very similar to those in distal peripheral nerve, although the number and density of collagen fibrils is less and they are not nearly as organized at the root level. Where spinal roots enter and exit the spinal cord, an irregular but well-defined transition from peripheral nerve to central nervous system tissue can be identified. This has been called the Obersteiner-Redlich zone. As the posterior root axons enter this zone near the dorsal aspect of the cord, Schwann cells give rise to oligodendrocytes, and the peripheral myelin sheath is replaced by central nervous system myelin. The central portion of the root is limited at its periphery by a layer of astrocytes enclosed by basement membrane. This basal lamina extends beyond the spinal cord to ensheath nerve fibers in the peripheral segment of the root and to form the perimeter of the most proximal stretch of peripheral endoneurium. Collagen fibers are found only on the peripheral side of the junctional zone (Berthold et al., 1993). As they leave the confines of the central nervous system, spinal roots enter and course through the subarachnoid space covered by a delicate multilamellar nerve root sheath (Haller, 1971). These fibers tent and then penetrate dura mater at the subarachnoid angle. Outside of the dural sac nerve roots gain their full investment of

18

BENN E. SMITH

DM

A

SA PM EP P RS Subarachnoid space

PM

EP

A Connective tissue space DM

epineurium, perineurium, and endoneurium, which continues distally as nerve trunks take their various and sometimes convoluted courses into the periphery. As dorsal root fibers approach the spinal cord, the epineurium fuses with dura and the endoneurium continues as far as the transition between roots and the dorsal root entry zone of the spinal cord (Fig. 1.14). The transition between central and peripheral myelin, the former produced by oligodendrocytes in the CNS and the latter by Schwann cells in the periphery, is not clearly demarcated at the point of emergence of the cranial nerves and spinal roots from the neuraxis. At some sites, and especially in the cranial nerves, tongues of glial tissue (glial bundles) extend a considerable distance outside the CNS. Seen in the oculomotor and other cranial nerves, this phenomenon is particularly pronounced in the seventh cranial nerve (Thomsen, 1887). As myelinated fibers exit the central nervous system they gradually become smaller in diameter. Like microscopic palm trees rooted in the brainstem or spinal cord, myelinated fibers progressively taper the further they proceed into the periphery. This phenomenon has been documented for a number of different nerves in various species including man, and is not explainable on the basis of branching, in that nerves

Fig. 1.14 Diagram of the relationships between the meninges of the spinal cord and the peripheral nerve connective tissue elements. A = arachnoid; DM = dura mater; EP = epineurium; En = endoneurium; P = pia mater; RS = root sheath (Haller and Low, 1971).

which have no branches also taper along their proximal to distal course (Smith, 1992). References Aguayo, AJ, Bray, GM, Terry, LC and Sweezy, E (1976) Three dimensional analysis of unmyelinated fibers in normal and pathologic autonomic nerves. Neuropathol. Exp. Neurol. 35: 136–151. Allt, G and Lawrtenson, JG (2000) The blood nerve barrier: enzymes, transporters and receptors – a comparison with the blood-brain barrier. Brain Res. Bull., 52: 1–12. Arroyo, EJ and Scherer, SS (2000) On the molecular architecture of myelinated fibers. Histochem. Cell Biol., 113: 1–18. Bergoffen, J, Scherer, SS, Wang, S, Scott, MO, Bone, LJ, Paul, DL, Chen, K, Lensch, MW, Chance, PF and Fischbeck, KH (1993) Connexin mutations in X-linked Charcot–Marie–Tooth disease. Science, 262: 2039–2042. Berthold, C-H and Skoglund, S (1967) Histochemical and ultrastructural demonstration of mitochondria in the paranodal region of developing feline spinal roots and nerves. Acta Soc. Med. Ups. 72: 37–70.

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Berthold, C-H, Carlstedt, T and Corneliuson, O (1993) The central-peripheral transition zone. In: PJ Dyck, PK Thomas, JW Griffin, PA Low and JF Poduslo (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 243. Berthold, C-H (1996) Development of nodes of Ranvier in feline nerve: an ultrastructural presentation. Microscop. Res. Tech., 34: 399–421. Bessou, P and Perl, ER (1969) Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J. Neurophysiol., 32: 1025–1043. Bischoff, A and Moor, H (1967) Ultrastructural differences between the myelin sheaths of peripheral nerve fibers and CNS white matter. Z. Zellforsch., 81: 303–310. Boyd, IA and Davey, MR (1968) Composition of Peripheral Nerves. Edinburgh, Livingstone. Brown, A (2003) Axonal transport of membranous and nonmembranous cargoes: a unified perspective. J. Cell Biol., 160: 817–821. Burgess, PR, Petit, D and Warren, RM (1968) Receptor types in cat hairy skin supplied by myelinated fibers. J. Neurophysiol., 31: 833–848. Chao, MV (2003) Retrograde transport redux. Neuron, 39: 1–2. Cheng, C and Zochodne, DW (2002) In vivo proliferation, migration and phenotypic changes of Schwann cells in the presence of myelinated fibers. Neuroscience, 115: 321–329. Cravioto, H (1965) The role of Schwann cells in the development of human peripheral nerves. An electron microscopic study. J. Ultrastruct. Res., 12: 634–651. Creange, A, Barlovatzmeimon, G and Gherardi, RK (1997) Cytokines and peripheral nerve disorders. Europ. Cytokine Network, 8: 145–151. Daube, JR (1996) Compound muscle action potentials. In: JR Daube (Ed.), Clinical Neurophysiology, F.A. Davis, Philadelphia, p. 214. Engel, AG and Franzini-Armstrong, C (2004) Myology. McGraw-Hill, San Francisco, pp. 3–595. Fabbretti, E, Edomi, P, Brancolini, C and Schneider, C (1995) Apoptotic phenotype induced by overexpression of wild-type gas3/PMP22: its relation to the demyelinating peripheral neuropathy CMT1A. Genes Dev., 9: 1846–1856. Farel, PB (1978) Reflex activity of regenerating frog spinal motorneurons. Brain Res., 158: 331–341. Finean, JB (1958) X-ray diffraction studies of the myelin sheath in peripheral and central nerve fibers. Exp. Cell Res. Suppl., 5: 18–32.

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Folpe, AL, Billings, SD, McKenney, JK, Walsh, SV, Nusrat, A and Weiss, SW (2002) Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am. J. Surg. Path., 26: 1620–1626. Gasser, HS and Erlanger, J (1927) The role played by the sizes of the constituent fibers of a nerve trunk in determining the form of its action potential wave. Am. J. Physiol., 80: 522. Gasser, HS (1941) The classification of nerve fibers. Ohio J. Sci., 41: 145. Gasser, HS (1955) Properties of dorsal root unmedullated fibers on the two sides of the ganglion. J. Gen. Physiol. 38: 709–728. Ghabriel, MN and Allt, G (1981) Incisures of Schmidt-Lanterman. Prog. Neurobiol. 17: 25–58. Gong, Y, Tagawa, Y, Lunn, MPT, Laroy, W, HefferLauc, M, Li, CY, Griffin, JW, Schnaar, RL and Sheikh, KA (2002) Localization of major gangliosides in the PNS: implications for immune neuropathies. Brain, 125: 2491–2506. Gutrecht, JA and Dyck, PJ (1970) Quantitative teased fiber and histologic studies of human sural nerve during postnatal development. J. Comp. Neurol. 138: 117–129. Haller, FR and Low, FN (1971) The fine structure of the peripheral nerve root sheath in the subarachnoid space in the rat and other laboratory animals. Am. J. Anat., 131: 1–19. Henneman, E, Somjen, G and Carpenter, DO (1965) Excitability and inhibitability of motorneurons of different sizes. J. Neurophysiol., 28: 599–620. Hirose, T, Tani, T, Shimada, T, Ishizawa, K, Shimada, S and Sano, T (2003) Immunohistochemical demonstration of EMA/Glut1-positive perineurial cells and CD34-positive fibroblastic cells in peripheral nerve sheath tumors. Modern Pathol., 16: 293–298. Hiscoe, HB (1947) Distribution of nodes and incisures in normal and regenerated nerve fibers. Anat. Rec., 99: 447. Hoffman, PN and Griffin, JW (1993) The control of axon caliber. In: PJ Dyck, PK Thomas, JW Griffin, PA Low, JF Poduslo (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, pp. 389–402. Hursh, JB (1939) Conduction velocity and diameter of nerve fibers. Am. J. Physiol., 127: 131. Jetten, AM and Suter, U (2000) The peripheral myelin protein 22 and epithelial membrane protein family. Prog. Nucleic Acid Res. Mol. Biol., 64: 97–129.

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Kernie, SG and Parada, LF (2000) The molecular basis for understanding neurotrophins and their relevance to neurologic disease. Arch. Neurol., 57: 654–657. Key, A and Retzius, G (1876) Studien in der Anatomie des Nervensystems und des Bindegewebes. Samson & Wallin, Stockholm. Lambert, EH and Dyck, PJ (1984) Compound action potentials of sural nerve in vitro in peripheral neuropathy. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 1030. Lanterman, AJ (1877) Über den feineren Bau der markhaltigen Nervenfasern. Arch. Mikrosk Anat. Entwicklungsmech. 13: 1. Light, AR and Perl, ER (1993) Peripheral sensory systems. In: PJ Dyck, PK Thomas, JW Griffin, PA Low, JF Poduslo (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, pp. 149–165. Low, PA, Vernino, S and Suarez G (2003) Autonomic dysfunction in peripheral nerve disease. Muscle Nerve, 27: 646–661. Martini, R (2001) The effect of myelinating Schwann cells on axons. Muscle Nerve, 24: 456–466. Meiggioli, MN, Howard, JF and Harper, CM (2004) Neuromuscular Junction Disorders. Marcel Dekker, New York, p. 3. Midroni, G and Bilbao, JM (1995) Normal anatomy of peripheral (sural) nerve. In: Biopsy Diagnosis of Peripheral Neuropathy. Butterworth-Heinemann, Boston, p. 13. Mirsky, R, Jessen, KR, Brennan, A, Parkinson, D, Dong, Z, Meier, C, Parmantier, E and Lawson, D (2002) Schwann cells as regulators of nerve development. J. Physiol. Paris, 96: 17–24. Mugnaini, E, Osen, KK, Schnapp, B and Friedrich, VL (1977) Distribution of Schwann cell cytoplasm and plasmalemmal vesicles (caveolae) in peripheral myelin sheaths. An electron microscopic study with thin sections and freeze-fracturing. J. Neurocytol., 6: 647–668. Mustafa, GY and Gamble, HJ (1979) Changes in axonal numbers in developing human trochlear nerve. J. Anat., 128: 323–330. Nageotte, J (1910) Incisures de Schmidt-Lanterman et protoplasma des cellules de Schwann. C R Acad Sci (Paris), 68: 39. Napolitano, L and Scallen, TJ (1969) Observations on the fine structure of peripheral nerve myelin. Anat. Rec, 163: 1–6. Nolano, M, Provitera, V, Crisci, C, Stancanelli, A, Wendelschafer-Crabb, G, Kennedy, WR and

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Santoro, L (2003) Quantification of myelinated endings and mechanoreceptors in human digital skin. Ann. Neurol., 54: 197–205. Ohcoa, J (1970) Isoniazid neuropathy in man: quantitative electron microscopic study. Brain, 93: 831–850. Ochoa, J (1971) The sural nerve of the human foetus: electron microscope observations and counts of axons. J. Anat., 108: 231–245. Ochoa, J, Fowler, JT and Gilliatt, RW (1972) Anatomical changes in peripheral nerves compressed by a pneumatic tourniquet. J. Anat., 113: 433–455. Olsson, Y, Kristensson, K and Klatzo, J (1971) Permeability of blood vessels and connective tissue sheaths in the peripheral nervous system to exogenous proteins. Acta Neuropathol., Suppl. 5: 61–69. Olsson, Y (1984) Vascular permeability in the peripheral nervous system. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 579. O’Sullivan, DJ and Swallow, M (1968) The fibre size and content of the radial and sural nerves. J. Neurol. Neurosurg. Psychiatry, 31: 464–470. Peters, A, Palay, SL and Webster, HdF (1991) The cellular sheaths of neurons. In: The Fine Structure of the Nervous System: Neurons and their Supporting Cells., Oxford University Press, New York, p. 212. Pleasure, D (1984) The structural proteins of peripheral nerve. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 441. Poduslo, JF (1984) Glycoproteins of the peripheral nervous system. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 494. Polydefkis, M, Griffin, JW and McArthur, J (2003) New insights into diabetic polyneuropathy. JAMA, 290: 1371–1376. Ranvier, L (1871) Recherches de l’histologie et la physiologie des nerfs. Arch. Physiol. I, Ser 4: 129. Ranvier, L (1878) Leçons sur l’histologie du systems nerveux. Paris, F. Savy. Rosenbluth, J (1976) Intramembranous particle distribution at the node of Ranvier and adjacent axolemma in myelinated axons of the frog brain. J. Neurocytol., 5: 731–745. Saito, A and Zacks, SI (1969) Ultrastructure of Schwann and perineurial sheaths at the mouse neuromuscular junction. Anat. Rec., 164: 379–390. Sanes, JR, Apel, ED, Burgess, RW, Emerson, RB, Feng, G, Gautam, M, Glass, D, Grady, RM, Krejci, E, Lichtman, JW, Lu, JT, Massoulie, J, Miner, JH,

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Moscoso, LM, Nguyen, Q, Nichol, M, Noakes, PG, Patton, BL, Son, YJ, Yancopoulos, GD and Zhou, H (1998) Development of the neuromuscular junction: genetic analysis in mice. J. Physiol. (Paris), 92: 167–172. Schmidt, HD (1874) On the structure of the dark or double-bordered nerve fiber. Mon Microsc. J. (Lond.), 11: 200. Schnapp, B and Mugnaini, E (1978) Membrane architecture of myelinated fibers as seen by freeze-fracture. In: SG Waxman (Ed.), Physiology and Pathobiology of Axons, Raven Press, New York, p. 83. Scholzen, T, Armstrong, CA, Bunnett, NW, Luger, TA, Olerud, JE and Ansel, JC (1998) Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems. Exp. Dermatol., 7: 81–96. Shantha, TR and Bourne, GH (1968) The perineural epithelium – a new concept. In: GH Bourne (Ed.), The Structure and Function of Nervous Tissue, Academic Press, New York, Vol. 1, p. 379. Shanthaveerappa, TR and Bourne, GH (1962) The “perineural epithelium,” a metabolically active, continuous, protoplasmic cell barrier surrounding peripheral nerve fasciculi. J. Anat., 96: 527. Shield, LK, King, RH and Thomas, PK (1986) A morphometric study of human fetal sural nerve. Acta Neuropathol. (Berl.), 70: 60–70. Smith, BE and Dyck, PJ (1992) Subclinical histopathological changes in the oculomotor nerve in diabetes mellitus. Ann. Neurol., 32: 376–385. Stewart, JD (1987) The Structure of the Peripheral Nervous System. In: Focal Peripheral Neuropathies, Elsevier, New York, p. 6. Stewart, JD (2003) Peripheral nerve fascicles: anatomy and clinical relevance. Muscle Nerve, 28: 525–541. Sunderland, S (1965) The connective tissues of peripheral nerves. Brain, 88: 841–854. Sunderland, S and Bradley, KC (1949) The cross-sectional area of peripheral nerve trunks devoted to nerve fibers. Brain, 72: 428–449. Takashima, H, Boerkoel, CF, De Jonghe, P, Ceuterick, C, Martin, JJ, Voit, T, Schroder, JM, Williams, A, Brophy, PJ, Timmerman, V and Lupski, Jr (2002) Periaxin mutations cause a broad spectrum of demyelinating neuropathies. Ann. Neurol., 51: 709–715. Thomas, PK (1963) The connective tissue of peripheral nerve: an electron microscope study. J. Anat., 97: 35–44.

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Thomas, PK and Ochoa, J (1984) Microscopic anatomy of peripheral nerve fibers. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 39. Thomas, PK and Ochoa, J (1984) Microscopic anatomy of peripheral nerve fibers. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 41. Thomas PK and Ochoa J (1984) Microscopic anatomy of peripheral nerve fibers. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 51. Thomas, PK and Ochoa, J (1984) Microscopic anatomy of peripheral nerve fibers. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 57. Thomas, PK and Olsson, Y (1984) Microscopic anatomy and function of the connective tissue components of peripheral nerve. In: PJ Dyck, PK Thomas, EH Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 97. Thomas, PK, Berthold, C-H and Ochoa, J (1993) Microscopic anatomy of the peripheral nervous system. In: PJ Dyck, PK Thomas, JW Griffin, PA Low, JF Poduslo (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, pp. 28–91. Thomas, PK, Berthold, C-H and Ochoa, J (1993) Microscopic anatomy of the peripheral nervous system. In: PJ Dyck, PK Thomas, JW Griffin, PA Low, JF Poduslo (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 60. Thomsen, R (1887) Ueber eigenthumliche aus veranderten Ganglienzellen hervorgegagene Gebilde is den Stammen der Hirnnerven des Menschen. Virchows Arch., 109: 459. Webster, HD (1993) Development of peripheral nerve fibers. In: PJ Dyck, PK Thomas, JW Griffin, PA Low, JF Poduslo (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, pp. 243–266. Williams PL and Landon DN (1964) The energy source of the nerve fibre. New Sci., 21: 166. Williams, PL, Warwick, R, Dyson, M and Bannister, LH (1989) Structure of the peripheral nervous system. In: Gray’s Anatomy. Churchill Livingstone, New York, p. 896. Willison, HJ and Yuki, N (2002) Peripheral neuropathies and antiglycolipid antibodies. Brain, 125: 2591–2625. Yao, JK (1984) Lipid composition of normal and degenerating nerve. In: PJ Dyck, PK Thomas, EH

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Lambert, R Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, Philadelphia, p. 510. Yin, X, Crawford, TO, Griffin, JW, Tu, P, Lee, VM, Roder, J and Trapp, BD (1998) Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J. Neurosci., 18: 1953–1962. Yoshikawa, H and Dyck, PJ (1991) Uncompacted inner myelin lamellae in inherited tendency to pressure palsy. J. Neuropathol. Exp. Neurol., 50: 649–657.

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Zhou, L and Griffin JW (2003) Demyelinating neuropathies. Curr. Opin. Neurol., 16: 307–313. Zoidl, G, Blass-Kampmann, S, D’Urso, D, Schmalenbach, C and Muller, HW (1995) Retroviral-mediated gene transfer of the peripheral myelin protein PMP22 in Schwann cells: modulation of cell growth. EMBO J., 14: 1122–1128.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 2

Physiology and function Christian Krarup* Department of Clinical Neurophysiology, the Neuroscience Center, Rigshospitalet, Denmark

2.1. Introduction The purpose of the clinical neurophysiological examination is to localize, identify, and specify pathophysiological abnormalities as consistent with disease affecting the peripheral nervous system (PNS), neuromuscular transmission or muscle and after integration with clinical and other paraclinical information to establish a specific diagnosis. To accomplish these goals, it is necessary to have a clear notion of the physiological characteristics of the individual systems, which methods are needed to study these systems, and how particular deviations from normal function reflect pathological abnormalities. In addition, recently it has become apparent that axon membrane function is fundamental for phenomena such as fasciculations, cramps and neuromyotonia (NewsomDavis, 1997; Mogyoros et al., 1997, 1998; Heidenreich and Vincent, 1998; Vincent et al., 1998; Kiernan et al., 2001b). These goals are by no means trivial since the pathophysiological correlates of pathological disturbances rarely are specific. It is, therefore, necessary to understand the limitations of the physiological methods and apply an integrated approach using different criteria to arrive at a comprehensive picture of the disorder. This chapter aims at discussing the physiology and function of peripheral nerve to assist the reader in understanding the methods and techniques covered in this section, which are used to investigate the different parts of the peripheral nervous system, whereas it is not intended to deal with these topics in detail. The main outcome of the neurophysiological studies is to determine whether there is loss of nerve fibers or whether their function is abnormal or both. The main parameters in routine

* Correspondence to: Christian Krarup MD DMSc FRCP Department of Clinical Neurophysiology NF3063, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark E-mail address: [email protected]. Tel: +45 3545 3060; fax: +45 3545 3264.

electrophysiological studies include conduction velocity and amplitudes of the evoked responses, and it is necessary to consider to what extent abnormalities associated with these parameters may be used to determine loss or abnormalities of function. In recent years, we have seen a marked development of insights into basic function and structure of the axon, glial cells and ion-channels and methodologies have been developed to investigate abnormalities in these structures in patients. In the future, we are likely to see these methods as integrated tools in clinical settings. Several textbooks describe the techniques of conduction studies in motor and sensory nerve fibers (Kimura, 1989; Brown and Bolton, 1993; Binnie et al., 1995; Aminoff, 1998; Daube, 2002). 2.2. Anatomy, structure, and function of peripheral nerve Peripheral nerves are defined as the part of the nervous system situated outside the central nervous system (CNS) demarcated by the leptomeninges. The glia surrounding axons of the PNS is derived from Schwann cells, and in the CNS from oligodendrocytes (Kleitman and Bunge, 1995). The division of the nervous system into the PNS and the CNS is to some extent artificial since parts of peripheral neurons are situated within the CNS. Only the thin unmyelinated postganglionic autonomic fibers are located wholly outside the CNS (Berthold and Rydmark, 1995). Even though peripheral nerve disorders by definition are located to the PNS, a number also affect the central parts of the PNS (Asbury and Johnson, 1978; Berger and Schaumburg, 1995). 2.2.1. Classification of fibers of the PNS Peripheral nerve fibers are classified according to morphology and function. The afferent system consists of myelinated and unmyelinated fibers that innervate different types of sensory receptors and accordingly convey different sensory modalities (see Kandel et al., Principles of Neural Science, 4th edition, 2000 (Gardner

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et al., 2000)). Myelinated fibers are grouped according to diameters into types Aα-δ in cutaneous nerves (touch, vibration, temperature, pain), whereas they are named I-III in muscle nerves (proprioception, pressure, pain) (Pearson and Gordon, 2000), and unmyelinated fibers consist of type C in cutaneous nerves and type IV in muscle nerves that innervate pain and temperature receptors. It is now known that unmyelinated fibers have different subtypes (Serra et al., 1999). The efferent system is divided in myelinated α-, γ- and δ-fibers that innervate extrafusal muscle fibers, muscle spindles and both, respectively. Autonomic postganglionic fibers are unmyelinated. In myelinated fibers (Fig. 2.1), each axon is surrounded by the specialized membrane of trains of single Schwann cells wrapped around the axon in lamellae (Fig. 2.1A, insert), and each Schwann cell is divided from the next at the node of Ranvier. In contrast, unmyelinated fibers are arranged in groups of 1–50 axons ensheathed in Schwann cells (referred to as Remak fiber, Fig. 2.1B). Each myelinated fiber and group of unmyelinated fibers are delimited from the endoneurium by a basal lamina (Fig. 2.1) (Behse, 1990; Berthold and Rydmark, 1995). The number of unmyelinated fibers is much greater than myelinated fibers (20 000–50 000 in the sural nerve) but the proportion of unmyelinated to myelinated fibers varies in different types of nerves (Ochoa and Mair, 1969; Behse, 1990). The distribution of motor and sensory myelinated fibers in humans is bimodal, with motor fibers classified as small 1–8 μm γ-fibers, and large 8–15 μm α-fibers (Lee et al., 1975), and sensory fibers ranging from small 1 μm Ad fibers to large 18 μm Aα and Aβ fibers (Fig. 2.2) (Buchthal and Rosenfalck, 1966; Behse, 1990; Caruso et al., 1992; Berthold and Rydmark, 1995). Unmyelinated fibers have small diameters of 1–2 μm.

Fig. 2.1 Myelinated (A) and unmyelinated (B) fibers from the sural nerve. A single axon is surrounded by compact myelin lamellae (A, inset); several axons are ensheathed by Schwann cell process in unmyelinated fibers. BM, basal lamina; *, axons; SC, Schwann cell processes. In (A) the thick straight arrow points at the inner mesaxon; the curved arrow points at the outer mesaxon (Courtesy of H. Schmalbruch, University of Copenhagen).

CHRISTIAN KRARUP

Individual myelinated fibers are subdivided into specialized regions (Berthold and Rydmark, 1995; Arroyo and Scherer, 2000; Peles and Salzer, 2000; Scherer and Arroyo, 2002) consisting of the node of Ranvier with a width of about 1 mm and the internodal segment with a length of 300–2000 mm proportional to the fiber diameter (Vizoso and Young, 1948). The myelin thickness and the number of lamellae are also proportional to the fiber caliber, and the ratio of axon/fiber diameter (g-ratio) is reasonably constant about 0.6, at least among the larger myelinated fibers (Boyd and Davey, 1968; Arbuthnott et al., 1980b; Behse, 1990). A g-ratio of about 0.6 is recovered in regenerated nerve though the proportionality between fiber diameter and internodal length is not reestablished (Vizoso and Young, 1948; Hildebrand et al., 1987). A constant relationship between the surface area and the myelin volume was found in normal, regenerated and remyelinated fibers (Smith et al., 1982a). 2.2.2. Molecular organization of myelinated fibres The specialized organization has important implications for the function of the nerve fiber, and the nodes of Ranvier and paranodes are formed by interaction between myelin and axon (Scherer, 1996) that occur during development (Vabnick and Shrager, 1998). The distribution of current along the axon before, during and after the action potential is determined by its biophysical passive properties and by the function and distribution of ion-channels (Waxman and Ritchie, 1985; Arroyo et al., 1999; Arroyo and Scherer, 2000; Scherer and Arroyo, 2002, 2004), which have many features in common in most mammals, including human nerve fibers (Scholz et al., 1993; Reid et al., 1999). During acute demyelination, the ability to propagate action

PHYSIOLOGY AND FUNCTION

25

Number of fibers

Mean fiber diameter distribution from normal sural nerve (n =10) (Behse, 1990) 2000 1800 1600 1400 1200 1000 800 600 400 200 0

Mean number of fibers = 6940 (range 5075−9460)

1

2

3

4

5

6 7 8 Fiber diameter (μm)

9

10

11

12

13

Fig. 2.2 Fiber diameter distribution from 10 normal sural nerves. The total number of myelinated fibers was calculated from sampling of 200–300 fibers in whole nerve biopsies multiplied by the total fascicular area. The bars indicate the mean number of fibers in each bin (1 μm) and the error bars indicate the standard deviation Calculated from data in Behse (1990).

potentials is impaired and the block of conduction may occur (Lafontaine et al., 1982). Nevertheless, continuous conduction can occur along demyelinated internodes, indicating that the internodal membrane is excitable (Bostock and Sears, 1978). Conduction along demyelinated internodes is insecure, and broadening of the action potential improves the safety factor (Bostock et al., 1978, 1981). Consistent with this internodal excitability was the increased number of Na+ channels, probably formed de novo rather than through redistribution (England et al., 1991), and immunocytochemistry studies have shown that incorporation of channels occurs at sites of axon-Schwann cell interaction (Dugandzija-Novakovic et al., 1995). After demyelination, saltatory-like conduction was resumed before remyelination, which suggested that increased concentration of Na+ channels occurred at future nodes of Ranvier (Smith et al., 1982b). The inward current during the action potential is carried by Na+ ions through specific voltage-gated channels. At the node of Ranvier, Na+ channels are concentrated at a density of 1000–2000 channels/μm2, whereas the density at the internode is only 4% of this at about 25 channels/μm2 (Barchi, 1995; Waxman, 1995). Even though the total number of Na+ channels at the internode is larger than at the node (Shrager, 1989), their low density is insufficient to carry action potentials during acute demyelination. Na+ channels are closed at the resting membrane potential but open at depolarization to threshold (activation) reaching a high conductance, each channel carrying as much as 10 000 ions during a single impulse. During this

inward current, the membrane potential approaches the reversal potential of Na+ of about +40 mV but repolarizes due to rapid inactivation of the channel in spite of depolarization. The Na+ channel activation by depolarization is associated with movement of an intramembraneous gating-charge (Dubois and Schneider, 1981; Chiu and Ritchie, 1981b; Ritchie, 1995), which opens the channel and which is blocked during inactivation. Voltage-gated ion-channels are composed of subunits, and K+, Na+, and Ca++ channels form part of a superfamily with six membrane-spanning segments of the subunit. The Na+ channel consists of a pore forming α-subunit with more than 2000 aminoacids and a MW of about 260 kDa and 24 transmembraneous segments (S1-6) in four domains (I-IV) (Fig. 2.3). The S4 segment is the likely voltagesensitive factor associated with charge movement during depolarization and the channel protein is subject to conformational changes during depolarization (Catterall, 1992). Cytoplasmic parts of the channel are involved in inactivation, and in addition to the a-subunit, the structure includes β-subunits that have MW in the order of 40 kDa and provide auxiliary functions for the ion permeability. Thus the a-subunits allow Na+ flux but co-expression of β1- and β2-subunits increases the activation and the inactivation rates (Catterall, 2000). More than 10 genes encode for several isoforms of voltage-gated Na+ channels (Goldin, 1999; Goldin et al., 2000), denoted as Nav1 for the first gene subfamily, and include 9 types. Nav1.6 is the isoform most widely distributed in mammalian motor and sensory fibers of both the CNS and the PNS

26

CHRISTIAN KRARUP

A

Na+

Exracellular Direction of passive movement for Na+

ΔV Intracellular Closed channel

Open channel

B P segment I Out

II + +

1 2 3 4 5

+ + 6

IV

+ +

1 2 3 4 5

+ +

In

III

6

1 2 3 4 5

+ +

+ + 6

1 2 3 4 5

+ +

6

+ + COOH

NH2

C

II

Na+

III

SIDE VIEW

II

III

I

IV

TOP VIEW I

IV

Selectivity filter

COOH

NH2 +

Fig. 2.3 Diagrammatic representation of axonal Na channels. (A) closed and open voltage gated channels inserted in the axolemma. (B) the α-subunit consisting of four domains (I-IV) each with 6 (1-6) membrane spanning segments. The S4 segment is the likely voltage sensitive factor and the S5-6 segments the pore forming parts of the channel. (C) the folded subunit as arranged in the axolemma (With permission from Hammond: Cellular and Molecular Neurobiology, © Academic Press.).

(Caldwell et al., 2000; Kearney et al., 2002), and mice lacking the gene that encode for the Nav1.6 have severe neurological disease (Kearney et al., 2002). Nevertheless, nodes of mice lacking Nav1.6 can conduct action potentials and show Na+ channels that stain for a panspecific channel type, indicating that there are several isoforms at the node of Ranvier (Caldwell et al., 2000; Peles and Salzer, 2000). In developing fibers there is a shift from Nav1.2 to Nav1.6 isoform during myelination, whereas this switch does not occur in unmyelinated fibers (Boiko et al., 2001; Kaplan et al., 2001; Kazarinova-Noyes and Shrager, 2002). The great majority of Na+ channels are tetrodotoxin (TTX) sensitive. TTX-resistant Nav1.9 channels also occur in dorsal root ganglia and may be involved in pain sensation (Dib-Hajj et al., 2002; Fang et al., 2002). These channels are

down-regulated and the TTX-sensitive Nav1.3 channel is up-regulated after neural trauma (Cummins and Waxman, 1997; Cummins et al., 2001), indicating that the channel isoforms may be modified in the adult mammalian organism. Although most Na+ channels are rapidly inactivating, 1–3% remain active at more positive membrane potentials (so-called persistent Na+ channels) that may arise from different types of channels or be due to a modality shift of the same isoform (Brown et al., 1994; Crill, 1996; Baker and Bostock, 1997). The segregation of Na+ channels at the nodal membrane (Ritchie and Chiu, 1981) may be explained by different mechanisms including physical restriction, soluble factors, cytoskeletal anchoring or molecules in the extracellular matrix (Barchi, 1995; Waxman, 1995; Peles and Salzer, 2000). The nodal gap is limited by the paranodal loops, and the Na+

PHYSIOLOGY AND FUNCTION

27

channels form complexes with several membrane proteins and extracellular matrix components directly or through ankyrin G, and the beta-units may contribute to the anchoring and segregation of Na+ channels to the nodal membrane (Fig. 2.4) (Davis et al., 1996; Arroyo and Scherer, 2000; Catterall, 2000; Peles and Salzer, 2000; Kazarinova-Noyes and Shrager, 2002; Scherer and Arroyo, 2002). In myelinated amphibian and mammalian, including human nerve fibres, there exist one type of Na+ channel and at least three types of K+ channels (Jonas et al., 1989; Scholz et al., 1993; Barchi, 1995; Vogel and Schwarz, 1995; Reid et al., 1999), fast, intermediate and slowly activated K+ channels. Fast activated K+

channels are blocked by 4-aminopyridine (4AP), and are located in the juxtaparanode in mammalian fibers, whereas the slowly activated K+ channels are located in the node and the internode and may be blocked by tetraethylammonium (TEA). The fast-activated K+ channels in mammalian peripheral nerve belong to the Kv1.1 and Kv1.2 alpha-subunits and the Kvβ2 subunit and consist of 4 membrane-spanning domains similar in configuration to the Na+ channel (Fig. 2.3) localized beneath the myelin and together with the protein Caspr2 bind to the myelin protein P0 (Arroyo et al., 1999; Rasband and Trimmer, 2001; Scherer and Arroyo, 2002) and participate in the formation of axoglial junctions (Arroyo and Scherer, 2000).

Kv1.5

Compact Myelin

Slo1

Microvilli Adaxonal Membrane ?

actin

?

?

Paranodal Myelin Loop

TAG-1

?

Ezrin Radixin Moesin

KIR2.3 KIR2.1 Caspr2

?

Kvβ2

PDZ?

pr

NF Band 4.1B

Kv3.1b

KCNQ2

Ca s

n cti nta Co

Kv1.2

β1

AnkyrinG

Tenascin-R

Connexin29

NF186

Kv1.1

Nr-CAM

Connexin32

Tenascin-C

15

5

?

α

β2

Spectrin βIVΣ1 Na+ Channel

Fig. 2.4 Specialization at nodes and paranodes of myelinated nerve fibers in the CNS and the PNS. The voltage gated Na+ are concentrated mainly at the node and the K+ at the juxtaparanode. Na+ channels are linked to the spectrin cytoskeleton via ankyrinG. The precise role of other molecules at the node are yet to be defined: the β subunit may interact with tenascin. The paranodal loops form the axoglial junction and are bound to the axolemma by tight junctions (Caspr). K+ channels are located at the juxtaparanode and tethered to the cytoskeleton via Caspr2 molecules (From Scherer et al., (2004) with permission).

28

The myelin is organized into compact and non-compact regions at the internode and the paranode, respectively, and contain a non-overlapping set of proteins (Arroyo and Scherer, 2000). In the PNS, the most abundant protein P0 is involved in the compacting of myelin at the internode as does the next most abundant protein myelin basic protein, MBP (Monuki and Lemke, 1995). Peripheral myelin protein 22 (PMP-22) is a transmembraneous protein localized to compact myelin considered to be a regulator of axon-glial interactions (Naef and Suter, 1998). As P0, myelin-associated glycoprotein (MAG) belongs to the Ig superfamily of neural adhesion molecules and is localized to the non-compacted portion of myelin, including the Schmidt-Lantermann incisures, the paranodal loops, and the inner and outer mesaxon. In addition, the non-compacted myelin contains a number of other molecules, connexin 32 and E-cadherin that link to the actin cytoskeleton and may have junction properties and participate in the intracellular traffic. Mutations in the genes that code for these myelin proteins are responsible for several inherited neuromuscular disorders. 2.2.3. Ion-channels and membrane potential The Hodgkin–Huxley model of generation of the action potential followed by repolarization included successive activation-deactivation of Na+ channels and of K+ channels that repolarize (outward rectification) the membrane following the action potential (Hodgkin and Huxley, 1952). The model was applicable in unmyelinated and myelinated amphibian nerve fibers (Frankenhaeuser and Huxley, 1964). The Na+ channels are voltage-gated and activated by depolarization of the membrane potential by about 10–20 mV even though some Na+ channels are inactivated at the resting membrane potential of 70–80 mV. Voltage clamp studies and the lack of effect of 4-AP on the action potential, however, have shown that K+ ions do not contribute to the repolarization in mammalianmyelinated fibers (Chiu et al., 1979; Brismar, 1980; Sherratt et al., 1980; Bostock et al., 1981). In contrast, during paranodal demyelination with access to the axonal membrane sealed under the myelin, the function of fast-activated K+ channels became apparent (Bostock et al., 1978; Brismar, 1979; Chiu and Ritchie, 1980, 1981a), and insight into this has stimulated attempts to ascertain the effect of broadening the action potential in patients with demyelinating neuropathy to improve propagation (Russell et al., 1995; Franssen et al., 1999). These electrophysiological findings are in keeping with the segregation of fast activated K+ channels to the

CHRISTIAN KRARUP

paranode, whereas they in the main lack at the node. The function of the paranodal K+ channels is to stabilize the membrane potential at the node and thus dampen depolarizations and avoid spontaneous activity (Waxman, 1995). In regenerated myelinated fibers, fastactivated K+ channels appear to influence the recovery after activity, as indicated by the effect of blocking fastactivated K+ channels (Gordon et al., 1991). The repolarization following the action potential in myelinated mammalian fibers is, therefore, due to rapid inactivation of Na+ channels, and an ohmic leak through the nodal membrane. The repolarization is delayed by a capacitative current from the paranodal region that has been charged during the action potential via a low-resistive pathway underneath the myelin, the so-called Barrett–Barrett pathway (Barrett and Barrett, 1982). The discharge through the Barrett–Barrett resistance is associated with the depolarizing afterpotential, which is dependent on the membrane potential and lasts several ms and is the mechanism behind the supernormal period (Barrett and Barrett, 1982; Blight, 1985; Bowe et al., 1987; David et al., 1995; McIntyre et al., 2002). In addition to the fast inactivated Na+ channels, 2–3% of Na+ channels remain open during depolarization (so-called persistent Na+ channels). Persistent Na+ channels are more numerous in sensory rather than motor fibers and responsible for the longer strength-duration constant in sensory than motor fibers (Baker and Bostock, 1997; Bostock and Rothwell, 1997). The slow K+ channels at the node and internode are not activated during the action potential but cause a late hyperpolarization associated with late subexcitability (Bergmans, 1973; Bostock and Bergmans, 1994) and they are blocked by TEA (Baker et al., 1987; Kocsis et al., 1987). The K+ channels have outward rectification properties. In addition, there are ion-channels at the internode, which are permeable to both Na+ and K+, that open during hyperpolarization, that are blocked by Cs+ and have inward-rectifying properties; these channels may protect the axon to the hyperpolarizing effect of prolonged activity and the consequent reduction in excitability due to activation of the electrogenic Na+/ K+-ATPase pump (Bostock and Grafe, 1985; Baker et al., 1987). These characteristics of myelinated fibers are important not only to understand the normal nerve fiber function but also for the development of clinical deficits and the disturbances in electrodiagnostic studies in patients with disorders of myelin, axons and neurons (Bostock et al., 1995; Kiernan et al., 1996; Kaji et al., 2000; Daskalova and Stephanova, 2001; Kiernan et al., 2002a, 2002b; Kuwabara et al., 2002b; Kaji, 2003).

PHYSIOLOGY AND FUNCTION

29

2.2.4. Studies of axonal membrane properties in situ The central parameters obtained at nerve conduction studies include the amplitudes and conduction velocities of the CMAP and SNAP and abnormalities are usually interpreted in terms of axonal loss or demyelination. Nevertheless, the conditions of nerve conduction studies do not allow insight into functional aspects of active and passive axonal properties that may be important during motor control and sensory activity and may further explain symptoms, such as fasciculations, cramps and paresthesia (Baker, 2000). Furthermore, slowing of nerve conduction may occur in axonal disorders and A

B Threshold reduction (%)

80 Threshold reduction (%)

may be due to either atrophy or ion-channel abnormalities. Investigation of axonal ion-channel or passive properties, however, requires the use of specialized studies that have been developed to evaluate changes in excitability of axons in situ (Bostock et al., 1998; Kiernan et al., 2000). These methods have been developed to study the effects of accommodation and activity on the axon membrane potential and access internodal properties that are not explicitly tested during nerve conduction studies and reveal differences in motor and sensory fibers (Fig. 2.5) (Kiernan et al., 2001c). The internode as well as the node of Ranvier contain rectifying channels and the electrogenic Na+/K+-ATPase

60 40 20 0 −20

20 0 −20 − 40 − 60 − 80 −100 −120

0

200

0

D

0

− 50

−100 − 400

50 100 150 Conditioning-test delay (ms)

200

60

50 Threshold reduction (%)

Polarizing current (% Threshold)

C

50 100 150 Conditioning-test delay (ms)

− 300

−200

−100

Threshold reduction (%)

40 20 0 −20 − 40

0

10 Interstimulus interval (ms)

100

Fig. 2.5 Measurements of excitability in motor (filled symbols) and sensory (open symbols) nerve fibers from a normal median nerve. The motor responses were evoked by stimulation at wrist and recording at the abductor pollicis brevis muscle and the sensory responses by recording at digit 2. Excitability was tested using the qtrack method (see text) during subthreshold depolarization for 100 ms (A) and 200 ms (C), and during hyperpolarization for 100 ms (B) and 200 ms (C), and following a single supramaximal pulse (D). The effects of depolarization and hyperpolarization differed substantially in motor and sensory fibers suggesting higher activation of internodal K+ channels during depolarization and of inward rectifying internodal channels during hyperpolarization of the latter. Following a single pulse, the recovery cycle showed that the refractory period was longer, the supernormal period at 6–8 ms smaller, and the late subexcitability smaller in sensory than in motor fibers consistent with effects of persistent Na+ channels. (From Moldovan, Lozeron, Krarup, unpublished.).

30

pump that fundamentally impinge on the ability of the fiber to propagate repetitive action potentials, recovery of membrane potential after activity, prevention of ectopic activity, and redistribution of ions following activity (Bostock et al., 1983; Bostock and Grafe, 1985; Kiernan et al., 1996; Zhou et al., 1999; Kiernan et al., 2000; Burke et al., 2001; Kuwabara et al., 2002a). Bostock (for details see Chapter 17) extended studies in experimental animals (Baker et al., 1987; Baker and Bostock, 1989) to the development of thresholdtracking techniques in human nerve (Bostock and Baker, 1988; Bostock et al., 1998). Such studies have shown that the same rules regarding accommodation could be described in myelinated fibers from humans and rats (Baker and Bostock, 1989). It was already found by Bergmans (Bergmans, 1973) in studies conducted on single human motor nerve fibers that single or repetitive activity was followed by changes in excitability, which were interpreted as being due to changes in membrane potential and activation of specific ion-channels and these findings were subsequently confirmed and extended in experimental animals (Bostock and Grafe, 1985). The detection of excitability changes was made feasible by the threshold-tracking technique, which measures the stimulus current necessary to clamp the amplitude of the CAMP at a specified value on the steep part of the stimulus-response relationship curve (Bostock et al., 1998). A wealth of information regarding the behavior of normal and pathological nerve fibers have been obtained using this technique to study strength-duration relationships, recovery of excitability following activity, and accommodation during subthreshold de- and hyperpolarization (Fig. 2.5) (Kiernan et al., 2000; Burke et al., 2001). Thus, studies have shown differences in sensory compared to motor studies regarding strength-duration relationships, recovery of excitability and accommodation to hyperpolarization,which are consistent with differences in persistent Na+ channels at the node and a more effective inward rectification. Changes in excitability have been found in patients with diabetes mellitus, amyotrophic lateral sclerosis, multifocal motor neuropathy, Guillain–Barré syndrome, and chronic inflammatory demyelinating polyneuropathy that raise the possibility that this type of studies may provide supplementary information regarding pathogenesis and functional disturbances (Bostock et al., 1995; Horn et al., 1996; Kiernan et al., 1996; Cappelen-Smith et al., 2000; Kaji et al., 2000; Cappelen-Smith et al., 2001; Cappelen-Smith et al., 2002; Kiernan et al., 2002a; Kuwabara et al., 2002b). In patients with diffuse

CHRISTIAN KRARUP

demyelinating neuropathy such as Charcot-MarieTooth type 1 and some cases of CIDP, the accommodation during electrotonus suggested the presence of membrane hyperpolarization (Sung et al., 2004). Interestingly, in long-term regenerated nerve, similar findings were obtained (Moldovan and Krarup, 2004a, 2004b), and these similarities may be due to hyperpolarization associated with the raised Na+ ions at the increased number of nodes of Ranvier and short internodal length, and subsequent hyperactivity of the electrogenic sodium/potassium pump. 2.3. Physiological studies of the PNS The function of nerve fibers is to propagate action potentials and investigations are based on the ability to elicit and record sensory and motor responses (for details see Chapter 5, Nodera and Kaji). Different methods are used to study single nerve fibers or groups of nerve fibers, sensory or motor fibers, or myelinated or unmyelinated fibers. Each of these methods has specific requirements and limitations due to differences in characteristics of the nerve fibers and their signals that must be considered when used for clinical or research purposes. In the clinical electrodiagnostic setting, studies are confined to large myelinated motor and sensory fibers, and responses evoked by electrical stimulation are derived from groups of fibers. Thus, disorders confined to a small number of fibers or to small fibers in partial lesions may not be detected in these studies. Moreover, the location of abnormalities outside sites accessible to conduction studies or involvement of ion-channels requires methods specifically aimed at elucidating such questions. Finally, the activity studied in the diagnostic set-up is highly artificial with single, spaced stimuli to elicit synchronized responses, whereas the activity of the nervous system during movement or sensation is characterized by bursts of repetitive activity, and the interaction and integration of this activity are better associated with clinical symptoms than single electrical stimuli. 2.3.1. Stimulation Electrical depolarizing stimuli (square pulses, 0.1–0.5 ms in duration, constant current or voltage) are applied through a surface or needle cathode to the motor or sensory fibers with sufficient strength to ensure that all fibers are stimulated above the threshold (Fig. 2.6) (for details see Chapter 5, Kaji). Supramaximal levels at 10–20% above the maximal response are required to

PHYSIOLOGY AND FUNCTION

31

Maximal response

Supramaximal stimulation

25

Response (mV)

20

15 a Response = −c⫻Stimulus 1 + b ⫻e

10 Threshold stimulation 5

Fig. 2.6 Stimulus-response relationship: Tibial nerve in cats is stimulated at ankle and responses are recorded from the plantar muscles via subcutaneous needle electrodes. The 0.2 ms negative rectangular stimuli were increased in 6% steps with two responses averaged for each step (open circles). The stimulus-response relationship (continuous line) is plotted for the 0.5–95% of supramaximal response (broken line). The parameters of the fit (R × R = 0.997) are a = 23.2847, b = 0.4412, c = 7.1630 (From Moldovan unpublished observations).

0 1

1.5

2

2.5

3

3.5

4

Stimulus (mA)

avoid submaximal stimulation due to movement of the electrode, and corresponds in most instances to almost five times the threshold stimulus when using surface electrodes (Lange et al., 1992) but maximal stimulation may be difficult or impossible to attain in demyelinated nerve fibers with low excitability (Meulstee et al., 1997; Krarup, 1999). It is often assumed that the negative relationship between threshold and fiber diameter demonstrated in experimental nerve (Gasser and Erlanger, 1927; Gasser and Grundfest, 1939) also holds for the clinical study; however, the latency of the first recorded motor unit potential is often not the shortest indicating that the anatomical localization of the fibers with respect to the electrical field determines the sequence of excitation (Kimura, 1989, 1997). Moreover, the latency and conduction velocity are also influenced by the stimulus current due to the rate of depolarization and the utilization time (Krarup et al., 1992; Carp et al., 2003). Needle electrode stimulation may be necessary to obtain maximal responses in deeply seated nerves such as motor cervical or lumbosacral plexus, roots or spinal nerves (Inouye and Buchthal, 1977; Liguori et al., 1992). Alternative stimulation methods include magnetic pulse stimulation of spinal roots, plexus or peripheral nerves but require standardization that differ from the use of electrical stimulation (Ravnborg et al., 1990; Ravnborg and Dahl, 1991; Bischoff et al., 1995; Ravnborg, 1996). Needle-electrodes for stimulation have the advantage of lower stimulus strength associated with less displacement of the site of excitation (Podivinski, 1965; Wiederholt, 1970), and less risk of activation of nearby nerves.

Even when stimulating the sensory nerve fibers at distal sites, such as fingers or toes, the use of electrical stimulation does not allow the study of the very distal segment of sensory fibers at their junction with receptors, which might be expected to reveal abnormalities early in the course of axonal neuropathies. There has been strong interest in the microneurographical evaluation of the function of individual sensory nerve fibers innervating receptors in both normal and diseased nerves (Hagbarth, 2002), and such studies have served to clarify the adequate stimulus and distribution of different tactile receptors (Johansson et al., 1980; Johansson and Vallbo, 1979; Knibestöl and Vallbo, 1970). Sampling may, however, be biased in diseased nerve, even though microneurography may show abnormalities in neuropathy (Mackel, 1985). Useful information may be obtained by recording the SNAP obtained by stimulation of groups of tactile receptors (Fig. 2.7), and this method has been used in both normal and diseased nerve to identify different types of receptors and to localize primary pathological changes (Buchthal, 1982a, 1982b; Hashimoto et al., 1989; Caruso et al., 1993; Krarup-Hansen et al., 1993; Krarup and Trojaborg, 1994; Simonetti et al., 1998; Baba et al., 2001). Tactile stimulation does not allow supramaximal activation of all nerve fibers, and sampling bias may, therefore, be a source of error. 2.3.2. Recording of the action potential in situ The arrangement of regions of internodal segments surrounded by myelin with high resistance and low capacitance gives the nerve fibers of small diameters

32 Fig. 2.7 Electrical and tactile stimulation of sensory nerve: Median nerve sensory potentials were evoked by electrical (top traces) or tactile stimuli (bottom traces, rate of indentation 400 μm/ms, indentation depth 300 μm) applied at the tip of digit III and recorded at wrist and elbow. Amplitudes, latencies and conduction velocities are shown below traces. The bottom trace represents the tactile stimulus (From Krarup, 2004).

CHRISTIAN KRARUP

Electrical − 3 μV +

Dig3tip-elbow 8 μV, 67 m/s Dig3tip-wrist

5 μV 14 μV, 3.4 ms, 55 m/s 0

20 ms Tactile T400 − 0.5 μV +

Dig3tip-elbow 1.4 μV, 69 m/s Dig3tip-wrist 1.8 μV, 4.0 ms T400

400 μm/ms, 300 μm

0

of less than 10–12 μm unique capacity to propagate action potentials at high velocity by optimizing the space and the time constants to depolarize the nodal membranes rapidly and efficiently during saltatory conduction (Ritchie, 1995; Rushton, 1951; Tasaki and Matsumoto, 2002). The voltage and current flows that occur during the nerve action potential are based on the core-conductor or the cable theory (Aidley, 2001) implying that the axon behaves like a poorly insulated cable. The action potential is associated with local circuit currents that arise during the explosive inward flux of Na+ ions lasting few tenths of a millisecond and drives ions forward along the interior of the axon depolarizing the next segment of the membrane causing an outward capacitative current. The forward extent of this local current is determined by the space constant and its rise time by the time constant of the axon, both parameters of the resistance and capacitance of the axon and its membrane (Hodgkin, 1938; Hodgkin and Rushton, 1946). The presence of this passive local outward current in front of the action potential can be observed when conduction is blocked (Hodgkin, 1937a, 1937b), and its role was further demonstrated by the fact that the conduction velocity can be drastically slowed by increasing the external resistance around the nerve fiber, through which current must flow according to the local circuit theory

20 ms

(Hodgkin, 1964). In myelinated nerve fibers, the forward local outward current is sufficient to depolarize the successive nodes of Ranvier (Huxley and Stämpfli, 1949). When the node is depolarized to threshold the current turns inward when the Na+-ion channels open, while the segment of the axonal membrane behind the active part of the membrane demonstrates a slower and smaller outward current during repolarization. Hence, the membrane during the action potential constitutes a series of current sinks (where the current enters the axon) and current sources (where the current leaves the axon) that form the basis for the extracellular voltage changes. This voltage drop is an approximation of the timedependent membrane depolarization associated with the action potential, but “nerve in situ does not have an action potential of constant shape, for the magnitude and the shape of the recorded deflections depend upon the distance of the [micro]electrode from the nerve” (Figs. 2.8 and 2.9) (p. 403, Lorente de Nó, 1947). The shape and amplitude of the action potential recorded from nerve or muscle are determined by the placement of the generator in interstitial tissue that constitutes a volume conductor. This constraint on the understanding of the derivation of the cellular and compound action potential from excitable tissue has been dealt with in various publications

PHYSIOLOGY AND FUNCTION

0.5 mv

A2 15 0 mm

S

3 mm

10 mm 1

2 3 4 5

1 ms

Fig. 2.8 Compound nerve action potentials recorded from myelinated bullfrog nerve placed in two-dimensional medium. The recording electrodes were placed at 0, 3, and 10 mm from the nerve (Modified from Lorente de Nó 1947).

(Buchthal and Rosenfalck, 1966; Woodbury, 1966; Andreassen and Rosenfalck, 1981; Kimura, 1989; Dumitru and DeLisa, 1991). Thus, the intracellular spike in a volume conductor is recorded as an approximate measure of the action current associated with the local membrane current sources and sinks, and highly dependent on the distance from the nerve at which electrodes are placed (Lorente de Nó, 1947; Buchthal and Rosenfalck, 1966). Since these currents occur in connection with charges on the axonal membrane, this can be viewed as a layer of charges of opposite sign (dipoles) and since the nerve fiber is small in comparison with the volume conductor in which it is placed, the change in distribution of dipoles during the action potential can be simplified to equivalent dipoles (Lorente de Nó, 1947). To explain the action potential, a double dipole was postulated, one with a positive pole in the direction of propagation followed by one with inverted polarity (Soto and Vega, 1990). Recording of the field potential set up by dipoles is described by solid angle measurements, and in the resting cell, the charges of the membrane are opposite and equal with no net

33

electrical field, and the solid angle therefore zero (Woodbury, 1966) consistent with the fact that no current is flowing. During an action potential, unequal dipoles associated with depolarization are associated with a current flow that is proportional to the size of the solid angle and diminishes with the square of the distance to the recording point. The action potential propagated toward the recording electrode, therefore, presents a positive charge associated with the local current source (Fig. 2.10), a negative dipole associated with the sink of the inward current of the active region, and finally the positive dipole associated with the trailing repolarization and current source of the leaving action potential. The nerve action potential recorded by a monopolar electrode, is therefore, triphasic with a steep positive phase associated with the passive outward current, followed by a negative phase due to the active depolarization and finally a slower and smaller positive phase due to a slower repolarization. During bipolar recording, the shape is determined by the interaction of the triphasic potentials of opposite polarity at the two electrodes. The CMAP recorded from the end-plate region has a steep negative onset since the end-plate provides a current sink and there is no advancing current source. Recorded outside the end-plate the CMAP has a positive onset due to the strong negative potential at the end-plate seen as a positive potential at the recording site. Hence, the latency is measured to the takeoff of the response from base line (Fig. 2.11). 2.3.3. Motor nerve conduction studies Motor nerve fibers are studied by applying electrical stimuli to the nerve trunk and recording the evoked responses from one or more muscles supplied by the nerve. The particular nerves of the upper or lower extremities or cranial nerves that are studied depend on the clinical context (for details, see Chapters 23–26). In mononeuropathies or asymmetrical polyneuropathies, the clinically affected nerve(s) are targeted in the study, whereas in symmetrical polyneuropathies, the strategy is aimed at demonstration of widely distributed abnormalities. 2.3.3.1. Recording of the compound muscle action potential (CMAP) The smallest response that can be obtained by electrical or voluntary activation is the compound response from the muscle fibers, which are innervated by a single α-motor neuron, the motor unit (MU). At

34

CHRISTIAN KRARUP

B

A

C 100 μv

Electrode

Surface at wrist

50 Measured

of skin

2

30

4 20 6

1mm

Calculated (II)

8 Median nerve

10

10 50μv

12

2

4

6

D Amplitude (100 = electrode at the surface of nerve)

14 I II III IV V mm from 16 center of nerve 18 20 mm below skin

0

22 24 26

8 10 12 14 16 18 20 22 24 26 mm below skin I

100 70

II

50

III 30 IV V

20

10 7

0 1 2 3 4 5 msec

0

2

4

6

8 10 12 14 16 18 20 22 24 26 mm below skin

Fig. 2.9 Recording of the orthodromic compound sensory action potential from the median nerve at the wrist to show the influence of distance from the nerve on the amplitude and shape of the response. The curves in C and D were calculated from data of Lorente de Nó (From Buchthal and Rosenfalck, 1966).

increasing stimulus strength, the recorded response is the sum of the recruited motor unit potentials (MUP), the compound muscle action potential (CMAP) (Fig. 2.9). The CMAP amplitude is dependent on the Fig. 2.10 Orthodromic compound sensory (A) and muscle (B) action potentials recorded from the median nerve and the abductor pollicis brevis muscle, respectively.

summation and cancellation of phases of the individual MUPs, and MUs placed deeper in large muscles contribute less to the CMAP than superficial MUs (Parry et al., 1977). The MU force measured at the muscle

Median motor and sensory nerve conduction study

A

Digit I - wrist 37.2 μV, 3.0 ms, 43 m/s

CSAP

− 10 μV +

Wrist - APB

B

9.8 mV, 3.1 msec 3 mV

CMAP

0

20 ms

PHYSIOLOGY AND FUNCTION

35

CMAP from the APB at the end-plate and outside the end-plate Distance: 72 mm Wrist-APB (end-plate)

– 3 mV + 3.1 ms

Fig. 2.11 Compound muscle action potentials recorded over (top) and outside (below) the end-plate zone. The latency of the CMAP to the first deviation from the base line was the same at the two recording sites independent of distance.

Distance: 96 mm Wrist-APB (outside-end-plate)

3 mV

0

20 ms

tendon may be less subject to the location of the MU within the muscle, and recording of muscle force as well as the CMAP may provide additional information (Kerns et al., 1994). The muscle action potential is a prerequisite for the development of force associated with the excitation-contraction coupling (Fig. 2.12) (Krarup and Horowitz, 1979; Krarup, 1981). In order to study this latter part of muscle physiology, tension, shortening, or work may provide important information regarding contractile properties and subject to fatigue in addition to the size of the MU (Chan et al., 1998; Brown et al., 2000; Chan et al., 2001). The latency of the CMAP is measured to the take off of the signal from baseline and is the result of conduction along the fastest fibers in the nerve. Due to the delay of conduction along terminal fibers and at the neuromuscular transmission, the latency from the most distal site of stimulation to the muscle is not translated

CMAP brachial biceps

10 mV

200 ms

1 kg Twitch tension elbow flexors

Fig. 2.12 Compound muscle action potential from the brachial biceps muscle (top) and the isometric twitch tension from the elbow flexors (bottom) evoked by single supramaximal stimulation of the musculocutaneous nerve.

into the corresponding conduction velocity but is designated the “distal motor latency” (DML, ms). The motor conduction velocity (MCV, m/s) is calculated between stimulation sites along the nerve. In certain pathological states the relationship between the conduction velocities along distal and more proximal parts of the motor nerve fibers are relevant since the abnormalities may be unevenly expressed, and the ratio between the DML and MCV is calculated as the “terminal latency index” (TLI): distal distance/DML/MCV. In demyelinating polyneuropathy associated with anti-MAG gammopathy, the TLI is characteristically decreased (Kaku et al., 1994; Attarian et al., 2001) in accordance with the predominantly distal affection (Lunn et al., 2002). 2.3.4. Sensory nerve conduction studies Differential investigation of sensory nerve fibers is obtained by the study of purely sensory nerves such as the sural or the saphenous nerves or sensory branches of mixed sensory-motor nerves (for details, see Chapter 7). Electrophysiological studies of sensory fibers differ from motor fibers in that the compound sensory action potential (SNAP) is recorded directly from the nerve. The small signal is more difficult to distinguish from noise and, therefore, the SNAP often requires digital summation or averaging to ensure reproducibility in particular in diseased nerve, where the SNAP is reduced in size due to loss of fibers or poor summation due to dispersion. A major difference between the diagnostic yield of sensory and motor responses is related to the small amplitude of the SNAP (Dawson, 1956; Gilliatt et al., 1965; Buchthal and Rosenfalck, 1966). Thus, though modern equipment has improved signal-tonoise ratio, there is less confidence in the pathological

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significance ascribed to the absence of a sensory than a motor response, in particular in the elderly. 2.3.4.1. Recording of the compound sensory action potential (SNAP) The SNAP may be recorded through surface or nearnerve electrodes. Surface electrodes have a diameter of 0.5–1 cm and are placed longitudinally on the skin above the nerve, for example the median nerve at the wrist or as ring electrodes at the digits, and have amplitudes of 5–50 μV. These electrodes allow resolutions of potentials of about 1 μV from noise, and the amplitude of the responses is dependent on the distance between the nerve and the electrode (Lim et al., 1995). In contrast, near-nerve electrodes require placement of an insulated needle with a 3-mm bared tip close to the nerve. Placement is optimized by stimulating through the needle while adjusting the threshold of an evoked motor (in mixed nerve) or sensory response (in sensory nerves) to sensory (Dyck et al., 1975), and hence cannot be fully assessed by a distal sensory nerve biopsy. Nevertheless, early literature in CIDP emphasized the utility of peripheral nerve biopsy in diagnosis, with cardinal features of ongoing demyelination with remyelination on teased fibers, and especially macrophage mediated-myelin stripping on electron microscopy (Dyck et al., 1975; Prineas and McLeod, 1976). The latter finding, where macrophage process are visualized in the process of penetrating and destroying myelin around an intact axon, is considered very suggestive of CIDP or Guillain–Barré syndrome, and rarely seen in other demyelinating conditions. In typical nerve biopsies the pattern of involvement is multifocal rather than diffuse—in an extreme case

an entirely normal nerve fascicle may be adjacent to one showing severe focal demyelination and/or axonal loss and/or onion bulb formation. Sometimes the endoneurial compartment appears “edematous,” with an amorphous substance accumulating predominantly in the subperineurial area. Inflammatory infiltration in peripheral nerves has been overemphasized as a feature in CIDP, occurring in only 10–50% of biopsies, and rarely impressive (Midroni and Bilbao, 1995; Bosboom et al., 1999; Bouchard et al., 1999). The cells tend to be found perivascularly, both in the epineurium and endoneurium. The infiltrating cells are predominantly T lymphocytes which immunostain positive for the pan-T Cell CD3 antigen. Plastic sections typically show combined features of axonal loss and active axonal degeneration, along with demyelinated axons, as well as thinly remyelinated axons (Fig. 3.3). Onion bulbs that consist of concentric lamellae of Schwann cell processes around a central axon, are seen in a significant minority of patients, variably prominent (Fig. 3.3B). If doubt remains as to the nature of a demyelinating process, electron microscopy is often useful in revealing whether the demyelination is due to primary macrophage-mediated myelin stripping (favoring

78

CIDP or GBS) or another cause. Rarely, electron microscopy will show this feature when light microscopy does not show convincing demyelination, and such a finding becomes the only clue that the patient might have a treatable inflammatory neuropathy (Haq et al., 2000). Similarly, teased fibers are more sensitive for detection of demyelination than examination of cross-sections, and may show demyelination or remyelination that is overlooked by other methods. The nerve biopsy pathology of GBS is essentially the same as that of CIDP, except that the changes are more acute, on average showing more prominent demyelination and less chronic axonal loss. Macrophage-mediated demyelination is the hallmark, and an EM search will usually show this finding (Brechenmacher et al., 1987). In the “axonal” form of Guillain–Barré syndrome macrophage-mediated demyelination is not a feature, and lymphocyte infiltration also seems minor. Instead the process appears to involve a penetration of the peripheral nerve by macrophages via the node of Ranvier, axonal degeneration rather than demyelination being the primary process (Griffin et al., 1996). Such findings are not likely to be seen in a sural nerve specimen taken far from the site of most active disease (root and nerve terminal). We have, however, observed adaxonal macrophages in nerve biopsy material on rare occasions, and our impression is that this finding is associated with more severe axonal loss. This was reported by other workers long prior to the identification of “axonal” GBS (Brechenmacher et al., 1981). GBS is a clinical diagnosis, and biopsy does not impact on management unless it reveals an alternative diagnosis—vasculitis most commonly. Hence, there is no role for nerve biopsy in suspected GBS unless highly atypical clinical or laboratory findings are present. 3.6.3.2. Utility of nerve biopsy in CIDP Despite the ability of nerve biopsy to reveal suggestive or pathognomonic findings for this relatively common and treatable cause of neuropathy, in recent years the role of this procedure in CIDP has diminished substantially. Workers generally agree that nerve biopsy has little added value in in patients with a clinical and electrophysiological picture highly suggestive of CIDP (Molenaar et al., 1998; Bosboom et al., 2001). In a significant minority of cases with CIDP, the typical biopsy findings are not seen, so a negative biopsy does not rule out the diagnosis, even if axonal degeneration predominates (Dyck et al., 1975; Prineas and McLeod, 1976; Barohn et al., 1989). Inflammatory

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infiltration, even if present, is nonspecific (Bosboom et al., 1999). Particularly telling is the study of Bosboom et al. (2001) who studied 21 consecutive biopsies in patients meeting criteria for CIDP in comparison to 13 patients with a chronic idiopathic axonal neuropathy (CIAP). Techniques included the full spectrum of pathological investigations, including light microscopy of thick and semi-thin sections, teased fibers, and morphometry. There was very substantial overlap in the teased fiber findings of demyelination/remyelination, inflammatory infiltration, and onion bulb formation between the two patient groups. Two experienced neuropathologists were unable to make a consistent distinction between the CIDP and CIAP group by reviewing teased fiber material from the two groups. The real value of nerve biopsy in CIDP emerges when the diagnosis is not suspected on clinical or electrophysiological grounds. Several studies have documented and emphasized the ability of pathological assessment to suggest CIDP when electrodiagnostic testing fails to do so, or the clinical picture is atypical (Chia et al., 1996; Haq et al., 2000; Logigian et al., 1994; Vallat et al., 2003) and this has been our experience also. Fiber teasing and electron microscopy are two means of pursuing the search for primary demyelination, and it is not clear if one method is superior to the other—very likely the yield of either method depends on the quality of preparation and intensity of examination of the tissue. Haq et al. (2000) found that electron microscopy was somewhat more helpful in detecting primary demyelination and predicting response to treatment. Some studies have suggested that pathological features of very active demyelination in CIDP may predict a more severe course (Bouchard et al., 1999; Haq et al., 2000), but other have failed to confirm this (Bosboom et al., 2001). In our experience, biopsy features do not predict disease course nor correlate with severity. One would expect that motor axon loss would be the principal predictor of prognosis, a matter best assessed electrophysiologically and clinically, not with a few millimeters of sensory nerve from the distal lower limb. 3.6.4. Amyloidosis A search for amyloid remains one of the major indications for nerve biopsy. However, amyloid usually deposits diffusely throughout the body, and in many instances it may be possible to document this using a

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biopsy site with less morbidity than nerve biopsy (skin and fat, salivary gland, muscle, bone marrow, or even kidney). The sensitivity of nerve biopsy in amyloid neuropathy is not known, but may be surprisingly low. Simmons et al. (1993) found only two of eight biopsies positive in patients ultimately shown to have amyloid neuropathy and we certainly have had negative nerve biopsies in patients subsequently documented to have amyloid neuropathy. This underscores the need to look for other tissues to sample. If nerve is taken, a combined procedure with muscle is well advised (Rajani et al., 2000). In addition, readily available sequencing of the transthyretin gene will identify nearly all patients with familial amyloidosis. Amyloid is an extracellular proteinaceous substance, which appears amorphous by light microscopy and fibrillar under the electron microscope. It is composed of beta-pleated sheets forming matted linear non-branching fibrils 7–10 nm in diameter. All amyloid types have a common constituent—amyloid P protein. Amyloid types are distinguished by their “major protein,” quantitatively the dominant component of the deposit. In primary amyloidosis, the major protein is immunoglobulin light chain; in familial neuropathic amyloidosis the major protein is usually a mutant transthyretin protein, and much less often

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Gelsolin or ApoLipoprotein A1 (Midroni and Bilbao, 1995). Secondary amyloid, in which the major protein is serum Amyloid A protein, is associated with chronic inflammatory disease, and neuropathy is NOT a clinical feature, even though the protein may be found in nerve or muscle specimens. Senile amyloid contains transthyretin as the major protein, but is nonpathogenic, tending to deposit in small quantities in a perivascular pattern in the very old (>80). We have seen this falsely interpreted as an indicator of amyloid neuropathy on occasion. Neuropathy is often the presenting manifestation of systemic amyloidosis (Rajani et al., 2000). A paraprotein is not initially known to be present or may remain undetectable in a significant minority of patients with primary amyloid neuropathy, and a family history of neuropathy is not present in all patients with familial amyloid neuropathy. Hence, nerve biopsy may provide the only means of making the diagnosis when all tests have been exhausted. The cardinal finding is detection of amyloid deposits (Midroni and Bilbao, 1995). These are seen best on Congo Red or Thioflavin-stained specimens, and small deposits are seen more dramatically under polarized light, where they demonstrate apple-green yellow birefringence (Fig. 3.6). Some non-amyloid

Fig. 3.6 Amyloid neuropathy, paraffin-embedded material. With Congo Red staining (A) endoneurial amyloid deposits are readily seen, and these stand out even more when the specimen is examined under polarized light (B), showing apple-green yellow birefringence.

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materials (fibrin, elastin, mast cell granules) may stain with Congo Red, but do not display birefringence. The amyloid can be seen in any compartment— endoneurium, perineurium, and epineurium, as well as the epineurial fat. Vascular accumulation is common (Rajani et al., 2000). Occasional inflammatory cells may be seen, but this is never a prominently inflammatory process. Axonal loss is always present, with myelin changes minor or absent (Rajani et al., 2000). Clinically, amyloid neuropathy can be a small fiber neuropathy at onset, and this is sometimes reflected in the nerve biopsy, where small myelinated and unmyelinated fibers can be lost disproportionately to large myelinated fibers—the opposite of what happens in most neuropathic processes. This can be recognized subjectively through visual inspection by an experienced pathologist, and can be demonstrated more rigorously using a fiber diameter histogram (Section 3.5.2.4). If such a pattern is seen, even in the absence of amyloid, an extended search for amyloid should be carried out, and if this is unrevealing additional nonneural tissues can be considered for biopsy. If amyloid is detected immunostaining is very helpful, as commonly available immunostains can identify whether the amyloid major protein is transthyretin or immunoglobulin light chains. These immunostains, however, can be both falsely negative and falsely positive, and should be performed in conjunction with control tissue staining, and in step-sections with Congo Red staining. Immunostaining is generally more reliable for frozen tissue than for paraffin embedded material. Although electron microscopy in theory can show amyloid fibrils where light-microscopic techniques do not, when the deposits are very small or predominantly found in the subperineurial region, this should be interpreted with great caution, as any non-congophilic fibrillar material seen in the endoneurial and subperineurial region is more likely to be oxytalan, a part of the elastic fiber system (Midroni and Bilbao, 1995). 3.6.5. Leprosy While in parts of the undeveloped world leprous neuropathy is a continuing management problem, even in highly-developed countries one may encounter the occasional unexpected finding of leprous neuropathy (personal experience, Gabriel et al., 2000; Said, 2002a). Origin from an endemic area is the most significant clue to a possible diagnosis of leprous neuropathy. In a majority of instances symptom onset is within a year of infection. However, the neuropathy

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can be very indolent and patients may present up to several years after departure from a high-risk area, so a high index of suspicion is required. If skin lesions are present, these rather than nerve should be biopsied to confirm a diagnosis. However, in “pure neuritic leprosy,” there will be no clue to the diagnosis other than possibly the epidemiological risk factors of the patient (Jacob and Mathai, 1988). The pathological findings in leprous neuropathy depend on the immune response of the patient to the bacillus (Midroni and Bilbao, 1995). Regardless of the subtype, the peripheral nerve is usually obviously enlarged. When little or no immune response to the bacilli is mounted, the disease is termed pluribacillary (lepromatous) leprosy with large numbers of organisms throughout many tissues, but especially the peripheral nerves that may provide a relatively protected site from the immune response. The typical finding is accumulation of M. leprae organisms in macrophages and Schwann cells, forming “foamy cells,” staining positively with special stains such as Fite or Auramine Rhodamine (Fig. 3.7A). Lymphocytic and epithelioid cell infiltration is a relatively minor feature, and the nerve architecture is generally preserved. In early onset of disease, there is relatively minor nerve fiber loss, with mild degrees of demyelination/remyelination noted. As the disease progresses axons are lost and an increasing degree of endoneurial fibrosis emerges. Electron microscopy can provide very dramatic evidence of M. leprae accumulation in a variety of cell types, but most prominently in non-myelinating Schwann cells (Fig. 3.7B), for which they have a special tropism (Rambukkana et al., 2002). At the other end of the immunological spectrum is paucibacillary (tuberculoid) leprosy—here the immune response is intense, and organisms are rarely or never seen even with special stains. Epithelioid histiocytes and giant cell granuloma formation is the hallmark, often with central caseation, and the process can be very destructive to the neural architecture. Perineurial infiltration with histiocytes is prominent, which brings perineuritis and sarcoidosis into the differential diagnosis. In the intermediate (“borderline”) histological range, one sees an intense inflammatory response dominated by lymphocytes, with some organisms still detectable. There is a spectrum of pathology, with more prominent histiocytes and less prominent organisms earning the designation “borderline tuberculoid,” and more prominent organisms with few or no histiocytes earning the designation “borderline leproma-

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Fig. 3.7 Leprous neuropathy. Resin-embedded Toluidine Blue stained cross-section of the endoneurium shows several “globi”-macrophages filled with M. leprae organisms. Thinly myelinated axons are seen. Electron microscopy (B) reveals intact-appearing M. leprae organisms (dark circle within clear halo) predominantly within non-myelinating Schwann cells, as well as M. leprae debris in a macrophage.

tous.” Perineurial inflammation is also common in borderline leprosy. Vasculitis can be seen in leprosy, probably in response to large quantities of M. leprae antigen released into the nerve and the resultant immune response. This is often accompanied by a multisystem diffuse inflammatory process (Erythema nodosum leprosum). Even in known neuritic leprosy, there may be a role for nerve biopsy, as the nerve specimen may provide a more accurate reflection of disease activity than skin biopsy specimens and thus impact on selection of the antibacterial regime (Chimelli et al., 1977; Nilsen et al., 1989). If suspicion for leprosy is strong, but the biopsy diagnosis cannot be confirmed by conventional methods, the paraffin embedded tissue may be used for PCR. 3.6.6. Sarcoidosis Although often suspected and rarely proven, this condition remains an indication for nerve biopsy. A muscle specimen should be taken at the same time, or even in preference to a nerve specimen, since the yield of

muscle biopsy is high even if the dominant process is neuropathic (Said et al., 2002b). Clinical findings are nonspecific: multifocal or diffuse, non-length dependent or distally predominant and symmetrical, usually with axonal electrophysiology, but rarely with demyelinating neuropathy—even conduction block (Midroni and Bilbao, 1995; Said et al., 2002b). The histological hallmark is the presence of non-caseating granulomata, with multinucleate giant cells variably present. The granulomata may occur in the epineurial or endoneurial compartments. Necrotizing angiitis can be part of the histological picture (Said et al., 2002b). Inflammatory infiltration of the perineurium is a somewhat special feature of sarcoid neuropathy, not seen in the more common inflammatory neuropathies such as CIDP or vasculitis. If seen this finding should prompt a further search for sarcoidosis even if no granulomas are present. There may be a clinical and histological overlap with a less common syndrome called Sensory Perineuritis, which may constitute a distinct clinicopathological entity or may represent a focal form of sarcoidosis in some cases (Krendel and Costigan, 1992; Midroni and Bilbao, 1995). Neuritic

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leprosy should also always be considered in the differential diagnosis of prominent perineurial inflammation and intraneural granulomata. 3.6.7. Paraprotein-associated neuropathies A variety of peripheral neuropathies may be seen in patients who have a circulating paraprotein. The accepted associations are listed in Table 3.6. In general, with the exception of immunoglobulin deposition disease, which is exceedingly rare, and amyloidosis, the diagnosis is generally made by non-invasive means. However, a brief review of the expected pathology is provided. It should be noted that in most patients who have a peripheral neuropathy and a circulating paraprotein the association may be co-incidental (two conditions common in elderly patients), and no specific pathology is expected or found. Much attention has been focused on IgM anti-Myelin Associated Glycoprotein (anti-MAG) neuropathy, because the causal connection is most convincing, and clinical, electrophysiological, and biopsy findings most unique (Midroni and Bilbao, 1995). Histologically, this is a mixed axonal and demyelinating neuropathy, with prominent but indolent demyelination/remyelination seen on light microscopy. Onion bulb formations are seen routinely, although they are not as dramatic as those seen in CMT-1 or some cases of CIDP. Mild inflammatory infiltration is often present. In this neuropathy, there is an increased prominence of occasional hypermyelinated fibers with redundant myelin loops, sometimes reminiscent of what is seen in Hereditary Neuropathy with Pressure Palsies, but to a much lesser degree (Sander et al., 2000). The most pathognomonic finding in anti-MAG neuropathy is “widely spaced myelin” seen on elecTable 3.6 Spectrum of paraprotein-associated neuropathies ●

● ● ● ● ●

●

IgM anti-Myelin Associated Glycoprotein (antiMAG) paraproteinemic neuropathy Amyloid neuropathy Immunoglobulin deposition disease CIDP associated with an IgG or IgA paraprotein Cryoglobulinemic neuropathy POEMS syndrome (polyneuropathy associated with organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) Neuropathy in osteosclerotic myeloma (overlap with POEMS)

tron microscopy, which is due to penetration of IgM paraprotein into the myelin sheath, separating this tightly wound lipid bilayer at its extracelluar interface, the intraperiod line (Figs. 3.8A, 3.9A). IgM immunostaining of myelin is readily identified on frozen tissues (Fig. 3.9B), but is less specific than the EM change. Macrophage mediated demyelination can also be seen in this neuropathy (Vital et al., 2000). The POEMS syndrome features a nonspecific light microscopic appearance with variable elements of indolent axonal degeneration and demyelination/ remyelination. A somewhat unique ultrastructural finding is uncompacted myelin (Fig. 3.8B), whereby the intracellular apposition of the myelin sheath layers is disrupted, separating the major dense line into two lines. Although a very careful search may be required, some report that the sensitivity of this finding for the POEMS syndrome approaches 100% (Vital et al., 2003). However, uncompacted myelin is not diagnostic, as it can be seen in an occasional patients with CIDP with or without a paraprotein, rare patients with Hereditary Neuropathy with Pressure Palsies, and more consistently in genetically determined neuropathy due to a mutation in the P0 protein (Gabreels-Festen et al., 1996; Vital et al., 2003). A picture clinically indistinguishable from CIDP without a circulating paraprotein also occurs in patients with a paraprotein. The histology appears to be that of typical CIDP (Vital et al., 2000) with no special axonal or myelin findings, although immunolabeling sometimes shows that the paraprotein deposits in the endoneurium (Midroni and Bilbao, 1995). Immunoglobulin deposition disease is a rare condition where monoclonal immunoglobulin light and/or heavy chains deposit diffusely in tissue, without forming amyloid. Neuropathy can occur in this condition, due to massive accumulation of immunoglobulin in the nerve (Midroni and Bilbao, 1995). Cryoglobulinemic neuropathy can reveal a wide spectrum of findings (Midroni and Bilbao, 1995). This condition may be more common than suspected due to its association with Hepatitis C, and skin lesions may not always be present (Gemignami et al., 2002). In some cases, necrotizing vasculitis is predominant, and the process is usually predominant or exclusively axonal in nature. More often nonspecific inflammatory changes are detected, or a bland loss of axons noted with no suggestion of inflammation. There have been rare reports of cryglobulin precipitate obstructing endoneurial microvessels (Prior et al., 1992).

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Fig. 3.8 Paraproteinemic neuropathy, Electron microscopy. Widely spaced myelin (A) is seen in this patient with the antiMAG syndrome. The separation of myelin layers occurs at the Intraperiod Line (extracellularly). This finding is specific for the anti-MAG syndrome. In Figure B, uncompacted myelin is seen, with separation occurring at the Major Dense Line (intracellularly). This finding is relatively nonspecific, and occurred in a patient with a paraproteinemic neuropathy but no evidence of the POEMS syndrome.

3.6.8. Genetically determined neuropathies The greatest change in the role of nerve biopsy over the past decade has been the emergence of non-invasive genetic testing for diagnosis of a genetically determined neuropathy. Early nerve biopsy literature abounded with descriptions of genetic neuropathies such as Charcot–Marie–Tooth disease (CMT), Hereditary Neuropathy with Pressure Palsies (HNPP), or Friedrich’s Ataxia. In many patients nerve biopsy does reveal pathognomonic or highly suggestive findings (HNPP, CMT-1), and in others it is quite nonspecific (CMT-2, Friedreich’s Ataxia). However, since genetic testing will now identify the vast majority of CMT-1 and CMT-X patients, essentially all HNPP patients, as well as many spinocerebellar ataxias and many metabolic diseases, the role of nerve biopsy has become quite limited. As of this writing, blood tests are still not available for most cases of type II CMT, but the histology is quite nonspecific in any case. For this reason, the discussion below is quite abbreviated and for further details of nerve pathology the reader is referred to more comprehensive monographs (Midroni and Bilbao, 1995). 3.6.8.1. Charcot–Marie–Tooth disease Histological features of CMT-1 are mostly similar regardless of the underlying mutation. There is a loss

of myelinated fibers to varying degrees, with prominent findings of demyelination/remyelination and diffuse onion bulb formation. The latter result from recurrent events of demyelination with remyelination occurring over long periods of time, with gradual accumulation of supernumerary Schwann cell processes in a concentric pattern around the axon. The process is quite indolent, and hence active demyelination (denuded axons) is almost never seen in adults. However, in young patients with CMT-1, the prominence of visible ongoing demyelination may lead to concern about CIDP and the pathological distinction between the two may be impossible— marked focality of pathology and inflammatory infiltration would favor CIDP (Gabreels-Festen et al., 1992). An uncommon ultrastructural finding that suggests the diagnosis of the P0 mutation (CMT1B) is the presence of uncompacted myelin (Gabreels-Festen et al., 1996) (see discussion of POEMS syndrome, Section 3.6.7), but this can rarely be seen in CIDP (Vital et al., 2003). In type II CMT, regardless of genetic basis, the pathology is nonspecific. Indolent axon loss dominates, with little debris noted on the biopsy—just the reduced number of axons. Some secondary demyelination occurs, resulting in myelin thickness often being reduced relative to axonal diameter. However,

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Fig. 3.9 Anti-MAG paraproteinemic neuropathy. Electron microscopy with anti-IgM immunogold staining tracks the entry of pathogenic IgM paraprotein into the myelin, entering from the extracellular compartment. Light microscopic immunofluorescence also reveals dense accumulation of IgM around the axons.

active demyelination is not seen. Efforts at axonal regeneration produce variably prominent regenerating clusters, but this can occur in any chronic neuropathy, genetic or acquired. X-linked CMT is due to a mutation either in the connexin32 gene, or in related nearby non-expressed genetic elements which control the expression of this protein. Again, the pathology is nonspecific, but just as

the condition is often considered “intermediate” between CMT-1 and CMT-2, so too is its pathology (Sander et al., 1998; Vital et al., 2001). Classic onion bulbs are not very frequent, but “pseudo onion bulbs” are quite typical. In these formations, a regenerating cluster is centered by a myelinated fiber and surrounded by several unmyelinated axons with their associated Schwann cells. Axon numbers are often

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relatively preserved in CMT-X, as large myelinated fibers degenerate or atrophy, but regenerative clustering provides some numeric compensation (Sander et al., 1998; Vital et al., 2001). Again, as is typical for genetic processes the pathology appears quite indolent, with no active axonal loss (i.e., Wallerian degeneration) or active demyelination visible on cross-sections, although teased fibers may show some ongoing axonal degeneration. 3.6.8.2. Congenital dysmyelinating neuropathies In pediatric practice, another group of genetically determined demyelinating neuropathies is important, presenting either with congenital neurological abnormalities or with symptom onset in early childhood, typically characterized by severe slowing of nerve conduction velocities to 2 h) may result in variable, but, longer recovery times due to structural changes within the nerve, namely, nodal intussusceptions causing paranodal demyelination. Acute conduction block in humans also occurs following very short periods of compression (< 1 h), seen for example in some cases of “Saturday night palsy” or peroneal nerve palsy localized to the fibular head; recovery usually occurs within days or at the most several weeks following onset. Other examples of rapid recovery following other mechanisms of compression are illustrated in Figs. 4.7 and 4.8. Occasionally, conduction block may persist for many months thereafter, such has been observed by the authors in cases of acute peroneal palsies and in animal studies (Fowler et al., 1972). One explanation for the long delay in recovery may be the result of paranodal swelling, which has been observed to last for several months following compression (Ochoa et al., 1972). In acute immune-mediated diseases such as GBS, recovery of conduction block is variable and is usually nonuniform throughout the course of the nerve (Fig. 4.9). In the more chronic immune mediated diseases, for example, CIDP or multifocal motor conduction block neuropathy, electrophysiological evidence of conduction block may persist for months to years despite normalizing of strength testing following treatment. Care should be taken, however, when attempting to correlate recovery of conduction block with clinical recovery. For example, in some cases where strength may have returned to normal,

increased temporal dispersion and waveform cancellation may so reduce the maximum “M” potential across previously blocked regions of the nerve, that it may be impossible to assess conduction block using electrophysiological studies. Conversely, there are those cases with residual clinical weakness despite electrophysiological recovery of conduction block. This group of patients is of particular interest because the weakness may be due to frequency dependent block, described earlier in the chapter. Neuropathies associated with vasculitis may be accompanied by electrodiagnostic findings, which may be mistaken for conduction block associated with demyelination, especially in the first few days following the onset of the neuropathy (Fig. 4.10). However after several days the compound muscle action potential distal to the block characteristically falls dramatically in a manner consistent with infarction of the nerve and Wallerian degeneration of the nerve distal to the site of the infarction. 4.11. Axonal degeneration 4.11.1. Wallerian degeneration Wallerian degeneration is a term used to describe the structural alterations in normal nerves distal to a crush injury or transection of the nerve and has been the subject of several reviews (Lieberman, 1971, 1974; Joseph, 1973; Thomas, 1974; Dyck, 1975; Urich, 1976; Allt, 1976; Sunderland, 1978, 1979, 1980; Asbury and Johnson, 1978; Selzer, 1980; Zochodne, 2000). The emphasis here is on those physiological abnormalities that accompany the early degenerative

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proximally for several millimeters and further in more extensive injuries. Reactive changes such as central chromatolysis develop in the parent motor neuron or dorsal root ganglion cells, the intensities of which are related to the proximity of the transection to the neuron and the age of the subject (Sunderland, 1978). Conduction velocities may be slowed up to 70 mm proximal to experimental transection or crush injuries, (Cragg and Thomas, 1961; Kuno et al., 1974a, 1974b; Mendell et al., 1976). Reasons for this occurring may be as a result of axonal atrophy (Cragg and Thomas, 1961; Aitkin and Thomas, 1962) and widening of the nodal regions along with internodal demyelination. (Dyck et al., 1981). Similar reductions in conduction velocities proximal to compressive or transection injuries have been reported in humans (Gilliatt, 1973; Stöhr et al., 1977; McComas et al., 1978). 4.11.3. Distal to the transection

Fig. 4.6 Left: Schematic of the relative positions of the stimulating electrodes at the levels of the wrist (S1), just distal to the tourniquet (S2), and proximal to the tourniquet (S3). Right: Selected records to illustrate the changes in the hypothenar (HT)’ “M” response to stimulation at the S1, S2 and S3 levels at various times prior to and after tourniquet inflation and following release of the tourniquet. Note: (1) the earliest evidence of conduction block occurs across the tourniquet between S2 and S3; (2) persistence of the distal “M” response (S1); (3) the overall cascade beginning at the most proximal level of stimulation (S3) and moving towards S1 and (4) the relative degree of conduction block and delay (From Yates, SK, Hurst, LN, Brown, WF (1981) The pathogenesis of pneumatic tourniquet paralysis in man. J. Neurol. Neurosurg. Psychiatry, 44: 759–767).

and later regenerative processes, both proximal and distal to the level of the injury, and which are most relevant to electrodiagnostic studies in humans. The physiological changes distal to the injury site are identical for both crush and transection injuries. There are, however, important distinctions between the two types of injury in the course of the subsequent repair and regenerative processes. 4.11.2. Proximal to the transection Even when a nerve has been cleanly transected, retrograde degeneration in the axon commonly extends

Following transection of the phrenic nerve in the rat, the earliest degenerative changes begin in the motor axon terminals and the endplates (Miledi and Slater, 1970). These changes are associated with cessation of both endplate potentials (EPPs) and miniature endplate potentials (MEPPs). The latent period between the transection and failure of neuromuscular transmission is proportional to the length of the distal stump (Miledi and Slater, 1970). Neuromuscular transmission fails before conduction failure in the nerve fibers (Miledi and Slater, 1970; Gilliatt and Hjorth, 1972; Wilbourn, 1977). Conduction velocities in the degenerating axons generally remain normal until transmission completely blocks; although conduction velocities may be reduced somewhat just prior to complete loss of excitability (Gilliatt and Hjorth, 1972; Wilbourn, 1977). In degenerating axons, transmission may be blocked at one or more points distal to the site of injury (Erlanger and Schoepfle, 1946). In humans, the nerve becomes unexcitable distal to a transection, within three to seven days (Gilliatt, 1973; Wilbourn, 1977). Hence, it is important for assessing the prognosis in incomplete transection to carry out the electrophysiological studies at least 7 to 10 days postinjury. In the early postdenervation period, the muscle membrane becomes partially depolarized. This is accompanied by the appearance of tetrodotoxinresistant action potentials and changes in the kinetics of the sodium channels (Thesleff, 1974). Thereafter, the extrajunctional regions of the membrane become

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Fig. 4.7 Recording from the thenar “M” potential during supination in a 67-year-old male with “dynamic” conduction block across the forearm as a result of nerve ischemia. The first and second waveforms for each study (A), (B), (C), (D) and (E) were elicited following stimulation of the median nerve at the wrist and elbow, respectively. Note: there was little change in conduction velocity despite progressive conduction block, which was complete at approximately 35 minutes of forearm supination. The conduction block recovered completely within 2 minutes of forearm pronatation (From Watson, BV, Parkes, AW, Brown JD (2002) Transient forearm conduction block in the median nerve. Muscle Nerve, 25: 456–460. Reprinted by permission of John Wiley & Sons, Inc).

much more sensitive to acetylcholine, indicating the development of more extrajunctional acetylcholine receptors. Denervated muscle membranes become more irritable. The latter is manifest by increased insertional activity, provoked by insertion or movement of a needle electrode in the affected muscle and the appearance of fibrillation potentials. Fibrillation potentials represent spontaneously generated single muscle fiber action potentials originating in the region of the old neuromuscular junction or at various extrajunctional sites along the muscle fibers. The latent period between the injury and the appearance of fibrillation activity is proportional to the length of the motor axons distal to their sites of interruption. For example, it may take three to four weeks for abnormal spontaneous activity to develop in the hand muscles following injuries to the C8–T1 roots or adjacent lower brachial plexus in humans. On the other hand, only one to two weeks may supervene between interrupting the C5–6 roots or adjacent upper brachial plexus and the appearance of fibrillation potentials in the rhomboid, spinatii, or deltoid muscles. In a similar length-dependent manner only seven to ten days may be required following acute injuries to the lumbar or sacral roots before fibrillation activity appears in the lumbosacral paraspinal muscles. Provided some part of the motor innervation is spared, within a short time, the

remaining intact motor axons begin to sprout terminal and preterminal collateral branches. These proceed to reinnervate those muscle fibers that have lost their innervation. This process changes the innervation patterns in the muscle and leads to grouping together of like-innervated muscle fibers. Following acute interruption of the axonal continuity by either crush or transection, regeneration of the axons in the proximal stump begins within 24 h. Fig. 4.11 illustrates the temporal-spatial progression of regeneration in a previously severed cat nerve. Sprouts and growth cones develop at the proximal cut ends of axons, sometimes within 24 h. Some sprouts appear to spring from nodal regions proximal to the injury site. One important distinction between crush and transection injuries affecting peripheral nerves lies with how the two affect the continuity of the Schwann cell basement membrane (see Asbury and Johnson, 1978). In the case of all but the most severe crush injuries, continuity of the basement membranes is retained while in the case of transection of the nerve, continuity is lost. Basement membrane tubes are continuous between the roots and the distal terminal axonal branches, and provided they remain intact, may serve as guides for the regenerating axon sprouts to cross the site of the injury in the shortest time and reach their intended peripheral targets (muscle or sense organs).

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Fig. 4.8 Example of nerve ischemia in the superficial peroneal (SP), deep peroneal (DP) and sural sensory nerves during noninvasive ankle distraction in a control subject. To simulate the noninvasive procedure used for ankle arthroscopy a force of 135 N (30 lbs) was applied to the ankle through an ankle distraction harness for 60 minutes. Stimulation of all 3 sensory nerves was done proximal to the harness throughout the procedure. Note: on an average, for the seven control subjects tested, reduction in the sensory amplitudes began to occur approximately 30 minutes into the study at distraction forces greater than 90 N (20 lbs) with almost complete conduction block at 60 minutes. Full recovery of the SP and DP sensory nerve amplitudes was seen in all cases studied within 5 minutes after the release of the harness. The sural nerve was spared as a result of the harness design (From Dowdy, PA, Watson, BV, Amendola, A, Brown, JD (1996) Noninvasive ankle distraction: relationship between force, magnitude of distraction, and nerve conduction abnormalities. Arthroscopy, 12: 64–69. Reprinted by permission of W.B. Saunders Company, an imprint of Elsevier).

Destruction or misalignment of basement membrane tubes, characteristic of rejoined sectioned peripheral nerves, creates severe problems because many sprouts may fail to successfully cross the injury site. Furthermore, of those that do, many are unable to find their matching basement membrane tubes in the distal stump and thereby eventually fail to find their natural target postsynaptic cells or end organs. Faulty regeneration patterns can lead to lasting weakness, sensory impairment, and bizarre reinnervation patterns. Injuries extending over any appreciable distance along the path of a nerve and those accompanied by an overly vigorous connective response only increase the latent period required for the axons to cross the injury site and reduce the numbers of nerve fibers able to successfully bridge the gap (Sunderland, 1978). Characteristically only 1 or 2 of the many developing axon sprouts make it to the periphery contained within a single basement mem-

brane tube. Such branches, if they mature and reach the periphery, can form the basis for various axon reflexes whose presence can sometimes be electrophysiologically identified in the clinic. The earliest regenerating axons are very thin and devoid of myelin sheaths. Their stimulus thresholds are characteristically very high and their conduction velocities very low (< 1–2 m/s) (Berry et al., 1944; Devor and Govrin-Lippmann, 1979). Conduction in some of these regenerating axons may be continuous, at least prior to myelination, although discontinuous conduction between closely spaced high concentrations of sodium channels cannot be excluded (Feasby et al., 1981a). Some of the latter loci could become nodal regions. Once myelination becomes established, the inward currents become limited to the nodal regions similar to normal nerve (Feasby et al., 1981a, 1981b). Progressive distal regeneration is accompanied by

108 Fig. 4.9 Plots of the maximum hypothenar “M” potential negative peak area (mVms) in response to supramaximal stimulation between wrist and spinal roots 5, 10, 18, 32, 39, 54, 59 and 66 days following the onset of paralysis in a patient with Guillain–Barre’ polyneuropathy. Shown for reference are the mean and 2 standard deviations lower limiting values from control data. Conduction block was complete at 10 days, but, recovery was apparent at the 32-day mark (From Brown, WF and Watson, BV (2002) Recording of electrical activity in nerve trunks and conduction in human sensory and motor nerve fibers. In: Neuromuscular Function and Disease, New York, W.B. Saunders Company, pp. 21–55. Reprinted by permission of W.B. Saunders Company, an imprint of Elsevier).

Fig. 4.10 Examples of acute “axonal” conduction block in a 62-year-old female presenting with a 2-week history of mononeuritis multiplex secondary to a vasculitis. Note, the proximal reduction in the corresponding “M” potentials following stimulation of median (Ax), peroneal (PF) and tibial (PF) nerves. Two weeks later, the results were more in keeping with axonal degeneration as demonstrated by a marked reduction in the distal thenar (median), anterolateral (peroneal) and abductor hallucis (tibial) “M” potentials. W, wrist; E, elbow; Ax, axilla; FH, fibular head; PF, popliteal fossa; A, ankle.

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progressive increases in the axonal diameters and the thickness of their myelin sheaths. These two processes proceed in a proximal to distal manner. Lower stimulus thresholds and progressive increases in impulse velocities parallel the structural maturations. At maturity, conduction velocities approach and sometimes reach normal values (Berry et al., 1944; Sanders and Whitterridge, 1946; Berry and Hinsey, 1947; Cragg and Thomas, 1964; Devor and GovrinLippmann, 1979). The failure to reach normal conduction velocities may have several explanations. For example, the multiplication of Schwann cells resulting in shorter internode lengths, smaller axon diameters, and thinner myelin sheaths in the regenerated nerve fibers might singly or together account for the slower conduction velocities. In humans, maximum conduction velocities may reach 80 or even 100% of their normal mean values following regeneration (Hodes et al., 1948; Struppler and Huckauf, 1962; Ballantyne and Campbell, 1973; Donoso et al., 1979; Buchthal and Kuhl, 1979). The latent period in humans, between the injury and the earliest detectable evidence of reinnervation is

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close to what might be expected, based on regeneration rates of 1–3 mm per day (Jasper and Penfield, 1946; see review by Sunderland, 1978). For example, when the median nerve has been accidentally transected at the level of the wrist, the earliest detectable motor responses in the thenar muscles to electrical stimulation proximal to the transection may take as long as 120 days or more to appear. When allowances are made for the time necessary to cross the transection site and establish enough functional end plates to produce a detectable M-potential, and when account is taken of the distance between the muscle and the transection site, the estimated maximum rate of regeneration was about 1–2 mm per day. Not all axons reach the target tissues at the same time; indeed, there can be very appreciable lags between the arrival of the first few axons and the bulk of the remaining nerve fibers. It is not known whether this range reflects variations in the rate of regeneration among individual nerve fibers or simply wide differences between different nerve fibers in the times they require to cross the injury site.

Fig. 4.11 Experimental model of nerve fiber regeneration in the cat. In this model, the lateral (peroneal) division of the sciatic nerve was transected and immediately re-sutured. Shown are the monophasic dorsal root potentials (DRPs) recorded in oil in response to stimulation of the nerve both proximal and distal to the site of the transection. The nerve was mounted on a tri-polar stimulating electrode (cathode central) and attached to a horizontal calibrated drive. The latter made it possible to stimulate the nerve at successive intervals as short as one mm. The exposed nerve in the thigh was kept warm (37˚C) in the mineral oil. (A) One week following transection, no DRP potential could be detected in response to stimulation of the distal stump 8 or more millimeters distal to the original transection. The large DRPs in response to stimulation 2 and 4 mm distal to the transection probably reflect the proximal spread of the stimulating current to the much lower-threshold regions just proximal to the transection. Continued

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Fig. 4.11, Cont’d (B) The DRPs at two and eight weeks respectively. Note that while a few nerve fibers have reached as far as 25 millimeters beyond the transection site, the main body of the regenerating nerve fibers has not progressed nearly as far. At the eight-week mark, many more fibers have successively bridged the original “gap” and extended much further into the distal stump. Indeed, at this time reinnervation of the peroneal innervated muscles just below the knee had already begun as revealed by substantial reductions in amount of fibrillation activity in these muscles.

The rate of axonal regeneration is not constant, but diminishes as the regeneration proceeds distally. The rate of regeneration may also be somewhat slower following transection rather than crush injuries (Sunderland, 1978). The safety factor for neuromuscular transmission at the immature neuromuscular junctions is commonly reduced and may fail when end plate potentials become subthreshold. Moreover, in some of the immature axon terminals and preterminal branches, where the conduction velocities are characteristically

reduced, transmission may fail, especially at branch points. With time and further maturation, presynaptic conduction and neuromuscular transmission become more secure. Using needle EMG electrodes, the earliest detected motor unit action potentials (MUAPs) are often quite short in duration, their amplitudes small and their shapes may occasionally be polyphasic. Before long, the MUAPs become increasingly hypercomplex in shape and the durations of the MUAPs increase, sometimes

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Fig. 4.11, Cont’d (C). Twenty-four weeks following transaction, the size of the DRP is much larger, approaching values elicited proximal to the transection. Note also the reduced temporal dispersion in the DRP, the latter no doubt reflecting the increasing diameters of the nerve fibers and myelination of the regenerating nerve fibers at this stage. (D). Serial DRPs in a control nerve (From Brown, WF (1984) Conduction in abnormal nerve. In: The Physiological and Technical Basis of Electromyography. Boston, Butterworth-Heinemann, pp. 37–94. Reprinted by permission of ButterworthHeinemann, an imprint of Elsevier).

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dramatically so. These changes reflect the ever-increasing number of muscle fibers contacted by the motor nerve fiber as well as wide differences between the arrival times of their respective muscle fiber action potentials within the pick-up territory of the electrode. The latter differences in arrival times, in turn, reflect wide differences among conduction times of the various preterminal and terminal motor nerve fibers within the motor unit as well as differences among the conduction velocities of the muscle fibers in the unit. Later, as the presynaptic motor nerve fibers mature and muscle fiber diameters become more uniform within the reconstituted motor units, the associated MUAPs increase in amplitude and become less temporally dispersed. One of the earliest signs or reinnervation is a reduction in the number of fibrillation potentials. Further regeneration and reinnervation increases the size of the compound “M” potential and the force generated by the muscle in response to a supramaximal stimulus delivered to the presynaptic nerve. The number of voluntarily recruited motor units steadily increases, although the order of recruitment may be somewhat upset following a previous transection of a nerve (Milner-Brown et al., 1974). Equivalent maturation in sensory axons is harder to detect. For example, it is possible to detect the presence of even one motor axon once innervation of a sufficient number of muscle fibers in the motor unit has taken place. However, the compound nerve action potential associated with regenerating sensory fibers is simply too small and temporally dispersed to detect even with near-nerve needle electrode recording techniques (Donoso et al., 1979; Buchthal and Kuhl, 1979). Where large numbers of nerve fibers fail to cross the site of the injury many of the “frustrated” sprouts may form a tangled ball or neuroma. Spontaneous discharges have been clearly shown in such experimental neuromas (Wall and Gutnick, 1974a, 1974b; Devor and Bernstein, 1982). These spontaneous afferent barrages in human neuromas may, in part at least, explain the pains, paresthesia, and phantom limb sensations experienced by these patients. 4.12. Neuromuscular transmission and conduction block in regenerating nerve fibers During reinnervation, the surviving axons sprout new terminals which, in most cases, migrate toward the original endplate regions of the denervated muscle fibers. The density of acetylcholine receptors within the endplate zone remains relatively normal within

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weeks following denervation (Slater and Vincent, 1992), however, a portion of these receptors carry embryonic-like properties resulting in unstable neuromuscular junctions (Loring and Salpeter, 1980; Gu and Hall, 1988). As a result of these newly formed, immature junctions, neuromuscular transmission often fails, possibly as a result of sub-threshold endplate currents. As also, nerve conduction may be blocked along the immature preterminal branches of the regenerating nerve fiber. Neuromuscular transmission failure can occur in any condition where there has been evidence of denervation. An example of this is often seen in motor neuron diseases where decrement can be observed, even at low frequencies (1Hz), while performing routine motor nerve conduction studies. Needle electromyography also often demonstrates the immaturity of axonal collateral sprouting with blocking of satellite or link potentials, observed during voluntary motor unit activation. Single-fiber EMG can also be used to demonstrate neuromuscular block, or increased jitter, in cases of faulty neuromuscular transmission during nerve regeneration. 4.13. Neuronopathies and axonopathies The Wallerian degeneration, that follows transection or crush of a nerve, is not representative of the types of degeneration seen in more slowly progressive primary axonal peripheral neuropathies. Traumatic interruption of the axon shuts down in all those metabolic and structural processes in the distal stump, which depend on axoplasmic transport of molecular constituents originating in the cell body. This contrasts with the situation in degenerative neuronal and axonal neuropathies where only a part of the metabolic or transport processes may be affected. Moreover, the cell bodies and proximal axons are not directly injured in traumatic injuries and, except in very proximal axonal lesions, are able to sustain repair and regeneration of the axon. By comparison, in degenerative neuronal and axonal neuropathies, the cell bodies or axons may well be dysfunctional for a variety of reasons and, therefore, are less capable of regenerating and sustaining their end organs, peripheral synaptic connections, or postsynaptic cells. Furthermore collateral sprouting and reinnervation and hypertrophy of muscle fibers may mask the severity of axon loss in the axonopathies or neuronopathies because of the comparatively much slower pace of these disorders in contrast to that of traumatic lesions.

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The distinction between the neuronopathies, where the primary injury is thought to be in the cell body, and axonopathies, where the injury site is thought to be to the peripheral axonal process, is at best arbitrary. Too little is known about the basic mechanisms involved to make this distinction anything more than speculative in most diseases. The term “dying-back” neuropathy was introduced by Greenfield (1954) and Cavanagh (1964) to describe those diseases where the primary abnormalities were thought to reside in the cell bodies. In response to dysfunctional changes in the cell bodies, the earliest degenerative changes begin at the distal extremities of the axonal processes (both central and peripheral) and progress toward the parent cell bodies, leading as the terminal event to degeneration and loss of the neuron. Detailed examination of experimental and human toxic neuropathies has led, however, to questions about the dying-back hypothesis (see review by Spencer and Schaumburg, 1976). These authors claimed that the patterns of axonal degeneration seen in these intoxications differed from the patterns expected in a dying-back neuropathy. For example, when the neurons are the primary site of the attack, the earliest and most severe degeneration should begin at the distal extremities of those neurons that have the largest peripheral volume to maintain (and perhaps the largest metabolic load). Degeneration should also begin earliest at the distal extremities of those neurons that have the longest and largest-diameter peripheral axons. This simple view has not turned out to be true in the case of some of the toxic neuropathies where degeneration begins not at the axon terminals, but at multiple preterminal sites. Spencer and Schaumburg (1976) also pointed out that although the degeneration does primarily involve the longest and thickest myelinated axons, exceptions do exist to this model. For example, in experimental acrylamide neuropathy, pacinian corpuscles begin to degenerate prior to the primary endings of muscle spindles (Schaumburg et al., 1974). Moreover, in experimental n-hexane neuropathy, nerve fibers, that innervate the calf muscles, degenerate before nerve fibers of equivalent diameter but longer length, such as those that innervate the feet (Spencer and Schaumburg, 1976, 1980). Whatever their precise mechanism(s), the general pattern of these degenerations is common to a wide variety of peripheral neuropathies (Spencer et al., 1978; Spencer and Schaumburg, 1980). The accompanying electrophysiological abnormalities have been documented in the various experimental models and in humans. They include:

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(1) Early receptor failures. For example, abnormal responses in muscle stretch receptors have been observed prior to any detectable change in conduction proximal to the receptor endorgans (Sumner and Asbury, 1975; Lowndes et al., 1978a, 1978b). (2) Selective losses of the largest-diameter myelinated axons. These losses may explain reductions in maximum conduction velocities in acrylamide neuropathy (Hopkins and Gilliatt, 1971). (3) Centripetal progression of conduction failure in the affected nerve fibers Ever more proximal progression of the degeneration of the nerve fibers is associated with the centripetal advance of border zone proximal to which conduction can be sustained without failure. Associated with the latter is the finding that the thresholds of affected nerve fibers are highest at the extremities of the degenerating fibers. (4) Preferential involvement of certain physiological types of axons and relative sparing of other axons of equivalent diameter. For example, in acrylamide neuropathy, sensory nerve fibers of equivalent diameter tend to be more involved than the motor axons (Sumner, 1980). Human peripheral nerves cannot be examined with the same precision as in experimental models. However, equivalent electrophysiological abnormalities have been observed in human neuronopathies and axonopathies. These include: (1) Maximum conduction velocities tend to remain within the normal range. In cases where the maximum conduction velocities fall below the normal range, there may be several explanations. For example, there may have been selective degeneration and loss of the fastest conducting nerve fibers or sufficiently severe losses of nerve fibers overall, that even on a random basis, the fastest-conducting nerve fibers were lost. In these two scenarios the slower conduction velocities may simply reflect the velocities of the remaining, normally slower-conducting nerve fibers. In the latter regard it is well to remember that there is about a 30% range in the conduction velocities of motor axons in normal human motor nerves. Alternatively, slower conduction velocities might be an indication of slowing of

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conduction in normally more rapidly conducting nerve fibers. Conduction velocities in such primary axonal or neuronal diseases might also be slowed because of axonal atrophy (Baba et al., 1982) and perhaps secondary demyelination. For these reasons, caution should be exercised while interpreting maximum conduction velocities because even maximum conduction velocities as low as 20–30 m/s might be seen at the late stages of primary axonal or neuronal diseases in the absence of primary demyelination, especially where only a few motor nerve fibers remain. (2) Disproportionate increases in terminal conduction times may be observed. In these disorders, the earliest structural abnormalities begin at or near the terminal extremities of the central and peripheral processes of the sensory and motor neurons (Spencer and Schaumburg, 1976). These degenerative changes may be associated with secondary paranodal and segmental demyelination and, later, the formation of shorter internodes. Such structural changes would be expected to slow conduction velocities and prolong terminal latencies and would explain the disproportionate prolongation in distal latencies sometimes observed in certain human metabolic and toxic neuropathies, although in some diseases such as alcoholic neuropathy this has not been observed (Behse and Buchthal, 1977). Progressive centripetal degeneration described by Sumner (1980) in acrylamide neuropathy would be a better explanation for the centripetal progressive loss of excitability in sensory nerve fibers reported by Casey and LeQuesne (1972) in alcoholic neuropathy. (3) Denervation and reinnervation. These phenomena are simply a direct consequence of the axonal degeneration and, in general, are more severe in distal than in proximal muscles. Other neurological disorders characterized by primary involvement of the neuron are the motor neuron diseases of which amyotrophic lateral sclerosis (ALS) is the most common example. The etiology of these disorders is not known but has recently been reviewed (Brown et al., 2000). The electrophysiological abnormalities in ALS (Chan and Brown, 2000) are similar to those in the primary axonopathies, except in ALS the “upper” motor neurons as well as the bulbar and

spinal motor neurons are among the primary targets (Hudson, 1981). 4.14. Can axonal neuropathies be distinguished from demyelinating neuropathies based on their conduction velocities? Is there a conduction velocity below which electromyographers can confidently speak of a primary demyelinating neuropathy? The answer is no. The reason being some motor neuronopathies and axonopathies may be associated with conduction velocities less than 50% of control values. Conduction tends to be most slowed in the distal segments of the longest nerve fibers and most apparent where there are only a few surviving motor nerve fibers supplying distal muscles such as the extensor digitorum brevis muscle in the foot. Possible explanations for such slowed conduction velocities in axonal neuropathies include axonal atrophy as well as secondary demyelination. Maximum motor conduction velocities in the less severely affected nerves of such cases tend to be much more normal in contrast to primary demyelinating neuropathies such as Charcot–Marie– Tooth type IB, where the conduction velocities are much more uniformly slowed. References Aitkin, JT and Thomas, PK (1962) Retrograde changes in fiber size following nerve section. J. Anat., 96: 121–129. Allt, G (1976) Pathology of the peripheral nerve. In: DN Landon (Ed.), The Peripheral Nerve. John Wiley & Sons, New York, pp. 666–739. Arroyo, EJ and Scherer, SS (2000) On the molecular architecture of myelinated fibers. Histochem. Cell Biol., 113: 1–18. Asbury, AK, Arnason, BG and Adams, RD (1969) The inflammatory lesion in idiopathic polyneuritis. Medicine, 48: 173–215. Asbury, AK and Johnson, PC (1978) Pathology of peripheral nerve. In: JL Bennington (Ed.), Major Problems in Pathology. W.B. Saunders, Philadelphia. Baba, M, Fowler, CJ, Jacobs, JM and Gilliatt, RW (1982) Changes in peripheral nerve fibers distal to a constriction. J. Neurol. Sci., 54: 197–208. Ballantyne, JP and Campbell, MJ (1973) Electrophysiological study after surgical repair of sectioned peripheral nerves. J. Neurol. Neurosurg. Psychiatry, 36: 797–805.

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Behse, F and Buchthal, F (1977) Alcoholic neuropathy: clinical, electrophsiological and biopsy findings. Ann. Neurol., 2: 95–110. Berry, CM, Grundfest, H and Hinsey, JC (1944) The electrical activity of regenerating nerves of the cat. J. Neurophysiol., 7: 103–115. Berry, CM and Hinsey, JC (1947) The recovery of diameter and impulse conduction in regenerating nerve fibers. Ann. NY Acad. Sci., 47: 559–572. Bostock, H and Rasminsky, M (1983) Potassium channel distribution in spinal root axons of dystrophic mice. J. Physiol., 340: 145–156. Bostock, H and Sears, TA (1978) The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. J. Physiol., 280: 273–301. Bostock, H, Sears, TA and Sherratt, RM (1981) The effects of 4-amionopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibers. J. Physiol., 313: 301–315. Bostock, H, Sherratt, RM and Sears, TA (1978) Overcoming conduction failure in demyelinated nerve fibers by prolonging action potentials. Nature, 274: 385–387. Brinkmeier, H, Kaspar, A, Wietholter, H and Rudel, R (1992b) Interleukin-2 inhibits sodium currents in human muscle cells. Pflugers. Arch., 173: 621–623. Brinkmeier, H, Wollinsky, KH, Hulser, PJ, Seewald, MJ, Mehrkens, HH, Kornhuber, HH and Rudel, R (1992a) The acute paralysis in Guillain–Barré syndrome is related to a Na+ channel blocking factor in the cerebrospinal fluid. Pflugers. Arch., 421: 552–557. Brown, RH, Meininger, V and Swash, M (2000) Amyotrophic Lateral Sclerosis. Martin Dunitz, London. Brown, WF (2002) Basic neurophysiology of nerve fibers. In: WF Brown, CF Bolton, MJ Aminoff (Eds.), Neuromuscular Function and Disease: Basic, Clinical, and Electrodiagnostic Aspects. W.B. Saunders, New York, pp. 1–20. Brown, WF (1984) The Physiological and Technical Basis of Electromyography. Butterworth, Boston, pp. 1–35. Brown, WF and Feasby, TE (1984) Conduction block and denervation in Guillain–Barré polyneuropathy. Brain, 107: 219–239. Brown, WF (1984) Conduction in abnormal nerve. In: The Physiological and Technical Basis of Electromyography. Boston, ButterworthHeinemann, pp. 37–94.

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 5

Principles of stimulation and recording Hiroyuki Nodera* and Ryuji Kaji Department of Clinical Neuroscience, Graduate School of Medicine, University of Tokushima, Japan

CHAPTER 1 5.1. Introduction

5.3. Electrodes

With the recent advances in computer technology, even a novice electromyographer can comfortably perform electrophysiological testing with the aid of a semi-automatic electromyography (EMG) device. However, a lack of basic knowledge in electronics or the appropriate settings of such a device prevents the operator from performing a proper assessment (or troubleshooting) of the obtained waveforms. This chapter deals with the practical aspects of instrumentation and recording, and presents a brief discussion on electronics.

Electrodes can be used for either stimulation or recording. This section will discuss only recording electrodes (stimulation through needle electrodes is discussed in the section on stimulators). Two types of recording electrode can be used: surface and needle electrodes. Both of these have strengths and drawbacks, and it is important to understand the unique characteristics of each type so that they can be used as appropriate. The electrical function of the electrodes is to allow the detection of action potentials generated by nervous tissue in the body. In general, a surface electrode is preferred for clinical nerve conduction studies (NCSs), since it records from all motor units (although with some limitations), whereas a needle electrode has a much smaller recording radius, making it less suitable for studying CMAPs.

5.2. Basic electrical components required for nerve conduction studies The minimal apparatus required to perform EMG/nerve conduction tests include electrodes, amplifiers, a visual display, loudspeakers, and a stimulator; the use of data storage devices is optional (Misulis, 1989; Gitter and Stolov, 1995; Kimura, 2001; Dumitru et al., 2002). The same apparatus can often be used for different techniques, but certain differences often exist in specific applications. For instance, a stimulator may not be necessary for surface EMG or sympathetic skin response. In addition, surface electrodes are used to obtain muscle action potentials (MAPs) from the many underlying motor units, whereas a needle electrode is used to target activities from the limited number of motor units located near to the tip of an electrode.

* Correspondence to: Ryuji Kaji, MD, PhD, Department of Clinical Neuroscience, Graduate School of Medicine, University of Tokushima, 2-50-1 Kuramotocho, TokushimaCity 770-8503, Japan. E-mail address: [email protected] Tel.: +81-88-633-7207; fax: +81-88-633-7208.

5.3.1. Surface electrodes By applying surface electrodes over the muscle or the nerve, it is possible to record transcutaneously the summated activity from many motor units or nerves, respectively. Given the different regions of the body that are recorded from and the possible purposes of those recordings, a variety of surface recording electrodes have been used in both the clinical and research setting (e.g., discs, bar electrodes with multiples discs embedded in plastic, self-adhesive disposable electrodes, and ring electrodes with adjustable steel electrodes). A disc electrode is made from a durable metal, which has good electrical conductivity for clinical use (e.g., silver, gold, stainless, nichrome, and platinum). Due to biological and environmental noise, the electrical activity from nervous tissue is usually obtained by making bipolar recordings with the reference electrode usually placed near to the recording site. The electrical activity of these two electrodes is processed and the difference between them is displayed on a cathode-ray tube (CRT) screen. Although this method presumes that the reference electrode is electrically inactive,

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waveforms can differ significantly by moving only the reference electrode, reflecting the electrical propagation into the reference. This is discussed further in the section on volume conduction. The biggest advantage of using surface electrodes over needle electrodes is that there is no pain involved because they are applied to the skin without puncturing it, but the waveforms obtained are less well defined due to the high impedance of the skin resulting in a reduction in the magnitude of the potential detected by the electrode. The interface between the skin and electrode ranges from 500 to 9 M (Swain et al., 1985; Panescu et al., 1993), and this can be effectively reduced by: (1) preparing clean electrodes; (2) using skin preparation and cleansing agents, if necessary, or rubbing with an alcohol-based preparatory solution; and (3) applying an electrode cream between the electrode and the skin surface. However, the use of excess amounts of electrode cream may result in unstable placement of the electrode or bridging between the active and reference electrodes. The choice of surface electrode has no definite answer. The electrical properties of each recording electrode can differ significantly, not only for a particular type of electrode, but also with respect to numerous factors such as its method of manufacture, the electrical material utilized, and the size of the electrode. Therefore, each laboratory should obtain normative data with their own particular recording electrodes. A disposable, self-adhesive electrode with a slightly larger surface area than the traditional disc electrode has recently been introduced, which obviates the need for electrode cream or adhesive tape. Whether the data obtained by using a disposable electrode are comparable to those obtained with a disc electrode is yet to be established. There is no agreement upon the appropriate size of the recording electrode (Bromberg and Spiegelberg, 1997), the most commonly used one being a flat or cup-shaped disc electrode with an average diameter of 1 cm and a recording radius of approximately 20 mm (Barkhaus and Nandedkar, 1994). The performance of larger electrodes has been studied, particularly in the field of motor conduction (Wee and Ashley, 1990; van Dijk et al., 1995; Tjon et al., 1996; Ferdjallah et al., 1999; Finsterer et al., 2002). Larger electrodes generally yield CMAPs with smaller amplitudes and areas, but with comparable conduction velocities and onset latencies. This is understandable because larger electrodes pick up potentials from larger regions with differing degrees of contribution to the CMAP (i.e.,

HIROYUKI NODERA AND RYUJI KAJI

a variable potential field in a region with high spatial gradients), thereby “averaging out” the electrical response and yielding a smaller-amplitude CMAP. The regular-sized “small” electrode has been used as an outcome measure for various therapeutic trials to monitor the progression of a disease (Hahn et al., 1996; Russell et al., 1996; Kaji et al., 1998). However, it is thought that the repeatability of the CMAP amplitude may be low due to inconsistent placement of the electrodes, because even the slightest shift in the placement of the active electrode can change the CMAP amplitude significantly (as the spatial gradient is high near the motor point). On the contrary, the longitudinal reliability of CMAP amplitudes appears to be slightly higher when using larger electrodes, which are presumably more suitable for longitudinal monitoring of CMAPs in clinical trials. Theoretically, a larger electrode “averages out” the potentials with different amplitudes underneath the electrode, and the relationship between the maximal motor point and the placement of the electrode may be less strict (unpublished data from Nodera and Kaji, see Fig. 5.1). 5.3.2. Needle electrodes The main advantages of using needle electrodes over surface electrodes are: (1) due to the close proximity of the active electrode to the potential generator and significantly lower impedance than surface electrodes, larger potentials are yielded for which the loss of highfrequency signals due to biological filtering is reduced (see discussion on filters); and (2) due to the smaller size of the electrode, potentials from a smaller number of motor units are obtained, making motor unit analysis easier. However, there are also drawbacks, such as: (1) the pain inflicted on the subject and the potential transmission of pathogens; (2) the high cost, whether using disposable or reusable (following autoclaving) electrodes; (3) lower reproducibility of the potentials, most significantly the action potential amplitude; and (4) the risk (albeit fairly low) of injuring nervous tissue or vasculature exists. Despite these drawbacks, the use of needle electrodes has been studied extensively, and it is believed that in normal individuals they do not usually cause an elevation of muscle enzyme levels (Finsterer et al., 2002). Still, great care should be taken when using needle electrodes in patients with significantly elevated levels of muscle enzymes or in patients with renal failure. Monopolar needle electrodes are made from stainless steel covered by a Teflon sleeve, and have an

PRINCIPLES OF STIMULATION AND RECORDING

CMAP amplitudes (mV)

Repeatability of conventional (“small”) vs. “large” electrodes

B

12 11 10 9 8 7 6 5 4 3 2

R small L small R large L large

1

2

3

4

Week

Fig. 5.1 Median motor nerve conduction study performed using a large E1 electrode covering a large area of the muscle belly (A). The CMAP obtained by the large recording electrode is smaller than that obtained by the small recording electrode, since the spatial gradient is high near the motor point and the effect is averaged out by the large electrode. The thin and long E2 recording electrode was placed around the interphalangeal joint for test-retest consistency. Compared with serial CMAP recordings achieved with a conventional disc recording electrode (a “small” electrode), those achieved with a large recording electrode are smaller and, more importantly, are more reproducible (B).

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average diameter of approximately 0.8 mm. The entire length of the electrode is insulated, apart from a 0.2-mm to 0.4-mm length at the distal tip, which is used for the recording. It has been shown that needles with only their tip bared provide a better signal-tonoise (S/N) ratio than those with a completely bare shaft, and are thus recommended for clinical use (Schoonhoven and De Weerd, 1984; Chu et al., 1987). Furthermore, since varying the length of the bared section of the needle electrode significantly alters the action potential parameters of motor units, particularly the amplitude and the area of the motor unit potentials (Chu et al., 1987), the length of the bared tip should always be taken into account when analyzing data. A surface electrode or a second needle electrode inserted into the subcutaneous tissue serves as a reference electrode. Coaxial concentric needle electrodes comprise a stainless-steel cannula with a wire in the center of the shaft. The difference is obtained between the electrical discharges recorded from the inside wire and the outside rim, the distance between which is very short, so that this needle electrode records potentials that have a lower amplitude and a smaller number of phases than a monopolar needle, which has a restricted recording radius (Howard et al., 1988; Pease and Bowyer, 1988; Nandedkar et al., 1990; Nandedkar and Sanders, 1991; Kohara et al., 1993; Dumitru et al., 1997; Joynt, 1998; Trojaborg, 1998). Hence, this type of the electrode is rarely used for NCSs, with the possible exception of studies that focus on single or only a few motor units. In NCSs, a needle electrode is typically used for near-nerve sensory recording, where an active electrode is inserted subcutaneously and the tip of the needle is set in close proximity to a nerve in order to obtain subtle discharges from that nerve (Rosenfalck, 1978; Oh et al., 1984; Smith, 1998; Wexler et al., 1998; Seo and Oh, 2002). A similar application is in microneurography, in which a thin tungsten needle electrode is inserted into a nerve trunk to obtain discharges from a single unmyelinated nerve. This method is used primarily for studies of the autonomic nervous system (including itching) and of sensory systems, with emphasis on neuropathic pain (to investigate myelinated and unmyelinated sensory fiber activities; Hallin and Torebjork, 1970, 1973; Handwerker et al., 1991; Schmelz et al., 1997; Kuwabara et al., 2000; Weidner et al., 2002; Schmelz et al., 2003), and for recording somatosensory, auditory, and visual evoked potentials.

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5.4. Electrode amplifiers In order to properly visualize biological electric signals ranging in size from microvolts to millivolts on visual displays, the signals must be significantly amplified. For example, if the actual amplitudes of the signal are 1 μV and 1 mV, amplification factors of ×1 000 000 and ×1000, respectively, are required to register on an oscilloscope display set at 1 V/cm. Several methods are currently employed to accomplish this significant degree of amplification. The first method is to multiply the amplifying effects by using a preamplifier with a gain of, for example, ×500, followed by several amplifier and attenuator stages to produce a gain of ×2–2000, depending on the range of the required output. The second method involves the use of differential amplifiers. Since the major source of signal noise originates from the surrounding environment and the current power lines, the magnitudes of which far exceed those obtained from biological tissues, amplifiers have been developed that cancel out the nonbiological noise recorded from both the active and reference electrodes (the common signal) whilst amplifying the remaining signals from both electrodes. This cancelled potential is called the common signal. The use of these differential amplifiers also effectively eliminates unwanted distant MAPs that affect equally both the active and reference electrodes. The effectiveness of a differential amplifier can be quantified using the common-mode rejection ratio (CMRR) (Perreault et al., 1993). The CMRR is defined as the ratio of the amplification of the difference signal to the amplification of the common-mode voltage. For example, a CMRR of 100000 means that the biological signals are amplified 100 000 times more significantly than unwanted noises appearing as the common-mode voltage. However, even when using a differential amplifier, it may not be possible to completely eliminate the unwanted noise because of, for example, unequal noise on the two electrodes due to different degrees of electromagnetic interference, or the existence of unequal contact impedance between the electrodes, which is very difficult to avoid. 5.5. Filters Most biological electrical potentials consist of a combination of complex discharges with variable frequencies. Fourier analysis of these complex discharges reveals the sum of sine waves of different frequencies as their constituents. In general, discharges from

HIROYUKI NODERA AND RYUJI KAJI

neurological tissue have frequencies ranging from 10/20 KHz. Activities outside of this range are most likely to be artificial and hence should not be included in analyses. For this purpose, a filter can effectively wipe out electrical activities below or above certain frequency: a low-frequency (high-pass) filter cutting out low-frequency activity and a high-frequency (lowpass) filter cutting out high-frequency activity (Maccabee and Hassan, 1992). Since setting the cutoff frequencies of filters inappropriately significantly alters waveforms, it is important to understand the effects of filters (Pease and Pitzer, 1990; Dumitru et al., 2002). If a low-frequency filter (LFF) is set too low, the most notable effect would be an unstable baseline due to the inclusion of very-low-frequency artificial discharges (from, for example, body movement). Conversely, if a LFF is set too high, the lowfrequency component of the biological discharge is removed, with the net effect of lowering the discharge amplitude and quicker return of the waveform to the baseline. If a high-frequency filter (HFF) is set too low, the high-frequency component of the biological discharge is omitted, resulting in delay of the onset latency (at which point the high-frequency component predominates for the discharge to rise quickly from baseline) and a less-steep rise from the baseline, a slight delay in the peak latency (which is less noticeable than that in the onset latency, since high-frequency discharges are not dominant at the peak), and, as an advantage, less-notable high-frequency background noise. Conversely, if the HFF is set too high, too much noise will be included in the waveform (Fig. 5.2). With these points in mind, although there is no universal agreement on this matter, the recommended filter settings for NCSs are as follows: (1) motor NCSs, LFF at 2–10 Hz and HFF at 10 kHz; and (2) sensory NCSs, LFF at 2–10 Hz and HFF at 2 kHz. In general, a body tissue acts as a low-pass (highfrequency) filter, resulting in smoothing of the signals. Hence, an electrode placed far away from the generator of the potential preferentially picks up lowfrequency signals, resulting in waveforms with a slow rise time and a low-pitched sound, erroneously interpreted as “neurogenic, reinnervated” potentials. 5.6. Visual displays As for other electrical visual aids (e.g., the computer screen and television), the CRT has long played a central role in the visual displays used for EMG/nerve

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A

Default filter setting

B

Lower LFF

C

Higher LFF

D

Lower HFF

E

Higher HFF

Fig. 5.2 Effects of varying the filter setting in a model of a CMAP recording. If the low-frequency filter (LFF) is set too low, the baseline becomes less stable due to inclusion of low-frequency discharges (B). Setting the LFF too high reduces the amplitude of the CMAP due to the omission of the slow component of the response (C). If the high-frequency filter (HHF) is set too low, the onset latency becomes longer, the rise time increases, and there is a slight decrease in the peak amplitude (D). If the HFF is too high, the signal contamination with artificial high-frequency noise occurs (E).

conduction tests. Although the digital screen has recently largely replaced the CRT, a basic understanding of how it works would help us to appreciate the basic principles underlying electrical visual displays. The CRT consists of an electron gun, deflecting apparatus, and luminescent screen, which together function essentially as a pointer that can be moved rapidly in two dimensions, whose intensity can be modulated. The electron gun produces a beam of high-speed electrons from a thermionic cathode that are focused to a small spot on the screen. The intensity of these electrons is regulated by the negative potential on a thimble, which is set in front of the cathode and has a small hole through which the electrons pass. A second anode set at a high potential, more than 500 V in most sets, then accelerates the electrons. The electron beam is guided by two deflecting plates set at 90˚ angles to one another (horizontal and vertical deflection plates). An electric field is established between these plates and the electrons are deflected accordingly onto a luminescent screen. When the electrons hit the screen, the phosphor is excited, and emits light.

A delay line is employed in the triggered sweep oscilloscope to retard the arrival of the vertical input waveform at the vertical deflection plates until the trigger circuit and time-base generator have had a chance to start the sweep of the beam. The effect of the delay line is that the leading edge of the vertical input waveform can be viewed on the screen. Thus, one can initiate the horizontal sweep on command for an electromyographer to set successive and recurring motor unit potentials at the beginning of each sweep, enabling detailed analysis. 5.7. Loudspeaker A loudspeaker is a device that converts electric signals into sound waves, and houses a driver that converts electrical audio signals into sound waves. Among the many types of drivers, by far the most common type is the moving-coil electrodynamic piston driver. It has a moving diaphragm that acts like a piston to move air backwards and forwards, thereby creating sound waves. Because the diaphragm can

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only operate effectively over a limited frequency range, multiple diaphragms are usually required for the faithful representation of sound. The sounds produced by different kinds of potentials during examination with a needle electrode are important, and are used for proper identification and analysis of the waveforms. Each potential has its own characteristic sound, and an experienced operator often relies heavily on these sounds rather than the waveforms themselves (Okajima et al., 2000). Owing to the HFF effect of body tissue, a potential that arises some distance from the recording electrode creates a low-pitched sound. The position of the needle must be adjusted until a clear, crisp sound (reflecting a short rise time due to a reduction of the HFF effect) from a nearby unit is obtained. 5.8. Artifacts Not all observed electrical activity originates from nerve or muscle. Although most of the discharges that arise from nonneural tissue or from outside the body have distinct discharge patterns, some others mimic those arising from neural tissue, and even an experienced examiner may have difficulty determining its origin. These artifacts may originate from several sources; for example, from a nonneural tissue, artificial devices, amplifier noise, defective apparatus, movement artifacts, and interference. Each of these are discussed separately here (Kimura, 2001; Dumitru et al., 2002). Artifacts from nonneural tissue can originate from any body tissue with the capability of generating electric signals, but only a few selected body systems can generate discharges that are intense enough to affect EMG or nerve conduction tests. The most notable artifact comes from the heart. Due to the regularity of the cardiac rhythm, it is fairly easy to identify this particular source, but artifacts from a patient with an irregular heart rhythm may be challenging. The cardiac artifact may be pronounced if the reference electrode is placed on the opposite limb to the recording electrode by crossing the midline of the body. Another potential source of the cardiac artifact is the pacemaker potential, which, because of its regularity, is sometimes easily mistaken for a fibrillation signal. Careful inquiry, simultaneous ECG recording, and the presence of synchronization with the pulsation of the blood vessels allow the identification of pacemaker potentials. As discussed above, the detected electric signal must be amplified 1000 to 1000 000 times for effec-

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tive visualization. Hence, even the slightest electrical noise inherent in an amplifier can produce a significant problem. These artifact can be generated by its components, including the resistors, transistors, and integrated circuits. For example, thermal noise, defined as the noise generated by thermal agitation of electrons in a conductor, is proportional to the square root of the absolute temperature and increases with the impedance in the input stage. Another sort of noise, microphonic noise, is caused by the unstable capacitance of various components, and is due mainly to mechanical vibration. In practice, amplifier noise is most evident when the tip of the needle electrode is in fatty tissue (which has a higher impedance than muscle), and high-frequency noise disrupts the baseline. This noise can often be decreased by repositioning of the needle. The most commonly encountered artifacts are attributable to defective apparatus. For example, a broken wire creates bizarre, often very-high-frequency noise that fluctuates with manipulation of the wire. In addition, a partially defective conductor may generate artifacts that occur simultaneously with muscle twitches. Inadvertent insulation of the electrode by blood protein or electrode cream may produce similar artifacts, requiring routine care of the surface of the electrodes by, for example, alcohol-based preparations. The largest source of noise may be the electrolyte-skin interaction, thus emphasizing the need for proper treatment of the skin prior to application of an electrode (Huigen et al., 2002). Movement artifact is produced when a patient contracts a muscle and the surface electrode slides over the skin, resulting in a change in the impedance between the skin and the surface electrode (Conforto et al., 1999). This artifact is often accompanied by sudden deflection of the baseline immediately following muscle twitches. Movement artifacts can be suppressed by encouraging the patient to remain still, immobilization of the region being studied (if possible), and proper fixation of the electrode by tape and, if necessary, by manual compression. Sweat may also alter the input impedance between the skin and the recording electrode, resulting in unsteadiness of the baseline. The sympathetic skin response takes advantage of this artifact in the assessment of autonomic nervous system function (Gutrecht, 1994; Arunodaya and Taly, 1995; Marchello et al., 1996). Another source of artifact that is often problematic for clinical evaluation is the 50- or 60-Hz interference generated by the surrounding electrical equipment (electrostatic

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and electromagnetic interference). Possible sources include, for example, electric fans, lamps, unused power cords plugged into wall outlets, CRT screens, and fluorescent lights. Occasionally, an electric source some distance from the EMG device can cause a noticeable interference; for example, the ignition system of an automobile in a nearby driveway. Similarly, interference from radio broadcasts and mobile phones can be recorded and lessened by relocating the EMG device in the examining room and refraining from using mobile phones. However, given the increasing prevalence of remote communications, these sources of interference may not be completely abolished (Uludag et al., 1997). This type of interference may be exaggerated when an examiner touches the subject, because the examiner’s body acts as an antenna. This type of potential interference may be of enormous clinical significance in bedside testing, especially in an intensive care unit, where the activity of numerous monitoring and therapeutic devices generate significant interference, and in some cases no satisfactory recording can be obtained. The best approach to avoid such interference would be to shield the room and unplug all of the electric apparatus which is, of course, impossible in practice. Thus, the most reasonable and practical approach for obtaining satisfactory waveforms is as follows: (1) to bundle the lead wires from the pickup and ground electrodes to minimize the area susceptible to the field of interference; (2) to attempt to relocate the wires relative to the patient and recording apparatus; and (3) to set a certain distance between the CRT monitor and the patient to avoid the interference from the monitor (Kimura, 2001). The stimulus artifact is another commonly observed artifact, potentially posing a major technical challenge in routine nerve conduction testing. It is essentially a volume-conducted potential of the electrical stimulation (see below on volume conduction) that propagates instantly throughout the body independent of nerve or muscle tissue. Hence, the onset of the stimulus artifact is earlier than that of neural responses, and if the magnitude of the artifact is large enough, the background activity fails to return to baseline, resulting in an illdefined onset latency and amplitude of the responses. The potential reasons for a large stimulus artifact are: (1) poor stimulus isolation from the ground; (2) insufficient separation between the stimulus and recording sites; (3) too great a distance between the active and reference electrodes; (4) excess use of electrolyte cream, resulting in surface spread of the potential;

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(5) high impedance of the stimulating skin region (e.g., callous skin); and (6) and the active and reference electrodes located on different isopotential lines produced by a situation often improved by rotating the anode while maintaining the position of the cathode over the intended nerve. Technical tips for reduction of the stimulus artifact are listed in Table 5.1. 5.9. Stimulators 5.9.1. Types of stimulation Various modes of stimulation can elicit a nerve action potential. For example, several research groups have managed to obtain sensory nerve action potentials (SNAPs) by mechanical, air-puff stimulation (Buchthal, 1980; Hashimoto et al., 1991; Kuwabara et al., 2000; Mizobuchi et al., 2000; Fig. 5.3). Although this “natural” stimulus allows the assessment of mechanoreceptors that are completely bypassed by electrical stimulation, the SNAPs obtained by nonelectrical stimulation are significantly smaller in amplitude than electrically elicited responses, presumably due to the activation of a smaller proportion of the nerve fibers. In practical neurophysiology, electrical stimulation is easy to perform and considered to be reliable method of eliciting potentials; hence, electrical stimulation is the focus of this section. Magnetic stimulation of the central and peripheral nervous systems is a unique alternative mode of stimulation, in that it can be used to stimulate practically any part of the nervous system with relative safety (please refer to Chapter 19).

Table 5.1 Stimulus artifact reduction (Modified from Dumitru et al., 2002) (1) Remove perspiration from skin between stimulator and recording electrodes (2) Use only a small amount of electrolyte cream beneath all electrodes (3) Place ground electrode next to active recording electrode between it and the cathode (4) Only use current strength and duration sufficient to achieve a supramaximal response (5) Reduce the impedance between the skin and all electrodes (6) Elevate the low-frequency filter (use sparingly, if at all because of tendency to distort the waveform) (7) Use a needle cathode (anode)

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Normal

Electric

10 μV 5 ms

Air-puff

5 μV 5 ms

Fig. 5.3 SNAPs obtained by conventional electrical stimulation (top) and air-puff stimulation (bottom) (Kuwabara et al., 2000). The SNAP obtained by air-puff stimulation is characterized by: (1) a smaller amplitude than the electrically stimulated response, since a more limited proportion of the nerve fibers can be stimulated; and (2) a longer distal latency, since air-puff stimulation follows the physiological sensory pathway through sensory receptors, as opposed to electrical stimulation that bypasses these receptors.

5.9.2. Constant-voltage and constant-current stimulators Successful recording relies strongly on the stability of the electrical stimulation, and application of constantvoltage and constant-current electrical stimulation provides two ways of achieving this. Constant-voltage stimulation involves delivering an adjustable voltage across the stimulators, independent of the current, whereas with constant-current stimulation a fixed level of electric current is delivered. As Ohm’s law implies (V = I × R, where V, I, and R denote voltage, current, and resistance, respectively), the level of electric current between the cathode and anode (and hence at the nerve) may vary significantly with fluctuating resistance (e.g., sweating or movement of the stimulator). Constant-voltage and constant-current stimulation generally allow a greater control of the stimulus, especially for studies requiring trains of stimuli. 5.9.3. Basis of electrical stimulation The basis of electrical stimulation is discussed briefly here; a more detailed description can be found in Chapter 2 of the book, “Physiology and Function.” Electrical stimulation is accomplished by applying a

cathode (the negative terminal of a source of electrical current, conventionally colored in black in neurophysiology) and an anode (the positive terminal, conventionally colored in red) in close proximity either transcutaneously or subcutaneously. A cathode attracts positive ions (cations) and an anode attracts negative ions (anions). An electric current will be set up in the underlying tissue in the direction of (by convention) the positive ions (i.e., from anode to cathode). The current of sufficient magnitude enables an underlying nerve to be stimulated as an uneven capacitor. The extracellular surface facing a nerve near the anode is discharged more positively by accumulating negative ions on the surface of a nerve (i.e., hyperpolarization) due to a capacitative effect. Similarly, the extracellular tissue under the cathode is less positively charged, with a less negative membrane potential existing intracellularly. Once the membrane potential under the cathode reaches a certain threshold, that portion of the nerve depolarizes to produce an action potential. In a normal myelinated nerve, the node of Ranvier offers the least resistance to current flow and is the most easily depolarized part of the nerve. Although in conventional neurophysiology the cathode has been recognized as “active” in terms of producing an action potential in an axon beneath it, the effect of anodal stimulation has been debated. “Anodal block” is a local block of nerve conduction caused by hyperpolarization of the nerve cell membrane by an electric stimulus produced by an anode. For example, one might wonder whether reversing the placement of the anode and cathode in a NCS would block the propagation of the action potential; prior studies have argued against the presence of anodal block in routine neurophysiological testing (Dreyer et al., 1993; Kirshblum et al., 1998; Wee et al., 2000). The effective use of an electrical stimulator will result in depolarization of a large area of an underlying nerve. An electrical square-pulse stimulus lasting less than 50 μs may fail to activate some high-threshold fibers, and is not recommended for routine use. On the other hand, electrical stimuli lasting longer than 1 ms tend to be poorly tolerated and are usually unnecessary (except for special techniques required for nerve excitability testing, for example). In a routine clinical setting, most electromyographers use a default stimulation duration of 0.1–0.2 ms, increasing this parameter until a supramaximal response is obtained. However, stimuli of short duration may fail to elicit a response in a patient with severe edema, adiposity, or demyelination (see discussion below), in which case, starting

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with a longer-duration stimulus may be necessary in order to avoid the administration of an excessive number of stimuli. In cases of edema and adiposity, and for research in which prolonged recording is required, the use of subcutaneous stimulation through a pair of needle electrodes could be advantageous. The use of electrodes placed subcutaneously avoids the highresistance cutaneous and transcutaneous tissues and can elicit nerve potentials more easily because of their proximity to the nerve, particularly in cases of edema and adiposity, or when testing a nerve that is located deep below the skin surface. It is not uncommon to develop a skin abrasion after applying a surface stimulator firmly enough to edematous skin in order to obtain nerve responses. In addition, since it is generally easier to achieve a more stable placement using a subcutaneous stimulator than a surface stimulator, the former would be more suitable for lengthy recording sessions, even though it is slightly invasive. A study in which the effects of different types of surface electrodes were investigated demonstrated that there were considerable differences in the torques and electrical impedances obtained between electrodes (i.e., selfadhering pregelled pads, solvent-activated conductive tape, carbonized conductive silicone rubber, and feltcovered metal plates). Therefore, the effective use of a stimulating electrode requires an understanding of its unique characteristics (Nelson et al., 1980). Due to the increased risk of electrical nerve injury, great care should be taken while performing the “nearnerve” technique. Attention should be paid to factors such as a short stimulus duration (e.g., less than 0.05 ms), low stimulus strength (e.g., less than 1.0 mA), and careful clinical observation (e.g., paresthesia and pain) to limit the strength of the stimulation (Rosenfalck, 1978). Particular caution should be exercised when stimulating in the constant-current condition with a needle that has only the tip bared, because the small tip area yields a local current of high intensity, possibly resulting in heat- or current-induced injury of the surrounding tissue (Pease et al., 1989). For the same reason, use of concentric needle electrodes with very short interelectrode distances should be avoided. Since activation thresholds change according to the diameter and degree of myelination (if any) of the axons, stimulation using either a transcutaneous or intradermal electrode generally results in activation of the thicker, heavily myelinated A-alpha fibers (which have a low stimulus threshold) first, followed at increasing stimulus intensities by smaller-diameter fibers with less myelination. Recently, an interesting attempt was made

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to selectively stimulate nociceptive A-delta or C-fibers by using an intraepidermal needle electrode (0.2 mm in depth) to stimulate only the free endings of a nerve located in a region of the epidermis where only nociceptive fibers are found (Inui et al., 2002). By applying electrical currents for longer periods, the current required to elicit the same amplitude of the response decreases. The intensity of an electric current of infinite duration necessary to produce a minimal response is called the rheobase. As the rheobase of a sensory nerve is lower than that of a motor nerve, longer-duration stimuli (e.g., 1 ms) preferentially stimulate sensory nerves, which is the theoretical basis of using long-duration stimuli to analyze the H-wave. Conversely, short-duration stimuli predominantly excite motor nerves. In a research setting, applying different modes of stimulation reveals the otherwise unidentifiable properties of nerves and axons (Bostock et al., 1998; Burke et al., 2001). First, applying two successive electrical stimuli reveals the aftereffects of the stimulation in a nerve (i.e., the recovery cycle). For up to 4 ms after the first stimulation, the stimulus intensity required to elicit a second response from a nerve increases significantly (i.e., the threshold of activation increases), suggesting decreased excitability (absolute and relative refractoriness) due to the transient inactivation of the Na+ channels that were opened during the action potential. Then, at 7 ms poststimulus (or slightly earlier), the nerve is more excitable than at baseline (supernormality), a phenomenon that can be explained by depolarization of the paranodal region due to propagation of the depolarization into the region. Another mode of stimulation, called threshold electrotonus, involves applying very long subthreshold electrical stimuli (e.g., 100–300 ms), which enables the activation of various ion channels to compensate for the changes in the membrane polarization induced by lengthy stimulation. Thus, threshold tracking, takes full advantage of the utility of different modes of stimulation, has shed light on the properties of axon membranes in various neurological conditions (discussed in detail in Chapter 17). Most modern EMG devices have several modes of stimulation that allow the stimulus frequency to be altered. By simply pressing a switch, one may apply either a single stimulus with increasing stimulation intensity or trains of stimuli at a regular frequency (usually 1–2 Hz for most routine NCSs) while increasing the intensity of the stimuli until a maximal response is obtained. Only one of these stimulation

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modes should be used in order to avoid the application of unnecessary stimuli to the subject. The most suitable frequency of stimulation depends on the type of testing being performed. For example, for a microneurographic recording of an unmyelinated sensory fiber, an initial stimulation frequency of 0.25 Hz (once every 4 s) or less is preferred due to its low conduction velocity (approximately 1 m/s) and frequency-dependent slowing (slower nerve conduction velocity with higher stimulation frequency due to a hyperpolarizing afterpotential; Hallin and Torebjork, 1970, 1973; Torebjork and Hallin, 1974; Weidner et al., 2002). In a patient with neuromuscular junction disorder, the preferred stimulation frequency is either 2–3 Hz (for the study of slow repetitive stimulation) or 20–50 Hz (for a rapid repetitive stimulation), but these may elicit a falsely low CMAP amplitude due to fatigue. In general, subjects are intolerant of high-frequency electrical stimulation at greater than 3–4 Hz, although this figure varies significantly between individuals. 5.9.4. Stimulation of demyelinated nerves In a demyelinated nerve (e.g., in chronic inflammatory demyelinating polyneuropathy and Charcot–Marie– Tooth disease type 1), the electrical threshold is often markedly increased, requiring stronger stimuli than a normal nerve so as to elicit a response (Cappelen-Smith et al., 2001). This is most likely due to demyelination in the paranodal region. In a normal state, the paranodal region is covered by layers of myelin sheaths that exhibit a very high electrical resistance. Hence, as Ohm’s law implies, the current through the paranode is very small and the majority of the current is directed to the node (with lower resistance), enabling efficacious stimulation at the node. In a demyelinated nerve, on the other hand, the high resistance at the paranode is not maintained and the electrical stimuli pass through both the nodal and paranodal regions, failing to achieve efficacious stimulation through the node, and thereby requiring much higher-intensity electrical stimuli for depolarization to occur. Hence, in severely denervated nerves (e.g., Dejerine–Sottas disease), even electrical stimulation at the strongest current available to the EMG device and with a long stimulus duration may fail to elicit a maximal response (Kaji, 2003). 5.10. S/N Ratio and averaging The relative amplitudes of the signal and the background noise (i.e., the S/N ratio) must be taken into

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account when assessing the observed signal, to avoid falsely interpreting the unwanted noise as a real neural response. Even when using the most appropriate technique and taking the greatest care, it may not be possible to abolish the background noise, and hence the intended nerve activity remains embedded in the noise (i.e., there is a low S/N ratio), especially in sensory NCSs due to the already relatively small response amplitude that is elicited. A simple and widely used method for removing background noise (and hence increasing the S/N ratio) is by averaging many epochs of the same evoked potential. By averaging several recordings with the same repeating stimuli, the activities unrelated to the stimuli (with no relationship in time) will cancel out and only evoked “true” potentials remain visible because they are time locked to the onset of the stimulation. In general, the S/N ratio improves in proportion to the square root of the number of epochs averaged. For example, averaging four responses improves the S/N ratio twofold. The recommended degree of averaging depends on the S/N ratio of the intended responses, and may range from few times to up to 30. Obviously, unnecessarily large numbers of epochs averaged should be avoided. When the amplitude of the intended response is very small, one should be very cautious about interpreting the observed response. The biggest source of error might be intermittent muscle activity (e.g., voluntary movements or tremor), because the amplitude of the MAP far exceeds that from a sensory nerve, and hence contamination by even a single MAP would not be completely canceled out and thus may be falsely interpreted as sensory activity. To avoid this, one should concentrate on the loudspeaker during the averaging for any possible MAP or other noise as a potential source for contamination. 5.11. Volume conduction and waveforms As mentioned in Section 5.3, a pair of electrodes is placed on the surface of a nerve or a muscle to record its action potential. For a successful recording, there must be a difference in electrical potential between the active electrode (E1) and the reference electrode (E2), where E1 is the electrode placed near to the nerve or muscle and E2 is placed away from the generator of the action potential (so that the direct potential change from the electronic generator is smaller at E2). The theory behind this is that E2 is electrically inactive; however, a significant degree of electrical activation of

PRINCIPLES OF STIMULATION AND RECORDING

E2 may occur (e.g., in ulnar motor conduction studies) and may affect the waveforms significantly, depending on the placement of E2 (Kincaid et al., 1993; Kincaid, 1999; McGill and Lateva, 1999). Traditionally, in electroneurophysiology, negativity at E1 relative to E2 is expressed as an upward deflection of the trace (“negative up, positive down”), although exceptions do exist. In practice, using either extracellular surface or needle electrodes, the extracellular (not the intracellular) potential is measured, and so that the recorded polarity of the extracellular component is the opposite of the intracellular one (i.e., in depolarization, the recorded potential is negative, and vice versa). Volume-conduction theory provides us with an understanding of the origins of the diphasic or triphasic waveforms of a nerve action potential or a MAP. First, imagine a nerve with its polarizing phase described as “inside negative, outside positive” and depolarizing phase as “inside positive, outside negative.” An intracellular nerve action potential has a duration of approximately 0.5 ms (Paintal, 1966), and given the normal conduction velocity of a nerve of 50 m/s and assuming that the length of the depolarized portion of a nerve is 25 mm [length (mm) = time (ms) × conduction velocity (m/s)], one can assume that a 25-mm length of “inside positive, outside negative” segment propagates an action potential at the speed of 50 m/s. As no potential difference is produced between the two isopotential segments in either the depolarizing or polarizing portion, the only regions that are potentially electrically significant enough to be recorded are both ends of the depolarized segment where portions of positive and negative polarity are located next to each other (a dipole, expressed as “+ −”). Hence, the electrical model that best represents the passage of a depolarized portion can be illustrated as quadripoles (“+ − − +”), or more simplified as tripoles (“+ − +”) that move in the nerve or the muscle (also described as leading and trailing dipoles; Stegeman et al., 1997; Dumitru, 2000). As the magnitude of a potential is proportional to the distance of an electrode from the source, a larger change in the action potential is detected in E1 (rather than E2), such that passage of a “+ − +” tripole by E1 is recorded as a triphasic waveform of an initial positive deflection, followed by negative and positive polarities (hence, shown as initial downward deflection from the baseline followed by the upward deflection, then again a downward deflection). If E1 is placed over the motor point where a MAP is generated, the lack of effect of the leading positive polarity changes the morphology

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a

G1

G2

G1

G2

b c d e

a⬘ b⬘ c⬘ d⬘

Fig. 5.4 Diphasic (top) and monophasic (bottom) recording of an action potential, that is represented by the shaded area. The impulse propagates from left to right, and no difference of potential was detected in a, c, and e. In b, the active electrode, G1 (E1) becomes negative relative to the reference electrode, G2 (E2). Similarly, G1 (E1) becomes positive relative to G2 (E2) in e. In the bottom trace, the shaded area on the right illustrates the killed end due to permanent depolarization, making G1 (E1) positive relative to G2 (E2) in a′, b′, and d′. In b′, there is no potential difference between G1 (E1) and G2 (E2), causing an upward deflection from the positive baseline to zero potential (modified from Kimura, 2001).

of the waveform from triphasic to biphasic (an initial negative followed by a positive deflection; Kimura, 2001; Dumitru et al., 2002; Fig. 5.4). 5.12. Field theory: “near-field” and “far-field” potentials The term “far-field potential” was taken from antenna theory and incorporated into clinical neurophysiology for use as a theoretical means of explaining brainstem auditory evoked potentials, where apparently potentials far from the recording electrodes are recorded (Stegeman et al., 1997). The terms “near-field” and “far-field” potentials are frequently used, but this is not technically correct, since all potentials are recorded at some distance from the potential generator and there is no consistent distinction between the two terms (AAEE, 1987). Still, with this caveat in mind,

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the concept of near-field and far-field potentials helps in the understanding of the different mechanisms of potential generation. Since the introduction of the concept into clinical neurophysiology, far-field potentials have been actively investigated and have been detected using other techniques (e.g., using somatosensory evoked potentials (SSEPs) and in peripheral nerve conduction studies). To understand far-field potentials, the opposite concept—near-field potentials—should first be understood. A near-field potential is defined as a waveform that clearly changes in amplitude, polarity, morphology, and usually latency when the active electrode is serially repositioned over small distances (Stegeman et al., 1997; Dumitru, 2000), as the source of the electric potential is presumably generated in close proximity to the active electrode. Conversely, far-field potentials can be defined as waveforms that do not fulfill the definition of a near-field potential (i.e., it does not change with repositioning the active electrode over small distances (i.e., a potential that is fairly stable in amplitude, polarity, and morphology, and usually latency). As discussed earlier, an action potential is recorded by the volume conduction of dipoles, with the assumption that the nerve has constant characteristics longitudinally (e.g., identical diameter, conduction velocity, and no curvature). Imbalance between the positive and negative poles in a dipole can generate a potential that can be detected not only by an active electrode in close proximity, but also by an electrode that is some distance from the site of action potential generation. This is considered to be the source of the far-field potentials observed in peripheral NCSs (Kimura et al., 1983; Machida et al., 1983; Kimura et al., 1984; Yamada et al., 1985; Kimura et al., 1986). Clinically, in motor unit action potentials and compound action potentials, a far-field potential can be recorded at the terminal phase of repolarization, and is observed as a long-lasting downward deflection. Examples of generators of far-field potentials include the following: (1) Fixed neural generators (e.g., the cardiac pacemaker). (2) “Boundary” or “junctional” potentials, that occur when leading/trailing dipoles propagate along a nerve with a varying diameter (e.g., from small to large cylinder) or different tissue resistances. As shown in Fig. 5.5 for an experimental antidromic sensory conduction study, along with the apparent sensory action potential (the latency

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of which increases as the nerve is stimulated more proximally), there are two potentials with consistent latencies irrespective of the stimulation site. These are considered to be far-field potentials generated at the wrist and the base of the digit. As to the reason why a potential generated at the junction has a constant latency irrespective of the stimulation site may be best understood by using the following analogy. An oncoming train (the axonal volley) becomes simultaneously visible (recorded as a far-field potential) to all bystanders at a distance (a series of recording electrodes) as it emerges from a tunnel (partition of the volume conductor), whereas the same bystanders see the train pass by at different times (recorded as a near-field potential)

Fig. 5.5 Stimulation of the left radial nerve 10 cm proximal to the styloid process of the radius, and serial recording of antidromic sensory potentials along the course of the radial nerve (A). There was an abrupt change of the volume conduction at the “0” level at the base of the second digit.

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Fig. 5.5, Cont’d (B). In the reference recording, the ring electrode was placed around the fifth digit, whereas the ring electrode was placed around the second digit distally in the bipolar recording. Note that in the reference recording, there were biphasic peaks (far-field potentials) with a stationary latency irrespective of the recording sites along the digits, first appearing near the wrist and at the base of the digit, respectively. This observation supports the theory that the far-field potential is produced at the boundary between two surrounding media with different conduction characteristics along the nerve.

depending on their position along the railroad (Kimura et al., 1986). (3) A change in the direction of neural propagation (e.g., bending of a joint, anatomical curvature). (4) The termination of excitable tissue, when sudden termination of propagation occurs resulting in the disappearance of the positive pole, then a surviving negative pole is no longer counterbalanced and a potential is generated (Stegeman et al., 1997). It is commonly believed that far-field potentials are generated at synapses, reflecting potentials generated at the cell bodies of second-order neurons. However, the SSEP studies have revealed that, on the contrary, the far-field potentials reflect primarily the physical

relationship between the nerve and the surrounding conducting medium, for example, at the shoulder and pelvic girdles where simple bending the shoulder joint alters the latency and morphology of the waveforms slightly, but significantly (Kimura et al., 1983, 1984). References Arunodaya, GR and Taly, AB (1995) Sympathetic skin response: a decade later. J. Neurol. Sci., 129: 81–89. Barkhaus, PE and Nandedkar, SD (1994) Recording characteristics of the surface EMG electrodes. Muscle Nerve, 17: 1317–1323. Bostock, H, Cikurel, K and Burke, D (1998) Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve, 21: 137–158.

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Bromberg, MB and Spiegelberg, T (1997) The influence of active electrode placement on CMAP amplitude. Electroencephalogr. Clin. Neurophysiol., 105: 385–389. Buchthal, F (1980) Action potentials in the sural nerve evoked by tactile stimuli. Mayo. Clin. Proc., 55: 223–230. Burke, D, Kiernan, MC and Bostock, H (2001) Excitability of human axons. Clin. Neurophysiol., 112: 1575–1585. Cappelen-Smith, C, Kuwabara, S, Lin, CS, Mogyoros, I and Burke, D (2001) Membrane properties in chronic inflammatory demyelinating polyneuropathy. Brain, 124: 2439–2447. Chu, J, Chan, RC and Bruyninckx, F (1987) Progressive teflon denudation of the monopolar needle: effects on motor unit potential parameters. Arch. Phys. Med. Rehabil., 68: 36–40. Conforto, S, D’Alessio, T and Pignatelli, S (1999) Optimal rejection of movement artefacts from myoelectric signals by means of a wavelength filtering procedure. J. Electromyogr. Kinesiol., 9: 47–57. Dreyer, SJ, Dumitru, D and King, JC (1993) Anodal block V anodal stimulation. Fact or fiction. Am. J. Phys. Med. Rehabil., 72: 10–18. Dumitru, D (2000) Physiologic basis of potentials recorded in electromyography. Muscle Nerve, 23: 1667–1685. Dumitru, D, Amato, A and Zwarts, M (2002) Electrodiagnostic Medicine. Hanley & Belfus, Philadelphia. Dumitru, D, King, JC and Nandedkar, SD (1997) Motor unit action potentials recorded with concentric electrodes: physiologic implications. Electroencephalogr. Clin. Neurophysiol., 105: 333–339. Ferdjallah, M, Wertsch, JJ and Harris, GF (1999) Effects of surface electrode size on computer-simulated surface motor unit potentials. Electromyogr. Clin. Neurophysiol., 39: 259–265. Finsterer, J, Mittendorfer, B, Neuhuber, W and Loscher, WN (2002) Influence of disposable, concentric needle electrodes on muscle enzyme and lactate serum levels. J. Electromyogr. Kinesiol., 1: 329–337. Gitter, AJ and Stolov, WC (1995) AAEM minimonograph #16: instrumentation and measurement in electrodiagnostic medicine—Part II. Muscle Nerve, 18: 812–824. Gutrecht, JA (1994) Sympathetic skin response. J. Clin. Neurophysiol., 11: 519–524. Hahn, AF, Bolton, CF, Pillay, N, Chalk, C, Benstead, T, Bril, V, Shumak, K, Vandervoort, MK and Feasby, TE (1996) Plasma-exchange therapy in chronic

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inflammatory demyelinating polyneuropathy. A double-blind, sham-controlled, cross-over study. Brain, 119 (Pt 4): 1055–1066. Hahn, AF, Bolton, CF, Zochodne, D and Feasby, TE (1996) Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study. Brain, 119 (Pt 4): 1067–1077. Hallin, RG and Torebjork, HE (1970) Microneurographic analysis of the fibre spectrum of human sensory nerve fascicles. Acta Physiol. Scand., 80: 24A–25A. Hallin, RG and Torebjork, HE (1973) Electrically induced A and C fiber responses in intact human skin nerves. Exp. Brain Res., 16: 309–320. Handwerker, HO, Forster, C and Kirchhoff, C (1991) Discharge patterns of human C-fibers induced by itching and burning stimuli. J. Neurophysiol., 66: 307–315. Hashimoto, I, Yoshikawa, K, Sasaki, M, Gatayama, T and Nomura, M (1991) Conduction velocity and temporal dispersion of the nerve volleys evoked by air-puff stimulation of the index finger and palm. Electroencephalogr. Clin. Neurophysiol., 81: 102–107. Howard, JE, McGill, KC and Dorfman, LJ (1988) Properties of motor unit action potentials recorded with concentric and monopolar needle electrodes: ADEMG analysis. Muscle Nerve, 11: 1051–1055. Huigen, E, Peper, A and Grimbergen, CA (2002) Investigation into the origin of the noise of surface electrodes. Med. Biol. Eng. Comput., 40: 332–338. Inui, K, Tran, TD, Hoshiyama, M and Kakigi, R (2002) Preferential stimulation of Adelta fibers by intra-epidermal needle electrode in humans. Pain, 96: 247–252. Joynt, RL (1998) The concentric versus the monopolar needle electrode. The case for monopolar needles. Muscle Nerve, 21: 1804–1806; discussion 1809. Kaji, R (2003) Physiology of conduction block in multifocal motor neuropathy and other demyelinating neuropathies. Muscle Nerve, 27: 285–296. Kaji, R, Kodama, M, Imamura, A, Hashida, T, Kohara, N, Ishizu, M, Inui, K and Kimura, J (1998) Effect of ultrahigh-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study. Muscle Nerve, 21: 1775–1778. Kimura, J (2001) Electrodiagnosis in diseases of nerve and muscle: principles and practice. Oxford University Press, New York.

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Kimura, J, Kimura, A, Ishida, T, Kudo, Y, Suzuki, S, Machida, M, Matsuoka, H and Yamada, T (1986) What determines the latency and amplitude of stationary peaks in far-field recordings? Ann. Neurol., 19: 479–486. Kimura, J, Mitsudome, A, Beck, DO, Yamada, T and Dickins, QS (1983) Field distribution of antidromically activated digital nerve potentials: model for far-field recording. Neurology, 33: 1164–1169. Kimura, J, Mitsudome, A, Yamada, T and Dickins, QS (1984) Stationary peaks from a moving source in far-field recording. Electroencephalogr. Clin. Neurophysiol., 58: 351–361. Kincaid, JC (1999) The compound muscle action potential and its shape. Muscle Nerve, 22: 4–5. Kincaid, JC, Brashear, A and Markand, ON (1993) The influence of the reference electrode on CMAP configuration. Muscle Nerve, 16: 392–396. Kirshblum, S, Cai, P, Johnston, MV, Shah, V and O’Connor, K (1998) Anodal block in F-wave studies. Arch. Phys. Med. Rehabil., 79: 1059–1061. Kohara, N, Kaji, R and Kimura, J (1993) Comparison of recording characteristics of monopolar and concentric needle electrodes. Electroencephalogr. Clin. Neurophysiol., 89: 242–246. Kuwabara, S, Mizobuchi, K, Toma, S, Nakajima, Y, Ogawara, K and Hattori, T (2000) “Tactile” sensory nerve potentials elicited by air-puff stimulation: a microneurographic study. Neurology, 54: 762–765. Maccabee, PJ and Hassan, NF (1992) AAEM minimonograph #39: digital filtering: basic concepts and application to evoked potentials. Muscle Nerve, 15: 865–875. Machida, M, Yamada, T and Kimura, J (1983) [“Far field potentials” after stimulation of the median and tibial nerve in man]. Nippon Seikeigeka Gakkai Zasshi, 57: 271–284. Marchello, L, Donadio, V and Montagna, P (1996) The sympathetic skin response: a neurological perspective. Funct. Neurol., 11: 283–299. McGill, KC and Lateva, ZC (1999) The contribution of the interosseous muscles to the hypothenar compound muscle action potential. Muscle Nerve, 22: 6–15. Misulis, KE (1989) Basic electronics for clinical neurophysiology. J. Clin. Neurophysiol., 6: 41–74. Mizobuchi, K, Kuwabara, S, Toma, S, Nakajima, Y, Ogawara, K and Hattori, T (2000) Single-unit responses of human cutaneous mechanoreceptors to air-puff stimulation. Clin. Neurophysiol., 111: 1577–1581.

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Nandedkar, SD and Sanders, DB (1991) Recording characteristics of monopolar EMG electrodes. Muscle Nerve, 14: 108–112. Nandedkar, SD, Tedman, B and Sanders, DB (1990) Recording and physical characteristics of disposable concentric needle EMG electrodes. Muscle Nerve, 13: 909–914. Nelson, HE, Jr., Smith, MB, Bowman, BR and Waters, RL (1980) Electrode effectiveness during transcutaneous motor stimulation. Arch. Phys. Med. Rehabil., 61: 73–77. Oh, SJ, Kim, HS and Ahmad, BK (1984) Electrophysiological diagnosis of interdigital neuropathy of the foot. Muscle Nerve, 7: 218–225. Okajima, Y, Tomita, Y, Ushijima, R and Chino, N (2000) Motor unit sound in needle electromyography: assessing normal and neuropathic units. Muscle Nerve, 23: 1076–1083. Paintal, AS (1966) The influence of diameter of medullated nerve fibers of cats on the rising and falling phases of the spike and its recovery. J. Physiol., 184: 791–811. Panescu, D, Cohen, KP, Webster, JG and Stratbucker, RA (1993) The mosaic electrical characteristics of the skin. IEEE Trans. Biomed. Eng., 40: 434–439. Pease, WS and Bowyer, BL (1988) Motor unit analysis. Comparison between concentric and monopolar electrodes. Am. J. Phys. Med. Rehabil., 67: 2–6. Pease, WS, Fatehi, MT and Johnson, EW (1989) Monopolar needle stimulation: safety considerations. Arch. Phys. Med. Rehabil., 70: 412–414. Pease, WS and Pitzer, NL (1990) Electronic filter effects on normal motor and sensory nerve conduction tests. Am. J. Phys. Med. Rehabil., 69: 28–31. Perreault, EJ, Hunter, IW and Kearney, RE (1993) Quantitative analysis of four EMG amplifiers. J. Biomed. Eng., 15: 413–419. Rosenfalck, A (1978) Early recognition of nerve disorders by near-nerve recording of sensory action potentials. Muscle Nerve, 1: 360–367. Russell, JW, Karnes, JL and Dyck, PJ (1996) Sural nerve-myelinated fiber density differences associated with meaningful changes in clinical and electrophysiologic measurements. J. Neurol. Sci., 135: 114–117. Schmelz, M, Schmidt, R, Bickel, A, Handwerker, HO and Torebjork, HE (1997) Specific C-receptors for itch in human skin. J. Neurosci., 17: 8003–8008. Schmelz, M, Schmidt, R, Weidner, C, Hilliges, M, Torebjork, HE and Handwerker, HO (2003)

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Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J. Neurophysiol., 89: 2441–2448. Schoonhoven, R and De Weerd, JP (1984) On the optimal choice of a recording electrode in electroneurography. Electroencephalogr. Clin. Neurophysiol., 58: 308–316. Seo, JH and Oh, SJ (2002) Near-nerve needle sensory conduction study of the medial calcaneal nerve: New method and report of four cases of medial calcaneal neuropathy. Muscle Nerve, 26: 654–658. Smith, T (1998) Near-nerve versus surface electrode recordings of sensory nerve conduction in patients with carpal tunnel syndrome. Acta Neurol. Scand., 98: 280–282. Stegeman, DF, Dumitru, D, King, JC and Roeleveld, K (1997) Near- and far-fields: source characteristics and the conducting medium in neurophysiology. J. Clin. Neurophysiol., 14: 429–442. Swain, ID, Wilson, GR and Crook, SC (1985) A simple method of measuring the electrical resistance of the skin. J. Hand Surg. [Br], 10: 319–323. Tjon, ATAM, Lemkes, HH, van der Kamp-Huyts, AJ and van Dijk, JG (1996) Large electrodes improve nerve conduction repeatability in controls as well as in patients with diabetic neuropathy. Muscle Nerve, 19: 689–695. Torebjork, HE and Hallin, RG (1974) Responses in human A and C fibers to repeated electrical intradermal stimulation. J. Neurol. Neurosurg. Psychiatry, 37: 653–664.

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Trojaborg, W (1998) The concentric versus the monopolar needle electrode. The case for concentric needles. Muscle Nerve, 21: 1806–1808. Uludag, B, Koklu, F and On, A (1997) A new source of electromyographic artifact: mobile phones. Muscle Nerve, 20: 121–122. van Dijk, JG, Tjon-a-Tsien, A and van der Kamp, W (1995) CMAP variability as a function of electrode site and size. Muscle Nerve, 18: 68–73. Wee, AS and Ashley, RA (1990) Relationship between the size of the recording electrodes and morphology of the compound muscle action potentials. Electromyogr. Clin. Neurophysiol., 30: 165–168. Wee, AS, Leis, AA, Kuhn, AR and Gilbert, RW (2000) Anodal block: can this occur during routine nerve conduction studies? Electromyogr. Clin. Neurophysiol., 40: 387–391. Weidner, C, Schmelz, M, Schmidt, R, Hammarberg, B, Orstavik, K, Hilliges, M, Torebjork, HE and Handwerker, HO (2002) Neural signal processing: the underestimated contribution of peripheral human C-fibers. J. Neurosci., 22: 6704–6712. Wexler, I, Paley, D, Herzenberg, JE and Herbert, A (1998) Detection of nerve entrapment during limb lengthening by means of near-nerve recording. Electromyogr. Clin. Neurophysiol., 38: 161–167. Yamada, T, Machida, M, Oishi, M, Kimura, A, Kimura, J and Rodnitzky, RL (1985) Stationary negative potentials near the source vs. positive farfield potentials at a distance. Electroencephalogr. Clin. Neurophysiol., 60: 509–524.

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CHAPTER 6

Motor nerve conduction studies Kerry H. Levin* Cleveland Clinic Foundation, OH, USA

6.1. Introduction Motor nerve conduction studies constitute a major element of the electrodiagnostic examination. They can identify features of demyelination and axon loss, they can define defects of neuromuscular junction transmission, and they can reflect severe muscle fiber loss. Stimulation is applied at distal and proximal sites along a nerve trunk. Recording of the resulting action potential occurs with surface electrodes overlying a muscle belly innervated by the stimulated nerve (Fig. 6.1). Features of a motor conduction study that can be analyzed include the amplitude, area, and configuration of the response waveform, as well as its latency and conduction velocity. 6.2. The compound muscle action potential Since the active recording electrode overlies a muscle belly, the recorded response is a compound muscle action potential (CMAP). In comparison, the sensory nerve action potential (SNAP) is recorded directly from a nerve trunk. The CMAP represents a summation in the volume conductor of all the individual muscle fiber action potentials activated by the stimulus and within the pick up territory of the active recording electrode. Normally, the CMAP is a biphasic waveform with an initial negative deflection. This configuration results from placement of the active recording electrode at the motor point of the muscle belly, where the muscle fibers are initially depolarized and their action potentials generated. In comparison, the sensory nerve action potential is normally a triphasic waveform with initial positive deflection, because the propagated

* Correspondence to: Kerry H. Levin MD, Department of Neurology, Desk S-90, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland OH 44195, USA. E-mail address: [email protected]. Tel.: +1-216-444-8370; fax: +1-216-445-4653.

depolarization along the nerve trunk approaches the recording electrode from the stimulation site. The CMAP is measured in millivolts, compared to microvolts for a sensory action potential, because the size of an action potential is proportional to the diameter of the excitable tissue from which it is derived. A number of factors contribute to the size and shape of a normal CMAP, including the geographical relationship between the active and reference recording electrodes, active recording electrode size, the effect of recording distance on CMAP size, the effect of filtering, and the effect of temperature. 6.2.1. Relationship between recording electrodes and CMAP shape Manipulating the electrode placement in a differential amplifier recording system can affect the amplitude of the recorded potential. This is especially necessary when recording sensory nerve action potentials in the microvolt range. Because the CMAP size is measured in millivolts, it is not necessary to space the active and reference recording electrodes so that the potential at the reference electrode site adds amplitude to the waveform. Rather, by minimizing the reference electrode’s contribution to the CMAP response, variability in response size due to imprecise electrode placement can be theoretically minimized, and standardization of the technique improved. This has traditionally been accomplished by applying the reference electrode over the tendon distal to the muscle belly on which the active electrode is applied. Recent work has confirmed that the reference electrode may not be electrically silent in relation to the active electrode. This is especially true for the ulnar and tibial motor nerve conduction studies, where the traditional reference electrode position can contribute a greater amount toward the main negative peak of the CMAP than does the active electrode (Kincaid et al., 1993; Brashear and Kincaid, 1996). This effect correlates with the double-peak appearance of the ulnar and

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Distance = 270 mm

7 mv

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Fig. 6.1 Median motor nerve conduction study, after stimulation at the elbow (A), and wrist (B). The measured distance between the two stimulation sites is 270 mm. (From Levin, 1993. Common focal mononeuropathies and their electrodiagnosis. J. Clin. Neurophysiol. 10: 181–189, reproduced with permission)

6.5 mV

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tibial CMAP. In comparison, the reference electrodes do not significantly contribute to the main negative component of the median and peroneal CMAPs. The large reference electrode contribution to the tibial response may result from the large amount of tibial muscle mass in the foot and its wider geographical distribution in the foot, compared to peroneal musculature. Far-field muscle potentials may also be contributing to this effect (Dumitru and King, 1991). An attempt to neutralize the effect of the reference electrode by placing it on the contralateral limb leads to further complications. With that montage, short latency components are recorded at the onset of the tibial CMAP when proximal stimulation studies are performed. These extra potentials are thought to be farfield components generated from muscle action potentials in the distal leg. They do not appear when the active and reference electrodes are ipsilateral, due to common mode rejection (Brashear and Kincaid, 1996). The size and shape of the ulnar CMAP obtained with the active electrode overlying the hypothenar region depend on the action potentials from all ulnar innervated hand muscles. Stimulating individual muscles, McGill and Lateva showed that the first peak of the negative phase of the CMAP is derived from hypothenar muscles, while the second peak is due to a volume conducted potential from interosseus muscles (McGill and Lateva, 1999). This contribution was altered by changing the relative positioning of the fingers, and could be affected by the presence of a temperature gradient in the hand. A reduction in the

interosseus contribution was obtained with the use of a combined reference from two electrodes, one on each tendon of the hypothenar muscle group. (Fig. 6.2) Muscle fiber length and muscle position have an effect on the shape of the CMAP. Examining the thenar CMAP, Lateva and colleagues showed that changes in CMAP shape and amplitude with thumb abduction are due to changes in termination time (point at which the muscle fiber action potential reaches the muscle-tendon junction) resulting from changes in muscle fiber lengths (Lateva et al., 1996). (Fig. 6.3) 6.2.2. Relationship between electrode size and CMAP There is a complicated relationship between the recording electrode size CMAP characteristics. This topic is treated in detail in Chapter 5. One study showed an advantage to the use of a larger electrode size (comparing a standard 10 mm diameter tin disc electrode with a disposable adhesive ground electrode measuring 2.9 × 2.65 cm) in regard to inter-operator and inter-study reproducibility of results (Tjon-ATsien et al., 1996). Their study did not show a significant change in CMAP amplitude, but larger electrodes tended to produce slightly longer distal latencies and slower mean conduction velocities. However, other authors identified the opposite; over the range of round disc electrode diameter from 4 to 14 mm, there was a 10% decrease in amplitude but no change in latency,

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Fig. 6.2 Cancellation of the interosseus contribution using a balanced reference. (A, C) Sums of the directly stimulated interosseus signals recorded by the b/dt and b/pt electrode configurations, and the “balanced reference” signal (b/br) formed by adding 1/3 times the signal to 2/3 times the b/pt signal, for two subjects. The interosseus contributions are almost completely canceled in the b/br signals. (B, D) The effects of length manipulation (solid line = neutral, dashed line = flexion of digits 2–4) are reduced in the b/br CMAP compared to the b/dt and b/pt CMAPs. (E) Electrode configuration for recording the balanced-reference signal. Reference electrodes are placed over both the distal and proximal tendons and are connected in parallel. The distal electrode has been cut in half to give an approximate 1 to 2 ratio between the dt and pt contributions (From McGill and Lateva, 1999, reproduced with permission from John Wiley and Sons, Inc.).

simultaneously electrically evoked components of the CMAP, due to different rates of conduction along motor nerve fibers (Schulte-Mattler et al., 2001). The lesser degree of temporal dispersion seen in CMAPs compared to SNAPs is attributed to the narrower range of conduction velocities along motor nerve fibers in a nerve trunk, and the broader duration of CMAPs (Fig. 6.5). Based on a mathematical model of the CMAP as a sum of asynchronous single nerve fiber action potentials, it has been estimated that there may be a 25-m/s difference between fastest and slowest fibers in a sensory nerve trunk, versus 11 m/s for motor fibers (Dorfman, 1984). For a SNAP, the lower

when recording over the abductor digiti minimi (Wee and Ashley, 1990). 6.2.3. Effects of distance from point of stimulation to recording site The CMAP generated at a proximal site of stimulation differs modestly from the CMAP obtained with distal simulation. (Fig. 6.4) The measurable differences include reduced amplitude and area, increased duration, and shallower initial negative slope of the proximally generated CMAP. These changes result from temporal dispersion, or desynchronization, of the

Abducted 90⬚ Abducted 45⬚ Relaxed Extended

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Fig. 6.3 CMAPs recorded at different thumb positions (extended, relaxed, abducted by 45˚, and abducted by 90˚) for 2 subjects (From Lateva and McGill, 1996, reproduced with permission from John Wiley and Sons, Inc.).

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Fig. 6.4 Ulnar CMAPs recording from the hypothenar eminence, resulting from stimulation at the wrist (1), below the elbow (2), above the elbow (3), at the axilla (4), and at the supraclavicular site (5). Vertical division = 5 mV; horizontal division = 5 ms.

amplitude obtained after proximal stimulation is likely related to physiological phase cancellation due to the velocity-related temporal dispersion of sensory action potentials over a nerve segment and the short duration

of sensory action potentials (Kimura et al., 1986). (Figs. 6.6 and 6.7) For motor NCS in normal subjects, most laboratories expect less than 20% decrease in the amplitude between the distal stimulation site and

Fig. 6.5 Median sensory nerve action potentials recording from digit 2, resulting from stimulation at the wrist (1), above the elbow (2), at the axilla (3), and at the supraclavicular site (4). Vertical division = 20 μV; horizontal division = 2 ms.

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Individual responses

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F

S

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S

Fig. 6.6 A model for phase cancellation between fast (F) and slow (S) conducting sensory fibers. With distal stimulation, two unit discharges summate in phase to produce a sensory action potential twice as large. With proximal stimulation, a delay of the fiber causes phase cancellation between the negative peak of the fast fiber and positive peak of the slow fiber, resulting in a 50% reduction in size of the summated response (From Kimura et al., 1986, with permission.).

elbow or knee, with the exception of the tibial study, where there can be up to 50% decrease in amplitude with proximal stimulation. The degree of temporal dispersion in a CMAP is related to the length of the conducted segment and the range of conduction velocities in the nerve trunk. Therefore, the impact will be greater along nerves in the leg, especially the tibial nerve. Using clinical measurements and Fourier analysis from 86 subjects, Schulte-Mattler et al., found that amplitude loss was most marked for the tibial (36%) and ulnar (21%) nerves, area loss for the median (12%) and ulnar (18%) nerves, and duration prolongation for the tibial (32%) and ulnar (17%) nerves (Schulte-Mattler et al., 2001). None of these findings was age dependent. Their data showed that the dependence of these variables on length was approximately linear. In a disease

state, the range between fastest and slowest motor fibers increases, and phase cancellation becomes more prominent along motor nerves (Lee et al., 1975). 6.2.4. Effects of filtering on the compound muscle action potential Electrophysiological recordings obtained from a differential amplifier can be altered by manipulating the bandwidth of frequencies allowed to contribute to the recording. Filter settings are chosen to maximize the contribution of frequencies close to the recording electrodes and minimize contamination of the recording by remote generators. Because amplitude, latency, and waveform configuration change as filter settings are altered, standard settings are required.

144

KERRY H. LEVIN Individual responses

Summated response

F

S

F S

Fig. 6.7 Same arrangement as in Fig. 6.6 to show the relationship between fast (F) and slow (S) conduction motor fibers. With distal stimulation, two unit discharges representing motor unit potentials summate to produce a muscle action potential twice as large. With proximal stimulation, long-duration motor unit potentials still superimpose nearly in phase despite the same latency shift of the slow motor fiber as the sensory fiber shown in Fig. 6.6. Thus, a physiological temporal dispersion alters the size of the muscle action potential only minimally, if at all (From Kimura et al., 1986, with permission.)

Increasing the low frequency filter setting tends to reduce CMAP amplitude, peak latency, and total waveform duration (Fig. 6.8). These effects are related to the filtering out of important low frequency components contributing to the overall size of the CMAP waveform. There is no effect on the onset latency of the CMAP (Dumitru and Walsh, 1988). Decreasing the high frequency filter tends to increase peak and onset latencies, and increase the negative spike component of the CMAP (Fig. 6.9). Onset latency becomes delayed because highfrequency components over a short duration at the onset of the waveform are filtered out, causing a “drop out” of the first part of the potential. There is little effect on the amplitude down to a frequency of 500 Hz. 6.2.5. Effects of temperature on the compound muscle action potential A decrease in muscle temperature corresponds with increased CMAP amplitude, duration, rise time, and area. Local cooling leads to increased voltage of muscle fiber action potentials (Ricker et al., 1977). This is the result of delayed voltage-gated sodium channel inactivation, leading to excess depolarization of the muscle fiber membrane and, subsequently, increased propagated action potential duration, spike height, and area (Scheopfle and Erlanger, 1941).

6.2.6. Sources of error in compound muscle action potential recordings Of all the motor NCS parameters, CMAP amplitude appears to have the least reproducibility (Bleasel and Tuck, 1991; Claus et al., 1993; van Dijk et al., 1994, Kohara et al., 2000). While mean motor nerve conduction velocities are highly reproducible, the coefficient of variation for CMAP amplitude and latency has ranged from 8.5–46% (Tjon-A-Tsien et al., 1996). Inability to reproducibly localize the optimum recording site appears to be the main cause of variability. Van Dijk et al. showed that a variability of 5–10 mm in the recording site could have a profound effect on CMAP amplitude (van Dijk et al., 1994). Variability in CMAP amplitude and latency recordings is even higher in patients with diabetic neuropathy (Tjon-A-Tsien et al., 1996). Other sources of error can be identified in the routine laboratory on a daily basis, although their contributions have not been studied scientifically. Submaximal stimulus intensity, imprecise stimulator placement, stimulus spread to adjoining nerve trunks, and temperature fluctuations all contribute to CMAP recording variability and error. The normal CMAP amplitude, configuration, or both may be altered in the presence of anomalous innervation. In the case of the median-to-ulnar

MOTOR NERVE CONDUCTION STUDIES

145 Fig. 6.8 Ulnar CMAPs recording from the hypothenar eminence, after stimulation at the wrist. Low filter setting is 2 Hz (1), 10 Hz (2), 20 Hz (3), 50 Hz (4), and 500 Hz (5). The high filter setting remains constant at 10 KHz. Vertical division = 10 mV; horizontal division = 5 ms.

crossover in the forearm (estimated to occur in 5–30% of arms), ulnar motor nerve fibers reside in the median nerve at the elbow, but switch back into the ulnar nerve trunk somewhere in the forearm. This leads to co-stimulation of median and ulnar motor fibers at the elbow but not at the wrist, giving rise to disparity between the CMAP waveforms at the two sites of stimulation (Chapter 14). 6.3. Motor conduction latency and velocity The speed with which an electrical impulse passes along a motor nerve trunk is a composite of the speeds of individual motor nerve fiber action potential propagations to the recorded muscle motor point. These are, in turn, related to the diameter of nerve fibers, temperature, stimulation intensity, and age.

6.3.1. Effects of temperature on motor conduction velocity Temperature has a marked effect on nerve conduction (see above). Nerve conduction velocity decreases in proportion to the decrease in temperature, without a significant influence from nerve fiber size. Conduction velocity can be measured to decline to as low as 1–2% of normal velocity, before conduction fails entirely at 7–8˚C (Paintal, 1965). The degree of change in conduction velocity with progressive change in temperature for upper extremity nerve trunks has been defined (Halar et al., 1980, 1983). For the median motor conduction velocity, there is a 1.5 m/s decline for every 1˚ C temperature decrease. The median motor distal latency increases by 0.2 m/s for each 1˚ C decrease in temperature. The

146

KERRY H. LEVIN

Fig. 6.9 Ulnar CMAPs recording from the hypothenar eminence, after stimulation at the wrist. The response with a latency of 2.8 ms corresponds to a high filter setting of 10 KHz, 2.9 ms corresponds to 2 KHz, 3.0 ms corresponds to 1 KHz, and 3.2 ms corresponds to 500 Hz. The low filter setting remains constant at 2 Hz. Vertical division = 5 mV; horizontal division = 2 ms.

ulnar motor conduction velocity decreases by 2.1 m/s for every 1˚ C temperature decrease, and the ulnar motor distal latency increases by 0.2 m/s for each 1˚C decrease in temperature. 6.3.2. Effects of age on motor conduction velocity Peripheral nerves at birth are not fully myelinated. Motor nerve conduction velocities in the neonate are about one half the adult values. The developmental process of myelination continues until the age of 3 to 5 years, when conduction velocities approach adult values (Wagner and Buchthal, 1972). Over the age of 50 years, conduction velocity declines by 1–2 m/s per decade. There is an associated progressive increase in distal latency. 6.3.3. Sources of error in obtaining motor conduction velocity A number of sources of error exist in the performance of NCS that can lead to spurious conduction velocities. Foremost among these is measurement of the dis-

tance over which the conduction is occurring. Landmarks easily shift on extremities, giving rise to significant variation in the same patient and among patients. These errors tend to be amplified over shortconduction distances (since the error is a larger proportion of the whole distance), and when conduction velocities are higher (Maynard and Stolov, 1972). Anatomy and nerve trunk position issues also predispose to a lack of reliability. When analyzing nerve conduction around a joint (classically the ulnar nerve as it courses around the elbow), the conduction distance varies according to whether the joint is flexed (the nerve is stretched to its fullest extent and lengthened) or extended (the nerve is kinked on itself and shortened). However, the latency of conduction remains the same, so that in the flexed elbow position, the calculated conduction velocity will be slower than in the extended elbow position. Stimulus spread can introduce error in the conduction velocity measurement. When the stimulus intensity is increased beyond the ideal supramaximal level, a shift in the location of nerve trunk depolarization can

MOTOR NERVE CONDUCTION STUDIES

change by 3–5 millimeters (Buchthal and Rosenfalck, 1966). If the stimulus spread occurs in the direction of the recording electrode, the true conduction distance is shorter than the measured distance, leading to a falsely increased conduction velocity. A theoretical consideration is the effect of passive lengthening or shortening of muscle fibers on latency and velocity of conduction. Measuring over a segment of a muscle fiber, Trontelj used single fiber recordings to show that stretching a muscle fiber could reduce its conduction velocity by 22%, while shortening the muscle fiber could increase the velocity by up to 33% (Trontelj, 1993). In another study, intramuscular stimulation of nerve fibers in the biceps brachii showed no significant change in impulse conduction velocity with muscle fiber length change when recording over the center fiber length, but a decrease in latency by as much as 24% occurred with muscle fiber shortening (Brown et al., 1996). In shortened muscle, the plasmalemma of a muscle fiber is folded and there are inpouchings of membrane known as caveolae (Dulhunty and Franzini-Armstrong, 1975). This may explain why the time taken for impulses to travel between individual sarcomeres, and to reach the end of a muscle is least in the shortened position. 6.4. Performing routine motor nerve conduction studies 6.4.1. Overview Nerve conduction studies and the needle electrode examination constitute the major components of the electrodiagnostic examination. In most clinical laboratories, the NCS are performed first, and guide the physician in the approach to the needle electrode examination. NCS require no active participation from the patient. Although the electrical stimulations are uncomfortable, they are tolerable to all but the most sensitive patients. They are indispensable for the electrodiagnosis of focal nerve lesions in the extremities and are the only way to gain physiological confirmation of the presence of demyelination. There are a number of limitations regarding the use and interpretation of motor NCS. First, very proximal portions of nerve trunks cannot be reliably accessed for stimulation. Second, because of unavoidable technical imprecision in performing motor NCS and because of a wide range of normal for CMAP amplitudes, detection of motor axon loss by NCS is relatively insensitive, unless over 50% of

147

nerve fibers have been lost. Comparison with the contralateral limb can improve the sensitivity, if the condition is unilateral. Third, motor NCS are also relatively insensitive to the presence of muscle fiber loss in myopathy. Individual clinical EMG laboratories differ in the technical aspects of performing motor nerve conduction studies. However, the basic approaches are similar in most laboratories. The following descriptions are considered standard techniques. 6.4.2. Setting up the electrodiagnostic machine Machine settings must be adjusted for proper motor nerve conduction study results. Settings to be adjusted include the filters, sweep speed, and gain. Filter settings for motor NCS should allow a wide recording bandwidth. The low filter setting is usually set at 2 Hz, and the high filter setting is 10 KHz. Because the CMAP response is large (measured in millivolts), the effect of contamination from CMAPs of neighboring muscle bellies is less important. Thus, the objective is to include as many of muscle fiber action potentials as possible in the summated CMAP of the recorded muscle. For each nerve trunk stimulation, the sweep speed needs to be adequate in order to capture the produced CMAP. Reliable measurement of the latency depends on a precise waveform offset from baseline. The visual characteristics of that take-off point change with changes in the sweep speed. Thus, in order to optimize reproducibility of technique, the sweep speed should be fast enough to capture CMAPs at all planned points of stimulation. Normal distal motor latencies recorded after stimulation at the wrist or ankle range from 3 to 6 ms in normal adults. In the arm, latencies measured at the hand muscles after stimulation at the elbow and supraclavicular sites of stimulation range from 6 to 10 ms, and 13 to 15 ms, respectively. In the leg, latencies measured at the foot muscles after stimulation at the knee range from 8 to 10 ms in normal adults. These values correlate directly with the length of the arm and leg. In disease states, latencies may increase by a factor of two or more. When no motor response is recorded after nerve stimulation, it is important to increase the sweep speed to identify the presence of a pathologically slowed response. The gain setting should also be chosen to maximize CMAP visibility and accuracy of measurement of amplitude and latency. Like the sweep speed, the gain

148

KERRY H. LEVIN

setting should be the same for all stimulation points of a given nerve trunk. This will avoid inaccuracies in the measurement of latency. Increasing the gain tends to increase onset latency (Dumitru and Walsh, 1988) (Table 6.1). 6.4.3. Stimulus guidelines and pitfalls For motor NCS, stimulus duration should be 0.2 ms initially. The stimulus voltage should be increased gradually until there is no further increase in CMAP amplitude. At that point, the stimulus voltage should be increased by another 10–20%, the so-called supramaximal stimulus intensity. If a maximum CMAP is not achieved, the duration should be increased, and the process repeated. Failure to use a supramaximal stimulus will result in the possibility of a less than maximal CMAP amplitude. On the other hand, excessive stimulation increases the possibility that nearby nerve trunks will be co-stimulated, leading to a falsely increased CMAP amplitude or a spurious waveform configuration. Co-stimulation is likely to occur between the median and ulnar nerve trunks at the wrist and above the elbow; among the median, ulnar, and radial nerve trunks at the axilla; and between the peroneal and tibial nerve trunks in the popliteal fossa. Excessive stimulation can also lead to stimulus jump beyond the region immediately under the stimulating electrodes. In general both the cathode and anode of the stimulator should be placed on the nerve trunk, with the cathode distal (and closest) to the recorded muscle. The anode may be swiveled off the nerve trunk when there is excessive shock artifact and when the usual placement causes direct muscle belly stimulation, as is the case when stimulating the facial nerve and recording over the nasalis muscle. Table 6.1 Effect of gain setting on the CMAP latency after median nerve stimulation at the wrist, recording over the abductor pollicis brevis muscle* Gain setting (mV/division)

Onset latency (m/s)

Amplitude (mV)

500 1000 5000 10 000

3.4 3.5 3.7 3.8

23 23

*The high and low frequency filters remained constant at 10 000 Hz and 10 Hz, respectively (Dumitru and Walsh, 1988).

Points of stimulation along a nerve trunk are limited to sites close to the skin surface. Routinely, these sites are at the wrist, elbow, ankle, and popliteal fossa. Nerve trunks can also be stimulated in the axilla and in the supraclavicular fossa. Specific nerve trunks are also accessible, such as the phrenic and spinal accessory nerves in the neck, and the facial and trigeminal nerves face. Needle electrodes used for stimulation may be able to reach some deep nerves, such as extra-spinal nerve roots. 6.4.4. Electrode placement and pitfalls Electrodiagnostic standard practice requires that the active recording electrode be placed over the motor point of the muscle belly innervated by the nerve trunk being stimulated. This location is identified by moving the electrode with each stimulus until a CMAP of maximal amplitude and initial negative deflection occurs. This task is relatively straightforward in the distal hand and foot muscles. The reference electrode is traditionally placed distal to the active recording electrode, on a relatively electrically silent structure such as a muscle tendon. As noted above, in actuality there is no electrically inactive site. The reference electrode is especially likely to contribute to the ulnar and tibial CMAP waveform appearance (Brashear and Kincaid, 1996). The task is more difficult when recording proximally (such as the forearm), where there are layers of overlapping muscles, either innervated by the same nerve trunk, or innervated by a nerve trunk that may be co-stimulated with the nerve trunk under investigation. In either case, there is a potential for generation of a spurious CMAP waveform that has an initial volume-conducted positive deflection, a falsely enlarged amplitude, or an altered configuration. A spurious CMAP may also be generated from hand muscles, such as the thenar group, when stimulating proximally at the axilla and supraclavicular site, where co-stimulation of the ulnar nerve is sometimes unavoidable. In this setting, volume-conducted components from closely positioned ulnar innervated muscles contaminate the thenar (median-derived) CMAP. Contamination of the thenar recording may be reduced by selectively recording from the thenar muscle group with an intramuscular needle electrode, thus decreasing the recording distance and minimizing the distant volume–conducted contributions. When stimulating the ulnar nerve proximally and recording from the hypothenar group in the hand, there is less chance of contamination from median nerve costimulation, since there are no large median innervated muscles in close proximity to the hypothenar group.

MOTOR NERVE CONDUCTION STUDIES

6.4.5. Calculating the conduction velocity Conduction velocity can be calculated easily after stimulating at two sites along a nerve trunk. The distal latency is the time elapsed from the point of distal (wrist or ankle) stimulus to the time of initial CMAP onset. This value is subtracted from the latency obtained when stimulating at the proximal site and recording from the muscle belly. After measuring the distance between the proximal and distal stimulation sites, it is simply a matter of completing the equation v = distance/time. The resulting value represents the conduction velocity in the forearm and foreleg, since the distal conduction has been subtracted out (Fig. 6.1). When a nerve trunk remains superficial over a whole segment of its length, it is possible to sequentially stimulate at short intervals. Examples include the median nerve at the wrist and palm, and the ulnar nerve across the elbow. Segmental conduction studies can be performed along short segments, as the stimulator is moved at 1 cm increments along the nerve, a technique described as inching. Inching has the potential to localize a focal nerve lesion (site of compression, entrapment, or focal demyelination) by demonstrating slowing or amplitude drop over a short nerve segment (Chapter 8). In general, a distal conduction velocity (from the distal-most site of stimulation to the muscle belly recording electrode site) is not calculated, because the latency of conduction over that segment includes conduction time along the small-diameter terminal axon branches, the neuromuscular junction transmission time, the time to depolarize the muscle membrane, and the time to generate a muscle fiber action potential. The distal latency is, therefore, longer than the latency over the same distance along a more proximal segment of the nerve. The difference between the distal latency and a more proximal latency over the same distance is described as the residual latency, and reflects the conduction time through terminal axons and the neuromuscular junction transmission time. Representative normal limits of some motor nerve conduction studies are displayed in Table 6.2. 6.4.6. Practical guidelines A number of practical guidelines will improve the reliability and sensitivity of motor NCS. At the hand the skin temperature should be maintained at 35˚C or above; at the foot the temperature should be at least 32˚C. When applying stimulation, it is critical to

149 Table 6.2 Normal limits of motor nerve conduction studies in a 40-year-old

Median Ulnar Peroneal Tibial

Amplitude Distal (mV) Latency (ms)

Conduction velocity (m/s)

>6 >7 >4 >6

>50 >50 >40 >40

160, < 180 > 180 < 160 > 160, < 180 > 180

19–79

19–49

195

50–79

< 160, > 180

0–3 m 4–6 m 7–9 m 10–12 m 13–18 m 19–24 m 25–36 m 37–48 m 49–60 m 61–72 m 30

8 10 8 10 10 10 7 6 7 10 31

Height cm

24–72 h 0–3 m 4–6 m 7–12 m 1–3 4–6 7–14 18–30 0–72 m

6–12 1–2 2–4 4–6 6–14 24 h–30

25 24 22 20 21 168

mean SD

25 20 20 20 20 21 22 19 86

range

n

Age yrs*

23.5 26.2 29.2 25 28.1 30.4

26.8

19.56 17.62 17.54 16.86 16.41 17.62 20.18 26.14

mean

limit

1.3 2 1.8 1.9 1.4 1.7

26.3 31.1 32.9 28.4 30.8 32.4

2.4 32.9

2.4 1.4 2 1.5 1.1 1.6 1.6 3

SD

Min Latency ms

0.2

1.03

mean

1.2

0.73

SD

2.6

2.5

limit

Side diff-Min Lat ms

24.3 27.2 30.3 25.6 28.8 31.3

27.7

mean

0.6 2 1.9 1.9 1.6 1.9

2.5

SD

limit

Mean Lat ms

26.15 33.32 36.75 41.69 51.86 55.72 59.68 63.83

17.31 17.44 17.91 19.44 23.23

mean

5 3.9 4.2 4.1 6.5 3.8 4.5 4.2

1.8 1.3 1.1 1.5 2.6

SD

limit

Max Velocity m/s

>50 in 97%**

87.5 60 63 60 30 30 85.7 66.7 100 80 90

66

mean

30

limit

Persistence % mean SD

limit

Amplitude μV

4.48

mean SD

8.92

Limit

Chronodispersion ms

12 11 12 14 14 17 152 51 101

80

n

168 25 20 20 20 20 21 22 19

35

22–58

35

24 h–30 24–72 h 0–3 m 4–6 m 7–12 m 1–3 4–6 7–14 18–30

20–64

22–58

18.26

mean SD

10)

Puksa 03 (20) 5 Males Females ELBOW Kimura 74 (10) 33 Kimura 83 (16) 65 Russo 85 (10) 30

Garcia et al., 00 (10)

Stimuli (number)

Continued

Table 9.1

0.73

0.92

0.76

0.25

mean

0.54

0.7

0.56

0.79

SD

2.1

2.3

1.9

limit

Side diff-Min Lat ms

23.9

mean

limit

1.7 30.2

SD

Mean Lat ms

64.3

27.37 34.8 37.9 44.7 52.91 56.47 51.5 64.58

62.2 67.8

mean

6.4

4.6 4.1 6 6.1 8.7 5.4 6.8 4.7

5.2 5.8

SD

56

limit

Max Velocity m/s

73.5

mean

15

limit

Persistence % mean SD

limit

Amplitude μV

2.2

0.9

mean SD

5.5

Limit

Chronodispersion ms

30–66

12–81

42 17.4 44.2 15.6 20–81 51

21

64

32 32 33

PeiogluHarmoussi 85 (200) PeiogluHarmoussi 85 (20) Males Females Guiloff 91 (60)

26.1 28.1 29.2

19.1

17.6

1.7 1.6 1.4

1

0.9

0.8

0.7 0.4

2.2 32

2.34 1.8 31.4

2

3 2.5

26–32

1

0.83 2.7

0.38 0.31

limit

Side diff-Latency ms

limit mean SD

175.5 (7.8) 27.3 1.8 162.4 (6.1) 24.3 1.3 27.9 2.5 32

150–162 163–175 176–190

7–12

15

20–64

5–7

15

30

3–5

25

15.9

14.6 14.7

26.02 26.2

0–1 1–3

139–183

19 12

9

27

30.5 29.9

mean SD

27.6

63

Height cm

Min Latency ms

65 54

38 21*

11–74 41.5

60

mean SD

28–58 35

range

33 17

n

Russo 85 (10)

WRIST Mayer 67 (min 10) Kimura 74 (10) Kimura et al. 74 (10) Eisen et al. 77(10) Weber 78 (20) Argyropoulos 79 (100) Kimura 83 (16) Kwast 84 (20-100)**7

Stimuli (number)

Age yrs^

65.3

61.7

56.7 56.6

58.9

55

45–60

57.2 4.7

4.8

3.5

2.9 3.1

2.6

limit

Max Velocity m/s

mean SD mean SD

Mean Lat ms

47.8 83.6

79.1

mean SD

14.7

10

2.4

limit

Persistence %

0.183 0.1 0.64 0.24

0.21

1.1

SD

%

range

F/M ratio amp

0.4–2.2

SD1.1

5.7

1.1

mean SD

3.7–10.8 9.8

3.3

1.5

1.2

1

0.9 1.3

range

5.32 2.7–11.3 1.8 1 0.7–5.9

5.5

3.6

3.6

3.1

2.5 3.6

mean

Chrondispersion Repeaters ms %

3.4

range

area

1.71 0.8–4.0

%

0.56 0.24 1.473 0.6–2.5 1.1

100–770

50–300 300

range max

Amplitude μV mean SD

F-waves. Normal values. Ulnar nerve (surface electrodes over abductor digiti minimi except where indicated)

Table 9.2

n

65 8 7 11 12 11 16 23

Nobrega et al. 01 (64) Puksa 03 (20)5 196 Males 73 Females 123 ELBOW Mayer 67 10 Kimura 74 (10) 33 Kimura et al. 74 (10) below elbow 17 above elbow 17 Eisen et al. 77 60

Garcia et al. 00 (10)

Zappia et al. 51 93** (10) Cai & Zhang 168 97 (>10) 25 20 20 20 20 21 22 19 Buschbacher 193 99 (10)

Stimuli (number)

Table 9.2 Continued

mean SD

1.8 32.9 1.9 28.4 1.4 30.8 1.7 32.4

29.2 25 28.1

30.4

1.8

2 2 1.6

26

26 23.5 23

28–58 35

11–74 41.5

20–27

1.9 28.9

23.7

14–94 44.1 19.16

1.6 1.6 1.37 0.76 1.41 1.48 2.2

1.3 26.3 2 31.1

2.74 1.39 1.24 1.45 1.88 1.74 1.92 2.14 2.5 32.9

2.4 32.8

0.1

0.2

0.81

1.1

3.1

0.94 0.69 2.3

limit

Side diff-Latency ms

limit mean SD

23.5 26.2

19.67 17.65 16.99 17.02 16.63 18.51 20.66 27.03 26.5

25

mean SD

9.4

< 160 > 180 < 160 > 160 > 180 > 180 < 160 > 160 < 180 > 180

Height cm

Min Latency ms

18.63 15.71 15.45 15.67 16 18.25 25.5

< 1–72 m < 1m 1–6 m 6–12 m 12–24 m 24–48 m 48–72 m 17–59 32.9

50–79

19–49

24 h–30 24–72 h 0–3 m 4–6 m 7–12 m 1–3 4–6 7–14 18–30 19–79

19–70 36.4 15.7

range

Age yrs^

24.8

27

31.3

30.3 25.6 28.8

24.3 27.2

27.7

27

1.9

2.2

1.9

1.9 1.9 1.6

0.6 2

2.5

58.2 61.1 62.3

59.4

27.12 33.26 38.19 42.43 51.89 55.36 61.31 62.97

2.2 57.2

3 5.4 5

4.7

4.54 3.52 3.94 4.42 7.07 5.17 4.27 4.77

5.1

limit

Max Velocity m/s

mean SD mean SD

Mean Lat ms

87.5 16.6

67.4 27.4

mean SD

15

0.57

limit

Persistence %

0.31

mean SD

range

Amplitude μV max SD

%

range

F/M ratio amp % 4.2

range

area

2.3

4.1

3.2

mean

SD0.8

SD1.3

range

mean SD

Chrondispersion Repeaters ms %

1.9 1.8 1.6 24

1.3 1.8 1.28 0.88 1.35 1.48 1.46 1.9

1

Recording with concentric needle electrodes Population median of individual median amplitudes given 2 Population median of individual maximal F/M ratios given 3 Population mean of individual median amplitudes or F/M ratios 4 Population mean of individual maximal amplitudes 5 Latencies given have had the distal motor latency substracted 6 Used in multiple regression equations 7 Number of nerves for each of the age groups

**

0.85 0.61 2.1

0.88 0.64 2.2

0.68 0.48 1.6

limit

Side diff-Latency ms

limit mean SD

1.7 27 1.5 1.3 1.2

^ Age in years except where indicated, h = hours, d = days, m = months * sides

21.9 21.5 20.3

23.1 22.6 24 24.8

mean SD

28–58

150–162 163–175 176–190

Height cm

Min Latency ms

16.64 14.93 14.91 14.41 14.69 16.53 18.14 23.42

mean SD

Age yrs^

24–72 h 0–3 m 4–6 m 7–12 m 1–3 4–6 7–14 18–30

24 h–30

20–64

Kimura 83 (16) above elbow 65 Russo 85 (10) 30

Cai & Zhang 168 97 (>10) 25 20 20 20 20 21 22 19 AXILLA Kimura 74 (10) 33 Kimura 74 (10) 17 Kimura 83 (16) 65

range

n

Stimuli (number)

Table 9.2 Continued

63.1 64.4

26.14 33.34 37.9 42.78 50.36 55.29 59.81 61.18

65.7

5.9 6.5

3.87 4.93 4.25 4.7 7.43 5.92 5.75 6.29

5.3

55

limit

Max Velocity m/s

mean SD mean SD

Mean Lat ms mean SD

limit

Persistence % mean SD

range

Amplitude μV max SD

%

range

F/M ratio amp %

range

area mean

range

mean SD

Chrondispersion Repeaters ms %

Stimuli

22–39

18 10

Doko-Guina 97 (6)

Cai & Zhang 97 (>10)

7 d–14 1–6 m 6–12 m 1–2 2–4 4–6 6–14 24 h–30

24–72 h 0–3 m 4–6 m 7–12 m 1–3 4–6 7–14 18–30 0–72 m

0–3 m 4–6 m

20 23 25 24 22 20 21 168

25 20 20 20 20 21 22 19 86

8 10

27.56 26.14 25.18 25.54 26.73 30.57 38.16 49.63

42.7

7 d–14

15.7

155

36.4

19–70

51

3.82 2.84 4.37 2.04 2.87 3.82 4.43 7.74

5.2

4.6

50.7

28–57

17

3.6

4.7

SD

65

44.6

51.3

mean

3.2 3.8 4.2 4

Height cm

147–160 46.3 163–175 49.3 178–193 52.8 48.4

8.7

SD

3.7

60

28

41.5

26

mean

56

limit

Min Latency ms

43.2

Kimura 83 (16) Petajan 85 (20–60+) Zappia et al., 93***(10) Parano et al., 93 (?)

11–74

60

7 21*

21–47

range

66

n

Left Argyropoulos et al., 78 Tonzola 81

ANKLE Kimura et al., 75 (10) Eisen at al., 77 (10) Fisher 78 (10) Right

(number)

Age yrs^

1.19

1.42

mean

1.17

1.04

SD

3.5

3.5

limit

Side diff-Latency ms

45.4

45.4

46.7

mean

5.1

5.5

4.4

SD

limit

40– 52.1 40.3 –52.7

Mean Lat ms

3.6

3.3

3.8

SD

22.63 28.18 33.83 38.76 41.37 46.91 48.48 49.74

22.07 23.11 25.86 25.98 29.52 29.98 34.27

4.56 5.42 6.19 3.18 3.43 5.24 3.08 5.52

1.46 1.89 1.35 1.95 2.15 2.68 4.29

47.7**** 6.6

49.8

59

53.3

mean

43

limit

Max Velocity m/s

12.5 40

46

37.2

73.1

35

38

Limit

25.3

4

0–753

0–803

SD

Persistence % mean

F-waves. Normal values. Peroneal nerve (recording over extensor digitorum brevis except where indicated)

Table 9.3

0.64

mean

0.6

SD

max

Amplitude μV SD

5.3

mean

7.1

SD

1.9

limit

Chrondispersion ms

0.9

mean SD

Repeaters %

mean

4.5

54.6

46

56.5

53.2 46.8 51.2

45.7 48.8

52

30–58 15–48

39.2 28.6

2.9 3.1 2.6

172–220** 37.6 172–220** 35.5 38.5

3.1

5

3

4.3

4.7

4.1 4.5 4.6

2.9 3.9

5.6

SD

Mean Lat ms mean

29.8

5.1

limit

6

1.58

2.4

SD

30.1

0.15

0.7

mean

22–39

38.2

4

64.2

60.5 58.1 60

47.2 54.6

60.5

limit

18 6

41.5

42.7

4.82 1.78 1.1 1.66 2.21 2.58 4.1

4.1 4.8 4.6

51.5 45.4 49.6

25.2 21.4 20.33 22.82 24.64 29.45 44.5

2.5 3.7

5.5

SD

43.6 47.1

50.2

mean

11–74

< 160 > 180 < 160 > 160 > 170 > 170 < 160 > 160 > 170 > 170

cm

Height

Side diff-Latency ms

60

26

202

SD

Min Latency ms

21–47

< 1–72 m 50 in 55%

limit

Max Velocity m/s

60

98

SD

271

285

max

Amplitude μV SD

6.4

3.3

mean

0.8

1.79

SD

limit

Chrondispersion ms

mean SD

Repeaters %

24 h–30 24–72 h 0–3 m 4–6 m 7–12 m 1–3 4–6 7–14 18–30

168 25 20 20 20 20 21 22 19

mean

3.74 2.76 2.68 3.36 2.46 3.44 4.75 7.63

46 35.5

limit

^ Age in years except where indicated, h = hours, d = days, m = months a Surface electrode in tibialis anterior * sides ** Distance from knee to L1 × 2 *** Recording with concentric needle electrodes **** Calculated using mean and not minimum F-wave latency 1 Latency values have the distal motor latency substracted 2 Considered in multiple regression equations 3 Range given 4 The author gives the mean % of absent responses 26.9% SD 19.6%

24.38 23.46 22.15 21.56 24.3 25.22 31.38 41.23

3.2

SD

Min Latency ms

39.9 157–195 30.5

21–43

65 10

Kimura 83 (16) Burke 89 (50 minimum)a Cai & Zhang 97 (>10)

SD

cm

mean

Height

range

n

(number)

Age yrs^

Stimuli

Continued

Table 9.3

1.24

1.25

mean

1.03

0.92

SD

3.5

3.1

limit

Side diff-Latency ms

33

mean

SD

Mean Lat ms

39.3

limit

22.23 28.46 34.84 39.17 41.67 49.62 49.74 50.85

53.7 59.2

mean

3.81 4.34 5.95 4.28 4.05 7.31 5.34 4.85

4.8

SD 44 55.7

limit

Max Velocity m/s mean

SD

Limit

Persistence % mean

SD

max

Amplitude μV SD

4.1

mean

SD

11

limit

Chrondispersion ms

mean SD

Repeaters %

15.7

41.1

15–67

50.6 55.4 47.7

163–175

178–193

4.7

23.48 29.29 35.03 40.52 43.64 48.43 50.61 50.68

44.4

2.85 2.34 2.63 3.71 2.66 4.01 4.45 2.39

5.4

4.3 44 77.4

34 38 80 80 80

1.01 3.3

49.9

52.6

4–6 m 7–9 m 10–12 m 13–18 m 19–24 m

1.26

1.04 3.5

100 93

limit mean

100

64

1.4

4.7 4.9

2.9

SD

mean

SD

25.4 6002

660

max

604 650 890

Amplitude μV

401 123 62–1001 374 130 236 105

SD

Persistence %

0–3 m

3.27 2.41 1.85 1.83 2.2 3.1 3.72 3.09

6

4.2 5 58

3.7

3.6

48.2 48.9

51.3

limit mean

Max Velocity m/s

76

26.92 28.59 23.93 23.78 25.44 31.07 36.32 48.27

46

47.3

147–160

4.8

3.3

4.3

Mean Lat ms

limit mean SD limit mean SD

Side diffLatency ms

24–72 h 0–3 m 4–6 m 7–12 m 1–3 4–6 7–14 18–30 0–72 m

24 h–30

36.4

28

22–39

18 15 16 42 49.1

47.4

19–70

Min Latency ms mean SD

11–74

Height cm

60

41.5

mean SD

52.3

range

66

n

Kimura 83 65 (16) Zappia et al., 51 93 (10) Cai & Zhang 168 97 (>10) 25 20 20 20 20 21 22 19 Doko-Guina 86 97 (6) Flex hall. 8 brevis 10 8 10 10 10

ANKLE Kimura et al., 75 (10) Eisen at al., 77 (10) Fisher 78 (10) Right Left Eisen et al., 79 (32) Tonzola et al., 81 Flex. hall. brevis

Stimulus (number)

Age yrs^

F-waves. Normal values. Tibial nerve (recording over abductor hallucis, except where indicated)

Table 9.4

299

SD

1.2

%

F/M

0.4

SD

7.8

8.8

SD

Repeaters %

mean SD limit mean

Chrondispersion ms

Panayiotopoulos et al., 80 29* Gastroc Soleus 29* Tonzola et al., 81 Soleus Kimura 65 83 (16)

20–72 20–72

42.6 42.6

28

22–39

15.7 15.7

163–175

147–160 32.6 39.6

29.1 32.8 29.48

Mean Lat ms

61.4 45.4 52.7 59.2 59.8 57.2 59.7 59 67

2.1 4.4 48

1.25

0.6

5.7

0.92 3.1

2.3

53 44.7 49.2 54 55.8 48.6 52.4 56.5 60

53.7

60.3 57.6

54.4

83

86

57 100 100 90

limit mean

4.8 44

517

max

75–1001350 120

SD

700

mean

Amplitude μV

75–1001370 169

SD

Persistence %

4.8 50.5–71.4 4.8 50.8–69.9

3.6

SD

Max Velocity m/s limit mean

2.7 26.2– 35.3 2.3 27– 35.3

5.6 2.4 3.1 4 5.3 4.4 3.4 4.2 5.2

limit mean SD limit mean SD

2.3 33.8 2.7 38.8 2.3

2.95

3.4

43.5 39.7

1.62 1.35 2.05 1.63 2.53 2.52

5.3 2.2 3 4 4.4 4.6 3.5 3.6 5.3

23.92 21.4 22 24.21 25.6 30.12

50.8 43.2 47.2 52 53.1 46.8 50.5 53.9 57.9

mean SD

30.5

16

41.5

< 160, > 180 < 160 > 160, < 170 >170, 180 160, 170, 180

Height cm

Side diffLatency ms

Left

mean SD

11–74

< 1–72 m 10) 25 20 20 20 20 21 22 19 Doko-Guina 86 97 (6) 8 Soleus 10 8 10 10 10 7 6 7 10

Stimulus (number)

Continued

Table 9.4

Mean Lat ms

34 1.18

0.98 3.3

30.8

limit mean SD limit mean SD

Side diffLatency ms

36.1 23.66 29.96 36.89 41.11 43.93 50.32 51.26 51.88

limit mean

3.33 2.61 3.92 4.08 3.34 5.99 4.32 3.58

SD

Max Velocity m/s

45 62.5 30 37.5 60 30 30 28.6 66.6 57.1 50

limit mean

SD

Persistence % mean

SD

Amplitude μV max

SD

%

F/M SD

3.6

5.7

SD

Repeaters %

mean SD limit mean

Chrondispersion ms

30.7

10.7

12

30.7

11.1

30 18–55 36.6

154 –188

167

29.6 6.4

21.9 1.4

22.7 6.7

10.7

12

30.7

20.5 1.9

49

20.4 4.8

17.8 –25.3

24.4

0.4 0.3 0.1 –3.1

0.55 0.5 0–1.7

30.3 8.3

24.3 6.2

20.6 2.2 20.8 4.9

10.7

78 12

11.2 1.11 8.9–13.4

13.9 2.5

Limit

Mean Lat6 ms

limit mean SD limit mean SD

Sides diff-Lat ms

10.6 1.23 8.5–13 0.87 0.7

12.3 1.6

mean mean SD

157–203 176.6

range

Min Latency ms

20.1 1.8

5

30.7

10.7

SD

Height cm

8

42 21–66 34.4

12

n range mean

Age yrs

F Cond. time ms

12.7 0.9 < 14.1

59.5 19.1

limit

3

2

10 12.7

mean SD

24.1

16.6

75

0–100 184

78

35.2

30.2

108 60–520

750

max SD

12–242

2.2

0.8

2.8

3.7

4.1

4.9

0.6

3.2 0.59

2.8

0.9

0.57

4.1

SD

0–3.33

range

Chronodispersion ms

limit mean SD mean

F/M Ratio %

23–273 127 66 41–423 4.6

45 100–210 280

50

31

90

limit

Amplitude6 μV

500 66–271

2350 4070

106

1070

0–100 145

26 0–100 154 17.5 19.5 300

29

0–100

200

limit mean SD

Persistence %

3.86 0.52 2.75–4.8 28.5

mean SD mean SD

Velocity7

Recording with concentric needle Stimulating cathode over zygomatic branch of the nerve, anode distally over presumed course of the nerve (Wedekind) or over mastoid (Zappia) Ground midway between recording electrode and lateral epicondyle. Stimulating electrode midway between ground and the lateral epicondyle, half way between radial and ulnar bones (Papathanasiou) or elbow (Zappia). 4 Stimulating electrode over the inguinal ligament 5 Stimulation at Erb’s point 6 Whether the mean is calculated including or excluding absent responses not stated 7 Calculated using the mean of the individual mean F-wave latencies 8 For amplitude 12 nerves were recorded on each side

1

Facial Nerve2 Zappia et al., 93 (10)1 Triangularis Wedekind et al., 01 (16–60) Nasalis Radial Nerve3 Fisher 78 (10) Ext.digit. comm Right Left Zappia et al., 93 (10)1 Ext.digit. comm Papathanasiou et al., 01 (16) Ext. indicis Femoral nerve4 Zappia et al., 93 (10)1 Vastus medialis WochnikDyjas et al., 96 (10) Vastus lat. Axillary nerve5 Zappia et al., 93 (10)1 (Deltoid)

Muscle

Nerve & Author (number of stimuli)

F-waves. Normal values. Facial, axillary, radial and femoral nerves

Table 9.5

LATE RESPONSES (F- AND A-WAVES): METHODOLOGY AND TECHNIQUES

(Panayiotopoulos, 1978) and that replacing the measurement of the distance of a nerve segment by the length of a limb or by height did not change significantly the error of the distance measurement (Panayiotopoulos, 1978; Kimura, 1978a). The F/M latency ratio (see below) was proposed to bypass the arguments about distance measurement (Eisen et al., 1977b). At present, it seems that whatever method is chosen, the measurements will be clinically useful provided the technique is standardized and applied in the same way to the control subjects to obtain normal values and to the patients. 9.2.4.3.3. F/M latency ratio. This ratio was originally described as useful in the evaluation of proximal entrapment syndromes (Eisen et al., 1977b). It has the advantage that no distance measurements are required. In essence, the F-wave shortest latency to the stimulation point minus the turn around time is divided by the latency of the M-response and this is then divided by 2 to express the ratio for one length of the pathway only (since the F-responses have an antidromic and an orthodromic arm). Thus, the following formula can be used for this ratio (Kimura, 1978b). F/M (F shortest latency – M latency) – 1(ms) latency ratio = M latency × 2(ms) The method provides a comparison of conduction proximal to the stimulation site with that distal to the stimulation site, including conduction in the neuromuscular junction. 9.2.4.3.4. F-wave mean latency. This measurement has been advocated by some (Fisher, 1982, 1992). It needs few stimuli and is reproducible. The problem is that its biological meaning is obscure. Most authors agree that F-wave latencies and conduction velocities are not normally distributed (see Section on Population of motor neurons generating F-waves) so that the mean latency is not a representative parameter of the F-wave population in an individual subject nor in a group of subjects. If anything, the median latency would be more representative (Petajan, 1985; Guiloff and Modarres-Sadeghi, 1991). The mean latency cannot be compared to conventional latencies or motor conduction parameters in peripheral nerves that measure either latency for the fastest motor fibers or maximum motor conduction velocity. The mean latency cannot be compared either with other techniques that

217

look at the spectrum of motor conduction velocities, such as collision (HOPF, 1962; Ingram et al., 1987), deconvolution of cMAP (Dorfman, 1984) or reconstruction of cMAP (Lee et al., 1975); these can be compared, however, with the distribution of F-wave latencies or F-wave conduction velocities (chronodispersion and tacheodispersion). 9.2.4.3.5. F-wave maximum latency. The difference between the fastest and the slowest F-wave is used to calculate chronodispersion and tacheodispersion (see below). The measurement is being increasingly used as chronodispersion is proving to be increasingly helpful in detecting abnormalities in motor conduction that may not necessarily involve the fastest conducting fibers. 9.2.4.3.6. Chronodispersion. This parameter was described as the scatter or dispersion of the relative latencies of a statistically significant number of consecutively recorded F-waves (Panayiotopoulos, 1979). One hundred F-waves were used in the original paper and probably not less than 60 stimuli should be used in clinical practice (Guiloff and Modarres-Sadeghi, 1991) (see sample size below). Panayiotopoulos plotted histograms of F-chronodispersion as a latency difference between each F-wave and the fastest F-wave in each individual. Marked differences were shown between five control subjects and five patients with chronic renal failure but without clinical or electrophysiological evidence of peripheral neuropathy. Patients showed significantly increased chronodispersion with a mean of 9.9 ms ± 1.3 difference between the fastest and the slowest F-wave compared to 6.4 ms ± 0.8 in the controls. In control subjects 26% of the F-waves had a latencies within 1 ms of the fastest F-wave whilst in patients only 10% did so. It was predicted that this method might be more sensitive than other F-wave parameters in the detection of motor peripheral nerve abnormalities (Panayiotopoulos, 1979), and there is increasing evidence that this is indeed the case (Weber, 1998). There is a need to increase normative data for chronodispersion. There is insufficient data in patient groups, perhaps because of the need to give large number of supra-maximal stimuli to obtain a representative value for chronodispersion. It is important to realize that to measure the true extent of chronodispersion in pathological conditions, it may be necessary to increase the sweep speed from 5 ms/division in the upper limb and 10 ms/division in the lower limb, to 10 ms/division and 200 ms/division,

218

respectively, or more. Frequent checks of sweeps with no stimulation are required during the recording to ascertain that “late responses” are not the result of poor relaxation with voluntary activation of units unrelated to the stimuli, which can be mistakenly taken as F-waves. 9.2.4.3.7. Tacheodispersion. This is a similar parameter to chronodispersion but normalises the data for distance (patient’s height and limb span). Thus, the criticisms and counter-criticisms levelled at estimating conduction velocity with F-waves also apply. The distribution of F-wave conduction velocities was shown to sample adequately the spectrum of conduction velocities of the motor axons of a peripheral nerve (Guiloff and Modarres-Sadeghi, 1991). The parameter is the distribution of conduction velocities of a statistically valid sample of consecutive F-waves as a description of the spectrum of conduction velocities of axons within a peripheral nerve in normal and pathological conditions (Chroni and Panayiotopoulos, 1993a, 1993b). The distance between the spinous process of C7, and of L1, and the point of stimulation, for the upper and lower limb, respectively, were used to calculate the distance. The velocity for the fastest F-wave is calculated by Kimura’s formula: Distance FCVmax = [(FLAT min −M lat −1) / 2 ]. Each F-wave velocity (FCVx) is calculated then by multiplying the FCVmax by the ratio of latencies of the shortest and of each x F wave (minus 1 ms of turnaround time for each latency) as follows: FCVx = FCVmax × (FLAT min −1 / FLATx −1) The distribution of F-wave conduction velocities of the sample can then be plotted. To normalise for different FCVmax in different subjects the individual F-wave CVs can be plotted as a difference from the fastest FCV in each subject (Guiloff and Modarres-Sadeghi, 1991). 9.2.4.3.8. F-wave duration. There is at present little or no hard data on this parameter to warrant its use in a clinical setting. Theoretically, its main determinant in normals is the temporal dispersion of the constituent mean 2–3 motor units of each F-wave. In a pathological situation, not only the abnormalities of motorneurons in the cord but also abnormalities in conduction in peripheral nerves will contribute to this parameter.

R.J. GUILOFF

9.2.4.3.9. F-wave amplitude. Mean or median amplitudes can be used. The mean peak to peak amplitude of the F-waves is measured in absolute values or as a proportion of the M-wave amplitude (F/M ratio) (Eisen and Odusote, 1979). Absent F-responses should be considered as 0 in order to calculate mean or median amplitude and the proportion of the motor neuron pool that generates F-waves (F/M ratio) (Kimura et al., 1984; Guiloff and Modarres-Sadeghi, 1991; Fisher, 1992; Fisher et al., 1994). An increase in mean or median amplitude cannot always be assumed to reflect an increase in the excitability of motor neurons. It may result from at least three mechanisms. First, an increase in the number of motor neurons backfiring with each stimulus; second, an increase in the frequency with which motor neurons backfire leading to an increase in persistence and third, pathology such as an increase in the size of the motor units producing F-waves. An increase in the F/M ratio to more than 5% is said to be common in upper motor neuron disorders (Eisen et al., 1977b; Eisen and Fisher, 1999). A reasonable estimate of mean or median amplitude can be made from a sample obtained with 20 stimuli or less (see below, sample size). 9.2.4.3.10. Persistence or frequency of F-waves. It is defined as the proportion of stimuli followed by detectable F-waves (Eisen et al., 1977a). Since F-waveforms are generally of low amplitude this parameter depends critically on the amplification used and on how noisy or not noisy the background is. Most authors accept minimum amplitudes of 20–40 μV and gains of 200 μV/division. However, increasing the gain to 100 or 50 μV/division can dramatically increase persistence if the baseline is suitably flat (Fig. 9.5). Accordingly, normative values need to specify clearly minimum amplitude and amplification used in the collection of data, and recordings in patients need to be done in exactly the same way to draw valid conclusions. Persistence can be established with relatively small number of stimuli (10–20) (see below, sample size). Changes in persistence may reflect a variety of mechanisms, such as changes in excitability, in motor neuron numbers, function or territory (Guiloff and ModarresSadeghi, 1991), or changes in peripheral motor conduction, in particular demyelination or focal conduction block. The values for persistence vary widely in normal subjects (see normative values in tables 9.1–9.5) and, in the peroneal nerve for example, can be as low as 30% in a population, or 0% in an individual.

LATE RESPONSES (F- AND A-WAVES): METHODOLOGY AND TECHNIQUES

9.2.4.3.11. F-wave repeaters. In clinical practice, with surface recordings and supra-maximal stimulation, repeater F-waves are waveforms with a shape that appears more than once when a number of stimuli are given. They can have different shapes, each of which can repeat more than once. The proportion of repeaters in an F-wave study can be expressed as percentage of repeater F-wave shapes or percentage of repeater F-waves (Fig. 9.5) (Peioglou-Harmoussi et al., 1985a; Macleod, 1987; Guiloff and ModarresSadeghi, 1991). To collect a representative sample of repeater shapes, 100 stimuli are required (see below, sample size). It is thus unlikely to be used as a parameter in routine nerve conduction studies. Further, its clinical utility is at present rather limited. 9.2.4.4. Sample size required In normal subjects each surface recorded F-wave represents the recurrent responses of only a small proportion (less than 5%) of the motor neuron pool supplying a muscle, after a supra-maximal antidromic volley stimulates all motor axons to that muscle. The desired objective for using the technique in clinical practice is to sample adequately the whole motor neuron pool, and their motor axons, supplying a muscle. Each of the parameters used are intended to measure features of such motor neuron pool and axons, be it excitability, maximal conduction velocity, or spectrum of conduction velocities. Therefore, it is important to establish how many stimuli need to be applied to obtain measurements of the F-wave parameters of interest that are not only accurate and reliable but also representative of the whole motor neuron pool of such muscle. This problem has been addressed in normal subjects by comparing the value of such parameters when a large number of stimuli are given with the values obtained when a smaller number of stimuli are applied. The number of stimuli usually taken as the “gold standard” is around 100. Panayiotopulos plotted five successive groups of 20 F-waves and showed that only a very small number of shortest F-waves could be elicited with 20 stimuli; he recommended that large number of stimuli may be needed for correct measurements (Panayiotopoulos et al., 1977). Marra compared minimal and mean latency of 3–5 and 20 F-responses to the average of 150–200 F-responses. He used recordings in himself and in two different control groups; twenty five controls were used to record the minimal latency of 3–5 F-responses, and twenty two subjects were used to

219

record responses to 150–200 stimuli. He found that a reliable estimate of the minimum F-wave latency would require at least 20 trials to approach the value obtained by 150–200 trials (Marra, 1987). The minimum latency F-response in the abductor digiti minimi was studied in100 normal subjects by delivering 100 stimuli to each of them. At least 60 stimuli were needed to be 95% certain that the minimum latency F-response had been obtained; the same minimum latency was obtained with 100 or 80 stimuli in all subjects (Barron et al., 1987). The minimum sample size required to obtain estimates for the various F-wave parameters close to those obtained with a “gold standard” sample size was reported in detail in 1991 (Guiloff and ModarresSadeghi, 1991). The abductor digiti minimi was used in 11 normal subjects who were all given 100 supramaximal antidromic stimuli to the ulnar nerve at the wrist. It was shown first that, if F-wave latency, amplitude, area and duration obtained with 100 stimuli are each considered a time series and an auto-correlation function of lag 1 is used, there is no significant variation over time for any of them, that is, there is no last period time dependency. It was then shown that these parameters, and persistence, were not significantly different for the F-waves evoked by five successive groups of 20 stimuli each. Finally, a number of parameters in randomly obtained samples of 5, 10, 20, 40, 60 stimuli were compared with those obtained with 100 stimuli. With 20 stimuli all 11 subjects showed a less than 1.5 ms difference in minimum latency with that obtained with 100 stimuli. This difference only improved to less than 1 ms with 60 stimuli and increased to less than 2 ms with 10 stimuli. In agreement with a previous study (Barron et al., 1987), with 60 stimuli 10/11 subjects had a minimum latency within 0.5 ms of that obtained with 100 stimuli. For median latency and amplitude, on average, all samples sizes gave values less than 0.3 ms and less than 0.01 mV difference respectively from those obtained with 100 stimuli. For maximum amplitude though, samples with 20 stimuli or less gave, on average, smaller amplitudes by 0.18 mV or more. Chronodispersion decreased, on an average, by 0.4 ms with 60 stimuli, by 1.2 ms with 40 stimuli, by 2.5 ms with 20 stimuli and by 3.1 ms with 10 stimuli. For persistence samples down to 20 stimuli gave 0.8% or less difference with 100 stimuli, but with 10 stimuli the difference increased to 3.3%. The mean % of repeater shapes found decreased dramatically with sample size, as expected, from 11.2% with 100 stimuli to 1.2% with

220

10 stimuli. The closest was 60 stimuli with 9.8%. The conclusion from this study was that for minimum and median latency, median amplitude and persistence samples obtained with 20 stimuli are clinically adequate. For maximum amplitude no less than 40 stimuli should be used. For chronodispersion and repeater shapes, samples of no less than 60 stimuli should be used (Fig. 9.5). With 10 stimuli, still a widely used sample size in clinical practice, only mean median latency and mean median amplitude were close enough to the “gold standard” figures obtained with 100 stimuli. These findings have been largely confirmed by others (Taniguchi et al., 1993; Fisher et al., 1994; Chroni et al., 1994, 1996; Raudino, 1997; Nobrega et al., 2001) though the precise departure from the “gold standard” varies in different studies. In any event, it is clear that for most parameters, the “normal values” depend critically on the number of stimuli used to obtain the sample of F-waves. It has been commented that for certain patient populations 20 stimuli may not be enough to establish a representative value for minimum latency (Chroni et al., 1994, 1996). There is a need to establish, with studies similar to those quoted here, the optimum sample size of F-waves to detect abnormal findings in patient populations with different pathologies. 9.2.4.5. Techniques in children A quiet and darkened room may be helpful and the presence of the parents may be valuable. Sedation may be required and does not alter the electrophysiological results (Wagner and Buchthal, 1972; Miller and Kuntz, 1986). Recordings of motor conduction or of F-waves in children can be made with an 80u stainless steel wire inserted in the muscle (Wagner and Buchthal, 1972), with concentric needle electrodes (Kwast et al., 1984) and, more frequently, with surface electrodes (DokoGuina and Jusic, 1997; Cai and Zhang, 1997; Garcia et al., 2000). Stimulation has been given with needle (Wagner and Buchthal, 1972) and, more frequently, with surface (Doko-Guina and Jusic, 1997; Cai and Zhang, 1997; Garcia et al., 2000) electrodes. The number of stimuli delivered has fluctuated from 10 to 100, usually 10. Most authors have used supramaximal stimuli of 0.1–0.2 ms duration. 9.2.4.6. Normative data Available normative data in adults and children from the literature are summarised in Tables 9.1 (median nerve), 9.2 (ulnar nerve), 9.3 (common peroneal

R.J. GUILOFF

nerve), 9.4 (posterior tibial nerve) and 9.5 (facial, axillary, radial and femoral nerves). The number of stimuli used, to obtain such data, is indicated in the tables. 9.2.5. Summary Surface recorded F-waves are mostly indirect late responses to supra-maximal stimulation of a mixed or motor peripheral nerve, mostly generated by recurrent discharges of, on average, 2–3 motor neurons. About 1–5% of the motor neuron pool responds to the supramaximal antidromic volley. All groups of motor neurons can produce F-waves but they are generated more frequently, or preferentially, by the faster motor neurons. Thus, the spectrum, but not the distribution, of conduction velocities of the motor axons of a peripheral nerve is reflected in the spectrum of latencies (chronodispersion) and conduction velocities (tacheodispersion) of the population of F-waves. Conventional and single motor unit F-wave studies indicate that the fastest or shortest F-wave indexes adequately the fastest motor axon as recorded in conventional motor conduction velocity studies. F-wave repeaters are F-waves with shapes that occur more than once during the recording. They are similar to other F-waves except that their amplitude and area are greater. They appear to represent groups of motor neurons that backfire together repeatedly, more than would be expected by chance, probably because of anatomical and functional arrangements between such motor neurons. The F-wave methodology and technique have been gradually refined over the years. Recordings are made with surface electrodes over the motor point or belly of a muscle. 20–25% supra-maximal stimuli at 1 Hz are used. Gain is usually set at 0.2 mV/division, filters are set a 20Hz–2kHz, sweep speed at 5 ms/division for the upper limb and 10 ms/division for the lower limb, but longer sweeps may be needed in pathological conditions. The position of the stimulator cathode and anode does not seem to be of importance. The number of stimuli delivered needs to ensure that the values obtained are representative of the population of motor units sampled by the method. This will depend on the parameters of interest. For routine recordings, 20 stimuli may be adequate for minimum latency or maximal conduction velocity, median latency, amplitude and persistence. Chrono and tacheodispersion require at least 60 stimuli and repeater studies 100 or more. However further work is required to establish the best sample size in pathological conditions.

LATE RESPONSES (F- AND A-WAVES): METHODOLOGY AND TECHNIQUES

The most commonly used parameters are minimum latency, F-wave maximum conduction velocity, chronodispersion and persistence. All measurements need to be related to age and temperature. All absolute latency measurements need nomograms relating them to limb length or height. Though shortest latency and F-wave maximal conduction velocity are wellestablished parameters, chronodispersion, tacheodispersion and persistence are increasingly being used, as they appear to be more sensitive in a number of pathological conditions. The method allows measuring motor conduction in the whole of the peripheral motor pathway or in defined proximal or distal segments of peripheral nerves. It is particularly suited for documenting abnormalities of motor conduction in proximal segments not testable by conventional motor conduction studies. 9.3. A-waves 9.3.1. Introduction and nomenclature A number of late responses have latencies intermediate between the M-response and the F-wave and Hresponses. They include motor axon reflexes (MARs) elicited with sub-maximal, but not maximal, stimulation (Fullerton and Gilliatt, 1965), indirect double discharges (IDDs) (Roth, 1974, 1985) or peripheral late wave responses (PLWs) (Tomasulo, 1982), elicited with either sub-maximal or, in routine F-wave recordings in humans, maximal stimulation. Ephaptic responses originating at the myo-axonal junction (MAERs) have also been described with the same range of latencies of MARs, IDDs and PLWs. (Roth, 1993). MAERs are recognized using both weak and strong stimuli and double stimulation techniques and also occur at latencies intermediate between the M- and the F-waves (Roth, 1993). Motor axon loop responses (MALRs) (Roth and Egloff-Baer, 1984) are also seen at latencies between those of the M- and F-waves. MALRs appear as late potentials, after the M-wave and before the F-wave, with proximal, but not with distal, nerve stimulation. A wealth of information on late motor responses can be found in Roth’s monography (Roth, 2000). There is no universally agreed definition of an “Awave,” nor a universally agreed methodology to record them. The term “A-wave” has been used to denote just motor axon reflexes (MARs) (American Association of Electromyography and Electrodiagnosis (AAEE), 1987), just indirect double discharges (IDDs) or

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peripheral late wave responses (PLWs) (Bischoff et al., 1996; Kornhuber et al., 1999) or both (Magistris and Roth, 1992; Rowin and Meriggioli, 2000). IDDs and PLWs may be different names for the same phenomenon looked at with different techniques (Magistris and Roth, 1992). Recently, stable and frequent constant waveforms reported to occur with supra-maximal stimuli within the latencies of F-waves or later have been also considered as “A-waves,” or similar to PLWs (Bischoff et al., 1996; Puksa et al., 2003a). However, the frequently occurring, constant shape and latency, waveforms that are recorded with latencies intermediate between the M- and F-waves during F-wave clinical recordings with surface electrodes and supra-maximal stimulation in patients with peripheral nerve disease, but also less frequently in normal subjects, are not recordings of motor axon reflexes as described originally (Fullerton and Gilliatt, 1965). They are probably, at least partly, recordings of IDDs or PLWs (Magistris and Roth, 1992; Bischoff et al., 1996; Rowin and Meriggioli, 2000). PLWs might also sometimes include MAERs within the waveforms recorded. These different late responses have been considered in detail separately below. 9.3.2. Motor axon reflexes (MARs) Fullerton and Gilliatt first described motor axon reflexes in humans in 1965 (Fullerton and Gilliatt, 1965) (Fig. 9.6). They recorded these all or none responses from 9 out of 25 patients with lower motor neuron lesions affecting the hand using both surface and coaxial intramuscular electrodes in abductor pollicis brevis, first dorsal interosseous or abductor digiti minimi. They used stimulus voltages continuously variable up to 300 V. These authors reported to have never seen responses of this type in normal subjects. MARs were only obtained with sub-maximal stimuli but once recorded, they appeared constantly with every stimulus and, also contrary to the F-waves, always with a constant latency, usually intermediate between the M- and F-waves, but sometimes longer (Magistris and Roth, 1992). By moving the stimulating electrode proximally along the course of the nerve there was a decrease in the latency of the response, whilst the latency of the M-response increased, indicating that conduction for MAR was initially in a proximal direction. The latency was too short for the response to be the result of an impulse travelling antidromically to the spinal cord and then back to the

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AR

S M

F

200 μV

0

10

R

20

30

40 msec

S

Fig. 9.6 Motor axon reflexes. Mr J. B. Cervical rib syndrome. Muscle action potentials from abductor digiti minimi recorded through surface electrodes. S = stimulus. In addition to M- and F-waves, a small potential (AR) is present with a latency of 20 ms. Eight successive individual traces are shown. Calibration bar 200 μV. See also text (Reproduced from Fullerton, Gilliatt (1965) J. Neurol. Neurosurg., Psychiat., 28: 1–11, with permission from the BMJ Publishing Group).

muscle. The MARs were always preceded by an Mresponse and always appeared in an all or none fashion. Increase in the intensity of the sub-maximal stimulus did not change the waveform but, at a critical level, resulted in a sudden disappearance of MAR. Needle recordings showed that at this stage there was a sudden jump in latency to a value close to the M-wave. Fullerton and Gilliatt interpreted these results as evidence that the weak stimulus excited antidromically one (afferent) branch of an axon spreading to a point of axonal branching, and passing then to another (efferent) branch of the same axon that would conduct orthodromically and produce the potential recorded as MAR. When the stimulation was increased, both branches of the axon would be stimulated distally and the branch previously producing the MAR suddenly produced its own M-response, which would have the same configuration as the MAR as the same muscle fibers would be activated. With a strong stimulus the MAR could not occur after the M-response of the second (efferent) branch because the antidromic wave generated in the second axon would collide with the MAR generating incoming antidromic impulse

from the first (afferent) axonal branch (Magistris and Roth, 1992). Fullerton and Gilliatt measured the conduction velocity in the afferent and efferent branch of the reflex in two patients. In one the afferent branch was fast conducting (50 m/s) and more excitable than the efferent branch (22 m/s). In the other both branches were slow conducting at 14.3 m/s (afferent) and 21 m/s (efferent), but the slowest conducting was more excitable. Others also accepted that MARs are mediated by motor axonal branching (Stalberg and Trontelj, 1970; Roth, 1978, 1979). The M-response of the first axonal (afferent), branch could not be demonstrated in the initial descriptions. This M-response has been subsequently recorded with a different waveform to the MAR produced by the second (efferent) branch, and within the same territory covered by the concentric needle electrode that was recording the MAR. Characteristically, the latency of this response increased with more proximal stimulation whilst that of the MAR in the other branch was decreased. During voluntary activity, the same two components of the MAR have appeared as coupled discharges with a constant interval between the two orthodromic (M) waveforms, the one in the second (efferent) branch having the same waveform as its MAR response (Roth, 1979; Magistris and Roth, 1992). Changes in latency of single muscle fibers potentials to stimuli of various strengths to nerve trunks and intramuscularly in normal subjects were also thought to be due to motor axonal reflexes (Stalberg and Trontelj, 1970). They found such changes in all four subjects with intramuscular stimulation and in some of the 9 subjects with nerve trunk stimulation. Fullerton and Gilliatt considered and rejected the possibility that MARs represented the responses to transmission of impulses through artificial synapses between two axons (Granit and Skoglund, 1945), because of the constant latency and waveform, the lack of fatigue with rapid rates of stimulation and the persistence with paired stimuli separated by 1 or 2 ms. Finally, they pointed out that axonal branching had been already demonstrated anatomically in normal fibers in man and in animals (Lavarack et al., 1951; Sunderland and Lavarack, 1953) and in cat muscle nerves deprived from their afferent fibers by previous removal of the dorsal root ganglia (Eccles and Sherrington, 1930). The subsequent arguments as to whether the responses described by Fullerton and Gilliatt represent motor axon reflexes or ephaptic transmission will be considered later.

LATE RESPONSES (F- AND A-WAVES): METHODOLOGY AND TECHNIQUES

Serial studies in patients with median and ulnar nerves acutely and totally severed in the arm, forearm or wrist, sutured by first intention, have been reported (Montserrat and Benito, 1990). The authors recorded the thenar or hypothenar muscles with surface electrodes and coaxial needles and stimulated the digital nerves of the corresponding fingers at least three times over periods of up to 11 years from the day of the surgical repair. The earliest response was seen at five months, and the latest at 18 months, after the repair. The reflex responses had constant, often complex, shapes and a greatly variable latency that was shorter in more distal lesions and the longer the time elapsed since re-innervation. The reflex responses were abolished by collision if a second stimulus was applied at the wrist, before the stimulus to the finger, with an interval shorter than the latency of the reflex response. Repetitive stimulation showed that the reflex response behaved like an M-wave. F- and H-waves were not studied but many of the responses had latencies intermediate between those of the M-wave and those expected for the F-response. The authors could not decide, with the data they had, whether the observed muscle responses resulted from axon reflexes or ephaptic transmission. They considered: (a) misdirected re-growth of a motor axon to a sensory endoneural tube mediating a true axon reflex; (b) ephaptic transmission from two re-grown axons, one sensory and one motor: and (c) ephaptic transmission from a motor axon misdirected to a sensory endoneural tube to another motor axon. 9.3.3. Indirect double discharges (IDD) Indirect double discharges were first reported in 1974 (Roth, 1974) and subsequently further studied (Roth, 1985; Magistris and Roth, 1992). These authors state that IDDs represent the same phenomenon as the late peripheral waves described with supra-maximal stimulation by Tomasulo (1982). IDDs are motor units recorded with needle electrodes using submaximal or maximal stimulation. They consist of two all or none identical waveforms elicited above a certain intensity of stimulation, one with a latency within the M-wave range and another with a latency intermediate between the M- and the F-wave (Fig. 9.7). With maximal stimulation only the second waveform is seen as the first becomes buried in the Mresponse. The first waveform of the IDD is the result of orthodromic conduction as its latency increases with

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1

2 3

4

5 6

7 1 mv 5 ms

Fig. 9.7 Example of an indirect double discharge (IDD). A 58-year-old patient with sensory motor polyneuropathy showing signs of demyelination and axon loss related to diabetes mellitus and amyloidosis. Stimulation: ulnar nerve. Recording: abductor digiti minimi (concentric needle electrode): (1) With maximal stimulation above the elbow, an intermediate latency response is recorded; it is sometimes followed by its F-response (not shown). In this case, the response is “constant” (evoked by every stimulus) and has a “stable” latency (no conspicuous variation in latency). (2–3) Graded intensity of stimulation performed above the elbow shows that it is one of the first potentials recruited; 2 all-or-none potentials of identical shape are now visible. (4) When stimulation is moved distally, to the wrist, the first potential has a shorter latency (indirect pathway); they correspond to the direct and indirect components of the IDD. At the wrist, the axon giving rise to the IDD has the lowest threshold to stimulation; the indirect component is never recorded without its direct counterpart. (4, 6) With an odd number of stimuli the indirect response is evoked by the last stimulus. (5, 7) With an even number of stimuli the indirect response is abolished by collision. (5–7) The direct response is evoked by every stimulus of the train. Reproduced from Magistris, MR et al. (1992) EEG. Clin. Neurophysiol., 85: 124–130, with permission from International Federation of Clinical Neurophysiology.

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more proximal stimulation. It is constant as it is present with every stimulus, and it is stable, as its latency is constant. It can be evoked by all the stimuli in a train. The second wave of the IDD is an indirect response requiring an antidromic arm as its latency decreases with more proximal stimulation. It is constant, appearing with every stimulus, in 50% of recordings. Its latency varies between 0.5 and 4 ms in 75% and is less than 0.5 ms in 25% of recordings. Further, the second wave can be abolished by an even number of multiple stimuli in a train from two upwards, but may appear in response to the last stimulus in a train with an uneven number of stimuli. 9.3.4. Peripheral late waves (PLW) Peripheral late waves were first reported in 1982 (Tomasulo, 1982). They were obtained with supramaximal stimulation, recorded with surface electrodes and had latencies intermediate between the M- and Fwave. Their latency decreased with more proximal stimulation, indicating a proximal direction of travel for the stimulus eliciting the response and a source proximal to the stimulation site for the orthodromic volley producing the PLW (Fig. 9.8). The PLW did not change; each different waveform repeated many times, unchanged, with trains of stimuli at a largely constant latency, with amplitudes usually lower than that of the F-waves. Tomasulo recorded from the

sole of the foot (flexor hallucis brevis, abductor hallucis and flexor digiti quinti). He took 39.4 ms as upper limit for the latency of the PLW, measured from the stimulus, calculated as the normal mean Fwave latency of 52.3 ms less three standard deviations (4.4 ms). Due to the characteristic latency of the PLW he concluded that they could not have a spinal origin. Constant waveforms within the F-waveform, or occurring later than F-waves, have been subsequently considered as PLW or A-waves (Bischoff et al., 1996; Puksa et al., 2003a) (Fig. 9.9). Conclusive proof that such constant waveforms within the F-wave or occurring later are not repeater F-waves, or that they are of non spinal origin and similar to the responses with intermediate latencies between the M- and the Fwaves, originally described by Roth and by Tomasulo, is not available. It is also not clear whether waveforms after the F-waves could represent F-waves generated by myo-axonal ephapses (Egloff-Baer and Roth, 1979) (see below). Tomasulo could not correlate the presence of PLW with peripheral nerve diseases. He found PLWs in the muscles of the foot of 21.5% of normals and in 35.7% of symptomatic patients, a statistically not significant difference (Tomasulo, 1982). Using stimulation protocols for F-waves, with 15–20 stimuli a number of authors, have confirmed that PLW can be seen in normal subjects (Raudino, 1989; Bischoff et al., 1996; Rowin and Meriggioli, 2000; Gozke et al., 2003). In the only study specifically addressing this point, they

M 6.5 msec

Stim

10 msec

25.5 msec

5.7 msec 26.5

100uv

Fig. 9.8 Peripheral late wave. Patient age 50 with diabetic neuropathy and burning feet. Recording is from the flexor hallucis brevis muscle, with maximal stimulation of the posterior tibial nerve at two sites in the ankle region separated by 2 cm. Upper trace: Stimulus at proximal site. Lower trace: Distal site. The M-response is earlier by 0.8 ms with distal stimulation, whereas the late response is delayed by 1 ms. The latency of the late response, 26.5 ms, is too short for conduction to the spinal cord and back. The response is probably due to reflection of an impulse from a site of demyelinatiom. Reproduced from Tomasulo,WNL (1982) Neurology, 32: 712–719 with permission.

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peripheral nerve disease than in normal subjects (Raudino, 1989; Bischoff et al., 1996; Rowin and Meriggioli, 2000). Both IDDs (Roth, 1974, 1985) and PLWs (Tomasulo, 1982) were originally postulated to be caused by proximal re-excitation of the motor axon, perhaps by a reflection of the ascending impulse at an area of discontinuity of the myelin sheath (Tomasulo, 1982). The arguments against this hypothesis, namely that IDDs and PLWs are mediated by ephaptic transmission between motor axons of different motor neurons are presented below.

early

9.3.5. Myo-axonal ephaptic responses (MAERs)

late

R Per n 0.5 mV 10ms

L Per n 0.5 mV 10 ms

Fig. 9.9 Early and late A-waves occurring before and after F-waves. Control subjects. Early (right common peroneal nerve) and late (left common peroneal nerve) A-waves before and after F-waves are marked by arrows. Dual gain is used; during the M-wave the gain is 10 mV/division and during the late responses it is 0.5 mV/division. In the examples shown the early A-waves occur following every stimulus, whereas the late A-wave does not occur every time. Not shown here are the A-waves occurring among the F-waves and combined multiple late and early A-waves. From Puksa et al. (2003) Muscle Nerve, 28: 626–629. Reprinted with kind permission from John Wiley and Sons, Inc.

were reported in 2% (median and ulnar nerves) to 14–25% (peroneal and tibial nerve, respectively) of normal subjects (Puksa et al., 2003a). They appear to be found in a higher proportions of patients with

Myo-axonal ephaptic responses are usually unstable motor unit responses with a latency intermediate between M- and F-waves. They might be confused with MARs or IDDs if not assessed appropriately and, therefore, classified as A-waves. Stimulation of peripheral nerve terminations by muscle action potentials was originally described in animals by Lloyd (1942). Physiological ephaptic responses in normal humans have been described as a result of re-excitation of a nerve by its own muscle potential (Epstein and Jackson, 1970; Roth and EgloffBaer, 1979; Egloff-Baer and Roth, 1979). Several motor units appear to be involved in the response that follows closely the M-wave (Roth and Egloff-Baer, 1979; Roth, 1993). MAERs have also been described in patients with chronic neuropathies (Roth and Magistris, 1985; Roth, 1993) as all or none inconstant motor unit action potentials occurring with an unstable latency, well after the M-wave and before the F-waves. All muscles studied had chronic partial denervation. The MAERs were recorded with needle or surface electrodes in the thenar, first dorsal interosseous, abductor digiti minimi and abductor hallucis muscles using variable stimulation intensities at different sites, and sometimes double stimulation techniques (Fig. 9.10). The range of maximum variation in latency in 20 MAERs in these patients was 0.2–1.5 ms, but 2 of the MAERs had a stable latency. They followed the M-wave by 12.5–45.5 ms. Only 6 of the 22 were evoked by every stimulus. They disappeared by stretching the muscle. The MAERs can be followed by F-waves of either the pre-ephaptic or in the post ephaptic motor unit. The cancellation of the post-ephaptic motor unit F-wave, by collision of the descending volley with the ascending one generated at the ephapse, when an MAER is evoked, seemed characteristic of this type of ephapse.

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1mV ER 10ms 1

ER

DR

2

DR DR2

ER ER2

3

Fig. 9.10 Myo-axonal ephaptic responses (ER). A 67-year-old woman with old carpal tunnel syndrome. Recording from the thenar muscles with a concentric needle electrode. One way ephapse between the muscle fibers of a reinnervated motor unit a ( ) and the contiguous post ephaptic axon of another motor unit b ( ). The recorded motor unit potential is that of b. The stimulation of the median nerve at the wrist is above threshold. The pre-ephaptic axon has the highest excitability and therefore the lowest stimulation threshold. There is desynchronization of the M-wave: (1) The evoked ephaptic response (ER) of motor unit b, by stimulating the lower threshold motor unit a, is constant and has an unstable latency. (2) Both motor units are stimulated. The direct response of motor unit b (DR) is constant and has a stable latency; it is followed by the ephaptic response of b evoked by the stimulation of a. (3) With paired stimuli to both axons a and b (interval S1−S2 = 10 ms) two direct responses are seen (DR and DR2), the ER is not cancelled and the second stimulus sometimes evokes a second ephaptic response (ER2). Reproduced from Roth, G (1993) EEG Clin. Neurophysiol., 89: 252–260 with permission from International Federation of Clinical Neurophysiology.

Evidence was presented to suggest that MAERs result from the one way ephaptic excitation of the distal portion of a motor axon or one of its branches by the synchronized potential of a group of re-innervated muscle fibers belonging to another motor unit. That the post-ephaptic structure is axonal was suggested by the close association between a late potential (IDD) and an MAER when they were recorded together, the first always closely preceding the second, suggesting that activation of a re-innervated unit led to activation of another unit producing the MAER. The possibility that the pre-ephaptic structure was axonal rather than

re-innervated muscle fibers could not be completely discarded. The MAER’s latency similar to that of IDDs, and the fact that the electrical signal would be far higher and more likely to excite the post-synaptic structure in a group of re-innervated muscle fibers than in a regenerating axon, favoured re-innervated muscle fibers as the pre-synaptic structure. A distinguishing feature of the MAER from a late potential (IDD) would be that maximal double stimulation always abolishes the second wave of the IDD because of collision between the descending response to the first stimulus and the antidromic volley to the second stimulus in the same motor axon. In the case of the one way ephapse however, the MAER to the first but not to the second stimulus would be abolished by double stimulation. The first post-ephaptic descending volley collides with, and is cancelled by, the second antidromic volley in the same post-ephaptic axon, whilst the second post-ephaptic descending volley can be recorded (Magistris and Roth, 1992). In practice, however, it was described that double stimulation evoking also the direct response had frequently, but not always, an inhibitory effect on the MAER and that “when the second direct response preceded the MEER by less than 15 ms, the MAER always disappeared.” Roth concluded that the inconstancy of the MAER and the variability of its latency related to the excitation of the post-ephaptic axon and that the refractory period of the myo-axonal ephaptic mechanism was much longer than that of axons. Thus, the distinction of MAERs from other late responses requires not only stimulation at different sites with varying intensities but also double stimulation (Roth, 1993). Further, the F-wave generated by the re-excitation of some axons by the ephapse can occur after the F-wave generated by axons stimulated directly. Such F-waves could be erroneously interpreted as late F-waves or A-waves. However, their latency increases with more proximal stimulation since the stimulus travels a longer way to the ephapse within the muscle that will trigger both an orthodromic and an antidromic volley in a neighboring motor axon (Egloff-Baer and Roth, 1979). 9.3.6. The motor axon loop response (MALR) (Fig. 9.11) These waveforms can appear as late responses with latencies intermediate between the M- and F-waves. They might be confused with MARs if not investigated adequately and therefore described as A-waves

LATE RESPONSES (F- AND A-WAVES): METHODOLOGY AND TECHNIQUES

A 1

S

LR

LR

2

B LR 3 BR

LR

4

BR

C BR

BR 6

Fig. 9.11 The motor axon loop response. A 33-year-old woman with a traumatic lesion of the brachial plexus. Recordings from the abductor pollicis brevis muscle. Weak ( ) or strong ( ) stimulation (S) of the median nerve. (1) at the axilla, (2) below the axilla, (3) at mid upper arm, (4) above the elbow, (5) at the elbow, and (6) at the wrist. In (A) only the late response is elicited (LR), even with very strong stimuli. In (B), the LR and the short latency response (BR) are evoked by weaker and stronger stimuli respectively. In C, only the BR is evoked. Its presence in the M wave was ascertained by the collision method (not shown). At this recording site, no response can be elicited by ulnar nerve stimulation at the wrist or elbow. The distances (cm) recorded were: 1–2 = 6.5; 2–3 = 3; 3–4 = 6; 4–5 =2; 5–6 = 22. Calibration bar = 5 mV, 2 ms. Reproduced from Roth, Egloff-Baer, (1984) Muscle Nerve, 7: 294–297, with permission from John Wiley and Sons, Inc.

in needle or surface unit recordings with sub-maximal stimulation. (Fig. 9.11). MALRs were described with concentric needle electrodes, surface stimulating electrodes with variable intensity, and sometimes a collision technique, in seven

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patients with median or ulnar nerve lesions, two with brachial plexopathies and one without clinical evidence of peripheral nerve lesion (Roth and EgloffBaer, 1984). The waveform was detected with proximal stimulation of the nerve trunk and the motor unit showed a stable late direct response, between the M- and the F-wave, with weak stimuli. When the stimulation reached a critical level, there was a sudden jump to a stable direct shorter normal latency. The short response was shown to be part of the M-wave. The latency difference between the two responses remained identical when stimulating the restricted segment of the nerve from where they could both be elicited. Above this segment, only the late response, and below it only the short latency one, were elicited. The authors suggested that the segment had a loop with a descending initial proximal portion kinking upwards with a reversal of the direction of conduction which becomes distal to proximal. The second segment would then kink downwards and this third and final segment would conduct in a proximal to distal direction. The proximal, initial, portion of the loop is the most excitable and proposed to be the origin of the late response. The final portion of the loop is the proposed origin of the shorter latency response. The recurrent section of the axon in the loop is the less excitable one, perhaps because it is furthest away from the stimulating electrode and produces no responses. The proposed kinked axons had normal conduction velocities. The late response was sometimes followed by its own F-wave with a longer latency than that of the F-waves of normal motor units embedded in the M-wave. The F-wave latency of the shorter latency waveform, at the segment where a late response can also be evoked with a weaker stimulus, is the same as the F-wave latency of the late response evoked at the same site. This is because the path for both F-waves includes the loop, for the stimulus evoking the short latency response during the antidromic afferent phase of the recurrent response and for the stimulus evoking the late response during the orthodromic efferent phase of the recurrent response. The authors quote anatomical evidence for the three portions of the loops residing in more than one nerve but propose than the whole loop may also be contained within one nerve. 9.3.7. Ephaptic transmission, axonal reflexes and recurrent re-excitation of motor axons Tomasulo suggested that the techniques used to describe human motor axon reflexes and peripheral

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late waves could not distinguish ephaptic transmission between the axons of two motor units from either the axonal branching proposed for MAR, or the recurrent re-excitation of motor axons at a proximal area of the axon proposed for the PLW (Tomasulo, 1982). The idea was later formally put forward as a hypothesis (Gilchrist, 1988). According to this hypothesis bi-directional ephaptic transmission between the axons of two motor units would result in “motor axon reflexes” and unidirectional ephaptic transmission would result in “peripheral late waves.” Cogent arguments against this hypothesis were presented in 1992 (Magistris and Roth, 1992) by comparing models of ephaptic transmission with the observed facts available for MAR, IDD and PWL. In the case of MARs observed features, not expected with bidirectional ephaptic transmission, were the stable latency of its F-waves, the lack of repetitive firing of MARs, the constant latency with stimulation above the site of reflection, the faster conduction above the site of reflection than in the branches, and the lack of an own firing rhythm in one of the potentials of the coupled discharge. In the case of IDDs and PLWs, observed features, not expected with unidirectional ephaptic transmission, were the constant recording of a direct response preceding the indirect response (unless buried in the M-wave), the cancellation of the indirect response by maximal double stimulation, the similar thresholds of the direct and indirect responses within the IDDs and their lack of F-waves with multiple latencies. 9.3.8. Methodology and techniques There is currently no agreed upon nomenclature for, nor agreed methodology or technique to study, Awaves, or to dissect the responses that may underlie the waveforms seen with an intermediate latency between the M- and F-waves, in a clinical setting. Bischoff and his co-workers suggested the following criteria to classify as A-waves the waveforms seen during 20 supra-maximal stimuli in protocols designed to record F-waves with surface electrodes (see above in the F-wave section): (A) Potentials of stable amplitude and shape; (B) variation in latency of less than 1.5 ms; and (C) occurrence in at least 8 out of 20 stimuli (Bischoff et al., 1996). In another study, criteria B was changed to less than 0.5 ms (Puksa et al., 2003a). With these criteria waves that are part of the F-waveforms or that occur later can be included, but cannot be separated from F-waves repeaters, longer latency F-wave repeaters or other late responses. The frequent occurrence of the waveforms (at least eight out of 20) was considered to be more likely in

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A-waves than in F-wave repeaters (Puksa et al., 2003a). These authors described A-waves intermixed with F-waves in lower, but not upper, limb nerves in 2% of normal subjects. An F-wave shape repeating 11 times out of 200 stimuli was seen in the abductor digiti minimi of two out of 21 (9.9%) normal subjects in one study (PeioglouHarmoussi et al., 1985a). A mean of 9.9% (up to 20% in individual subjects) of repeater shapes out of 1398 F-wave shapes were seen in the abductor digiti minimi of 30 normal subjects following 60 stimuli in another study. Up to nine of these repeater shapes repeated 5 or more times (Guiloff and Modarres-Sadeghi, 1991). Three examples of repeater F-waves in the thenar eminence of patients with carpal tunnel syndrome are illustrated by Macleod (1987). One shows 16 late repeater F-waves out of 39 successive sweeps, another shows just the same F-wave repeater occurring 13 times in 49 sweeps and a further one shows a repeater occurring 13 times in 34 sweeps. Similar data for F-waves in the lower limbs are not available so that a comparison with the data on A-waves available in the lower limbs (Puksa et al., 2003a) is not possible at present. Waveforms occurring near the M-waves, whether IDDs, PWLs or MALRs, may be separated from late components of the M-wave with changes in the stimulation site. More distal stimulation should show an increase in the latency of IDDs and PLWs and disappearance of MALRs. More proximal stimulation should show IDDs and PLWs, but not MALRs, to be closer to the M-wave. Late F-waves associated with myo-axonal ephapses have a longer latency the more proximal the stimulation site (Egloff-Baer and Roth, 1979). Studies with simultaneous needle and surface recordings, double stimulation techniques and variable intensities and sites of stimulation may help in clarifying whether the constant shape and latency waves seen within the F-waveform, or after it, when using F-wave protocols with supra-maximal stimulation are A-waves (i.e., motor axon reflexes, direct double discharges or peripheral late waves), repeater F-waves or other late responses such as late F-waves associated with myo-axonal ephaptic responses. It has been suggested that intermediate latency late responses are best studied looking at all or none potentials with needle recordings. MARs can then, for example, be separated from IDDs when the direct response is hidden in the M-wave, by using the double stimulation technique (Magistris and Roth, 1992). It seems doubtful, however, that such methodology will be widely applied in routine clinical settings.

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9.3.9. Summary The term “A-wave” has been used to denote motor axon reflexes, indirect double discharges and peripheral late waves with intermediate latencies between those of the M- and F-waves or all of them. It has also been used recently for constant and frequent late responses to supra-maximal stimulation within the F-wave waveform or occurring after the F-waves. Other potentials with latencies between those of the M- and F-wave include myo-axonal ephaptic responses and motor axon loop responses. The F-waves of myo-axonal ephapses and some repeater F-waves may also occur after the usual Fwaves. All these responses may be seen in normal subjects. The various late responses can be differentiated using a number of techniques including needle recordings of all or none potentials, stimulation of varying intensities and at various sites, double stimulation and trains of stimuli, all of which are not usually used in routine clinical investigation. The frequent constant waveforms of stable intermediate latency between M- and F-waves, usually termed A-waves, seen during routine F-wave studies with surface recordings and supra-maximal stimulation, are likely to be IDDs or PLWs. They may be caused by the recurrent re-excitation of motor axons at a proximal point of discontinuity of the myelin sheath. References American Association of Electromyography and Electrodiagnosis (AAEE) NC (1987) AAEE glossary of terms in clinical electromyography. Muscle Nerve, 10 (suppl): G5–G6. Andersen, H, Stalberg, E and Falck, B (1997) F-wave latency, the most sensitive nerve conduction parameter in patients with diabetes mellitus. Muscle Nerve, 20: 1296–1302. Argyropoulos, CJ, Panayiotopoulos, CP and Scarpalezos, S (1978) F- and M-wave conduction velocity in amyotrophic lateral sclerosis. Muscle Nerve, 1: 479–485. Argyropoulos, CJ, Panayiotopoulos, CP, Scarpalezos, S and Nastas, PE (1979) F-wave and M-response conduction velocity in diabetes mellitus. Electromyogr. Clin. Neurophysiol., 19: 443–458. Barakan, TH, Downman, CBB and Eccles, JC (1949) Electric potentials generated by antidromic volleys in quadriceps and hamstring motoneurones. J. Neurophysiol., 12: 393–424.

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LATE RESPONSES (F- AND A-WAVES): METHODOLOGY AND TECHNIQUES

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 10

Reflex responses, silent period and long latency reflexes Josep Valls-Solé a, * and Günther Deuschlb a

Unitat d’EMG, Servei de Neurologia, Hospital Clínic, Facultad de Medicina, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain b Department of Neurology, Christian-Albrechts-Universität Kiel, Germany

10.1. Introduction The integration of sensory inputs into the motor commands for purposeful voluntary or automatic actions (sensorimotor integration) is a very complex function of the central nervous system. With regard to somatosensory inputs, reflex motor responses to external stimuli range from the simplest tendon jerk to quite elaborated behavioral responses. Probably one of the most important accomplishments of human kind has been the development of a sufficient supraspinal control of reflex behavior, in such a way that, to a certain extent, we are able to selectively suppress the unwanted reflex responses, or let them fully manifest with no limitations, if necessary. Typically, simple monosynaptic reflexes are less subjected to control than the complex long latency ones. Many clinical neurophysiological studies can be performed to show how the central nervous system exerts its control over the reflexes and, also, to document the loss of such control in certain neurological diseases. Reflexes involving motor responses can be monosynaptic or polysynaptic. Monosynaptic reflexes follow a segmental reflex arc, and are of relatively short latency. The most widely known monosynaptic reflex is the tendon jerk, which is the muscle response to mechanical activation of muscle stretch receptors. The action potential linked to the reflex muscle response is known as the T-wave. A similar muscle response can be obtained if the Ia fibers are depolarized by relatively weak electrical shocks applied to the supplying nerve. The response obtained in this way is known as

*Correspondence to: Josep Valls-Solé, MD, Unitat d’EMG, Servei de Neurologia, Hospital Clínic. Villarroel, 170 Barcelona, 08036, Spain. E-mail address: [email protected] Tel.: +34 93 2275413; fax: +34 93 2275783.

the H-reflex. Both, mechanical taps and electrical shocks are unnatural stimuli and, consequently, the reflexes induced by these stimuli are likely to be of little functional use. However, they are of great importance for both clinical work in patients with neurological diseases, and research in physiology of sensorimotor circuits. A stimulus activating somatosensory afferents of any type is capable of inducing polysynaptic reflexes. These reflexes may implicate multilevel spinal and supraspinal pathways and are of relatively long latency (long-latency reflexes). As a difference with monosynaptic reflexes that always have a predominant excitatory component, the polysynaptic longlatency reflexes can be either excitatory or inhibitory and, most commonly, they have both effects combined. To make these effects apparent, the examiner requires the use of specific methodological conditions. For instance, the responses to certain stimuli may be so weak that they will only appear if the motor system is already engaged in a voluntary contraction. Maintaining a background contraction allows also for identifying the inhibitory component of the reflex response, as a transient decrease of the tonic level of voluntary contraction. In other instances, a stimulus may not induce a reflex response on its own, but is able to modulate the reflex response to another sensory stimulus in the same reflex circuit or in a distant one. A number of these studies use the H-reflex as a probe for the effects of other stimuli. In the following paragraphs, we shall review the physiology of monosynaptic and polysynaptic reflexes, and describe methods and technical specifications for performing reflex studies and using them in the assessment of peripheral nerve disorders. The reader can also find useful information in the literature devoted to technical recommendations, published elsewhere (Gitter and Stolov, 1995a,b; Bischoff et al., 1999; Deuschl and Eisen, 1999).

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10.2. Monosynaptic reflexes 10.2.1. The T-wave 10.2.1.1. Physiological and technical considerations The T-wave results from monitoring the muscle response elicited by a mechanical tap to the tendon with a hammer containing an electronic device that triggers the oscilloscopic sweep. The tap induces a stretch of muscle spindles, which activate the Ia afferent fibers, sending an afferent volley to the spinal cord. The Ia afferent terminals have monosynaptic excitatory connections with the alpha motoneurons innervating the stretched muscle. If the motoneuronal excitatory postsynaptic potential (EPSP) is synchronized and large enough, several motoneurons will discharge, producing a physically evident movement or muscle contraction. Electrophysiological recording of the T-wave permits to quantify the reflex response observed in clinical practice. The electromyograph should be set for external triggering by the built-in hammer switch. Usually, a time window of 50 ms is long enough to reproduce the whole response in any human muscle, and a gain of 0.5 mV per division is enough to reproduce the response recorded within a bandpass frequency range of 10 to 1000 Hz. The most reliable parameter to measure in the T-wave is the onset latency, while its amplitude is less reproducible. The examiner has to be aware of some methodological constraints, which also apply to the clinical assessment of tendon jerks: A variable

Fig. 10.1 Elicitation of the H-reflex in the soleus muscle. (A) Diagram of the circuits of the H-reflex. S = Stimulus; R = Recording. (B) Electrode placement. (C) Recordings obtained with progressively increasing the stimulus intensity from the top downwards (recruitment curve). The stimulus is applied at the arrowhead (S). (D) Graphic plot showing the changes in the amplitude of the H-reflex and the Mwave, obtained with increasing stimulus intensity, expressed in percentage of the maximum amplitude of the M-wave.

strength of the tap will give rise to a different response latency and size; a variable degree of relaxation of the agonist and antagonist muscles may inhibit or facilitate the reflex response, and a different position of right and left limbs could be responsible for an asymmetry in the size of the response. Therefore, for the T-wave to furnish reliable data, the recording electrodes should be placed symmetrically in the muscles of either side, and reflexes should be tested by maintaining the same position of each limb to avoid differences in the degree of tonic muscle contraction. With these precautions, the strength of the tap seems not to produce significant changes in onset latency (Malcolm, 1951). It was once believed that the excitability of the tendon jerk depended on the existence of a selective drive from gamma motoneurons to intrafusal fibers. The hypothesized constant traffic of impulses in gamma efferents was considered responsible for the possibility to elicit the reflex response in the resting condition in ankle flexor muscles (Landau et al., 1960; Dietrichson, 1971). However, microneurography studies have demonstrated the absence of efferent activity directed to muscle spindles in relaxed subjects (Vallbo et al., 1979). Also, Burke and coworkers demonstrated the absence of changes in the nerve afferent discharges to ankle taps during anaesthetic blockade of the sciatic nerve, assumed to block the gamma drive (Burke et al., 1981a) or during central nervous system manoeuvres of reflex reinforcement

A

B Recording Stimulator

S

A

R

M

C

H

D Size (% of M)

S

M H

Stimulus intensity (mA)

REFLEX RESPONSES, SILENT PERIOD AND LONG LATENCY REFLEXES

(Burke et al., 1981b). These experiments demonstrated that the size of the monosynaptic reflex depends on the spinal excitability state rather than on the fusimotor drive. 10.2.1.2. Methods of clinical interest for the study of peripheral nervous system disorders with the T-wave The most important asset of the T-wave is its apparent simplicity. It can be applied to the study of lesions of proximal nerve segments (both, radicular and plexular) or to the study of polyneuropathies. It is likely to be asymmetrically abnormal in patients with unilateral radiculopathies involving the muscles in which it can be easily obtained (soleus and quadriceps in the lower limbs, and triceps, biceps and brachioradialis in the upper limbs. It is usually delayed in disorders causing slowness of conduction velocity in large axons (Kuruoglu and Oh, 1992). Absence of the T-wave, together with a decrease in the amplitude of the sensory nerve action potentials, may be one of the first objective signs of nerve damage in patients with distal axonal neuropathies (Sandler et al., 1969). A particularly interesting muscle for T-wave examination is the masseter muscle. The mandibular reflex is elicited by tapping to the chin. However, it is often difficult to discern whether the reflex is normal in both sides, or even whether it is present at all, by inspection only. Therefore, electromyographic monitoring of the masseter or temporalis muscle response is of paramount importance in the evaluation of suspected brainstem lesions (Hopf et al., 1991; Hopf, 1994). The mandibular reflex circuit is also particular regarding the location of the cell bodies. In contrast to those of all other muscles in the body, the proprioceptive neurons of the jaw muscles lie within the neuraxis, protected by the blood-brain barrier from peripheral circulating agents (Graus et al., 1987). This is actually an important piece of information for the diagnosis of some disorders involving immunological aggressions to sensory neurons of the Gasserian ganglia, such as in some patients with Sjögren’s syndrome. These patients might have abnormalities in multiple cranial nerve reflexes induced by cutaneous stimuli, which are conveyed by sensory neurons lying in the Gasserian ganglia but, since the antibodies do not pass the blood-brain barrier, the mandibular reflex is left intact (Valls-Solé et al., 1990). This observation easily separates patients with sensory neuronopathies from those with axonal neuropathies, which may also be present in patients with connective tissue diseases (Lecky et al., 1987).

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10.2.2. The H-reflex 10.2.2.1. Physiological and technical considerations The H-reflex, named in the honor of Paul Hoffmann, the physiologist who described it for the first time in 1918, is a monosynaptic reflex that results from activation of alpha motoneurons by electrically induced Ia afferent excitatory volleys. The H-reflex is commonly examined in the soleus muscle. However, it is also easily elicitable in other muscles, such as the quadriceps and wrist flexors. It may also be observed in thenar muscles, tibialis anterior, and many other muscles, if a slight facilitation is induced with voluntary contraction (Cowan et al., 1986). Indeed, voluntary contraction can be used safely to study the H-reflex in muscles other than the soleus, since the contractioninduced facilitation allows for distinguishing more clearly the H-reflex from the M-response in proximal muscles (Burke et al., 1989). 10.2.2.1.1. The H-reflex in the soleus muscle. The frequency band pass, gain, and sweep speed of the electromyograph recommended for recording the H-reflex are the same as those used in the study of the soleus T-wave, i.e., a band pass of 10 to 1000 Hz, a recording window of at least 50 ms, and a gain of at least 0.5 mV. The main difference in the set up for the study of the T-wave and the H-reflex is the use of an electrical stimulus, rather than a tendon tap, for elicitation of the H-reflex. In the most conventional procedure, the electrical stimulus is applied to the posterior tibial nerve at the level of the popliteal fossa. Stimuli of relatively low intensity and long duration, typically 0.5 or 1 ms, are the most appropriate for selective depolarization of the Ia afferent terminals (Panizza et al., 1989a). Bipolar stimulation electrodes are perfectly suitable for all purposes in the study of the Hreflex. However, the use of the cathode placed over the nerve and the anode placed over the patella (as shown in Fig. 10.1) may be a safer procedure for selective activation of the Ia fibers in some cases (Hugon, 1973). There are several methods for recording the soleus H-reflex. The most common procedure is to attach the recording electrode over the soleus muscle around the point in which the two gastrocnemius muscles joint the Achilles tendon (slightly distal to the midcalf). The reference electrode is usually placed about 3 cm distally, and the ground electrode is located at a point between the stimulating and the recording electrode. In this way, the H-reflex may show a triphasic form, with a small initial positivity, because the active

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electrode picks up the soleus activity as an approaching vector through the mass of the gastrocnemius muscles. The soleus response may be recorded as an initially negative deflection, without the volume conducted positivity, by placing the active electrode just medial to the tibia, at a midpoint between the tibial tubercule and the medial malleolus (Daube, 1979; Kimura, 2001). The latency of the H-wave should be measured at the point of its initial deflexion, whether positive or negative, since this is the point of onset of reflex activity in the soleus. As with the T-wave, care should be taken with regard to the position of the knee and ankle joints. Both should be slightly flexed to avoid stretching of the gastrocnemius in the knee, which would prevent the stimulating current to reach the nerve, and unnoticed contraction of the tibialis anterior, which would cause reciprocal attenuation of the H-reflex. The soleus H-reflex has a latency of about 30 ms, while the direct M-wave recorded in the same muscle with supramaximal stimulus intensity occurs at a latency of about 5 ms. The latency of the H-reflex is similar to that of the F-wave, which can be elicited in the same muscle by the same stimulating electrode, using larger intensities. Therefore, the examiner must be aware of the characteristics that allow to distinguish relatively easily between the two responses (Table 10.1). The latency of the H-reflex (and, also, that of the F-wave) correlates well with subject’s height (Schimsheimer et al., 1987) and leg length (Braddom and Johnson, 1974). The best position for a careful evaluation of the soleus H-reflex physiological characteristics is with the subject seated, and a soft cushion supporting the knee slightly flexed at about 120 degrees, and the ankle joint passively flexed at about 110 degrees. Relatively sophisticated equipment can be used to stabilize the leg in order to have a more reliable determination of H-reflex amplitude changes (Hultborn et al.,

J. VALLS-SOLÉ AND G. DEUSCHL

1987). Studies involving measurement of the mechanical consequences of the reflex activation require monitoring of the force of the reflex muscle contraction, which may be done through a force transducer placed against the sole of the foot, or the ankle joint movement, which is done through movement transducers placed across the joint. A simple accelerometer attached to the moving segment may also be used to monitor movement if a constant control of the position of the ankle joint is not required. 10.2.2.1.2. The H-reflex in muscles other than the soleus. Apart from the soleus, the H-reflex can be elicited at rest in the flexor carpi radialis (FCR) and in the vastus medialis (VM), although the response is not as consistent as in the soleus. For a response to be accepted as an H-reflex, the response has to fulfill the following criteria: 1. It has to have a latency consistent with the reflex arc. A conduction velocity of 60–80 m/s, characteristic of the large fibers responsible for the H-reflex, would correspond to a latency of 17–21 ms in the FCR, and of 19–26 ms in the VM 2. The action potential amplitude should decrease with increasing the stimulus intensity: The H-reflex should be elicited by stimuli of an intensity below threshold for the alpha motor axons. With increasing the stimulus intensity it should first increase and then decrease together with a progressive increase in the M-wave. 3. It should disappear or diminish significantly with vibration applied to the muscles of the forearm. The stimulus duration and intensity are similar to those used for the soleus H-reflex. For the FCR H-reflex, the recording electrodes are placed over the belly of the flexor carpi radialis, usually at about 1/3 of the distance between the medial epicondyle and the radial styloid (Jabre, 1981). In monopolar recording, the reference electrode may be

Table 10.1 Differences between the H-reflex and the F-wave Observation

H-reflex

F-wave

Stimulus intensity (relative to threshold for the M-wave) Largest amplitude (relative to amplitude of the M-wave) Onset latency Shape of the action potential Effect of a weak tonic muscle contraction Effect of increasing the stimulus intensity Effect of vibration

Subthreshold About 50% Rather constant Smooth and constant Increase in amplitude Decrease in amplitude Inhibition

Suprathreshold About 5% Variable Irregular and variable Increase in persistence Increase in persistence No effect

REFLEX RESPONSES, SILENT PERIOD AND LONG LATENCY REFLEXES

placed at a certain distance, away from median nerve innervated muscles. However, good responses can be obtained also with bipolar recording electrodes. The stimulus is applied to the median nerve at the elbow, with a stimulus duration of 0.5 or 1 ms, and allowing enough time between successive stimuli to avoid refractory effects. Even with these precautions, the Hreflex of the forearm muscles cannot be elicited in up to 10% of healthy volunteers. Although the use of surface recording electrodes is generally acceptable (Jabre, 1981), and is usually preferred for assessment of reflex excitability (Day et al., 1984), it should be pointed out that Deschuytère et al. (1976) who first described this reflex, found it in all his patients using needle electrodes. For the VM H-reflex, the recording electrodes are placed over the vastus medialis at the distal 1/3 of a line joining the middle point of the inguinal fold and the internal aspect of the knee. The stimulus is applied to the femoral nerve at the inguinal fold. Due to the depth of the nerve, it may be convenient to exert some pressure with the electrode against the superficial

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tissue, and the help of a sandbag may be considered after careful positioning of the stimulating electrodes (Valls-Solé et al., 1998). 10.2.2.1.3. The afferent volley eliciting the H-reflex. Although the H-reflex is considered to be a monosynaptic reflex, there is no consistent proof for that in humans. Certainly, the onset of the action potential should reflect the motoneuronal excitation induced by the fastest afferent fibers. The size of the motoneuronal EPSP generating a motor response can be calculated in humans as the density of the action potentials forming the predominant spike of the peristimulustime-histogram (Mao et al., 1984). An example of such recordings from the soleus H-reflex is illustrated in Fig. 10.2. In humans, the EPSP generating the soleus H-reflex by the electrical stimulation of the posterior tibial nerve has a duration of 3.5–5.5 ms (Ashby and Labelle, 1977; Burke et al., 1984). During this time, other afferent inputs may reach the same motoneurons after a synaptic delay in spinal interneurons and their action potentials summate to the

A C

50 ms

S

B

cusum

S

ms

Fig. 10.2 Analysis of the soleus H-reflex using the peri-stimulus-time-histogram (psth). A needle is inserted in the soleus muscle and focussed to pick up the activity of a single motor unit action potential. The subject is requested to make a weak contraction to steadily activate that motor unit at a stable frequency. An electrical stimulus at the appropriate intensity is delivered to the posterior tibial nerve in such a way that it elicits the H-reflex repetitively in the middle of a 500 ms epoch window (A). After a predetermined number of stimuli (i.e., after collection of 100 traces), an histogram is made in which each motor unit action potential is represented in the exact time in which it occurred along the 500 ms window (B). The excitatory effect of the stimulus is recognized by the accumulation of MUAPs at the corresponding response time (at about 30 ms in the case of the soleus H-reflex). The steepness and width of the peak of the psth reflect the strength and the duration of the EPSP, respectively. Another way of representing the changes in excitability of the motoneurons affected by the stimulus is the cumulative sum (cusum) of the points gathered in the psth histogram (C). To do that, the running average of a number of consecutive time bins of the psth (i.e., 5 bins) is plotted against time for each ms of the epoch. For instance, the average of the bins 1 to 5 gives rise to the first point, that of the bins 2 to 6 to the second point, and so on. The curve shows a nice response representing the effect of the stimulus on the activated motoneuron pool.

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developing response (Burke et al., 1981b, 1984). Furthermore, inhibitory inputs from Ib or type II fibers activated in the posterior tibial nerve also reach the motoneurons some time later, and generate motoneuronal inhibitory postsynaptic potentials (IPSPs), contributing to the termination of the action potential (Pierrot-Deseilligny et al., 1981). These observations lead to suggest that the size of the H-reflex does not depend only on the size of the excitatory afferent volley, nor on the excitability of the alpha motoneurons, but also on the excitability of some propriospinal interneurons, whose postsynaptic potentials will contribute to the peak and the termination of the action potential (Burke, 1985). 10.2.2.1.4. Presynaptic control of Ia terminals. The number of Ia afferent axons activated by the stimulus is not the only factor determining the size of the EPSP generated in the motoneurons by Ia afferent terminals. Another functional mechanism at play is presynaptic inhibition of those excitatory inputs before they reach the motoneurons (Frank and Fuortes, 1957; Hultborn et al., 1987; Rudomin, 1990). The mechanism of presynaptic inhibition was first demonstrated in the cat motoneurons by showing that the EPSP generated by group Ia fibers was depressed after conditioning stimulation of flexor muscles group I afferents, while there was no change in the size of the antidromic potential. This same behavior can be easily reproduced in humans by using vibration (Delwaide, 1973). Vibratory stimulation at the Achilles tendon that depolarizes Ia afferent fibers, causes inhibition of the soleus H-reflex and, at the same time, tonic activation of motoneurons (the tonic vibration reflex). Even though the H-reflex is inhibited, the motoneurons remain excitable through other pathways like the antidromic volleys, eliciting the F-wave (Hultborn et al., 1987) or the descending volleys generated by transcranial magnetic stimuli, eliciting the motor evoked potential (Nielsen and Petersen, 1994). It is already known that the Ia afferents activate the alpha motoneurons through a monosynaptic connection. However, colaterals from the same afferents terminate in spinal interneurons, which depolarize the Ia axons just before the synaptic terminal. These spinal interneurons, known as “primary afferent depolarization” (PAD) neurons, would establish axo-axonal connections to depolarize the Ia terminals, causing a reduction of transmitter release at the arrival of excitatory inputs. Another mechanism that could be responsible for similar effects would be postsynaptic remote

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dendritic inhibition (Rudomin, 1990). In this scheme, the Ia terminals would establish their excitatory synapse with distal dendrites of alpha motoneurons, giving room for blockade from other synaptic terminals in the same dendrite. The concept of presynaptic inhibition is very important for understanding physiological mechanisms of motor control over reflex responses (Stein, 1995). Neurons in charge of presynaptic inhibition are probably under the control of descending tracts (Rymer et al., 1979; Valls-Solé et al., 1994). Therefore, the CNS can use this mechanism to modulate the amount of Ia afferent terminal excitation desired at any given moment or with any given condition. Combining simultaneous presynaptic inhibition and postsynaptic excitation is like pressing at the same time the clutch and the accelerator to maintain the car ready for a speedy departure. The motoneurons are therefore set in a condition of preparation for very rapid firing. 10.2.2.1.5. The H-reflex recruitment curve. The Hreflex is best elicited with electrical stimuli of low intensity and relatively long duration, typically, 0.5 or 1 ms (Panizza et al., 1989a). A stimulus of an intensity slightly above the threshold for depolarization of the Ia afferents should induce the H-reflex as the only response of the soleus muscle, avoiding concomitant activation of motor axons. Bipolar stimulation electrodes are perfectly suitable for all purposes in the study of the H-reflex. However, the use of the cathode placed over the nerve and the anode placed over the patella may be a safer procedure for separate activation of the Ia fibers in some cases (Hugon, 1973). Increasing the stimulus intensity causes the H-reflex to increase and the direct M-response to stimulation of motor axons to appear. In normal subjects, a stimulus intensity slightly above threshold for activation of motor axons gives rise to a H-reflex of larger amplitude than the M-wave. As the stimulus intensity increases, the H-reflex amplitude continues to increase up to a certain size and then decreases to completely disappear. Progressively increasing the intensity of the stimulus causes depolarization of some motor axons together with the Ia axons. By increasing the stimulus intensity, more Ia afferent fibers will become depolarized, generating a larger afferent volley. Even though the afferent volley will be able to activate a larger number of alpha motoneurons, the size of the H-reflex will decrease rather than increase with increasing stimulus intensity. This may be due

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to collision between orthodromic and antidromic volleys in the motor axons (Magladery and McDougal, 1950) or, most likely, to active inhibition of alpha motoneurons induced by antidromic excitation of recurrent inhibitory (Renshaw) interneurons (Gottlieb and Agarwal, 1976). Renshaw’s cells induce inhibition not only in the parent motoneuron but also in neighboring motoneurons (Renshaw, 1941). Therefore, extinction of the H-wave reflects in part the effects of recurrent inhibition, a subject that will be dealt with in more detail below. Because of its physiological details, the recruitment curve of the H-reflex should be kept in mind in any studies in which the size of the H-reflex is taken as a measure of motoneuronal excitability to sensory stimuli. The following points of reference of the recruitment curve should be considered: The intensity threshold for the elicitation of the H-reflex; the intensity threshold for inducing the M-response, the amplitude of the H-reflex at M-threshold, the maximal amplitude of the H-reflex, the amplitude of the M-wave at maximal H, and the ratio between maximal H and maximal M. Both the amplitude of the H-reflex at M-threshold and the maximal amplitude of the H-reflex are usually described in percentage of the M-wave amplitude. 10.2.2.1.6. The H-reflex excitability recovery curve. Short interval repetitive elicitation of the H-reflex leads to a decrease in the H-reflex size. This is taken as an evidence for the conditioning effects of a stimulus, and has lead to the development of the paired shock technique for the study of the H-reflex excitability recovery curve. Taborikova and Sax (1969) were the first to describe the changes occurring in the H-reflex as a result of a conditioning posterior tibial nerve electrical stimulus. These authors showed an early phase of inhibition, attributed to depletion of neurotransmitter, a phase of relative reduction of inhibition, between 100 and 250 ms, attributed to a long-loop facilitation operating through bulbar and cerebellar centers, and a continuation of the inhibition up to more than 1000 ms. Actually, later studies demonstrated that post activation depression of excitability was not completely recovered until more than 8 seconds after the preceding stimulus (Crone and Nielsen, 1989). The paired (conditioning and test) shock technique for the assessment of the H-reflex excitability recovery has the important drawback of the fact that the test

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H-reflex is not necessarily generated in the same motoneurons that have been activated by the conditioning H-reflex, and other factors modifying the excitability of the motoneurons, such as recurrent inhibition and after-hyperpolarization, affect the results. In an attempt to overcome this problem, Pierrot-Deseilligny and Bussel (1975) proposed a method to study more carefully the early part of the H-reflex excitability recovery curve, and the effects of recurrent inhibition (see below). These authors made sure that the H-reflex elicited by the test stimulus was due to activation of the same motoneuron pool giving rise to the response to the conditioning stimulus by provoking a conduction block in all other motoneurons using a test stimulus of supramaximal intensity. On doing so, Pierrot-Deseilligny and Bussel (1975) obtained evidence for the participation of recurrent inhibition in the early part of the excitability recovery curve. An observation of interest for clinical studies is that the inhibitory effect of repeated stimulation is reduced during voluntary contraction (Burke et al., 1989). Therefore, higher stimulation rates during voluntary contraction can be used for assessment of the H-reflex in muscles in which it is not usually obtained at rest. 10.2.2.1.7. The H-reflex as a measure of the spinal excitability state. Because of the monosynaptic nature of the early part of the response, the H-reflex can be safely used as a measure of segmental motor excitability, and of its control by descending pathways (Schieppati, 1987). The efficacy of afferent inputs in activating the alpha motoneuron depends on the excitability state of the H-reflex arc, including the motoneuron itself, the interneurons mediating presynaptic inhibition of the Ia terminals, and other propriospinal interneurons. Indeed, the excitability of the soleus H-reflex arc is known to change in relation to a large number of conditions (Misiaszek, 2003). Two main questions are, however, largely unsolved: What descending pathways are actually carrying the modulatory effects? and What is the exact target of those modulatory effects? 10.2.2.1.7.1. Modulation of the soleus H-reflex by remote muscle contraction. Various maneuvers cause modulation of the soleus H-reflex in humans. Probably the first to be considered, and the most known, is the Jendrassik maneuver. Remote contraction of

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a muscle induces facilitation of both the tendon jerk and the H-reflex (Delwaide and Toulouse, 1981; Miyahara et al., 1996; Zher and Stein, 1999). The temporal profile of the Jendrassik maneuver was accurately studied by Delwaide and Toulouse (1981). These authors divided the facilitation in three different phases, the first one due to a general preparatory state, before any EMG activity could be seen, the second one related to the descending motor command, that would activate not only the muscle in which the voluntary contraction was intended but also other muscles in the body, and the third due to a long-loop reflex generated in the re-afferentation during contraction. According to Zher and Stein (1999), the increase in the size of the H-reflex related to a remote muscle contraction is in part due to removal of presynaptic inhibition. However, Gregory et al. (2001) were unable to find any change in the amount of presynaptic inhibition in heteronymous afferents from the quadriceps muscle. Many studies have examined the physiology of the H-reflex changes preceding a voluntary movement in reaction time experiments. In these experiments, an imperative signal (IS) gives the subject the instruction to begin moving and, in certain paradigms, the IS is preceded by a warning signal that announces the incoming instruction. Some time after the IS, the size of the H-reflex increases progressively until onset of EMG activity in the agonist muscle, and decreases in the antagonist (Michie et al., 1976; Eichenberger and Rüegg, 1983; Schiepati, 1987). Schieppati et al. (1986) showed that the increase of the H-reflex size preceding muscle contraction, or its decrease preceding the release of an ongoing contraction, occurred independently of changes in the amount of EMG activity, confirming that this modulation takes place at a presynaptic level. Furthermore, premovement enhancement of the H-reflex size was not modified by changing kinesthetic aspects of the movement (Collins et al., 1993), and was found to be timelocked to the movement itself rather than to the IS when changing the complexity of the reaction (Hasbroucq et al., 2000). Thus, these experiments pointed out to the fact that the H-reflex enhancement prior to a reaction is related to the motor commands issued for the actual movement execution rather than to any sensory feedback signals. A different behavior has been reported during forewarning (i.e., the time between the warning signal and the IS). During this time, the H-reflex of the agonist muscle undergoes non-specific changes, which occur regardless whether the intended movement is planned for the

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soleus muscle itself or for distant muscles (Brunia and Vuister, 1979). The presentation of the warning signal induces a small increase of the H-reflex, probably related to an arousal effect. In forewarning periods of 1000 ms, Gerilovsky et al. (1983) found that this increase was followed by a decrease, occurring at about 800 ms, for the H-reflex to increase again together with the arrival of the IS. Such a decrease could be due to a presynaptic effect on Ia afferent terminals since the excitability of the motoneuron itself seems not to change. Many other physical activities lead to soleus Hreflex modulation, probably the most relevant ones being postural changes (Koceja et al., 1993; Trimble, 1998; Goulart et al., 2000) and walking (Dietz et al., 1979; Capaday and Stein, 1986; Faist et al., 1996). Koceja et al. (1993) reported a decrease in the H-reflex size in standing compared to sitting, even though the soleus muscle exhibits tonic EMG activity while standing. This is probably the consequence of an increase in the excitability of the soleus motoneurons, with a concomitant increase in the amount of presynaptic inhibition of the Ia afferent terminals (Goulart et al., 2000). The temporal profile of the changes occurring in the soleus and tibialis anterior H-reflex size during the sit-to-stand movement have been studied by Goulart and Valls-Solé (2001). The H-reflex of the tibialis anterior undergoes an early increase preceding the initial phasic burst seen in this muscle at the beginning of the movement. This is followed by a decrease coinciding with the progressive increase of the soleus H-reflex size. At the end of the maneuver, the soleus H-reflex size decreases again, probably due to the intervention of mechanisms of presynaptic inhibition. During walking, different investigators have reported facilitation of the soleus H-reflex size in the stance phase and inhibition in the swing phase (Dietz et al., 1979; Faist et al., 1996; Capaday and Stein, 1986). Not only physical but also mental activities cause a change in the size of the H-reflex. These include mental rehearsal of a movement (Bonnet et al., 1997), alertness (Hodes, 1967) or focussed attention (Honore et al., 1983). 10.2.2.1.7.2. Modulation of the soleus H-reflex by remote external stimuli. External activation of specific descending tracts causes also modulation of the soleus H-reflex in humans. Vestibulo-spinal tract activation with galvanic stimuli caused facilitation of the H-reflex (Kennedy and Inglis, 2001). External activation of the reticulospinal tract by auditory stimuli has

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also been reported to cause enhancement of the soleus H-reflex by several authors, Rossignol and MelvillJones (1976) examined the sound-related changes of the H-reflex size in volunteers who were hopping to the rhythm of a musical instrument. These authors reported the synchronization of hopping with the strong beats of the musical piece, in such a way that the motor events were timed to make best use of the auditory facilitation of the segmental reflex. Delwaide and Schepens (1995) confirmed the finding of Rossignol and Melvill-Jones (1976), and demonstrated that the audiospinal facilitation was abnormal in patients with reticulospinal tract dysfunction (Delwaide et al., 1993). Finally, activation of the corticospinal tract with cortical stimulation causes also modulation of the soleus H-reflex. Using electrical stimuli, Cowan et al. (1986) reported a short latency, short duration phase of facilitation of the H-reflex of various muscles. However, the soleus H-reflex was inhibited rather than facilitated. This was attributed to the fact that corticospinal projections to the soleus muscle are mainly inhibitory. With transcranial magnetic stimulation (TMS), the soleus Hreflex shows two phases of facilitation (Goulart et al., 2000). The first one occurs at intervals between 5 and 30 ms and is assumed to represent the facilitation of the reflex due to the generation of a soleus motoneuronal EPSP. The second one, occurring between 50 and 100 ms, is presently of unknown origin. However, some results may indicate that it may be mediated by subcortical structures and, more specifically, by the reticulospinal tract, probably activated through corticoreticular connections. In cats, the H-reflex is modulated by direct stimulation of the mesencephalic locomotor region (Gosgnach et al., 2000), an observation that is in line with the changes of the H-reflex size during walking reported in humans. Regarding the target of the effects, it is important to notice that vestibular stimulation in cats induced a change in the presynaptic inhibition of Ia afferent terminals (Rudomin and Schmidt, 1999). Electrical or mechanical stimuli applied anywhere in the body are also capable of inducing changes in the size of the soleus H-reflex. Gassel and Ott (1970) showed that cutaneous stimuli of the dorsal and plantar surfaces of the distal foot in humans induced opposite effects on the soleus H-reflex, with short latency facilitation with stimulation of the dorsum, and inhibition with plantar stimulation. These effects were followed by a prominent late increase of excitability with both stimuli. Later, the same authors demonstrated that such late facilitation occurred with widespread

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cutaneous stimulation (Gassel and Ott, 1973). The short latency effects were considered to be a local sign due to the segmental effects induced by activation of type II cutaneous afferents, while the late facilitatory effects were thought to be the consequence of a widespread, multilevel, spinal effect induced by group III fibers activated by the same cutaneous stimuli. The effect would be transmitted through propriospinal circuits up to the brainstem, according to the concept of the spino-bulbo-spinal reflex, proposed by Shimamura and Livingston (1963). These authors proposed that small myelinated fibers would activate such a spinal long-loop reflex by sending inputs centripetally to the reticular formation where they will produce a bilateral descending efferent ventral root discharge. Even though the existence of spino-bulbo-spinal tracts has not been proven so far, the effects of cutaneous nociceptive stimulation over the H-reflex have continued to be shown in different research studies. The electrical stimuli used to elicit the H-reflex unavoidably activate the skin receptors lying below the cathode. Although this nociceptor afferent discharge will not influence the size of the H-reflex elicited by the same stimulus because of a different conduction velocity, it will likely be partly influencing the excitability of the reflex arc to subsequent stimuli. This possibility was examined by Sabbahi and DeLuca (1981), who showed that the excitability recovery of the soleus H-reflex was enhanced when they applied a topical anaesthetic to the skin of the popliteal fossa. The interaction between pain and muscle afferents has been the subject of more recent studies (Le Pera et al., 2001), demonstrating a late inhibitory effect of tonic muscle pain on the H-reflex. 10.2.2.1.7.3. Propriospinal circuits for inhibitory control of motoneuronal firing. Whatever the source of the modulatory inputs, the last step in the central control of H-reflex excitability is made through spinal interneurons with inhibitory projections to the motoneurons (postsynaptic inhibition) or to the Ia afferent terminals themselves (presynaptic inhibition). These circuits which are summarised in Table 10.2, are available to neurophysiological study using the relatively complex techniques developed by PierrotDeseilligny and coworkers (Pierrot-Deseilligny et al., 1981; Pierrot-Deseilligny and Mazières, 1984a,b). Reciprocal inhibition is mediated by Ia inhibitory interneurons. These interneurons receive excitatory inputs from Ia muscle afferents, and project to the motoneurons of the physiologically antagonistic

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Table 10.2 Propriospinal inhibitory mechanisms Mechanism

Interneurons implicated

Neurotransmitter

Tests

Ia inhibition Ib inhibition Renshaw inhibition Presynaptic inhibition

Ia inhibitory interneuron Ib inhibitory interneuron Renshaw cell PAD* interneurons

Glycine Glycine Glycine GABA

Reciprocal Autogenetic Recurrent Presynaptic

* PAD: Primary afferent depolarization

muscle, in which they induce a disynaptic IPSP (Fig. 10.3A). The Ia interneurons impinging on the extensor muscles, and the alpha and gamma motoneurons innervating flexor muscles, are supposed to receive parallel inputs from descending pathways (“alpha-gamma linkage with reciprocal Ia interneuron coactivation”). The electrophysiological evidence for reciprocal inhibition was first obtained in the leg muscles by Mizuno et al. (1971). These authors attempted to activate the Ia inhibitory interneuron projecting to soleus alpha motoneurons by stimulating the large Ia afferent fibers from the pretibial muscles. However, it turned out that the hypothesized disynaptic decrease of the soleus H-reflex amplitude to peroneal nerve stimuli was present only when the subject maintained a voluntary dorsal flexion. In subjects at rest, these authors reported the observation of two H-reflex suppression phases of long latency, suggesting that other mechanisms were at play (Mizuno et al., 1971). Voluntary contraction would have caused an inhibition of central origin because of the alpha-gamma linkage with reciprocal Ia-interneuron coactivation. Therefore, it was believed that the spinal circuit of Ia reciprocal inhibition could not be demonstrated neurophysiologically because the effect was too week. A few years later, however, Day et al. (1984) reported that the circuit in the forearm muscles was different to that of the leg muscles in such a way that the inhibition of the H-reflex of the forearm muscles by a radial nerve shock was indeed present at rest. Interestingly, Day et al. (1984) reported also two long latency phases of H-reflex suppression following the disynaptic phase, similar to those described by Mizuno et al. (1971). Since then, conditioning of the median nerve H-reflex by electrical stimulation of the radial nerve has been considered the paradigmatic test for reciprocal inhibition. The test is very useful for the evaluation of patients with forearm dystonia (Rothwell et al., 1988; Nakashima et al., 1989; Panizza et al., 1989b;

Deuschl et al., 1992). Appropriate methodological recommendations have been put forward by Fuhr and Hallett (1993). Autogenetic Ib inhibition is mediated by Ib inhibitory interneurons. These interneurons receive excitatory inputs from Ib Golgi tendon organ afferents, and project to the homonymous and synergistic motoneurons, in which they induce a disynaptic IPSP (Fig. 10.3B). It is to be noted, however, that the Ib interneuron receives also inputs from the Ia fibers. During contraction, Golgi tendon organs are very sensitive to muscle stretch. When a stretch occurs (for instance, due to a tendon tap), the stretch receptors are activated and induce the monosynaptic reflex, but both the Ia afferents themselves, and the Ib afferents, will activate the Ib interneuron and inhibit the motoneuron with a delay of 1 synapse. The circuit of Ib inhibition is available to electrophysiological testing with the individual at rest, thanks to the fact that the nerve from the gastrocnemius medialis muscle does not carry Ia afferents for soleus motoneurons (Pierrot-Deseilligny et al., 1979). A low intensity electrical stimulus given to the nerve from the gastrocnemius medialis muscle will, therefore, activate the Ib afferents. The subsequent activation of the Ib inhibitory interneuron will cause disynaptic inhibition on the synergistic soleus motoneurons. This takes place in the form of a small decrease of the amplitude of the soleus H-reflex between 4 and 6 ms after the gastrocnemius medialis nerve stimulus. As in the case of the Ia interneuron, the Ib inhibitory interneuron receives many different inputs from descending tracts. It is to note that the dorsal reticulospinal system originating in the nucleus reticularis gigantocellularis (NRGC) sends facilitatory projections to the Ib interneurons (Takakusaki et al., 1994), and inhibitory projections to the Ia interneuron (Delwaide et al., 2000). Dysfunction of the reticulospinal system may be the cause of an abnormal subcortical state of preparation for the execution of

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a motor action in patients with Parkinson’s disease (Delwaide et al., 2000). Recurrent inhibition is mediated by Renshaw interneurons. These interneurons receive excitatory inputs from the first axonal collateral from alpha motoneurons, and project to the homonymous and

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neighboring motoneurons (Renshaw, 1941), in which they induce a disynaptic IPSP (Fig. 10.3C). PierrotDeseilligny and Bussel (1975) devised an electrophysiological method to assess recurrent inhibition with the soleus H-reflex. The method requires a stimulator capable of delivering two stimuli of different

A

B Supraspinal innervation

SOL IA interneurons

P.A.D.

P.A.D. Test

GM α

α α

Cond.

IA afferents IA afferents

1a

1b

1c

= excitation = inhibition

Reciprocal innervation

C

D

Vibratory Inhibition

H reflex

40 α Mn

ACh

Control

Ren

20

Gly α Mn

Millivolts

ACh

10

Vibration

H vib.

0 40 120 200 Volts

Motor axon Renshaw’s cell

M

30

Control

Vibration

F wave 100 μV 10 msec

Motor neuron

Fig. 10.3 Propriospinal inhibitory circuits available to neurophysiological study with the H-reflex. (A) Reciprocal inhibition. This is mediated through the Ia inhibitory interneuron, which is activated by Ia afferents of one muscle and have inhibitory projections to the motoneurons of the antagonist muscle. There is neurophysiological evidence for three distinct phases of reciprocal inhibition, the first one is suggested to be postsynaptic, following a dysynaptic circuit; the second one is suggested to be presynaptic, occurring at a latency of about 10 ms, and the third is suggested to follow a polysynaptic circuit. (B) Autogenetic (homonymous) inhibition. This is mediated through the Ib inhibitory interneuron, which is activated by axons coming from receptors located at the Golgi tendon organs. The Ib inhibitory interneuron has inhibitory projections to the homonymous motoneurons. The only known evidence for the inhibitory Ib effects is a single phase of weak inhibition. (C) Recurrent inhibition. This is mediated by the Renshaw’s cell, which is innervated by the first collateral stemming from the main axon and has inhibitory projections to the parent motoneuron. Evidence for the effects of Renshaw’s inhibition is obtained with techniques using paired shocks and consists in a long lasting inhibition. (D) Presynaptic inhibition. This is mediated by primary afferent depolarization (PAD) neurons acting over the Ia afferent terminals from the same muscle. Evidence for presynaptic inhibitory effects on the homonymous Ia afferents are obtained with the application of vibratory stimuli, while the effects on heteronymous Ia afferents can be objectivated in the facilitatory effects of quadriceps Ia afferents over the soleus H-reflex.

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intensity through the same pair of electrodes. The first stimulus is of low intensity, capable of inducing a small amplitude H-reflex (H1). The second stimulus, of supramaximal intensity and, therefore, activating massively all efferent and afferent fibers, should be delivered 10 to 15 ms after the first. At that moment, there should be an orthodromic volley descending in the motor axons after the activation of a few motoneurons by the first stimulus. However, such volley will not be able to generate any action potential because it will collide with the antidromic volley induced in all motor axons by the second, supramaximal, stimulus. The collision will abolish all action potentials in those motor axons and, therefore, let the specific population of motoneurons activated by the first stimulus free from any inhibition and ready to fire again when the new excitatory input arrives after activation of the Ia afferents by the second stimulus. This will result in the generation of new H reflex, termed H′. However, H′ is always smaller than H1. If the amplitude of H1 is made to increase by increasing the intensity of the conditioning stimulus, there will be first an increase in the amplitude of H′, which will be followed by a progressive decrease when the intensity reaches a certain level. This decrease is due to the effects of Renshaw cell activation on the motoneuron pool involved in the generation of H1. The smaller the H′ with respect to H1, the larger the recurrent inhibition (PierrotDeseilligny and Mazières, 1985). The beauty of such a method lies actually in the fact that a similar chain of events can be considered partly responsible for silent periods and rebounds induced by stimuli applied to mixed nerves when there is traffic of impulses during voluntary contraction (see the paragraph on Silent Period below). Renshaw cells inhibit the homonymous motoneuron, other neighboring motoneurons, and also the Ia inhibitory interneurons projecting to the antagonist muscle (Houk et al., 1970). Descending central nervous system command may cause either facilitation or inhibition of the excitability of Renshaw cells. Presynaptic inhibition is mediated by axo-axonal synapsis in Ia afferent terminals themselves. The interneurons in charge of such inhibition are known as “primary afferent depolarization” neurons. These interneurons receive excitatory inputs from many sources and project to the terminal, causing its depolarization and the consequent depletion of neurotransmitter for new inputs not to be able to go through. As an important difference with respect to the other spinal mechanisms of motor control discussed so far, presynaptic

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inhibition takes place at a presynaptic level (Fig. 10.3D), therefore, leaving the motoneuron uninfluenced. Methods for electrophysiological testing of presynaptic inhibition involve activation of the Ia afferents of the same muscle by means of vibration (Wong et al., 1977; Pierrot-Deseilligny and Mazières, 1985). A slightly more sophisticated technique has also been developed to test presynaptic inhibition (Hultborn et al., 1987). This is based on the heteronymous facilitation induced by quadriceps Ia afferents on the soleus motoneurons. In their experiment, Hultborn et al. (1987) quantified the effects of vibration on the soleus H-reflex as a percent decrease of the size of the response during vibration. Then made a compensation of the size of the H-reflex by increasing the stimulus intensity until the vibrated Hreflex reached the same size as the control H-reflex. The next step was to induce a facilitation of the soleus H-reflex by activating the quadriceps Ia afferents. It was shown that during vibration, heteronymous facilitation decreased, demonstrating that presynaptic inhibition occurs in heteronymous and homonymous inputs alike and to the same extent. Interneurons responsible for presynaptic inhibition receive inputs from descending motor pathways, even though the exact source of these inputs is largely unknown. As described earlier, presynaptic inhibition is an important strategy of the central nervous system for control of reflexes. 10.2.2.2. Methods of clinical interest for the study of peripheral nervous system disorders with the H-reflex The study of the H-reflex is useful in various clinical conditions. As in all other neurophysiological methods, however, the assessment of the H-reflex on its own does not furnish enough information for reaching a specific diagnostic conclusion. The examiner has to bear in mind that only the combination of various tests is able to bring the evidence for localization of the abnormality or pathophysiologic understanding of lesion mechanisms. Of course, the final interpretation of all results has to be made in the context of the clinical neurological evaluation. 10.2.2.2.1. The H-reflex in the assessment of radiculopathies. The study of the H-reflex and the F-wave is to the assessment of radiculopathies as the study of nerve conduction is to the assessment of nerve entrapment. The electrophysiological approach to the diagnosis of radiculopathy should show the functional damage of a root, which is independent from the structural damage shown by radioimaging techniques (Nardin et al., 1999). The study of the H-reflex should

REFLEX RESPONSES, SILENT PERIOD AND LONG LATENCY REFLEXES

be undertaken whenever there is suspicion of a S1 radiculopathy or lumbar canal stenosis. It should be taken into account, however, that the H-reflex is equally affected by processes at the root level (preganglionic) and those at the plexus level (postganglionic). Therefore, the topographic location of the lesion requires the confirmation of normal sensory nerve action potentials. The soleus H-reflex is absent or has an abnormally prolonged latency in 100% of patients with S1 radiculopathy (Braddom and Johnson, 1974; Aiello et al., 1981; Sabbahi and Kahlil, 1990), and in only upto 26% of patients with L5 radiculopathy (Schuchmann, 1978; Rico and Jonkman, 1982). In patients with neurogenic claudication, conventional electrophysiological tests may not show positive signs at rest. Pastor and Valls-Solé (1998) studied the behavior of the soleus H-reflex before and after walking for 30 min, showing that exercise caused a transient increase in the H-reflex threshold relative to that of the M-wave in 10 patients with neurogenic claudication. 10.2.2.2.2. The H-reflex in the assessment of polyneuropathies. In all kinds of polyneuropathies, the H-reflex may be absent, suggesting conduction block in, or functional loss of, large afferent axons. The value of the study of late responses (H-reflex and F-wave) in the diagnosis of polyneuropathies has been compared to that of sensory nerve conduction studies. Different types of polyneuropathies may lead to a different type of abnormality in the H-reflex. Hence, a delayed but still present H-reflex might be consistent with predominantly demyelinating polyneuropathy, while absence of response or abnormally high threshold would be consistent with a predominantly axonal polyneuropathy (Guiheneuc and Bathien, 1976; Albers, 1993). The absence of the H-reflex is commonly paralleled with absence of the Achilles tendon jerk and the soleus T-wave. However, there are instances in which the Hreflex may be present and the Achilles tendon lost. This may occur in predominantly distal axonal polyneuropathies in which axons can be damaged only in their most distal part, preventing mechanical activation of the stretch receptors by the mechanical stimulus, but not electrical activation of the fibers at the popliteal fossa. Presence of a weak Achilles tendon with absence of the H-reflex can also occur. This would be the case in some patients with predominant loss of, or reduced excitability in, large axons. If activation threshold is increased in the Ia fibers, there may be no margin for their isolated or predominant activation. The electrical stimulus

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intended to activate the Ia fibers would always depolarize some alpha motor axons, which antidromic volley may prevent the observation of the H-reflex. The Achilles tendon jerk can still be present if enough Ia fibers are left intact for them to convey the mechanical activation of stretch receptors. The typical pattern of an S1 radiculopathy, i.e., absence of the H-reflex with preservation of the sensory nerve action potential, may also be found in polyradiculoneuropathies at the early stages of the disease. Characteristically, in the Guillain–Barré syndrome, the tendon jerks are lost and the H-reflex is absent at a moment in which there may be a complete nerve conduction block at a radicular level, with preserved excitability in distal nerve segments (Lachman et al., 1980). In a series of diseases with involvement of peripheral and central nervous system, the study of the H-reflex might be helpful for understanding the underlying pathophysiological mechanisms. This is the case, for instance, in spino-cerebellar disorders. In Friedreich’s ataxia, the involvement of dorsal root ganglia should cause the sensory nerve action potential amplitude to decrease and the H-reflex to be absent (Hugues et al., 1968). However, some patients with early onset cerebellar ataxia may have completely normal reflexes even though they show a noticeable sensory loss and absence of response in sensory nerve conduction studies (Harding, 1981). This clinical condition, known as Friedreich’s ataxia with retained reflexes (FARR) has a slightly better prognosis than the classical form. 10.2.2.2.3. The H-reflex in the assessment of diseases modifying the excitability of the motoneurons. The Hreflex is usually of normal latency in patients with motoneuron disease. However, its excitability might be enhanced. When in doubt, the observation of a Hreflex in muscles in which it is not normally observed unless during facilitation by voluntary contraction, may help to rule out chronic polyneuropathy and favor the diagnosis of motoneuron disease. The H-reflex is also useful in the study of the stiff-man syndrome. In this syndrome, patients have painful spasms induced by involuntary activation of spinal motoneurons. Abnormalities in the inhibitory control of alpha motoneurons are supposed to underlie the pathophysiology of this syndrome. In a group of 11 patients with stiff-man syndrome, Floeter et al. (1998a) have consistently found an abnormal decrease in vibratory inhibition of the H-reflex, and more scattered abnormalities in other propriospinal inhibitory circuits.

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10.3. Oligo- and poly-synaptic reflexes elicitable at rest Any electrical stimulus applied over a nerve trunk gives usually rise to a large afferent volley. The effects of that volley in the central nervous system may not be apparent in the majority of nerves when the muscle is at rest. Noteworthy exceptions in healthy human subjects are the orbicularis oculi reflex, the nociceptive withdrawal reflexes, and a few others. Most of these reflexes are known as exteroceptive reflexes. 10.3.1. The blink reflex 10.3.1.1. Physiological and technical considerations The blink reflex consists on a stimulus-triggered eyelid closure involving mainly activation of the orbicularis oculi muscle and relaxation of the levator palpebral muscle. The most commonly used stimulus in clinical practice is an electrical stimulus to the supraorbital nerve (Kimura et al., 1969; Shahani, 1970). An adequate stimulus duration is 0.2 ms, whereas the stimulus intensity is, usually, 2 to 4 times perception threshold. The reflex response of the orbicularis oculi to supraorbital nerve electrical stimulation consists of two separate components: an early ipsilateral R1; and a later bilateral R2 response. R1 is a pontine reflex, while R2 is presumably relayed through a more complex route including the pons and lateral medulla (Kimura and Lyon, 1972; Ongerboer de Visser and Kuypers, 1978). A mechanical tap over the glabella also elicits a blink reflex. Although the stimulus is a gentle tap, this is a cutaneous rather than a stretch reflex, probably relayed via the same polysynaptic reflex pathways as the electrically elicited blink reflex (Shahani, 1970). Response recording is done with surface electrodes. The active recording electrode is placed on the lower aspect of the orbicularis oculi muscle and the reference electrode 2–3 cm lateral. Careful placement of the electrodes may help reduce the stimulus artifact that may sometimes make it difficult to determine the exact onset latency of R1. A low-frequency cutoff of 200 Hz or more may also be helpful. Although it is recommendable that reference values are obtained at each laboratory for their own comparison to patients, normative values have been published by several authors (see, for instance, Kimura, 2001). The upper limit for R1 latency is 13.0 ms, and the latency difference between the two sides in the same subject must be less than 1.2 ms. The upper limit of normal latency for the R2 is 40 ms on the side of stimulation and 41 ms on the contralateral side, and the latency

J. VALLS-SOLÉ AND G. DEUSCHL

difference between the ipsilateral and the contralateral R2 evoked simultaneously by stimulation on one side should not exceed 5 ms. 10.3.1.2. Methods of clinical interest for the study of peripheral nerve disorders with the blink reflex The R1 response is relatively stable with repeated trials and is therefore better suited for assessing nerve conduction through the trigeminal and facial nerves. Analysis of R2, however, is essential in determining whether a lesion involves the afferent or efferent arc of the reflex. With a lesion of the trigeminal nerve, R2 is slowed or diminished bilaterally when the affected side of the face is stimulated (afferent delay), while stimulation of the unimpaired nerve gives rise to normal responses. With a lesion of the facial nerve, R2 is abnormal on the affected side (efferent delay), while the responses are normal in the unaffected side, regardless of the side of stimulation. 10.3.2. Withdrawal reflexes to nociceptive inputs 10.3.2.1. Physiological and technical considerations Fibers of small diameter are not normally accessible to direct electrophysiological tests using conventional methods. The most suitable methods for the study of small fibers are described in Table 10.3. A short train of electrical impulses applied to the sole of the foot, or to the posterior tibial or sural nerves at the ankle causes a reflex response leading to the withdrawal of the leg from the painful stimulus (nociceptive reflex). The response recorded in biceps femoris and tibialis anterior is made of two components, the RII and the RIII. The RII component is usually obtained at a relatively low, nonpainful, stimulus intensity. The RIII is obtained at a high intensity stimulation and is recruited in parallel with an increasingly painful sensation. When recording in the short head of the biceps femoris, the first muscle to be activated after a painful stimulation of the foot, response latency is 50–70 ms for the RII, and 80–130 ms for the RIII (Willer, 1983). The RII response is probably due to activation of large group A afferents, while the RIII response should be due to activation of Aδ and C fibers. The RIII response is largely inconsistent, and poorly comparable among individuals. Withdrawal reflex responses have been also recognized in the upper limb to noxious cutaneous stimuli (Floeter et al., 1998b). Reflex responses to nociceptive stimuli can also be generated in pelvic floor and facial muscles. The bulbocavernosus reflex (Vodusek et al., 1983) is usually obtained by applying electrical stimuli to the dorsal

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Table 10.3 Methods for neurophysiological evaluation of activity in pain and small fiber systems

Sensory pathways Standardized sensory testing Vibrometer Thermotest Algometer Laser stimulation

Touch and pain sensations Vibratory sensation Warm, cold, heat nociception and cold nociception sensations Pressure and pressure nociception sensation Pain sensation

Reflex responses Painful electrical stimulation Sudomotor function Blood pressure Heart rate

Reflex withdrawal motor responses Sudomotor skin response. Postganglionic axonal reflexes Baroreflex functions Cardiovagal functions

nerve of the penis or clitoris. Recording can be done through needle electrodes inserted in the bulbocavernosus muscle or in the anal or vesical sphincter muscles. It is also possible to record the response from the anal sphincter using surface electrodes. Reflex responses of facial muscles are obtained with relatively high intensity electrical stimuli to the median or tibial nerves. The clinical correlate of these responses is the palmomental reflex (Dehen et al., 1975). The reflex circuit of the facial responses to peripheral nerve stimulation is not known, but it may involve transcortical pathways. 10.3.3.2. Methods of clinical interest for the study of peripheral nerve disorders with nociceptive reflexes. The RIII response has been utilized in studies on efficacy of analgesic drugs, but it is not applied to clinical evaluation of patients. Nevertheless, the withdrawal reflexes to nociceptive stimuli may be a valuable tool to examine the function of small fibers. The bulbocavernosus reflex is abnormally large and has a shorter latency in patients with neurogenic bladder due to upper motor neuron disease, and is absent or has a prolonged latency in patients with cauda equina or conus medullaris lesions (Ertekin and Reel, 1976). The analysis of facial responses to peripheral nerve stimuli may help in the assessment of several peripheral and central disorders (Miwa et al., 1996; Valls-Solé et al., 1997). 10.4. Silent period 10.4.1. Physiological and technical considerations The silent period is defined as the transient absence or significant decrement of EMG activity during sustained voluntary muscle contraction. It may be due to actions taking place at the motoneuron cell body itself

or at the motor axons. An example of a silent period taking place initially at the motoneurons is the inhibition induced by postsynaptic inputs, for instance with external activation of descending tracts using transcranial magnetic stimulation (TMS). An example of a silent period due to effects taking place initially at the level of the motor axons is the inhibition caused by electrical stimulation of peripheral nerves. In both conditions, the silent period may be either the actual consequence of an inhibitory input, or the aftereffect of an excitatory input. These two mechanisms lead to a different type of silent period (Ashby, 1995). When it is the consequence of an inhibitory input, the silent period occurs as an initial event, without any facilitatory phase preceeding the decrement of EMG activity. When it is the after effect of an excitatory input, the silent period occurs after an initial EMG burst. 10.4.1.1. The silent period due to actions taking place at the motoneuron cell body Inputs of various sources are able to evoke direct effects on alpha motoneurons. One example of those is TMS, which has actually brought renewed interest for the events taking place during the silent period (Haug et al., 1992). Induction of a silent period with TMS involves discharging the magnetic coil on the scalp over the motor cortex area at a variable intensity during sustained muscle contraction. Low-intensity TMS is able to induce a silent period in hand muscles without preceding motor evoked potential, possibly due to activation of cortico-cortical inhibitory connections (Wassermann et al., 1993). With high intensity TMS, the silent period divides into two parts (Fuhr et al., 1991): the initial part attributable to effects of the descending volley on the spinal interneuronal and motoneuronal machinery, and the final part, due to cortical inhibition. The silent period

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after TMS can be induced in many muscles, including those ipsilateral to the side of stimulation (Wassermann et al., 1991), which physiological particularities are of great interest in the evaluation of interhemispheric inhibitory connections. Once they have been activated, alpha motoneurons are more difficult to reach firing threshold again. This is due to after-hyperpolarization (AHP), a condition that takes place in part because of potassium accumulation in the outer membrane space. The AHP is a means to regulate the rate of repetitive firing of individual neurons receiving a constant excitatory input. This is for instance what determines the firing frequency of alpha motoneurons that are continuously bombarded by inputs from a high frequency depolarizing current. The AHP is also the main feature underlying the EMG silent period occurring after synchronous firing of motoneurons. The length of the AHP may also be modulated by the central nervous system. For instance, this has been the case for shortening of the AHP in rats after stimulation of the raphe-spinal serotoninergic projections (Bayliss et al., 1995). If different motoneurons are activated according to their centrally driven random firing mode, their respective action potentials, and the corresponding AHP that follows, will occur at random intervals from each other. However, the addition of an extra facilitatory or inhibitory impulse reaching the motoneuronal membrane will be capable of synchronizing either the firing or the silence of some motoneurons. Synchronization will be followed by an inevitable series of events. With facilitatory inputs, the synchronous firing will cause an action potential that will be inevitably followed by a silent period because of the synchronization of the AHP period. With inhibitory inputs, the synchronous absence of firing will cause a silent period that will be inevitably followed by a facilitatory phase due to more motoneurons being ready to fire. If the technique of EMG modulation is used, any synchronizing event, like, for instance, the posterior tibial nerve eliciting the H-reflex, will induce a series of facilitatory and inhibitory phases of EMG activity, in a kind of oscillatory pattern (Fig. 10.4). In natural circumstances, the motoneurons receive a continuous bombardment of excitatory and inhibitory inputs. Usually, the effects of the inputs reaching the motoneuron during the AHP period are not evident, except if they do so when the AHP is approaching its end. Their effects can be demonstrated with the construction of the peri-stimulus time histogram of single motor units, recorded with needle electrodes during a weak contraction. If the action potential of a single motor unit is made to fire regularly at a stable fre-

J. VALLS-SOLÉ AND G. DEUSCHL

50 ms 0.2 mV

Fig. 10.4 Modulation of the soleus EMG activity by stimuli inducing the H-reflex. The EMG activity was rectified and 100 epochs of 500 ms duration averaged. The stimulus to the posterior tibial nerve is represented by the thin vertical line and the background level of EMG activity is shown by the double head arrow at the beginning of the trace. Note the small M wave just after the stimulus, the large H-reflex, and the series of clonuslike oscillations induced in the ongoing EMG activity.

quency, and a stimulus is applied at random intervals with respect to the motor unit action potential, the effects observed illustrate the phenomenon of AHP and its relationship with the silent period. If the stimulus finds the motoneuronal membrane excitability rising from the depth of the AHP, it will make that motoneuron fire again but, this time, at a shorter latency (i.e., will be recruited by the stimulus). On the contrary, if the stimulus finds the motoneuronal membrane excitability decreased, the motoneuron will not be activated, and will remain silent until another input becomes effective. The motor units that have been brought to fire will then remain silent for the whole length of the AHP period, and the ones that have not been recruited by the stimulus will fire at their normal pace. As a consequence, there will be a time window in which there will be no motor unit action potentials, the silent period. This will span between the action potentials generated by the motoneurons recruited and those not recruited by the stimulus. With a fixed intensity of the stimulus eliciting the events, the length of the silent period depends on (1) the mean interspike interval of the motor units that were active during contraction; and (2) the proportion of these units that were brought to threshold. 10.4.1.2. The silent period due to actions taking place in the motor axons A different picture arises when the peripheral nerve is activated directly with an external source of depolarization, i.e., when an electrical stimulus is applied to the nerve. This is actually the easiest method to elicit a silent period in routine clinical practice. Several peripheral nerves are accessible to supramaximal electrical stimulation. The stimulus used to induce the peripheral nerve silent period is usually the same as that used to induce a supramaximal compound muscle

REFLEX RESPONSES, SILENT PERIOD AND LONG LATENCY REFLEXES

action potential in the supplied muscle. The time window required to evaluate the whole length of the silent period should be at least of 200 ms. Maintaining a voluntary contraction involves random activation of motoneurons and their axons. The depolarizing volley induced by the external supramaximal activation of motor axons will travel orthodromically to induce the synchronized M-response, and antidromically to induce effects at a motoneuronal level. The first antidromic event will be the collision with the motor axons that happened to be activated at that moment. Note that those axons will be clear of any antidromic or orthodromic impulse for a certain time, which explains the first part of the silent period after the M-wave. In the axons in which the antidromic volley does not find any ongoing activity, the antidromic excitatory volley will reach the motoneuron, where it may induce a reverberating potential to travel again orthodromically and give rise to the F-wave. At the same time, however, the antidromic volley will reach the first axonal collateral and activate the Renshaw’s cell. This will produce inhibition of the homonymous and neighboring motoneurons (Renshaw, 1941), causing a long lasting silent period. In the mean time, descending excitatory inputs might have reached the motoneurons that were freed of any impulse because of the collision between orthodromic and antidromic volleys. These will not have recurrent inhibition on their own, and a number of them would have not undergone the inhibition induced by Renshaw cells in neighboring motoneurons. Therefore, they will give rise to a burst of action potentials, appearing in the middle of the silent period. This burst is known as the voluntary potential (Kimura, 1977), because it grows with the degree of contraction. It also grows with the length of the nerve supplying the muscle under study because of the higher probability of collision. Electrical stimuli to peripheral nerves cannot selectively activate motor axons unless specific preparations are used (Gandevia et al., 1984). Therefore, activation of sensory fibers will also contribute to the last part of the silent period by way of inhibitory inputs impinging on motoneurons. Figure 10.5 shows an example of the silent period elicited in thenar muscles to median nerve stimuli. When the stimulus is applied to purely sensory nerves, the effects on spinal motoneurons will vary depending on various factors such as the nerve stimulated, the muscle recording from, and the action being performed (Uncini et al., 1991). The silent period is of longer latency than the one induced with stimulation of a mixed nerve, and it begins with inhibition. Therefore,

253

Silent period

S 20 ms F

V

0.2 mV

S

Fig. 10.5 The silent period induced in thenar muscles by median nerve stimuli. The EMG activity has been rectified and 20 consecutive trials have been averaged. Two traces recorded with the same methodology are superimposed to see consistency of the results. The stimuli are given at the arrow and marked with ‘S’. Two different degrees of intensity of contraction were used, mild for the upper traces and strong for the lower traces. Note the two bursts interrupting the silent period. The first, labelled F, corresponds to a potential generated in the spinal cord at a segmental level. The second, labelled V, corresponds to the ‘voluntary’ potential (see text). Note the increasing size of the V potential with the intensity of contraction.

it is likely due to motoneuronal IPSPs. These may be caused by inputs from inhibitory interneurons, possibly Renshaw’s cells, activated by mildly myelinated type II fibers. The depth and duration of the silent period induced by sensory nerves is directly proportional to the intensity of the stimulus and inversely proportional to the strength of muscle contraction (Caccia et al., 1973; Uncini et al., 1991). After the silent period, there is a rebound of EMG activity, which is the consequence of membrane excitability recovery taking place after the IPSP. The silent period to cutaneous inputs can be interpreted as part of a complex long latency reflex response induced by the sensory stimulus and, as such, its physiological particularities are going to be discussed together with those of the long latency reflexes. 10.4.2. Methods of clinical interest for the evaluation of peripheral nervous system disorders with the silent period 10.4.2.1. The silent period of extremity muscles The silent period has not much use for the evaluation of peripheral nervous system disorders (Ford et al.,

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1995). Possibly the most known method for inducing a silent period is the application of an electrical stimulus over the median nerve at the wrist, while the subject is maintaining a weak muscle contraction of hand muscles by holding an object between thumb and index. Like other neurophysiological events reflecting conduction velocity, the latency of the silent period is going to be delayed in polyneuropathies implying a slow conduction velocity of afferent and efferent fibers. However, since at least part of the silent period is due to the action at the central nervous system, the peripheral delay may be counteracted by the normal central nervous system conduction and, therefore, will be milder in comparison to the results of peripheral nerve conduction studies. Another area in which the silent period may be of interest is in the assessment of diseases causing changes in the inhibitory control of motoneurons (Ford et al., 1995). This is the case with the tetanus infection (Fernández et al., 1988; Poncelet, 2000), in which neurotransmitter mediated inhibition of motoneurons is impaired and, therefore, inhibitory inputs carried by sensory afferents after peripheral nerve stimulation cannot generate IPSPs. The initial part of the silent period elicited by peripheral nerve stimuli that is due to the electronic collision between orthodromic and antidromic volleys, is usually preserved. 10.4.2.2. The silent period of the masseter muscles (masseter inhibitory reflex) Sustained voluntary activity of the masseter muscles is transiently interrupted after stimuli of various kinds. The most common method of examining the masseter inhibitory reflex (MIR) is an electrical stimulus applied to the mentalis nerve at its exit from the mandibular bone at the chin while subjects are asked to clench their teeth. This produces two phases of suppression of EMG activity (exteroceptive suppression [ES], or silent period [SP]). The early phase is called MIR1, ES1, or SP1, and the second phase is called MIR2, ES2, or SP2 (Cruccu and Ongerboer de Visser, 1999). Some subjects with bad dentures are not able to activate their masseter muscles and use the facial muscles instead. In these cases, no suppression of the EMG activity can be elicited either with a tap to the chin or with an electrical stimulus, because there is no silent period in most facial muscles. This should obviously not be mistaken for an abnormal MIR. Quantitative studies of the excitability of the brainstem inhibitory interneurons require measurement of response size (e.g., area of suppression): the level of

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background EMG activity must be kept constant. The signals must either be full-wave rectified and averaged, or examined by superimposing several trials. As with the blink reflex, the MIR provides information on the site of the lesion by analyzing whether the pattern of abnormality is afferent, mixed, or efferent. The efferent pattern of lesion is extremely rare except in conditions such as a purely motor trigeminal neuropathy and hemimasticatory spasm (Cruccu and Deuschl, 2000). ES1 is delayed in patients with demyelinating polyneuropathies and also in patients with severe diabetic polyneuropathy (Cruccu and Deuschl, 2000). ES2 is far less sensitive than ES1 to lesions along the reflex arc. Being mediated by a multisynaptic chain of interneurons, however, it is modulated by suprasegmental influences. 10.5. Long-latency reflexes as a result of modulation of sustained EMG activity Some long latency reflex responses are very small and only elicitable during muscle contraction. The elicitation of long latency reflexes during a sustained contraction allows for the recording of both, excitatory and inhibitory events, which would appear as an increase or a decrease of the amount of EMG activity with respect to the background level of activity recorded during the same muscle contraction without the interference of the stimuli. Therefore, superimposition or averaging of several traces may be required to demonstrate and quantify excitatory and inhibitory reflex responses. The technique of performing this type of examination using an electronically rectified electromyographic recording is sometimes referred as to the “modulation of electromyographic activity”. Using this method, facilitatory and inhibitory reflex phenomena can be quantified with respect to the level of background activity. 10.5.1. Long-latency reflexes of hand muscles Long-latency reflexes in extremity muscles can be elicited with various natural stimuli like muscle stretch (Rothwell, 1990) sudden leg displacements when standing (Dietz, 1993), or cutaneous airpuffstimulation (Deuschl et al., 1995). They consist of a series of reflexes depending on the eliciting stimulus. Their physiological function is to adapt movement in the stimulated extremity according to ongoing sudden changes of the external conditions. Methods to

REFLEX RESPONSES, SILENT PERIOD AND LONG LATENCY REFLEXES

reliably obtain the long latency reflexes of hand muscles without sophisticated equipment have been well standardized (Cruccu and Deuschl, 2000). These involve median nerve or radial superficial nerve stimulation while recording from thenar muscles during maintenance of a contraction of the opponens pollicis done by leaning the thumb at the fifth finger (Fig. 10.6). The reflex responses recorded in this way are termed long-latency reflex I-III (LLR I-III), following median nerve stimulation, and cLLR I-III following radial superficial nerve stimulation (Deuschl and Lücking, 1990). Median nerve stimulation at the wrist, at an intensity just below motor threshold, gives rise to a H-reflex, at a latency of 25–34 ms. This is followed by the LLR I, in about 30% of the normal subjects, the LLR II, in 100% of normal subjects, and the LLR III, in about 20% of normal subjects. The latency of these reflexes depends on the height of the subject. Table 10.4 shows the normal values on latency, amplitude and duration of the hand LLRs. Hand muscle reflexes are mainly used to diagnose alterations within the central nervous system like in myoclonus, multiple sclerosis, parkinsonian syndromes and choreatic syndromes (Deuschl et al., 1988, 1989; Cruccu and Deuschl, 2000). In case of peripheral nerve lesions, delayed motor conduction can be identified on the basis of prolonged nerve conduction leading to a delay of the whole reflex pattern. Desynchronization of the afferent volley, however, A

Primary motor cortex

Primary sensory cortex

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leads to absence of the reflex pattern. In some cases it may be of interest to see proximal changes of the peripheral nerve conduction that can be assessed with LLR-testing. 10.5.2. Other cutaneo-muscular reflexes Cutaneo-muscular reflexes elicited by stimulation of digital sensory nerves are less standardized and more difficult to obtain (Caccia et al., 1973; Jenner and Stephens, 1982). The subject should wear the surface recording electrodes attached over the 1st interosseous or thenar muscles, while electrical stimuli are given to the digital nerves of the index finger by way of ring electrodes or to any other cutaneous nerve of the hand (Deuschl and Lücking, 1990). The subject is asked to maintain a steady background contraction of the muscle under examination. The EMG activity is rectified and several epochs of, for instance, 500 ms, should be averaged time locked to the electrical stimulus. In this way, the amount of EMG activity will be modulated according to the excitatory or inhibitory effects of the stimulus. Excitatory effects will induce a more synchronous firing of motoneurons, and more motoneurons to fire at a certain time, increasing the size of the averaged EMG activity. Inhibitory effects will cause the opposite. Excitatory effects are labelled E waves, and inhibitory effects are labelled I waves (Fig. 10.7). The E and I waves are numbered B H-reflex I LLR II

LLR – II pathway following muscle and cutaneous stimulation

II LLR III Thalamus

III 0

Nucleus cuneatus I

100

200 (ms)

cLLR II 100 μV

skin

H-reflex pathway

Spinal cord

II cLLR III III 0

100

200 (ms)

muscle

Fig. 10.6 (A) Reflex pathways of the hand muscle reflexes. (B) Normal patterns of reflexes elicited by stimulation of the median nerve (upper set of graphs) and radial superficial nerve (lower set of graphs), in three normal subjects (I-III) (Adapted from Cruccu and Deuschl, 2000 with permission from International Federation of Clinical Neurophysiology.).

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Table 10.4 Normal values of the hand muscle reflexes following median nerve stimulation (HR and LLR) or radial superficial nerve stimulation (cLLR) in 102 normal subjects (age, 18–85 years) Mean

SD

SE

Count

Minimum

Maximum

28.9 40.6 50.3 76.0 37.6 50.2 75.9

2.4 2.5 3.2 4.6 2.6 3.0 3.6

0.2 0.5 0.3 1.0 1.0 0.3 0.7

102 26 102 20 7 100 31

24.1 36.8 43.1 70.3 35.0 43.0 70.0

35.4 47.2 59.3 92.1 43.0 60.0 82.0

B: Amplitude HR LLR I LLR II LLR III cLLR I cLLR II cLLR III

1.9 0.4 1.2 0.8 0.4 1.2 0.8

1.1 0.1 0.6 0.5 0.2 0.5 0.5

0.1 0.0 0.1 0.1 0.1 0.0 0.1

102 25 102 20 7 100 31

0.3 0.2 0.3 0.3 0.1 0.3 0.3

4.8 0.8 3.0 2.3 0.6 2.5 2.4

C: Duration HR LLR I LLR II LLR III cLLR I cLLR II cLLR III

10.4 8.9 22.3 27.6 10.0 24.0 27.7

2.5 7.8 5.4 8.7 3.7 6.6 6.2

0.2 1.5 0.5 2.0 1.4 0.7 1.1

102 25 101 20 7 100 31

6.0 3.0 12.0 9.0 7.0 9.0 15.0

17.0 46.0 40.0 44.0 17.0 50.0 40.0

A: Latency HR LLR I LLR II LLR III cLLR I cLLR II cLLR III

according to their order of appearance (E1, I1, E2, etc.). Some studies have also addressed foot muscle reflexes (Claus and Jakob, 1986). Meinck et al. (1983) reported on the utility of the cutaneo-muscular reflexes in the assessment of disor-

ders causing changes in the excitability of motoneurons. Abnormalities of leg cutaneo-muscular reflexes have been reported in four patients with the stiff-leg syndrome (Brown et al., 1997), in whom cutaneous electrical stimuli induced long-lasting spasms.

Fig. 10.7 The cutaneo-muscular reflex elicited in the 1st interosseous to electrical stimulation of the index finger. Two traces are superimposed to see the consistency of the result. The subject was maintaining the index finger straight against the weight of a small book. Electrical stimuli were applied with ring electrodes to the index finger.

20 ms E2

0.2 mV

E1 L

I1 S

I2

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CHAPTER 11

Nerve root stimulation Daniel L. Menkes* University of Tennessee Health Sciences Center at Memphis, TN, USA

11.1. Introduction Root stimulation (RS) techniques are capable of activating the proximal portions of the motor and sensory nerve roots resulting in nerve action potentials. While sensory nerve action potentials (SNAPs) are usually recorded directly, motor nerve potentials are usually recorded in the form of their induced compound muscle action potentials (CMAPs). All nerve action potentials are composed of subcomponent waveforms that demonstrate some degree of temporal dispersion (TD) over increasing distances. Given the lower amplitude of the sensory nerve action potentials, normal degrees of physiological TD limit the distance over which sensory nerves can be conducted and recorded, necessitating the use of somatosensory evoked potential techniques (Menkes, 2002a). In contrast, compound muscle action potentials are three orders of magnitude greater than their SNAP counterparts and can evaluate motor nerve conduction studies (NCS) over greater distances despite the effects of normal physiological TD. However, motor NCS in the upper extremity are infrequently performed proximal to the arm and the lower extremity is infrequently conducted proximal to the knee. Depending on an individual’s limb length, these techniques may exclude between 20 and 50% of the motor nerve from analysis. Motor NCS in these segments are more technically difficult to perform because of the distance of the excitable nerve fibers from the skin surface where conventional surface electrical stimulation is usually applied. Since the electric field is generated between the cathode and anode, physical separation of the anode and cathode will enlarge the electrical field and depolarize all excitable tissue within that region if * Correspondence to: Daniel L. Menkes, MD, Department of Neurology, University of Tennessee Health Sciences Center at Memphis, 855 Monroe Avenue, Link Building, Room 415, Memphis, TN 38163, USA. E-mail address: [email protected] Tel: +1-901-448-6199; fax: +1-901-448-7440.

the stimulus is of sufficient intensity. RS methodologies enlarge the size and current density of the electrical field so that the proximal portions of the motor nerve roots are stimulated. Therefore, RS methods provide a means by which motor NCS may be performed from the motor nerve roots to the target muscle. Similar to conventional motor NCS, pathological conditions may manifest as either latency prolongation or changes in waveform morphology such as non-physiological TD or proximal conduction block (PCB). Nerve conduction velocity calculations are less useful as the exact distance traversed is difficult to measure accurately. While F-waves and H-reflexes provide some assessment of these proximal segments, they only evaluate a small proportion of the largest and fastest conducting fibers evaluated by NCS. If only one large motor fiber capable of conducting an F-wave is unaffected by the underlying pathology, then a normal F-wave minimum latency (FWML) may be recorded. Conversely, significant degrees of either myelin dysfunction or axon loss may result in absent F-waves. Thus, the observation of absent F-waves associated with a normal distal CMAP is not pathognomonic for acquired demyelination. The same analogy may be applied to H-reflexes wherein a normal H-reflex latency may be noted when one large sensory fiber, the interneuron and one large motor fiber are unaffected by the proximal pathology. Similarly, an absent H-reflex may be noted in a variety of conditions other than proximal demyelination. For example, one could consider a patient with multifocal motor neuropathy with conduction block in the tibial nerve 5 cm distal to the popliteal fossa. The tibial late responses, F-waves or H-reflexes, may or may not be prolonged to the degree necessary to diagnose acquired demyelination with confidence. However, stimulation of the tibial nerve at the popliteal fossa that demonstrated non-physiological TD or PCB would confirm myelin dysfunction as the underlying pathological mechanism. Had the pathology been located in the thigh instead of distal to the knee, then motor NCS would not demonstrate either of these findings as the stimulation

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site is distal to the affected site. In this situation, stimulation of the tibial nerve proximal to the pathologic site could demonstrate these findings. RS is the method by which proximal stimulation is accomplished. However, RS techniques should be viewed as complementary tests to late response testing. The correlation between F-wave minimum latencies prolonged into the demyelinating range and RS abnormalities was reported in one case series of 31 patients where demyelinating abnormalities were noted in a total of 77 motor nerves (Menkes et al., 1998). F-wave minimum latency prolongation associated with a PCB was noted in 11 nerves, prolonged F-waves alone in 24 nerves and PCB alone in 42 nerves. Therefore, failure to have performed RS studies would have missed PCBs in over 50% of the affected nerves. Therefore, RS should be performed in cases of suspected proximal demyelination even when the FWML is not prolonged into the “demyelinating range.” However, RS need not be performed when sufficient F-wave and other neurodiagnostic abnormalities that meet established criteria for demyelination are observed. In summary, RS techniques extend the range of traditional motor NCS. This chapter will review RS methods, discuss the evidence for site of stimulation, discuss the merits and drawbacks of these techniques and discuss the clinical utility of this methodology. 11.2. Overview of root stimulation methods Although RS techniques activate the motor nerve roots, they have many similarities to conventional motor NCS. Both techniques rely upon supramaximal stimulation of the largest, most heavily myelinated subpopulations of the motor nerves. Strict adherence to proper technique with regard to stimulation and recording parameters to insure reproducibility is essential. As with any normative data, each laboratory ought to obtain its own normal controls from a representative sample of the general population. Alternatively, the technique must be performed in exactly the same manner as published in the literature. In each case, stimulation must be performed at least twice in order to demonstrate waveform presence and reproducibility. With the exception of thoracic and upper lumbar magnetic nerve root stimulation (MNRS) techniques, all RS methodologies are highly reproducible. Various techniques and their normal values have been summarized in another text along with illustrations of these techniques (Oh, 1993). Normal values used in the author’s laboratory are summarized in the appended tables.

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It cannot be overemphasized that root stimulation techniques activate these structures distal to the axon hillock. Therefore, RS techniques do not evaluate the entire length of the motor axons in the peripheral nervous system. This may be one explanation as to why there are cases of acquired demyelinating neuropathies that do not manifest PCB. There are two main methods in root stimulation studies: electrical and magnetic. Electrical nerve root stimulation (ENRS) utilizes an invasive method with monopolar needles wherein the electrical field distribution is widened by physically separating the cathode and the anode. In contrast, magnetic nerve root stimulation (MNRS) is a painless, noninvasive method wherein a magnetic field is used to induce an electrical field within the proximal portions of the motor nerves. Since MNRS is noninvasive, it can be undertaken on people with a bleeding diathesis or on those who require anticoagulation. Its main limitation is that most magnetic stimulators produce a lower electrical field density than is generated by ENRS techniques. A complete discussion of magnetic stimulation physiology is beyond the scope of this chapter but is discussed elsewhere (Chokroverty, 1990). The main reason is that invasive ENRS insures that the electrical field is generated in close proximity to the motor nerve roots whereas the magnetic stimulator induces an electrical field at a greater distance. Since the electrical field strength decreases as an inverse square of the distance, MNRS techniques are more susceptible to small changes in distance. One main criticism of RS techniques is that it is highly technique-dependent, requiring an additional degree of expertise; analogous to the differences between routine needle EMG and single fiber EMG, (SFEMG). While it is true that SFEMG and RS require an advanced skill set, the information that may be obtained from RS increases the sensitivity of diagnosing pathology in the proximal portions of the motor nerves. Since small changes in distance will result in a significant change in electrical field density, strict adherence to technique and avoidance of common pitfalls is essential. MNRS techniques are even more prone to small changes in magnetic stimulator positioning because of the greater distance from the targeted excitable nerve tissue. Unlike electrical fields, the energy in a magnetic field is not conserved so all of the energy is not transferred into the induced electrical field. Moreover, the greatest magnetic field intensity is generated at the skin surface, resulting in a smaller electrical field density at the motor nerve root. This effect is greatly pronounced in persons of large girth that results in an even greater distance between the skin and the target site.

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RS techniques also impose strict interpretation guidelines to insure specificity at the expense of sensitivity. Since suboptimal techniques will have a greater impact on proximal conduction studies, profound changes in CMAP morphology must be observed in order to diagnose proximal motor nerve pathology with confidence. As in more distal segments of the peripheral nervous system, significant CMAP morphology changes are identified based on significant changes in amplitude, duration or both. A simplified mathematical model of normal physiological TD demonstrated that phase cancellation could not account for greater than a 50% reduction in amplitude and area, (Rhee et al., 1990). Physiological conduction block is thus defined electrophysiologically as a 50% reduction in amplitude and area, whereas TD is defined as a 50% reduction in amplitude but not area that is associated with a significant increase in CMAP duration, (Ad Hoc Subcommittee on AIDS, 1991). Since etiologies other than acquired demyelinating polyneuropathies can result in such findings, it is important to exclude confounding possibilities such as electrode shift, compression neuropathies, pseudo-conduction block, and changes due to physiological TD in CMAPs with greatly reduced amplitude. Latency abnormalities may be used but they tend to be less sensitive and specific. 11.2.1. Overview of common root stimulation pitfalls Electrode shift may occur when the examiner asks the patient to shift position during the procedure or if the electrode shifts position because it is not tightly applied to the skin surface. Just as the ulnar nerve needs to be stimulated with the elbow bent in a certain position, nerve root stimulation requires that the patient maintain the same, specific posture throughout the procedure. In the author’s laboratory, the patient is seated in a backless chair with the elbows and knees bent at a 90–110° angle with the feet resting on a stool. The recording electrodes are placed snugly on the skin surface so that electrode shift is minimized during the procedure. The patient is also instructed to minimize any movement during the procedure. Any motor nerve conduction studies previously performed will have to be repeated so that the root stimulation data are compared to the distal CMAP data with the limbs and the recording electrodes in the same relative position. The median, ulnar and peroneal nerves are liable to compression even in those persons who do not have an underlying neuropathy. For example, a patient with an

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ulnar neuropathy across the elbow may demonstrate a 60% reduction in CMAP amplitude and area when comparing the below elbow stimulation CMAP waveform to the one obtained by stimulating above the elbow. For this reason, it would be incorrect to conduct the ulnar nerve at the wrist and proceed directly to nerve root stimulation and attribute the 60% reduction in amplitude and area to a PCB at the level of the motor nerve root. For this reason, the median nerve must be conducted up to the antecubital fossa, the ulnar nerve above the elbow and the peroneal nerve above the fibular head. Eliminating the confounding variable of a compression neuropathy is an important preliminary step in all RS techniques. Pseudo-conduction block is another common source of error for these studies. Consider a patient with a C8–T1 radiculopathy who presents one week after the onset of neck pain and weakness in the hand intrinsic muscles. Since Wallerian degeneration may not be completed until 3 weeks after the precipitating event, the distal portions of the motor axons may still be excitable. The ulnar nerve in this hypothetical patient might demonstrate a normal CMAP amplitude of 7 mV at the wrist, at the below elbow site, and at the above elbow site in addition to a value of 3 mV obtained from a cervical root stimulation. It would be incorrect to attribute this finding to PCB as the finding is due to incomplete Wallerian degeneration and the appearance of a pseudo-conduction block. Electromyographers who perform RS techniques within 3 weeks of symptom onset need to be aware of this potential pitfall. Another common source of a systematic error is that due to normal physiological temporal dispersion, as all CMAPs manifest less synchrony with more proximal stimulation given that the subcomponent motor fibers have different maximum conduction velocities. The amount of separation depends on the total distance traversed. Therefore, a distal CMAP is likely to have a greater amplitude and a shorter duration than a CMAP obtained by proximal stimulation. This becomes more problematic with lower CMAP amplitudes as fewer subcomponent fibers contribute to the CMAP. Thus, the CMAP duration increases in inverse proportion to the CMAP amplitude. This will lead to accentuated degrees of TD with increasing distance in CMAPs with a reduced amplitude. Root stimulation techniques are especially prone to this potential systematic error as the stimulus site to target muscle distance is significant greater than is generally noted with more distal stimulation. In order to insure

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specificity, the target muscle to be examined must demonstrate a minimum amplitude of 1mV at its distal stimulation site. Moreover, the median, ulnar and peroneal nerves must be conducted above common sites of compression such that the CMAP obtained from root stimulation may be properly analyzed. One final source of systematic error is the failure to appreciate that absence of evidence is not evidence of absence. Just as normal late response studies do not exclude the diagnosis of proximal demyelination, RS studies that demonstrate neither PCB nor significant TD do not exclude PCB either. This has led to significant confusion in the literature wherein new syndromes such as MAMA and DADS are invoked in order to explain cases in which there is no conduction block noted and yet the patient responds to immunomodulating therapy (Saperstein et al., 2001). Most of these reports were done in the absence of RS techniques so that proximal demyelination with secondary axon loss cannot be excluded as the underlying pathophysiology. RS techniques minimize the probability of arriving at an erroneous conclusion. In those cases where RS failed to demonstrate evidence of proximal demyelination, distal nodal conduction failure or distal demyelination would result in relative inexcitability of numerous motor axons. This would result in low amplitude CMAPs, relatively normal conduction velocities and the absence of PCB; features traditionally associated with axonal neuropathies. While the appearance may be “axonal,” distal demyelination cannot be excluded (Reid et al., 2001). Thus, a RS study that fails to document PCB does not exclude the presence of distal myelin dysfunction, mild degrees of proximal myelin dysfunction or both (Menkes, 2002b). While findings of PCB or TD strongly support the diagnosis of myelin dysfunction, the absence of these findings does not exclude the diagnosis. In summary, motor NCS, late responses and RS studies are far more specific then they are sensitive.

DANIEL L. MENKES

Fig. 11.1 Electrical cervical root stimulation technique at C5–C6.

ipsilateral hand intrinsic muscles, this method uses a monopolar needle inserted over the transverse process of C7 with the anode placed at T1. Another methodology is to widen the electrical field distribution by stimulating all nerve root levels contributing to a limb’s innervation by placing a monopolar needle at the rostral edge of the nerve roots to be excited and placing the anode 1–2 at the caudal edge of the nerve roots to be excited, (Menkes et al., 1998). For RS studies to the same ipsilateral hand intrinsic muscles, the monopolar needle is placed at the C5–C6 interspace with the anode over T2. For lumbosacral nerve RS to peroneal and tibial nerve innervated muscles, the monopolar needle may be placed at L1 as depicted in Fig. 11.3 or at L5 as depicted in Fig. 11.4. Each of these techniques has its inherent advantages and disadvantages that will be discussed in subsequent sections.

11.3. Electrical nerve root stimulation (ENRS) Electrical nerve root stimulation techniques enlarge the size of the electrical field so that all electrically excitable tissues between the anode and the cathode are activated during the stimulus. Two main methods have been described as depicted in Figs. 11.1 and 11.2. One method involves placing a monopolar needle above the specific nerve root to be activated and the anode placed one level caudal to that site (Berger et al., 1987). When RS is used for conduction to the

Fig. 11.2 Electrical cervical root stimulation at C7.

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Fig. 11.3 Lumbosacral monopolar needle nerve root stimulation technique at L1.

11.3.1. Common electrical nerve root stimulation pitfalls Proper technique is absolutely essential to performing ENRS. All patients who are about to undergo this technique should give their verbal informed consent. The patient should be aware that this technique is invasive and should be queried as to whether or not they have a bleeding diathesis or are receiving anticoagulation. Patients who are at risk of prolonged or excessive bleeding should not undergo this procedure. The patient should also be informed that there may be discomfort on monopolar needle insertion and during the electrical stimulation. This is not only good medical practice but it increases the probability of patient cooperation. Once the informed consent has been obtained,

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the patient should be seated in a backless chair with their feet placed upon a stool in order to reduce the probability that the patient will move. The electrodes should be applied to the target muscles to be examined and the motor nerves should be conducted above the common sites of compression. Once accomplished, monopolar needle placement is in order. The monopolar needle electrode must be placed 1 cm lateral to the midline, ipsilateral to the side to be examined and inserted down to the periosteum of the transverse process of the vertebral level to be stimulated. It is essential that the person’s axial anatomy be taken into consideration. Longer monopolar needles will be required on individuals with greater mass. Irrespective of the needle length used, the monopolar needle must be placed such that the needle tip rests within the periosteum of the transverse process of the vertebral level needed for nerve root stimulation. Proper placement will usually result in a palpable resistance when the monopolar needle is advanced. The patient often winces slightly when the periosteum is contacted. If asked to describe the sensation, most patients will describe it as a dull “tweak” or “fullness” in that area. The needle should be inserted such that there is minimal lateral or rotational motion with manipulation. Lack of resistance or significant motion usually implies improper placement. It is also important to ensure that the anode is properly placed as well. The anode is usually applied on the skin surface in the midline of the spinal column at a caudal vertebral level. Failure to place these properly may result in submaximal stimulation of the underlying structures. It is also important to deliver two stimuli in order to insure reproducibility. Non-reproducibility is often due to one or more of the following technical factors; monopolar needle placement, monopolar needle movement, submaximal stimulation due to patient anatomical factors, electrode shift, and a distal CMAP of the target muscle demonstrating a CMAP amplitude less than 1 mV. There are additional pitfalls of ENRS that are unique to each region being examined that are discussed in subsequent sections. 11.4. Magnetic nerve root stimulation (MNRS)

Fig. 11.4 Lumbosacral monopolar needle nerve root stimulation technique at L5.

Irrespective of the vertebral level stimulated, most magnetic stimulation techniques apply a circular magnetic coil centered over the nerve root to be stimulated 1–2 cm lateral to the edge of the vertebral column, (see Figs. 11.5–11.9). Most commercially available magnetic stimulators generate a magnetic field strength of approximately 2 tesla. The full output of

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Fig. 11.5 Magnetic cervical root stimulation technique at C5–C6.

Fig. 11.7 Thoracic magnetic stimulation technique.

Fig. 11.6 Magnetic cervical root stimulation technique at C8–T1.

Fig. 11.8 Lumbosacral magnetic stimulation over vertebral L1.

the magnetic stimulator is used in order to induce an electrical field at a 90-degree angle to the magnetic field. This will result in painless activation of excitable electrical structures within the induced electrical field. As will be described in subsequent sections, the commercially available magnetic stimulators generate a less dense electrical field than is obtained with ENRS. This is due to a variety of factors including distance from the nerve root, characteristics of magnetic fields versus electrical fields and nerve root geometry.

nerve root stimulation techniques are applicable here as well. Since the magnetic stimulator is held against the skin surface of the spinal column, it is not necessary to query the patient regarding a bleeding diathesis or anticoagulation. However, contraindications to magnetic resonance imaging studies are also contraindications to MNRS. If no contraindications are present, the patient should be reassured that MNRS techniques are painless although there may some degree of associated axial muscle contraction. It is important that the distance between the nerve roots and the magnetic stimulator be minimized so that the probability of submaximal stimulation is reduced. It is also important to insure that maximum magnetic stimulator output is utilized in all MNRS techniques. Both stimulation methods and potential pitfalls are unique to each particular region of the vertebral column that is

11.4.1. Common magnetic nerve root stimulation pitfalls All of the pitfalls regarding patient positioning, proper performance of motor nerve conduction studies, and avoiding common diagnostic pitfalls common to all

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Fig. 11.9 Lumbosacral magnetic stimulation over vertebral L5.

assessed. For this reason, these issues are covered in greater detail in those particular subsections. 11.5. Stimulation sites of ENRS versus MNRS These comparisons are possible for motor nerve conduction studies (NCS) to target muscles with easily obtainable F-waves. These nerves include the median nerve to the abductor pollicis brevis (APB), the ulnar nerve to the abductor digiti minimi (ADM) and the tibial nerve to the flexor hallucis brevis (FHB). RS, motor NCS and F-wave minimum latency (FWML) techniques stimulate the largest and most heavily myelinated motor fibers. The FWML incorporates the time required to ascend the motor fibers in antidromic fashion, 1 ms of “turn around” time at the level of the axon hillock and the time required to descend in the normal orthodromic fashion down to the target muscle. If 1 ms is subtracted from the FWML, then the result is the amount of time required to travel antidromically from the site of stimulation to the axon hillock and down to the target muscle. If the distal motor latency (DML) is added to this value, this represents twice the time required for the signal to travel from the axon hillock to the target muscle. Thus, the calculated F-wave motor nerve root latency (FWRL) is defined as 1/2 [(FWML-1) + DML]. In this manner, motor nerve root latencies derived from ENRS and MNRS studies can be compared to those calculated from the FWML (Cros et al., 1990). Electrical root nerve stimulation studies performed by Mills and co-worker demonstrated that the cervical latency to the ADM was on average 1.6 ms less than the calculated FWRL consistent with a site of stimula-

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tion distal to the axon hillock and near the exit of the nerve roots through the intervertebral foramen, (Mills and Murray, 1986). Based on a proximal conduction velocity of 60 ms, this indicates that the site of stimulation is an average of 9.6 cm distal to the axon hillock (Kimura, 1974). However, a later study found no significant difference between these values and inferred that the site of excitation was within millimeters of the axon hillock (Cros et al., 1990). Cros and his coworkers also reported no statistically significant difference in the average cervical root latency between 12 pairs of ENRS and MNRS within the same subjects although there was a trend indicating a slightly longer latency from ENRS. These authors also noted a high degree of correlation, (r = 0.97), between the ulnar FWML and the latency derived directly from MNRS. However, the lumbosacral spine differs from the cervical spine in that there are two potential sites of stimulation: one near the T12 spinous process that activates the motor axons adjacent to the conus medullaris; the other, at the level where the motor nerve roots exited the spinal canal (Maertens de Noordhout et al., 1988). This was noted in a subsequent report wherein the latencies to the quadriceps and tibialis anterior were significantly shorter with MNRS when stimulated at the T12–L1 vertebral level, (Ugawa et al., 1990). A subsequent report with L5–S1 vertebral level stimulation did not observe any significant differences in latency between electrical and magnetic techniques to either the TA or the FHB (MacDonnell et al., 1992). FWML analysis to FHB by these authors indicated that the site of stimulation was approximately 13 cm distal to the anterior horn cell pool innervating this muscle. A subsequent study using L1 vertebral level stimulation demonstrated no significant differences between the FWRL and the ENRS latencies (Menkes et al., 1998). Analysis of these data also revealed a high degree of correlation (r = 0.91), between the calculated FWRL and the ENRS latency to FHB. This author previously reported that MNRS at L1 did not produce a reproducible CMAP in the FHB in 50% of the normal subjects (Menkes et al., 1994). Both MacDonnell et al. (1992) and Menkes et al., (1994) concurred that lumbosacral MNRS was very difficult to accomplish at levels rostral to L4 whereas Ugawa et al. did not report this difficulty (Ugawa et al., 1990). One possible explanation is that Ugawa and his colleagues used a more powerful magnetic stimulator that achieved a peak flux of 4.6 tesla as opposed to the magnetic stimulator used by the other groups that reached a peak flux of only 1.5 tesla. The average stature of Ugawa and his coworkers’ subjects

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was significantly less (range 153–178 cm) than the studies by MacDonnell and his co-workers (range 157–193 cm) and Menkes and his colleagues (range 155–196 cm). It is also likely that Ugawa’s controls had significantly smaller body mass indices than those encountered by the other authors. The combination of a shorter, leaner subject and a more powerful magnet would greatly lessen the probability of nerve root inexcitation at the T12–L1 vertebral level. All of these studies suggest that there are two potential sites of motor nerve root stimulation, one near the axon hillock and the other at the exit of the nerve root through the intervertebral foramen. Thus, it is important to insure that normal values used in assessing a patient are done in exactly the same manner as the published technique. It should also be emphasized that RS techniques that activate the more distal site will not detect pathology affecting the motor nerve roots between the site of proximal stimulation, adjacent to the axon hillock, and the intervertebral foramen. 11.6. Cervical root stimulation techniques Cervical MNRS and ENRS techniques are performed in a similar manner although published ENRS techniques vary the site of monopolar needle placement. Both techniques utilize maximum stimulation using the same band pass filter settings as those used for routine motor NCS. ENRS utilizes a maximum current of 100 mA or a voltage of 400 V at a duration of 1 ms. MNRS utilizes 100% output of the magnetic

stimulator. Therefore, it is imperative that the electromyographer use normal values that were obtained in an identical manner. For MNRS, the identical magnetic stimulator should be used. Tables 11.1 and 11.2 summarize some normal values for both cervical MNRS and ENRS methodologies used in the authors’ laboratory. Latencies are provided for the biceps, triceps, ADM and APB. Regardless of whether MNRS or ENRS is used for stimulation, recordings over the median nerve innervated APB merit a separate discussion because these studies require a collision technique. 11.7. Abductor pollicis brevis collision technique The C8 and T1 motor nerve roots innervate both the thenar and hypothenar muscles. Therefore, RS at these levels will activate all motor fibers in both the median and ulnar nerves. The CMAP recorded from the APB in this situation will be the algebraic sum of the subcomponent sine and cosine waves from all nearby muscles including those with ulnar nerve innervation. Depending on the waveforms of these adjacent ulnar innervated muscles, there may be an additive effect on the APB CMAP that might obscure a conduction block. Conversely, there may be a phase cancellation effect resulting in a false manifestation of abnormal temporal dispersion or a conduction block. In order to overcome this confounding variable, a collision technique must be employed in order to eliminate the contribution of the ulnar nerve innervated muscles to the APB CMAP. This technique is similar to the one used

Table 11.1 Summary of magnetic cervical root stimulation data Latency data

Amplitude data

Target muscle

Reference

Mean ± SD (ms)

Upper limit (mean ± 3 SD)

Biceps Biceps Biceps Deltoid Triceps APB– no collision APB– no collision APB– no collision ADM ADM

Ingram et al, 1988 Cros et al., 1990 Ugawa et al., 1990 Ugawa et al., 1990 Cros et al., 1990 Ingram et al, 1988 Oh et al., 1993 Ugawa et al., 1990 Cros et al., 1990 Oh et al., 1993

5.3 ± 0.42 6.3 ± 0.8 5.3 ± 0.8 5.0 ± 1.0 6.0 ± 0.85 13.0 ± 0.96 14.0 ± 1.3 11.8 ± 1.0 13.8 ± 1.5 13.84 ± 1.51

6.6 8.7 7.7 8.0 8.55 15.9 17.9 14.8 18.3 18.37

Amplitude (mean ± SD)

6.6 ± 5.5

5.7 ± 5.4

5.3 ± 2.5

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Table 11.2 Summary of electrical cervical root stimulation data Latency data

Amplitude data

Target muscle

Reference

Mean ± SD (ms)

Upper limit (mean ± 3 SD)

Deltoid Biceps Biceps Biceps Triceps Triceps APB–no collision APB– w/collision ADM ADM

Ugawa et al., 1990 Menkes et al., 1998 Ugawa et al., 1990 Cros et al., 1990 Cros et al., 1990 Menkes et al., 1998 Ugawa et al., 1990 Menkes et al., 1998 Cros et al., 1990 Menkes et al., 1998

4.7 ± 0.6 5.7 ± 0.45 5.0 ± 0.8 5.8 ± 0.8 5.4 ± 0.85 5.2 ±1.0 12.0 ±1.2 14.3 ± 1.1 14.1 ± 1.5 14.4 ± 1.6

6.5 7.05 7.4 8.2 7.95 8.2 15.6 17.6 18.6 19.2

to evaluate a potential Martin-Gruber anastomosis, (see Figs. 11.10 and 11.11). The ulnar nerve is stimulated with simultaneous recordings over the APB and ADM. This technique requires an electromyograph capable of delivering two separate stimuli at a fixed interstimulus interval. The stimulus intensity is slowly increased until the ulnar nerve is being supramaximally stimulated with no negativity noted over the APB CMAP that is being recorded simultaneously. This APB CMAP should

Amplitude (mean ± SD)

16.3 ± 4.5 9.9 ± 5.5 10.0 ± 5.4 16.3 ± 5.3 8.4 ± 2.8 6.6 ± 2.5 8.0 ± 2.6

only demonstrate an initial positivity, as depicted in Fig. 11.11. This value is the amount of stimulation that will be given over the ulnar nerve prior to the RS that will occur 6 ms later. This will result in an ulnar nerve antidromic impulse that will “collide” with the descending RS volley that will eliminate the contribution of the C8–T1 nerve roots to the ulnar nerve that would normally activate muscles adjacent to the APB. Figure 11.12 demonstrate the APB and ADM CMAP waveforms without the collision technique. The APB Fig. 11.10 Ulnar nerve collision technique.

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demonstrates different morphology from that usual observed on conventional nerve conduction studies because of the contribution to the APB CMAP from adjacent ulnar nerve innervated muscles. By contrast, Fig. 11.13 demonstrates normal APB waveform morphology and the absence of an ADM CMAP due to an effective collision technique. 11.8. Electrical nerve root stimulation techniques

Fig. 11.11 Waveforms showing supramaximal ulnar stimulation and no median stimulation. [Note the initial positivity of the APB CMAP.]

Fig. 11.12 Waveforms in a normal subject without the collision technique. [Note the initial positivity of the APB CMAP.]

Many different techniques have been advocated but all of them attempt to increase the probability of nerve root stimulation by widening the distribution of the electric field by separating the anode and the cathode. The cathode is a monopolar needle placed at the appropriate vertebral level down to the periosteum 1 cm lateral to the midline on the side to be stimulated and in contact with the transverse spinous process. The anode, usually a circular ground electrode, is placed caudal to the cathode so that the electrical field can activate all excitable tissue between these sites. The maximum output of the electromyograph is used; 100 mA or 400 V at a duration of 1 ms with the filters set at a band pass

Fig. 11.13 Waveforms in a normal subject with the collision technique. [Note that the normal morphology of the APB CMAP has been restored and that no ADM CMAP is observed]

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of 10 Hz to 10 kHz. The gain is set at 2–5 mV per division at a sweep of 5 ms per division. Stimulation may be performed at C5–C6 for the biceps, triceps, APB and ADM as depicted in Fig. 11.1. If the ADM and APB are the only target muscles of interest, then stimulation at the C7 transverse process may be performed as depicted in Fig. 11.2 (Berger et al., 1987). 11.8.1. Specific cervical electrical nerve root stimulation pitfalls Although cervical ENRS with the cathode at C7 and the anode at T2 produces a higher electrical field density at the C8–T1 nerve roots, pneumothorax is a known risk of this procedure (Sander et al., 1997). Stimulation at C5–C6 produces similar waveforms and has no reported incidence of pneumothorax, (Sander et al., 1999). Therefore, cervical nerve root stimulation should be performed first at the C5–C6 level. Stimulation at the C7 level may be performed at the electromyographer’s discretion in order to confirm an abnormality noted at C5–C6. Prior to performing this technique, the patient should be informed of the potential for pneumothorax and instructed to report any symptoms of dyspnea. Any such symptoms should be evaluated emergently. Great care must be taken in order to insure that the needle is inserted 1 cm lateral to midline so that the thecal sac is not pierced with a resulting traumatic myelopathy. For similar reasons, the needle must be advanced slowly in order to avoid trauma to surrounding tissue. 11.9. Magnetic nerve root stimulation techniques Unlike ENRS, MNRS techniques are noninvasive and painless. Most studies have reported data using magnetic field strengths of less than 2.2T. It must be emphasized that the spinal cord is not directly stimulated. One of the first publications by Barker and his co-workers noted that optimal cervical MNRS stimulation site was just lateral to the spinal column as close to the exit foramina as possible as illustrated in Fig. 11.3 (Barker et al., 1987). Other authors confirmed that the maximum amplitude from cervical MNRS is obtained by centering the coil over the spinous processes of C3, C4, C5, or C6 (Chokroverty et al., 1991). Another study reported that MNRS to the biceps, triceps and ADM were highly reproducible (Cros et al., 1990). These authors noted that the latencies from MNRS were statistically similar to those obtained from ENRS but that the amplitudes observed

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from MNRS were significantly less than those derived from ENRS. 11.9.1. Specific cervical magnetic nerve root stimulation pitfalls While there is no risk of traumatic neural structural injury, it should be recalled that metallic objects in or around the stimulated region may react to the sudden change in magnetic field density. The safety of this technique in patients with vagal nerve stimulators, cardiac pacemakers and previous penetrating trauma from metallic objects is unknown. Until such data are available, patients should be questioned as to whether or not they have any contraindication to magnetic or electrical stimulation in this region. If there is any question, then neither ENRS nor MNRS should be performed. Another potential pitfall is failure to maintain the proper positioning of the magnetic stimulator throughout the MNRS study. Small changes in magnetic stimulator orientation can have profound effects on the electrical field density and geometric distribution. It is essential that both the patient and the examiner maintain the same relative position throughout the study. 11.10. Summary/Comparison Magnetic nerve root stimulation and ENRS both produce statistically similar latencies with cervical RS. A statistically prolonged latency with either technique may be found with motor nerve root pathology. However, the amplitudes derived from MNRS are significantly lower than those obtained from ENRS. The report by Cros and his co-workers demonstrated that the ratio of the CMAP from MNRS to ENRS was 0.66 for the biceps, 0.57 for the triceps and 0.8 for the ADM. However, the range of these ratios to the ADM was 0.9 to 1. In another publication that examined 30 normal subjects, MNRS did not elicit CMAPs from the ADM in 4 subjects and from the APB in three subjects, (Oh, 1993). However, no collision technique was used in order to eliminate the contribution of ulnar-innervated muscles from the APB CMAP. While it is possible that phase cancellation may have contributed to the APB findings, the ADM abnormalities cannot be explained on this basis. Another group of authors reported similar findings as well as the observation that ENRS was more painful than MNRS especially at the C5–C6 site, (Evans et al., 1990). Thus, MNRS may be used as a screening test for proximal pathology. If no significant latency prolongation or

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amplitude reduction is noted, then ENRS need not be performed. However, any abnormalities noted on MNRS must be confirmed with ENRS prior to diagnosing abnormal temporal dispersion or a PCB. 11.11. Thoracic root stimulation techniques 11.11.1. Electrical nerve root stimulation The techniques for the thoracic region follow the same basic principles as those described in the previous section. However, there is a paucity of human subject data on ENRS in this region as there have been concerns regarding inducing cardiac arrhythmias. However, a canine model demonstrated no adverse effect on cardiac function with direct spinal cord electrical stimulation at T9–T10 at 50 mA or greater at 50 Hz for a duration of 1–2 seconds, (DiMarco et al., 1999). Another study of lumbosacral root stimulation with the dorsal insertion of a needle cathode at S1–S2 and the anode placed ventrally over the midpoint between the umbilicus and the tip of the xiphoid process did not report any adverse cardiac events (Troni et al., 1996). Despite these studies, it is likely that additional animal model data will be required before local IRBs will approve thoracic ENRS studies in human volunteers so that normal data may be obtained. 11.11.2. Magnetic nerve root stimulation This technique has been used to evaluate motor nerve root latencies from the thoracic region. One publication described thoracic region magnetic stimulation with a circular coil placed over the posterior axillary line and recording CMAPs from the upper rectus abdominus, external oblique and intercostals (Chokroverty et al., 1995). These authors reported that one patient with diabetic radiculoneuropathy demonstrated prolonged latencies to these muscles. The utility of this technique remains to be confirmed by other authors. Neither these authors nor another group that stimulated the thoracic region between T2 and L3 with the coil centered over each interspace between these levels reported any adverse events with MNRS (Tsugi et al., 1993). Despite these studies, the same caveats regarding cervical MNRS apply to thoracic stimulation as well. 11.11.3. Discussion Thoracic MNRS has been conducted without any reports of adverse events. However, this technique has

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limitations not encountered in other spinal regions. F-waves are difficult to obtain from thoracic musculature because of the relatively short distances involved between the axon hillock and the target muscle. In distal limb muscles, the distance along the nerve allows for the CMAP discharge to complete and the largest motor axons to return to their resting potentials prior to the arrival of the depolarizing F-wave volley. In shorter nerve segments, the largest motor axons have not returned to their resting potential by the time the F-wave volley arrives at the motor end plate. Thus, F-wave methods cannot be used to calculate the site of MNRS activation although it is likely that it does occur proximal to the motor nerve root exit from the intervertebral foramen (Chokroverty et al., 1995). These authors remark that the latency of the potentials remains relatively stable but the CMAPs have highly variable amplitudes and thus the waveforms do not always reproduce. Therefore, any electrophysiologic diagnosis made on the basis of thoracic MNRS should be based solely upon latency criteria. However, a prolonged latency is difficult to interpret without knowing the amplitude with certainty as motor latencies prolong in proportion to the degree of axon loss whereas pathology of the myelin sheath is more likely to produce a prolonged latency out of proportion to the degree of amplitude reduction. Therefore, thoracic MNRS techniques may not reliably distinguish a diabetic thoracic radiculopathy due to demyelination versus a variant of diabetic radiculoplexus neuropathy that is a vasculopathy (Dyck and Windebank, 2002). 11.12. Lumbosacral root stimulation techniques These techniques are relatively similar to those conducted in the cervical region with some minor differences. The first is that the usual target muscles examined are the femoral nerve innervated rectus femoris (RF), the peroneal nerve innervated tibialis anterior (TA) or extensor digitorum brevis (EDB) and the tibial nerve innervated flexor hallucis brevis (FHB). Of these target muscles, F-waves are most reliably obtained from the FHB, less reliably from the peroneal innervated muscles and are generally unobtainable from the RF for reasons described in the previous section. This region has two potential sites of stimulation, adjacent to the axon hillock and near the exit of the nerve roots from the intervertebral foramen (Maertens de Noordhout et al., 1988). More distal stimulation is likely whenever the caudal portions of the vertebral column are stimulated and when a more

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powerful magnetic stimulator is used for motor nerve root excitation. Therefore, all patient data must be compared against laboratory-specific normal values or in exactly the same manner as the technique published in the literature. This may be the explanation for the wide range of normal values published in the literature. Unlike the cervical spine, the distance between the anterior horn cell pool and the nerve root exit from the intervertebral foramen is much longer. If one assumes a proximal conduction velocity of 50 m/s in the lumbosacral spine, then RS techniques activate the S1 nerve root approximately 13 cm distal to the anterior horn cells (MacDonnell et al., 1992). Thus, this technique omits a significant portion of the proximal nerve root segments. By contrast, stimulation of the L1 region activates these nerve roots adjacent to the axon hillock (Ugawa et al., 1990). Another significant difference from cervical region RS is that there is relatively little contribution of muscles innervated by other nerves to the RF, TA and FHB CMAPs. Therefore, no collision technique is required. 11.12.1. Electrical nerve root stimulation Previous sections have discussed methodologies by which the nerve roots may be stimulated at or about the L1 vertebral level which should activate the motor roots near the axon hillock as depicted in Fig. 11.3. Alternatively, stimulation at the L5–S1 level is more likely to activate the motor nerve roots as they exit their intervertebral foramina as illustrated in Fig. 11.4. Tables 11.3 and 11.4 list some of the normative data for each of these techniques. Irrespective of the tech-

nique used, a monopolar needle is inserted down to the periosteum of the transverse process ipsilateral to the target muscles being evaluated. The target muscles commonly evaluated include the tibialis anterior (TA) and the flexor hallucis brevis (FHB). The stimulus is given as maximum output of the electromyograph, either 400 V or 100 mA at a stimulus duration of 1 ms. The filter settings are the same as for conventional NCS with a band pass of 10 Hz to 10kHz. The display gain is usually set at 2mV per division with a sweep of 10 ms per division. Figure 11.14 demonstrates normal TA and FHB CMAP waveforms acquired with ENRS at L1. Any abnormality noted at the L1 nerve root level should be confirmed with stimulation at the L5–S1 level. 11.12.1.1. Specific lumbosacral electrical nerve root stimulation pitfalls Unlike the cervical region, there is much less risk of inadvertently traumatizing the spinal cord when stimulating at L1 and virtually no risk when stimulating at the L5 spinal level. However, the distance to the transverse processes in this region are often significantly greater than in the cervical region. Therefore, longer monopolar needles must be used in order to insure contact with the periosteum. Performing all preparatory nerve conduction studies with the patient bent forward at the waist by 10–30° may minimize this pitfall. The tibial and peroneal nerves should be conducted in the same relative position. The tibial nerve should be conducted at the ankle and at the popliteal fossa. The peroneal nerve should be conducted at both the fibular head as well as in the popliteal fossa. The EDB CMAP is less reliable

Table 11.3 Summary of magnetic lumbar root stimulation data Latency data

Amplitude data

Target muscle

Reference

Mean ± SD (ms)

Upper limit (mean ± 3 SD)

Quadriceps Tib Ant Tib Ant Tib Ant FHB FHB FHB

Ugawa et al., 1990 MacDonell et al., 1992 Menkes et al, 1994 Ugawa et al., 1990 MacDonell et al., 1992 Menkes et al., 1994 Ugawa et al., 1990

6.1 ± 0.7 13.6 ± 1.2 14.3 ± 1.2 12.7 ± 1.6 24.7 ± 2.2 26.7 ± 3.2 22.9 ± 2.2

8.2 17.2 17.9 17.5 31.3 36.3 29.5

* Expressed as a percentage of the distal amplitude.

Amplitude (mV) (mean ± SD) 36% ± 25* 0.84 ± 0.65 (see text) 25% ± 17.4* 0.83 ± 0.99 (see text)

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Table 11.4 Summary of electrical lumbar root stimulation data Latency data

Amplitude data

Target muscle

Reference

Mean ± SD (ms)

Upper limit (mean ± 3 SD)

Quadriceps Rectus Femoris Tib Ant Tib Ant Tib Ant Tib Ant FHB FHB FHB Soleus

Ugawa et al., 1990 Zileli et al., 2002 MacDonell et al., 1992 Menkes et al., 1994 Ugawa et al., 1990 Zileli et al., 2002 MacDonell et al., 1992 Ugawa et al., 1990 Menkes et al., 1994 Zileli et al., 2002

8.0 ± 1.4 9.8 ± 1.6 13.5 ± 1.2 15.6 ± 1.3 14.8 ± 1.5 14.6 ± 1.3 24.7 ± 2.2 22.9 ± 2.2 27.0 ± 1.5 15.2 ± 1.4

12.2 14.6 17.1 19.5 19.3 18.5 31.3 29.5 31.5 19.4

Amplitude (mV) (mean ± SD)

66% ± 31* 3.0 ± 1.2

64% ± 19* 7.8 ± 2.0

* Expressed as a percentage of the distal amplitude.

because the motor fibers to this muscle are liable to compression at the fibular head as well as at the extensor retinaculum. For this reason, the TA should be used instead of the EDB for assessing proximal conduction block affecting the motor fibers of the peroneal nerve.

Another potential pitfall is the failure to stimulate at both the L1 and L5 nerve root levels. Clinical weakness in a target muscle with unremarkable RS studies at L5 should suggest an abnormality proximal to the motor nerve root exit from the its vertebral foramen. In such instances, stimulation at L1 should be performed in order to evaluate for evidence of proximal myelin dysfunction based upon abnormal degrees of temporal dispersion or PCB. If L1 is stimulated first and such abnormalities are noted, then stimulation at L5 may help localize the pathological site as being either proximal or distal to the motor nerve root exit from the intervertebral foramen. 11.12.2. Magnetic nerve root stimulation

Fig. 11.14 Waveforms from electrical nerve root stimulation technique performed at L1.

Several studies have illustrated that MNRS produces a motor nerve root latency statistically equivalent to what is obtained from ENRS. However, the CMAPs are less reproducible and tend to be lower in amplitude than those obtained from ENRS. One report compared the ratio of L5–S1 ENRS and MNRS to the distally evoked CMAP. The ENRS ratio was 0.64 for the FHB and 0.66 for the TA whereas MNRS ratios were 0.25 for the FHB and 0.36 for the TA (MacDonnell et al., 1992). These authors hypothesized that MNRS did not generate enough magnetic flux density to insure supramaximal nerve root stimulation. This finding was more remarkable at the L1 nerve root level wherein 50% of normal subjects did not have an evocable CMAP over the TA or FHB and the others had amplitudes one order

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of magnitude less than those evoked by ENRS at the same level (Menkes et al., 1994). One solution advocated by Ugawa and his co-workers was to use a more powerful magnetic stimulator capable of generating 4.6 T (Ugawa et al., 1990). However, this magnetic stimulator is not commercially available. Another solution was to use a V-shaped coil analogous to the shape of a bird with a large wingspan (Maccabee et al., 1996). This large coil was then centered over the lumbosacral spine in order to generate the most reproducible CMAPs. While this modification allowed for stable CMAP latencies, there still remained a wide variation in amplitude. 11.12.2.1. Specific lumbosacral magnetic nerve root stimulation pitfalls. The same pitfalls noted in cervical MNRS apply to this region save for the fact that vagal nerve stimulators and cardiac pacemakers are unlikely to be affected by 2.2 tesla magnetic stimulators. In contrast, indwelling catheters containing metal or intrathecal pumps are much more likely to be affected by magnetic fields in this region. Until the safety of this technique is well established, such patients should not undergo either ENRS or MNRS procedures in this area. The commonly used magnetic stimulators do not generate an electrical field density similar to what is achieved with ENRS. This becomes even more problematic when the magnetic field is more distant from the electrically excitable tissue that is targeted. Therefore, patients with larger body frames or significant girth are less likely to have CMAPs similar in amplitude to those generated distally by conventional NCS. In such persons, ENRS is the preferred technique. 11.12.3. Summary/Comparison As with cervical RS techniques, MNRS in the lumbosacral spine can be used as a noninvasive means of determining the motor nerve root latency to a particular target muscle. It may also be used as a screening test for a PCB. If no block is found, then ENRS need not be performed. Conversely, all amplitude abnormalities must be confirmed with ENRS. 11.13. Indications for root stimulation studies Because RS studies are a means of extending the scope of motor NCS; they have essentially the same indications for evaluating motor nerve pathology in

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the proximal portions of the peripheral nerves. RS studies have been advocated for a variety of conditions that result in motor weakness from interference with normal motor nerve function including motor neuron diseases, radiculopathies, brachial plexopathies, and acquired demyelinating polyneuropathies. These disorders produce some combination of changes in motor nerve latency/conduction velocity or CMAP amplitude. Therefore, any disorder that can result in a change in either of these parameters may merit investigation with RS techniques. However, RS should only be performed when conventional studies are non-diagnostic. Each of these indications will be discussed briefly. Root stimulation was initially introduced as a technique used to assess patients for cervical radiculopathy. In one early study, RS detected all 18 patients who had clinical evidence of a radiculopathy whereas needle EMG detected only 11 (Berger et al., 1987). Radiography was abnormal in six of the seven patients examined but none of these patients were reported to have surgical confirmation of these lesion. Subsequent studies have not demonstrated the same degree of sensitivity and specificity reported by these authors. A review by Fisher stated that since there is no “gold standard” by which radiculopathies are diagnosed, evidence-based medicine cannot be applied to the various methodologies but needle EMG was the best established technique (Fisher, 2002). An independent review by Levin assessed much of the same literature and concluded that needle EMG was the most sensitive and specific superior to evoked potentials, late responses and RS studies (Levin, 2002). While RS studies may detect cases of nerve root pathology in the absence of needle EMG changes, it is unclear if these findings would result in a significant difference in the management of patients who present with a radiculopathy. A direct comparison of MNRS to motor NCS, late responses and needle EMG for lower extremity radiculopathies reported that MNRS studies had an overall sensitivity of 40% at L5 and S1 whereas needle EMG has a sensitivity of 90% for L5 and 80% for S1 (Weber and Albert, 2000).The consensus of opinion is that the clinical utility of RS studies for the diagnosis of radiculopathy is uncertain. By contrast, RS has been shown to be useful in assessing patients for the presence or absence of PCB; one of the hallmarks of saltatory conduction failure. It is important to differentiate patients with lower motor neuron variants of motor neuron disease from those with motor neuropathies that might respond to

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treatment. A study by Raynor and her co-authors, subsequently replicated in other laboratories, did not detect any electrophysiologic evidence of PCB in 59 nerves of 32 patients referred with motor neuron disease (Raynor et al., 1998). A subsequent study of RS studies performed with transcranial magnetic stimulation techniques did not demonstrate evidence of PCB in any of 121 patients with motor neuron disease including 22 patients with pure lower motor neuron presentations (Triggs et al., 1999). Restated, these studies suggest that PCB should not be observed in patients with motor neuron disease. Conversely, two independent studies reported that RS could identify PCB in acquired demyelinating polyneuropathies. One study that only assessed for PCB in the ulnar nerve, observed this finding in 8/31 patients suspected of having an acquired demyelinating polyneuropathy (Jaspert et al., 1995). These authors also reported that resolution of the PCB correlated with clinical recovery. A subsequent study reported that RS demonstrated PCB in 20/31 patients suspected of having an acquired myelinopathy whereas this finding was never observed in any of the normal or pathological controls (Menkes et al., 1998). Therefore, RS studies should be performed in any patient with a pure lower motor neuron-type of weakness. Those with PCB should be evaluated for the presence of an acquired myelin-dysfunction neuropathy. Conversely, patients suspected of having a lower motor neuron variant of motor neuron disease should undergo RS studies in order to document the absence of PCB that would suggest an alternative diagnosis. One caveat is that absence of evidence is not evidence of absence. A treatable neuropathy is not excluded if there is no evidence of PCB. Root stimulation has also been reported as being useful in detecting PCB across the brachial plexus. One case report discussed that C8 NERS demonstrated PCB across the lower trunk of the brachial plexus in a patient with thoracic outlet syndrome (Felice et al., 1999). Another publication reported that MNRS reliably differentiated brachial plexopathies with segmental demyelination from those with axon loss (Oge et al., 1997). These authors reported that acquired demyelinating polyneuropathies and “suspension” plexopathies demonstrated electrophysiologic features of PCB, whereas motor neuron disease, n-hexane neuropathy and “neurogenic thoracic outlet syndrome” did not. Evidence-based medicine analysis cannot be applied to these techniques given that there is no universal agreement on what constitutes the “gold standard” for the diagnosis of demyelinating brachial plexopathies, the

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thoracic outlet syndrome and acquired demyelinating polyneuropathies. Therefore, any abnormalities noted on RS studies need to be placed in the clinical context of that patient’s presentation. 11.14. Conclusion Root stimulation techniques allow for an evaluation of the most proximal portions of the motor nerves. RS may be performed using magnetic or monopolar needle stimulation techniques. The latency and CMAP amplitude to the target muscle can be directly measured. Absolute latency prolongation or evidence of PCB or abnormal degrees of TD are the most clinically useful findings. For all routinely studies target muscles, the latency and amplitude may be assessed directly from RS techniques. However, a collision technique is required for motor NCS of the median nerve to the APB. MNRS techniques are less useful than ENRS techniques but may be used as a screening examination. If no abnormalities are noted on MNRS studies, then the more invasive ENRS studies may be omitted. Otherwise, ENRS studies should be performed. References Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force (1991) Research criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy. Neurology, 41: 617–618. Barker, AT, Freeston, I, Jalinous, R, Eng, B and Jarratt, J (1987) Magnetic stimulation of the human brain and peripheral nervous system: an introduction and the results of an initial clinical evaluation. Neurosurgery, 20: 100–109. Berger, AR, Busis, NA, Logigian, EL, Wierzbicka, M and Shahani, BT (1987) Cervical root stimulation in the diagnosis of radiculopathy. Neurology, 37: 329–332. Chokroverty, S (1990) Magnetic stimulation in clinical neurophysiology. Boston, ButterworthHeinemann Medical, 308 pp. Chokroverty, S, Deutsch, A, Guha, C, Gonzales, A, Kwan, P, Burge, R and Goldberg, J (1995) Thoracic spinal and nerve root conduction: a magnetic stimulation study. Muscle Nerve, 18: 987–991. Chokroverty, S, Picone, MA and Chokroverty, M (1991) Percutaneous magnetic coil application of human cervical vertebral column: site of stimula-

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tion and clinical application. Electroencephalogr. Clin. Neurophysiol., 81: 359–365. Cros, D, Chiappa, KH, Gominak, S, Fang, J, Santamaria, J, King, PJ and Shahani, BT (1990) Cervical magnetic stimulation. Neurology, 40: 1751–1756. DiMarco, AF, Romaniuk, JR, Kowalski, KE and Supinski, G (1999) Pattern of expiratory muscle activation during lower thoracic spinal cord stimulation. J. Appl. Physiol., 86: 1881–1889. Dyck, PJ and Windebank, A (2002) Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve, 25: 477–491. Evans, BA, Daube, JR and Litchy, WJ (1990) A comparison of magnetic and electrical stimulation of spinal nerves. Muscle Nerve, 13: 414–420. Felice, KJ, Butler, KB and Druckemiller, WH (1999) Cervical root stimulation in a case of classic neurogenic thoracic outlet syndrome. Muscle Nerve, 22: 1287–1292. Fisher, MA (2002) Electrophysiology of radiculopathies. Clin. Neurophysiol., 113: 317–335. Ingram, D, Thompson, A and Swash, M (1988) Central motor conduction in multiple sclerosis: evaluation of abnormalities revealed by transcranial magnetic stimulation of the brain. J. Neurol. Neurosurg. Psychiatry, 51: 487–494. Jaspert, A, Claus, D, Grehl, H, Kerling, F and Neurndorfer, B (1995) Value of PCB study in diagnosis of inflammatory neuropathies. Nervenartz, 66: 445–454. Kimura, J (1974) F-wave conduction velocities in the central segments of the median and ulnar nerves. Neurology, 24: 539–546. Levin, K (2002) Electrodiagnostic approach to the patient with suspected radiculopathy. Neurol. Clin., 20: 397–421. Maccabee, PJ, Lipitz, ME, Desudchit, T, Golub, RW, Nitti, VW, Bania, JP, Willer, JA, Cracco, RQ, Cadwell, J, Hotson, GC, Eberle, LP and Amassian, VE (1996) A new method using neuromagnetic stimulation to measure conduction time within the cauda equina. Electroencephalogr. Clin. Neurophysiol., 101:153–166. Macdonell, RA, Cros, D, Shahani, BT (1992) Lumbosacral nerve root stimulation comparing electrical with surface magnetic coil techniques. Muscle Nerve, 15:885–890. MacLean, IC and Taylor, RS (1975) Nerve Root Stimulation to Evaluate Brachial Plexus Conduc-

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tion. Abstracts of Communications of the Fifth International Congress of Electromyography. Rochester MN, 47 pp. Maertens de Noordhout, A, Rothwell, JC, Thompson, PD, Day, BL and Marsden, CD (1988) Percutaneous electrical stimulation of lumbosacral nerve roots in man. J. Neurol. Neurosurg. Psychiatry, 51: 174–181. Menkes, DL (2002a) Proximal conduction techniques: somatosensory evoked potentials, magnetic stimulation and root stimulation. In: T. Bertorini (Ed.) Clinical Evaluation and Diagnostic Tests for Neuromuscular Disorders, ButterworthHeinemann Inc., Woburn, pp. 209–238. Menkes, DL (2002b) Axonal multifocal motor neuropathy without conduction block or other features of demyelination. Neurology, 59: 1666. Menkes, DL, Hood, DC, Ballesteros, RA and Williams, DA (1998) “Root stimulation improves the detection of acquired demyelinating polyneuropathies.” Muscle Nerve, 21: 298–308. Menkes, DL, Ring, SR, Chiappa, KH and Cros, D (1994) Cortical Magnetic Stimulation to the Lower Extremities: Normal Controls and 14 Pathologic Cases. Abstracts of the American Academy of Neurology, Washington, DC. Mills, KR and Murray, NMF(1986). Electrical stimulation over the human vertebral column. Which neural elements are excited? Electroenceph. Clin. Neurophysiol., 63: 582–589. Oge, AE, Boyaciyan, A, Gurvit, H, Yazici, J, Degirmenci, M and Kantemir, E (1997) Magnetic nerve root stimulation in two types of brachial plexus injury: segmental demyelination and axonal degeneration. Muscle Nerve, 20: 823–832. Oh, SJ (1993) Clinical electromyography: nerve conduction studies. Magnetic and High-Voltage/LowImpedance Electrical Stimulation Tests. Williams and Wilkins Inc., Philadelphia, IInd ed., pp. 406–446. Raynor, EM, Shefner, JM, Ross, MH, Logigian, EL and Hinchey, JA (1998) Root stimulation studies in the evaluation of motor neuron disease. Neurology, 50: 1907–1909. Reid, V, Black, K, Menkes, DL, Siao, P and Cros, D (2001) Chronic inflammatory demyelinating polyneuropathy. In: D Cros (Ed.). A Practical Approach to Diagnosis and Management, Williams and Wilkins, Philadelphia, pp. 85–107. Rhee, EK, England, JD and Sumner, AJ (1990) A computer simulation of conduction block: effects

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produced by conduction block versus interphase cancellation. Ann. Neurol., 28: 146–156. Sander, HW, Menkes, DL, Triggs, WJ and Chokroverty, S (1999) Cervical root stimulation at C5–C6 excites C8–T1 nerve roots and minimizes pneumothorax risk. Muscle Nerve, 22: 766–768. Sander, HW, Quinto, CM, Murali, R and Chokroverty, S (1997) Needle cervical root stimulation may be complicated by pneumothorax. Neurology, 48: 288–289. Saperstein, DS, Katz, JS, Amato, AA and Barohn, RJ (2001) Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve, 24: 311–324. Triggs, WJ, Menkes, D, Onorato, J, Yan, RS, Young, MS, Newell, K, Sander, HW, Soto, O, Chiappa, KH and Cros, D (1999) Transcranial magnetic stimulation

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identifies upper motor neuron involvement in motor neuron disease. Neurology, 53: 605–611. Troni, W, Bianco, C, Coletti Moja, M and Dotta, M (1996) Improved methodology for lumbosacral nerve root stimulation. Muscle Nerve, 19: 595–604. Tsugi, S, Murai, Y and Yarita, M (1993) Cortical somatosensory evoked potentials evoked by magnetic stimulation of thoracic and lumbar roots. Neurology, 43: 391–396. Ugawa, Y, Kohara, N, Shimpo, T and Mannen, T (1990) Magneto-electrical stimulation of central motor pathways compared with percutaneous electrical stimulation. Eur. Neurol., 30: 14–18. Zileli, B, Ertekin, C, Zileli, M and Yunten, N (2002) Diagnostic value of electrical stimulation of lumbosacral roots in spinal stenosis. Acta Neurol. Scand., 105: 221–227.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 12

Motor unit number estimation in peripheral neuropathies Mark B Bromberg* Department of Neurology, University of Utah, UT, USA

12.1. Introduction Motor nerves are involved in the majority of peripheral neuropathies, and most neuropathies include axonal degeneration. Assessing the degree of axonal loss in peripheral neuropathies is challenging. Estimates of severity of sensorimotor neuropathies are primarily qualitative, based on clinical symptoms, clinical scales, or sensory nerve studies. Motor nerve denervation cannot be accurately measured from muscle strength or routine electrodiagnostic studies due to the compensatory effects of collateral reinnervation. However, the electrophysiologic technique of motor unit number estimation (MUNE) is not affected by collateral reinnervation, and remains the only method that can provide a quantitative estimate of the number of motor units innervating a muscle. This chapter reviews the pathophysiology of denervation and collateral reinnervation and its effect on routine electrodiagnostic testing. The underlying principles and methodology of MUNE are presented. Experience with MUNE assessing the degree of axonal loss in peripheral neuropathies is reviewed. The reader is directed to the proceedings of a recent symposium on MUNE for more details about the technique (Bromberg, 2003b). 12.2. Pathophysiology of denervation and reinnervation The concept of a motor unit is easily grasped, but it is experimentally difficult to visualize the muscle fibers that make up a single motor unit. Single motor units can be studied by the technique of glycogen depletion where single ventral root axons are isolated

*

Correspondence to: Dr. Mark B Bromberg, MD, PhD, Department of Neurology, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA. E-mail address: [email protected] Tel.:+1-801-585-5884; fax: +1-801-585-2054.

and stimulated continuously to deplete glycogen stores in the muscle fibers of that motor unit (Edström and Kugelberg, 1968). From such studies in the rat, the following features of motor units have been elucidated. It is rare for muscle fibers from the same motor unit to lie adjacent to each other. The tesselation of muscle fibers observed on routine histologic sections of muscle represent fibers from many motor units. Muscle fibers of a single motor unit occupy restricted cross-sectional areas within the whole area of the muscle, and at any given site in a muscle, the areas of 20 or more motor units overlap. With partial axonal loss, surviving terminal motor axons sprout collateral branches to reinnervate the denervated muscle fibers. Glycogen depletion studies reveal the following motor unit changes with reinnervation (Kugelberg et al., 1970). Reinnervation leads to a higher density of muscle fibers belonging to the surviving motor units, and more muscle fibers of the same motor unit will be adjacent to each other. Reinnervation is shared by many motor units within the muscle, observed as fiber type grouping on histologic sections. With early axonal loss, collateral reinnervation successfully reinnervates most denervated muscle fibers. However, there are limitations to collateral reinnervation, and fascicular boundaries within muscle restrict the extent of sprouting. With extensive axonal loss reinnervation is inadequate and greater numbers of muscle fibers remain denervated (Cohen et al., 1987). In slowly progressive neuropathies, distal muscle weakness will not be apparent until 80% of motor neurons are lost (McComas et al., 1971b). 12.3. Limitations of routine electrodiagnostic testing Routine electrodiagnostic studies used to assess peripheral neuropathies measure axonal loss and conduction velocity. The sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) are useful, particularly for determining

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conduction velocity. For measures of axonal loss, the SNAP may be unrecordable when 50% of fibers remain (Rosenfalck, 1978). CMAP amplitude reflects the number of innervated muscle fibers, and amplitude values fall only when the extent of denervation exceeds the capacity for reinnervation and a sufficient percentage of muscle fibers remain denervated. In slowly progressive denervating disorders, there will be sufficient time for maximal reinnervation, and CMAP amplitude may not fall below the lower limits of normal until 50–80% of motor axons have been lost (McComas et al., 1971b). Needle EMG is sensitive to the effects of denervation and reinnervation, signaled by abnormal spontaneous activity (positive waves and fibrillation potentials) and changes in motor unit action potential (MUAP) recruitment, amplitude and waveform configuration. However, changes are customarily expressed by subjective scales (1+ to 4+), which represent qualitative estimates of denervation (Kimura, 2001). Few studies compare subjective EMG scaling with objective motor unit estimates (Schulte-Mattler et al., 2000). Single fiber EMG (SFEMG) measurement of fiber density is the most sensitive electrodiagnostic test for denervation (Stålberg et al., 1975). Fiber density measurements are based on the recording radius of a special SFEMG electrode, and values represent the closeness of muscle fibers from the same motor unit.

Fiber density values rise with collateral reinnervation, and fall when decompensation occurs (Stålberg, 1982). Correlations, therefore, are poor between fiber density values and MUNE values, CMAP or MUAP measurements (Bromberg and Larson, 1996). 12.4. Principles of motor unit number estimation Motor unit number estimation is a physiologic estimate of the number of motor units innervating a muscle or group of muscles (McComas et al., 1971a). MUNE values are calculated from the ratio (Fig. 12.1): maximal compound muscle action potential (CMAP ) amplitude or area . average single motor unit potential (MUP ) amplitude or area The principle behind MUNE is simple in concept, but there are a number of issues that have been extensively reviewed (McComas et al., 1971a; Brown and Milner-Brown, 1976; Slawnych et al., 1990; McComas, 1991; Bromberg, 2003b). Several different MUNE techniques have been developed (Table 12.1) to deal with some of these issues. The various MUNE techniques differ in the manner in which S-MUPs are obtained. 12.4.1. Muscles studied

− 100 μV +

− 2 mV +

Fig. 12.1 Incremental MUNE technique. (Top trace): Incremental responses of extensor digitorum brevis following excitation of deep peroneal nerve with threshold and slightly suprathreshold stimuli. (Bottom trace): Maximal compound muscle action potential (Modified from McComas et al. (1971a) Functional compensation in partially denervated muscles. J. Neurol. Neurosurg. Psychiatry, 34: 453–460, with permission from the BMJ Publishing Group).

When MUNE is applied to distal lower extremity muscles involved in peripheral neuropathies, the extensor digitorum brevis (EDB) muscle may be studied in isolation, but most MUNE determinations include estimates from a group of muscles innervated by one nerve. Examples in the leg are tibial-innervated abductor hallucis and other intrinsic foot muscles, and examples in the arm are median-innervated thenar eminence and ulnar-innervated hypothenar eminence muscles. Proximal muscles, such as the biceps-brachialis muscle group, can also be studied with certain MUNE techniques (Table 12.1) (McComas, 1991). 12.4.2. Compound muscle action potential The maximal CMAP is determined by the same techniques used in routine motor nerve conduction studies. Recording electrodes are placed in a belly-tendon arrangement, and the nerve is electrically activated by percutaneous stimulation to achieve the maximal CMAP. The recording electrodes are left in place to

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Table 12.1 Different MUNE techniques used to assess axonal loss in peripheral neuropathiesa MUNE Technique

Advantages

Incremental stimulation

●

Multiple point stimulation

●

●

Applicable to any EMG machine Passive testing; patient cooperation not necessary Applicable to any EMG machine Avoids alternation Passive testing; patient cooperation not necessary Samples range of nerve fibers Passive testing; patient cooperation not necessary

●

Applicable to distal and proximal muscles

●

●

Can provide quantitative intramuscular motor unit action potential data

●

●

● ●

Statistical

Disadvantages

●

●

● ●

● ● ●

Spike triggered averaging

a

Alternation leading to an over estimate of the MUNE Applicable to distal muscles only Applicable to distal muscles only

Assumes Poisson statistics Requires proprietary software Applicable to distal muscles only Requires intramuscular needle EMG electrode Active testing; requires patient cooperation

Techniques differ in the manner in which surface motor unit potentials (S-MUPs) are obtained.

record the surface representation of single motor unit potentials (S-MUPs). It is preferable that the active recording electrode be accurately positioned over the motor point to achieving maximal CMAP amplitude, and this position is associated with a steep waveform rise time (Bromberg and Spiegelberg, 1997). Optimal positioning of the active electrode is important in serial MUNE studies to ensure reproducibility of the maximal CMAP, or to enhance the ability to detect changes over time. However, with respect to MUNE estimates, any variation from the optimal placement of the active recording electrode will be manifest equally in CMAP and S-MUP waveforms, and MUNE values will not be affected (Bromberg and Abrams, 1995). 12.4.3. Single motor unit potential waveforms Individual S-MUPs waveforms within a muscle or group of muscles vary in size and shape, (Fig. 12.2), but typically have an initial negative deflection followed by a terminal positive deflection (Fig. 12.2). Occasional S-MUPs are recorded with almost entirely positive waveforms. These are considered to most likely represent volume-conducted motor units from adjacent muscles. Accordingly, they are usually not included in calculating the average S-MUP value (Bromberg, 2003a). Total waveform duration can be challenging to assess due to difficulties in accurately determining the onset and termination points. Peak-topeak amplitude is readily measured, and negative peak

amplitude and area are measured by extending the prewaveform baseline across the negative portion of the waveform. The distribution of S-MUP amplitudes from normal muscle spans one order of magnitude, from approximately 20 to 200 μV peak-to-peak amplitude (Bromberg and Abrams, 1995). Occasionally very low amplitude S-MUPs are recorded, but they are considered to represent motor units from distant muscles. Accordingly, S-MUPs with negative peak amplitude 10). (2) The stimulating electrode is moved to different sites along the nerve to obtain single S-MUPs. If point-by-point averaging is used, the effects of phase cancellation from late arriving waveforms will be problematic, unless the waveforms are aligned by their onset. 12.5.2.5. Modifications Single motor unit potentials are obtained one at a time, which can be time consuming. A modification, called adapted multiple point stimulation technique (AMPS), has been developed that combines incremental and multiple point stimulation (Wang and Delwaide, 1995). At each site along the nerve, the stimulation intensity is raised to obtain a two or threestep envelope. Template subtraction is used to separate individual S-MUP waveforms. A suitable number of S-MUPs can be obtained from five to six sites along the nerve, reducing the time required for the study.

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12.5.3. Statistical motor unit number estimation Technique 12.5.3.1. Principles The statistical technique is a novel approach using Poisson statistics to determine the average response based on the variability of the response (Daube, 1995). When multiple stimuli are delivered at a constant stimulation intensity, the evoked response will vary from trial-to-trial (envelope of responses). It can be assumed that this response variability reflects the addition and loss of axons to the response, and thus represents the phenomena of alternation. Poisson statistics assumes that the underlying changes represent discrete steps or axonal responses, and the statistical variance of the amplitude of the response over many trials is equal to the mean value of the change in the response, which is the average value of the S-MUP. 12.5.3.2. Methods Surface electrodes are placed and a maximal CMAP is recorded. The subject should remain at complete rest to prevent adventitious movements (Daube, 2003). The stimulating electrode is fixed and the nerve is “scanned” with a series of 30 stimuli delivered with increasing intensity from just subthreshold to just maximal to generate the total envelope of evoked responses (Fig. 12.6). This scan of the evoked response is used to identify portions of the response envelope that will be sampled. Usually, three to four regions are sampled to determine the variance and S-MUP amplitude value at each of these regions. The variance of the response in each region is determined by applying sets of 30 stimuli. For each set of 30 stimuli, the variance is calculated and an average S-MUP area determined. Repeated sets of 30 stimuli are performed until the standard error of the different determinations is 30% (Shefner et al., 1999; Lomen-Hoerth and Olney, 2001; Daube, 2003). 12.5.3.5. Modifications (1) A number of modifications have been proposed to determine the specific regions of the scan curve, which should be tested and the size of the tested regions (Olney et al., 2000; Lomen-Hoerth and Olney, 2001). The proprietary software automatically selects the regions to be tested, and each region includes about 6% of the total CMAP amplitude. The software also allows the operator to determine those regions. One paradigm uses four set regions of 15–25% of the

maximal response, 25–35%, 35–45%, and 45–55% (Bromberg, 2003a). (2) There are a number of different methods to calculate average S-MUP values that are used to determine the final MUNE. One source of variability in the final MUNE value is reliance on the smallest S-MUP value to calculate the MUNE for the untested regions of the CMAP. A modification weights the S-MUP values obtained from the tested regions to obtain a more representative average S-MUP value (Fig. 12.5) (Shefner et al., 1999). Note that the weighted average technique relies on the metric of negative peak amplitude while the conventional technique relies on negative peak area. A consensus for performing the statistical MUNE technique is available (Bromberg, 2003a).

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12.5.4. Spike triggered averaging motor unit estimation number technique 12.5.4.1. Principles The incremental, multiple point stimulation and statistical MUNE techniques rely on electrical stimulation of the nerve to activate S-MUPs. An alternative method to activate single motors is by voluntary contraction of the muscle (Brown et al., 1988). Individual motor units are identified from weak interference patterns and used to trigger a signal averager to extract the surface representation of the motor unit.

MARK B BROMBERG

T r c 1

500 μV

2

12.5.4.3. Advantages (1) The intramuscular electrode can also be used to obtain quantitative motor unit action potential (MUAP) data, such as amplitude, duration, number of phases and turns. (2) This technique can be applied to proximal muscles because only limited access to the nerve is required to generate a maximal CMAP, whereas longer lengths of nerve are required for the controlled stimulation protocols with the other techniques. 12.5.4.4. Issues and Pitfalls (1) Care must be taken to avoid spurious trigger potentials (Bromberg and Abrams, 1995). (2) There is concern for a sampling bias to early recruited motor units. However, comparison studies between different MUNE techniques indicate no significant bias (Stein and Yang, 1990; Doherty and Brown, 1993). 12.5.4.5. Modifications In the conventional spike triggered averaging technique, single intramuscular potentials are isolated.

5 ms 500 μV

5 ms 3

12.5.4.2. Methods Two recording channels are used, one for surface recording and the other for intramuscular electrode recording. Surface electrodes are placed and a maximal CMAP is recorded. A weak interference pattern is generated and the intramuscular electrode is adjusted to isolate the discharge of one motor unit (Fig. 12.7). A voltage level trigger is set to detect the motor unit’s discharge pattern, and the trigger signals from that motor unit are used for spike triggered averaging of the surface response of the motor unit. The electrode is moved to another site in the muscle and another S-MUP is obtained. Ten to fifteen responses are collected and averaged to obtain the average S-MUP used to calculate the MUNE value.

10 ms

500 μV

N: 2 4A

4B

4C

N: 6

N: 40 5 ms 50 μV

Fig. 12.7 Determination of S-MUPs by spike triggered averaging. (Trace1) Intramuscular needle EMG signal in free run mode. (Trace 2) Intramuscular needle EMG signal with isolation of single motor unit potential (middle of trace) by setting a voltage trigger (horizontal line). (Trace 3) Intramuscular needle EMG signal of isolated motor unit potential after averaging. Averaged motor unit potential can be assessed for quantitative EMG analysis. (Trace 4A) Surface EMG signal corresponding to intramuscular EMG signal isolated by spike triggering (averaged 2 times; N: 2). Note concurrent background surface EMG activity from other motor units. (Trace 4B) Surface signal averaged 6 times. (Trace 4C) Surface signal averaged 40 times. Note clear isolation of surface S-MUP. Averaged S-MUP can be assessed for negative peak amplitude and area.

Signal decomposition algorithms have been developed to identify four to eight single intramuscular potentials from the interference pattern, and each motor unit potential can be used for spike triggered averaging of the corresponding S-MUPs (Stashuk, 1999; Doherty

MOTOR UNIT NUMBER ESTIMATION IN PERIPHERAL NEUROPATHIES

and Stashuk, 2003). Decomposition-enhanced spike triggered averaging reduces the time necessary to obtain 10–15 S-MUPs and increases the total number of S-MUPs that can be obtained. 12.6. MUNE in peripheral neuropathies Motor unit number estimation has been used to assess the degree of axonal loss and the extent of collateral reinnervation in a number of peripheral neuropathies. Examples are reviewed in this chapter, and other examples are also discussed in other chapters.

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12.6.4. Charcot–Marie–Tooth neuropathies The spike triggered averaging MUNE technique has used to assess and compare the degree of motor unit loss in CMT1A and CMT2 subjects (Lawson et al., 2003; Lewis et al., 2003). MUNE values in ulnar innervated hypothenar muscles were low in both CMT types in proportion to clinical weakness, supporting axonal loss as the final pathological stage for all forms of CMT. MUNE values were also low in a proximal muscle (biceps-brachialis), more marked in CMT2 than CMT1A, suggesting less of a length-dependent process in CMT2.

12.6.1. Diabetic neuropathy Studies using the incremental stimulation MUNE technique indicate that axonal loss was more prominent than clinically suspected. Among diabetic subjects with no symptoms or signs of peripheral neuropathy, MUNE values were reduced to approximately 50% of control values in EDB and thenar muscles (Brown and Feasby, 1974). In subjects with stocking distribution of sensory symptoms, reductions were more severe, and some subjects had only one or two motor units in the EDB muscle. Axonal loss was greater than predicted from nerve or muscle biopsy data or from routine needle EMG data, and demyelination (slowed conduction velocity) was of lesser importance. 12.6.2. Uremic neuropathy Studies using the incremental stimulation MUNE technique in patients requiring hemodialysis showed that two-thirds had MUNE values in the EDB muscle within the normal control range (Hansen and Ballantyne, 1978). In patients with reduced MUNE values, S-MUP amplitude and area values were increased, supporting axonal loss rather than demyelination and conduction block as the underlying pathologic mechanism. The capacity for reinnervation was felt to be less in uremic neuropathy than in diabetic neuropathy. 12.6.3. Alcoholic neuropathy The incremental stimulation MUNE technique was used, and subjects without neuropathy symptoms had MUNE values in the EDB muscle similar to normal control values, while those with symptoms had reduced MUNE values (Ballantyne et al., 1980).

12.6.5. Guillain–Barré Syndrome The incremental stimulation MUNE technique has been used to separate the pathologic effects of demyelination from axonal loss (Martinez-Figueroa et al., 1977). Lower MUNE values and larger S-MUP amplitudes were associated with greater clinical severity. 12.6.6. Acute motor axonal neuropathy Acute motor axonal neuropathy is a unique form of the Guillain–Barré syndrome with a good prognosis for recovery despite axonal involvement (McKhann et al., 1993). Statistical MUNE has been used to study factors in the recovery process (Kuwabara et al., 2001). The earliest electrophysiologic changes (at 2 months) were increased CMAP and S-MUP amplitudes, and MUNE values did not begin to increase until 3 months. 12.6.7. Critical illness weakness The statistical MUNE technique, along with other electrophysiologic techniques, was performed to differentiate between neuropathic and myopathic causes of weakness (Trojaborg et al., 2001). Normal MUNE values were found in the setting of a markedly reduced CMAP values, reduced responses to direct muscle stimulation (Rich et al., 1997), myopathic changes on needle EMG, and muscle biopsy findings consistent with myopathy. 12.6.8. Median neuropathy at the wrist Using the incremental stimulation MUNE technique, values could be as low as three to five motor units when atrophy and weakness was present (Brown,

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1973). The presence of fibrillation potentials did not predict the degree of motor unit loss. Using the statistical MUNE technique in subjects with mild symptoms, no significant loss of motor units was found (Cuturic and Palliyath, 2000). 12.6.9. Ulnar neuropathy at the elbow The statistical MUNE technique was used in an attempt to increase diagnostic sensitivity (Jillapalli et al., 2003). MUNE values were not reduced when estimates were made proximal to the elbow, but average SMUP values determined from the proximal site were significantly lower than at distal sites. The reduction in CMAP amplitude across the elbow was more than matched by the lower SMUP amplitude, leading to insignificant MUNE changes across the elbow. A small number of large-diameter nerve fibers are likely affected in focal compressive neuropathies. Conduction block in these fibers results in the diagnostic fall in CMAP amplitude across the lesion site. However, conduction block of these fibers also shifts the sample of SMUPs to smaller values, leading to an unremarkable change in MUNE values. 12.7. Summary Motor unit number estimation is a unique electrophysiologic tool that can provide quantitative estimate the number of motor units innervating a muscle or group of muscles because it is unaffected by the effects of collateral reinnervation. Routine nerve conduction studies provide only qualitative estimates of motor unit loss. MUNE is most informative in quantitatively assessing motor axonal loss in slowly progressive neurogenic disorders, including peripheral neuropathies, where there is sufficient time for maximal collateral reinnervation that obscures the clinical and routine electrophysiologic assessment of denervation. In these situations MUNE has demonstrated more motor nerve degeneration than suspected. There are a number of MUNE techniques available suited to the study of peripheral neuropathies, and many can be used without special equipment. References Arasaki, K, Tamaki, M, Hosoya, Y and Kudo, N (1997) Validity of electromyograms and tension as a means of motor unit number estimation. Muscle Nerve, 20: 552–560.

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Ballantyne, J and Hansen, S (1974) A new method for the estimation of the number of motor units in a muscle. 1. Control subjects and patients with myasthenia gravis. J. Neurol. Neurosurg. Psychiatry, 37: 907–915. Ballantyne, J, Hansen, S, Weir, A, Whitehead, J and Mullin, P (1980) Quantitative electrophysiological study of alcohol neuropathy. J. Neurol. Neurosurg. Psychiatry, 43: 427–432. Bromberg, M (1993) Motor unit estimation: reproducibility of the spike-triggered averaging technique in normal and ALS subjects. Muscle Nerve, 16: 466–471. Bromberg, M (2003a) Consensus. In: M Bromberg (Ed.), Motor Unit Number Estimation. Elsevier, Amsterdam, Vol. 55, pp. 335–338. Bromberg, M (Ed.) (2003b) Motor Unit Number Estimation (MUNE). Vol. 55. Elsevier, Amsterdam. Bromberg, M and Abrams, J (1995) Sources of error in the spike-triggered averaging method of motor unit number estimation (MUNE). Muscle Nerve, October: 1139–1146. Bromberg, M and Larson, W (1996) Relationships between motor-unit number estimates and isometric strength in distal muscles in ALS/MND. J. Neurol. Sci., 139: 38–42. Bromberg, M and Spiegelberg, T (1997) The influence of active electrode placement on CMAP amplitude. Electroencephalog. Clin. Neurophysiol., 105: 385–389. Brown, W (1973) Thenar motor unit count estimates in the carpal tunnel syndrome. J. Neurol. Neurosurg. Psychiatry, 36: 194–198. Brown, W and Feasby, T (1974) Estimates of functional motor axon loss in diabetes. J. Neurol. Sci., 23: 275–293. Brown, W and Milner-Brown, H (1976) Some electrical properties of motor units and their effects on the methods of estimating motor unit numbers. J. Neurol. Neurosurg. Psychiatry, 39: 249–257. Brown, W, Strong, M and Snow, R (1988) Methods for estimating numbers of motor units in bicepsbrachialis muscles and losses of motor units with aging. Muscle Nerve, 11: 423–431. Cohen, M, Lester, J, Bradley, W, Brenner, J, Hirsch, R and Silber, D et al. (1987) A computer model of denervation-reinnervation in skeletal muscle. Muscle Nerve, 10: 826–836. Cuturic, M and Palliyath, S (2000) Motor unit number estimate (MUNE) testing in male patients with mild to moderate carpal tunnel syndrome.

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Electroencephalog. Clin. Neurophysiol., 40: 67–72. Daube, J (1995) Estimating the number of motor units in a muscle. J. Clin. Neurophysiol., 12: 585–594. Daube, J (2003) MUNE by statistical analysis. In: M Bromberg, (Ed.). Motor Unit Number Estimation (MUNE). Elsevier, Amsterdam, Vol. 55. pp. 51–71. Doherty, T and Brown, W (1993) The estimated numbers and relative sizes of thenar units as selected by multiple point stimulation in young and older adults. Muscle Nerve, 16: 355–366. Doherty, T and Stashuk, D (2003) Decompositionbased quantitative electromyography: Methods and initial normative data in five muscles. Muscle Nerve, 28: 204–211. Doherty, T, Stashuk, D and Brown, W (1993) Determinants of mean motor unit size: Impact on estimates of motor unit number. Muscle Nerve, 16: 1326–1331. Edström, L and Kugelberg, E (1968) Histochemical composition, distribuiton of fibers and fatiguability of single motor units. J. Neurol. Neurosurg. Psychiatry, 31: 424–433. Galea, V, DeBruin, H, Cavasin, R and McComas, A (1991) The numbers and relative sizes of motor units estimated by computer. Muscle Nerve, 14: 1123–1130. Hansen, S and Ballantyne, J (1978) A quantitative electrophysiological study of uraemic neuropathy. Diabetic and renal neuropathies compared. J. Neurol. Neurosur. Psychiatry, 41: 128–134. Jillapalli, D, Bradshaw, D and Shefner, J (2003) Motor unit number estimation in the evaluation of focal conduction block. Muscle Nerve, 27: 676–681. Kadrie, H, Yates, S, Milner-Brown, H and Brown, W (1976) Multiple point electrical stimulation of ulnar and median nerves. J. Neurol. Neurosurg. Psychiatry, 39: 973–985. Kimura, J (2001) Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice. FA Davis Company, Philadelphia. Kugelberg, E, Edström, L and Abbruzzese, M (1970) Mapping of motor units in experimentally reinnervated rat muscle. J. Neurol. Neurosurg. Psychiatry, 33: 319–329. Kuwabara, S, Ogawara, K, Mizobuchi, K, Mori, M and Hattori, T (2001) Mechanisms of early and late recovery in acute motor axonal neuropathy. Muscle Nerve, 24: 288–291.

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Lawson, V, Smith, A and Brombert, M (2003) Assessment of axonal loss in Charcot–Marie–Tooth neuropathies. Exp. Neurol., 184: 753–757. Lewis, R, Li, J, Fuerst, D, Shy, M and Krajewski, K (2003) Motor unit number estimate of distal and proximal muscles in Charcot–Marie–Tooth disease. Muscle Nerve, 28: 161–167. Lomen-Hoerth, C and Olney, R (2000) Comparison of multiple-point and statistical motor unit number estimation. Muscle Nerve, 23: 1525–1533. Lomen-Hoerth, C and Olney, R (2001) Effect of recording window and stimulation variables on the statistical technique of motor unit number estimation. Muscle Nerve, 24: 1659–1664. Martinez-Figueroa, A, Hansen, S and Ballantyne, J (1977) A quantitative electrophysiological study of acute idiopathic polyneuritis. J. Neurol. Neurosurg. Psychiatry, 40: 156–161. McComas, A (1991) Invited review: Motor unit estimation: Methods, results, and present status. Muscle Nerve, 14: 585–597. McComas, A, Fawcett, P, Campbell, M and Sica, R (1971a) Electrophysiological estimation of the number of motor units within a human muscle. J. Neurol. Neurosurg. Psychiatry, 34: 121–131. McComas, A, Sica, R, Campbell, M and Upton, A (1971b) Functional compensation in partially denervated muscles. J. Neurol. Neurosurg. Psychiatry, 34: 453–460. McKhann, G, Cornblath, D, Griffin, J, Ho, T, Li, C and Jiang, Z et al. (1993) Acute motor axonal neuropathy: A frequent cause of acute flaccid paralysis in China. Ann. Neurol., 33: 333–342. Olney, R, Yuen, E and Engstrum, J (2000) Statistical motor unit number estimation: Reproducibility and souces of error in patients with amyotrophic lateral sclerosis. Muscle Nerve, 23: 193–197. Rich, M, Bird, S, Raps, E, McLukskey, L and Teeneer, J (1997) Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve, 20: 665–673. Rosenfalck, A (1978) Early recognition of nerve disorders by near-nerve recording of sensory action potentials. Muscle Nerve, 1: 360–367. Schulte-Mattler, W, Georgiadis, C, Tietze, K and Zierz, S (2000) Relation between maximum discharge rates on electromyography and motor unit number estimates. Muscle Nerve, 23: 231–238.

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Shefner, J, Jillapalli, D and Bradshaw, D (1999) Reducing intersubject variability in motor unit number estimation. Muscle Nerve, 22: 1457–1460. Slawnych, M, Laszlo, C and Hershler, C (1990) A review of techniques employed to estimate the number of motor units in a muscle. Muscle Nerve, 13: 1050–1064. Stålberg, E (1982) Electrophysiological Studies of Reinnervation in Als. Raven Press, New York. Stålberg, E, Schwartz, M and Trontelj, J (1975) Single fibre electromyography in various processes affecting the anterior horn cell. J. Neurolog. Sci., 24: 403–415.

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Stashuk, D (1999) Decomposition and quantitative analysis of clinical electromyographic signals. Med. Eng.Phy., 21: 389–404. Stein, R and Yang, J. (1990) Methods for estimating the number of motor units in human muscles. Ann. Neurol., 28: 487–495. Trojaborg, W, Weimer, L and Hays, A (2001) Electrophysiologic studies in critical illness associated weaknes: myopathy or neuropathy -a reappraisal. Clin. Neurophysiol., 112: 1586–1593. Wang, F and Delwaide, P (1995) Number and relative size of thenar motor units estimated by an adapted multiple point stimulation method. Muscle Nerve, 18: 969–979.

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CHAPTER 13

Pelvic floor conduction studies David B. Voduˇsek* University Medical Center, Ljubljana, Slovenia

13.1. Introduction Electrophysiological exploration of the sacral neuromuscular system (which is also involved in function of the lower urinary tract, the anorectum and the sexual response) has always been somewhat remote from mainstream clinical neurophysiology. EMG of the external anal sphincter was described as early as 1930 (Beck, 1930), but it was not until the 1950s that more workers became interested in the topic. Rattner et al. (1958) used EMG to demonstrate the presence of the bulbocavernosus reflex; the first latency recording (“conduction” study) in the lower sacral segments was probably the electrically elicited and EMG recorded bulbocavernosus reflex by Rushworth (1967). Pudendal nerve velocity was not measured until later; it was performed using long needle stimulation electrodes (Chantraine et al., 1973). The first cerebral somatosensory evoked potentials (SEP) on electrical stimulation in the anogenital area were reported in 1980 (Freeman et al., 1980). Motor evoked potential (MEP) in sphincter muscles and sympathetic skin responses (SSR) in the perineum were reported in the late 1980s, thus completing the electrophysiological evaluation battery for the sacral neuromuscular system. In this chapter, the relevant anatomy is presented first, followed by common features of uroneurophysiological testing, and it concludes with individual tests described and critically evaluated. 13.2. Anatomy Pelvic floor usually refers to the total layer closing the bony pelvic outlet, i.e., the sum of layers, the most cranial being the peritoneum and the most caudal

* Correspondence to: David B. Voduˇsek, MD, DSc, Professor of Neurology, and Medical Director, Division of Neurology, University Medical Center, Zaloˇska Cesta 7,1525 Ljubljana, Slovenia. E-mail address: [email protected].

being the skin of the perineum; the middle layers are predominantly muscle, usually referred to as “pelvic floor muscles.” As such, it is defined by the International Continence Society—ICS (ICS Pelvic Floor Clinical Assessment Group, in preparation). The term “pelvic floor” has also been employed as an all-inclusive term, including all of the above plus all the nerves and pelvic organs (Olsen and Rao, 2001). This usage seems to be a new variant of the old neurology jargon “sphincters,” with which all the sacral area and functions were covered. In this chapter, the term “pelvic floor” is used according to ICS terminology. The lower urinary tract, anorectal and sexual functions are—for the sake of brevity, where applicable— subsumed under “sacral functions”. Contrary to the above usage of the term “pelvic floor muscles,” anatomists discern the “muscles of the pelvis” (levator ani, being subdivided into several parts—pubococcygeal, puborectal, iliococcygeal, iliosacralis—and the coccygeus muscle), and the “muscles of the perineum” (muscle of the anal triangle—the external anal sphincter; and muscles of the urogenital triangle— sphincter urethrae, transversus perinei, bulbocavernosus, ischiocavernosus, and in the female, in addition, the compressor urethrae and the urethrovaginal sphincter) (Williams et al., 1995). The external anal sphincter is usually described as being composed of three parts (a subcutaneous part, a superficial and a deep part—the latter merging into the puborectalis). Electromyographically, only the subcutaneous and a “deep” part can be distinguished (Podnar et al., 1999). The location of muscles for needle insertion is described below. Only the superficial perineal muscles (the subcutaneous external anal sphincter and the bulbocavernosus in the male) can be “reached” by surface skin electrodes, but special surface type electrodes have been constructed to access the levator ani transvaginally or transrectally and the urethral sphincter transurethrally. The levator ani is innervated by segments S2, S3, and probably S4, the motor axons reaching the muscle from above and below. The anteromedial part is most

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commonly innervated by the pudendal nerve and the posterolateral part by direct branches from the sacral plexus (Williams et al., 1995). The innervation by sacral nerves may be more important than that from the pudendal nerve. In contrast to the external anal sphincter, the puborectalis is not thought to be innervated by the pudendal nerve (Percy et al., 1981) but others have reported CMAP from this muscle on pudendal nerve stimulation (Allen et al., 1990). The innervation of the striated urethral sphincter is still somewhat controversial; its most important nerve is probably the pudendal, but it may also receive (some) S2–4 axons from above, via pelvic nerves. The external anal sphincter is innervated by the inferior rectal branch and a recurrent branch from the perineal nerve (both branches of the pudendal nerve, S2, S3). It may also receive innervation from a direct branch from the sacral plexus-S4 (Williams et al., 1995). Perhaps it should be added that each half of the circular external anal sphincter (and the urethral sphincter) is innervated by its own ipsilateral nerves. An experimental study in monkeys showed a substantial overlap of innervation of the external anal sphincter (Wunderlich and Swash, 1983), probably related to interdigitation of muscle fascicles in the anterior part of the circular muscle. The pudendal nerve is derived from ventral divisions of the second, third and fourth sacral ventral rami. It leaves the pelvis via the greater sciatic foramen, enters the gluteal region, and crosses the sacrospinous ligament close to the ischial spine. It then re-enters via the lesser sciatic foramen into the pelvis again, and is situated on the lateral wall of the ischiorectal fossa (in the pudendal or Alcock’s canal, together with the internal pudendal artery). Its main branches are the inferior rectal nerve (for the external anal sphincter and anal skin), the perineal nerve (with muscular branches for the urethral sphincter and other perineal muscles, including a recurring branch for the external anal sphincter and skin branches for the perineum), and the dorsal penile/clitoral nerve. The branching—from the sacral plexus onwards—is quite variable (Williams et al., 1995). The pudendal nerve (branches) are most dependably located (for stimulation, but originally for anaesthetic block) close to the sciatic spine and the sacrospinous ligament, which can be palpated transvaginally or transrectally. 13.3. Electrophysiological equipment and techniques The principles of stimulation and recording are the same in uroneurophysiology as in general clinical neurophys-

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iology, and the same electrophysiological equipment is used. For electrical stimulation in the perineum, 0.1–0.5 ms long electrical pulses are applied; reflex responses may be elicited using double pulse (or train) stimulation, with a 3 ms interstimulus interval. No consensus on standard techniques of conduction studies in the pelvic region has been achieved so far. Only pudendal SEP recordings are performed in a fairly uniform fashion in different laboratories. The recommendation on individual technique will be from the author’s laboratory, with other approaches being mentioned for comparison. Any type of surface electrode, as used in general clinical neurophysiology, is applicable in the anogenital region (bipolar, ring, disposable stick-on electrodes, etc.), for recording and stimulation. The earlobe-clip EEG electrode, for instance, has been found to be practical for electrical stimulation of the clitoris and labia (Voduˇsek, 1990a). Because of the special anatomical conditions, various custommade surface type electrodes have been introduced by individual authors; only a few have been commercialized and more widely accepted. A catheter-mounted ring electrode fitting on a Foley catheter was devised by Nordling et al. (1978), with the electrodes being positioned 2–3 cm below the catheter balloon in women and 2–5 cm below in men. The vaginal electrode consists of a pair of silver chloride electrodes on a disposable flexible vinyl foam pad; it is inserted into the vagina so that it lies immediately behind the urethral sphincter (Lose et al., 1985). The anal plug electrode consists of two recording surfaces mounted on a hourglass-shaped electrode, which is inserted into the anal canal. The St Mark’s pudendal electrode is a specially designed assembly of surface electrodes, one pair for stimulation and another pair, at a distance of 3 cm, for recording. It has been constructed to fit onto a gloved index finger, for pudendal nerve stimulation and external anal sphincter response recording transrectally (Kiff and Swash, 1984). A special monopolar stimulating probe for transrectal pudendal nerve stimulation has been proposed (Lefaucheur et al., 2001). In uroneurophysiology, standard concentric needle EMG electrodes are used not only for EMG, but also for recording direct and reflex muscle responses, in case a selective recording is required, particularly if stimulation is non-selective, such as for MEP (Voduˇsek and Zidar, 1988). The required needle electrodes can be short if used to examine the external anal sphincter or the female urethral sphincter, but long electrodes are required for examination of the male urethral sphincter and the pubococcygei.

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SFEMG electrodes have been used to record direct and reflex responses from pelvic floor muscles for research purposes (Trontelj et al., 1974; Voduˇsek and Janko, 1990). Intramuscular “hooked wire” electrodes (introduced with an injection needle, which is then withdrawn) are being used for intraoperative recording of sphincter MEP and reflex responses (Voduˇsek and Deletis, 2002). 13.3.1. Recommendation for use and placement of electrodes Only surface electrodes are used for stimulation in routine diagnostic tests. Surface electrodes are also used for recording SEP, SSR and the sensory neurogram of the dorsal penile nerve; they can also be used to record sacral reflex responses unless very selective response detection is required. In the author’s laboratory, cup and stick-on electrodes are used for recording SEP, SSR and the bulbocavernosus reflex, while standard bipolar electrodes, ring electrodes (for the penis), and EEG ear clip electrodes (for the clitoris and labia) are used for stimulation. Concentric needle EMG electrodes are used for recording CMAP and MEP in our laboratory. We adhere generally to the consensus statement for investigation of patients with urinary incontinence (i.e., if a uroneurophysiological investigation is necessary at all to diagnose a peripheral neurogenic lesion in an individual patient, concentric needle EMG is the investigation of choice—Fowler et al., 2002). Therefore, we would use a concentric needle EMG electrode in the patient, anyhow. Extending concentric needle EMG with a conduction study that involves recording from pelvic floor muscles only means planning the examination accordingly, so that the needle electrode can be used for all tests without reinsertion. What is lost in “invasiveness” is gained in selectivity (and validity: see respective paragraphs) of recording CMAP and MEP. Consideration should also be given to the “invasiveness” and discomfort caused by inserting catheter electrodes, foam cylinders and plug electrodes. The external anal sphincter is the most practical indicator muscle for lower sacral myotomes because it is easy to access, and its examination is not too uncomfortable. To examine the subcutaneous external anal sphincter, the needle electrode should be inserted subcutaneously about 1 cm from the anal orifice, to a depth of a 3–6 mm under the non-keratinized epithelium. For the deeper external anal sphincter

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muscle, 1–3 cm deep insertions are made at the anal orifice, at an angle of about 30˚ to the anal canal axis (Podnar et al., 1999). At a depth of 5 cm, the puborectalis (levator ani) is reached (Sato et al., 2001). The pubococcygeus (levator ani) muscle can be located by transrectal or transvaginal palpation and reached transcutaneously from the perineum or transvaginally. A needle electrode can be inserted into the male bulbocavernosus muscle 2–3 cm in front of the anal orifice, about 1 cm from the midline. The female bulbocavernosus muscle can be reached either transmucosally, by needle insertion medially to the labia minora, or through the skin lateral to the labia majora c. 2–3 cm below the level of the clitoris. In both sexes, the bulbocavernosus is the first muscle to be reached in the indicated region after passing through the subcutaneous fat, which is of quite variable breadth in different subjects. The male urethral sphincter is reached by the needle electrode transcutaneously from the perineum, about 4 cm in front of the anus. The electrode is advanced towards the finger tip palpating transrectally the apex of the prostate. The female urethral sphincter can be reached periurethrally, with a needle insertion 0.5 cm lateral to the urethral orifice. (Because of the submucosal plexus of the female urethra, bleeding after needle removal is common, but complications have never been encountered by the author.) Local anesthetic gel before insertion of needle electrodes is not used, and should not be resorted to in case it might interfere with the conduction study. 13.4. Motor tests 13.4.1. Perineal muscle compound muscle action potential and terminal motor latency testing Testing of motor conduction velocity for the deeplying pudendal nerve has been described using stimulating needle electrodes close to the sciatic spine and in the perineum, and recording CMAP from the external anal sphincter and urethral sphincter (Chantraine et al., 1973). A mean velocity of c. 57 m/s was reported. The distal latencies obtained in this study—as one can judge from the report—were between 3.6 and 4.4 ms. These values can be compared to the urethral sphincter CMAP latency of 4.8 ms (SD 1.5 ms) obtained on similar stimulation of the pudendal nerve transperineally with needle electrodes (Voduˇsek and Light, 1983). Due to uncertainty as to the estimated nerve length, the validity of pudendal

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nerve velocity measurement is questionable; because of invasiveness, it has not been pursued. The direct muscle response (from the external anal sphincter and other perineal muscles), i.e., the compound muscle action potential (CMAP) or M-wave, can also be obtained on stimulation with a bipolar surface electrode placed perianally or perineally (Pedersen et al., 1982; Voduˇsek et al., 1983). Thus, measured distal latencies of CMAP, as recorded with concentric needle electrodes from the external anal sphincter, the bulbocavernosus and the urethral sphincter muscles are in the same range as reported by Voduˇsek and Light (1983). The most widely employed technique for obtaining the distal motor latency for the external anal sphincter was introduced by Kiff and Swash (1984), who applied the stimulus to the pudendal nerve transrectally. This has come to be called the “pudendal nerve terminal motor latency” test (in the literature referred to as PNTML; so much so, that some authors use the term “PNTML response” instead of M-wave or CMAP!). A special electrode has been constructed especially for this test—the St Mark’s pudendal electrode (see above). Using this method, the distal motor latency for the anal sphincter CMAP has been widely reported to be below 2 ms; in a recent study, the median value was 1.7 ms (range 1.3–3.4 ms—for the right PNTML) (Morren et al., 2001). Indeed, the normal upper latency limit used in many laboratories is 2.2 ms (Allen et al., 1990; Hill et al., 2002) in others 2.5 ms (Olsen and Rao, 2001). There are some recent reports on longer normal PNTML latencies as originally reported—ranging up to 5.6 ms, with a mean value close to 3 ms; the mean value in subjects over 50 years being 3.5 ± 0.4 ms (Lefaucheur et al., 2001). There are technical difficulties in obtaining “symmetrical” CMAP from the left and right side of external anal sphincter with the St Mark’s electrode, a consequence of using the same hand for both left and right stimulation and recording. For this reason, a reusable stimulating monopolar probe (a curved metallic rod with a handle) was designed to be used as the cathode, along with a surface electrode glued to the skin above the sciatic spine serving as the anode. External anal sphincter CMAP recorded with surface adhesive electrodes placed unilaterally over the anal verge was reported as being less distorted, their mean latency being 3.7 ± 0.9 ms (Lefaucheur et al., 2001). These values are close to those reported using the transperineal method (Voduˇsek et al., 1983). The St Mark’s device can also be used as a bipolar stimulation electrode only; it is practical to deliver

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stimulation to pudendal nerve (branches) close to the ischial spine (via the rectum or vagina). If a cathetermounted electrode is used for recording, CMAP from the striated muscle of the urethral sphincter can be obtained and its distal latency measured. This test is called the “perineal terminal motor latency” (PeTML); 2.4 ms has been suggested as the upper cutoff normal latency (Smith et al., 1989). If CMAPs in the different perineal muscles (bulbocavernosus, ischiocavernosus, etc.) are recorded with a concentric needle EMG electrode, the latencies are typically longer (Voduˇsek and Light, 1983; Robert et al., 1998). It seems that the puzzle of discrepant latencies can be resolved by taking into consideration the results from the external anal sphincter MEP study by Sato et al. (2000), who reported a stepwise latency increase in the MEP (on magnetic stimulation over the sacrum) when recorded with a concentric needle EMG electrode at different depths from the perianal skin (at 5.0, 3.8, 2.4, and at 1.5 cm; i.e., recorded consecutively from the puborectalis to the deep, superficial and perhaps subcutaneous external anal sphincter muscle). Similarly, with St Mark’s electrode stimulation, the CMAP from the deep part of the external anal sphincter has a shorter latency than the CMAP from the subcutaneous part (Voduˇsek, unpublished data). It is, therefore, suggested that the St Mark’s recording, i.e., with surface electrodes inside the anal canal, is less selective and less well defined than the concentric needle EMG recordings; as the latency reading is always of the shortest latency, the PNTML would mostly reflect the CMAP of deeper striated muscles and not the superficial and subcutaneous external anal sphincter, from which concentric needle EMG recordings have been typically obtained in other studies, reporting significantly longer latencies. Still, the typical PNTML from most reports is curiously short, particularly if one considers the length of the pudendal nerve branch from the sciatic spine to the external anal sphincter, which is 8 cm; this should make the PNTML slightly longer than the distal latency of the median nerve (Lefaucheur et al., 2001). In fact, PNTML may reflect depolarization of short nerve branches of deep pelvic floor muscles close to the motor point. Pudendal nerve terminal motor latency has been found in some studies to increase with age (Lefaucheur et al., 2001), but not in others (Barrett et al., 1989). The amplitude of CMAP theoretically reflects the number of excitable motor units in the striated muscle,

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but few authors seem to find amplitude recordings useful (Mastropietro et al., 2001). The amplitudes obtained by the St Mark’s electrode are typically small (median value 135 mV, range 67–257 mV—Morren, 2002). Some authors report larger amplitudes, varying from 0.3 to 3 mV (Wiesner and Jost, 2001). Most of the reports on PNTML do not contain CMAP amplitude data at all. 13.4.2. Recommendation In our laboratory, we record CMAPs in perineal muscles (with a concentric needle EMG electrode) only in very selected patients, to demonstrate innervated muscle in patients with denervation lesions, but not to diagnose subclinical “neuropathy” (Fig. 13.1). We apply electrical stimulation to the perineum (with a bipolar surface electrode), or transrectally (with the St Mark’s electrode). We do not consider latency of the direct response in any pelvic floor muscle in any type of patient as an isolated parameter; we assess the presence/absence of the response, and in selected patients qualitatively compare CMAP, MEP and the bulbocavernosus reflex. Pudendal nerve terminal motor latency, being a test of distal motor conduction, cannot measure motor unit loss, denervation or reinnervation. Experts differ in

A

B

1 ms

1 mV

Fig. 13.1 CMAP of the external anal sphincter as recorded with a concentric needle EMG electrode at 3 cm depth from anal epithelium (A), and as recorded by St. Marks electrode (B); (stimulation with St Mark’s electrode in both instances; two consecutive responses are superimposed). Recorded in a 37-year-old male patient recovered after L1 fracture with no residual symptoms of sacral dysfunction.

their opinions as to the clinical usefulness of the test. Its use in isolation, as a single neurophysiological parameter tested to define “pudendal neuropathy,” and thus “prove” (or rule out) the neurological origin of a patient’s disorder, does not seem to be good neurophysiological practice. Holding a similar view, the American Gastroenterological Association rejected PNTML as a useful technique (AGA, 1999). So far, no standardized technique has been generally accepted either for the external anal sphincter or any other perineal muscle CMAP recording on pudendal nerve stimulation. St Mark’s method is mostly used, particularly among proctologists. It appears that enthusiasm for the test is waning. We recommend that each laboratory make an informed decision on technique and its application, being aware of all the pitfalls. 13.4.3. Anterior sacral root (cauda equina) stimulation Motor evoked potentials from perineal muscles on sacral root stimulation were reported soon after the method for deep electrical stimulation was introduced into clinical neurophysiology; stimulation was delivered at T12/L1 and L4/L5 (Swash and Snooks, 1986). When it became available, magnetic stimulation was introduced (Opsomer et al., 1989). Recording of motor evoked potentials following magnetic stimulation is less often successful than with electrical stimulation, at least with standard coils, (Opsomer et al., 1989; Loening-Baucke et al., 1994) and stimulus artefacts are commonly a major problem (Brostrom et al., 2003b), which is not the case with electrical stimulation. Positioning of a ground electrode between the recording electrodes and the stimulating coil may decrease this problem, but it is particularly important to pay attention to careful technique: everything must be kept dry; cables removed from the magnetic field, and the strength of stimulation and the position of the coil adjusted. Recently, normative MEP values recorded with concentric needle EMG electrodes from the urethral sphincter and the puborectal muscle using magnetic stimulation over the upper lumbar spine and over the sacrum in adult women have been reported. Sacral latency is positively correlated with height. The mean value for the puborectalis is 4.1 ms (range: 3.8–4.4 ms), and for the urethral sphincter 4.7 ms (range: 4.2–5.1 ms) (Brostrom et al., 2003b). Needle EMG rather than non-selective surface electrodes should be used to record from the pelvic floor, particularly the sphincter responses following

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electrical or magnetic stimulation of the cauda equina since both methods depolarize underlying neural structures in a non-selective fashion and activate all muscles innervated by lumbosacral segments (Brostrom et al., 2003a). It has been shown that responses from gluteal muscles may contaminate recordings from the external anal sphincter and lead to error (Voduˇsek and Zidar, 1988). “Contamination” with the shortest latency response may be the origin of some reports with unexpectedly short MEP latencies from the external anal sphincter or the urethral sphincter (see also latencies of CMAP on pudendal nerve stimulation). Latencies of MEP (on magnetic stimulation over the sacrum) from different parts of the external anal sphincter complex differ at different depths from the anal skin (Sato et al., 2000), and this can only be ascertained with selective, i.e., needle, electrodes. The latencies are shortest from the 5 cm deep recording site (puborectalis) and longest from the 1.5 cm deep recording site (the superficial or subcutaneous external anal sphincter); the values are 3.8 and 10 ms (median values), respectively, in young subjects (Sato and Nagai, 2002); the values are slightly longer for middle-aged subjects (Sato et al., 2000). The latency obtained from surface electrodes on an intrarectal probe was 3.4 ms (median value) (Sato and Nagai, 2002), which is close to the 3.3 ms median latency reported by Morren et al. (2001). These surface electrode recordings may reflect the activity in deeper pelvic floor muscles (and not—as it is implicitly understood—the close-by superficial part of the external anal sphincter), but they may also be contaminated by gluteal activity (Voduˇsek and Zidar, 1988). Therefore, surface MEP recordings do not seem to be reliable witnesses of external anal sphincter function, attractive as they are because of their non-invasiveness. As Sato et al. (2001) point out, differential involvement of the anal sphincter complex after childbirth may be another argument in favor of selective concentric needle EMG MEP recordings. Concomitant recording of PNTML and MEP latency from a perineal muscle should, in theory, distinguish proximal from distal lesions (Morren et al., 2001), but because of the questionable validity of surface recordings, such measurements should rely on concentric needle EMG recordings. The validity of this approach in clinical practice has not been established. Deep electrical stimulation over the back being more focal, “cauda equina conduction” can be estimated on stimulation at two levels (T12 and L4/5), and recording from the external anal sphincter (Swash

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and Snooks, 1986); the measurement can, in fact, be extended to include S3 (Voduˇsek, 1996). The usefulness of “cauda equina conduction testing” in clinical practice has not been established. Electrical stimulation with needle electrodes at vertebral laminae Th12–L1 to elicit M-waves in the bulbocavernosus and external anal sphincter muscle has also been described (Ertekin and Mungan, 1993). At present, similar recordings are performed as a test of “good” stimulating electrode position for therapeutic electrical sacral root S2 and S3 stimulation in the course of a trial of “neuromodulation” treatment in patients with sacral dysfunction. 13.4.4. Motor evoked potential of smooth muscles Whether or not parasympathetic efferents can be stimulated using magnetic stimulation remains controversial (Craggs et al., 1999); it seems unlikely that smalldiameter nerve fibers can be depolarized, and claims that motor-evoked potentials from the detrusor can be produced following magnetic stimulation of the cauda equina (Bemelmans et al., 1991) have been revised. 13.4.5. Motor evoked potentials on motor cortex stimulation Using electrical or magnetic stimulation, it is possible to depolarize the motor cortex and record a response from the pelvic floor (Rossini et al., 1987; Voduˇsek and Zidar, 1988; Opsomer et al., 1989; Brostrom et al., 2003a, 2003b). Magnetic stimulation is less unpleasant than electrical stimulation, which has now been abandoned as a means of stimulating the motor cortex in awake subjects, but is still used for intraoperative monitoring (Voduˇsek and Deletis, 2002). To obtain pelvic floor muscle responses, the posterior edge of the magnetic coil is applied with direct contact to the skin 2 cm behind Cz (of the 10–20 EEG system); the intensity of the stimulation is progressively increased until a response is recorded from the muscle; then the stimulation is repeated with the same intensity during a transient and moderate voluntary contraction of the pelvic floor, i.e., “facilitation,” which leads to shortening of the latency of the MEP. Muscle responses may be recorded from the urethral and the anal sphincters and from the bulbocavernosus muscles. It is advisable to use selective, i.e., needle recording for the reasons stated above (Voduˇsek and Zidar, 1988; Brostrom et al., 2003a). Results have been reported for the various perineal and pelvic floor muscles in healthy

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subjects, i.e., the bulbocavernosus muscle (Voduˇsek and Zidar, 1988; Ertekin et al., 1990), the urethral sphincter (Thiry and Deltenre, 1989), the external anal sphincter (Voduˇsek and Zidar, 1988; Ertekin et al., 1990) and the levator ani muscle (Ertekin et al., 1990), but these did not amount to valid “normative” values. Recently, normative values for the urethral sphincter and the puborectal muscle in adult women have been reported for transcranial magnetic stimulation; mean value for the urethral sphincter is 20.3 ms (range: 19.6–21.0 ms; nonfacilitated) and 17.8 ms (range: 17.1–18.4 ms; facilitated). The values for the puborectalis were quite similar (Brostrom et al., 2003b). By performing the stimulation at two different sites (brain and spinal roots), it is possible to derive three different conduction times: a total conduction time, a peripheral conduction time and a central conduction time (Fig. 13.2). The total conduction time can be measured both at rest and during a facilitation procedure (Opsomer et al., 1989). MEP latencies from different laboratories using different types of stimulating devices and recording electrodes differ, probably due to differences related to the selectivity of recording and the uncertainty of the actual depolarization site of magnetic stimulation. A “central conduction time” from the brain to the lumbar spine, and another from the brain to sacral stimulation site can be distinguished, (“corticospinal conduction time,” and “central conduction time,” respectively). A “cauda equina conduction time” can also be obtained. The mean values reported for corticospinal and central conduction times for the urethral sphincter were 9.5 and 13.0 ms for facilitated, and 11.9 and 15.4 ms for non-facilitated testing, respectively. The “cauda equina conduction time” has a mean value of 4 ms (as measured in a group of 30 women) (Brostrom et al., 2003b). There are no data on the sensitivity and specificity of the pelvic floor muscle MEP test (either for presence/absence, amplitude or latencies and conduction times) nor are there reports involving larger numbers of patients. Demonstrating the presence of a MEP on stimulation over the lumbosacral spine may occasionally be helpful in patients with poor voluntary or reflex activation of pelvic floor muscles. It may also assist in the differentiation of sensory from motor limb involvement of the sacral reflex arc. 13.4.6. Recommendation The test is used only in very few selected patients in the author’s laboratory, as, for instance, in patients

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19.3

A 50 μV 10 ms 8.7

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4.4

C 50 μV 5 ms

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8.7

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Fig. 13.2 MEPs recorded by concentric needle in the external urethral sphincter of a 51-year-old woman. Cortical (A), thoracal (B), and sacral (C) stimulation. Central motor conduction time (CMCT) is calculated as cortical lumbar latency (** = 10.6 ms). Cauda equina motor conduction time is calculated as lumbar—sacral latency (* = 4.3 ms) (From Brostrom et al., 2003b with permission from John Wiley and Sons, Inc.).

with poor voluntary contraction of pelvic floor muscles, without other signs of motor system involvement. In the author’s laboratory, magnetic stimulation of the motor cortex, and (if bothersome artefact is encountered) electrical (Digitimer 180) stimulation over the spine (stimulation sites L1 or S3) is used, and recordings are obtained with concentric needle EMG electrodes at specified depths of the external anal sphincter, from the urethral sphincter, or the bulbocavernosus muscle. A well-formed response is suggestive of preserved long motor tracts; latencies are not evaluated other than qualitatively, in comparison to CMAP and bulbocavernosus reflex. Absence of the MEP is interpreted cautiously.

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13.5. Sensory tests 13.5.1. Sensory neurography By placing a pair of stimulating electrodes across the glans and a pair of recording electrodes across the base of the penis, a nerve action potential can be recorded (with an amplitude of about 10 mV) (Bradley et al., 1984). It can also be recorded by stimulating transrectally (Amarenco and Kerdraon, 1999) or transperineally, but it cannot be elicited in all normal subjects (Voduˇsek, unpublished). The method can obviously only be used in males. In principle, this technique would help to differentiate between sensory and motor fiber involvement and be of value in the diagnosis of sensory neuropathy. It could also help to differentiate between a supra- and infraganglion denervation in a patient with penile sensory loss, but the sensitivity and specificity of the test are not known, and it does not seem to be popular in clinical practice. 13.5.2. Neurography of dorsal sacral roots In a study using epidural electrodes for recording, root potentials were obtained in 13 out of 22 subjects (Ertekin and Mungan, 1993) on electrical stimulation of the dorsal penile nerve. Compound sensory root action potentials on electrical stimulation of the dorsal penile and clitoral nerve may be directly recorded intraoperatively when the sacral roots are exposed (Voduˇsek et al., 1990). This has been found helpful in preserving roots (rootlets) identified as carrying signals from genital organs in spastic children undergoing dorsal rhyzotomy and also in decreasing the incidence of postoperative voiding dysfunction (Deletis et al., 1992: Huang et al., 1997). The intraoperative test has also been adopted for this purpose. 13.6. Somatosensory evoked potentials 13.6.1. Spinal somatosensory evoked potentials Spinal SEP can be recorded on stimulating the dorsal penile nerve and recording with surface electrodes at the level of the Th12–L2 vertebrae (and the S1, Th6 or iliac spine as reference); the recorded potential reveals the postsynaptic segmental spinal cord activity (Haldeman et al., 1982). Spinal SEP peak latency is 12.6 ms (SD 1 ms), but pudendal spinal SEP are difficult to record in obese male subjects and in women

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(Voduˇsek, 1990a). Recordings are, thus, not really useful in patients. On stimulation of the dorsal penile nerve, even with epidural electrodes, sacral root potentials could only be recorded in 13, and cord potentials in nine of 22 subjects (Ertekin and Mungan, 1993). Latencies of these spinal SEPs were c. 12 ms (Ertekin and Mungan, 1993), substantiating the results obtained by surface recording (Haldeman et al., 1982; Voduˇsek, 1990b). 13.6.2. Pudendal somatosensory evoked potentials On electrical stimulation of the dorsal penile or clitoral nerve, a cerebral SEP can be recorded (Haldeman et al., 1982, 1983; Opsomer et al., 1986; Voduˇsek, 1990a, 1990b). This SEP is as a rule of highest amplitude at the central recording site Cz–2 cm: Fz of the International 10–20 EEG System (Guérit and Opsomer, 1991) and is highly reproducible. The first positive peak at about 40 ms (called P1 or P40) is clearly defined in healthy subjects using a stimulus 2–4 times the sensory threshold current strength (Voduˇsek, 1990a, 1990b). Later, negative (at c. 55 ms) and then positive waves show considerable intersubject variability. Similar results have been obtained in many laboratories (Haldeman et al., 1982, 1983; Opsomer et al., 1986). It is a common practice to establish the “threshold” for the electrical stimulus perception as applied to the penis/clitoris (or other stimulation site) at the beginning of a pudendal SEP recording session. The obtained threshold value is then used to formulate the necessary strength of the stimulus used to elicit SEP. As a rule, a two to four times “threshold” current intensity is used, and the bulbocavernosus reflex from the perineum is recorded simultaneously (Voduˇsek, 1996). The common technique of stimulating the dorsal penile/clitoral nerve with surface electrodes depolarizes both nerves; therefore, the test is not likely to reveal unilateral lesions. Unilateral stimulation is, however, feasible, even in women (Voduˇsek 1990a; Yang et al., 2000). Cerebral SEP on penile/clitoral stimulation was reported as possibly being an useful intraoperative monitoring method in patients with cauda equina or conus at risk during a surgical procedure (Voduˇsek et al., 1990; Cohen et al., 1991). Pudendal SEP is a robust electrophysiological test used in many laboratories; reports on normative data are compatible. It has been proposed particularly for assessment of patients with spinal cord lesions (Schmid et al., 2003).

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13.6.3. Evoked potential mapping There have been some reports on EEG brain mapping (over up to 32 different sites) and magnetic brain mapping (Guérit and Opsomer, 1991), on electrical stimulation of the pudendal nerve. Mapping techniques have no current clinical application in patients with suspected neurogenic sacral dysfunction. 13.6.4. Pudendal cerebral somatosensory evoked potential on mechanical stimulation Mechanical stimuli, delivered to the distal penis by a custom-designed electromechanical hammer, elicit cerebral SEP comparable to standard electrical stimulation in male children (Podnar et al., 1997). Painless mechanical stimulation is obviously preferable to electrical stimulation when investigating children, but no clinical usefulness has yet been established. 13.6.5. Cerebral somatosensory evoked potential on electrical stimulation of visceral afferents Cerebral SEP can also be obtained on electrical stimulation of the bladder urothelium (Badr et al., 1982; Sarica and Karacan, 1986). Stimulation is delivered by catheter-mounted electrodes. The technique is painful, as urethral local anaesthetic jelly cannot be used. It is important to use bipolar stimulation for such recordings; otherwise somatic afferents are depolarized (Hansen et al., 1990). The reported SEP have a maximum amplitude of 1 mV or less over the midline (Cz2 cm: Fz), and are of variable configuration, so that it may be difficult to identify the response in some control subjects (Hansen et al., 1990; Ganzer et al., 1991). The typical latency of the most prominent negative potential (N1) has been reported to be about 100 ms, but data from different authors vary (Sarica and Karacan, 1986; Hansen et al., 1990; Ganzer et al., 1991). Cerebral SEP have been reported on both electrical rectal (Meunier et al., 1987; Loening-Baucke et al., 1991); and mechanical rectal stimulation (Pratt et al., 1979; Loening-Baucke et al., 1995) with variable results. A recent study has confirmed that electrical stimulation reliably elicits SEP in healthy subjects, but two different morphologies were obtained (P1N1P2N2 and N1P2N2P2, the latency of the first peak being in the range of 54–119 ms in 14 subjects) (Hobday et al., 2000). Mechanical stimulation, however, failed to elicit recognizable responses in three out of 14 sub-

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jects. Generally, responses on mechanical stimulation had lower amplitudes and longer latencies than their electrically elicited counterparts, however, they demonstrated the same two patterns (Hobday et al., 2000). Somatosensory evoked potential to stimulation of the bladder neck and rectum is difficult to record and extremely variable even in normal subjects, so its validity to prove abnormality in patients is questionable. 13.6.6. Recommendation In the author’s laboratory, pudendal cerebral SEP are recorded on electrical stimulation of the dorsal penile/clitoral nerve with surface electrodes (and exceptionally on mechanical stimulation of the penis or clitoris with an electromechanical hammer) in selected patients who present the discrepancy between perineal sensory symptoms and clinical findings, and always with simultaneous sacral reflex recording (Fig. 13.3). The SEP is recorded with surface cup electrodes from Cz-2 cm: Fz. For reflex recording surface, cup electrodes are placed perianally/perineally. Two consecutive series of 128 responses are averaged. Rectangular electrical pulses of 0.1 ms duration at 2–4 times sensory threshold strength are applied at 2 Hz. Occasionally, such stimuli do not elicit the reflex, which can, however, be demonstrated in these patients in a follow-up recording using a double stimulus (see paragraph on sacral reflexes). The absence of SEP is abnormal. The normal latency of P40 is below 47 ms. 13.7. Sacral reflexes The term “sacral reflexes” refers to the electrophysiologically recordable responses of perineal/pelvic floor muscles to electrical stimulation in the uro-genito-anal region. The anal and the bulbocavernosus reflexes are elicited as part of the clinical examination. Both have the afferent and efferent limb of their reflex arc in the pudendal nerve, and are centrally integrated at the S2–S4 cord levels. As the observation of the response (visually, or by palpation) may leave the clinician uncertain, EMG recording of the reflex response was introduced (Rattner et al., 1958), with later replacement of the mechanical stimulus used clinically by electrical pulses (Rushworth, 1967). The common method is to use single electrical pulses delivered to the dorsal penile nerves (Ertekin and Reel, 1976;

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2 μV

7 μV 10 mV

Fig. 13.3 Pudendal SEP (upper trace) and bulbocavernosus reflex (lower trace) in a woman complaining of perineal/genital anesthesia. The cerebral SEP and sacral reflex were recorded simultaneously. Two consecutive averages of 128 responses were superimposed. Cerebral SEP was recorded from Cz-2 cm: Fz; sacral reflex from the anal sphincter, with cup electrodes. Stimulation was performed with surface (ear clip EEG) electrodes. The dorsal clitoral nerve was stimulated with rectangular electrical pulses at 2 Hz (pulse duration 0.2 ms). The patient reported not feeling the stimulus. The stimulation was just suprathreshold for the bulbocavernosus reflex.

Krane and Siroky, 1980; Voduˇsek et al., 1983), but mechanical stimuli triggering the EMG recording (Podnar et al., 1997), and magnetic pulse stimulation (Loening-Baucke et al., 1994) have also been reported. The reflex can also be tested in women by electrical stimulation of the dorsal clitoral nerve (Bilkey et al., 1983; Voduˇsek, 1990a). Reflex responses in both genders can also be elicited by electrical stimulation perianally (Pedersen et al., 1978; Voduˇsek et al., 1983), or in the perineum (Yang and Bradley, 2000). The pudendal nerve itself may be stimulated transrectally, transvaginally (Contreras Ortiz et al., 1994) or by selective stimulation with needle electrodes (Voduˇsek et al., 1988). Sacral reflex responses recorded with needle electrodes can be analyzed separately for each side of the external anal sphincter or each bulbocavernosus muscle (Krane and Siroky, 1980). This is important because unilateral or asymmetrical lesions are common. Unilateral stimulation of the penis along with a unilateral anesthetic block has been reported (Amarenco and Kerdraon, 2000). On application of stronger stimulus unilaterally to the shaft of the penis or clitoris, bilateral depolarization of the dorsal nerves cannot be excluded. But unilateral stimulation of the pudendal nerve can be achieved and it has also been described in women (Yang et al., 2000). The bulbocavernosus reflex has been shown to be a complex response, often forming two components (Krane and Siroky, 1980; Voduˇsek and Janko, 1990). The first component is actually the one usually accepted as the “bulbocavernosus reflex.” It is stable, does not habituate, and it is thought to be an oligosynaptic reflex response (Voduˇsek and Janko, 1990).

The synaptic organization of this early component is ipsilateral (Amarenco and Kerdraon, 2000). The second component has a latency similar to that of the sacral reflex evoked by stimulation perianally or from the proximal urethra; it is not always demonstrable as a discreet response. The two components of the bulbocavernosus reflex may behave somewhat differently in control subjects and in patients. Whereas in normal subjects it is usually the first component that has a lower threshold, in patients with partially denervated pelvic floor muscles, often the first reflex component cannot be obtained with single stimuli, but the later reflex component can be elicited on strong stimulation (Krane and Siroky, 1980). This may cause confusion, as very “delayed” reflex responses may be recorded in patients, (implying “pathological conduction”) not recognizing the possibility that it is not a delayed first component but an isolated second component of the reflex. The situation can be clarified by using double stimuli, which facilitate the reflex response and may reveal the first component, which was not obvious on stimulation with single stimuli in such a patient (Rodi and Voduˇsek, 1995). A complete reflex arc lesion should not be inferred by the absence of a response if only single pulse is used for stimulation. EMG recording of the bulbocavernosus reflex has been shown to be more sensitive than the clinically assessed reflex response in males and particularly in females (Blaivas et al., 1981); the clinical method may also produce false positive results (Wester et al., 2003). The recording of the reflex latency should increase the sensitivity to record abnormalities, but the true sensitivity and specificity of this additional parameter are not known. A mean latency between

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c. 31 and 38 ms has been reported (Ertekin and Reel, 1976; Krane and Siroky, 1980; Bilkey et al., 1983; Voduˇsek et al., 1983). Values between 43 and 45 ms are usually suggested as the upper normal limit for the shortest latency obtained on eliciting a series of reflex responses. A more than 3 ms side to side latency difference of the early bulbocavernosus reflex component is considered abnormal (Amarenco and Kerdraon, 2000). Electrical stimulation with catheter-mounted electrodes positioned at the bladder neck/proximal urethra elicits reflex responses in pelvic floor muscles (Bradley, 1972; Sarica and Karacan, 1987). The latter reflexes are often referred to as “vesicourethral” and “vesicoanal,” depending from which muscle the reflex response is recorded. Sacral reflex responses obtained on bladder neck/proximal urethra and perianal electrical stimulation have mean latencies between c. 50 and 65 ms (Bradley, 1972; Pedersen et al., 1978; Voduˇsek et al., 1983). It is clear that the sacral reflexes obtained on bladder neck/proximal urethral stimulation have a different afferent limb. These are visceral afferent fibers accompanying pelvic nerves, which are thin myelinated fibers and have a slower conduction velocity than the thicker pudendal afferents. The anal reflex (the long latency external anal sphincter response on stimulation of the perianal region), may also depend on thin myelinated afferent fibers, as it is produced by a nociceptive stimulus. (On perianal stimulation, a short latency response—the CMAP of external anal sphincter—can be recorded concomitantly, as a result of depolarization of motor branches to the external anal sphincter; Voduˇsek et al., 1983). The latency of any sacral reflex depends not just on conduction through peripheral pathways, but also on transmission through the spinal cord interneuronal system. Shorter latencies of sacral reflexes have been reported in patients with suprasacral cord lesions (Bilkey et al., 1983). It has been shown that sacral reflexes cannot be elicited in normal children during voiding (Sethi et al., 1989). Sacral reflex latency measurement is thus not a straightforward indicator of conduction in the peripheral parts of the reflex arc (i.e., demonstrating or ruling out “neuropathy”). Furthermore, delayed conduction does not directly imply organ dysfunction. In a report on patients with hereditary motor and sensory demyelinating neuropathy, the bladder and sexual function were unremarkable, but sacral reflex responses delayed (Voduˇsek and Zidar, 1987). Care should thus be taken in the interpretation of a delayed reflex.

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Continuous intraoperative recording of sacral reflex responses on penile/clitoral stimulation is feasible if double pulses (Deletis and Voduˇsek, 1997) or a train of stimuli are used (Rodi and Voduˇsek, 2001). The usefulness of such intraoperative monitoring in patients with conus/cauda at risk during surgery has been postulated, but not yet established. 13.7.1. Sacral reflex on mechanical stimulation Mechanical stimulation of the genitals has been used to elicit bulbocavernosus reflex in both sexes (Dykstra et al., 1987) and has been found to be a robust technique. Either a standard commercially available reflex hammer or a customized electromechanical hammer can be used (Podnar et al., 1997). Such stimulation is painless and can be used in children or adults. The latency of the bulbocavernosus reflex elicited mechanically is comparable to the electrically elicited reflex in the same patient, but may be either slightly shorter or longer due to the particular electromechanical device used (Podnar et al., 1997). In fact, reflex recruitment of motor unit firing occurs promptly in the pelvic floor muscles on any type of mechanical stimulation anywhere in the body. If the mechanical stimulus is applied with a device that can trigger the EMG recording apparatus, the latency of the “sacral reflex response” can be measured. Recently, such reflex responses were reported following a suprapubic tapping stimulus, as recorded in the bulbocavernosus muscle by EMG (Amarenco et al., 2002). In this case, the authors hypothesize that the stimulus may actually depolarize bladder wall tension receptors. 13.7.2. Recommendation In the author’s laboratory, bulbocavernosus reflex is the only regularly used test of conduction in lower sacral segments. It is never tested in isolation, but rather as a complementary test to concentric needle EMG, or to pudendal SEP recording. In the latter case, it is recorded with surface electrodes from the perineum or perianally. Electrical (and exceptionally mechanical) stimuli are delivered to the penis or clitoris (see pudendal SEP). At least ten consecutive responses are recorded after the response has stabilized on slowly increasing the strength of stimulation over the threshold to a “supramaximal” level. As a rule, regular stimulation is delivered at a frequency of 1 Hz. Presence of response is taken as proof of the patency of the S2–S4 reflex arc. The shortest latency

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out of 10 consecutive reflex responses obtained on strong stimulation should be below 44 ms, but the test is not interpreted as an isolated parameter to diagnose abnormal conduction in the peripheral reflex arc. 13.8. Autonomic nervous system tests in the sacral region It is the autonomic nervous system (the parasympathetic part in particular) that is most relevant for sacral functions. It has been argued that local involvement of the sacral nervous system (such as trauma, compression, etc.) will usually involve somatic and autonomic fibers simultaneously. However, there are pathological conditions, as a consequence of which purely isolated lesions can occur, such as mesorectal excision of carcinoma. There is at present no generally accepted electrophysiologic test by which the parasympathetic nervous system innervation of the pelvic viscera could be directly assessed. 13.8.1. Sympathetic skin response Sympathetic skin response is the only electrophysiological method directly testing sympathetic fibers innervating the pelvic region. It can be recorded from perineal skin and the penis (Ertekin et al., 1987). The stimulus used in clinical practice is an electric pulse delivered to an upper or lower limb mixed nerve, but the genital organs can also be stimulated. For best results, one recording electrode is positioned on the perineum (anteriorly to the anal sphincter) and the other on the mons pubis (Opsomer et al., 1996). The latency of perineal SSR following stimulation of a median nerve at the wrist has been reported to be between 1.5 (Opsomer et al., 1996) and 2.3 s (Daffertshofer et al., 1994) and was obtainable in all normal subjects from the perineal skin, but not from the penis. Responses demonstrated a large variability. The mean latency of the perineal SSR elicited on electrical stimulation of the median and dorsal penile nerves is the same (Opsomer et al., 1996). Amplitudes (but not latencies) were reported to be reduced in older subjects (Ertekin et al., 1987). It is commonly suggested that only an absent SSR can be considered abnormal. 13.9. Usefulness of clinical neurophysiological tests of conduction The introduction of conduction tests to the pelvic region led to the belief that electrophysiology would

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resolve the issues of “idiopathic” or etiologically unclear sacral/pelvic floor disorders, both in general, and in the individual patient. The contribution of electrophysiological tests has indeed not been negligible, but the tests of conduction have not proven as helpful in clinical work as many had expected. Although practically all introduced tests of conduction continue to be of research interest, they are, in the author’s opinion—with the exception of sacral reflexes—diagnostically relevant only in very selected individual patients. In the individual patient with sacral dysfunction, who presents with symptoms of a neurological condition, the contribution of neurophysiological tests of conduction is mainly in refining the functional anatomical diagnosis of the lesion, which may contribute to the prognosis (Schmid et al., 2003). The actual application of tests depends on the attitude of the clinician, particularly related to his interest in supporting a clinical diagnosis with documented results of tests. Expert consensus on the use of electrophysiological tests in incontinent patients suggests their potential usefulness in patients with peripheral lesions, particularly quantitative concentric needle EMG, and of the conduction tests bulbocavernosus reflex (Fowler et al., 2002). In the individual patient with sacral dysfunction who presents without signs or symptoms of a neurological condition, the contribution of neurophysiological tests of conduction is controversial and expected to be helpful only in very selected patients. One of the possible beneficial uses is in candidates for particular types of incontinence surgery or implantation of electrostimulation devices for therapy of pelvic organ dysfunction. The PNTML test is not recommended for routine use in anorectal dysfunction (AGA 1999). Sensory root neurography, bulbocavernosus reflex testing, anal MEP and pudendal SEP have also been introduced for intraoperative monitoring (Voduˇsek and Deletis, 2002) to help prevent lesions of the neural structures at risk from the surgical procedure. So far, the actual benefit for outcome has only been demonstrated for electrophysiological intraoperative identification of sacral roots worth of preservation during rhyzotomy in spastic children (Huang et al., 1997). In individual patients, the author would consider applying uroneurophysiological tests very selectively, always as an extension of an uroneurological examination. Testing would be considered particularly in the presence of neurological symptoms and signs, and never as a screening procedure applied in every patient with a particular sacral dysfunction (incontinence,

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etc.). In patients with known or suspected peripheral neuromuscular lesions, the following tests are suggested: concentric needle EMG for testing one or more pelvic floor muscles (as indicated by the clinical problem), and sacral reflex testing (bulbocavernosus reflex). In well-defined patient groups, other test combinations may prove helpful, such as pudendal SEP, bulbocavernosus reflex and SSR in spinal cord injury patients (Schmid et al., 2003). Further research should better define the validity, sensitivity and specificity of the pelvic floor conduction tests. References AGA (1999) American Gastroenterelogical Association medical position statement on anorectal testing techniques. Gastroent., 116: 732–760. Allen, R, Hosker, G, Smith, A and Warrell, D (1990) Pelvic floor damage and childbirth: a neurophysiological study. Br. J. Obst. Gyn., 97: 770–779. Amarenco, G and Kerdraon, J (1999) Pudendal nerve terminal sensitive latency: technique and normal values. J. Urol., 161: 103–106. Amarenco, G and Kerdraon, J (2000) Clinical value of ipsi- and contralateral sacral reflex latency measurement: a normative data study in man. Neurourol. Urodyn., 19: 565–576. Amarenco, G, Bayle, B, Ismael, SS and Kerdraon, J (2002) Bulbocavernosus muscle responses after suprapubic stimulation: analysis and measurement of suprapubic bulbocavernosus reflex latency. Neurourol. Urodyn., 21: 210–213. Badr, G, Carlsson, CA, Fall, M, Friberg, S, Lindstrom, L and Ohlsson, B (1982) Cortical evoked potentials following the stimulation of the urinary bladder in man. Electroenceph. Clin. Neurophysiol., 54: 494–598. Barrett, JA, Brocklehurst, JC, Kiff, ES, Ferguson, G and Faragher, EB (1989) Anal function in geriatric patients with faecal incontinence. Gut, 30: 1244–1251. Beck, A (1930) Elektromyographische untersuchungen am sphincter ani. (Ein beitrag zum tonusfrage). Pflugers Arch., 224: 278–292. Bemelmans, BLH, Van Kerrebroeck, Ph. EV and Debruyne, FMJ (1991) Motor bladder responses after magnetic stimulation of the cauda equina. Neurourol. Urodyn., 10: 380–381. Bilkey, WJ, Awad, EA and Smith, AD (1983) Clinical application of sacral reflex latency. J. Urol., 129: 1187–1189.

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Ertekin, C and Mungan, B (1993) Sacral spinal cord and root potentials evoked by the stimulation of the dorsal nerve of penis and cord conduction delay for the bulbocavernosus reflex. Neurourol. Urodyn., 12: 9–22. Ertekin, C and Reel, F (1976) Bulbocavernosus reflex in normal men and in patients with neurogenic bladder and/or impotence. J. Neurol. Sci., 28: 1–15. Ertekin, C, Ertekin, N, Mutlu, S, Almis, A and Akcam, A (1987) Skin potentials (SP) recorded from the extremities and genital regions in normal and impotent subjects. Acta Neurol. Scand., 76: 28–36. Ertekin, C, Hansen, MW, Larsson, LE and Sjodahl, R (1990) Examination of the descending pathway to the external anal sphincter and pelvic floor muscles by transcranial cortical stimulation. Electroenceph. Clin. Neurophysiol., 75: 500–510. Fowler, CJ, Benson, JT, Craggs, MD, Voduˇsek, DB, Yang, C and Podnar, S (2002). Clinical Neurophysiology [Chapter 4]. In: P Abrams, L Cardozo, S Khoury, A Wein (Eds.), Incontinence 2nd International Consultation on Incontinence. Health Publication Ltd., Plymouth, pp. 391–424. Freeman, NV, Burge, DM, Soar, JS and Sedgwick, EM (1980) Anal evoked potentials. Z Kinderchir., 31: 22–30. Ganzer, H, Madersbacher, H and Rumpl, E (1991) Cortical evoked potentials by stimulation of the vesicourethral junction: clinical value and neurophysiological considerations. J. Urol., 146: 118–123. Guérit, JM and Opsomer, RJ (1991) Bit-mapped imaging of somatosensory evoked potentials after stimulation of the posterior tibial nerves and dorsal nerve of the penis/clitoris. Electroenceph. Clin. Neurophysiol., 80: 228–237. Haldeman, S, Bradley, WE and Bhatia, N (1982) Evoked responses from the pudendal nerve. J. Urol., 128: 974–980. Haldeman, S, Bradley, W, Bhatia, N and Johnson, B (1983) Cortical evoked potentials on stimulation of pudendal nerve in women. Urol., 21, 6: 590–593. Hansen, MV, Ertekin, C and Larsson, LE (1990) Cerebral evoked potentials after stimulation of posterior urethra in man. Electroenceph. Clin. Neurophysiol., 77: 52–58. Hill, J, Hosker, G and Kiff, ES (2002) Pudendal nerve terminal motor latency measurements: what they do and do not tell us. Brit. J. Surg., 89: 1268–1269.

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Hobday, DI, Hobson, A, Furlong, PL, Thompson, DG and Aziz, Q (2000) Comparison of cortical potentials evoked by mechanical and electrical stimulation of the rectum. Neurogastroenterol. Mot., 12: 547–554. Huang, JC, Deletis, V, Voduˇsek, DB and Abbott, R (1997) Preservation of pudendal afferents in sacral rhizotomies. Neurosurgery, 41: 411–415. Kiff, ES and Swash, M (1984) Normal proximal and delayed distal conduction in the pudendal nerves of patients with idiopathic (neurogenic) faecal incontinence. J. Neurol. Neurosurg. Psychiatry, 47: 820–823. Krane, RJ and Siroky, MB (1980) Studies on sacralevoked potentials. J. Urol., 124: 872–876. Lefaucheur, JP, Yiou, R and Thomas, C (2001) Pudendal nerve terminal latency: age effects and technical considerations. Clin. Neurophysiol., 112: 472–476. Loening-Baucke, V, Read, NW and Yamada, T (1991) Cerebral evoked potentials after rectal stimulation. Electroenceph. Clin. Neurophysiol., 80: 490–495. Loening-Baucke, V, Read, NW, Yamada, T and Barker, AT (1994) Evaluation of the motor and sensory components of the pudendal nerve. Electroenceph. Clin. Neurophysiol., 93: 35–41. Loening-Baucke, V, Anderson, RH, Yamada, T and Yi-Xiu Zhu, BS (1995) Study of the afferent pathways from the rectum with a new distension control device. Neurology, 45: 1510–1516. Lose, G, Tanko, A, Colstrup, H and Andersen, JT (1985) Urethral sphincter electromyography with vaginal surface electrodes: a comparison with sphincter electromyography recorded etc. J. Urol., 133: 815–818. Mastropietro, M, Fuller, E and Benson, JT (2001) Electrodiagnostic features of responders and nonresponders to sacral neuromodulation test stimulation. Int. Urogynecol. Suppl., 1, 12: S24. Meunier, P, Duclaux, R, Collet, L and Chery-Croze, S (1987) Endorectal cerebral evoked potentials in humans. Int. J. Neurosci., 37: 193–196. Morren, GL (2002) Evaluation of the sacroanal motor pathway by magnetic and electric stimulation in patients with fecal incontinence. The authors reply. Dis. Colon Rectum, 44: 709–710. Morren, GL, Walter, S, Lindehammar, H, Hallböök, O and Sjödahl, R (2001) Evaluation of the sacroanal motor pathway by magnetic and electric stimula-

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tion in patients with fecal incontinence. Dis. Colon Rectum, 44: 167–172. Nordling, J, Meyhoff, H, Walter, S and Andersen, J (1978) Urethral electromyography using a new ring electrode. J. Urol., 120: 571–573. Olsen, AL and Rao, SSC (2001) Clinical neurophysiology and electrodiagnostic testing of the pelvic floor. Gastroenterol. Clin. North Am., 30: 33–54. Opsomer, RJ, Guerit, JM, Wese, FX and Van Cangh, PJ (1986) Pudendal cortical somatosensory evoked potentials. J. Urol., 135: 1216–1218. Opsomer, RJ, Caramia, MD, Zarola, F, Pesce, F and Rossini, PM (1989) Neurophysiological evaluation of central-peripheral sensory and motor pudendal fibers. Electroenceph. Clin. Neurophysiol., 74: 260–270. Opsomer, R, Boccasena, P, Traversa, R and Rossini, P (1996) Sympathetic skin responses from the limbs and the genitalia: normative study and contribution to the evaluation of neurourological disorders. Electroenceph. Clin. Neurophysiol., 101: 25–31. Pedersen, E, Harving, H, Klemar, B and Torring, J (1978) Human anal reflexes. J. Neurol. Neurosurg. Psychiatry, 41: 813–818. Pedersen, E, Klemar, B, Schroder, J and Torring, J (1982) Anal sphincter responses after perianal electrical stimulation. J. Neurol. Neurosurg. Psychiatry, 45: 770–773. Percy, JP, Neill, M, Parks, A and Swash, M (1981) Electrophysiological study of motor nerve supply of pelvic floor. Lancet, 1: 16–17. Podnar, S, Rodi, Z, Lukanovic, A, Trsinar, B and Voduˇsek, DB (1999) Standardization of anal sphincter EMG: technique of needle examination. Muscle Nerve, 22: 400–403. Podnar, S, Voduˇsek, DB, Trsinar, B and Rodi, Z (1997) A method of uroneurophysiological investigation in children. Electroenceph. Clin. Neurophysiol., 104: 389–392. Pratt, H, Starr, A, Amile, RN and Politoske, D (1979) Mechanically and electrically evoked somatosensory potentials in normal humans. Neurology, 29: 1236–1244. Rattner, WH, Gerlaugh, RL, Murphy, JJ and Erdman, WJ (1958) The bulbocavernosus reflex: I. Electromyographic study of normal patients. J. Urol., 80: 140–141. Robert, R, Prat-Praadal, D, Labat, JJ, Bensignor, M, Raoul, S, Rebai, R and Leborgne, J (1998) Anatomic basis of chronic perineal pain: role of the pudendal nerve. Surg. Radiol. Anat., 20: 93–98.

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Rodi, Z and Voduˇsek, DB (1995) The sacral reflex studies: single versus double pulse stimulation. Neurourol. Urodyn., 14: 496–497. Rodi, Z and Voduˇsek, DB (2001) Intraoperative monitoring of the bulbocavernosus reflex: the method and its problems. Clin. Neurophysiol., 112: 879–883. Rossini, PM, Caramia, MD and Zarola, F (1987) Central motor tract propagation in man: studies with non-invasive, unifocal, scalp stimulation. Brain Res., 415: 211–225. Rushworth, G (1967) Diagnostic value of the electromyographic study of reflex activity in man. Electroenceph. Clin. Neurophysiol., 25: 65–73. Sarica, Y and Karacan, I (1986) Cerebral responses evoked by stimulation of the vesico-urethral junction in normal subjects. Electroenceph. Clin. Neurophysiol., 65: 440–446. Sarica, Y and Karacan, I (1987) Bulbocavernosus reflex to somatic and visceral nerve stimulation in normal subjects and in diabetics with erectile impotence. J. Urol., 138: 55–58. Sato, T, Konishi, F and Kanazawa, K (2000) Variations in motor evoked potential latencies in the anal sphincter system with sacral magnetic stimulation. Dis. Colon Rectum, 43: 966–970. Sato, T, Konishi, F, Minakami, H, Nakatsubo, N, Kanazawa, K, Sato, I, Itoh, K and Nagai, H (2001) Pelvic floor disturbance after childbirth. Vaginal delivery damages the upper levels of sphincter innervation. Dis. Colon Rectum, 44: 1155–1161. Sato, T and Nagai, H (2002) Pudendal nerve “complete” motor latencies at four different levels in the anal sphincter system in young adults. Dis. Colon Rectum, 45: 923–927. Schmid, DM, Curt, A, Hauri, D and Schurch, B (2003) Clinical value of combined electrophysiological and urodynamic recordings to assess sexual disorders in spinal cord injured men. Neurourol. Urodyn., 22: 314–321. Sethi, RK, Bauer, SB, Dyro, FM and Krarup, C (1989) Modulation of the bulbocavernosus reflex during voiding: Loss of inhibition in upper motor neuron lesions. Muscle Nerve, 12: 892–897. Smith, A, Hosker, G and Warrell, D (1989) The role of pudendal nerve damage in the aetiology of genuine stress incontinence in women. Br. J. Obst. Gyn., 96: 29–32. Swash, M and Snooks, SJ (1986) Slowed motor conduction in lumbosacral nerve roots in cauda equina

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lesions: a new diagnostic technique. J. Neurol. Neurosurg. Psychiatry, 49: 808–816. Thiry, AJ and Deltenre, PF (1989) Neurophysiological assessment of the central motor pathway to the external urethral sphincter in man. Br. J. Urol., 63: 515–519. Trontelj, JV, Janko, M, Godec, C, Rakovec, S and Trontelj, M (1974) Electrical stimulation for urinary incontinence. A neurophysiological study. Urol. Int., 29: 213–220. Voduˇsek, DB (1990a) Pudendal somatosensory evoked potential and bulbocavernosus reflex in women. Electroenceph. Clin. Neurophysiol., 77: 134–136. Voduˇsek, DB (1990b) Pudendal somatosensory evoked potentials. Neurologia, 39: 149–155. Voduˇsek, DB (1996) Evoked potential testing. Urol. Clin. North Am., 23: 427–445. Voduˇsek, DB and Deletis, V (2002) Intraoperative neurophysiological monitoring of the sacral nervous system. In: V Deletis, JL Shils (Eds.), Neurophysiology in Neurosurgery. A Modern Intraoperative Approach, Elsevier Science, California, pp. 197–217. Voduˇsek, DB and Janko, M (1990) The bulbocavernosus reflex. A single motor neuron study. Brain, 113: 813–820. Voduˇsek, DB and Light, JK (1983) The motor nerve supply of the external urethral sphincter muscles: an electrophysiologic study. Neurourol. Urodyn., 2: 193–200. Voduˇsek, DB and Zidar, J (1987) Pudendal nerve involvement in patients with hereditary motor and sensory neuropathy. Acta Neurol. Scand, 76: 457–460.

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Voduˇsek, DB and Zidar, J (1988) Perineal motor evoked responses. Neurourol. Urodyn., 7: 236–237. Voduˇsek, DB, Janko, M and Lokar, J (1983) Direct and reflex responses in perineal muscles on electrical stimulation. J. Neurol. Neurosurg. Psychiatry, 46: 67–71. Voduˇsek, DB, Plevnik, S, Janez, J and Vrtacnik, P (1988) Detrusor inhibition on selective pudendal nerve stimulation in the perineum. Neurourol. Urodyn., 6: 389–393. Voduˇsek, DB, Deletis, V, Abbott, R and Turndorf, H (1990) Prevention of iatrogenic micturition disorders through intraoperative monitoring. Neurourol. Urodyn., 9: 444–445. Wester, C, FitzGerald, MP, Brubaker, L, Welgoss, J and Benson, JT (2003) Validation of the bulbocavernosus reflex. Neurourol. Urodyn., 22: 589–592. Wiesner, A and Jost, WH (2001) Electrophysiologic testing of pelvic floor: some remarks. Dis. Colon Rectum, 44: 708–709. Williams, PL, Bannister, LH, Berry, MM, Collins, P, Dyson, M, Dussek, JE and Ferguson, MWJ (1995) Gray’s Anatomy, Churchill Livingstone, New York, International Student edition 2092 pp. Wunderlich, M and Swash, M (1983) The overlapping innervation of the two sides of the external anal sphincter by the pudendal nerve. J. Neurol. Sci., 59: 91–109. Yang, C and Bradley, WE (2000) Reflex innervation of the bulbocavernosus muscle. Br. J. Urol. Int., 84: 857–863. Yang, C, Bowen, J, Kraft, G, Uchio, E and Kromm, B (2000) Cortical evoked potentials of the dorsal nerve of the clitoris and female sexual dysfunction in multiple sclerosis. J. Urol., 164: 2010–2013.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 14

Anomalies of innervation J. Gert van Dijk* Department of Neurology and Clinical Neurophysiology, Room K5Q-108, Leiden University Medical Centre, PO Box 9600, 2300 RC The Netherlands

14.1. Introduction 14.1.1. The nature of innervation anomalies Of the many pitfalls associated with nerve conduction testing anomalies of innervation are among the most common, arguably the least understood, and certainly among the most difficult to remember. The innervation of muscles is subject to a considerable deal of interindividual variability at all anatomical levels (Falconer and Spinner, 1985). Examples are the relative contributions of various root levels to the innervation of a particular muscle, the variability of structures such as the brachial plexus, and the order and place in which branches to specific muscles arise from a particular nerve. This chapter will focus on the following groups of anomalies: those affecting the brachial plexus, muscles innervated by unusual nerves, abnormal branching patterns of a nerve, and anomalous branches connecting two different nerves. A few anomalous muscles are also discussed, although these do not represent anomalies of innervation. This list does not imply that all anatomical variants are discussed at equal length. Instead, attention will be focused on those anomalies that may cause clinical and electrodiagnostic confusion (Sonck et al., 1991; Gutmann, 1993). The words “anomaly” and “anastomosis” will be used in this chapter to conform with the majority of the published literature, although neither is applicable, strictly speaking. In anatomy, the word “anomaly” has the specific meaning of a departure beyond normal variation, and signifies a functional handicap to go

*Correspondence to: Department of Neurology and Clinical Neurophysiology, Room K5Q-108, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: [email protected] Tel.: +31-71-526 3960; fax: +31-71-5248 253.

along with the structural abnormality (Sañudo et al., 2003). It is important to realize that the variations discussed in this chapter do not affect the functions in any way and should, therefore, preferably not be called “anomalies”. The word “stoma” (opening, mouth) is imbedded in the term “anastomosis,” which by extension should be reserved for hollow structures. Nerves may have “connections”. 14.2. Brachial plexus 14.2.1. Pre- and postfixation The brachial plexus is normally largely formed by five nerve roots: C5, C6, C7, C8 and T1 (Fig. 14.1). By way of splitting and joining these roots form trunks, then cords, and finally the major nerves innervating the arm. In addition, the C4 and T2 roots normally give off branches that join the C5 and T1 roots, respectively. When the branch from C4 is large, the branch from T2 is usually small or even absent, and the plexus is said to be “prefixed”. When the T2 contribution is large, the one from C4 is often small, forming a “postfixed” plexus (Sunderland 1991; Uysal et al., 2003). In a study of 100 fetuses, the normal pattern was found in 71.5% (Uysal et al., 2003). A prefixed plexus was found in 25.5%, and a postfixed one in only 2.5%. Sizable contributions from C4 as well as from T2 were seen in 0.5%. Unfortunately for clinical practice, it is not clear what the presence of pre- and postfixation means for muscle innervation (Sunderland, 1991). One may think that the innervation of the muscles is simply shifted upwards or downwards by one segment. In a prefixed plexus, the deltoid might be innervated through C4 and the hand muscles through C7. There is no evidence for or against this view, however. Instead of this “shifted” innervation, there may be a rearrangement of functions over various roots. In this view, a large C4 contribution to the brachial plexus would

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C4

roots and other structures in various combinations. These two factors mean that it may be considered somewhat naïve to localize a lesion of the brachial plexus based exclusively on electrodiagnostic data. Another anatomical variant that deserves mention is how the C7 root innervates muscles supplied by the ulnar nerve; many textbooks mention such an innervation for the flexor carpi ulnaris muscle. However, drawings of the brachial plexus commonly do not show any pathway that allows C7 fibers to reach the ulnar nerve. Detailed studies have shown that some strands allow C7 fibers (Fig. 14.1) to reach the ulnar nerve (Sunderland, 1991).

C5

Sup. T. MC Lat. C.

C6

Ax Med. T. Med

C7 Post. C.

Rad

C8 Uln

T1

Inf. T.

Med. C.

T2 Fig. 14.1 The main structures of the brachial plexus. Note that the C4 and the T2 roots normally provide branches to the C5 and T1 roots. When the C4 contribution is large and the T2 contribution small or absent, the plexus of “prefixed”. If the T2 contribution is large and the C4 contribution small, it is “postfixed”. The dotted lines show strands that occur commonly, and that allow C7 fibers to reach the ulnar nerve. Inf. T. = inferior trunk, Med. T. = medial trunk, Sup. T. = superior trunk, Lat. C. = lateral cord, Post. C. = posterior cord, Med. C. = medial cord, MC= musculocutaneous, Ax = axillary, Rad = radial. Med = median, Uln = ulnar.

only mean that muscles normally supplied through C5 or C6 roots are now partly innervated by the C4 root, without assuming any abnormality for the innervation of muscles supplied through C8 and T1 roots. Likewise, a large T2 root in a postfixed plexus may contribute to the innervation of intrinsic hand muscles, without affecting the function of the upper plexus. 14.2.2. Other plexus variants The brachial plexus is not only variable on the level of roots, but also on the level of divisions and cords (Uysal et al., 2003). On the trunk level, the inferior trunk was absent in 9%, and the superior trunk in 1%. The absence of a trunk does not imply that the roots ended in a cul-de-sac, but rather that the branching pattern differed from the normal one. The number of aberrant branching patterns was higher for cords than for trunks. Together, such features mean that the various trunks, divisions and cords are subject to unpredictable variations with regard to their root composition (Sunderland, 1991). Traumatic lesions of the brachial plexus usually concern lesions of multiple

14.2.3. Musculocutaneous/median nerve anomalies The musculocutaneous and median nerves often show combined abnormalities (Fig. 14.2). These may be found in the brachial plexus, but also further distal in the course of the nerves. In systematic studies, variations were found in 73 (26.4%) of 276 arms (Choi et al., 2002) or in 22 (13.9%) out of 158 arms (Venieratos and Agnostopoulou, 1998). The abnormality most often concerned the presence of one or two extra branches between the two nerves: one branch was seen in 73% of anomalies, and two branches in 7% (Choi et al., 2002). These branches could run from the musculocutaneous nerve proximally to the median nerve distally, but branches in the other direction were also seen. It should be understood that the mere presence of a branch does not reveal whether it carries motor or sensory fibers, nor which muscles, if any, are innervated through such a branch. The observation that a branch left nerve A proximally and joined nerve B distally suggests that motor nerve fibers ran from nerve A to nerve B, but this may not be taken as a certainty. Especially when connections form an ansa (Latin for “handle”) the directions of fibers cannot be inferred at all. The musculocutanous nerve may also be “absent,” that is to say it does not form the extension of the lateral cord (Fig. 14.2B). The absence may also be rephrased to state that the median and musculocutaneous nerves are fused (Choi et al., 2002), and the fused nerve is then called the median one. In some cases, the median nerve may give off branches to the biceps and brachialis muscles in the arm (Sunderland, 1991), but the fused nerve may also split again distally to form the two separate nerves. As said, it is not known how such anomalies of branching affect the innervation of individual

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C5

313

Sup. T.

MC Lat. C.

C6

Ax

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Fig. 14.2 Musculocutaneous/median nerve abnormalities. (A) Some of the various possible connecting branches between the two nerves. (B) The musculocutaneous nerve is “absent,” meaning that there is a fused nerve that may also be described as a combination of the median and musculocutaneous nerves. This nerve then often splits into two separate nerves, but may also remain undivided.

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muscles. It may be that the muscles are supplied by their normal roots, and that only the intermediate pathway is abnormal. No studies were found where such anomalies affected clinical decision making or electrodiagnosis. The most likely error to be made might be that a lesion of both nerves was presumed to exist where the lesion in reality concerned the fused nerve. Such anomalies are probably of greater relevance to surgeons working in the area of the brachial plexus than to physicians practicing electrodiagnostic medicine. 14.2.4. Plexus anomalies in distal nerve anastomoses It will be argued later in this chapter that anomalies such as the Martin–Gruber anastomosis may be accompanied by another aberrant route in the plexus. In the Martin–Gruber anastomosis, fibers that “belong” in the ulnar nerve run in the median nerve proximally. This may imply that they reach the median nerve through an aberrant pathway in the brachial

(b)

plexus. This is further explained in the appropriate sections. 14.3. Muscles innervates by unusual nerves 14.3.1. Brachialis muscle and the radial nerve As early as 1919, a patient was described who could still contract part of the brachialis muscle although the musculocutaneous nerve had been severed completely (Spinner et al., 2003). Mention was later made of a partial innervation of this muscle by the radial nerve. A large-scale study of its incidence was published in 2002 (Mahakkanakrauh and Somsarp, 2002). In 152 arms of 76 cadavers, a branch of the radial nerve to the brachialis muscle was found in 124 arms, or 81.6%. The branch always innervated the inferolateral part of the muscle, and this was the same area showing MRI changes in two cases with radial nerve lesions (Spinner et al., 2003). In view of this very high percentage, the word “anomaly” should not be used, and the brachialis muscle should be added to the list of

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muscles normally receiving dual innervation (the flexor pollicis brevis and the pectineus muscles are other examples). A teased-fiber study showed that the fibers in the radial nerve branch derived from the C6 and C7 roots, in contrast to those of the musculocutaneous nerve branch, that originated in the C5 and C6 roots (Yan et al., 1998). The existence of this branch has two implications. Firstly, a degree of elbow flexion strength might remain present in lesions of the upper plexus or of the musculocutaneous nerve. Secondly, lesions of the radial nerve might cause some weakness of elbow flexion. Clinical experience does not support these logical consequences. This discrepancy requires an explanation. Firstly, the amount of muscle tissue supplied through the branch might be so small that the force it may exert might be inconsequential. Secondly, observations as described above may have been attributed to the brachioradialis muscle, which is also an elbow flexor innervated by the radial nerve. Thirdly, if the radial nerve branch to the brachialis muscle is largely innervated through the C6 root, it will be paralyzed in upper plexus lesions along with other C5 and C6 muscles; so elbow flexion will not be spared at all. These considerations suggest that the branch can only cause sparing of flexion in upper plexus lesions under two circumstances: the first is an isolated lesion of the musculocutaneous nerve, and the second is a C5 and C6 lesion combined with and innervation of the branch through the C7 root. Needle electromyography of the brachialis muscle is rarely performed, so there is not much chance of encountering the effects of this dual innervation by accident. It is conceivable that a comparison of the inferolateral with other parts of the brachialis muscle might have a role in needle electromyography, comparable to that of the brachioradialis muscle: the pathways start in the C5 and C6 roots but follow different paths to the two parts of the brachialis muscle. The importance of this “anomaly” needs further study. 14.3.2. Intrinsic hand muscles The anatomy of the intrinsic hand muscles is more complicated than many textbooks would have it (Homma and Sakai, 1992). Of the thenar muscles, only the APB had a clearly defined and separate muscle belly; the FPB, OP and ADD were found to form a fused muscle mass. In the same study, the hypothenar muscles showed a fusion of the ADM and FDM muscles (Homma and Sakai, 1992). The FPB had two

J.G. VAN DIJK

heads in 44 out of 68 hands, and one head in the remaining 24 hands (Ajmani, 1996). In view of such differences in muscle anatomy, variations in their innervation are not surprising. According to most textbooks, the median nerve innervates the APB, OP and part of the FPB, while the other part of the FPB and all hypothenar muscles are innervated by the ulnar nerve. Of these muscles, the APB was exclusively innervated by the median nerve in all 68 hands (Ajmani, 1996). The OP muscle was innervated by the median nerve only in 56 hands, by the ulnar nerve only in six nerves, and it received dual innervation in six hands (Ajmani, 1996). The FPB was innervated by the median nerve only in 38 hands, by both nerves in 24 hands, and by the ulnar nerve only in six hands (Ajmani, 1996). Unique innervation by the ulnar nerve concerned cases where the FPB had only one head. The presence of a connection between the median and ulnar nerves may underlie these differences. This Riche–Cannieu anastomosis is discussed in Section 14.5.4. 14.3.3. Motor fibers in the sural nerve There are two reports mentioning contraction of foot muscles following stimulation of the sural nerve, that is normally exclusively sensory (Liguori and Trojaborg, 1990; Ragno and Santoro, 1995). In both cases stimulation at several sites over the sural nerve showed the response to be “direct” in nature, i.e., it was not a reflex. The muscles innervated through the sural nerve concerned those of the little toe, and not the big toe. 14.4. Abnormal branching patterns of a nerve 14.4.1. Accessory peroneal nerve 14.4.1.1. Anatomy The extensor digitorum brevis (EDB) and extensor hallucis brevis (EHB) muscles on the dorsal aspect of the foot are normally innervated by the deep peroneal nerve, running on the volar aspect of the ankle. The lateral aspect of the EDB may be innervated by the accessory deep peroneal nerve, that branches off from the superficial peroneal nerve high in the leg, but below the fibular head. The branch reaches the EDB from behind the lateral malleolus (Fig. 14.3). Anatomical studies have shown that the accessory deep peroneal nerve is, in fact, always present, contributing to the innervation of the peroneus brevis

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innervated in its entirely through the accessory branch, meaning that volar ankle stimulation will not result in any CMAP over the EDB. 130%

Large contribution

90%

Small contribution

Fig. 14.3 Accessory deep peroneal nerve. The anomalous branch innervates the lateral part of the EDB, so stimulation at the volar aspect of the ankle will excite only part of the muscle, in contrast to fibular head stimulation. Stimulation behind the lateral malleolus will reveal the course of the missing axons. The figure shows a prototypical test result, in which the anomalous branch has a large contribution to EDB innervation. As a result, the CMAP following volar ankle stimulation is quite small. The one following fibular head stimulation may be larger, which is conspicuously abnormal. When the contribution is small, however, the volar ankle CMAP may still be larger than the one from the fibular head, the amplitude of which shows the effects of temporal dispersion. This effect may explain why most such anomalies go unnoticed.

muscle and sending sensory branches to the ankle region (Kudoh et al., 1999). For the present discussion, it is more relevant that it does not always extend to the EDB muscle: this occurred in 16 of the 24 dissected legs (Kudoh et al., 1999). 14.4.1.2. Nerve conduction findings 14.4.1.2.1. Essential features. In a peroneal nerve study, the presence of an accessory deep peroneal nerve has the effect that stimulation at the volar aspect of the ankle cannot excite the entire EDB muscle, as its lateral part is innervated by the aberrant branch (Fig. 14.3). Stimulation at the fibular head and in the popliteal fossa will however excite the entire EDB through both the normal and the aberrant route. The amplitude of the CMAP will, therefore, be larger, following proximal than distal stimulation. Stimulating behind the lateral malleolus will evoke a CMAP over the EDB muscle. In rare cases the EDB muscle is

14.4.1.2.2. Literature review. The frequency of occurrence of the anomalous branch has been systematically studied by stimulating behind the lateral malleolus in unselected subjects. It was found in 358 (24.3%) of 1415 subjects (Stamboulis, 1987), 13 (25%) of 52 subjects (Neundörfer and Seiberth, 1974), and 14 (28%) of 50 subjects (Lambert, 1969). When present, it is frequently bilateral: this was so in 8 of 14 cases (Lambert, 1969) and in 157 (44%) of 358 subjects (Stamboulis, 1987). To summarize, one may expect anomalous innervation of part of the EDB to occur in one in four individuals, a very appreciable number. As stated earlier, it supplies the lateral part of the EDB. This was shown by Lambert (1969), who observed which toes moved on excitation of the nerve: the anomalous branch most often moved the fourth toe, sometimes the third and fourth toe, and once the fifth toe. This is surprising, as the EDB does not normally have a belly for the fifth toe: it extends the second, third and fourth toes. A cartographic CMAP study showed that the region over the lateral aspect of the EDB where its effect can be observed is quite small (Van Dijk and Van der Hoeven, 1998). The high rates of occurrence of this anomalous nerve contrast with daily practice, where it is rare to find that the distal peroneal CMAP is smaller than the proximal one; certainly less often than one in four legs. The missing cases may be explained in two ways: the first holds that its effects may easily be missed, depending on the recording site (Van Dijk and Van der Hoeven, 1998). The second explanation is based on the only systematic set of amplitude measurements (Stamboulis, 1987): the CMAP amplitude corresponding to the anomalous branch was lower than 0.1 mV in 19% of cases, and between 0.1 and 0.5 mV in 41% (In one of 358 subjects the EDB was wholly innervated through the anomalous branch). There were no data on amplitudes evoked by the normal branch, other than that the amplitude due to the anomalous branch was larger than that due to the normal branch in only 5% of the anomalies found (Stamboulis, 1987). This suggests that the number of fibers running behind the lateral malleolus is usually small. Accordingly, most of the fibers run a normal course, so the CMAP found through stimulation on the normal ankle site is only a bit smaller than it should be: say 90% of what it should be. Normally, the

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degree of amplitude decay over the peroneal nerve is quite pronounced, so the proximal CMAP may be 80% of the value at the ankle. Thus, the distal CMAP can be smaller than it should be due to the anomalous innervation, and still be bigger than the proximal one due to temporal dispersion (Fig. 14.3). 14.4.1.3. Clinical consequences As outlined above, most cases of an accessory peroneal nerve are likely to be missed, which probably does not harm the diagnostic process very much. It does harm a proper understanding of nerve conduction: the hypothesis outlined above implies that an accessory peroneal nerve masks the amplitude decay over the leg to some degree. The degree of amplitude decay of tibial nerve CMAPs is usually higher than that of peroneal nerve CMAPs. If accessory peroneal nerves would all be taken into account, normal values for the amplitude decay of the peroneal nerve would be closer to those for the tibial nerve. The accessory deep peroneal nerve may be compressed, and collision neurography may be of benefit in such cases (Sander et al., 1998). In the author’s experience, stimulating at several sites behind the lateral malleolus may reveal a decrease of conduction velocity of this nerve. 14.5. Anomalous branches connecting two nerves 14.5.1. Principles Of the four anomalies to be discussed here, the Martin–Gruber, Marinacci and Riche–Cannieu anastomoses all concern motor nerve fibers crossing from the median to the ulnar nerve or vice versa. It will be argued that all three represent “normal innervation” to the extent that the hand muscles innervated through the branch are in fact innervated by their normal nerves. The “anomaly” resides in the fact that the fibers in question run in the “wrong” nerve proximally, from where they cross to the “proper” nerve. From that point on, they follow normal pathways to the muscles. For the purpose of simplicity, the hand muscles will be divided into four groups, based on their use in nerve conduction testing. The first, the “median thenar” group, consists of muscles in the thenar eminence innervated by the median nerve: these are the abductor pollicis brevis (APB) muscle, the opponens pollicis muscle (OP) and the superficial head of the flexor pollicis brevis (FPB) muscle (Fig. 14.4). The

Fig. 14.4 Normal hand anatomy. In this and following figures, each line represents a population of neurons innervating a particular muscle group. Only those intrinsic hand muscle groups are shown that are commonly used for nerve conduction studies. These are the hypothenar muscles, the FDI, the ulnar thenar muscles (ADD and part of the FPB), and the median thenar muscles (APB, OP and part of the FPB). Bold circles over a muscle region indicate that the recordings shown near the nerve stimulation sites are recorded from that muscle group. This figure shows median nerve CMAPs (top) for a thenar recording, and ulnar nerve CMAPs (bottom) for the hypothenar recording. Proximal CMAPs are slightly smaller than distal ones due to normal temporal dispersion.

three other groups are all innervated by the ulnar nerve. They are the “ulnar thenar” group, i.e. the adductor pollicis (ADD) and the deep head of the FPB, the first dorsal interosseous (FDI) muscle and finally the hypothenar muscles: the abductor digiti minimi (ADM), flexor digiti minimi and the opponens digiti minimi. The remaining hand muscles (lumbricals and the other interosseous muscles) play relatively small roles in a discussion of innervation anomalies. Unfortunately, this pattern is not as fixed as one might wish for; the FPB and to a lesser extent the OP receive innervation from the ulnar and median nerves in various proportions (Hopf and Hense, 1974; Sonck et al., 1991; Homma and Sakai, 1992; Ajmani, 1996) (see also Section 14.3.2). In the Martin–Gruber anastomosis, the anomalous fibers can innervate one or more groups of these three ulnar hand muscle groups. The fibers cross from the median to the ulnar nerve in the forearm, from where they reach these muscles in normal fashion. It is the impulse direction in these motor fibers that explains the term “median-to-ulnar,” frequently used for the Martin–Gruber anastomosis. The term is not suitable to describe sensory fibers running in the same anastomosis, as impulses would then travel in an “ulnar-to-median” direction. The presence of sensory fibers in these three anastomoses is rare, which is just as well, as terminology would then be confusing.

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The extremely rare Marinacci anastomosis concerns the opposite, ulnar-to-median pattern, in which fibers for “median thenar” muscles cross from in the forearm the ulnar nerve proximally to gain a normal course in the median nerve distally. The less rare Riche–Cannieu anastomosis also concerns an ulnar-to-median anastomosis, in which fibers for “median thenar” muscles run in the ulnar nerve for almost their entire length, and only cross towards the median nerve in the hand, where they follow its course for a few cm before entering the muscles. For each of the four anomalies, the discussion will focus on anatomical data, nerve conduction testing, and on which disorders are made more difficult to detect by their presence. Before doing so, the presence of innervation anomalies will be placed against a background of other possible pitfalls. 14.5.1.1. Amplitude discrepancies The Martin–Gruber and Marinacci anomalies have in common that a number of motor nerve fibers leave one nerve and join the other between two stimulation sites. As a result, the number of fibers excited distally and proximally are not the same, even though supramaximal stimulation is used at both sites. This is reflected in an abnormal change in CMAP amplitude between the two sites: either the distal amplitude is much larger than the proximal one, or the other way around. The differential diagnosis of these anomalies, therefore, concerns anything that can lead to a similar amplitude discrepancy (Fig. 14.5). Three causes will be discussed shortly (Van Dijk, 2000): 1. Abnormal temporal dispersion and conduction block Due to differences in conduction velocity between the axons in a nerve, impulses take longer or shorter to travel across a given length of nerve. As explained elsewhere in this volume, this causes a systematic difference between proximal and distal CMAPs: proximal CMAPs are usually longer in duration and lower in amplitude. The magnitude of the amplitude decay depends on many factors, including the nerve under scrutiny and recording electrode site (Van Dijk et al., 1994). For median and ulnar nerves, amplitude percentages are normally higher than 80%. It is less well appreciated that phase rearrangement can occasionally also cause percentages to be slightly higher than 100%, particularly when the recording electrodes are placed slightly off the optimum site (van Dijk et al.,

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1

2

3

4

A

4

3

1

B Fig. 14.5 An amplitude discrepancy concerns either the finding that the distal CMAP is disproportionately larger than the proximal one (A), or the reverse. (B) Results are here shown for a median nerve, but the logic applies elsewhere as well. In each case there are a number of possible explanations, indicated by numbers: “1” refers to inframaximal stimulation, “2” to a conduction block, “3” to an innervation anomaly, and “4” to costimulation of another than the intended nerve.

1994). Values higher than 100% should always be viewed with caution, however. Demyelinating neuropathies may increase the difference in velocity between the fastest and the slowest fibers, thereby causing “abnormal temporal dispersion”: the changes in amplitude and duration over a length of nerve are then much larger than normal. “Blocking” occurs in compression neuropathies and demyelinating polyneuropathies, and concerns a complete cessation of impulse propagation of a number of axons at a site in the nerve. Here it is sufficient to realize that blocking and abnormal temporal dispersion cause proximal CMAPs to have much lower amplitudes than distal ones. 2. Costimulation with coregistration Surface stimulation always carries the risk that the current is not restricted to the intended nerve, but spreads to a neighboring one, which duly excites its own set of muscles. This is only a problem when this unintended muscle activity is picked up by the recording electrodes, i.e. when costimulation is combined

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with coregistration. Its effect is that the CMAP resulting from stimulation at that site is abnormally large. “Coregistration” is usually labeled “volume conduction,” which is true but not very precise. Recording a CMAP always depends on the physical process of “volume conduction” of electrical potentials, regardless of whether one does or does not wish to record this particular CMAP. In effect, the term should not be reserved for problem situations. Unfortunately, coregistration is all too common. Many common recording sites easily allow activity of neighboring muscle groups to be recorded. For instance, an electrode placed over the APB will always record activity from the other median thenar muscles, from ulnar thenar muscles, and from the FDI, when excited. Electrodes over the FDI always record activity generated in median thenar muscles following stimulation of the median nerve (Streib and Sun, 1983). Likewise, electrodes placed on the extensor digitorum brevis (EDB) and extensor hallucis brevis on the dorsum of the foot, innervated by the peroneal nerve, definitely record activity from tibial-innervated foot muscles (Amoiridis et al., 1996; Magistris and Truffert, 1997). Electrodes placed over the tibial-innervated abductor hallucis (AH) muscle will pick up activity from other tibial-innervated foot muscles, and notably also from the peroneal-innervated dorsal foot muscles (Amoiridis et al., 1996; Magistris and Truffert, 1997). The habit of choosing a specific muscle to describe a recording site hampers a constant awareness of this

liability. To ensure the opposite effect, “thenar”, “hypothenar,” “dorsal foot” and “foot sole” will be used to describe recording sites in this chapter. Costimulation is most likely to occur when the nerves lie near one another and when stimulus intensity is high. It is, therefore, more likely to occur at the wrist or the axilla than the elbow. In the lower limbs it is most likely to happen in the popliteal fossa, and it is more likely in small people than tall ones. Examples of high intensity causing costimulation are carpal tunnel syndrome and compression neuropathy near the fibular head: the diseased nerve is hard to excite, leading to high intensity and costimulation of a healthy nerve in the vicinity. 3. Inframaximal stimulation In inframaximal stimulation not all fibers in a nerve are excited, so the resulting CMAP is abnormally low. This is most likely to occur where nerves lie deeply, such as the tibial nerve in the popliteal fossa. Disorders in which nerves require high stimulation intensity, as occurs in some demyelinating diseases, are also more likely to cause inframaximal stimulation. Its effect is that the CMAP resulting from that site is abnormally small. Together with innervation anomalies, these effects mean there may be up to four explanations for an observed amplitude discrepancy over a nerve segment (Fig. 14.5). Table 14.1 shows which explanations apply for which nerves. The best way to deal with such an

Table 14.1 Amplitude discrepancy Test Distal amplitude abnormally higher than proximal Median/thenar Ulnar/hypothenar Peroneal/dorsal foot Tibial/foot sole Distal amplitude abnormally lower than proximal Median/thenar Ulnar/hypothenar Peroneal/dorsal foot Tibial/foot sole

Inframaximal

Costimulation

Anomaly

Disorder

At elbow or higher At elbow or higher At fibular head or higher At popliteal fossa

Ulnar at wrist

Marinacci (rare)

Median at wrist

Martin–Gruber

None

None

None

None

Block or abn. dispersion Block or abn. dispersion Block or abn. dispersion Block or abn. dispersion

Ulnar at elbow or higher Median at elbow or higher Tibial at popliteal fossa Peroneal at popliteal fossa

Martin–Gruber Marinacci (rare) Accessory peroneal None

At wrist At wrist At ankle At ankle

None None None None

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eventuality probably depends on experience. An experienced electromyographer may decide whether it is the large or the small CMAP that is abnormal for a particular patient, and may base the choice on how to proceed on this: when a CMAP is felt to be abnormally small, inframaximal stimulation is the likely culprit, whereas an abnormally large CMAP suggests costimulation. Watching the movement evoked by the stimuli also helps to detect costimulation. With less experience a systematic approach is warranted. Usually, checking for inframaximal stimulation by stimulating the site with a low amplitude again is the easiest action to be taken. It is possible to address the other explanations one by one, but often time can be saved by performing a complete “double nerve study.” This involves placing additional recording electrodes over a muscle group of a neighboring nerve. Stimulating the nerve under study as well as the other nerve distally and proximally, while recording from both muscles at once, provides the most complete information. If this is combined with observation of the evoked movement, it should be possible to solve the puzzle. The resulting set of eight CMAPs should allow the problem to be identified under normal circumstances. When more information is needed about the anastomosis, three muscle groups (thenar, hypothenar and FDI) may be recorded simultaneously while the two nerves are stimulated at two sites each. Note that this approach primarily aims at discovering the cause of an amplitude discrepancy during a clinical test, and not so much at a thorough investigation of the properties of an innervation anomaly. This may require more exhaustive testing, described below. 14.5.2. Martin–Gruber anastomosis 14.5.2.1. Anatomy This anastomosis was described by Martin in 1763 and Gruber in 1870 (Erdem et al., 2002; Amoiridis, 2003). Recent studies (Rodriguez-Niedenführ et al., 2002a, 2002b) described an anatomical classification, based on the presence on one communicating branch (pattern I) or on two connecting branches (pattern II). This was refined by indicating the source of the branch on the median nerve: type A indicates a source on the branch to the superficial forearm flexor muscles, type B on the trunk of the median nerve, and type C on the anterior interosseous nerve. Their study of 236 arms revealed 31 cases (13.1%) of Martin–Gruber anastomosis, of which pattern I was found in 29 cases and pattern II in two. Type C was the most common with

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15 cases, followed by type A in 13 cases and type B in three cases (Rodriguez-Niedenführ et al., 2002b). The branches most often take an oblique route across the forearm, but an arcuate one occurs as well (RodriguezNiedenführ et al., 2002b); “arcuate” here means that a branch curves away from one nerve and is seen to curve back up to join another. The branches arise from the median nerve or its branches an average of 6 cm (range 2.5–8 cm) distal to the medial epicondyl, and join the ulnar nerve an average of 8.4 cm (range 5–12 cm) distal to it (Taams, 1997). This means that the branches lie quite proximally in the forearm, and are commonly fairly short. The anastomosis is most often found on one side only, although bilateral cases have been found (six out of 25 cases) without a sex preference (RodriguezNiedenführ et al., 2002a, 2002b). These recent studies did not confirm earlier reports of a preference for the right side; instead, of unilateral cases 13 were found on the left side and 6 on the right side. The percentage of cases described in earlier reports varies: 6.7% in 30 arms (Sarikcioglu et al., 2003), 15.2% in 250 arms (Gruber in Amoiridis, 2003), 10.5–44% (Mannerfelt, 1966), or 21.3% (Nakashima, 1993). While these measurements vary considerably, a conservative estimate is that a Martin–Gruber anastomosis can be expected to occur in at least one out of ten arms, or high enough to treat it as something to be expected. It should be stressed that anatomical data do not indicate whether the anomalous branch carries motor or sensory fibers, and do not reveal which muscles are innervated through it, nor the direction of the fibers. This holds particularly for arcuate branches (Leibovic and Hastings, 1992). Early anatomists labeled oblique branches that connected to the median nerve more proximally than to the ulnar one as “median to ulnar,” and may have counted some arcuate branches among such connections, although nothing can be inferred about the direction of impulse in motor fibers in such branches (Leibovic and Hastings, 1992). All these features are important for the detection of the anomaly, and for its clinical implications. 14.5.2.2. Nerve conduction findings 14.5.2.2.1. Essential features. The fibers in the Martin–Gruber anastomosis run from the median nerve proximally in the forearm to the ulnar nerve slightly more distally. Most reports describe that these fibers are motor in nature, although there are a few reports describing the presence of sensory fibers as

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well (Claussen et al., 1996; Simonetti, 2001). Although some reports do not specify which of the intrinsic hand muscles are innervated through the anastomosis (Kimura et al., 1976; Gutmann, 1993; Amoiridis, 1992a, 1992b) others suggest that the fibers innervate muscle groups normally innervated by the ulnar nerve (Sonck et al., 1991) the thenar ulnar and hypothenar muscle groups, and the FDI. In effect, the only uncertainty about this concerns the thenar muscles, and most specifically the FPB. Ascribing the innervation of the separate and quite small muscles in the hand to the anomalous connection can only be done with highly selective recordings with concentric needle electrodes. One such study was found, and it indicated that the APB was never involved, and the OP in 7% of Martin–Gruber cases (Amoiridis, 1992a). It is, therefore, a slight oversimplification to state that the Martin–Gruber anastomosis only concerns muscles innervated by the ulnar nerve, but this does help to remember its nature. With this in mind, it is only the proximal course of the fibers that is aberrant: their course is wholly normal from the point where they enter the ulnar nerve. It is only rarely realized (Sachs et al., 1995) that an aberrant course in the forearm probably also indicates a second anomalous course more proximally (Fig. 14.6). It seems likely that the muscles receive their innervation from the usual roots, i.e. the C8 and T1 ones, although there are no data to indicate or refute this. The fibers involved would normally gain the ulnar nerve through the inferior trunk and the medial cord, but to reach the median nerve they must depart from there to the median nerve. This hypothesis suggests that the Martin–Gruber anastomosis is, in fact, a correction for a wrong turn taken in the brachial plexus. Electrophysiological data indicate that the anastomosis affects the three muscle groups with unequal

frequency (Kimura et al., 1976; Sun and Streib, 1983; Amoiridis and Vlachonikolis, 2003; Sarikcioglu et al., 2003). The FDI is most often affected, followed by the hypothenar group, while ulnar thenar muscles are the least often affected. Percentages were 34, 16 and 12%, respectively (Sun and Streib, 1983). Accordingly, these three presentations have been distinguished as separate types (with the FDI as type II, hypothenar muscles as type I, and thenar muscles as type III). However, this classification does not allow room for combinations, which are the rule rather than the exception. Kimura et al., 1976 who did not study the FDI, reported that thenar and hypothenar muscles were both affected in 82% of 77 hands, that hypothenar muscles were solely affected in 17% and thenar muscles solely in 1%. In Sun and Streib’s study (1983) of 51 cases, the FDI was always affected. In order of descending frequency, the combinations were: FDI alone in 43.1%, all three groups in 23.5%, FDI and hypothenar in 21.5%, and FDI and thenar in 11.8%. Instead of defining more types for all possible combinations, the anastomosis will be labeled according to the muscle(s) involved. Nerve conduction findings are similar for all three muscle groups (Figs. 14.7–9). The case for the hypothenar muscles is easiest to understand (Fig. 14.7). An ulnar nerve study, recording from the hypothenar eminence, will show a normal distal CMAP, but the CMAP obtained from a below-elbow site will be abnormally small, and this will also be the case for stimulation sites higher up. This is because the ulnar nerve has gained fibers through the anastomosis. The presence of a Martin–Gruber anastomosis can be demonstrated by stimulating the median nerve in the elbow. Without a Martin–Gruber anastomosis, this only produces a small positive-going CMAP over the hypothenar eminence (Sun and Streib, 1983) as

C5 MC

Fig. 14.6 Proximal route in median-to-ulnar anastomosis. The median-to-ulnar Martin–Gruber anastomosis in the forearm is indicated by an arrow. It is possible that the fibers also follow an aberrant course proximally: coming from C8 and T1 roots, the fibers may take a “wrong turn” into the median nerve, instead of continuing directly into the ulnar nerve. Inf. = inferior, Med. = medial, MC = musculocutaneous, Ax = axillary, Rad = radial. Med = median, Uln = ulnar.

C6

Ax Med

C7 Rad C8

T1

Inf. Trunk

Med. Cord

Uln

ANOMALIES OF INNERVATION

Fig. 14.7 Martin–Gruber anastomosis affecting the ADM. The arrow in this and following studies indicates the nerve study that would show up during routine studies. In this case, this concerns ulnar nerve stimulation with a hypothenar recording. The test results in a normal amplitude for the distal CMAP (all fibers run there), but an abnormally low one for the proximal CMAP (some fibers do not run there). This resembles a conduction block. The presence of MGA can be shown by stimulating the median nerve while recording from the hypothenar muscles: the fibers lost by one nerve were gained by the other. Note that a common median nerve study, recording from the thenar eminence, will be wholly normal.

Fig. 14.8 Martin–Gruber anastomosis affecting the FDI. The situation is comparable to Fig. 7: the ulnar nerve study will show a putative conduction block, and median nerve stimulation with recording from the FDI is required to prove that the amplitude loss is due to a Martin–Gruber anastomosis. The electrodes over the FDI are likely to pickup volumeconducted activity from median thenar muscles, with a variable shape and possibly a positive beginning.

evidence of coregistration. A negative-going CMAP suggests a Martin–Gruber anastomosis, but this is confirmed with more clarity when the median nerve is also stimulated distally. When this shows no CMAP or a small positive-going potential over the hypothenar muscles, it is clear that the median nerve has lost fibers in its course. The essence of the Martin–Gruber anastomosis is, thus, that the median nerve’s loss is the ulnar nerve’s gain. Note that the loss of the median nerve and the gain of the ulnar nerve can both be expressed in mV. One might expect the values to be equal, but they may differ by about 1 mV (Sun and

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Fig. 14.9 Martin–Gruber anastomosis affecting thenar muscles. Note that the muscles innervated by the anastomosis are not “median thenar” muscles, but “ulnar thenar” ones. It is not common practice to perform a conduction study of the ulnar nerve with a thenar recording, so the MGA will in this case not come to light while performing an ulnar nerve study, but during a median nerve study. Electrodes over the thenar eminence will pick up activity from both thenar muscle groups. Stimulating the median nerve in the wrist results in a normal CMAP, but median elbow stimulation results in an overly large CMAP. Testing for MGA now involves stimulating the ulnar nerve and recording from the thenar eminence, with a same result as in the other Martin–Gruber variants. The proximal CMAP may have an initial positive beginning.

Streib, 1983). This can be explained through effects of normal temporal dispersion and the fact that measuring amplitude decay of the fibers involved in the anastomosis is an estimate, influenced by phase cancellation effect of median and ulnar CMAPs, themselves also affected by amplitude decay. Note that the abnormal findings will be confined to tests recording from the hypothenar eminence. Neither a median nerve/thenar recording nor an ulnar nerve/FDI recording need show abnormalities. An anastomosis affecting the FDI (Fig. 14.8) will result in similar findings. This is most likely to show up in an ulnar nerve/FDI study, where the initial presentation will again resemble a block in the forearm. Carrying out a median nerve/FDI study will show up the median nerve’s loss. The measurement is complicated by the fact that an FDI recording will record potentials from median thenar muscles (Streib and Sun, 1983), so distal median nerve stimulation may show a CMAP. This begins with a small initial positive phase in the majority of cases (Streib and Sun, 1983). The median nerve’s loss becomes apparent by comparing the distal and proximal CMAP waveforms. In this situation, an ulnar nerve/hypothenar study may be wholly normal (unless the anastomosis affects this muscle group as well). A median nerve/thenar study may be affected, however, as volume-conducted

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potentials from the FDI may be recorded over the thenar eminence. This will happen only on proximal median stimulation, as that is where the FDI fibers are excited. An anastomosis affecting ulnar nerve/thenar muscles will not normally show up in an ulnar nerve study, as thenar muscles are not normally used for this purpose (Fig. 14.9). Instead, it is likely to be detected in a median nerve/thenar study, which will show that the median nerve is losing fibers. Stimulating the ulnar nerve while still recording from thenar muscles shows that the fibers are gained by the ulnar nerve. Note that both ulnar and median nerve stimulation usually result in thenar CMAPs, although the CMAPs following ulnar nerve stimulation usually start with a positive phase and vary considerably in shape (Streib and Sun, 1983). 14.5.2.2.2. Literature review. Under clinical circumstances the only reason to identify a Martin–Gruber anastomosis is to avoid erroneous conclusions regarding abnormality. The procedure described above and in Section 14.1.2, using leads on two or three muscle groups and stimulating the ulnar and median nerves distally and proximally, is usually sufficient. If this approach does not result in clear results, it may be necessary to eliminate the risks of costimulation and coregistration altogether. Concentric needle electrodes in appropriate muscles increase the certainty that a specific muscle is indeed activated, at the cost of amplitude information. This method was used by Amoiridis (1992a) and showed the following muscles to be affected, in decreasing order: FDI and hypothenar both 94%, ADD in 71%, FPB in 60%, OP in 7% and APB never (50 arms). Near-nerve needle stimulation electrodes may be used to avoid costimulation. Together, both measures provide the best proof of abnormal nerve communications. Finally, collision neurography may be used to prove that impulses take a specific pathway (Kimura et al., 1976; Sander et al., 1997; Amoiridis et al., 1998; Amoiridis and Vlachonikolis, 2003). In the situation of Fig. 14.7, showing an anastomosis affecting hypothenar muscles, stimulating the median nerve results in the elbow results in a hypothenar CMAP. When the median nerve is stimulated nearly simultaneously at the wrist, all impulses from proximal stimulation will be blocked through collision, unless they escape this fate because they run through the anastomosis (Kimura et al., 1976). The technique is explained in greater detail elsewhere in this volume.

J.G. VAN DIJK

There have been many attempts using nerve conduction studies to determine how often a Martin–Gruber anastomosis occurs. Unfortunately, the criteria used to define it varied considerably. Some authors used qualitative CMAP amplitude criteria without stating their magnitude (Amoiridis, 1992a; Sarikcioglu et al., 2003; Amoiridis and Vlachonikolis, 2003), or defined a magnitude for the difference in amplitudes distally and proximally of at least 25% (Sun and Streib, 1983; Oh et al., 1995; Claussen et al., 1996), or of 20% (Uchida and Sugioka, 1992), or of at least 1 mV (Erdem et al., 2002; Crutchfield and Gutmann, 1980). The resulting estimates of the frequency of occurrence of Martin– Gruber anastomosis also vary: 27 of 100 (27%) subjects (Erdem et al., 2002), two of 60 (3%) arms (Sarikcioglu et al., 2003), 51 of 150 (34%) arms (Sun and Streib, 1983), 32 of 100 (32%) arms (Amoiridis, 1992b), 27 of 50 (54%) arms when CMAPs were used and 23 (46%) arms when collision was used (Amoiridis and Vlachonikolis, 2003) and 57 of 328 arms (17%) in a collision study excluding the FDI (Kimura et al., 1976). Somewhat surprisingly, not one of these methods focused on the essence of the Martin–Gruber anastomosis, i.e. that an amplitude gain of the ulnar nerve must be accompanied by a loss of the median nerve. Van Dijk and Bouma (1997) added the gain of one to the loss of the other, which sum in normal subjects results in a value near zero, and yields a positive value in case of a Martin–Gruber anastomosis. This was performed for thenar, hypothenar and FDI CMAPs in 150 hands, and the distribution was studied. It was hoped that the histograms would show separate peaks for Martin–Gruber arms and normal arms, but this was not the case. This suggests that there is no minimal number of motor units in Martin–Gruber cases. Accordingly, there is no simple cutoff point allowing a certain distinction between normal and Martin–Gruber arms. The data were also used to calculate the rate of occurrence, using some of the criteria outlined above. The estimates varied considerably (unpublished data). This indicates that it is probably not possible to determine the existence and thus the rate of occurrence of a Martin–Gruber anastomosis accurately using surface stimulation and recording techniques. However, one encounters a Martin–Gruber with enough crossing fibers to cause a problem often enough to mean that noone should be allowed to do nerve conduction testing without knowing about it. Documented cases of sensory fibers running through the anastomosis are rare. Claussen et al.

ANOMALIES OF INNERVATION

(1996) stimulated the little finger and recorded a sensory potential near the median nerve at the elbow in a case with a clear motor Martin–Gruber anastomosis. Surface electrodes were used to measure the sensory potentials. Incidentally, these authors showed that even this recording technique was prone to pick up volume-conducted signals, as these were found over the ulnar nerve at the wrist in 93% of cases following stimulation of the index finger. Simonetti (2001) searched for sensory crossover using a near-nerve technique in 24 arms with motor anastomosis. Small responses over the median nerve were found in 10 arms after stimulation of the little finger, but disappeared after local anesthesia of the ulnar nerve, proving costimulation. Believable sensory crossover was reported in two subjects. These results show that sensory crossover does occur, but is probably rare. The results underline that even near-nerve recordings may be subject to volumeconducted responses. 14.5.2.3. Clinical consequences 14.5.2.3.1. Conduction block. The detection of demyelination in nerve conduction testing is very important for the recognition of a number of treatable polyneuropathies. As the presence of a Martin–Gruber anastomosis resembles a conduction block of the ulnar nerve in the forearm, there is a real risk that a Martin–Gruber anastomosis is mistaken for a conduction block. True conduction blocks also occur in compression neuropathies, and a block at such sites is not accepted as evidence for a demyelinating polyneuropathy (Olney et al., 2003). Unfortunately, exclusion of a Martin–Gruber anastomosis before accepting a block of the ulnar nerve was not stipulated in these criteria. It is theoretically possible that a true block of the median nerve is masked by a Martin–Gruber anastomosis, but no reports of this were found. 14.5.2.3.2. Carpal tunnel syndrome. The detection of a carpal tunnel syndrome may be hampered by the presence of a Martin–Gruber anastomosis, as illustrated in Fig. 14.10. An anastomosis concerning the FDI is shown in Fig. 14.10A: distal median nerve stimulation may result in a thenar CMAP with a prolonged latency and a reduced amplitude, as expected with carpal tunnel syndrome. When the median nerve is stimulated in the elbow, a complex CMAP ensues, formed in part by the fibers through the normal pathway in the median nerve (“M”): this partial CMAP also has a prolonged latency and a small amplitude.

323

‘M’ ‘U’

A

‘M’ ‘U’

B Fig. 14.10 Martin–Gruber anastomosis and carpal tunnel syndrome. The presence of a carpal tunnel syndrome is indicated by a rhomboid shape over the median nerve in the wrist. Distal median nerve stimulation will result in a prolonged distal motor latency and possibly a reduced amplitude. Stimulation of the median nerve in the elbow produces an odd CMAP, one component of which is formed by fibers with a normal course in the median nerve, with a prolonged latency, indicated with “M”. Other fibers run through the anastomosis to innervate the FDI (A) and/or the ulnar thenar muscles (B) through the ulnar nerve (“U”). These bypass the carpal tunnel, and arrive with a normal latency. As a result, the conduction velocity of the median nerve test can be too high. The waveform following proximal median nerve stimulation may have a long duration, and start with an initial positive phase, dependent to a degree on whether the anastomosis concerns the FDI or thenar muscles.

However, the fibers running through the anastomosis (“U”) reach the FDI with a normal latency, and the corresponding partial CMAP will often present itself as a positive-going potential over the thenar eminence. These two CMAPs are measured in summation, however, resulting in one or more of the following features: an odd shape (Sander et al., 1997); an initial positivity (Gutmann, 1977; Gutmann et al., 1986); and a very high conduction velocity, caused by the fibers through the anastomosis that bypass the obstruction in the carpal tunnel (Gutmann, 1993; Sander et al., 1997). It is even possible that the latency of the proximal CMAP is shorter than that of the distal one, resulting in an impossible “negative velocity.”

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Searching for a Martin–Gruber anastomosis while recording from the FDI will establish its presence. Results from the proximal median stimulation can then be left out of consideration for the carpal tunnel syndrome; the distal findings may still be used. Detection of a carpal tunnel is also hampered when the anastomosis concerns ulnar/thenar muscles (Fig. 14.10B). In this case, the rerouted fibers need not produce an initial positive phase, but the odd waveform and the unbelievably high velocity persist. The detection is similar to that explained above. 14.5.2.3.3. High median nerve lesions. A high lesion of the median nerve in a case of Martin–Gruber anastomosis will cause paralysis of median nerve muscles, but also of muscles normally innervated by the ulnar nerve, depending on which muscles are innervated through the anastomosis. The paralysis will therefore present as indicating an additional lesion of the ulnar nerve. If the anastomosis carries many fibers, the clinical presentation may suggest an “all median hand” (see Section 14.5.3). 14.5.2.3.4. Ulnaropathy at the elbow. A severe lesion at the elbow or higher will surprisingly leave the function of some ulnar-innervated muscles intact. Again, this may present as an “all median hand” if many fibers run through the anastomosis. Attention has been drawn to the fact that the anomalous branch may join the ulnar nerve in the across-elbow segment (Marras and Midroni, 1999). Its occurrence has been confirmed by others (Daube personal communication). On an acrosselbow study, and even on an inching study, the result resembles a block in the elbow segment and thereby a compression neuropathy. This means that there are two caveats before accepting a block as proving a compression neuropathy at the elbow. Firstly, it should not be the only evidence; on an inching study a latency change should accompany the amplitude change. Secondly, if there is no latency change, a Martin–Gruber anastomosis should be ruled out as the explanation. Systematic studies investigating the presence of an anastomosis in cases of possible block are needed to show how often this can be attributed to an anastomosis. 14.5.3. Marinacci anastomosis 14.5.3.1. Anatomy The Marinacci anastomosis concerns an “ulnarto-median” anastomosis in the forearm, and is the opposite of the Martin–Gruber anastomosis. Here, the

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aberrant fibers innervate median thenar muscles; these fibers run proximally in the ulnar nerve and cross over to the median nerve in the forearm (Fig. 14.11). As in the Martin–Gruber syndrome, the terminology “ulnar-to-median” is only appropriate for motor nerve fibers. It is extremely rare and this explains why much less is known about its features than for the Martin–Gruber anastomosis. For instance, no information was found whether there is any predilection for any of the median thenar muscles (APB, OP and part of the FPB). Only one case was found in which the course of the aberrant branch was described. This concerned a patient in whom an unusual branch was seen during surgery for carpal tunnel syndrome (Stancic et al., 2000), and in whom motor nerve conduction testing was carried out postoperatively. The case is unique in the sense that it contains the only information about the location of the branch: it joined the median nerve very close to the hand, at a position very close to the normal stimulation site of the median nerve in the wrist. The point where the branch departed from the ulnar nerve was not visualized. There is no way to know whether this very distal joining is common in the Marinacci anastomosis or not: surgery for carpal tunnel syndrome presents a bias in that only a distal joining can be found. The only other anatomical data about Marinacci anastomosis are that it was not found in a number of systematic searches: no such branches were found in 250 arms of 125 bodies (Gruber in Streib, 1979), nor in 30 forearms of 15 bodies (Sarikcioglu et al., 2003). It was not mentioned in a study on Martin–Gruber anastomosis of 236 arms of 118 bodies (RodriguezNiedenführ et al., 2002a, 2002b), which may indicate

Fig. 14.11 Marinacci anastomosis. This anastomosis concerns fibers to median thenar muscles, that run in the ulnar nerve before they cross to the median nerve in the forearm. Its effect on a median nerve study is that the proximal amplitude will be too low, resembling a conduction block. Performing an ulnar nerve study while recording from the thenar shows that the fibers run in the ulnar nerve proximally.

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its absence. Together, these data indicate that a Marinacci anastomosis occurs less often than once in 516 arms. The presence of the anastomosis in the forearm suggests that there must also be an abnormality more proximally, but this has not been described. It is not known which roots innervate the muscles innervated through the anomalous branch. Median thenar muscles are normally innervated through the C8 and T1 roots. Assuming that this also holds for the Marinacci anastomosis, the fibers must end up in the ulnar nerve proximally in the forearm instead of in the median nerve. The most straightforward assumption is that they reach this point running alongside the C8/T1 fibers destined for ulnar-innervated hand muscles, i.e., through the inferior trunk and the medial cord (Fig. 14.12).

sis is that the ulnar nerve must gain what the median nerve loses over the forearm, so for the ulnar nerve below-elbow stimulation should result in a larger CMAP than holds for wrist stimulation. Note that one should always expect to obtain a CMAP over the APB following ulnar nerve stimulation, due to ulnar thenar muscles. Proving the existence of a Marinacci anastomosis is very similar to searching for a Martin–Gruber anastomosis. The first step should be to test the median and ulnar nerves distally and proximally, while recording from the thenar and hypothenar muscles, preferably simultaneously. In view of the very low a priori likelihood of a Marinacci anastomosis, a convincing demonstration will probably require near nerve stimulation and recording with concentric needle electrodes.

14.5.3.2. Nerve conduction findings 14.5.3.2.1. Essential features. Figure 14.11 shows the essential features of the Marinacci anastomosis: some motor fibers destined for median thenar muscles run in the ulnar nerve proximally in the forearm, and cross over to follow a normal course in the median nerve distally in the forearm and further on. In a median nerve study, this will show up as a normal thenar CMAP after wrist stimulation, and an abnormally small one following elbow stimulation. Following the general logic outlined in Section 14.1, there are three explanations: inframaximal stimulation at the elbow, co-stimulation at the wrist, and a Marinacci anastomosis (Table 14.1). In view of its extreme rarity, a Marinacci anastomosis is probably the least likely explanation. Performing an ulnar nerve study with stimulation at the wrist and at the elbow (preferably below the elbow, to avoid possible abnormalities at the sulcus) will be helpful to distinguish between the three possibilities. The essence of the Marinacci anastomo-

14.5.3.2.2. Literature review. The rarity of the Marinacci anastomosis is reflected in the low number of papers describing its presence. Systematic studies on the Martin–Gruber anastomosis did not report any case in 60 forearms (Sarikcioglu et al., 2003), 100 arms (Amoiridis, 1992a), 50 arms (Amoiridis and Vlachonikolis, 2003), 656 arms (Kimura et al., 1976), and it was not mentioned in a study of 100 arms (Erdem et al., 2002). Thus, it seems to occur less often than once in about 800 arms. Only few papers describe clearcut cases. Marinacci’s original description (1964) could not be obtained, but two typical cases were found (Streib, 1979; Stancic et al., 2000). The data in some other descriptions are hard to understand, in that distal ulnar nerve stimulation did not result in any CMAP over the APB at all, or in that there was an amplitude decay for both the ulnar and median nerves recorded over the APB (Meenakshi-Sundaram et al., 2003). Other reports are also difficult to interpret (Golovchinsky,

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Fig. 14.12 Proximal route in ulnar-to-median anastomosis. An ulnar-to-median anastomosis in the forearm (Marinacci) or in the hand (Riche–Cannieu) is indicated by an arrow. These fibers may have taken an aberrant route proximally: coming from C8 and T1 roots, they may have continued into the ulnar nerve, instead of branching off into the median nerve. Inf. = inferior, Med. = medial.

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1990; see also Amoiridis, 1992b and Golovchinsky, 1995). Finally, there is one description of a crossover of sensory but not motor fibers in the forearm (Hopf, 1990): needle stimulation of the radial side of the middle finger resulted in a SNAP over the median nerve in the wrist and over the ulnar nerve at the elbow. This contrasts strongly with the usual finding of normal sensory nerve testing in cases of Marinacci anastomosis (Streib, 1979). The case described by Hopf (1990) appears to depart significantly from the “typical” Marinacci pattern, and may represent a unique anomaly. 14.5.3.3. Clinical consequences In theory, a Marinacci anastomosis may cause a similar set of problems with the detection of abnormality as holds for the Martin–Gruber anastomosis, but its extreme rarity indicates that all other possibilities should be exhaustively searched before the presence of a Marinacci anastomosis may be concluded. 14.5.3.3.1. Ulnar nerve lesions. If the anastomosis is present, an ulnaropathy at the elbow may definitely complicate diagnosis, as fibers running to the “median thenar” groups of muscles may be affected in addition to typical ulnar nerve groups. The presenting picture, therefore, suggests a lesion of both the median and ulnar nerves, a combined C8/T1 root lesion, or of the inferior trunk. In effect, this presentation suggests an “all ulnar hand.” 14.5.3.3.2. Median nerve lesions. A proximal severe lesion of the median nerve in case of a Marinacci communication will leave the function of the medianinnervated hand muscles surprisingly intact. In fact, this is the pattern suggesting an “all ulnar hand,” first described by Marinacci (1964), to whom the condition owes its name. In case of carpal tunnel syndrome, median nerve tests will be complicated by the pseudoblock in the forearm. This will not affect distal motor latency, however, as all fibers destined for the median-innervated hand muscles reach the hand through the carpal tunnel, regardless of whether they run in the median or the ulnar nerve more proximally. A Marinacci anastomosis resembles a conduction block in the forearm of the median nerve. It is so rare that it does not seem necessary to exclude it before counting a pronounced amplitude loss of the median nerve in the forearm as a conduction block.

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14.5.4. Riche–Cannieu anastomosis 14.5.4.1. Anatomy Like the Marinacci anastomosis, the Riche–Cannieu anastomosis concerns the innervation of median thenar muscles by fibers running for part of their course in the ulnar nerve (Fig. 14.13). The difference resides in the place of the anastomosis: instead of in the forearm, the fibers cross over in the hand, from the deep branch of the ulnar nerve to the recurrent branch of the median nerve (Falconer and Spinner, 1985). The shape of the connection does not betray the course of the fibers: the fibers do not run obliquely between the nerves but form an arcuate connection (Harness and Sekeles, 1971). It may be conjectured that there is a corresponding proximal aberrant course as well (Sachs et al., 1995). Anatomical studies showed its presence in three of ten hands (Falconer and Spinner, 1985), three out of 20 hands (Cannieu in Falconer and Spinner, 1985), 27 out of 35 hands (Harness and Sekeles, 1971), and 13 out of 68 hands (Ajmani, 1996).

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B Fig. 14.13 Riche–Cannieu anastomosis. The Riche–Cannieu anastomosis lies distal to the usual stimulation sites in the wrist, which explains why it does not result in an amplitude discrepancy between distal and proximal stimulation sites. If the number of aberrant fibers is low (A), the only abnormality is that median nerve CMAPs are lower in amplitude than they should be. Ulnar nerve CMAPs recorded from the same spot will be overly large, but as this is not a common test, this will not be apparent. If there are hardly or no motor fibers with a normal course in the median nerve (B) median nerve stimulation will not result in CMAPs at all.

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Although the number of studies is limited and their results rather different, even the lowest count suggests that the Riche–Cannieu anastomosis is not very rare. 14.5.4.2. Nerve conduction findings 14.5.4.2.1. Essential features. Although the Riche–Cannieu anastomosis is an ulnar-to-median anastomosis, just like the Marinacci anastomosis, its effect on nerve conduction testing is quite different. The Marinacci and Martin–Gruber anastomoses have in common that the anastomosis is located between the distal and proximal stimulation points of the two nerves, and that explains why one nerve’s gain is the other nerve’s loss. In the Riche–Cannieu anastomosis, the anastomosis lies distal to the usual stimulation sites, so there is no apparent gain/loss phenomenon. When the number of nerve fibers involved is limited (Fig. 14.13A), median/thenar stimulation will result in CMAPs, albeit of a smaller amplitude than might be expected. It is not common to record ulnar/thenar CMAPs, so the fact that these are larger than normal will go unnoticed. Other ulnar nerves studies should be normal, so the anastomosis is only apparent as low amplitudes following median nerve stimulation. If the median thenar muscles are completely innervated through the anastomosis, this situation is taken to its extreme consequence: median nerve stimulation does not result in thenar CMAPs, although the function of the muscles is intact (Fig. 14.13b). As sensory fibers follow their normal course, median nerve SNAPs will be present in normal fashion. 14.5.4.2.2. Publications. Although there are two studies in which attempts were made to estimate how often the Riche–Cannieu anastomosis occurs using nerve conduction techniques, the results are questionable. Both compared CMAP amplitudes over muscles such as the APB following median and ulnar nerve stimulation (Kimura and Ayyar, 1984; Raudino, 1989). Any CMAP following ulnar nerve stimulation over the APB appears to have been interpreted as due to an anastomosis, without considering coregistration at all. Remaining publications concern case reports, mentioning complete innervation of median thenar muscles through the anastomosis (Dumitru et al., 1988; Ganes, 1992; Rao et al., 1995; Sachs et al., 1995; Nobrega et al., 1997; Refaeian et al., 2001) more often than incomplete cases (Dyro, 1983; Russomano et al., 1995; Saperstein and King, 2000). Where sensory tests were performed, these did not depart from the

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normal innervation, showing that the anastomosis involves motor but not sensory fibers. 14.5.4.3. Clinical consequences 14.5.4.3.1. Median nerve lesions. In either proximal or distal lesions of the median nerve, including carpal tunnel syndrome, a Riche–Cannieu anastomosis spares the function of the median thenar muscles, as the innervating fibers do not run through the median nerve. This will contrast strongly with the findings of nerve conduction testing, as explained above. If the lesion is severe, the sparing of median thenar muscles may give rise to the observation of an “all ulnar hand”. Compatible findings have been described for a high median nerve lesion (Russomano et al., 1995) and for carpal tunnel syndrome (Dyro, 1983; Nobrega et al., 1997; Refaeian et al., 2001). 14.5.4.3.2. Ulnar nerve lesions. As for median nerve lesions, the level of the lesion is irrelevant to understand the consequences of a Riche–Cannieu anastomosis. Here, median thenar muscles will be affected in addition to the expected loss of function in an ulnar nerve lesion, raising suspicions about an affliction of both nerves, a brachial plexus or root lesion. Cases found in the investigation of ulnaropathy have been reported (Dumitru et al., 1988; Saperstein and King, 2000). The clinical presentation may be described as an “all ulnar hand”. 14.5.5. Sensory anastomoses in the hand (Berrettini anastomosis) 14.5.5.1. Anatomy The Riche–Cannieu anastomosis concerns a connection between the deep motor branches of the median and ulnar nerves. A less-well known anastomosis connects the superficial palmar sensory branches of the same two nerves. The term “Berrettini branch” was coined in 1991 (Stancic et al., 1999) to honor a description from 1741. This anastomosis is the norm rather than the exception, as it was seen in 40 (80%) of 50 hands (Meals and Shaner, 1983), 26 (100%) of 26 hands (Don Griot et al., 2002), 81 (81%) of 100 hands (Stancic et al., 1999), and 45 (90%) of 50 hands (Ferrari and Gilbert, 1991). The connections most commonly arise from the ulnar nerve proximally and join the third common digital nerve distally (Fig. 14.14). However, transverse branches, networks and branches in the other direction have also been described (Meals and Shaner, 1983; Ferrari and

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Fig. 14.14 Berrettini anastomosis. (Top): the expected sensory innervation pattern of the fingers on the palmar side of the hand (thumb nerves not shown). The border between the innervation areas of the median and ulnar nerves lies on the ring finger. As in other Figures, each line represents a separate population of axons. The table shows in which fingers SNAPs may be expected after stimulation of the median and ulnar nerves. (Middle): the most common-anastomosis pattern. The radial side of the ring finger (dark gray) receives innervation from both nerves. This does not alter the pattern of where SNAPs may be expected. (Bottom): the next common Berrettini pattern: the ulnar side of the middle finger also receives dual innervation. Its consequence is that ulnar stimulation may result in a SNAP over the middle finger, possibly with a low amplititude. As this is not usually tested, the anastomosis is likely to go unnoticed.

Gilbert, 1991; Stancic et al., 1999; Don Griot et al., 2002). For clinical purposes, it is more relevant to know which fingers are innervated through the anastomosis. Several microscopic studies followed the course of the fibers through it (Meals and Shaner, 1983; Ferrari and Gilbert, 1991; Stancic et al., 1999; Don Griot et al., 2002). The most commonly affected region is the

radial side of the ring finger: when an anastomosis is present, this area is innervated by both nerves rather than exclusively by the median nerve (Fig. 14.14). This was seen in 11 of 26 hands (Don Griot et al., 2002) and in 23 of 38 hands with a communication (Meals and Shaner, 1983). The next most common pattern concerned the radial side of the ring finger as well as the ulnar side of the middle finger: this was seen in 10 of 38 hands with a communication (Meals and Shaner, 1983) and 10 of 26 hands (Don Griot et al., 2002). Other patterns are very rare, and include dual innervation of the ulnar side of the ring finger (Meals and Shaner, 1983; Don Griot et al., 2002). Very rarely does the median nerve carry fibers to the ulnar one as well (Meals and Shaner, 1983). Two points deserve special attention as they have consequences for the diagnosis of nerve lesions. Firstly, it is not entirely clear how many of the fibers in the finger nerve are derived from the anastomosis, and how many from the “normal” nerve. If all or a large majority of the fibers are derived from the anastomosis, this results in a shift of the border between median and ulnar nerve territories. If the anastomosis and the “normal” nerve contribute equally to the number of fibers in the finger nerve, then the connection would cause a dual innervation but no such shift. Clinical testing in patients with nerve transactions revealed that a well-described border was observed in some patients; the border could run according to the expected textbook pattern, but also elsewhere. In others areas of decreased perception lay at the border between areas of normal and lost feeling, suggesting areas of dual innervation (Don Griot, pers. comm.). Secondly, a few areas never received dual innervation: these are the thumb and index fingers and the ulnar side of the little finger (Don Griot et al., 2002). 14.5.5.2. Nerve conduction findings There are no systematic reports on the impact of the Berrettini anastomosis on nerve conduction testing. In fact, not many can be expected, for its presence is likely to go unnoticed for two reasons. The first reason has to do with the fact that it is virtually impossible to record a SNAP just from one side of the finger. Ring electrodes will, by their very nature, record from both sides of a finger, and selective placement of electrodes on one side of a finger does not abolish the chance that volume-conducted potentials may be recorded from the other side of the finger. Stimulation of either the ulnar or the median nerve usually produces a SNAP over the ring finger,

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because each of the two nerves innervate one half of the finger. The most common Berrettini variant may only alter the relative contribution of the two nerves to the innervation: the ulnar nerve will contribute more and the median nerve less. The corresponding SNAP amplitude differences will likely go unnoticed in clinical practice. The second common Berrettini variant (Fig. 14.14) does not alter the reasoning much: for the ring finger the situation remains the same, but stimulation of the ulnar nerve may now also result in a SNAP over the middle finger. Recording the middle finger while stimulating the ulnar nerve is obviously not a normal test procedure. In fact, it is almost only used to check for costimulation of the median nerve (Laroy et al., 1999). The fact that the Berrettini anastomosis is not rare indicates that the third finger is not optimal for this purpose. The thumb and the index fingers are never affected by a Berrettini anastomosis and are, therefore, much better suited to check for unintentional stimulation of the median nerve. The presence of exclusive innervation of the ring finger by either the median or the ulnar nerve has been studied in 2047 hands (Laroy et al., 1999). No evidence of this was found and this strengthens the idea that the Berrettini anastomosis does not cause the border between median and ulnar nerve territories to shift. Attention has been drawn to the possible influence of an anastomosis on the results (Don Griot and Hage, 2000). The second reason why a Berrettini anastomosis may go unnoticed is that the number of fibers running through the anastomosis may form only 10–30% of the total number of fibers (Ferrari and Gilbert, 1991). If that is the case, SNAP amplitudes will be affected only a little, and this source of variability will be overshadowed by all other sources of variability affecting SNAP amplitudes. 14.5.5.3. Clinical consequences The presence of a Berrettini anastomosis explains why some lesions of the median or ulnar nerves result in an unexpected pattern of sensory loss. The best examples concern complete transactions of a nerve (Don Griot et al., 2002). In the author’s opinion, the finding that many patients with carpal tunnel syndrome indicate a “wrong” area of sensory complaints does not necessarily indicate the presence of a Berrettini anastomosis. Inaccurate reports may represent a tendency of patients to answer to a doctor’s question even when they are uncertain about the answer.

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The existence of the anastomosis is more important for hand surgeons, who should know of its existence to avoid injuring it. 14.6. Related concepts 14.6.1. “All ulnar hand” The “all ulnar hand” is largely a clinical concept, resulting from observations of nerve lesions in which the pattern of weakness did not conform to expectation. An example is a clear-cut severe lesion of the ulnar nerve at the elbow, in which hand muscles normally innervated by the median nerve are unexpectedly paralyzed, in addition to the hypothenar and interosseous muscles. Such observations lead to the conclusion that the ulnar nerve at the site of the lesion must contain fibers for these “median nerve” muscles. The same conclusion may be also be drawn from a severe lesion of the median nerve, that surprisingly leaves the function of the APB, OP and partial FPB intact. In this case, the conclusion must be that the median nerve at the site of the lesion does not contain the fibers for these muscles. The Riche–Cannieu anastomosis can explain both types of observations leading to an “all ulnar hand,” i.e. following ulnar nerve lesions (Dumitru et al., 1988; Sachs et al., 1995; Saperstein and King, 2000) as well as median nerve ones (Russomano et al., 1995; Refaeian et al., 2001). The differential diagnosis of the “all ulnar hand” concerns lesions of C8 and T1 roots and the lower brachial plexus, particularly the inferior trunk. 14.6.2. “All median hand” The “all median hand” is also a clinical concept. The two observations giving rise to it are a severe lesion of the median nerve that also causes paralysis of the hypothenar and interosseous muscles, and a severe lesion of the ulnar nerve that leaves the function of the same muscle groups surprisingly intact. The reasoning is similar: the fibers run somewhere else than expected. A proximal transection of the ulnar nerve without paralysis of hypothenar and interosseous muscles was described by Marinacci and Von Hagen (1965). This case (not the one that gave rise to the Marinacci anastomosis) would now probably be recognized as a Martin–Gruber anastomosis affecting all three ulnar muscle groups in the hand to a large degree. The differential diagnosis of the all median hand is similar to that of the all ulnar hand.

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14.6.3. “All-tibial foot” Three patients have been described in whom the EDB (and one presumes the extensor hallucis brevis muscle as well) on the dorsum of the foot were thought to be innervated by the tibial nerve instead of by the peroneal nerve (Linden and Berlit, 1994; Glocker et al., 1995; Linden, 1995), giving rise to the concept of an “all tibial foot”. Nerve conduction tests in all three cases had shown that stimulation of the peroneal nerve at the ankle or higher failed to produce a CMAP placed over the extensor digitorum brevis muscle, while stimulation of the tibial nerve produced wellformed CMAPs with an initial negative peak. These observations evoked critical replies (Amoiridis et al., 1996; Magistris and Truffert, 1997), to the effect that electrodes placed on the dorsum of the foot will record activity from tibial-innervated foot muscles through volume conduction. Both critics provided factual data that this is the case. This does not indicate anomalous innervation, but volume conduction of normal responses. Some clinical data were presented supporting the concept of an all tibial foot, in the form of toe extension following tibial nerve stimulation, and a lack of denervation in the extensor digitorum muscle despite an otherwise severe peroneal nerve lesion (Linden and Berlit, 1994; Glocker et al., 1995; Linden, 1995), but their strength as proof is debatable. The best way to prove the existence of such an anomaly electrophysiologically would be to use a concentric needle to record muscle activity, as this is much less sensitive to volume conduction. In contrast to surface electrode recordings, needle recordings in foot muscles did not show activity on stimulating the “wrong” nerve (Amoiridis et al., 1996; Magistris and Truffert, 1997). In conclusion, the existence of an “all tibial foot” has not been proven with electrodiagnostic means. As there is no anatomical proof either, this anomaly may not exist. Those attempting to prove its existence should take particular care to avoid the common pitfall of coregistration: placing a surface electrode over a muscle does not restrict the measurement to that muscle. 14.7. Anomalous muscles 14.7.1. Extensor muscles of the hand The muscles extending the fingers are prone to anatomical variability. The normal situation consists of an extensor digitorum communis muscle with four

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tendons, and an extensor indicis proprius muscle extending the index finger, so there are two extensor tendons running to the index finger. The muscle belly of the extensor indicis proprius may lie unusually distally, even reaching the dorsum of the hand (Tan and Smith, 1999). It may become entrapped under the retinaculum extensorum during flexion of the wrist, causing local pain. Of the other anomalies, the extensor digitorum brevis manus muscle deserves mention. This is a small muscle on the dorsum of the hand, rather similar to the EDB on the dorsum of the foot. It usually has only one tendon, running to the index finger (Tan and Smith, 1999). It is not uncommon for the extensor indicis proprius muscle to be absent in such cases. It is not as rare as one might expect: anatomical studies reported incidence values from 1 to 9% (Tan and Smith, 1999). A large clinical study found it to be present in 1.1% of 3404 adults (Gama, 1983). It is present as a mass on the dorsal surface on the hand that may be mistaken for a ganglion (Gama, 1983). It appears to cause pain relatively often. It is innervated by the posterior interosseous nerve (Gama, 1983; McManis and Daube, 1989). 14.7.2. Anomalous muscles in Guyon’s canal Anatomical studies revealed anomalous muscles in Guyon’s canal in 22–25% of subjects (Harvie et al., 2004). These muscles represent variants of the abductor digiti minimi muscle. Their importance lies in the fact that they can cause compression of the ulnar nerve. A recent study used ultrasound to detect these muscles, and found them to be present in 35% of 116 wrists (Harvie et al., 2004). References Ajmani, MI (1996) Variations in the motor nerve supply of the thenar and hypothenar muscles of the hand. J. Anat., 189: 145–150. Amoiridis, G (1992a) Median-ulnar nerve communications and anomalous innervation of the intrinsic hand muscles: An electrophysiological study. Muscle Nerve, 15: 576–579. Amoiridis, G (1992b) Frequency of ulnar-to-median nerve anastomosis. Letter to the editor. Electromyogr. Clin. Neurophysiol., 32: 255–256. Amoiridis, G, Schöls, L, Meves, S and Przuntek, H (1996) Fact and fallacy in clinical and electrophysiological studies of anomalous innervation of the intrinsic foot muscles. Muscle Nerve, 19: 1227–1228.

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Amoiridis, G, Schöls, L, Przuntek, H and Wöhrle, J (1998) Collision technique in Martin-Gruber anastomosis. Muscle Nerve, 21: 1354–1360. Amoiridis, G and Vlachonikolis, IG (2003) Verification of the median-to-ulnar and ulnar-to-median nerve motor fiber anastomosis in the forearm: an electrophysiological study. Clin. Neurophysiol., 114: 94–98. Choi, D, Rodriguez-Niedenführ, M, Vázquez, T, Parkin, I and Sañudo, JR (2002) Patterns of connections between the musculocutaneous and median nerves in the axilla and arm. Clin. Anat., 15: 11–17. Claussen, GC, Ahmad, BK, Sunwoo, IN and Oh, SJ (1996) Combined motor and sensory median-ulnar anastomosis: report of an electrophysiologically proven case. Muscle Nerve, 19: 231–233. Crutchfield, CA and Gutmann, L (1980) Hereditary aspects of median-ulnar nerve communications. J. Neurol. Neurosurg. Psychiatry, 43: 53–55. Don Griot, JPW, van Kooten, EO, Zuidam, JM, Prosé, LP and Hage, JJ (2002) Internal anatomy of the communicating branch between the ulnar and median nerves in the hand and its relevance to volar digital sensibility. J. Hand Surg., 27A: 143–146. Don Griot, JPW and Hage, JJ (2000) Has the exclusive ulnar or median innervation of the ring finger been shown not to exist? Clin. Neurophysiol., 111: 1522–1523. Dumitru, D, Walsh, NE and Weber, CF (1988) Electrophysiological study of the Riche–Cannieu anomaly. Electromyogr. Clin. Neurophysiol., 28: 27–31. Dyro, FM (1983) Ulnar innervation of opponens pollicis. Electromyogr. Clin. Neurophysiol., 23: 257–260. Erdem, HR, Ergun, S, Erturk, C and Ozel, S (2002) Electrophysiological evaluation of the incidence of Martin-Gruber anastomosis in healthy subjects. Yonsei Med. J., 43: 291–295. Falconer, D and Spinner, M (1985) Anatomic variations in the motor and sensory supply of the thumb. Clin. Orthop. Rel. Res., 195: 83–96. Ferrari, GP and Gilbert, A (1991) The superficial anastomosis on the palm of the hand between the ulnar and median nerves. J. Hand Surg., 16B: 511–514. Gama, C (1983) Extensor digitorum brevis manus: a report on 38 cases and a review of the literature. J. Hand Surg., 8: 578–582. Ganes, T (1992) Complete ulnar innervation of the thenar muscles combined with normal sensory

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fibres in a subject with no peripheral nerve lesion. Electromyogr. Clin. Neurophysiol., 32: 559–563. Glocker, FX, Deuschl, G and Lücking, CH (1995) Traumatic lesion of the common peroneal nerve with complete foot drop and preserved dorsiflexion of the toes—An innervation anomaly. Muscle Nerve, 18: 926. Golovchinsky, V (1990) Ulnar-to-median anastomosis and its role in the diagnosis of the median nerve at the elbow and at the wrist. Electromyogr. Clin. Neurophysiol., 30: 31–34. Golovchinski, V (1995) Frequency of ulnar-to-median nerve anastomosis revisited. Letter to the editor. Electromyogr. Clin. Neurophysiol., 35: 67–68. Gutmann, L (1977) Median-ulnar nerve communications and carpal tunnel syndrome. J. Neurol. Neurosurg. Psychiatry, 40: 982–986. Gutmann, L, Gutierrez, A and Riggs, JE (1986) The contribution of median-ulnar communications in diagnosis of mild carpal tunnel syndrome. Muscle Nerve, 9: 319–321. Gutmann, L (1993) AAEM minimonograph #2: Important anomalous innervations of the extremities. Muscle Nerve, 16: 339–347. Harness, D and Sekeles, E (1971) The double anastomotic innervation of thenar muscles. J. Anat., 109: 461–466. Harvie, P, Patel, N and Ostlere, SJ (2004) Prevalence and epidemiological variation of anomalous muscles at Guyon’s canal. J. Hand Surg., 29B: 26–29. Homma, T and Sakai, T (1992) Thenar and hypothenar muscles and their innervation by the ulnar and median nerves in the human hand. Acta Anat., 145: 44–49. Hopf, HC (1990) Forearm ulnar-to-median nerve anastomosis of sensory axons. Muscle Nerve, 13: 654–656. Hopf, HC and Hense, W (1974) Anomalien der motorische Innervation an der Hand. Z EEG-EMG, 5: 220–224. Kimura, I and Ayyar, DR (1984) The hand neural communication between the ulnar and median nerves: electrophysiological detection. Electromyogr. Clin. Neurophysiol., 24: 409–414. Kimura, J, Murphy, MJ and Varda, DJ (1976) Electrophysiological study of anomalous innervation of intrinsic hand muscles. Arch. Neurol., 33: 842–844. Kudoh, H, Sakai, T and Horiguchi, M (1999) The consistent presence of the human accessory deep peroneal nerve. J. Anat., 194: 101–108.

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ANOMALIES OF INNERVATION

Sander, HW, Quinto, C and Chokroverty, S (1997) Median-ulnar anastomosis to thenar, hypothenar, and first dorsal interosseous muscles: Collision technique confirmation. Muscle Nerve, 20: 1460–1462. Sander, HW, Quinto C and Chokroverty, S (1998) Accessory deep peroneal nerve: collision technique diagnosis. Muscle Nerve, 21: 121–123. Sañudo, JR, Vázquez, R and Puerta, J (2003) Meaning and clinical interest of the anatomical variations in the 21st century. Eur. J. Anat., 7(Suppl. 1): 1–3. Sarikcioglu, L, Sindel, M, Ozkaynak, S and Aydin, H (2003) Median and ulnar nerve communication in the forearm: An anatomical and electrophysiological study. Med. Sci. Monit., 9: BR351–BR356. Simonetti, S (2001) Electrophysiological study of forearm sensory fiber crossover in Martin–Gruber anastomosis. Muscle Nerve, 24: 380–386. Sonck, WA, Francx, MM and Engels, HL (1991) Innervation anomalies in upper and lower extremities: potential clinical implications. How to identify with electrophysiologic techniques? Electromyogr. Clin. Neurophysiol., 31: 67–80. Spinner, RJ, Pichelmann, MA and Birch, R (2003) Radial nerve innervation to the inferolateral segment of the brachialis muscle: From anatomy to clinical reality. Clin. Anat., 16: 368–369. Stanˇci´c, MF, Mi´covi´c, V and Poto cˇ njak, M (1999) The anatomy of the Berrettini branch: Implications for carpal tunnel release. J. Neurosurg., 91: 1027–1030. Stanˇci´c, MF, Burgi´c, N and Mi´covi´c, V (2000) Marinacci communication. Case report. J. Neurosurg., 92: 860–862. Stamboulis (1987) Accessory deep peroneal nerve. Electromyogr. Clin. Neurophysiol., 27: 289–292. Streib, EW (1979) Ulnar-to-median nerve anastomosis in the forearm: electromyographic studies. Neurology, 29: 1534–1537. Streib, EW and Sun, SF (1983) Martin–Gruber anastomosis: electromyographic studies. Electromyogr. Clin. Neurophysiol., 23: 261–270.

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 15

Other pitfalls and sources of errors Amer Al-Shekhlee and David C. Preston Case Western Reserve University, University Hospitals of Cleveland, OH, USA

15.1. Introduction Electrodiagnostic (EDX) studies play a key role in the evaluation of peripheral nerve diseases. Among EDX studies, nerve-conduction studies (NCS) and needle electromyography (EMG) are most often employed. These studies yield critical information about the underlying disorder and allow other laboratory tests to be used in a more appropriate and efficient manner. For instance, the laboratory evaluation of an acquired demyelinating neuropathy is quite different from one that is chronic and axonal. In many cases, the information gained from EDX studies leads to specific medical or surgical therapy. However, the value of this information relies on two important and complementary processes: (1) correct data collection; and (2) correct data interpretation. If the data is not technically accurate, then correct data interpretation can never occur, either at the time of the study, or later by other treating physicians. Performed correctly, EDX studies rely upon collecting and amplifying very small bioelectric signals in the millivolt and microvolt range. Accomplishing this is technically demanding, with a large number of physiologic and non-physiologic factors that can significantly interfere with the accuracy of the data. Failure to recognize these technical factors can result in type I and type II errors: (1) making a diagnosis of an abnormality when none is present (i.e., convicting an innocent man); and (2) making a diagnosis of no abnormality when one is present (i.e., letting a guilty man go free). Although both are important, type I errors are potentially more serious (i.e., labeling a patient as abnormal when the “abnormalities” are unrecognized technical errors) as

*Correspondence to: David C. Preston, MD. University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44016-5098, USA. E-mail address: [email protected] Tel.: +216 844-7776; fax: +216 844-7624.

they can lead to inappropriate testing and treatment (e.g., the patient with a C8 radiculopathy who is labeled as an ulnar neuropathy at the elbow from a measurement error may undergo ulnar transposition surgery, etc.). Recognizing technical factors and sources of error are also essential in improving the efficiency of the EDX study and reducing patient discomfort. This chapter addresses the commonly encountered pitfalls and other source of errors according to their importance in daily practice and whether they represent physiological or non-physiological factors (Tables 15.1 and 15.2). 15.2. Nerve conduction studies 15.2.1. Physiological factors 15.2.1.1. Temperature Among physiologic variables that effect EDX studies, temperature is the most important (Table 15.3). Cooler temperatures result in impaired inactivation of nerve sodium channels and, subsequently, prolong the time of depolarization. For myelinated fibers, conduction velocity is primarily determined by the time delay of depolarization that occurs at the nodes of Ranvier. Hence, prolonged depolarization times result in slowed conduction velocities for the nerve being studied. In addition, longer channel opening time results in a larger influx of sodium. Subsequently, each nerve fiber depolarization is larger and longer. On NCS, this results in higher amplitudes and longer durations [Fig. 15.1] (Hodgkin and Katz, 1949; Rutkove, 2001). Sensory and motor conduction velocities decrease linearly with increasing temperature on average of 5% per degree centigrade with different studies demonstrating a range of 1.3–2.4 m/s/ °c) (De Jesus et al., 1973; Kimura, 1984). Similarly, distal latencies prolong on an average 0.2–0.3 m/s/ °c of cooling. As noted above, amplitudes increase and durations prolong with cooling as well (Hodgkin and Katz, 1949; Kimura, 1984). A linear effect of temperature has

336 Table 15.1 Common pitfalls and sources of errors in NCS Physiological factors ● Temperature ● Age ● Height ● Proximal versus distal segments Non-physiological factors ● Stimulation-related issues ■ Supramaximal, submaximal and co-stimulation ■ Stimulus artifact ■ Reversing stimulator polarity ■ Virtual cathode and bridging ● Recording-related issues ■ Electrode impedance mismatch ■ Filtering ■ Electronic averaging ■ Electrode placement ■ Sweep speed and sensitivity in cursor placement ■ Reproducibility of data ■ Distance measurements

Table 15.2 Common pitfalls and sources of errors in needle EMG Physiological factors ● Age ● Temperature ● Normal variability within the same muscle and between different muscles Non-physiological factors ● Filters ● Electrical noise ● Correct needle placement ● Number of muscles to sample ● Waveform interpretation

Table 15.3 The effects of cooling on nerve conduction studies and needle EMG Slowed nerve conduction velocities Prolonged distal latencies Increased SNAP and CMAP amplitudes and duration Increased MUAP duration, amplitude and phases Decreased insertional activity Increased myotonic discharges

AMER AL-SHEKHLEE AND DAVID C. PRESTON

also been demonstrated with sensory nerve action potential (SNAP) duration and amplitude (Bolton et al., 1981). In general, SNAP amplitudes are more sensitive to the effect of cooling than that of compound motor action potentials (CMAPs). This results from the fact that the duration of individual sensory nerve fiber action potentials is shorter than that of individual motor unit action potentials. The normal process of phase cancellation is more prominent when individual fiber action potential durations are shorter. Thus, when cooling occurs, individual sensory nerve fiber action potentials prolong; there is less phase cancellation, resulting in a higher compound nerve action potential. The converse occurs with excessive heating. At temperatures of 42 °C, an average reduction in amplitude of 27% occurs while duration shortens 19% and conduction velocity increases 11% (Rutkove et al., 1997). A skin temperature of 34–36 °C is often selected for EDX studies of the upper extremities and 32–34 °C for the lower. There may be significant inter-individual variation in limb temperature even when ample time is allowed to equilibrate in a warm laboratory. Moreover, there is marked variation of neural temperature over the course of a given nerve with a gradual trend toward cooler temperatures from proximal to distal and deep to superficial within the respective limb. In a warm limb, skin surface temperature is typically 1–2 °C warmer compared to the near nerve temperature (Behse and Buchthal, 1971; DeJesus, 1973) The opposite is often true in a cooler limb, where the skin temperature is lower than the near nerve temperature. One can easily understand that if cool temperatures are not appreciated and corrected, false positive diagnoses can occur. Most common are the diagnoses of peripheral neuropathy (from diffusely reduced conduction velocities) and distal entrapment neuropathies (from prolonged distal latencies). In addition, among patients with axonal peripheral neuropathies, cooling may slow nerve conduction velocity into the range associated with demyelination, which could then profoundly alter the electrodiagnostic impression, subsequent evaluation and treatment. To avoid the pitfalls associated with temperature, every electromyography must first appreciate the importance of temperature on EDX studies and routinely measure and monitor distal limb temperatures. If the limb is cool, it should be warmed with heating pads or radiant heat. If the limb is profoundly cool, warm water immersion is best employed. To maintain a constant temperature, an external radiant heating

OTHER PITFALLS AND SOURCES OF ERRORS

337 Fig. 15.1 Temperature effect on nerve conduction studies. Median antidromic sensory studies, stimulating wrist, recording second digit. Same patient at different limb temperatures. Note that with cooler limb temperature (top), distal latency and conduction velocity slow, while duration and amplitude increase (Preston and Shapiro, 1998).

20 μV 1 ms

T = 27 ⬚C

T = 33 ⬚C

DL = 3.1 ms CV = 42 ms Duration = 3.0 ms Amplitude = 46 μV

DL = 2.5 ms CV = 52 ms Duration = 1.7 ms Amplitude = 36 μV

lamp with feedback control is optimal. However, when external heating is employed, another source of error may occur. The skin surface temperature may rise more rapidly compared to underlying nerve temperature. For limbs that are profoundly cool, it may require 20–40 min for the underlying nerve temperature to equilibrate [Fig. 15.2] (Halar et al., 1980; Franssen and Wieneke, 1994). If not recognized, this may result clinically in a situation after warming where conduction velocity increases as more time passes despite a constant skin temperature. If limb warming is not possible or difficult to achieve (e.g., portable studies in the intensive care unit), then one should employ a correction factor. Most commonly used are 1.5–2.5 m/s/ °c for conduction velocity, and 0.2 ms/°c for distal latency. However, one should appreciate the fact that these correction factors are derived primarily from individuals with normal nerves. Such may not hold true for all diseased nerves. Hence, it is always preferable to rewarm a limb than use a correction factor (Halar et al., 1980).

dependent, with nerve conduction velocities in full term infants approximately half those of adult normal values (Thomas and Lambert, 1960). Conduction Minutes 60 40

Tibial NCV

20 0 20

24

26

28

30

32

28

30

32

Temperature ⬚C

60 40

Sural NCV

20 0 20

15.2.1.2. Age Age primarily affects nerve conduction velocity and waveform morphology, most prominently at the extremes of age (i.e., the very young and the very old). One of the most important determinates of nerve conduction velocity is the presence and amount of myelin. Beginning in utero, the process of myelination is age-

22

22

24

26

Temperature ⬚C

Fig. 15.2 Warming time and conduction velocity. The time required for conduction velocity of the tibial (upper) or sural (lower) nerve to reach 95% of its limit value is plotted against the skin temperature prior to warming (Reproduced from Franssen, H., Wieneke, GH, 1994 with permission of John Willey & Sons, Inc.).

338

velocity rapidly increases after birth and reaches approximately 75% of adult normal values by one year of age and to the adult range by age 3–5 years. Nerve conduction velocities are even slower in the premature infants, in the range of 14–28 m/s (Kimura, 1984). Among adults, conduction velocities decrease slightly with age, most likely as a consequence of the normal loss of motor and sensory neurons that occur with aging. This is more prominent for individuals older than 60 years of age where conduction velocity decreases approximately 0.5–4.0 m/s/decade for both sensory and motor studies (Taylor, 1984; Rivner et al., 1990). Thus, when setting cutoff values of normal conduction velocities, age must be taken into account. For example, where a peroneal motor conduction velocity of 36 m/s would be slow in a 20-year-old, this velocity would be considered normal for age 80. The amplitudes of both sensory and motor potentials both decline with age (Falco et al., 1994; Rivner et al., 2001). For example, sural sensory amplitudes may decrease as much as by 50% by age 70, underscoring the need to use age-based normal values for amplitudes as well as for conduction velocities (Jacobs and Love, 1985). 15.2.1.3. Height Height also influences conduction velocities, with taller individuals having slower conduction velocities than shorter ones (Rivner et al., 1990; Takano et al., 1991). Anatomically, peripheral nerves taper in diameter as they run distally in a limb. As conduction velocity is dependent on axonal diameter (i.e., the larger axon, the faster the conduction velocity), taller individuals will have more tapered nerves in their distal limbs and hence slightly slower conduction velocities (Campbell et al., 1981). In practice, the effect of height on conduction velocity is relatively minor and only clinically important in individuals who are very tall. Even in such individuals, the lower limit of normal conduction velocity needs to be adjusted by at most 2–4 m/s. However, the effect of height is especially relevant to the interpretation of late responses (F-responses and H-reflexes) and somatosensory evoked potentials (SSEPs). The circuitry of these responses extends the length of the limb, twice the length of the limb, and twice the length of the proximal lower limb for the SSEP, F-response, and H-reflex, respectively. In some situations, the effect of height is not relevant when relative latencies are compared between a symptomatic

AMER AL-SHEKHLEE AND DAVID C. PRESTON

and contralateral asymptomatic limb. However, normal values of absolute latency for these potentials must be based on limb length or height. Failure to do so will result in taller individuals being labeled as having “abnormal” late responses and SSEPs. 15.2.1.4. Proximal versus distal segments Similar to the effect of height, conduction velocities are slower in distal compared to proximal nerve segments. This occurs as the result of tapering of axonal diameter distally, as well as from the fact that distal limb temperatures are usually lower than those proximally. In motor studies of the median, ulnar and sciatic nerves, proximal segments have been documented 6–12% faster than distal segments (Mayer, 1963; Gassel, 1964). 15.2.2. Non-physiological factors 15.2.2.1. Stimulus related factors 15.2.2.1.1. Supramaximal, submaximal and co-stimulation. In order to obtain correct, reliable and reproducible data during NCS, it is essential that all nerve fibers are stimulated at all locations. If the current is too low, not all fibers will be depolarized (submaximal stimulation). Conversely, if it is too high, current may spread and depolarize nearby nerves (co-stimulation). Both submaximal stimulation and co-stimulation are common technical errors that may easily lead to inaccurate data interpretation. Different degrees of current intensity are required in different anatomical locations and in different individuals in order to depolarize all nerve fibers. For example, the current intensity needed to stimulate the median nerve at the wrist is much less than the current needed for the tibial nerve at the popliteal fossa. At each stimulation site, it is essential that the technique of supramaximal stimulation be employed to ensure that all axons of a given nerve are depolarized. To achieve supramaximal stimulation, the current intensity is slowly increased until the amplitude of the recorded potential reaches a plateau. The current intensity is then increased an additional 20–25% to ensure the potential no longer increases [Fig. 15.3]. The technique needs to be employed at all locations. One of the common pitfalls is to stop increasing the current once the potential is within the normal range. In this case, the potential may be “normal” but not supramaximal. Submaximal stimulation can lead to a multitude of potential errors and misinterpretations of the data including the following [Fig. 15.4]:

OTHER PITFALLS AND SOURCES OF ERRORS

339

5 mV 2 ms

Current

Amplitude Latency

6.0 mA

4.5 mV

3.6 ms

7.2 mA

6.8 mV

3.5 ms

9.0 mA

9.3 mV

3.5 ms

11.0 mA

1.5 mV

3.2 ms

14.0 mA

10.5 mV 3.1 ms

(1) Distal axonal loss. In nerves where stimulation is only employed at a single distal site (e.g., most sensory nerve studies), submaximal stimulation will mimic the pattern of axonal loss (i.e., reduced amplitude and normal latency). (2) Conduction block. In the case that the distal stimulation is supramaximal but the proximal site is submaximal, the pattern can be mistaken from a conduction block. This error is especially serious in that the presence of conduction blocks in a peripheral neuropathy usually signify an acquired demyelinating peripheral neuropathy, often treated with immunosuppressive or immunomodulating therapy. (3) Anatomic variants. In the case of the ulnar nerve, submaximal stimulation at the below-elbow site

5 mV/D

3 ms/D

Amplitude = 8.3 mV

Amplitude = 3.7 mV

Fig. 15.4 Submaximal stimulation. Ulnar motor study, stimulating wrist and below-elbow sites, recording the first dorsal interosseous muscle. Note that the amplitude at the below-elbow site is significantly lower than the wrist site. This is a technical error caused by the proximal stimulation not being supramaximal. If not recognized and corrected, submaximal stimulation at a proximal site may be mistaken for a partial conduction block, or in the case of the ulnar nerve, a Martin–Gruber anastomosis.

Fig. 15.3 Supramaximal stimulation. Median motor study, stimulating wrist, recording the abductor pollicis brevis, with increasing stimulator currents. To ensure all axons are stimulated, supramaximal stimulation is required for all nerve conduction studies. Supramaximal stimulation is achieved by increasing the stimulator current until the recorded potential has reached maximal amplitude. To ensure supramaximal stimulation, the current should then be increased by an additional 25% to ensure the amplitude does not increase further (bottom trace). Note that the latency decreases as supramaximal stimulation is approached (Preston and Shapiro, 1998).

will mimic the pattern of a Martin–Gruber anastomosis. Similarly, submaximal stimulation of the peroneal nerve at the ankle will mimic the pattern of an accessory peroneal nerve. In order to avoid submaximal stimulation, one may be tempted to routinely use higher-stimulation intensities. However, beyond being painful for the patient, this practice can also lead to technical errors from spread of the stimulus to nearby adjacent nerves (co-stimulation). Co-stimulation can also result in a multitude of interpretation errors including the following [Fig. 15.5]: (1) Obscuring distal axonal loss. Co-stimulation results in recording higher amplitudes than are truly present. In the case of distal axonal loss where the amplitude of the potential is reduced, costimulation may “normalize” the amplitude and obscure the pattern of axonal loss. (2) Conduction block. In case co-stimulation occurs at the distal stimulation site, the pattern will mimic a conduction block. As noted above, this error is especially serious as conduction blocks usually signify an acquired demyelinating peripheral neuropathy. (3) Obscuring a conduction block. In case a true conduction block is present between distal and proximal stimulation sites, co-stimulation at the proximal site will result in an inappropriately higher amplitude and thus will obscure the presence of a conduction block. (4) Anatomic variants. In the case of the ulnar nerve, co-stimulation at the wrist can mimic the pattern of a Martin–Gruber anastomosis. Similarly, costimulation of the peroneal nerve at the knee can mimic the pattern of an accessory peroneal nerve.

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AMER AL-SHEKHLEE AND DAVID C. PRESTON

10 mV/D

87 mA

37 mA

3 ms/D

Amplitude = 10.4 mV

Amplitude = 7.5 mV

Fig. 15.5 Co-stimulation. Ulnar motor study, stimulating wrist and below-elbow sites, recording the first dorsal interosseous muscle. Note that the amplitude at the below-elbow site is significantly lower than the wrist site. In this case, an error is caused by excessive current at the wrist that stimulates the ulnar nerve as well as the adjacent median nerve (i.e., co-stimulation). Note the stimulus current intensities noted at the beginning of each trace. In general, for normal individuals, currents exceeding 50 mA with a duration of 0.2 ms often will result in co-stimulation of adjacent nerves. If not recognized and corrected, costimulation at a distal site may be mistaken for a partial conduction block, or in the case of the ulnar nerve may mimic a Martin–Gruber anastomosis.

Co-stimulation is unavoidable at some stimulation sites such as Erb’s point where nerve bundles run in close proximity. However, for routine NCS (median, ulnar, radial, peroneal, and tibial), co-stimulation can be avoided by paying attention to the several important points. First, for most normal individuals, co-stimulation of the median and ulnar nerves at the wrist and elbow sites, and the peroneal nerve at the lateral popliteal fossa often occurs at stimulus intensities > 50 mA (0.2 ms pulse duration). Thus, once stimulus intensities increase beyond this point, the electromyography needs to appreciate the increased possibility of co-stimulation. Second, while watching the amplitude of the waveform increase when increasing the stimulus intensity, the shape of the waveform will often change abruptly when co-stimulation occurs. For instance, the normal dome shape of a median motor response may abruptly develop a bifid morphology, signifying the ulnar nerve is now being co-stimulated. Third, co-stimulation can often be avoided by ensuring the stimulator is directly over the nerve. By doing so, much less current is required to achieve supramaximal stimulation and co-stimulation is easily avoided. The technique of ensuring the stimulator is optimally placed over the nerve is easily learned. The stimulator is placed over a site where the nerve is expected to run based on anatomic landmarks. The stimulus intensity is slowly increased until the first small submaximal potential is recorded. At this point, the stimulus current is held constant, and the stimulator is moved parallel to the initial stimulation site, both slightly laterally and then

slightly medially. The position that yields the highest response is the position closest to the nerve. As the stimulus intensity is low, this procedure is not painful for the patient. Once the optimal position is determined, the current is then increased to supramaximal. One is often surprised how little current is required to obtain supramaximal stimulation using this technique and how the efficiency and patient tolerance of the procedure improves. Lastly, co-stimulation can often be avoided if attention is paid to the muscle twitch. For example, stimulation of the median nerve at the wrist results in a limited contraction of the thenar eminence and first two lumbricals. As the ulnar nerve innervates most of the intrinsic hand muscles, ulnar nerve stimulation results in a more widespread flexion contraction of the hand. Thus, as the current intensity increases and co-stimulation begins, the observer will witness a change in the muscle twitch. This also applies to the lower extremities, especially at the popliteal fossa where the tibial nerve is in close proximity to the peroneal nerve. The normal twitch of peroneal nerve results in ankle dorsiflexion and eversion whereas the tibial nerve twitch results in plantarflexion and inversion of the ankle. Thus, when stimulating the peroneal nerve at the knee, the normal twitch of ankle dorsiflexion will change to plantarflexion and inversion when the tibial nerve is co-stimulated. 15.2.2.1.2. Stimulus artifact. During routine NCS, the current from the stimulator depolarizes the underlying nerve, but also spreads via volume conduction

OTHER PITFALLS AND SOURCES OF ERRORS

through the tissues within the limb and is seen at the recording electrodes. In the past, the stimulus or shock artifact served a useful purpose as a marker to measure latencies from. However, if the stimulus artifact is large, it may interfere with the potential of interest, and can alter latency, conduction velocity and amplitude measurements [Fig. 15.6]. Stimulus artifact is particularly problematic when recording small potentials (e.g., sensory and mixed studies) which require high gain and when the distance between the stimulator and recording electrodes is short. Several measures are necessary to prevent or reduce stimulus artifact including the following: (a) Proper grounding. The ideal location for the ground is between the stimulator and the recording electrodes.

20 μV/D

1 ms/D

CV = 54 m/s Amplitude = 42 μV

CV = 50 m/s Amplitude = 40 μV

CV = 43 m/s Amplitude = 25 μV

Fig. 15.6 Stimulus artifact and measurement error. Median antidromic sensory study, stimulating wrist, recording second digit. Stimulus artifact can be influenced by rotating the anode while maintaining the cathode in place. Large positive stimulus artifacts (top trace) may result in artifactually large amplitudes, shorter latencies and faster conduction velocities. Large negative stimulus artifacts (bottom trace) create more serious errors. They may result in artifactually low amplitudes, prolonged latencies, and slowed conduction velocities.

341

(b) Reducing electrode impedance. Since all potentials recorded during EDX studies are processed through a differential amplifier, any electrical noise including a stimulus artifact, can be reduced if the noise is the same at both the active and reference recording electrodes (i.e., the noise is cancelled out). Cleaning the skin well, applying a proper amount of electrode gel and having the electrodes well taped to the skin are all important. The use of coaxial cables will also reduce stimulus artifact. (c) Reduce the stimulus intensity. This is best accomplished by ensuring that the stimulator is in the ideal location directly over the nerve (see earlier section). (d) Increase the distance between the stimulator and the recording electrodes if possible. (e) Avoid crossing the stimulator and recording electrode cables. (f) Rotating the anode of the stimulator while maintaining the position of the cathode [Fig. 15.6]. This method can often reduce or eliminate the stimulus artifact (Kornfield et al., 1985). In most patients, rotating the anode 70–105˚ flattens the baseline and allows the potential of interest to be recorded more accurately. 15.2.2.1.3. Reversing stimulator polarity. During routine NCS, the distance between the stimulator and active recording electrode is measured to determine a conduction velocity. The nerve is depolarized under the cathode of the stimulator with a hyperpolarization occurring under the anode. Thus, the cathode of the stimulator is normally placed facing the recording electrode. If the stimulator is inadvertently reversed, so the anode is facing the recording electrodes, two potential errors may occur. First, a hyperpolarized area under the anode may prevent action potential propagation along the nerve (i.e., anodal block) and theoretically could then abolish or attenuate the response of interest [Fig. 15.7]. The issue of anodal block is more of theoretic concern and is rarely seen clinically. Studies have shown no significant difference in amplitude, duration or morphology of CMAP or SNAP waveforms (Dreyer et al., 1993; Wee et al., 2000). More important is the distance error that occurs when the cathode and anode are reversed. The measured distance will be from the anode to the active recording electrode instead of the cathode to the active recording electrode. For most stimulators, the true distance will

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Stimulator

Cathode

Anode +

G1

G2

−

Fig. 15.7 Anodal block. If the cathode and anode are reversed, anodal block may theoretically occur. With stimulation, the nerve depolarizes beneath the cathode and travels in both directions, while the segment under the anode may hyperpolarize. This hyperpolarization may block the action potential that originates at the cathode and prevent it from proceeding past the anode (Preston and Shapiro, 1998).

be underestimated by 2.5–3 cm, resulting in an artifactual prolongation of distal latency in the range of 0.3–0.4 ms and slowing of the conduction velocity of approximately 10 m/s (Preston and Shapiro, 1998). This results in a pattern of prolonged sensory and motor distal latencies, slowed distal sensory conduction velocities, but normal motor conduction velocities (as motor NCS require two stimulation sites and the calculation of conduction velocity does not depend on the distal latency which is subtracted out) [Fig. 15.8]. A reversed stimulator, if not recognized, could lead to the mistaken diagnoses of peripheral neuropathies or distal entrapment neuropathies. 15.2.2.1.4 Virtual cathode and bridging. In addition to co-stimulation of adjacent nerves, excessive current can rarely result in a virtual cathode effect. During NCS, the assumption is made that depolarization occurs directly under the cathode. However, if the current is excessive, the site of depolarization may actually be distal to the cathode. When this occurs, the distal latency does not correlate to the measured distance, as the true distance of nerve depolarization is less than what is measured on the surface from the active recording electrode to the stimulator cathode. Excessive stimulation can also be caused by bridging. Current spreads along the path of least resistance. If excessive electrode paste is present on the skin, current may travel from cathode to anode by way of a bridge on the skin and bypass the nerve below. This leads to the need to use excessive current to depolarize the underlying nerve, which then leads to stimulus artifacts, virtual cathode and co-stimulation of adjacent nerves.

15.2.2.2. Recording related factors 15.2.2.2.1. Electrode impedance mismatch. Electrical noise is present in the EMG laboratory from a variety of sources, most often computers, lights, heaters and telephones. Outside of the EMG laboratory, particularly in the intensive care unit, there may be many other sources of electrical noise from ventilators, fluid pumps, monitors and other electrical devices. In the USA, electrical current is delivered as an alternating current (AC) at 60 Hz and a line voltage of approximately 120 V. Thus, 60 Hz electrical interference is the most common electrical artifact encountered in EDX studies. All potentials recording during EDX studies are amplified via a differential amplifier (Barry, 1991). Here, the signal at the reference input is subtracted from the active input and then amplified. If the active and reference inputs are contaminated with the same electrical noise, the noise is subtracted out leaving only the signal of interest to be amplified (common mode rejection) [Fig. 15.9]. Thus, the key in eliminating electrical interference is to ensure that any electrical noise is the same on both the active and reference recording electrodes. This is accomplished by avoiding or reducing electrode impedance mismatch. Impedance is an electrical term combining the effect of resistance to current flow for a direct current (DC) current and capacitance for an AC current. Electrode impedance is dependent on a variety of factors including the cable, the recording electrode, the electrode gel, and skin preparation. Of these, proper skin preparation may be the most important (Perreault et al., 1993). Skin preparation requires cleaning of the skin of any dirt, oil and lotions with alcohol or acetone. Advising

OTHER PITFALLS AND SOURCES OF ERRORS

343

5 mV/D

3 ms/D

3.8 ms Cathode and anode: correct position

4.2 ms Cathode and anode: reversed

Stimulator

Cathode

Anode

G1

G2

Measured distance True distance

Fig. 15.8 Stimulator cathode and anode reversed. Both traces: ulnar motor study, stimulating wrist, recording the first dorsal interosseous muscle. Top trace: correct stimulator position with the cathode facing the active recording electrode. Bottom trace: stimulator cathode and anode are reversed with the cathode facing away from the active recording electrode. If the stimulator cathode and anode are inadvertently reversed, artifactual slowing occurs. This error usually prolongs the latency by 0.3–0.4 ms. The prolonged distal latency is a result of the measured distance being shorter than the true distance traveled. The true distance is the measured distance plus the distance between the stimulator cathode and anode.

patients against using oil or lotion prior to testing is very helpful. All electrodes need to be well secured to the skin with a reasonable amount of conducting paste. All cables should be of the same type, preferably coaxial, and must be intact without any frayed or broken connections. Indeed, all cables eventually develop metal fatigue and may fray or break, especially at points of attachment. 15.2.2.2.2. Filtering. Following differential amplification, the signal will pass through two sets of filters: a low-frequency (or high-pass) and a high-frequency (or low-pass) filter. The low-frequency filter attenuates signals below a set frequency while allowing higher frequencies signals to pass. The high-frequency filter attenuates signals above a set frequency while allowing lower frequencies to pass through. By allowing the signal to pass through a certain “pass band,” some unwanted electrical noise can be excluded. The

pass band varies for different electrical studies. For the sensory and mixed studies, filters typically have a narrower pass band (20 Hz–2 kHz) than those for motor studies (10 Hz–10 kHz). Maintaining the same set of filter settings is necessary to obtain reproducible data. Although filters are intended to exclude unwanted signals, they do impact the recorded signal of interest. The low-frequency filter primarily affects the duration of the potential (i.e., decreasing the low-frequency filter may reduce baseline wandering but will decrease the duration of the potential). Conversely, the highfrequency filter primarily affects the amplitude of the potential (i.e., decreasing the high-frequency filter may filter out high-frequency noise, but may also decrease the amplitude of the potential [Fig. 15.10] (Clancy et al., 2002). In the past, filter settings had to be manually set for each study. Presently, nearly all EMG machines have filter settings present. Thus, inaccurate filter settings are much less of a problem.

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R1

−

R1

+

R1 = R2

G1

G2 60 Hz

R1

−

R1

+

R1 = R2

G1

G2

60 Hz

R1

−

R1

+

R1 < R2

G1

G2

Fig. 15.9 Differentiation amplification and electrode impedance mismatch. All signals recorded during nerve conduction studies result from differential amplification. The signal present at the reference electrode (G2) is subtracted from the signal seen at the active electrode (G1) and is then amplified (top trace). Each recording electrode has its own impedance or resistance, modeled as R1 and R2 above, for the active and reference electrodes, respectively. If R1 and R2 are identical, any 60 Hz interference will induce a similar electrical noise at both inputs (middle trace). This noise will then be subtracted out, and only the signal of interest will be amplified. However, if electrode impedances are mismatched (R1 < R2), then the amount of electrical noise will be different at the two inputs (bottom trace). Some of the electrical noise will then be amplified, often obliterating or obscuring the signal of interest (bottom trace).

However, if the filters are altered, they can become a source of error. 15.2.2.2.3. Electronic averaging. Electrical noise may occasionally contaminate a potential despite filtering and best efforts to eliminate electrode imped-

ance mismatch. Most often, this occurs when recording small potentials in the microvolt range, typically sensory and mixed nerve studies. In this situation, electrical noise can be reduced or eliminated by employing electronic averaging. With electronic averaging, serial stimulations are digitized and then

OTHER PITFALLS AND SOURCES OF ERRORS 20 μV/D

2 ms/D

345 10 μV/D

2 ms/D

Amplitude = 30 μV Single input High-Frequency filter = 2 kHz

Averaging = 10

Amplitude = 16 μV High-Frequency filter = 0.5 kHz

Fig. 15.10 High-frequency filter and sensory nerve action potentials. Median sensory study, stimulating the wrist and recording digit 2. Top trace: high-frequency filter is set at 2 kHz. Bottom trace: 0.5 kHz. Note that as the higher frequencies are filtered out (bottom trace), the amplitude of sensory potential markedly decreases.

mathematically averaged. As electrical noise is random, positive and negative phases of electrical noise will cancel each other out as a greater number of stimulations are averaged, leaving the potential of interest. Electronic averaging is especially helpful in clarifying the electrical baseline so that onset latency and amplitude can be correctly measured [Fig. 15.11]. 15.2.2.2.4. Electrode placement. Improper placement of the active and reference recording electrodes is a common source of error during NCS. Different types of errors occur depending if motor or sensory studies are performed. For motor studies, the correct electrode montage employed is the so-called “belly-tendon” method where the active (G1) electrode is placed over the center of the muscle belly (where the muscle end-plate is usually found) and the reference (G2) electrode placed distally on the tendon of the same muscle. If G1 is misplaced off the end-plate, the morphology of the CMAP changes, usually with an initial positive deflection and a lower baseline-negative peak amplitude [Figs. 15.12 and 15.13]. If an initial positive deflection is present, it is essential to move the active electrode to optimize the

Fig. 15.11 Electronic averaging. Median sensory study, recording digit 2, stimulating the wrist. Top trace: single stimulation. Note that the potential is present but that there is significant baseline noise. Bottom trace: electronic averaging of ten stimulations. With the averaged trace, the noise is much improved, and the signal of sensory response is more clearly seen, and that the onset latency and amplitude are more accurately measured.

amplitude measurement and simplify the measurement of latency. In some cases where a muscle is severely atrophic, determining the motor point can be difficult and the best judgment should be taken. Not as well appreciated is the possibility of technical errors if the G2 electrode is misplaced. In the belly-tendon montage, it is generally assumed that the tendon is electrically inactive. Although this is true for some nerves, it is not so for others, especially the ulnar and tibial nerves where the reference electrode is usually electrically active (Brashear and Kincaid, 1996). As there is no muscle over the tendon, this “tendon potential” is likely a volume conducted far-field potential from proximal depolarizing muscles [Fig. 15.14]. Indeed, in many cases, much of the CMAP amplitude is actually generated from the tendon-potential. These tendon potentials are predominantly positive. Thus, the depolarization from G1 (which is negative) minus the tendon potential on G2 (which is positive) creates a larger negative potential. The key to avoid errors from misplacing G2 is consistency. For instance, if the right ulnar nerve is studied with G2 at the base of the fifth digit, but the left ulnar nerve is studied with G2 placed distally on the fifth digit, different, asymmetric amplitudes may result based only on the difference in the position of G2.

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10 mV/D

3 ms/D

Fig. 15.12 Motor studies: active recording electrode off the motor point. Ulnar motor study, recording the first dorsal interosseous, stimulating the wrist. Top trace: the active electrode (G1) properly placed over the motor point of the muscle. Bottom trace: if G1 is placed off the motor point, the morphology of the CMAP changes, usually with an initial positive deflection.

For sensory and mixed studies, the errors associated with improper recording electrode position are different. Typically, sensory and mixed potentials are recorded with G1and G2 placed 3–4 cm apart from each other with both electrodes over the course of the nerve. Depolarization first travels under G1 and then

5 mV/D

proceeds under G2. If G2 is placed too closely to G1, the segment of nerve which is depolarized may occur simultaneously under both electrodes resulting in a lower amplitude response due to a cancellation effect (Buchthal and Rosenfalck, 1966) [Figs. 15.15 and 16]. This error is easy to avoid by ensuring that the distance between G1 and G2 is correct. The more common pitfall occurs when both G1 and G2 are not optimally placed over the course of the nerve. Tissue acts as a high-frequency filter; thus the more tissue between the recording electrodes and the nerve, the more high frequencies are attenuated. As amplitude is predominantly a high-frequency response, the amplitude of the sensory or mixed potential will be reduced if the recording electrodes are not optimally placed [Fig. 15.17]. In addition, as a result of changes associated with volume conduction, the latency of the response may also change. Most sensory and mixed nerves are at risk for this pitfall, including the commonly performed palmar mixed studies, lateral antebrachial, medial antebrachial, superficial radial, sural, saphenous and superficial peroneal sensory nerves. Recording electrodes for sensory and mixed studies are placed based on anatomic landmarks. As most nerves cannot be seen or palpated, the recording electrodes may not be initially placed in the optimal position directly over the nerve of interest.

3 ms/D

G2 Amplitude = 7.8 mV

G1

Amplitude = 5.6 mV G2 G1

Fig. 15.13 Active electrode position and amplitude on motor studies. Ulnar motor study recording the hypothenar muscles and stimulating the wrist. The optimal position to evoke the maximal amplitude is over the motor point. When the active electrode is off the motor point, often a positive initial deflection will be noted alerting the examiner. However, this may not occur, especially when nearby muscles are also depolarized. Repositioning the active electrode may often result in higher amplitudes. This is especially important when comparing potentials from one side to the other.

OTHER PITFALLS AND SOURCES OF ERRORS

5 mV/D

347

3 ms/D

G2 Amplitude = 8.3 mV

Amplitude = 7.2 mV

G1

G2 G1

Amplitude = 5.6 mV

G2

Fig. 15.14 Reference electrode position and amplitude on motor studies. Recording electrodes for motor studies are placed in the “belly-tendon” montage. In theory, the depolarization occurs under the muscle belly and the reference electrode over the tendon is electrically neutral. However, the tendon may be electrically active, especially when studying the ulnar and tibial nerves. This tendon potential occurs as the result of volume conduction of proximal potentials and in the case of the ulnar nerve gives the motor response its characteristic bifid morphology. Note that in the three traces how the morphology and amplitude of the motor response changes as the reference electrode is changed. This underscores the need for consistency in placing both the reference and active electrodes when performing motor studies.

G1

The median and ulnar antidromic studies are an exception, as the recording electrodes are placed over the digits and one can always be assured that the recording electrodes are placed as close to the nerve as possible (i.e., directly over the digital nerves). To avoid this pitfall, one needs to move the recording electrodes from the initial position slightly medially and then slightly laterally to determine which position yields the largest response. It is often surprising how moving the recording electrodes so minimally can affect the amplitude of the response. Failure to do so can often result in technical errors, especially when comparing amplitudes from one limb to another. 15.2.2.2.5. Sweep speed and sensitivity in cursor placement. Both the sweep speed and sensitivity can affect latencies and conduction velocities when setting the cursors for both motor and sensory studies. With increasing sensitivity, onset latency measurement will often decrease [Fig. 15.18]. Conversely, with decreasing sweep speed, the latency measurement is likely to increase [Fig. 15.19]. If not recognized, this may lead to errors, especially if cursors for different traces are set with different sensitivities and sweep speeds. To avoid this pitfall, it is essential to be consistent in using the same sensitivity and sweep speed when setting cursors for all stimulating sites of a nerve in the same test. 15.2.2.2.6. Reproducibility of data. Serial testing is sometimes employed to judge improvement or worsening of a disease process. This includes clinical trials

where NCS may be used as an endpoint to assess the response to a new therapy or monitor for possible toxicity. In a controlled setting, serial nerve conduction studies measurements in normal subjects are more reliable when performed by the same examiner over a period of time (intra-examiner variability) than compared to different examiners (inter-examiner variability) (Chaudhry et al., 1991). The mean difference in conduction velocities of serial studies in normal subjects done by the same examiner are generally in the range of 2–4 m/s (Oh, 1993). Amplitudes may vary as well, with one intra-examiner study of ten normal subjects showing a mean difference in SNAP amplitudes ranging from 6 to 16% (pers. comm.). These variations may become clinically important, particularly in borderline results. In addition, side-to-side comparisons are commonly performed, especially in patients with unilateral symptoms. In one pilot study of 15 normal patients, the ratio of smaller to larger SNAP amplitude from side-to-side was as low as 0.5 for the median and ulnar nerves, and 0.4 for the radial, musculocutaneous, sural and superficial peroneal nerves (pers. comm.). Thus, if the normal limb has a 20 μV SNAP amplitude, in order to be abnormal, the symptomatic limb has to have an amplitude less than 10 μV for median and ulnar nerves, and 8 μV for the radial, musculocutaneous, sural and superficial peroneal nerves. Some intra- and inter-examiner variability may be explained by differences in limb temperature between exams. In addition, variability can be introduced from

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A

G1

G2

A

B

G1

G2

B

G1

G2

C

G1

G2

C

G1

G2

D

G1

G2

D

G1

G2

E

G1

G2

E

G1

G2

Recorded sensory potential G1−G2 4 cm

G1

G2

Recorded sensory potential G1−G2 1 cm

Fig. 15.15 Influence of distance between active and reference recording electrodes for sensory studies. The distance between the active and reference recording electrodes influences the amplitude of sensory nerve action potentials (SNAPs). The SNAP is the result of the difference in electrical activity between the active and reference recording electrodes. The segment of depolarized nerve proceeds first under the active electrode (left B) and then travels distally beneath the reference electrode (left D). If the active and reference electrodes are too close, they may briefly become electrically active at the same time (right C), resulting in a lower amplitude potential. For the usual range of nerve conduction velocities in sensory and mixed nerve studies, separating the active and reference recording electrodes by 3–4 cm will ensure that depolarization does not occur under both electrodes simultaneously (Preston and Shapiro, 1998).

differences in distance measurements and how latency markers are placed (Maynard and Stolov, 1972). Thus, it is always preferable to standardize the methods of temperature and distances measurement, maintain the same temperature during testing and, if possible, have the same examiner to perform serial testing on the same patient.

15.2.2.2.7. Distance measurements. Calculation of a valid conduction velocity relies upon correct latency and distance measurements. One assumes that the surface distance measured with a tape or ruler approximates the true distance of the underlying nerve. In general, this is true with some significant exceptions. The most important one clinically is the ulnar nerve at

OTHER PITFALLS AND SOURCES OF ERRORS

20 μV/D

20 ms/D

349

G1−G2 distance 1.0 cm

Amplitude = 14 μV

Amplitude = 25 μV

2.5 cm

Fig. 15.16 Influence of distance between active and reference recording electrodes for sensory studies. Median sensory studies, stimulating the wrist and recording digit 2. The distance between the G1 and G2 of the recording electrodes is 1.0 cm (top), 2.5 cm (middle) and 4.0 cm (bottom). Note that the much smaller amplitude when the recording electrodes are 1.0 cm apart. In this case, the active and reference electrodes are so close that the segment of depolarized nerve may occur simultaneously at both electrodes, resulting in a lower amplitude potential.

4.0 cm Amplitude = 28 μV

the elbow. Distance measurements across the elbow are notoriously inaccurate if the elbow is in the extended elbow position (Campbell et al., 1991). In this case, the true length of the nerve is underestimated, and the calculated conduction velocity is artifactually slowed. Autopsy studies have shown that the length of the ulnar nerve across the elbow is measured more accurately when the elbow is held in the flexed rather than extended position. Surface disease measurements can also be difficult in nerves that are deep or run in a circuitous course in a limb. For instance, the true length of the radial nerve is difficult to measure as the it winds around the humerus and takes a somewhat winding course through the forearm. Measuring the distance with obstetrical calipers, especially between the elbow and arm, reduces some of this error. Because of this difficulty in measuring the true nerve length, considerable inaccuracies can occur when studying the radial nerve where conduction velocities are sometimes calculated as factiously fast (>75 m/s). 15.3. Needle electromyography Many of the technical factors that influence NCS are equally relevant to the needle electrode examination (NEE) portion of the EDX study. In addition, there are some additional pitfalls that are unique to this part of the study. Recognizing technical sources of error is

often more difficult during the NEE as the determination needs to be made in real time as potentials are seen and heard. One usually does not have the luxury of being able to study a waveform on a printout or adjust cursors on a trace as can be done for NCS. 15.3.1. Physiological factors 15.3.1.1. Temperature Since action potentials are generated in muscle fibers in a similar manner that occurs in nerve fibers, it is not unexpected that temperature can affect the NEE as well (Dlouha et al., 1980). However, the effects of temperature are usually less prominent on NEE than NCS, as muscles are located deeper, as thus warmer, in the limb than most nerves studied during NCS. However, if a limb is very cool, temperature can affect both spontaneous and voluntary activity. In general, cooling decreases spontaneous depolarizations of muscle fibers. Thus, the amount of active denervation (i.e., fibrillation potentials and positive sharp waves) will decrease with cool limb temperatures (Rack and Fox, 1987). The only benefit on cool limb temperatures on spontaneous activity is that they may unmask and increase the number of myotonic discharges (Ricker et al., 1986). In this less common situation, intentional cooling of a limb can be helpful in increasing the yield of observing myotonic discharges.

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2 ms/D

Amplitude = 38 μV

Median nerve Recording electrode

Amplitude = 31 μV Median nerve Recording electrode

Amplitude = 12 μV Median nerve Recording electrode

Fig. 15.17 Effect of distance between recording electrodes and nerve. Median mixed nerve study, stimulating the palm and recording over the wrist. Top trace: recording electrodes directly on the median nerve. Middle trace: recording electrodes placed 0.5 cm laterally. Bottom trace: recording electrodes placed 1.0 cm laterally. If the recording electrodes are moved off the nerve (middle and bottom traces), maintaining the same distance, the following changes occur: onset latency shifts to the left, peak latency remains relatively unchanged, and amplitude drops markedly. In nerve conduction studies, side-to-side comparisons between amplitudes are often made, looking for asymmetry. One can easily appreciate that if the recording electrodes are placed lateral or medial to the nerve on one side and directly over the nerve on the other side, one might be left with the mistaken impression of a significant asymmetry in amplitude. When the location of the underlying nerve is not certain, it is important to try several recording electrode positions to ensure that the maximal amplitude is obtained.

During the assessment of voluntary activity, the configuration of motor unit action potentials (MUAPs) can alter significantly with cooler limb temperatures. Similar to the effect on CMAP morphology during NCS, cooling increases the duration, amplitude and polyphasia of the MUAP (Rutkove, 2001). For example, the mean MUAP duration of the biceps increases 15% at 30˚C and 25% at 25˚C (Buchthal et al., 1954). Thus, when combined with the effect of cooling on NCS (i.e., slowed conduction velocities and distal latencies), MUAPs may be misinterpreted as neuropathic, and increase the possibility of an erroneous conclusion of a peripheral neuropathy or distal entrapment neuropathy.

15.3.1.2. Age Age has a significant effect on MUAP morphology (Table 15.4). At birth, MUAPs are small, reflecting the physical size of the motor units. As a child grows, motor unit territory increases with MUAP size increasing as well. However, through adult life, there is a progressive increase in the duration and polyphasia of MUAPs. This occurs likely as the result of the normal loss of motor neurons with aging and the compensatory process of reinnervation. The loss of motor units has been estimated to be approximately 1% per year, beginning in the third decade of life, which then increases rapidly after 60 years (Tomlinson and

OTHER PITFALLS AND SOURCES OF ERRORS

351

5 mV

5 mV 2 ms

2 ms

3.0 ms

3.4 ms

1 mV

5 mV 1 ms

2 ms

3.4 ms 3.1 ms

5 mV 0.8 ms 100 μV 3.5 ms 2 ms

2.9 ms

Fig. 15.18 Latency measurement and sensitivity. Median motor study, stimulating wrist, recording the abductor pollicis brevis, using varying sensitivities, with sweep speed held constant. Latency measurements should always be made using the same sensitivity. Note that as sensitivity is increased, latency measurement decreases (Preston and Shapiro, 1998).

Irving, 1977). If the effect of age on MUAP morphology is not appreciated, it may result in overcalling MUAPs as abnormal, especially in the elderly. What might be an abnormal mean MUAP duration in a 20year-old may be normal in an 80-year-old. The ability to appreciate and distinguish normal from mildly abnormal MUAP morphology in different age groups improves with experience; it is clearly one of the more difficult tasks for an electromyographer to master.

Fig. 15.19 Latency measurement and sweep speed. Median motor study, stimulating wrist, recording the abductor pollicis brevis, using varying sweep speeds, with sensitivity held constant. Latency measurements should always be made using the same sweep speed. Note that as sweep speed decreases, latency measurement usually increases (Preston and Shapiro, 1998).

15.3.1.3. Normal variability within the same muscle and between different muscles MUAP properties vary within a muscle and between different muscles. Within a muscle, there is a normal bell-shaped distribution curve of MUAP size. In sampling MUAPs from the same muscle, different size MUAPs will be encountered with larger MUAPs generally occurring at higher levels of activation. In neuropathic conditions, the curve shifts to the right toward larger sizes, and in myopathic disorders, the curve shifts to the left toward smaller sizes. Due to the normal variability of MUAP size within a single muscle, normal values of duration and amplitude are based on the mean of at least 20 MUAPs (Buchthal and Rosenfalck, 1966). Thus, it is essential that MUAP morphology in any given is muscle is not based on one or two units, but on a mean of many different MUAPs.

7.9–10.1 8.0–10.8 8.1–11.2 8.6–12.2 9.5–13.2 11.1–14.9 11.8–15.7 12.8–16.7 13.3–17.3 13.7–17.7

0–4 5–9 10–14 15–19 20–29 30–39 40–49 50–59 60–69 70–79

6.4–8.2 6.5–8.8 6.6–9.1 7.0–9.9 7.7–10.7 9.0–12.1 9.6–12.8 10.4–13.6 10.8–14.1 11.1–14.4

Biceps

7.2–9.3 7.3–9.9 7.5–10.3 7.9–11.2 8.7–12.1 10.2–13.7 10.9–14.5 11.8–15.4 12.2–15.9 12.5–16.3

Triceps 7.1–9.1 7.2–9.8 7.3–10.1 7.8–11.0 8.5–11.9 10.0–13.4 10.7–14.2 11.5–15.1 12.0–15.7 12.3–16.0

Thenar 8.3–10.6 8.4–11.4 8.5–11.7 9.0–12.8 9.9–13.8 11.6–15.6 12.4–16.5 13.4–17.5 13.9–18.2 14.3–18.6

ADM 7.2–9.2 7.3–9.9 7.4–10.2 7.8–11.1 8.6–12.0 10.1–13.5 10.7–14.3 11.6–15.2 12.1–15.8 12.4–16.1

Quad., BF 6.4–8.2 6.5–8.8 6.6–9.1 7.0–9.9 7.7–10.7 9.0–12.1 9.6–12.8 10.4–13.6 10.8–14.1 11.1–14.4

Gastroc. 8.0–10.2 8.1–11.0 8.2–11.3 8.7–12.3 9.6–13.3 11.2–15.1 11.9–15.9 12.9–16.9 13.4–17.5 13.8–17.9

Tib. Ant.

6.8–7.4 5.9–7.9 5.9–8.2 6.3–8.9 6.9–9.6 8.1–10.9 8.6–11.5 9.4–12.2 9.7–12.7 10.0–13.0

Per. Long.

Leg muscles

6.3–8.1 6.4–8.7 6.5–9.0 6.9–9.8 7.6–10.6 8.9–12.0 9.5–12.7 10.3–13.5 10.7–14.0 11.0–14.3

EDB

3.7–4.7 3.8–5.1 3.9–5.3 4.1–5.7 4.4–6.2 5.2–7.1 5.6–7.4 6.0–7.9 6.3–8.2 6.5–8.3

Facial

(ADM, abductor digiti minimi; BF, biceps femoris; Quad., quadriceps; Gastroc, gastrocnemius; Tib. Ant., tibialis anterior; Per. Long., peroneus longus; EDB, extensor digitorum brevis (Buchthal and Rosenfalck, 1955).

Deltoid

Age of subjects

Arm muscles

Mean MUAP duration based on age and muscle group

Table 15.4

352 AMER AL-SHEKHLEE AND DAVID C. PRESTON

OTHER PITFALLS AND SOURCES OF ERRORS

It is also essential to appreciate that there is also significant variability in MUAP size between different muscles in the same individual (Table 15.4). Motor unit territory and the number of muscle fibers per motor unit varies among different muscles. In general, MUAPs are smaller in proximal compared to distal muscles. This difference is most pronounced in sampling the cranio-bulbar muscles which normally have very small MUAP sizes. However, even among muscles which are located at a similar proximal distal position in a limb, there may be differences in MUAP size. For instance, the mean MUAP duration of the first dorsal interosseous is longer than that of the abductor pollicis brevis. Incorporating all of the information above, the determination of whether a muscle is normal or abnormal needs to be based on sampling many MUAPs within the muscle, and knowing the normal mean size of the MUAP for the particular muscle and age of the patient. 15.3.2. Non-physiological Factors 15.3.2.1. Filters Similar to NCS, filters are employed during the NEE to minimize electrical noise. However, as noted above, filters also can attenuate or distort the potential of interest. Decreasing the high-frequency (low-pass) filter during the NEE reduces MUAP amplitude and the number of phases (Gitter and Stolov, 1995). On the contrary, raising the low-frequency (high-pass) filter decreases the duration of the MUAP. Thus, MUAP morphology can easily be altered by changing the filter settings. For instance, a normal MUAP can be made to appear “myopathic” by raising the low-frequency filter (i.e., decreasing the duration) and lowering the highfrequency filter (i.e., decreasing the amplitude). Spontaneous activity is also influenced by filter settings. As fibrillation potentials are brief spikes with a significant high-frequency component to their morphology, lowering the high-frequency filter can significantly decrease the amplitude of fibrillation and other similar potentials. 15.3.2.2. Electrical noise Similar to NCS, most electrical interference encountered during the NEE is 60 Hz noise from nearby electrical devices. Proper grounding is essential for electrical safety as well as for reduction of this electrical interference. The use of a concentric needle electrode will help reduce electrode impedance mismatch

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in contrast to a monopolar needle that requires an accompanying surface reference electrode. Sometimes, one of the best options to reduce 60 Hz interference is to turn off lights or unplug other electrical devices in the vicinity. In rare situations, even when a device is in the off position, it still may be drawing some current. The authors recently encountered a wall-mounted ophthalmoscope in the EMG laboratory as a source of significant electrical interference even when it was in the off position. Only after physically unplugging the electrical cord from the wall was the electrical interference eliminated. Of course, reducing 60 Hz activity is especially problematic when performing a portable study in the intensive care unit, where one does not have the option of turning off or unplugging interfering electrical devices. 15.3.2.3. Correct needle placement The interpretation of whether the NEE of a muscle is normal or abnormal is predicated on the needle electrode being in the muscle of interest. Although this may appear self-evident, correct needle electrode placement can be particularly problematic either when examining morbidly obese patients or when sampling muscles which are either atrophic or anatomically deep. Correct needle electrode placement first relies upon the knowledge of normal anatomic landmarks. In addition, most muscles can be visualized and palpated before inserting the needle electrode. In the situations noted above, the electromyographer may lose one or more of these methods that allow for correct needle electrode placement. The presence of insertional activity and/or voluntary MUAPs can always indicate that the needle electrode is in muscle, as opposed to fascia or adipose tissue. However, if the needle electrode is not in the intended muscle, both type I and type II errors can occur in interpretation. In the case of a severely atrophic muscle, it is often easy to pass the needle through the atrophic muscle into an adjacent muscle. If that adjacent muscle is normal, a type II error of interpretation will occur (i.e., making a diagnosis of no abnormality when one is present). Correct needle placement is not difficult for superficial muscles that can be seen and palpated. However, this is often not the case in morbidly obese patients where normal anatomic landmarks are obscured by adipose tissue. In some obese patients, muscles are so deep that they are not within the reach of standard length needle electrodes. Using longer needles in these situations may be contraindicated if nearby

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anatomical structures pose a risk (e.g., sciatic nerve and the gluteus maximus, the pleura and lower cervical/thoracic paraspinal muscles, etc.). In all situations, correct needle placement in deep muscles that cannot be seen or palpated is a challenging task. Even more difficult is sampling a deep muscle that lies between superficial and deeper muscles (e.g., rhomboids between the trapezius and paraspinal muscles, etc.). In these cases, the needle may be inserted at the correct skin location, but if it is too superficial or too deep, it will be in a different muscle. In all of these situations, the key to correct needle interpretation is to first ensure that the needle is in the correct muscle. After inserting the needle based on anatomic landmarks, this is best accomplished by having the patient slightly activate the muscle of interest. If the needle is in the correct location, crisp MUAPs will be easily seen at low levels of activation. The low level of activation needs to be emphasized. Many adjacent muscles will co-contract at higher levels of activation. It is also useful to have the patient purposively activate adjacent muscles to ensure crisp MUAPs are not present. For instance, when sampling the flexor digitorum longus, it is helpful to have the patient plantarflex the ankle and then invert the ankle, to ensure the needle is not in the soleus or the tibialis posterior, respectively. 15.3.2.4. Number of muscles to sample In the interpretation of an EDX study, variables not often considered are the choice of how many and which muscles are sampled during the NEE. For every study, the need to be thorough and to rule in or rule out a diagnosis must be weighed against the length of the study and the patient’s tolerance of the NEE. If too few muscles are sampled, the risk of a type II error increases. This is more likely to occur when the pathology is mild or multifocal. Less well appreciated is the fact that many entrapment neuropathies are multifocal in nature. When external compression of a nerve occurs, it is common that some fascicles within the nerve are affected where others are relatively spared. For instance, the tensor fascia lata and gluteus medius share the same nerve (superior gluteal) and root (L4-L5-S1) innervation. Despite this, it is not uncommon to see one muscle affected and one spared in some compressive L5 radiculopathies, presumably from preferential fascicular involvement. Thus, a pitfall in NEE interpretation can occur from assuming a study is normal when too few muscles have been sampled. This issue has been most studied in the EDX of

AMER AL-SHEKHLEE AND DAVID C. PRESTON

radiculopathy, one of the most common referral diagnoses to any EMG laboratory (Dillingham et al., 2000, 2001). For those radiculopathies that can be confirmed by NEE, a minimum screening examination of at least five muscles representing different myotomes is required. The yield improves slightly when screening additional muscles, but does not increase further when the number of sampled muscles is greater than eight. 15.3.2.5. Waveform interpretation A discussion of waveform recognition on NEE is beyond the scope of this chapter. However, there are several common situations in waveform recognition that can result in significant interpretation errors if not recognized at the time of the study by the electromyographer. 15.3.2.5.1. Differentiating end-plate spikes from fibrillation potentials. The end-plate zone is found near the center of the muscle belly and commonly encountered during NEE. Normal spontaneous activity arises in or near the end-plate. Among these potentials are end-plate spikes, thought to be generated by the needle electrode irritating and depolarizing a terminal nerve twig, then resulting in a subsequent muscle fiber action potential. End-plate spikes are a normal finding, but can be confused with fibrillation potentials. Both end-plate spikes and fibrillation potentials are muscle fiber action potentials. Hence, they both have a brief spike morphology. However, they differ in their firing pattern and initial deflection of the waveform. Fibrillation potentials fire at a regular rate and have an initial negative deflection. In contrast, end-plate spikes are irregular and sputtering in their firing pattern with an initial positive deflection. If not recognized by the examiner, a type I error in interpretation may occur. 15.3.2.5.2. Differentiating myotonic discharges from denervating potentials. Myotonic discharges occur as the result of spontaneous depolarizations of muscle fibers, similar to spontaneous potentials seen in active denervation (i.e., fibrillation potentials and positive sharp waves). Thus, essentially both have the same basic waveform morphology. They are differentiated, however, by their stability and firing pattern. Myotonic discharges wax and wane in amplitude and frequency, whereas fibrillation potentials and positive sharp waves are stable and firing in a regular manner. The pitfall in interpretation occurs as denervation potentials are common and myotonic discharges are

OTHER PITFALLS AND SOURCES OF ERRORS

uncommon in clinical practice. Thus, the rare patient with myotonic discharges can be misdiagnosed as having active denervation. Myotonic discharges are important to recognize as they are seen only in a certain set of disorders, and thus, their presence narrows the differential diagnosis. However, equally or more importantly, it is essential not to interpret myotonic discharges as denervating potentials. More than one patient with myotonia congenita has been erroneously given the diagnosis of motor neuron disease on the basis of an electromyographer misinterpreting myotonic discharges as denervating potentials. 15.3.2.5.3. “EMG disease.” Several reports have documented a syndrome of benign increased insertional activity, also known as “EMG disease” or “snap, crackle or pop” phenomena (Wilbourn, 1982; Wright et al., 1988). The etiology is unknown but felt to be related to a mechanical excitation of either the muscle membrane, muscle spindle or tendon organ. Some have speculated that this condition may represent a forme fruste of myotonia congenita. On NEE, trains of potentials are seen that vary in length, amplitude and interpotential interval. The potentials may be mono-, bi-, tri-, or multiphasic in appearance, but most often have the positive wave morphology. Because of this variability in morphology, a distinctive sound is generated which has been termed “snap, crackle or pop” (SCP) (Wilbourn, 1982). This condition is usually encountered in young, muscular men, often with a predilection for the gastrocnemius muscle. These potentials have no clear clinical significance. Patients are usually asymptomatic and muscle biopsies have revealed no pathological findings (Wiechers and Johnson, 1979). During routine NEE, it is not uncommon to find increased insertional activity limited to the medial gastrocnemius muscle; whether this represents a form of “EMG disease” is unknown. It is important that electromyographers are aware of this syndrome. Hence, increased insertional activity in the absence of other findings should always be interpreted with caution. 15.3.2.5.4. End-stage muscle. In the late phase of any chronic neuromuscular disorder, muscles can be so damaged that it is referred to as end-stage. When this occurs, muscle is mostly replaced by fibrous and adipose tissue with only a few muscles remaining. On muscle biopsy, the features of end-stage muscle from a neuropathic condition often cannot be differentiated from end-stage muscle from a myopathic disorder.

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The same is true for the NEE where end-stage muscle frequently displays decreased insertional activity, markedly decreased recruitment of MUAPs and variable, though often small, MUAP morphologies. Clinically, end-stage muscle is most often seen in the dystrophies, spinal muscular atrophies, old polio, late motor neuron disease, and in the quadriceps of inclusion body myositis. Although abnormal, care needs to be taken when interpreting end-stage muscle on NEE when trying to reach a conclusion if the condition is neuropathic or myopathic. Similar to selecting an appropriate muscle for biopsy, the ideal muscle to select is one that is involved but not end-stage. 15.3.2.5.5. Differentiating activation from recruitment. During voluntary contraction during the NEE, one of the most important parameters to interpret is the number of MUAPs present for a given firing rate. Decreased numbers of MUAPs, referred to as decreased recruitment, are primarily seen in neuropathic disorders. Activation is the ability to increase the firing rate. Activation is a central process with poor activation seen in diseases of the central nervous system (CNS) or as a manifestation of pain, poor cooperation or functional disorders. Normally, when asked to contract fully, many different MUAPs fire and overlap on the screen, creating an interference pattern. A reduced interference pattern can result from either decreased recruitment or decreased activation. The pitfall in interpretation occurs when decreased activation is misdiagnosed as decreased recruitment (i.e., a central process is mislabeled as a peripheral disorder). Too much attention is often paid to whether the interference pattern is full or not, when the key question to answer is: are the number of different MUAPs appropriate for the firing rate? The ratio of firing rate to MUAPs is approximately 5:1 with the maximal firing rate for most muscles in the range of 30–50 Hz. An incomplete interference pattern from reduced activation is recognized by a reduced firing frequency. In these cases, the recruitment (i.e., the number of MUAPs) is actually appropriate for the level of activation. 15.4. Conclusions The EDX of peripheral nerve diseases is technically demanding with numerous physiologic and non-physiologic variables that can influence the test results. Although it is not possible to control all variables, knowledge of the commonly encountered ones

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discussed above is essential in order to many avoid pitfalls which can occur during daily practice. Consistency of how the testing is performed and interpreted are key in reducing variability and avoiding pitfalls in electrodiagnosis. References Barry, DT (1991) AAEM minimonograph #36: basic concepts of electricity and electronics in clinical electromyography. Muscle Nerve, 14: 937–946. Behse, F and Buchthal, F (1971) Normal sensory conduction in the nerves of the leg in man. J. Neurol. Neurosurg. Psychiatry, 34: 404–414. Bolton, CF, Sawa, GM and Carter, K (1981) The effects of temperature on human compound action potentials. J. Neurol. Neurosurg. Psych., 44: 407–413. Brashear, A and Kincaid, JC (1996) The influence of the reference electrode on CMAP configuration: leg nerve observations and an alternative reference site. Muscle Nerve, 9: 63–67. Buchthal, F, Pinelli, P and Rosenfalk, P (1954) Action potential parameters in normal human muscle and their physiological determinants. Acta Physiol. Scand., 32: 219–229. Buchthal, F and Rosenfalck, P (1955) Action Potential parameters in different human muscles. Acta Psych. et. Neurol. Scand., 30: 121–131. Buchthal, F and Rosenfalck, A (1966) Evoked potentials and conduction velocity in human sensory nerves. Brain Res., 3: 1–122. Campbell, WW, Pridgeon, RM, Riaz, G, Astruc, J and Sahni, KS (1991) Variations in anatomy of the ulnar nerve at the cubital tunnel: pitfalls in the diagnosis of ulnar neuropathy at the elbow. Muscle Nerve, 14: 733–738. Campbell, WW Jr, Ward, LC and Swift, TR (1981) Nerve conduction velocity varies inversely with height. Muscle Nerve, 4: 520–523. Chaudhry, V, Cornblath, DR, Mellits, ED, Avila, O, Freimer, ML, Glass, JD, Reim, J, Ronnett, GV, Quaskey, SA and Kuncl, RW (1991) Inter- and intra-examiner reliability of nerve conduction measurements in normal subjects. Ann. Neurol., 30: 841–843. Clancy, EA, Morin, EL and Merletti, R (2002) Sampling, noise-reduction and amplitude estimation issues in surface electromyography. J. Electromyogr. Kinesiol., 12: 1–16. De Jesus, PV, Hausmanowa-Petrusewicz, I and Barchi, RL (1973) The effect of cold on nerve con-

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duction of human slow and fast nerve fibers. Neurology, 23: 1182–1189. Dillingham, TR, Lauder, TD, Andary, M, Kumar, S, Pezzin, LE, Stephens, RT and Shannon, S (2000) Identifying lumbosacral radiculopathies: an optimal electromyographic screen. Am. J. Phys. Med. Rehabil., 79: 496–503. Dillingham, TR, Lauder, TD, Andary, M, Kumar, S, Pezzin, LE, Stephens, RT and Shannon, S (2001) Identification of cervical radiculopathies: optimizing the electromyographic screen. Am. J. Phys. Med. Rehabil., 80: 84–91. Dlouha, H, Donselaar, Y, Teisinger, J and Vyskocil, F (1980). Effect of temperature and ouabain on the Na+–K+ activated membrane ATPase and electrogenic ionic pump of the golden hamster and mouse diaphragm. Physiol. Bohemoslov., 29: 543–552. Dreyer, SJ, Dumitru, D and King, JC (1993) Anodal block V anodal stimulation. Fact or fiction. Am. J. Phys. Med. Rehabil., 72: 10–18. Falco, FJ, Hennessey, WJ, Goldberg, G and Braddom, RL (1994) Standardized nerve conduction studies in the lower limb of the healthy elderly. Am. J. Phys. Med. Rehabil., 73: 168–174. Franssen, H and Wieneke, GH (1994) Nerve conduction and temperature: necessary warming time. Muscle Nerve, 17: 336–344. Gassel, MM (1964) Source of error in motor nerve conduction studies. Neurology, 14: 825–835. Gitter, AJ and Stolov, WC (1995) AAEM minimonograph #16: instrumentation and measurement in electrodiagnostic medicine–Part I. Muscle Nerve, 18: 799–811. Halar, EM, DeLisa, JA and Brozovich, FV (1980) Nerve conduction velocity: relationship of skin, subcutaneous and intramuscular temperatures. Arch. Phys. Med. Rehabil., 61: 199–203. Halar, EM, DeLisa, JA and Soine, TL (1983) Nerve conduction studies in upper extremities: skin temperature corrections. Arch. Phys. Med. Rehabil., 64: 412–416. Hodgkin AL and Katz, B (1949) The effect of temperature on the electrical activity of the giant axon of the squid. J. Physiol., 109: 240–249. Jacobs, JM and Love, S (1985) Qualitative and quantitative morphology of human sural nerve at different ages. Brain, 108: 897–924. Kimura, J (1984) Principles and pitfalls of nerve conduction studies. Ann. Neurol., 16: 415–429. Kornfield, MJ, Cerra, J and Simons, DG (1985) Stimulus artifact reduction in nerve conduction. Arch. Phys. Med. Rehabil., 66: 232–235.

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Maynard, FM and Stolov, WC (1972) Experimental error in determination of nerve conduction velocity. Arch. Phys. Med. Rehabil., 53: 362–372. Mayer, RF (1963) Nerve conduction studies in man. Neurology, 13: 1021–1030. Oh, SJ (1993) Clinical electromyography: Nerve Conduction Studies, Lippincott Williams & Wilkins Publishers, Philadelphia, IIIrd ed., 816 p. Perreault, EJ, Hunter, IW and Kearney, RE (1993). Quantitative analysis of four EMG amplifiers. J. Biomed. Eng., 15: 413–419. Preston, DC and Shapiro, BE (1998) Electromyography and Neuromuscular Disorders. ButterworthHeinemann, Boston, 581 p. Preston, DC and Shapiro, BE (2002) Needle electromyography. Fundamentals, normal and abnormal patterns. Neurol. Clin., 20: 361–396. Rack, PM and Fox, JE (1987) The effects of cold on a partially denervated muscle. J. Neurol. Neurosurg. Psychiatry, 50: 460–464. Ricker, K, Rudel, R, Lehmann-Horn, F and Kuther G (1986) Muscle stiffness and electrical activity in paramyotonia congenita. Muscle Nerve, 9: 299–305. Rivner, MH, Swift, TR, Crout, BO and Rhodes, KP (1990) Toward more rational nerve conduction interpretations: the effect of height. Muscle Nerve, 13: 232–239. Rivner, MH, Swift, TR and Malik, K (2001) Influence of age and height on nerve conduction. Muscle Nerve, 24: 1134–1141. Rutkove, SB (2001) Effects of temperature on neuromuscular electrophysiology. Muscle Nerve, 24: 867–882.

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Rutkove, SB, Kothari, MJ and Shefner, JM (1997) Nerve, muscle, and neuromuscular junction electrophysiology at high temperature. Muscle Nerve, 20: 431–436. Takano, K, Kirchner, F, Steinicke, F, Langer, A, Yasui, H and Naito, J (1991) Relation between height and the maximum conduction velocity of the ulnar motor nerve in human subjects. Jpn. J. Physiol., 41: 385–396. Taylor, PK (1984) Non-linear effects of age on nerve conduction in adults. J. Neurol. Sci., 66: 223–234. Thomas, JE and Lambert, EH (1960) Ulnar nerve conduction and H-reflex in infants and children. J. Appl. Physiol., 15: 1–9. Tomlinson, BE and Irving, D (1977) The numbers of limb motor neurons in the human lumbosacral cord throughout life. J. Neurol. Sci., 34: 213–219. Wee, AS, Leis, AA, Kuhn, AR and Gilbert, RW (2000) Anodal block: can this occur during routine nerve conduction studies? Electromyogr. Clin. Neurophysiol., 40: 387–391. Wiechers, DO and Johnson, EW (1979) Diffuse abnormal electromyographic insertional activity: a preliminary report. Arch. Phys. Med. Rehabil., 60: 419–422. Wilbourn, AJ (1982) An unreported, distinctive type of increased insertional activity. Muscle Nerve, 5: S101–S105. Wright, KC, Ramsey-Goldman, R, Nielsen, VK and Nicholas, JJ (1988) Syndrome of diffuse abnormal insertional activity: case report and family study. Arch. Phys. Med. Rehabil., 7: 534–536.

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CHAPTER 16

Collision testing Howard W. Sander* Weill Medical College of Cornell University and Peripheral Neuropathy Center, NY, USA

16.1. Introduction The collision technique involves the interaction of two action potentials propagated toward each other from opposite directions on the same nerve fiber. The refractory periods of the two potentials prevent propagation past each other (AAEM, 2001). The physiology underlying the refractory period relates to a temporary inability of sodium channels to re-open following passage of an impulse. The absolute refractory period ranges from 0.5 to 1 ms and the relative refractory period lasts for 3–5 ms (Kimura, 2001). In routine clinical practice, collision testing is used most commonly during motor nerve conduction studies to allow for distinction between separate components of an evoked response that are conveyed via two different nerve pathways. Stimulations may be delivered simultaneously or separated by a time delay, termed interstimulus interval (ISI). In motor nerve conduction studies assessing for anatomic variants, the first stimulus is often applied to a distal nerve segment from which the clinician wishes to suppress (abolish) an evoked response. The second stimulus is applied to a more proximal nerve segment from which an evoked response is being assessed. Assuming appropriate timing, the nerve will be in the refractory period, when the volley from the second stimulation arrives, preventing further propagation and preventing the recording of a response derived from this nerve fiber. The recorded response, therefore, will reflect only those components that are conveyed via an alternate route. The most common application of this technique, as described by Kimura (1976a), Kimura et al. (1976b), has been to aid in electrodiagnosis of patients with

*Correspondence to: Howard W. Sander, M.D. Associate Director, Peripheral Neuropathy Center, 635 Madison Ave, Suite 400, New York, NY 10022, USA. E-mail address: [email protected] Tel.: +1-212-888-8516; fax: +1-212-888-9206.

suspected Martin Gruber Anastomosis (MGA). The methodology for this indication will be described in detail in this chapter. Additionally, there are several other applications used in clinical practice, and the technique has also been useful in some research studies. 16.2. Animal studies A special type of stimulation technique has been developed and applied to animals in which the stimulator is constructed to cause a collision at the stimulation site. This allows unidirectional motor nerve stimulation (van den Honert and Mortimer, 1981a). The repetitive use of this stimulation technique has been suggested as a potential therapeutic technique to relieve conditions of excessive motor nerve discharge, such as spasticity or intractable hiccups (van den Honert and Mortimer, 1981b). Identification of the fiber type in individual rat afferent root fibers has been determined using collision. A mechanical stimulation is given to the skin prior to a nerve trunk electrical stimulus, and a single nerve fiber recording is made at the root level. The nerve fiber conduction velocity can be determined based on the interstimulus interval at which a response can be recorded. This allows a distinction between A-delta or C-fibers (Handwerker et al., 1991). The activity of the cervical sympathetic nerves in response to various experimental conditions affecting the autonomic nervous system can be measured using collision (Hellstrom et al., 1999). The anatomy of cutaneous arborization of A deltafiber nociceptors has been studied in monkeys. Collision studies locate the position of the branch point where the daughter fibers in a cutaneous field join the parent axon. Peng et al. (1999) have shown that branching occurs quite proximal to the site of termination with a mean distance of 5.4 ± 1 cm.

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In rats with an L5 lesion, epidurally recorded evoked potentials following sciatic nerve stimulation yielded a more robustly abnormal response when a colliding stimulus was administered to the L6 root. This could have potential for clinical intraoperative monitoring in humans (Taniguchi et al., 2002). 16.3. Equipment set-up Collision studies are most commonly performed for the evaluation of motor nerve conduction studies. In this case the filter settings should be adjusted to typical settings already in use in the laboratory. Typical cutoff frequencies would be 10–10 000 Hz. The sweep speed should be adjusted to allow sufficient time to record the last volley. This is often a slightly longer sweep speed than typically used for motor nerve conduction studies, e.g., 5 or 10 ms per division. In modern computerized equipment, the sweep trigger may be adjusted to either the first or the second stimulation. In some cases, it may be helpful to have the machine trigger on the second stimulus, but have the display begin a preset number of ms before the second stimulation appears. This technique will facilitate using the machine’s capabilities to calculate latencies and conduction velocities in cases where the second stimulus is the experimental stimulus. The amplifier gain should be adjusted commensurate with the size of the evoked potential. This may range from 200 μV to 10 mV. 16.4. Recording and stimulating electrodes Collision studies almost always require two independent stimulators, with separate adjustments for current and stimulus duration. The first stimulation delivered is often referred to as S1. The second stimulation delivered is often referred to as S2. Recording and stimulating locations are determined by the study being performed. Avoidance of stimulus spread with unintentional activation of nearby nerves is particularly important in collision studies, as this may lead to an erroneous conclusion. Care should therefore be taken to attempt to avoid overstimulation. While setting up a collision study, it is often helpful to have a two channel recording that includes the territory of an adjacent nerve that could potentially be affected by stimulus spread. This will aid in optimization of the stimulus intensity and electrode location. The electromyographer should ensure that there is no significant stimulus spread by adjust-

HOWARD W. SANDER

ing electrode positioning and avoidance of excessive stimulus intensity. For example, with stimulation at the wrist, electrode placement should be slightly lateral to the nerve for median nerve stimulation, and slightly medial to the nerve for ulnar nerve stimulation (Sander et al., 1998a). If necessary, needle stimulation can be employed. Once the location has been determined, the stimulating electrode is often taped into a fixed position. Another technical issue relates to the orientation of the colliding stimulus electrode. This issue is likely to be of little clinical relevance (Young and Triggs, 1998). However, it seems prudent to orient the stimulator with the negative electrode (cathode) proximal to the positive electrode (anode) to avoid the theoretical problem of anodal block, which could minimize the proximal propagation of the volley (Sander, 1996). 16.5. Timing of stimuli The interstimulus interval between the two stimulations should be adjusted appropriately to the study being performed. Examples of typical interstimulus intervals for various applications are found in Section 16.6. In typical upper extremity studies, the distal stimulation will be delivered first to allow for the orthodromically conducted CMAP from this stimulus to have finished, prior to the onset of the CMAP elicited by the second, more proximal stimulus. The ISI should be long enough to ensure that the response to the second stimulus is not superimposed on the orthodromically conducted response to the first stimulus. However, the ISI should be short enough to be certain that the nerve is still in the refractory period when the second stimulus arrives. The upper limit of the ISI is, therefore, the conduction time between two stimulus sites. The adjustment of the ISI is probably best accomplished by choosing a relatively short interstimulus interval for initial attempts, and then increasing by the interstimulus interval by small variations (e.g., 0.5 ms). Typical interstimulus intervals for collision studies range from 0 to 7 ms. 16.6. Detailed discussion of each of the methods 16.6.1. Conduction velocity Routine nerve conduction studies typically only measure the maximum nerve conduction velocity,

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which reflects conduction only of the fastest fibers. Collision studies can be used to measure the speed of the intermediate conducting and slowest fibers within a nerve. A simple collision technique to assess conduction velocity combines supramaximal proximal stimulus with a simultaneous submaximal distal stimulus, to preferentially excite large diameter, fast conducting fibers. This allows for collision to occur only in the fast fibers, and only a response conveyed via the slow fibers will be recorded. Unfortunately, technical factors preclude this method from being accurate as the

Control

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location of individual fascicles in relation to the stimulating electrode is another important factor in determining the order of activation of nerve fibers (Kadrie et al., 1976; Preston et al., 1994; Kimura, 2001). In 1962, Hopf described a technique that involves a series of paired supramaximal stimuli that are delivered with increasing ISIs (see Fig. 16.1). Stimuli with a short ISI cause collision of all the fibers. As the ISI increases, some faster fibers will escape collision. The minimal ISI at which the full M wave is restored allows for an indirect calculation of

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Fig. 16.1 Schematic representation of collision techniques used for conduction velocity determination. The Harayama technique incorporates the top three techniques. The modified Kimura technique was originally used to assess the nerve refractory period. The time relationships between the stimuli and evoked responses are shown on the right. In the control, a single stimulus is delivered to the nerve at a proximal site. In the modified Kimura technique, the interval between the first stimulus (S1) and the second stimulus (S2) is fixed in order to ensure that the orthodromic impulse elicited by S1 collides with the antidromic one from S2 near the S2 site. The interval between S2 and the third stimulus (S3) is varied in the same way as the S1–S2 interval in Hopf’s technique. In Hopf’s technique, the S1 is delivered at a distal site and the S2 is delivered at a proximal site with an interstimulus interval (ISI). In Ingram’s technique, the S1–S2 interval is varied as in Hopf’s technique, and the S2–S3 interval is fixed to ensure a collision between the antidromic impulses elicited by S2 and the orthodromic one from S3 (Reproduced from Harayama et al. (1991), with permission from International Federation of Clinical Neurophysiology).

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the slowest fibers (Hopf, 1962). Hakamada et al. (1982) used the Hopf technique to establish detailed normative values for the slowest and fastest nerve conduction velocities in infants and childhood. Rossi et al. (1981) used Hopf’s technique in mild peripheral neuropathies, and found that it provided only limited additional information beyond routine studies. Rossi et al. (1983) used the Hopf technique in myotonic dystrophy and noted an inconsistent reduction in the maximal and minimal motor nerve conduction velocities. Leifer (1981) evaluated motor nerve conduction velocity distributions using the Hopf technique combined with computerized waveform analysis and a correction factor for the refractory period. The validity of the assumptions for the correction factor has been questioned (Nix et al., 1989). Nix, along with Hopf as a coauthor, described a computerized improvement of the original Hopf technique with measurement of area rather than amplitude (Nix et al., 1989). Ingram et al. (1987a) has pointed out the numerous limitations of the Hopf technique. It does not correct for the longer refractory periods in nerves with slow conduction velocities. Additionally, there are errors introduced by the subnormal period, and the velocity recovery effect. The subnormal period occurs during the relative refractory period of a nerve during which time the conduction velocity of the nerve fiber is slowed (Faisst and Meyer, 1981). Therefore, there is transient slowing of the proximal orthodromic impulse during the subnormal period, causing nonuniform conduction along the nerve fiber and introducing error into the study. The velocity recovery effect is a distortion of the muscle response when two stimulations are delivered to a muscle in quick succession (Stalberg, 1966). In order to obtain a more accurate estimation of the slowest conducting fibers, several other methods have been used. These usually add a third stimulation site, vary the interstimulus interval, or may use computer assistance in data interpretation. Kimura (1983) described a technique that allows for a direct calculation of the slowest fiber velocities, by colliding the fastest fibers (Fig. 16.2). This paradigm uses supramaximal stimulations. A proximal stimulation, e.g. axilla S(A1), is followed with a varying ISI by a distal stimulation, e.g. wrist S(W). A third proximal stimulation S(A2) is then delivered at an ISI fixed to the wrist stimulation. The interval between S(A1) and S(W) varies between approximately 6 and 8 ms, which is sufficiently long to cause collision from the S(W) only in the slow fibers, allowing the S(W)

HOWARD W. SANDER

elicited impulses in the fast fibers to continue propagating proximally. S(A2) is then delivered at 6 ms following S(W). The impulses from S(A2) then collide only with the S(W) elicited impulses in the fast fibers, allowing the slower fibers to continue to propagate. With increasing ISIs, the M-response amplitude declines and latency increases, as only the slowest of fibers contribute to the response. The conduction velocity of the slowest fibers can then be calculated from the M-response elicited with the highest ISI before the response became absent. The latency changes do not correspond exactly to the difference in ISIs. This is presumably because the length of the unmyelinated terminal motor branches in which conduction is very slow varies between nerve fibers. Ingram (1987a) described a modification the Kimura (1983) technique to determine conduction velocity. Both these techniques minimize errors in measurement by assessing the slowest fiber velocity when the response amplitude becomes absent, which is technically easier than determining when the amplitude reaches a maximum. Arasaki et al. (1991) however, have indicated that consequently there is difficulty with determination of the maximum conduction velocity. Despite this concern, maximum velocity may be easily measured with traditional methods, without the need for collision studies. Ingram’s technique has the advantages of minimizing error due to the velocity recovery effect and the subnormal period. Gilliatt et al. (1976) described a collision technique in animal studies that was then adapted in animals by Nakanishi et al. (1986), and later in humans by Nakanishi et al. (1989). This stimulation technique involves a submaximal distal stimulation and two different proximal stimulation sites. The technique also uses a computerized subtraction for analysis. Using this technique, normal maximal and minimal conduction values have been described (Arasaki et al., 1991), the findings in ALS have been described (Nakanishi et al., 1989), and the normal values in F and S type motor units have been described (Arasaki, 1992). Harayama et al. (1991) described a method of measuring conduction velocity distributions using a combination of techniques (Fig. 16.1). In essence, the Hopf technique (1962) is used primarily. Then a correction for the distortion in CMAP size caused by the velocity recovery effect (Stalberg, 1966) is applied using a modification of Kimura’s refractory period collision technique (1976c). In addition, another correction, based on an equation, is applied to correct for the refractory period of the nerve at the point of stimulation. Hirata

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2.5 mV 5 ms

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Fig. 16.2 Collision study to determine nerve conduction velocity range. (A) Compound muscle action potentials recorded by surface electrode placed over the abductor digiti minimi after stimulation of the ulnar nerve. The diagrams on the left show orthodromic (solid line) and antidromic (dotted line) impulses generated by three stimuli. S(A1), S(W), and S(A2) delivered at the axilla, wrist and axilla, respectively. Note the collision between the orthodromic impulse from S(A1) and antidromic impulse of S(W) in slow conducting fibers (S), and between the orthodromic impulse of S(A2) and antidromic impulse of S(W) in the fast-conducting fibers (F). The orthodromic impulse of S(A2) propagates along the slow-conducting fibers and elicits the second compound muscle action potential. (B) Paired supra-maximal axillary stimuli combined with a single stimulus at the wrist (cf. bottom trace in A). The first axillary stimulation, S(A1) preceded the wrist stimulation, S(W) by intervals ranging from 6 to 8 ms. in increments of 0.2 ms. Adjusting the second axillary shock, S(A2), to recur always 6 ms after S(W) automatically determined interstimulus interval between S(A1) and S(A2). The figures on the left illustrate latency determination with a fast sweep triggered by S(A2) and displayed after a predetermined delay of 6 ms (from Ingram et al. (1987a) and Kimura, 2001, with permission from Elsevier and Oxford University Press, Inc, respectively).

et al. (2000) have applied the Harayama collision technique in ALS and X-linked bulbospinal muscular atrophy patients. In both conditions, abnormal conduction slowing was demonstrated. Caccia et al. (1992a) evaluated motor nerve conduction velocity distributions in diabetes using Hopf’s method. All diabetic subjects had peroneal motor conduction velocity slowing, but only those requiring insulin also had ulnar motor nerve conduction velocity slowing. A larger follow up study of diabetics without clinical neuropathy by the same authors found altered conduction velocity distributions in 82% of motor nerves and 58% of the sensory nerves (Bertora et al., 1998). The conduction velocity range in sensory nerves has also been evaluated using collision. Using a method similar to the Hopf method, stimulations are performed at the first and third phalanges, with recording at the wrist. In diabetics without clinical neuropathy, there is a loss of the slower (Caccia et al., 1992b)

or intermediate (Caccia et al., 1993) conducting velocities. This is hypothesized to represent an early change of subclinical diabetic neuropathy. Okajimaa et al. (1998) used the Harayama collision technique to evaluate the relationship between conduction velocities between individual nerve fibers and the muscle fibers innervated by that nerve within a motor unit. Muscle fiber conduction velocity was determined using surface electrode array over the muscle. The findings have indicated only a weak correlation between the nerve conduction velocity and the muscle fiber conduction velocity of human motor units, indicating the Henneman size principal (Henneman et al. 1965) is only weakly applicable to muscle fiber conduction velocity. Rutten et al. (1998) examined experimentally cooled human nerves using a combination of two collision techniques described by Ingram et al. (1987a,b). The combination of these techniques was

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successful in demonstrating temporal dispersion with an expected increase in the range of motor conduction velocities caused by lowered temperature. The authors suggest that this paradigm can be used as an in vivo experimental model for demyelination. Facial nerve conduction velocity distributions have also been studied using Hopf’s collision method in Bell’s palsy (Saito, 1991). 16.6.2. Conduction block Collision studies can be used during patient care to demonstrate conduction block within the brachial plexus (Watson et al., 2001). Roth and Magistris

(1989) used the collision technique to identify the presence of motor conduction block despite the presence of associated desynchronization. This technique was used for ulnar neuropathy at the elbow and peroneal neuropathy at the fibular head (Fig. 16.3). In this paradigm, a stimulation is first given proximal to the site of possible conduction block. A second stimulation is then given distally at the wrist or ankle. A third stimulation is then delivered just distal to the site of possible conduction block. The response that is elicited from the third stimulation reflects the fibers that did not have conduction block, and thus eliminates desynchronization as a confounding factor.

A Sae Sbe

Sw

B

Sbe

Sbe

Sw

Fig. 16.3 Collision study to demonstrate conduction block CB at the elbow (=). (A) Three stimuli (black circles) are successively applied above the elbow (Sae), at the wrist (Sw), and below the elbow (Sbe). A first collision occurs at the wrist and a second below the elbow. The axons that are not blocked are assumed to be have impaired conduction velocities (desynchronization) at the level of the conduction block. Full arrows represent impulses that evoke a response. Note that the double collision suppresses desynchronization by virtually displacing the CB. (B) Control curve. The first stimulus is applied below the elbow (Sbe) and the CB has no effect of the response evoked by the third stimulus. The last curve shows superimposition of both responses to Sae-Sw-Sbe and Sbe-Sw-Sbe (from Roth and Magistris, 1989, with permission from Nauwelaerts Publishing House).

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16.6.3. Refractory period Analysis of the refractory period of motor nerves can be ascertained with the use of a collision technique. Hopf and Lowitzsch (1975) used a technique with maximal paired distal stimuli and a single proximal stimulus. Betts et al. (1976) evaluated motor nerve refractory periods using paired supramaximal stimulation at a distal site with a proximal recording. Computer subtraction was used to separate the two responses. This technique was limited by failure to take into account the subnormal period. To circumvent errors related to neuromuscular and muscle fiber transmission time, Kimura (1976c, 2001);

Kimura et al. (1978) described the use of a paradigm with maximal paired proximal stimulations (axilla) and a single distal stimulation (wrist) (Fig. 16.4). A wrist stimulation is combined with two axilla stimulations. The range of the absolute refractory periods is determined by varying the time interval between the wrist and first axillary stimulation, which varies the location along the nerve at which the collision occurs. The intervals at which the second axillary stimulation-elicited response becomes recordable and when it is completely restored, is used to measure the minimum and maximum refractory periods. The duration of the relative refractory period of the most excitable fibers can be determined by varying

Collision technique Site of stimulation Axilla S(A)

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Collision Wrist and axilla S(A)

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S(W)

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5 mV 5 ms

Fig. 16.4 Kimura’s collision method for determination of nerve refractory period. Compound muscle action potential recorded over the abductor digiti minimi after ulnar nerve stimulation. The diagrams on the left show collision between orthodromic (solid arrows) and antidromic (dotted arrows) impulses. Axillary stimulation, S(A), given 6 ms after the wrist stimulus S(W), triggered sweeps. With single stimulation at the axilla and at the wrist (middle trace), the orthodromic impulse elicited by S(A) collided with antidromic impulse of S(W) form the wrist. With paired shocks at the axilla (bottom trace), M(A2) appeared because the first axillary stimulus, S(A1), cleared the path for the second stimulus S(A2) (from Kimura et al. (1978) with permission from the BMJ Publishing Group and Kimura, 2001, with permission from Oxford University Press, Inc.).

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the interval between the axilla stimulations, which increases the time between the occurrence of the collision and the application of the second axillary stimulus. The latencies at which the second axillary-stimulation elicited response first becomes recordable and when it is fully restored in amplitude, is used to calculate the range of the absolute refractory periods of the most excitable fiber (least refractory fiber). Additionally, the recovery pattern of the amplitude and latency, with increasing interstimulus intervals allows assessment of differences in refractory period recovery along the length of the nerve. Using this technique, Kimura et al. (1978); Kimura (2001), were able to quantify some of the refractory properties of human motor nerve fibers (Fig. 16.5).

Normal control

Vernea (1979) evaluated the refractory period and conduction velocity range in normal patients and diabetic patients using the conduction velocity method of Hopf, but with a correction for the refractory period using the technique described by (Kimura, 1976c). Ingram et al. (1987b) described a double collision method to measure the refractory period. This technique uses two distal and two proximal stimuli (Fig. 16.6). The first proximal and first distal stimulations are delivered simultaneously, with the second proximal delivered at a fixed time later. The second distal stimulation is then delivered with varying interstimulus intervals. This allows for recovery the of conduction velocities without varying the interval between the proximal stimuli. The analysis requires a computer-

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Fig. 16.5 Collision studies to evaluate refractory period in a normal and a Guillain–Barre syndrome patient. (A) Paired axillary shocks, S(A1) and S(A2), of just maximal intensity combined with a single wrist stimulus, S(W). Interstimulus intervals between S(A1) and S(A2) ranged from 0.6 to 3.0 ms. S(A2) first appeared (small arrows) at an interstimulus interval of 0.8 ms and recovered completely by 3 ms. The patient with the Guillain–Barre syndrome showed delayed and incomplete recovery. (B) Paired axillary stimuli, S(A1) and S(A2), of just maximal intensity combined with a single wrist stimulus, S(W) (cf. bottom trace in A). Delivering S(A1) 6 ms after S(W) allowed collision to occur 1.5 ms after S(A1). The interstimulus intervals between S(A1) and S(A2) ranged from 1.2 to 3.0 ms in increments of 0.2 ms. The figures on the left show amplitude measurements with a slow sweep triggered by S(W). The figures on the right illustrate latency determination with a fast sweep triggered by S(A2) and displayed after a predetermined delay of 11 ms (Kimura, 1976c, 2001; Kimura et al., 1978; with permission from Oxford University Press, Inc.).

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Fig. 16.6 Double collision technique for evaluating nerve refractory period. Paired supramaximal stimuli (downward pointing arrowheads), are delivered at proximal and distal sites. The proximal interstimulus interval is fixed a value exceeding the refractory period range, typically 4 ms. The effect of increasing the distal interstimulus interval on the late (test) muscle response is shown (A–C). Increasing interstimulus interval is represented by the increasing spatial separation of the stimuli. Maximal nerve volleys are represented by large arrows, and submaximal volleys by small arrows. The dashed lines delineate the analysis window (Reproduced from Ingram et al. (1987b), with permission from The International Federation of Clinical Neurophysiology).

aided digital subtraction of two of the responses. This technique eliminates error related to the subnormal period (Faisst and Meyer, 1981) in which the amplitude does not recover even though most of the refractory period has passed because of some residual conduction slowing, and also eliminates errors related to the velocity recovery effects, which is a distortion of the muscle response when two stimulations are delivered to a muscle in quick succession (Stalberg, 1966). The double-collision technique demonstrated that the degree of dispersion of the human refractory period is less than previously thought. 16.6.4. F-wave generation Kimura et al. (1984) used collision studies to assess the physiology of F-wave generation. The study concluded that F-waves are generated without preferential involvement of a specific motor neuron pool. This was demonstrated using progressive collision blockade of F-waves from the faster conducting axons, which yielded recordable F-waves in a proportionally decreasing persistence from the slower conducting axons.

16.6.5. Fasciculations The origin of fasciculations in amyotrophic lateral sclerosis has been evaluated using the collision technique. In one paradigm (Wettstein, 1979), a peripheral nerve is stimulated at random intervals at a proximal location (e.g. ulnar nerve at elbow), and needle electromyography is recorded distally (Fig. 16.7). If a fasciculation and an identical motor unit potential are recorded temporally close together, this is proof that the fasciculation originated proximal to stimulation site. If only a fasciculation is recorded, this indicates that the fasciculation originated distal to the stimulation site, and the proximal antidromic volley from the fasciculation collided out the stimulation evoked response. Using this technique, multiple sites of origin of fasciculations were demonstrated, including both proximal and distal to the knee and elbow, with a predominance of distal origin. In another technique, a single motor unit electromyographic recording is connected to a triggering device. (Conradi et al., 1982). When a fasciculation is recorded, the nerve is then stimulated 40 cm proximal to the muscle. If no

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Fig. 16.7 Collision to evaluate origin of fasciculations. (A) Stimulation at elbow. (B) A fasciculation that originates proximal to the elbow (zigzag arrow) can evoke a response in proximity to the electrical stimulation evoked response. (C) A fasciculation originating distal to the elbow (zigzag arrow) will be recorded in isolation, as there will be collision of the electrical stimulation evoked action potential (from Wettstein, 1979 with permission from John Wiley and Sons, Inc.).

response is subsequently recorded following the nerve stimulation, this indicates that the fasciculation had originated distally, and had collided out the propagating potential from the nerve stimulation. If a response is recorded from the stimulation, this indicates that the fasciculation has originated proximal to the site of nerve stimulation. Using this technique, and in combination with the observation that the shape of fasciculations varied, a distal multifocal origin of fasciculations was demonstrated. 16.6.6. Double discharges The physiology of double discharges evoked by nerve stimulation has been studied using the collision technique. The double discharge was shown to have a distal origin, as indicated by the colliding effects of a concomitant physiologically generated antidromic backresponse from the peripheral location (Roth, 1980). 16.6.7. Motor unit estimation The collision technique can be helpful in motor unit estimation studies to determine whether two motor unit action potentials with similar configurations are

generated by the same motor unit. This improves accuracy by counting individual motor units only once (Aoyagi et al., 2000). 16.6.8. Submaximal stimulation of nerve fibers Preston et al. (1994) studied the physiology of nerve fiber activation with submaximal stimulation. Using collision studies with progressively increasing submaximal stimulations at different sites, a non-uniform order of activation of nerve fibers was demonstrated. This suggests that intraneural topography probably plays a significant role in the likelihood of activation of a particular fiber to a submaximal stimulus. This finding has important implications for other collision techniques that employ submaximal stimulation with the presumption that the size of the fiber is the only determinant of activation in response to a particular submaximal stimulus level. 16.6.9. Site of activation following percutaneous high voltage stimulation over the lumbosacral spine The collision technique has been used to determine the site of activation following percutaneous high

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voltage stimulation over the lumbosacral spine (Maertens de Noordhout et al., 1988). Stimulations are applied simultaneously to the tibial and peroneal nerves at the ankle, along with high voltage percutaneous electrical stimulation over the lumbosacral spine. This collision from the ankle stimulations abolishes the direct orthodromically conducted M response from the spinal stimulation and also the distal stimulus elicited F-wave. This allows only the F-wave from the percutaneous lumbosacral stimulation to be propagated, as this traverses the segment proximal to the stimulation site. The difference in latencies between the orthodromic M-wave from percutaneous lumbosacral stimulation (which is measured without a collision study) and the percutaneous lumbosacral stimulation F-wave latency measured with the collision technique, allows the site of stimulation to be determined. The findings indicate that percutaneous lumbosacral high voltage electrical stimulation causes excitation at two sites: near the spinal cord and at the root exit site in the intervertebral foramen. 16.6.10. Site of activation following percutaneous high voltage stimulation over the lumbosacral spine A similar procedure has been used to determine the site of activation following percutaneous stimulation over the cervical spine (Mills and Murray, 1986). Ulnar nerve stimulation at the wrist or Erb’s point stimulation is administered with cervical electric stimulation. The findings indicate that the site of percutaneous electric cervical root stimulation is at the site of exit from the foramina. As C8 level cervical electrical root stimulation delivered with a needle occurred at an identical latency to electrical cervical root stimulation, the authors also concluded that electrical cervical root stimulation causes excitation at the site of exit from the foramina.

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motor volley is not propagated proximal to the motor neuron, a collision occurs within the spinal cord only in the sensory pathways, allowing for discrimination between sensory and motor components. Unfortunately, two studies using this technique have reported differing results. One study found combined modality involvement (Pereon et al., 2002), while another study indicated primarily sensory fiber involvement (Toleikis et al., 2000). This discrepancy suggests that technical factors must be carefully attended to when performing and interpreting these studies. 16.6.12. Magnetic stimulation of peripheral nerve and brain stem The site of activation by magnetic stimulation of peripheral nerve has been studied with collision. With recording from the hypothenar eminence, electrical stimulation at the wrist is followed by stimulation in the upper arm, which is either electrical or magnetic. With incremental increases in interstimulus interval, there are increasing differences between the electrical and magnetic stimulation M-response amplitudes. This suggests that the magnetic stimulation-induced site of stimulation is spatially dispersed across the nerve (Cros et al., 1990). The physiology of magnetic stimulation of the brainstem has been assessed with collision. Simultaneous brainstem and cortical magnetic stimuli cause abolition of the response from cortical stimulation. This indicates that magnetic stimulation at the brainstem activates large diameter fibers of the corticospinal tract. Simultaneous brainstem magnetic stimulation and electrical ulnar stimulation, causes abolition of the brainstem stimulation response, indicating that magnetic brainstem stimulation generates a single descending volley (Ugawa et al., 1994).

16.6.11. Neurogenic mixed evoked potentials

16.6.13. Mechanism of spasticity in spinal cord injury

Neurogenic mixed evoked potentials are used for spinal cord monitoring during surgery. They are recorded from leg nerves following direct spinal cord stimulation during surgery. There has been debate as to the relative contribution of sensory and motor fibers comprising the response. Collision studies have been used to aid in this distinction. In these studies, a mixed nerve in the leg is stimulated first and then the spinal cord is stimulated at a high thoracic level. As the

The mechanism of spasticity in spinal cord injury patients has been studied using collision. Shefner et al. (1992) used collision of H-reflexes with paired tibial nerve stimuli, first with a submaximal stimulus and then with a supra-maximal stimulus (Fig. 16.8). In normals an H′reflex is always present in response to the second supramaximal stimulus. The H’ amplitude reflects activity of recurrent inhibition. In spinal cord injury, the H′reflex is often absent indicating

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5 msec after S1

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Fig. 16.8 Collision to evaluate recurrent inhibition with the conditioned H-reflex. Left panel (A): orthodromic 1a afferent and antidromic responses in one of two motor axons shortly after a submaximal stimulus (S1). As no antidromic impulse is evoked in motor axon Z, an H-reflex can be transmitted. Middle panel (B): H-reflex volley evoked by S1 (H1) collides with antidromic volley produced by supra-maximal stimulation S2. This collision removes the antidromically conducted impulse in motor axon Z, thus allowing the axon to be activation by the afferent volley evoked by S2. Right panel (C): In contrast, collision of antidromic and orthodromic impulses in axon X prevents a reflex response in that axon. The conditioned H-reflex (H′) is therefore only present in motor axons that had participated in the H reflex (H1) evoked by S1 (from Shefner et al., 1992, with permission from Lippincott, Williams and Wilkins).

increased recurrent inhibition probably mediated via renshaw cells. 16.6.14. Assessment of voluntary effort, central muscular drive, and correlation between muscle force and electrical potential Kimura (1977, 2001) used collision studies to measure the amount of voluntarily elicited recruitment (Fig. 16.9). With first dorsal interosseous recording, ulnar-wrist and axilla stimuli are simultaneously delivered. At rest, an compound muscle action potential is elicited only from the wrist stimulation [M(W)]. The axilla stimulation-elicited response [M(A)] is not recorded due to the collision. When this same technique is performed during voluntary muscle contraction, the antidromic impulses from the wrist

first collide with the voluntary impulses. The distal stimulus cannot completely block the axilla stimulation-evoked response. The recorded response, termed M(V), represents the degree of voluntary activation. The greater the number of voluntary volleys, the more the wrist stimulus will be collided prior to arrival of the axilla evoked impulses, creating a higher amplitude M(V). Furthermore, there is a linear relationship between the amplitude of M(V) and the force generated at the time of the stimulation (Fig. 16.10). When combined with needle electromyography, this technique can be employed to gain insights into the relationship between motor unit discharge patterns and degree of force generated. It can also aid in studies of central fatigue, as it can create an assessment of the degree of neuromuscular activation (Gandevia, 1996).

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Collision technique Right ulnar nerve

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Fig. 16.9 Collision studies to assess central muscular drive. Compound muscle action potentials, M(W) and M(A), from the first dorsal interosseous and muscle force (straight line). At rest, the antidromic impulse from wrist stimulation eliminates the orthodromic response from the axilla by collision. With muscle contraction (bottom trace), M(V) appears in proportion to the number of axons in which the voluntary impulse first collides with the antidromic impulse from the wrist (from Kimura, 1977 and Kimura (2001) with permission from Elsevier and Oxford University Press, Inc., respectively).

16.6.15. Anomalies Anatomic variants are discussed in detail in the clinical section of this text. In this section, the application of the collision techniques will be discussed. 16.6.15.1. Martin Gruber Anastomosis Martin Gruber Anastomosis (MGA) is a common anatomic variant in which an accessory branch of the median nerve joins the ulnar nerve in the forearm and

may innervate any of the hand muscles. Collision studies (Fig. 16.11), may be used to assess for each of these possibilities (Kimura, 1976a, Kimura et al., 1976b; Sander et al., 1997). 16.6.15.1.1. MGA type I (hypothenar) and II (first dorsal interosseous). Median nerve innervation of the hypothenar or first dorsal interosseous muscles conveyed via axons joining the ulnar nerve. If a hypothenar eminence or first dorsal interosseous

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Right ulnar nerve

6 kg 4 kg 2 kg 0 kg M(2) M(W)

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M(W)

M(6)

5 kg 3 kg 1 kg

0 kg

M(1) M(W)

M(3) M(W)

M(W)

M(5)

M(W) M(W) 2.5 mV 5 ms

Fig. 16.10 Collision studies to correlate muscle force with electrical activity. Same stimulation (open arrow) and recording as in the bottom trace of Fig. 9. Muscle force range from 0 to 6 kg (straight line). In the last trace, paired stimuli (closed arrow) delivered at the wrist elicited the second M(W) to appear with the same time delay as M(V). The second M(W) equaled the first in amplitude, indicating the integrity of the neuromuscular excitability (from Kimura (1977) and Kimura (2001), with permission from Elsevier and Oxford University Press, Inc., respectively).

CMAP is recorded following median nerve-elbow stimulation, a collision study can abolish this response and confirm the presence of a MGA. With hypothenar eminence or first dorsal interosseous recording, ulnarwrist stimulation is followed by median-elbow stimulation. The MGA-derived CMAP previously evoked by median-elbow stimulation nerve will be collided out, and there will be no response or a small CMAP with an initial positivity reflecting volume conduction from distant median innervated muscles. 16.6.15.1.2. MGA type III. Median nerve innervation of the thenar muscles conveyed via axons joining the ulnar nerve. If a Type III MGA is still suspected, two separate collision studies can be employed for confirmation. First, the component of the thenar response conveyed via the ulnar nerve can be abolished. With thenar eminence recording, ulnar-wrist stimulation is followed by median-elbow stimulation. The MGA derived CMAP component previously evoked by median-elbow stimulation will be collided out, and

there will be a response remaining that is smaller (amplitude or area) than that elicited by median-elbow stimulation alone. This component reflects conduction through the median nerve only. The response remaining will, therefore, look like the response from stimulation of the median nerve at the wrist alone. Second, the component of the thenar response conveyed via the median nerve can be abolished (Fig. 16.12). With thenar eminence recording, median-wrist stimulation is followed by median-elbow stimulation. The component of the median-elbow stimulation CMAP that is conveyed via the median nerve will be collided out, and there will be a response remaining that is smaller in amplitude or area than that elicited by median-elbow stimulation alone. This component reflects conduction through the ulnar nerve only. This response should have an amplitude or area approximately similar to the increase in amplitude or area that was observed with comparison of the median-elbow and median-wrist stimulation elicited responses, with thenar recording.

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1A- Thenar recording MW

ME

UW

2.5 mV UW

5 ms

ME

1B - Hypothenar recording UW

UE

MW

ME 1 mV

UW 5 ms ME

1C - First dorsal interosseous recording UW

UE

MW

ME 2.5 mV UW

5 ms ME

Fig. 16.11 Collision studies in Martin Gruber Anastomosis. Compound muscle action potentials with thenar (A), hypothenar (B), and first dorsal interosseous (C) recording. Stimulation sites: UW: ulnar nerve at the wrist, UE: ulnar nerve slightly below the elbow, MW: median nerve at the wrist, ME: median nerve at the elbow. Large arrows indicate the location in which a component previously present following ME stimulation alone, has been abolished by an UW stimulation shortly preceding a ME stimulation (from Sander et al. (1997), with permission from John Wiley and Sons, Inc.).

16.6.15.1.3. MGA with sensory crossover. Collision studies can be used to assess the anatomy of aberrant sensory innervation. Valls-Sole (1991) collided orthodromic sensory finger stimulation with either median or ulnar stimulation at the wrist, with recording at the cubital fossa or upper arm, in a patient with a Martin–Gruber anastomosis. This study demonstrated the presence of aberrant sensory innervation that did not arise from the Martin–Gruber anastomosis. This study supported the hypothesis that Martin–Gruber anastomosis affects only motor fibers. 16.6.15.2. Ulnar-to-median anastomosis at the forearm This anomaly has only rarely been described (Scelsa, 2000). If this is suspected, the following collision studies may be performed for confirmation: (1) With hypothenar, first dorsal interosseous, or thenar recording, median-wrist stimulation is followed by ulnar-elbow stimulation. This would attempt to abolish the component conveyed through the anastomosis leaving only the component conveyed via the ulnar nerve. (2) With hypothenar, first dorsal interosseous, or thenar recording, ulnar-wrist stimulation is followed by ulnar-elbow stimulation. This would attempt to abolish the component conveyed through the ulnar nerve leaving only the component conveyed via the anastomosis. 16.6.15.3. Accessory deep peroneal nerve Accessory deep peroneal nerve (ADPN) is a common anatomic variant in which an anomalous branch from the superficial peroneal nerve winds posterior to the lateral malleolus and innervates the lateral aspect of the extensor digitorum brevis muscle (EDB). It is suspected that with EDB recording, common peroneal nerve stimulation at the fibular head (FHS) evokes a greater amplitude or area CMAP than deep peroneal nerve (DPN) stimulation at the anterior ankle. Posterolateral ankle stimulation over the ADPN will usually evoke a primarily negative CMAP and verify its presence. If pathology affecting the nerve is present, however, two collision studies may be employed to determine whether the ADPN or the deep peroneal nerve itself is affected (Sander et al., 1998b). First, with EDB recording, ADPN stimulation at the posterolateral ankle is followed by peroneal nerve stimulation at the fibular head. This will abolish the ADPN component, leaving only the component conveyed via the deep peroneal nerve. Second, with EDB recording, deep peroneal nerve stimulation at the anterior ankle is

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Anomalous Site of stimulation

Hypothenar

Ulnar nerve

Wrist (S1) Median nerve

Thenar

S1

S1

Elbow (S2)

S2

S2

Wrist (S1) and elbow (S2) S2

S1

S1 S2

0.5 mV 5 ms

Fig. 16.12 Collision studies in Martin Gruber anastomosis with thenar recording. S1: median nerve wrist stimulation. S2: median nerve elbow stimulation. In the middle trace, a large compound muscle action potential obscures a small response due to a median-ulnar anastomosis. In the bottom trace, collision has separated the anomalous response (from Kimura et al. (1976b) ©1976, American Medical Association. All rights reserved, and Kimura (2001), with permission from Oxford University Press, Inc.).

followed by peroneal nerve stimulation at the fibular head. This will abolish the component conveyed via the deep peroneal nerve, allowing for recording only of the component conveyed via the ADPN (Fig. 16.13).

combining stimulation of the fifth digit with either hypothenar palmar stimulation or ulnar mixed nerve stimulation.

16.6.15.4. Ulnar palmar cutaneous nerve Collision studies have been used to validate the technique of an ulnar palmar cutaneous nerve conduction study involving stimulation of the hypothenar palm (Stowell and Gnatz, 1992). The collision technique was used to show that spread of stimulation is not a significant factor. The studies were performed by

F waves elicited from axilla stimulation normally superimpose upon the orthodromically conducted M-response, and preclude accurate identification. Using a collision study, with simultaneous stimulation at the axilla and wrist, the F-wave can be isolated as the M-response is abolished by collision (Kimura, 1974, 2001).

16.6.16. F-waves from proximal stimulation sites

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AAS

A

B

PLAS

FHS

C AAS

D FHS PLAS

E FHS

1 mV 5 ms

Fig. 16.13 Collision studies in accessory deep peroneal neuropathy. Peroneal motor nerve conduction studies recording over extensor digitorum brevis. (A) Anterior ankle stimulation (AAS) of deep peroneal nerve (DPN). (B) Posterolateral ankle stimulation (PLAS) of accessory deep peroneal nerve (ADPN). (C) Fibular head stimulation (FHS) of common peroneal nerve. (D) AAS followed by FHS. Arrow and bracket indicate the ADPN derived component (which is delayed) remaining after the DPN component has been abolished by collision. (E) PLAS followed by FHS. Arrowhead and bracket indicate the DPN derived component remaining after the ADPN component has been abolished by collision (from Sander et al. (1998b), with permission from John Wiley and Sons, Inc.).

16.6.17. Axilla, Erb’s point, and cervical root stimulation The thenar eminence has innervation conveyed via the median and ulnar nerves. Motor nerve conduction studies with thenar recording, and with stimulation at axilla, Erb’s point, or cervical root level (electrical or magnetic) will excite both the median and ulnar nerves, and lead to a thenar CMAP with combined median and ulnar components. A proximal conduction block or proximal conduction slowing in the fibers forming the median nerve may not be detected due to this dual innervation. A collision study should there-

fore be employed when performing these proximal stimulations to eliminate this error (Kimura, 1976a; Sander et al., 1999). With thenar eminence recording, ulnar-wrist stimulation is followed by the stimulation at the axilla, Erb’s point, or cervical roots (Fig. 16.14). This will abolish the component conveyed via the ulnar nerve and allow for determination of pathology in the fibers that contribute to the median nerve. An ISI of 5–7 ms. is usually satisfactory. Occasionally, during hypothenar recording, following stimulation at the axilla, Erb’s point, or cervical root a volume conducted response with an initial positivity from median innervated muscles may be observed. A collision study may then be helpful (Kimura, 1976a). With hypothenar eminence recording, a median-wrist colliding stimulus is followed by stimulation at axilla, Erb’s point, or cervical roots (Fig. 16.15). This will abolish the component conveyed via the median nerve and allow for determination of pathology in the fibers that contribute to the median nerve. An ISI of 5–7 ms is usually satisfactory. 16.6.18. Hemifacial spasm The physiology of hemifacial spasm has been evaluated using collision studies. In hemifacial spasm, there is a phenomenon termed a delayed response that is evoked as a distant response in muscles either innervated by the branch stimulated, or innervated by a different branch. The delayed response may have double or multiple discharges, which can be eliminated by collision. Roth et al. (1990) showed that double or multiple discharges in hemifacial spasm are generated both at ephapses and at the motor neuron. The collision studies, in particular, showed that a bi-directional response including a “back wave” must have been generated at the ephaptic site. 16.6.19. XII–VII anastomosis surgery The collision technique has been used to study the electrophysiologic findings recorded following XII–VII anastomosis surgery. While performing blink reflex studies R1-like responses are recorded, despite severe facial neuropathy. Collision techniques allowed demonstration that antidromic impulses move from supraorbital to zygomatic locations, identifying the responses as being related to ephapses (Montero et al., 1996).

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Site of stimulation

Wrist (S1)

S1

Ulnar nerve

Hypothenar

Median nerve

S1 Thenar

S2

Elbow (S2)

S2

S3

Axilla (S3)

Axilla (S3) and wrist (S4)

S3

S3

S3 + S4 S4

3 mV 5 ms

Fig. 16.14 Collision study with axillary stimulation and thenar recording in a patient with carpal tunnel syndrome. Median nerve stimulation at the wrist (S1) and elbow (S2) elicits a response with increased latency. Stimulation at the axilla (S3) elicits a response conveyed via the ulnar and median nerves. With ulnar wrist stimulation (S4) preceding the axilla stimulation, the median derived component can be analyzed in isolation (from Kimura (1976a) and Kimura (2001) with permission from Lippincott, William and Wilkins and Oxford University Press, Inc., respectively)

16.7. What is measured As most collision studies involved motor nerve conduction, typically the recorded response is a CMAP. In addition to the typically measured parameters of

latency, amplitude, and area, the shape of the response should also be subjectively interpreted. Visual comparison of waveform morphology is important to ascertain whether there has been stimulus spread, and whether collision has occurred.

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Site of stimulation

377

Hypothenar Ulnar nerve

Wrist (S1) Median nerve

S1 Thenar

S1

Elbow (S2) S2 S2

Axilla (S3) S3

S3 S4

Axilla (S3) and wrist (S4) S3

S3 + S4

5 mV 5 ms

Fig. 16.15. Collision study with axillary stimulation and hypothenar recording in a patient with tardy ulnar palsy. Ulnar nerve stimulation at the wrist (S1) and elbow (S2) elicits a response with increased latency. Stimulation at the axilla (S3) elicits a response conveyed via the ulnar and median nerves. With median wrist stimulation (S4) preceding the axilla stimulation, the ulnar-derived component can be analyzed in isolation (from Kimura (1976a, 2001), with permission from Lippincott, Williams and Wilkins and Oxford University Press, Inc., respectively).

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Handwerker, HO, Kilo, S and Reeh, PW (1991) Unresponsive afferent nerve fibres in the sural nerve of the rat. J. Physiol., 435: 229–42. Harayama, H, Shinozawa, K, Kondo, H and Miyatake, T (1991) A new method to measure the distribution of motor conduction velocity in man. Electroencephalogr. Clin. Neurophysiol., 81: 323–331. Hellstrom, F, Roatta, S, Johansson, H and Passatore, M (1999) A technique for estimating activity in whole nerve trunks applied to the cervical sympathetic trunk, in the rabbit. Neurosci. Lett., 277: 95–98. Henneman, E, Somjen, G and Carpenter, DO (1965) Functional significance of cell size in spinal motoneurons. J. Neurophysiol., 28: 560–580. Hirata, A, Iijima, M, Motoyoshi, K and Kamakura, K (2000) Maximal and minimal motor conduction velocity in amyotrophic lateral sclerosis and Xlinked bulbospinal muscular atrophy measured by Harayama’s collision method. J. Clin. Neurophysiol., 17: 426–433. Hopf, HC (1962) Untersuchungen uber die unterschiede in der leitgeschwindigkeit motorishcer nervenfasern beim menschen. Duetsch. Z. Nervernheilk., 183: 579–588. Hopf, HC and Lowitzsch, K (1975) Relative refractory periods of motor nerve fibres. In K Kunze, JE Desmedt (Eds.), Studies on Neuromuscular Diseases Proceedings of the Internation Symposium (Giessen), Karger, Basel, pp. 264–267. Ingram, DA, Davis, GR and Swash, M (1987a) Motor nerve conduction velocity distributions in man: results of a new computer-based collision technique. Electroencephalogr. Clin. Neurophysiol., 66: 235–243. Ingram, DA, Davis, GR and Swash, M (1987b) The double collision technique: a new method for measurement of the motor nerve refractory period distribution in man. Electroencephalogr. Clin. Neurophysiol., 66: 225–234. Kadrie, H, Yates, SK, Milner-Brown, HS and Brown, WF (1976) Multiple point electrical stimulation of ulnar and median nerves. J. Neurol. Neurosurg. Psychiatry, 39: 973–985. Kimura, J (1974) F-wave velocity in the central segment of the median and ulnar nerves. A study in normal subjects and in patients with Charcot–Marie–Tooth disease. Neurology, 24: 539–546. Kimura, J (1976a) Collision technique. Physiologic block of nerve impulses in studies of motor nerve conduction velocity. Neurology, 26: 680–682.

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Kimura, J, Murphy, MJ and Varda, DJ (1976b) Electrophysiological study of anomalous innervation of intrinsic hand muscles. Arch. Neurol., 33: 842–844. Kimura, J (1976c) A method for estimating the refractory period of motor fibers in the human peripheral nerve. J. Neurol. Sci., 28: 485–490. Kimura, J (1977) Electrical activity in voluntarily contracting muscle. Arch. Neurol., 34: 85–88. Kimura, J, Yamada, T and Rodnitzky, RL (1978) Refractory period of human motor nerve fibres. J. Neurol. Neurosurg. Psychiatry, 41: 784–790. Kimura, J (1983) Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice. F.A. Davis, Philadelphia, Ist ed. Kimura, J, Yanagisawa, H, Yamada, T, Mitsudome, A, Sasaki, H and Kimura, A (1984) Is the F wave elicited in a select group of motoneurons? Muscle Nerve, 7: 392–399. Kimura, J (2001) Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice., Oxford University Press, New York, IIIrd ed. Leifer, LJ (1981) Nerve fiber conduction velocity distributions: motor nerve studies using collision neurography. Prog. Clin. Biol. Res., 52: 233–263. Maertens de Noordhout, A, Rothwell, JC, Thompson, PD, Day, BL and Marsden, CD (1988) Percutaneous electrical stimulation of lumbosacral roots in man. J. Neurol. Neurosurg. Psychiatry, 51: 174–181. Mills, KR and Murray, NM (1986) Electrical stimulation over the human vertebral column: which neural elements are excited? Electroencephalogr. Clin. Neurophysiol., 63: 582–589. Montero, J, Serra, J and Montserrat, L (1996) Axon reflexes or ephaptic responses simulating blink reflex R1 after XII-VII nerve anastomosis. Muscle Nerve, 19: 848–852. Nakanishi, T, Tamaki, M, Mizusawa, H, Akatsuka, T and Kinoshita, T (1986) An experimental study for analyzing nerve conduction velocity. Electroencephalogr. Clin. Neurophysiol., 63: 484–487. Nakanishi, T, Tamaki, M and Arasaki, K (1989) Maximal and minimal motor nerve conduction velocities in amyotrophic lateral sclerosis. Neurology, 39: 580–583. Nix, WA, Luder, G, Hopf, HC and Luth, G (1989) A computerized re-evaluation of the collision technique. Electromyogr. Clin. Neurophysiol., 29: 391–397.

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CHAPTER 17

Assessment of nerve excitability properties in peripheral nerve disease Cindy S.-Y. Lin,a Matthew C. Kiernan,b David Burkec and Hugh Bostocka,* a

Sobell Department, Institute of Neurology, University College London, Queen Square, UK , bPrince of Wales Medical Research Institute, University of New South Wales and Institute of Neurological Sciences, Prince of Wales Hospital, Australia, and cOffice of Research and Development, College of Health Sciences, The University of Sydney, Australia

17.1. Introduction Objective assessment of the damage to the nerve trunk in patients with peripheral neuropathy normally involves nerve conduction studies (NCS) and electromyography. Conventional NCS measurements of the latency and amplitude of compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) are made with supramaximal stimuli and provide information about the number of conducting fibres and the conduction velocity of the fastest. Velocity measurements are often used to distinguish between axonal and demyelinating pathologies, but they are by no means specific: conduction slowing can be caused by membrane depolarization or hyperpolarization, sodium channel blockade, axonal thinning or remyelination with short internodes, as well as by demyelination and cooling. Some of these factors are better assessed by using submaximal stimuli to measure nerve excitability properties, rather than by means of conventional NCS. This chapter is concerned with nerve excitability studies, determining the particular current required to excite axons (i.e., their threshold). The threshold current for exciting a nerve (or a specified fraction of the fibres in a nerve) provides little information on its own. It depends on what fraction of the applied current accesses the axons, as well as on their membrane properties. The power of modern nerve excitability studies has come in part from using computer-assisted stimulus control to measure thresh*Correspondence to: Professor Hugh Bostock, Sobell Department of Movement Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. E-mail address: [email protected] Tel.: +44-(0)20-7837-3611 × 4187; fax: +44-(0)-20-7813-3107.

olds, in part from using comparisons between pairs of threshold measurements to eliminate the uncertainty about current access, and in part from using a combination of different stimulation methods to change the threshold current, to provide multiple clues as to which membrane properties may be abnormal. Here, after introducing the ion channels responsible for excitability, we will focus on the methodology of excitability testing techniques currently used in assessing peripheral nerve function. We will describe the different types of excitability property, such as strength-duration behavior, recovery cycle and threshold electrotonus that can be readily measured in peripheral nerve, and their biophysical basis. We will then describe a recently developed protocol for testing multiple excitability properties in a single, brief recording session, and some of the ways in which the results of this test can be interpreted to provide evidence of membrane changes in disease. Finally, some of the limitations of nerve excitability testing will be discussed. 17.1.1. Biophysical basis of nerve excitability 17.1.1.1 Ion channels Axonal excitability depends primarily on the presence of high concentrations of Na+ channels in the nodal membrane, but it is also controlled by a variety of other types of ion channel and ion pumps, that affect the excitability through their effects on membrane potential. Two functionally distinct types of sodium current can be distinguished, although only one molecular species (Nav1.6) has been described at nodes of Ranvier (Caldwell et al., 2000). The classical transient Na+ current (INat in Fig. 17.1) is activated rapidly by membrane depolarization and then inactivates, so that further Na+ ions cannot pass no matter how much the membrane is depolarized. About 98%

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Nat

Nap Ks

Na+

Ks

Kf

IH

Lk

Kf

ATP

Na+

K+

Na+

K+

Fig. 17.1 Schematic diagram of a myelinated axon showing main components contributing to electrical excitability. Principle ion channels/conductances: Nat = transient Na+, Nap = persistent sodium, Kf = fast potassium (concentrated in the paranodal region), Ks = slow potassium, IH = hyperpolarization-activated cation current, Lk = leak (voltage independent, various). Principle pump: Na+/K+-ATPase.

of the sodium current behaves in this way. The remaining persistent Na+ current (INap) is activated equally rapidly, but at membrane potentials that are ~10–20 mV more negative (i.e., less depolarized), so that it contributes disproportionately to subthreshold excitability behavior. At the most negative potentials over which the current activates, inactivation is minimal, giving rise to a persistent inward leak of sodium ions at the resting potential. Both “persistent” and “transient” components of the Na+ current have been recorded in rat dorsal root ganglia cells (Baker and Bostock, 1997, 1998; Kiernan et al., 2003), and excitability studies indicate both are present in human peripheral nerve (Bostock and Rothwell, 1997). There are many types of K+ channel on axons (Vogel and Schwarz, 1995; Reid et al., 1999), but we can restrict this discussion to two groups of voltagegated K+ channel: those with fast kinetics and those with slow kinetics. There are few fast K+ channels (Kf in Fig. 17.1) at the human node of Ranvier such that, when modelling the action potential, K+ channels can be ignored (Schwarz et al., 1995). In mammalian axons, repolarization is achieved by inactivation of Na+ channels and current leak to the internode (Ritchie, 1995). Fast K+ channels are located in a tight band in the paranodal region where they contribute to the resistance of the internodal membrane and limit the depolarizing afterpotential responsible for superexcitability (see later). Slow K+ channels (Ks in Fig. 17.1) are, like Na+ channels, more concentrated at

the node than in the internode, but their kinetics are too slow to allow them to affect the action potential directly. They help determine the resting membrane potential and contribute to accommodation to longlasting depolarizing stimuli. Their partial activation during an action potential gives rise to the late subexcitable phase of the recovery cycle, and to the more pronounced hyperpolarization and subexcitability (H1) that follows a brief train of impulses (see below). There are channels on the internode that are activated slowly by hyperpolarization, pass both Na+ and K+ ions, and produce accommodation to the hyperpolarization. These channels, therefore, produce a form of inward rectification, but since this term is used to describe a different type of K+ channel, the current is now usually referred to as IH, the hyperpolarizationactivated cation current (Pape, 1996), and its biological role is probably to limit the hyperpolarization that occurs when axons conduct trains of impulses. 17.1.1.2. Interactions between nodal and internodal membrane potentials The node and internode are electrically linked, by current pathways through and under the myelin sheath (Barrett and Barrett, 1982). This means that changes in potential of the node spread to the internode, but slowly, because of the large capacitance of the internodal axolemma. This results in slow activation/deactivation of voltage-dependent channels on the internodal membrane. In turn, the potential of the internodal membrane affects the node, without

ASSESSMENT OF NERVE EXCITABILITY PROPERTIES IN PERIPHERAL NERVE DISEASE

17.1.2. Quantifying nerve excitability: thresholds and threshold tracking The term “threshold” in general is used to describe the minimal intensity or value of a signal that will produce a response or specified effect. However, it has different meanings in different contexts. In the context of nerve excitability studies, “threshold” usually means “threshold current,” the minimal current required to excite a single axon or group of axons (as distinct from the “threshold potential,” which is the membrane potential at which an all-or-none response is initiated). For single axons, the threshold current is defined as the current that excites the unit on 50% of occasions. Excitation is probabilistic, because of the finite number of sodium channel molecules at a node, and the probability of a given stimulus causing excitation varies from 0 to 1 over a “grey area” of about 6% of threshold. This means that even though one can often excite a single human motor unit selectively with surface electrodes to determine its threshold (Bergmans, 1970; Bostock and Baker, 1988), numerous trials are required to estimate the threshold current accurately. Also, the lowest threshold unit may well not be representative. It is more efficient and more useful to record compound muscle action potentials (CMAPs) or sensory nerve action potentials (SNAPs) and to define the threshold as the stimulus required to excite a target response that is a specific fraction of the peak compound action potential (Fig. 17.2). If the fraction selected is at the steepest point of the stimulusresponse curve (usually between 30 and 50%), then the threshold can be defined most accurately with a minimal number of stimuli.

100 Depolarization 80 Size of response (%)

appreciable delay since the nodal capacitance is very small. This two-way interaction between the nodal and internodal compartments of the axon is illustrated by the mechanism of the depolarizing afterpotential and superexcitability (see Section 17.2.3.1). Approximately 99.9% of axonal membrane is internodal so that, despite the lower channel densities, there are many more channels on the internode than on the node. Resting membrane potential is determined by those channels that are open at or near rest (both voltage-dependent and voltage-independent) and by the activity of the Na+/K+ pump, and this implies that it is largely determined by the properties of the internodal membrane. The major contributors are probably slow and fast K+ channels, persistent Na+ channels, and the Na+/K+ pump.

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Fig. 17.2 Stimulus-response curve. The “threshold” for a compound action potential can conveniently be defined as the stimulus intensity that evokes a specific fraction (e.g., 50%) of the maximal response. Changes in excitability, such as those caused by changes in membrane potential, shift the stimulus-response curve to the right or left, and are measured as changes in threshold.

Threshold tracking, the process of adjusting the stimulus so that the response is as close as possible to a target value, is facilitated for compound action potentials if the stimulus-response curve is recorded first. Then the amount required to change the stimulus, following a change in the response, can be predicted from the response error (i.e., the difference between the actual and target responses) and the slope of the stimulus-response curve. It may seem strange to use the terms “threshold” and “threshold tracking” when the response being tracked is, say, 50% of maximum, far above the minimal detectable response. However, such a compound action potential “threshold” can be regarded as the threshold of the single unit that is recruited when the action potential is 50% of maximum, which is likely to be much more representative of the axons in the nerve, as well as much more easy to determine, than the threshold of the most excitable unit. Although threshold tracking can be applied to determine nerve excitability at rest, this measurement is of limited value because it depends on tissue impedances and electrode placement, as well as on axonal membrane properties. Comparisons between two thresholds are generally of more value. In the next section, we will describe the nerve excitability properties

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determined from changes in nerve excitability induced: (1) by changing stimulus duration; (2) by one or more conditioning impulses; and (3) by subthreshold-polarizing currents. In each case, the measurements of axonal excitability reflect the membrane properties of the axons only at the site of stimulation, in contrast to conventional NCS measurements, which are determined by the whole length of nerve between the stimulation and recording sites.

Weiss’ formula is widely used in experiments to calculate tSD (Weiss, 1901; Bostock, 1983; Mogyoros et al., 1996). In this formulation, τSD equates to chronaxie (the stimulus duration corresponding to a threshold current that is twice rheobase, Fig. 17.3). Rheobase is the threshold current (or estimated threshold current in mA) if the stimulus duration could be infinitely long. Because there is a linear relationship between stimulus charge and stimulus duration, rheobase and τSD can be calculated from the thresholds measured using just two stimulus durations (Bostock and Bergmans, 1994; Mogyoros et al., 1996). Rheobase and τSD are both properties of the nodal membrane. τSD averages 0.46 ms in human motor axons and 0.67 ms in sensory axons of peripheral nerve (Mogyoros et al., 1996). These values are much longer than the passive time constant of the nodes of Ranvier (~50 μs) because the effects of subthreshold current pulses are prolonged by the local response of low threshold Na+ channels, particularly by persistent Na+ channels (Bostock and Rothwell, 1997). These channels are also important in determining repetitive and spontaneous activity, and this is why τSD can be a clinically important excitability parameter.

17.2. Nerve excitability properties 17.2.1. Strength-duration properties

2 ⫻ rheobase Rheobase

17.2.2. Activity-dependent excitability properties 17.2.2.1. Recovery of excitability following a single impulse The excitability of nerve fibers depends on their history of activation. Following conduction of a single nerve impulse, an axon undergoes a well-characterized and reproducible sequence of excitability changes before

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As the duration of a test stimulus increases, the strength of the current required to activate a single fiber or a specified fraction of a compound action potential decreases. Strength-duration time constant (or chronaxie) and rheobase are parameters that describe the strength-duration curve, i.e., the curve that relates the intensity of a threshold stimulus to its duration (Fig. 17.3). Strength-duration time constant (τSD) is an apparent membrane time constant inferred from the relationship between threshold current and stimulus duration, and provides a measure of the rate at which threshold current increases as the duration of the test stimulus is reduced to zero (Noble and Stein, 1966; Bostock, 1983). In human peripheral nerve, the strength-duration relationship is described remarkably well by Weiss’ empirical law: Q = I.t = Irh (t + tSD) where Q = stimulus charge; I = stimulus current of duration t; Irh = rheobasic current.

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Fig. 17.3 The strength-duration curve showing the relationship between stimulus strength and stimulus duration. Left: rheobase is defined as the threshold for stimuli of infinitely long duration, while chronaxie is defined as the duration of a threshold stimulus that is twice rheobase. Right: if stimulus charge (current × duration) is plotted against duration, the points fit a straight line (Weiss relationship), with slope = rheobase, and chronaxie = strength-duration time constant, given by negative intercept on x-axis.

ASSESSMENT OF NERVE EXCITABILITY PROPERTIES IN PERIPHERAL NERVE DISEASE

returning to its resting state. First there is the “absolute refractory” period during which the axon is inexcitable and a propagated action potential cannot be generated, regardless of the strength of the stimulus. Subsequently, the axon becomes “relatively refractory” during which an action potential may be generated but only if a stronger than normal stimulus is used. In human large myelinated axons, the relative refractory period is generally short, lasting less than 3 ms in most human studies (Gilliatt and Willison, 1963; Hopf, 1976). Adrian and Lucas (1912) first observed that following the relative refractory period, the axons both become more easily excited (superexcitable period) and also conduct impulses at a greater velocity than in the resting state (supernormal period). Following the superexcitable/supernormal period, there is an additional period of decreased excitability (late subexcitability), before membrane potential settles back to its resting state. This predictable sequence of excitability changes constitutes the recovery cycle (see Fig. 17.4). The mechanisms responsible for both the absolute and relative refractory periods are fairly well known: absolute refractoriness is due to inactivation of transient Na+ channels, and the relative refractory period is due to the gradual recovery of Na+ channels from inactivation (Hodgkin and Huxley, 1952). The refractory period increases with membrane depolarization and decreases with membrane hyperpolarization (Kiernan et al., 1996b; Burke et al., 1998; Kiernan and Bostock, 2000). Because of its sensitivity to polarization, refractoriness can be used as an indicator of membrane potential. However, the refractory period is also sensitive to temperature and may be prolonged by cooling (Gilliatt and Willison, 1963; Bergmans, 1970;

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Stys and Ashby, 1990; Burke et al., 1999; Kiernan et al., 2001a) because of slowed channel kinetics at lower temperatures. Superexcitability is due to a depolarizing afterpotential. During the action potential, there is a large influx of Na+ ions at the node, which is not offset by an equal efflux of K+ ions, so the axon as a whole is left with a net depolarizing charge, spread over nodal and internodal axolemma. During the action potential, the node depolarizes the internode, as the internode helps repolarize the node, both ending depolarized by a few mV (Barrett and Barrett, 1982). After the action potential, the large capacitance of the internode enables it to keep the node depolarized for tens of milliseconds. In myelinated axons, the superexcitability is strongly dependent on membrane potential: background depolarization reduces Na+ influx, and increases K+ efflux, thus reducing the charge imbalance during the action potential; also the opening of paranodal and internodal K+ channels at rest short-circuits the afterpotential and reduces its duration (Barrett and Barrett, 1982; David et al., 1992, 1995). Conversely, hyperpolarization increases and prolongs the depolarizing afterpotential and superexcitability. Superexcitability can therefore also be used as an indicator of membrane potential. Finally, the long-lasting phase of late subexcitability reflects hyperpolarization of the membrane potential, due to current through slow K+ channels at the nodes of Ranvier. These channels are activated during the action potential (and also during the depolarizing afterpotential) and deactivate slowly (Baker et al., 1987; Schwarz et al., 1995). Late subexcitability is not simply sensitive to resting membrane potential (ER),

Fig. 17.4 Recovery cycle. Schematic diagram of recovery cycle recorded from motor axons in human peripheral nerve, showing relative refractory, superexcitable and late subexcitable periods. Excitability changes are determined by threshold tracking at various intervals after a supramaximal conditioning stimulus.

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but to the electrochemical gradient for K+ ions, i.e., to the difference between ER and the potassium equilibrium potential (EK), which is normally on the hyperpolarized side of ER. This means that if axons are depolarized by passing a current (i.e., without changing EK), then the electrochemical gradient for K+ ions is increased and subexcitability is increased. On the other hand, if axons are depolarized by raising extracellular K+, as occurs during ischemia, EK is depolarized towards or beyond ER, and late subexcitability is abolished (Kiernan and Bostock, 2000). Late subexcitability is, therefore, not such a good indicator of membrane potential as superexcitability, but it can provide information about extracellular K+ levels. 17.2.2.2. Excitability changes following impulse trains When normal axons conduct a train of impulses, the axonal membrane hyperpolarizes. In his classical studies on frog sciatic nerve, Gasser (1935) recognized two phases of post-tetanic hyperpolarization, a short-lasting P1 phase and a long-lasting P2 phase (so named, because a hyperpolarizing afterpotential is recorded extracellularly as positive). Bergmans (1970) described two corresponding phases of increased threshold in single human motor axons in vivo, and called them H1 and H2 (since they are due to hyperpolarization). 17.2.2.2.1. Brief impulse trains (H1). The depth of the post-tetanic subexcitability during the H1 period reaches a maximum after 7–10 impulses, whereas the subexcitability of the H2 phase continues to increase as train duration increases. H1 represents the accumulation of late subexcitability and is due to activation of slow K+ channels (Bergmans, 1970; Baker et al., 1987; Taylor et al., 1992; Burke, 1993; Miller et al., 1995; 1996; Lin et al., 2000). H1 increases the threshold of cutaneous afferents in the median nerve by up to 40%, but this decays over the ensuing ~100 ms (Lin et al., 2000). In rat nerve preparations, H1 can be abolished by tetraethylammonium ions, which block slow K+ channels (Baker et al., 1987; Eng et al., 1988; Waxman and Ritchie, 1993). The major function of slow K+ conductances appears to be spike-frequency adaptation and the limiting of repetitive firing on prolonged depolarization (Bostock, 1995). 17.2.2.2.2. Long impulse trains (H2 and pumpinduced hyperpolarization). Bergmans’ second component of activity-dependent threshold increase (H2) is produced by long trains of impulses. With increasing frequency and duration of impulse train, H2

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reaches a limit in amplitude, but no limit in duration: after stimulation at 300 Hz for 30 min, recovery can take nearly 3h (Bergmans, 1970; Bostock and Bergmans, 1994). H2 is attributed to activation of the electrogenic sodium pump (Na+/K+-ATPase). As Na+ ions gradually accumulate intra-axonally during a train, the Na+/K+ pump accelerates, pumping 3 Na+ ions out of the axon in exchange for 2 K+ ions pumped inwards. The net outward charge displacement constitutes the electrogenic pump current, which hyperpolarizes the axon and increases threshold. H2 is diminished by cooling or ischemia (Bergmans, 1970; Gordon et al., 1990) and can be abolished by replacement of Na+ ions with Li+ or choline, which do not activate the pump, or by ouabain, which blocks it (Ritchie and Straub, 1957; Schoepfle and Katholi, 1973; Bostock and Grafe, 1985; Morita et al., 1993). Human cutaneous afferents also exhibit H2, with properties consistent with activity of the electrogenic Na+/K+ pump (Kiernan et al., 1997b), although after prolonged, high-frequency trains (e.g., 200 Hz for 10 min) H2 is preceded by a period of reduced threshold, associated with paresthesias (Applegate and Burke, 1989). Vagg et al. (1998) reported that motor axons underwent significant hyperpolarization with the natural activity associated with a voluntary contraction, i.e., that post-tetanic (or activity-dependent) hyperpolarization was likely to be a functionally important phenomenon. This issue was addressed in patients with demyelinating neuropathies. It was found that natural activity could precipitate conduction block in patients with chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy (Cappelen-Smith et al., 2000; Kaji et al., 2000). 17.2.3. Excitability changes induced by subthreshold polarizing currents 17.2.3.1. Latent addition Very brief (submilliseconds) pulses produce changes in membrane potential confined to the node of Ranvier and myelin sheath. These changes in potential add to the changes in potential induced by a subsequent test stimulus, provided that it is delivered before the effects of the first have died away. Tasaki referred to this phenomenon as latent addition. Latent addition has two components: a passive component corresponding to the time constant of the node of Ranvier (~50 μs), and an active component due to changes in Na+ channel activation. Near-threshold depolarizing

ASSESSMENT OF NERVE EXCITABILITY PROPERTIES IN PERIPHERAL NERVE DISEASE

pulses produce a local response, which can be recorded by latent addition. Latent addition also provides a way of detecting Na+ currents active at the resting potential (primarily persistent Na+ current) since they are deactivated by hyperpolarizing pulses and recover with a time constant much slower than the passive nodal time constant. Figure 17.5 illustrates latent addition recordings from sensory fibres in a normal human ulnar nerve. Pairs of 60 μs square-wave stimuli were applied: the first, the conditioning stimulus, was subthreshold, and the second, the test stimulus, tracked the threshold for the compound nerve action potential. Strength-delay curves are plotted for conditioning stimuli ±90% of threshold. The depolarizing response has a complicated shape, corresponding to the time course of the local response. The hyperpolarizing

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response, however, can be resolved by curve-fitting into the sum of two exponentials. The shorter exponential corresponds to the nodal time constant, and the longer one is determined by de-activation of the resting (persistent) Na+ current. These two factors, nodal time constant and persistent Na+ current also help to determine the strength-duration time constant, and there is a close relationship between latent addition and strength-duration behavior (Bostock and Rothwell, 1997). No clinical studies have yet been published using this technique but, in principle, it can be used to differentiate between changes in strengthduration time constant due to passive membrane properties and those due to Na+ currents. A limiting factor is that threshold currents for the 60-μs pulses are high, and may easily exceed the current capabilities of the stimulator.

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Fig. 17.5 Latent addition in a human sensory nerve. Changes in threshold produced by hyperpolarizing (top section) and depolarizing (bottom section) conditioning stimuli of 60 μs duration, fixed at ±90% of the current required to produce the test response. The conditioning-test interval was increased from 0 to 0.5 ms in 20 μs steps. The decay of the threshold increase produced by the brief hyperpolarizing current is well fitted with the sum of two exponential components (c): a fast component (a), with time constant close to 50 μs, corresponding to the passive nodal time constant, and a slower component (b), related to resting sodium current. The decay of the threshold decrease produced by near-threshold depolarizing currents is prolonged by a local response.

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17.2.3.2. Threshold electrotonus Changes in potential of the nodal membrane spread into the internode, but slowly because of the resistance of the myelin sheath and consequently the slow charging of the internodal capacitance. This results in slow activation/deactivation of voltage-dependent channels on the internodal membrane. Although Na+ channel density is insufficient for the internodal membrane to generate an action potential, the changes in resistance of the internodal membrane and in the current stored on it will affect the behavior of the node (Baker, 2000). The only physiological method available to examine the behavior of internodal conductances in human subjects in vivo is the technique of threshold electrotonus. This technique measures the threshold changes produced by prolonged depolarizing or hyperpolarizing currents, which are too weak to trigger action potentials (subthreshold currents). The

term “threshold electrotonus” reflects the fact that under most circumstances, the threshold changes parallel the underlying electrotonic changes in membrane potential (Bostock and Baker, 1988; Bostock et al., 1998). Threshold electrotonus and its component phases are illustrated in Fig. 17.6. The changes in threshold on the left were produced by 100 ms polarizing currents with intensities of ±40% of the unconditioned threshold, using 1 ms test pulses. The conditioning current is illustrated in the lower panel. Such currents are normally quite innocuous, and form part of a standard clinical nerve excitability test (see Section 17. 3.1). On the right are plotted responses to 300 ms pulses, ±40% and −80% of threshold, for sensory and motor fibres. In contrast to the recovery cycle, threshold changes are conventionally plotted as threshold reductions, with depolarizing responses upwards, to match the conventional way of plotting B

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Fig. 17.6 Threshold electrotonus and its phases. (A) Average motor responses to 100-ms polarizing currents (±40% of threshold) from 38 subjects, showing fast (F) and slow (S1, S2) components and small inter-subject variability (thick lines: mean, thin lines: mean ± SD). Stimuli were applied to ulnar nerve at wrist, CMAP recorded from hypothenar muscles. (Reproduced from Bostock, H, Cikurel, K, Burke, D (1998). Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve, 21: 137–158, by permission of John Wiley & Sons, Inc.) (B) Comparison between mean motor and sensory responses to 300-ms current pulses (±40%, –80% of threshold) from 8 subjects, showing an additional component of threshold electrotonus (S3), an accommodation to the hyperpolarization produced by the hyperpolarization-activated cation current, IH. (Reproduced from Bostock, H, Burke, D, Hales, JP (1994): Differences in behaviour of sensory and motor axons following release of ischemia. Brain, 117: 225–234, by permission of Oxford University Press).

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changes in membrane potential induced by such currents (i.e., electrotonus). There are different phases of threshold electrotonus. In response to depolarizing current pulses, there is an initial fast phase that corresponds to the applied current (the “F” phase). A polarizing current 40% of threshold unsurprisingly reduces threshold by 40%. This is followed by further depolarization that develops slowly over some tens of milliseconds as the current spreads to and depolarizes the internodal membrane (the “S1” phase). The threshold decrease (i.e., the extent of depolarization) reaches a peak ~20 ms after the onset of the current pulses, dependent on its strength, and threshold then starts to return slowly towards the control level. This reduction in excitability is termed accommodation, and is due to activation of a hyperpolarizing conductance with slow kinetics. The use of K+ channel blocking agents indicate that the slow accommodative process is due to activation of slow K+ channels, which are located on both the node and the internode (Baker et al., 1987; Bostock and Baker, 1988; Bostock et al., 1998). When the DC pulse is terminated, threshold increases rapidly and there is then a slow overshoot before it gradually recovers to control level. The overshoot is due to the persistence of the increase in slow K+ conductance, which deactivates slowly. With long-lasting hyperpolarizing DC pulses, there is a fast increase in threshold, proportional to the applied current, analogous to the comparable phase with depolarizing currents (the “F” phase). Then threshold continues to increase as the hyperpolarizing spreads to the internode. This “S1” phase starts as a mirror image of the S1 phase with depolarizing current but soon diverges, because hyperpolarization closes K+ channels (slow nodal and fast and slow internodal K+ channels), and this increases the amplitude and time constant of S1. At ~150 ms after the start of the strong DC hyperpolarizing current shown in the right hand panel, S1 reaches a maximum and threshold begins to decrease towards the control level. This accommodative phase (S3) produces “inward rectification” and is due to activation of the hyperpolarization-activated current IH (Pape, 1996). Although IH has slow activation and deactivation kinetics, and is best detected with very long current pulses, it does activate and affect threshold earlier than 100 ms. On termination of the hyperpolarizing DC pulses, threshold rapidly decreases and then undergoes a slow, depolarizing undershoot as IH slowly deactivates and the slow K+ conductance is reactivated.

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17.2.3.3. Current-voltage relationship Just as the activation of different voltage-dependent channels in a cell can be revealed by plotting a currentvoltage (I/V) relationship, it can be convenient to plot the threshold changes at the ends of a series of long current pulses of different amplitudes as a currentthreshold relationship. This is conventionally done with threshold increase (hyperpolarization) to the left, threshold decrease (depolarization) to the right, depolarizing current to the top and hyperpolarizing current to the bottom, to correspond to a conventional I/V plot (see below, Fig. 17.8C). Outward rectification due to K+ channel activation causes a steepening of the curve in the top right quadrant, and the steepening of the relationship in the bottom left quadrant indicates inward rectification due to activation of IH. 17.3. Nerve excitability techniques used in clinical studies 17.3.1. Automated recording of multiple nerve excitability properties (TROND protocols) 17.3.1.1. Excitability properties of motor axons To increase the clinical applicability of these threshold-tracking techniques, a highly automated excitability testing protocol, allowing rapid acquisition of many different excitability parameters, was developed for a course on nerve excitability held in Trondheim, Norway (Kiernan et al., 2000). This “TROND” protocol uses the slope of the stimulus-response curve to optimise the threshold tracking, and passes automatically from one test to another to minimize delays. A complete set of threshold measurements can be generated within about 9 min (Fig. 17.7), and the derived excitability properties are illustrated in Fig. 17.8, which shows data from a single subject superimposed on the 95% confidence limits for normal subjects (Kiernan et al., 2000). For the standard recordings, as in Figs. 17.7 and 17.8, stimuli are applied to the median nerve at the wrist, and CMAPs recorded from APB. The stimulating electrodes should be non-polarizable, incorporating an Ag/AgCl interface, and about 1 cm in diameter (e.g., “Red Dot” electrodes, 3M Co.), with the active electrode (cathode) over the nerve and the reference electrode about 10 cm proximal, not over the nerve. Electrode placement should be such as to minimize the threshold current. Recording electrodes are less critical but should be of consistent diameter (since that affects CMAP amplitude) and placed over the belly of

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Fig. 17.7 Raw data recorded from a single subject using the TROND protocol. (A) Stimulus-response relationships for stimuli of 0.2-ms duration (thick line) and 1.0-ms duration (thin line). (B) Threshold electrotonus measurement with polarizing currents of +40% (thin line) and −40% (thick line) of resting threshold. (C) Current-threshold relationship recorded at the end of 200-ms polarizing currents. (D) Recovery cycle for interstimulus intervals from 200 to 2 ms. The “peak CMAP” amplitudes in the second row of B-D show that, after each change of conditioning stimulus, the test CMAP tracked rapidly to the target response, which was 40% of the maximal CMAP in A. “Delay” refers to the interval between the onset of the conditioning stimulus and the test stimulus, and allowed the threshold electrotonus and recovery cycle data to be replotted as in Fig. 17.8. (Reproduced from Kiernan, MC, Burke, D, Andersen, KV, Bostock, H (2000) Multiple measures of axonal excitability: a new approach in clinical testing. Muscle Nerve, 23: 399–409, by permission of John Wiley & Sons, Inc.)

the muscle and base of the thumb. Recording equipment requirements are as for conventional nerve conduction studies. Stimulation requires a linear bipolar constant current stimulator, with an output range of at least ±50 mA. Suitable equipment may soon be available commercially (Digitimer Ltd. who also distribute the Qtrac software that runs the TROND protocol, see www.digitimer.com). After the operator has checked that the equipment and program are correctly set up for recording CMAP amplitudes, control passes to the computer, which determines all subsequent stimulus waveforms and amplitudes. The stimulus-response curve is first measured in 6% stimulus increments with stimuli of 0.2 and 1 ms duration (Figs. 17.7A and 17.8A). Since strengthduration time constant can be estimated from thresh-

olds with just two stimulus durations (see Section 17.2.2 above), the time constants can be estimated for different fractions of the compound muscle action potential, and this may help in the detection of inhomogeneity among axons (Fig. 17.8D). Inhomogeneity can also be indicated by the shape of the normalized stimulus-response curve (Fig. 17.8B). The program then sets a target response on the steepest part of the stimulus-response curve between 30 and 50% of the maximal CMAP, to ensure accurate threshold measurements, and starts threshold tracking with 1 ms test stimuli, using the slope of the (1 ms) stimulus-response curve to optimise efficiency. Three different types of excitability property, as described in Section 17.2, are then measured in turn: first threshold electrotonus to 100-ms polarizing currents, set to ±40% of the

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Fig. 17.8 Multiple measures of excitability obtained with the TROND protocol. Recording from a single subject (filled circles and solid lines) superimposed on mean and 95% confidence limits for a normal subject. (A) Absolute stimulus-response relationships. (B) Normalized stimulus-response relationship. (C) Current-threshold relationship. (D) Distribution of strength-duration time constants. (E) Threshold electrotonus. (F) Recovery cycle. (Reproduced from Kiernan, MC, Burke, D, Andersen, KV and Bostock H (2000) Multiple measures of axonal excitability: a new approach in clinical testing. Muscle Nerve, 23: 399–409, by permission of John Wiley & Sons, Inc.)

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unconditioned threshold (Figs 17.7B and 17.8E), the current-threshold relationship for polarizing currents of 200 ms duration, varying from +50 to −100% of threshold (Figs 17.7C and 17.8C) and finally the recovery cycle following a single supramaximal conditioning stimulus (corresponding to the peak stimulus used earlier in the stimulus-response curve) (Figs 17.7D and 17.8F). To allow for any drift in baseline threshold (as can occur due to sweating), conditioned and unconditioned thresholds are tracked in parallel: thus for threshold electrotonus, polarizing current amplitude is rotated between the values 40, −40 and 0% of the unconditioned threshold. For the recovery cycle, the sequence of stimuli is more complicated. To prevent the response to the supramaximal conditioning stimulus from interfering with the measurement of the response to the test stimulus when the conditioningtest delay is short, 3 conditions are tested in turn: test alone, conditioning alone, and conditioning + test. The response to the conditioning stimulus alone is then subtracted on line from the response to the conditioning/test combination, so that the response measured is due solely to the second action potential. In early studies of threshold electrotonus, the test stimulus was applied once each at a regularly spaced intervals after the start of the 100 ms polarizing current, but in the “TROND” protocol the threshold is determined more accurately at each selected delay after the start of the polarizing current. This is achieved by repeating the stimulus until a prescribed number (3 for threshold electrotonus, 4 for recovery cycle) of the stimuli are judged by the computer program to provide an acceptable estimate of the threshold, either because the response is within 10% of the target response, or because successive responses bracket the target. Only then is the delay altered. To keep the overall recording time short, a limited number of delays has been programmed, as indicated in Figs. 17.7–17.8, with the intervals adjusted according to the expected rate of change of threshold. Individual excitability parameters (such as peak superexcitability) that can be derived from these “TROND” recordings are listed in Section 17.3.1.3. The interpretation of abnormalities in the excitability properties is addressed in Section 17.3.3. 17.3.1.2. Excitability properties of sensory axons The same principle as used for the motor “TROND” protocol has also been used to study sensory fibres (Kiernan et al., 2001c). Because of the poorer signal-

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to-noise ratio of sensory nerve action potentials, averaging of some waveforms was introduced, and the number of acceptable estimates required for each threshold measurement increased, so that the recording time increased from 9 min to an average of ~20 min for normal control subjects. Also, stimulus widths were reduced from 0.2 and 1 ms to 0.1 and 0.5 ms, to reduce the temporal dispersion in the response to 1 ms stimuli at threshold. Unfortunately, however, in many neuropathies, the reduced amplitude of sensory nerve action potentials precludes satisfactory threshold tracking without time-consuming averaging, and no clinical studies have yet been published with this protocol. 17.3.1.3. Useful excitability parameters A program (MEMSTATS) is available to extract up to 29 parameters from the data files generated by the TROND protocol for making statistical comparisons between patient groups. These parameters include straightforward measurements comparable to those used in nerve conduction studies (i.e., amplitude and latency), measures related to absolute excitability (i.e., threshold for 50% maximal response, rheobase), and also a number of excitability indices derived from threshold ratios, which show little variance between normal subjects, but in many cases are very sensitive to changes in membrane potential or other membrane properties. Thus, from the normalized stimulusresponse curve (Fig. 17.8B), a slope factor indicating threshold spread is obtained from the ratio between the thresholds for 75 and 25% maximal responses; from the current/threshold relationship (Fig. 17.8C), the resting slope relates to the resting input resistance, while the maximal hyperpolarized slope relates to activation of IH. The derivation of strength-duration time constant from the stimulus-response curves has already been described. From the recovery cycle (Fig. 17.8F), values of peak superexcitability and subexcitability relate to resting membrane potential (ER) and to (ER − EK), respectively, as described in Section 17.2.2.1, while the relative refractory period (i.e., the delay at which the threshold first returns to its resting value) is sensitive to membrane potential and temperature. From the threshold electrotonus curves (Fig. 17.8E), several values are commonly measured, with the conventional designation TEa (x–y ms), where a can have the values d for depolarization or h for hyperpolarization and x–y indicates the range of delays over which the waveform is averaged. Unless otherwise specified, a polarizing current of ±40% of

ASSESSMENT OF NERVE EXCITABILITY PROPERTIES IN PERIPHERAL NERVE DISEASE

unconditioned threshold is assumed. Thus TEd (90–100 ms) indicates the mean threshold reduction for stimuli delivered between 90 and 100 ms after the start of a 40% depolarizing current, a value that is particularly sensitive to membrane potential (see below).

TROND protocol) since the delay at which this occurs may change and is not known in advance. Instead, Burke and colleagues have performed a number of studies in which measures of refractoriness and superexcitability are defined by the threshold changes at specific constant delays. Figure 17.9A illustrates a 5channel tracking protocol, which can be used to follow changes in the following parameters, and Fig. 17.9B its use to document changes during ischemia: The amplitude of the maximal compound potential recorded on channel 1 determines the amplitude target for the submaximal test potentials on the other channels. In addition, as discussed below, this recording is subtracted from the responses in channels 4 and 5 so that the conditioned test potentials can be measured uncontaminated by the conditioning

17.3.2. Tracking excitability parameters during experimental manoeuvres If a nerve is not in a steady state, it may be of interest to be able to estimate a number of excitability parameters as a function of time. For this purpose, it is best to select parameters that are unambiguously determined by just two measurements. Thus, to track changes in superexcitability, it is not practical to determine the peak superexcitability (as can be done with the A

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Fig. 17.9 Threshold tracking excitability changes induced by ischemia. (A) Sequence of pulse combinations used for tracking multiple excitability parameters as a function of time (see text). (B) Excitability indices for median sensory fibers during and after 13 min of ischemia. Mean data for 8 subjects (± SEM). Ischemia is indicated by the filled horizontal bar, starting at 5 min. Top panel: threshold changes measured using 0.1 ms test stimuli normalized to the pre-ischaemic control levels for median afferents. Second and third panels: refractoriness and superexcitability expressed as the change in threshold for the test potential as percentage of unconditioned threshold. Bottom panel: τSD, calculated off-line from the thresholds measured using test stimuli of 0.1 and 1.0 ms duration.

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potential. Thresholds for unconditioned test stimuli of 0.1- and 1-ms duration are estimated from T2 and T3, respectively, where Tn is the stimulus intensity on channel n. Strength-duration time constant (τSD) is estimated from the thresholds using two different stimulus durations according to Weiss’ Law (see Section 17.2.1), i.e., τSD = ((T2−T3) × 0.1)/(T3 − (T2 × 0.1)) ms. Rheobase is similarly estimated as (T3 − (T2 × 0.1))/0.9. Refractoriness is measured at the conditioning-test interval of 2 ms, and is expressed as the percentage increase in current required to produce the target potential, i.e., (T4 − T2)/T2 × 100. Supernormality is measured as the percentage decrease in threshold 7 ms after a maximal volley, i.e., (T 5− T2)/T2 × 100. For both refractoriness and supernormality, to avoid a contamination of the conditioned response by the response to the conditioning stimulus, it is necessary to subtract the response to channel 1 (equal to the response to the conditioning stimuli) from the response to the combined conditioning + test stimulus on-line, and to base the threshold tracking on the difference. Multi-channel tracking protocols of this sort have been used to follow the complex changes in nerve excitability occurring during experimental manoeuvres such as ischemia (produced with a sphygmomanometer cuff, Fig. 17.9B) or hyperventilation (Mogyoros et al., 1997b). 17.3.3. Inferring changes in membrane properties from changes in excitability parameters Since nerve excitability properties depend in a complicated way on the interaction between membrane potential and all the voltage-dependent ion channels at the nodes and in the internodes (see, Section 17.1.1), the task of deducing the biophysical basis of abnormal excitability recordings from patients with peripheral nerve disease is, in general, difficult and uncertain. At present, nerve excitability studies can provide hard evidence that a disorder of nerve excitability exists, but usually only weak clues as to the likely cause at the membrane level. In the future, with the development of accurate mathematical models of nerve excitability, it may become possible to make such inferences objectively and with a definable degree of certainty. So far, the best evidence for alterations in specific membrane properties has come from conditions in which the abnormalities can be reproduced by experimental manoeuvres, or for which mechanisms

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can be evaluated in animal models. It is reasonable to assume, for example, that if all the excitability abnormalities of a nerve can be reproduced experimentally by a manoeuvre that induces membrane hyperpolarization, and if depolarizing the nerve by applied current reverses all these abnormalities, then the nerve must be hyperpolarized, even though there was no a priori reason to expect such an abnormality. Such has been the intriguing finding in several patients with multifocal motor neuropathy with conduction block (MMN)(Section 17.3.3.1.2). 17.3.3.1. Changes in membrane potential Changes in membrane potential affect all voltagegated ion channels and, therefore, also affect nerve excitability properties. These changes have been documented with the TROND protocol for normal axons, comparing the effects of changing membrane potential by applying DC polarizing currents with those occurring during ischemic depolarization and postischemic hyperpolarization (e.g., Fig. 17.10) (Kiernan and Bostock, 2000). The study by Kiernan and Bostock (2000) has proved useful for interpreting abnormal nerve excitability properties in patients, as illustrated here by the examples of membrane depolarization in uraemia and membrane hyperpolarization in MMN. 17.3.3.1.1. Membrane depolarization. Average electrotonus and recovery cycle recordings from nine patients with chronic renal failure, taken just before undergoing regular haemodialysis, are illustrated in Fig. 17.11C (Kiernan et al., 2002b), and compared with recordings from normal nerves subject to ischemia (Fig. 17.11A). A strong family resemblance between the excitability changes is evident. Potentialsensitive parameters were significantly abnormal in the uraemic patients, in the direction consistent with membrane depolarization. This study not only provided convincing evidence that chronic renal failure is associated with membrane depolarization, but it also provided a clear indication of the mechanism operating in this set of patients. The potential-sensitive parameters were all significantly correlated with serum K+ concentration, and the regression lines relating log [K+] to each parameter indicated that patients with normokalemia had normal excitability parameters. The levels of membrane depolarization indicated by the excitability abnormalities were consistent with the theoretical sensitivity of membrane potential to extracellular [K+] (Kiernan et al., 2002b).

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Fig. 17.10 Excitability measures and membrane polarization. Effects of DC polarizing currents in the range ±1mA (D = depolarizing, H = hyperpolarizing) on nerve excitability properties of single subject. There were four intensities of depolarization and four of hyperpolarization, the resting data being the fifth trace in each panel. (Reproduced from Kiernan, MC, Bostock, H (2000) Effects of membrane polarization and ischaemia on the excitability properties of human motor axons. Brain, 123: 2542–2551, by permission of Oxford University Press.)

17.3.3.1.2. Membrane hyperpolarization. Evidence for membrane hyperpolarization has been adduced from TROND recordings in two conditions. One was a single patient with acute hypokalemia, induced by drinking a large volume of carbonated beverage (Kuwabara et al., 2002a). In this case, the membrane hyperpolarization was expected, just as membrane depolarization is expected in hyperkalemia. The other study was more surprising, and has been alluded to above: in six patients with multifocal neuropathy the nerves, tested distally to the sites of conduction block, showed evidence of membrane hyperpolarization

(Kiernan et al., 2002a). Electrotonus and recovery cycle data resembled that in post-ischemic nerves hyperpolarized by rebound hyperactivity of the electrogenic sodium pump (Fig. 17.11A, B). The potential-sensitive parameters were all abnormal in the direction indicating hyperpolarization, and these and other excitability parameters could be normalized by applying a weak depolarizing current at the recording site. In the light of the similarity to pumpinduced hyperpolarization, it was proposed that the distal hyperpolarization may have been caused by increased intracellular [Na+], diffused from the site of

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Fig. 17.11 Changes in threshold electrotonus and recovery cycle recorded in ischemia, multifocal motor neuropathy (MMN) and chronic renal failure (CRF). A: C = control, I1 = 5 m ischemia, I2 = 15 m ischemia, PI = 5 m after release of ischemia. B,C: dashed lines controls (mean ± SEM), circles and error bars: patients (mean ± SEM). Excitability changes in CRF patients resemble those in normal subjects during ischemic depolarization, and those in MMN patients resemble those during postischemic hyperpolarization.

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conduction block, which by implication should be depolarized, allowing a steady-state abnormal influx of Na+ ions (Kiernan et al., 2002a). 17.3.3.2. Changes in specific ion conductances Inferences about changes in specific ion conductances have necessarily been more indirect, in the absence of experimental manipulation of these variables in normal subjects. One early (pre-TROND) study of threshold electrotonus in diabetic neuropathy provided evidence that IH, the hyperpolarization-induced cation current, is reduced in a proportion of these patients (Horn et al., 1996). In this case, the evidence was based on the observations that the abnormality was restricted to the hyperpolarizing electrotonus responses, and that the effects were most conspicuous in sensory fibers (which appear to express a greater IH conductance, see Fig. 17.5B) and increased with prolongation of the hyperpolarizing current. Supporting evidence for this interpretation was later produced by a study of rats, made diabetic by treatment with streptozotocin (Yang et al., 2001). They showed a similarly reduced accommodation to prolonged hyperpolarizing currents, relative to control rats, and further insights into the mechanism of this phenomenon were obtained by blocking it with aldose reductase inhibitors. Inference about another ion conductance was drawn from a recent TROND study on MachadoJoseph disease (Kanai et al., 2003). In this case, threshold electrotonus and recovery cycles were relatively normal, but strength-duration time constants were significantly prolonged, suggesting excessive persistent Na+ currents (see Section 17.2.1). This led the authors to introduce treatment with mexiletine, to reduce these currents. They reported a partial normalization of strength-duration time constants and a dramatic reduction of disabling muscle cramps in eight patients (Kanai et al., 2003). This appears to be the first time that an apparently effective treatment has been initiated on the basis of nerve excitability testing. 17.4. Limitations of nerve excitability studies 17.4.1. Limitations of threshold tracking methods Threshold measurements only test the nerve at the point of stimulation, so unlike conduction studies they are not useful for focal neuropathies, unless it is possible to stimulate at or close to the lesion site (as in the case of MMN). Threshold tracking tests only the axons with thresholds close to the chosen target

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response, so that conditions affecting the excitability of only a minority of axons, whether the least or the most excitable, may be undetected. The TROND protocol avoids this limitation for measurements of strength-duration time constant and rheobase by recording full stimulus-response curves, but the other excitability properties do not provide information about either the most excitable or the least excitable axons in the nerve. It goes without saying that threshold-tracking methods provide information only about those axons that are conducting. Axons that have degenerated or which are blocked between stimulation and recording site cannot be tested. This means that serial measurements can remain unchanged, or even show improvement, despite a progressive loss of axons, as can occur in amyotrophic lateral sclerosis. 17.4.2. Limitations due to nerve accessibility A major limitation of current nerve excitability testing methods is that they are restricted to sites where the peripheral nerve passes close to skin, such as the ulnar and median nerves at elbow and wrist. Otherwise, the threshold currents would be high and the polarizing currents that are set to fractions of threshold would be painful and could burn the skin. However, in many diseases affecting nerve excitability it is the most distal portion of the nerve where membrane abnormalities are most pronounced, as inferred from the predominantly distal origin of most ectopic discharges (Layzer, 1994). Accordingly, a study of motor axons in neuromyotonia (Kiernan et al., 2001b) failed to find evidence for a membrane abnormality responsible for the hyperexcitability, and a study of Guillain– Barré patients (Kuwabara et al., 2002c) found normal membrane properties at the wrist, despite prolonged distal latencies and an increased refractory period of transmission in patients with the axonal form of the disease. To address this limitation, TROND studies have been made on more distal parts of the median nerve: Walters et al., (2001) showed that axons innervating abductor pollicis brevis could be tested satisfactorily in the palm, and more recently Kuwabara and colleagues have stimulated at the motor point, measuring muscle movement recorded with an accelerometer, rather than muscle action potentials (Kuwabara et al., 2004). Recovery cycles cannot be measured satisfactorily by this method, except at short intervals, because the movement to the conditioning stimulus affects the threshold to the test stimulus. With motor

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point stimulation, the pattern and sequence of motor unit recruitment will, inevitably, differ from that with nerve trunk stimulation.

value in diagnosis, though, based on group data, it has already proved valuable in understanding the pathophysiology of neuropathies (Table 17.1).

17.4.3. Limitations as a diagnostic tool

17.4.4. Limitations on availability of hardware and software

In most neuropathies studied so far, even when highly significant differences in excitability parameters can be demonstrated between groups of patients and appropriate controls, the variability has been such that single patients can seldom be allocated unambiguously to one group or the other based on a single test. It remains to be seen whether excitability testing is of

A major current limitation on the use and development of nerve excitability studies is the lack of availability of suitable equipment. At the time of writing, there is no commercially available stimulator appropriate for automatic threshold tracking, and Bostock’s Qtrac software (© Institute of Neurology, London) for

Table 17.1 Clinical studies of axonal excitability Disorders Auto-immune neuropathy Acquired Neuromyotonia (aNMT) Hereditary neuropathy Charcot–Marie–Tooth disease (CMT) Neuropathies in medical conditions Diabetic polyneuropathy

Uraemic Neuropathy Mononeuropathies Carpal Tunnel Syndrome (CTS)

Neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS)*/Motor Neuron Disease (MND)

Machado-Joseph Disease Toxic and nutritional neuropathies Taxol-cisplatin

Acquired hypokalemic paralysis Demyelinating polyneuropathies Multifocal Motor Neuropathy (MMN) Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Guillain–Barré syndromes (GBS)/(AMAN and AIDP)

References

(Maddison et al., 1999); (Kiernan et al., 2001b) (Nodera et al., 2003) (Weigl et al., 1989); (Strupp et al., 1990); (Horn et al., 1996) (Kuwabara et al., 2002b) (Kiernan et al., 2002b) (Mogyoros et al., 1997a); (Kiernan et al., 1999); (Cappelen-Smith et al., 2003) (Bostock et al., 1995); (Horn et al., 1996); (Mogyoros et al., 1998a; 1998b); (Kanai et al., 2003)

(Quasthoff et al., 1995); (Hanauske et al., 1995); (Schilling et al., 1997) (Kuwabara et al., 2002a) (Kaji et al., 2000); (Kiernan et al., 2002a) (Cappelen-Smith et al., 2000); (Cappelen-Smith et al., 2002a); (Cappelen-Smith et al., 2000); (Cappelen-Smith et al., 2001); (Cappelen-Smith et al., 2002b) (Sung et al.,2003); (Kuwabara et al., 2002c)

ASSESSMENT OF NERVE EXCITABILITY PROPERTIES IN PERIPHERAL NERVE DISEASE

running the TROND protocols is only available for obsolete PCs running DOS. Unless a major manufacturer of EMG equipment takes up the challenge of hardware and software development, it is unlikely that nerve excitability studies will spread beyond the confines of a few enthusiastic clinics, or that the full potential of these techniques will be realised.* *

Note added in proof: Bostock’s Qtrac software has recently been rewritten for modern PCs running Windows, and Digitimer Ltd (www.digitimer.com) have developed an appropriate stimulator for clinical nerve excitability studies.

17.5. Conclusions All neuropathies will affect the excitability of the involved axons, but routine nerve conduction studies are specifically designed to eliminate differences in axonal excitability so that the size and conduction velocity of maximal volleys can be documented. Much additional information can be obtained about the properties of disturbed axons from studies of their excitability properties. Such studies are still in their infancy, but there are already a number of reports in the literature for a variety of neuropathic disturbances (Table 17.1), though all are more concerned with pathophysiological mechanisms than disease diagnosis. It is too early to know whether studies of axonal excitability have diagnostic value, but a user-friendly protocol (the TROND protocol) was developed specifically so that testing could be an “add-on” to routine diagnostic studies. Using this protocol, a number of useful measures of axonal excitability can be obtained in ~10 min. References Adrian, E and Lucas, K (1912) On the summation of propagated disturbances in nerve and muscle. J. Physiol. (Lond.), 44: 68–112. Applegate, C and Burke, D (1989) Changes in excitability of human cutaneous afferents following prolonged high-frequency stimulation. Brain, 112: 147–164. Baker, M, Bostock, H, Grafe, P and Martius, P (1987) Function and distribution of three types of rectifying channel in rat spinal root myelinated axons. J. Physiol. (Lond.), 383: 45–67, 45–67. Baker, MD (2000) Axonal flip-flops and oscillators. Trends. Neurosci., 23: 514–519.

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Baker, MD and Bostock, H (1997) Low-threshold, persistent sodium current in rat large dorsal root ganglion neurons in culture. J. Neurophysiol., 77: 1503–1513. Baker, MD and Bostock, H (1998) Inactivation of macroscopic late Na+ current and characteristics of unitary late Na+ currents in sensory neurons. J. Neurophysiol., 80: 2538–2549. Barrett, EF and Barrett, JN (1982) Intracellular recording from vertebrate myelinated axons: Mechanism of the depolarizing afterpotential. J. Physiol. (Lond.), 323: 117–144. Bergmans, J (1970) The Physiology of Single Human Nerve Fibres. Vander. Bergmans, J (1982) Repetitive activity induced in single motor axons: a model for pathological repetitive activity. In: WJ Culp and J Ochoa (Eds), Abnormal Nerves and Muscles as Impulse Generators, Oxford University Press, New York, pp. 393–419. Bostock, H (1983) The strength-duration relationship for excitation of myelinated nerve: computed dependence on membrane parameters. J. Physiol. (Lond.), 341: 59–74. Bostock, H (1995) Mechanisms of accommodation and adaptation in myelinated axons. In: SG Waxman, JD Kocsis and PK Stys (Eds.), The Axon, Oxford University Press, New York, pp. 311–327. Bostock, H and Baker, M (1988) Evidence for two types of potassium channel in human motor axons in vivo. Brain Res., 462: 354–358. Bostock, H and Bergmans, J (1994) Post-tetanic excitability changes and ectopic discharges in a human motor axon. Brain, 117: 913–928. Bostock, H, Cikurel, K and Burke, D (1998) Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve, 21: 137–158. Bostock, H and Grafe, P (1985), Activity-dependent excitability changes in normal and demyelinated rat spinal root axons. J. Physiol. (Lond.), 365: 239–257. Bostock, H and Rothwell, JC (1997) Latent addition in motor and sensory fibres of human peripheral nerve. J. Physiol. (Lond.), 498: 277–294. Bostock, H, Sharief, MK, Reid, G and Murray, NM (1995) Axonal ion channel dysfunction in amyotrophic lateral sclerosis. Brain, 118: 217–225. Burke, D (1993) Microneurography, impulse conduction, and paresthesias. Muscle Nerve, 16: 1025–1032. Burke, D, Mogyoros, I, Vagg, R and Kiernan, MC (1998) Quantitative description of the voltage dependence of axonal excitability in human cutaneous afferents. Brain, 121: 1975–1983.

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Burke, D, Mogyoros, I, Vagg, R and Kiernan, MC (1999) Temperature dependence of excitability indices of human cutaneous afferents. Muscle Nerve, 22: 51–60. Caldwell, JH, Schaller, KL, Lasher, RS, Peles, E and Levinson, SR (2000) Sodium channel Na(v)1.6 is localized at nodes of Ranvier, dendrites, and synapses. Proc. Natl. Acad. Sci. USA, 97: 5616–5620. Cappelen-Smith, C, Kuwabara S, Lin, CS and Burke, D (2002a) Abnormalities of axonal excitability are not generalized in early multifocal motor neuropathy. Muscle Nerve, 26: 769–776. Cappelen-Smith, C, Kuwabara, S, Lin, CS, Mogyoros, I and Burke, D (2000) Activity-dependent hyperpolarization and conduction block in chronic inflammatory demyelinating polyneuropathy. Ann. Neurol., 48: 826–832. Cappelen-Smith, C, Kuwabara, S, Lin, CS, Mogyoros, I and Burke, D (2001) Membrane properties in chronic inflammatory demyelinating polyneuropathy. Brain, 124: 2439–2447. Cappelen-Smith, C, Lin, CS and Burke, D (2003) Activity-dependent hyperpolarization and impulse conduction in motor axons in patients with carpal tunnel syndrome. Brain, 126: 1001–1008. Cappelen-Smith, C, Lin, CS, Kuwabara, S and Burke, D (2002b) Conduction block during and after ischaemia in chronic inflammatory demyelinating polyneuropathy. Brain, 125: 1850–1858. David, G, Barrett, JN and Barrett, EF (1992) Evidence that action potentials activate an internodal potassium conductance in lizard myelinated axons. J. Physiol. (Lond.), 445: 277–301. David, G, Modney, B, Scappaticci, KA, Barrett, JN and Barrett, EF (1995) Electrical and morphological factors influencing the depolarizing afterpotential in rat and lizard myelinated axons. J. Physiol. (Lond.), 489: 141–157. Eng, DL, Gordon, TR, Kocsis, JD and Waxman, SG (1988) Development of 4-AP and TEA sensitivities in mammalian myelinated nerve fibers. J. Neurophysiol., 60: 2168–2179. Gasser, HS (1935) Changes in nerve-potentials produced by rapidly repeated stimuli and their relation to the responsiveness of nerve to stimulation. Am. J. Physiol., 111: 35–50. Gilliatt, RW and Willison, RG (1963) The refractory and supernormal periods of the human median nerve. J. Neurol. Neurosurg. Psychiatry., 26: 136–147.

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Kiernan, MC, Hart, IK and Bostock, H (2001b) Excitability properties of motor axons in patients with spontaneous motor unit activity. J. Neurol. Neurosurg. Psychiatry, 70: 56–64. Kiernan, MC, Lin, CS, Andersen, KV, Murray, NM and Bostock, H (2001c) Clinical evaluation of excitability measures in sensory nerve. Muscle Nerve, 24: 883–892. Kiernan, MC, Mogyoros, I and Burke, D (1996a) Changes in excitability and impulse transmission following prolonged repetitive activity in normal subjects and patients with a focal nerve lesion. Brain, 119: 2029–2037. Kiernan, MC, Mogyoros, I and Burke, D (1996b) Differences in the recovery of excitability in sensory and motor axons of human median nerve. Brain, 119: 1099–1105. Kiernan, MC, Mogyoros, I and Burke, D (1999) Conduction block in carpal tunnel syndrome. Brain, 122: 933–941. Kiernan, MC, Mogyoros, I, Hales, JP, Gracies, JM and Burke, D (1997b) Excitability changes in human cutaneous afferents induced by prolonged repetitive axonal activity. J. Physiol. (Lond.), 500: 255–264. Kiernan, MC, Walters, RJ, Andersen, KV, Taube, D, Murray, NM and Bostock, H (2002b) Nerve excitability changes in chronic renal failure indicate membrane depolarization due to hyperkalaemia. Brain, 125: 1366–1378. Kuwabara, S, Bostock, H, Ogawara, K, Sung, JY, Misawa, S, Kitano, Y, Mizobuchi, K, Lin, CS and Hattori, T (2004) Excitability properties of human median axons measured at the motor point. Muscle Nerve, 29: 227–233. Kuwabara, S, Kanai, K, Sung, JY, Ogawara, K, Hattori, T, Burke, D and Bostock, H (2002a) Axonal hyperpolarization associated with acute hypokalemia: Multiple excitability measurements as indicators of the membrane potential of human axons. Muscle Nerve, 26: 283–287. Kuwabara, S, Ogawara, K, Harrori, T, Suzuki, Y and Hashimoto, N (2002b) The acute effects of glycemic control on axonal excitability in human diabetic nerves. Intern. Med., 41, 360–365. Kuwabara, S, Ogawara, K, Sung, JY, Mori, M, Kanai, K, Hattori, T, Yuki, N, Lin, CS, Burke, D and Bostock, H (2002c) Differences in membrane properties of axonal and demyelinating Guillain– Barré syndromes. Ann. Neurol., 52: 180–187. Layzer, RB (1994) The origin of muscle fasciculations and cramps. Muscle Nerve, 17: 1243–1249.

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Lin, CS, Mogyoros, I and Burke, D (2000) Recovery of excitability of cutaneous afferents in the median and sural nerves following activity. Muscle Nerve, 23: 763–770. Maddison, P, Newsom-Davis, J and Mills, KR (1999) Strength-duration properties of peripheral nerve in acquired neuromyotonia. Muscle Nerve, 22: 823–830. Miller, TA, Kiernan, MC, Mogyoros, I and Burke, D (1995) Activity-dependent changes in impulse conduction in normal human cutaneous axons. Brain, 118: 1217–1224. Miller, TA, Kiernan, MC, Mogyoros, I and Burke, D (1996) Activity-dependent changes in impulse conduction in a focal nerve lesion. Brain, 119: 429–437. Mogyoros, I, Kiernan, MC and Burke, D (1996) Strength-duration properties of human peripheral nerve. Brain, 119: 439–447. Mogyoros, I, Kiernan, MC and Burke, D (1997a) Strength-duration properties of sensory and motor axons in carpal tunnel syndrome. Muscle Nerve, 20: 508–510. Mogyoros, I, Kiernan, MC, Burke, D, Bostock, H (1997b) Excitability changes in human sensory and motor axons during hyperventilation and ischaemia. Brain, 120: 317–325. Mogyoros, I, Kiernan, MC, Burke, D and Bostock, H (1998a) Ischemic resistance of cutaneous afferents and motor axons in patients with amyotrophic lateral sclerosis. Muscle Nerve, 21: 1692–1700. Mogyoros, I, Kiernan, MC, Burke, D and Bostock, H (1998b) Strength-duration properties of sensory and motor axons in amyotrophic lateral sclerosis. Brain, 121: 851–859. Morita, H, Shindo, M, Yanagawa, S and Yanagisawa, N (1993) Neuromuscular response in man to repetitive nerve stimulation. Muscle Nerve, 16: 648–654. Noble, D and Stein, RB (1966) The threshold conditions for initiation of action potential by excitable cells. J. Physiol. (Lond.), 187: 129–162. Nodera, H, Bostock, H, Kuwabara, S, Sakamoto, T, Asanuma, K, Sung, JY, Ogawara, K, Hattorri, N, Hirayama, M, Sobue, G and Kaji, R (2004) Nerve excitability properties in Charcot–Marie-Tooth disease type 1A. Brain, 127: 203–211. Pape, HC (1996) Queer current and pacemaker: The hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol., 58: 299–327. Quasthoff, S, Grosskreutz, J, Kühn, M, Schilling, T and Hanauske, AR (1995) Taxol-cisplatin neuropathy caused by membrane leak and axonal depolarization:

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An in vivo and in vitro study. J. Neurol., 242/6: S145–S145. Reid, G, Scholz, A, Bostock, H and Vogel, W (1999) Human axons contain at least five types of voltagedependent potassium channel. J. Physiol. (Lond.), 518: 681–696. Ritchie, JM (1995) Physiology of axons. In: SG Waxman, JD Kocsis and PK Stys (Eds.) The Axon., Oxford University Press, New York, pp. 68–96. Ritchie, JM and Straub, RW (1957) The hyperpolarization which follows activity in mammalian nonmedullated fibres. J. Physiol. (Lond.), 136: 80–97. Schilling, T, Heinrich, B, Kau, R, Herzog, M, Quasthoff, S, Diergarten, K, Rastetter, J and Hanauske, AR (1997) Paclitaxel administered over 3 h followed by cisplatin in patients with advanced head and neck squamous cell carcinoma: a clinical phase I study. Oncology, 54: 89–95. Schoepfle, GM and Katholi, CR (1973) Posttetanic changes in membrane potential of single medullated nerve fibers. Am. J. Physiol., 225: 1501–1507. Schwarz, JR, Reid, G and Bostock, H (1995) Action potentials and membrane currents in the human node of Ranvier. Pflugers. Arch., 430: 283–292. Strupp, M, Bostock, H, Weigl, P, Piwernetz, K, Renner, R and Grafe, P (1990) Is resistance to ischaemia of motor axons in diabetic subjects due to membrane depolarization? J. Neurol. Sci., 99: 271–280. Stys, PK and Ashby, P (1990) An automated technique for measuring the recovery cycle of human nerves. Muscle Nerve, 13: 750–758. Sung, JY, Kuwabara, S, Kaji, R, Ogawara, K, Mori, M, Kanai, K, Nodera, H, Hattori, T and Bostock, H (2004) Altered nerve membrane properties at the wrist correlate with clinical profiles in chronic

inflammatory demyelinating polyneuropathy. Muscle and Nerve, 29: 28–37. Taylor, JL, Burke, D and Heywood, J (1992) Physiological evidence for a slow K+ conductance in human cutaneous afferents. J. Physiol. (Lond.), 453: 575–589. Vagg, R, Mogyoros, I, Kiernan, MC and Burke, D (1998) Activity-dependent hyperpolarization of human motor axons produced by natural activity [In Process Citation]. J. Physiol. (Lond.), 507: 919–925. Vogel, W and Schwarz, JR (1995) Voltage-clamp studies on axons: macroscopic and single-channel currents. In: SG Waxman (Ed.) The Axon: Structure, Function and Pathophysiology, Oxford University Press: Oxford, New York, pp. 257–280. Walters, RJ, Kiernan, MC, Murray, NM and Bostock, H (2001) Distal excitability properties of median motor axons. Muscle Nerve, 24: 1695–1698. Waxman, SG and Ritchie, JM (1993) Molecular dissection of the myelinated axon. Ann. Neurol., 33: 121–136. Weigl, P, Bostock, H, Franz, P, Martius, P, Muller, W and Grafe, P (1989) Threshold tracking provides a rapid indication of ischaemic resistance in motor axons of diabetic subjects. Electroencephalogr. Clin. Neurophysiol., 73: 369–371. Weiss, G (1901) Sur la possibilité de rendre comparables entre eux les appareils servant à l’excitation électrique. Arch. Ital. Biol., 35: 413–446. Yang, Q, Kaji, R, Takagi, T, Kohara, N, Murase, N, Yamada, Y, Seino, Y and Bostock, H (2001) Abnormal axonal inward rectifier in streptozocininduced experimental diabetic neuropathy. Brain, 124: 1149–1155.

Glossary

(Nernst) potential for the ion. The term is also used in the sense of an ionic pathway or channel. Depolarization When the membrane potential becomes less negative, as occurs during anoxia or ischemia. Electrotonus Changes in membrane potential evoked by subthreshold depolarizing or hyperpolarizing current pulses Fanning-in Threshold electrotonus waveforms in which the responses to depolarizing and hyperpolarizing currents deviate less than normal from baseline, and come closer together with time. Typically occurs with background axonal deploarization. Fanning-out Threshold electrotonus waveforms deviating more than usual from baseline with time during the polarizing currents. Typically occurs with background hyperpolarization.

Accommodation The tendency of excitability to return towards the resting level despite a sustained depolarizing or hyperpolarizing stimulus. Activation The time-dependent growth of a voltagedependent membrane conductance after a change in membrane potential. Chronaxie The stimulus duration for which the threshold current is twice the rheobase. Chronaxie is equal to the strength-duration time constant when Weiss’ law is obeyed. Conductance The conductance GX of a channel permeable to the ion X is given by GX = IX/(Em−EX) where Em is the membrane potential and EX the equilibrium

ASSESSMENT OF NERVE EXCITABILITY PROPERTIES IN PERIPHERAL NERVE DISEASE H1, H2 Hyperpolarizing after-effects of trains of impulses, causing an increase in threshold. H1 saturates after a few impulses, but H2 increases in duration with train length. Hyperpolarization When the membrane potential becomes more negative. IH Hyperpolarization-activated cation current. Inward rectification The passing of more current in the inward than the outward direction. This term is sometimes used for the IH conductance, but now more often for a potassium channel KIR. Latent addition Addition of the effects of two very brief closely spaced current pulses on nerve excitability. Membrane potential Voltage difference across the axonal membrane (inside-outside). Refractoriness The decrease in excitability during the relative refractory period after a nerve impulse. It may be expressed quantitatively as the percentage increase in threshold when a test stimulus is preceded by a conditioning stimulus at an interval within the relative refractory period (e.g. 2 ms). Refractory period (Absolute) The period immediately after a nerve impulse during which an axon cannot be excited, however great the stimulus. Refractory period (Relative) The period between the end of the absolute refractory period and the start of the superexcitable period, when an axon may be excited but its threshold is increased. Rheobase (Irh) The threshold current (or estimated threshold current) for a stimulus of infinitely long duration. Strength-duration time constant (τSD) An apparent membrane time constant inferred from the relationship between threshold current and stimulus duration, defined as the ratio of charge threshold, for very brief stimuli, to rheobase.

403

Subexcitability (Late) A decrease in excitability (increase in threshold) occurring after the superexcitability following an impulse. Subnormality (Late) Term often used interchangeably with late subexcitability (but perhaps better restricted to the accompanying decrease in conduction velocity). Subthreshold (A stimulus) too weak to trigger an action potential. Superexcitability An increase in excitability (or reduction in threshold current) commonly observed shortly after a nerve impulse. It may be expressed quantitatively as the percentage change in threshold when a test stimulus is preceded by a conditioning stimulus at an interval within the superexcitable period (e.g. 7 ms). Supernormality Term often used interchangeably with superexcitability (but perhaps better restricted to the accompanying increase in conduction velocity). Threshold (current) The stimulus current required to excite a single unit, or to evoke a compound potential that is a defined fraction of the maximum. Threshold electrotonus Threshold changes produced by prolonged subthreshold depolarizing or hyperpolarizing currents, normally corresponding to the induced change in membrane potential (i.e. electrotonus). Threshold tracking Adjustment of stimulus intensity (usually by computer) to produce a test potential of specified size. Weiss’ Law An empirical formula for the strength-duration relationship, which is closely followed by myelinated fibres: the stimulus charge [Q, i.e. the product of stimulus current (I) and the duration (t)] at threshold is directly proportional to stimulus duration.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

405

CHAPTER 18

Conduction velocity distribution Wilhelm J. Schulte-Mattler* Neurologische Klinik und Poliklinik, Universität Regensburg, Germany

18.1. Introduction Peripheral nerves consist of thousands of nerve fibers with individual diameters and myelin sheaths. Because the conduction velocity of myelinated fibers is mainly determined by their myelin sheaths, nerve conduction studies are well established to detect and characterize neuropathies that affect the peripheral myelin. However, the routinely measured maximum nerve conduction velocity (NCV) reflects only a small proportion of the total nerve-fiber population, namely the fastest conducting fibers. Only if these fibers are demyelinated, the maximum NCV is reduced. As many neuropathies, especially early during their time course, do not affect all of the fastest conducting fibers, it is desirable to study the conduction velocity not only of that subpopulation but also of the total nerve-fiber population. Ideally, the result of such study would be a histogram of the conduction velocities of the nerve fibers, the conduction velocity distribution (Figs. 18.1 and 18.2). Theoretically, the conduction velocity distribution could be determined by measuring the individual conduction velocity of each fiber in a nerve. It is obvious that this approach is not feasible. Hence the conduction velocity distribution must be somehow calculated or estimated from compound action potentials, which—by definition—are the summation of nerve fiber action potentials recorded from a nerve trunk. An illustration of this summation is given in Fig. 18.3, while a more formal mathematical approach is included in the appendix section below.

For clinical purposes, it is necessary to know whether a conduction velocity distribution is normal or not. Thus, it must somehow be compared with normative data. One way to achieve this is to determine parameters characterizing the conduction velocity distribution and to compare only the parameters with the respective normal values. As an example, the conventional maximal conduction velocity of a nerve segment is such a parameter, as it is the upper border of the conduction velocity distribution (Fig. 18.1). Other potentially sensible parameters are: the width of the conduction velocity distribution (the maximal minus the minimal conduction velocity), or the percentage of fibers with a velocity below a certain limit. The example illustrates that a method that just provides a parameter of the full conduction velocity distribution may well be of clinical value. Methods to measure the full conduction velocity distribution require considerable mathematical processing of the bioelectric signals recorded from the patients, or are significantly more time consuming than the conventional electrodiagnostic methods, or both. Methods that do not provide the full conduction velocity distribution but some important parameters of it, are currently available for the use in a clinical setting. Both kinds of methods will be reviewed in the following. As small myelinated and unmyelinated nerve fibers cannot be studied with the available electrodiagnostic methods, the following discussion concerns only large myelinated nerve fibers. 18.2. Methods requiring special electrodes 18.2.1. The near nerve technique

*Correspondence to: PD Dr. med. Wilhelm J. SchulteMattler, Neurologische Klinik und Poliklinik, Universität Regensburg, Universitätsstr 84, 93053 Regensburg, Germany. E-mail address: [email protected]. Tel.: +49-941-941-3311; fax: +49-941-941-3005.

The method itself is described in Chapter 7 of this volume. It is mentioned here also, because abnormalities of the conduction velocity distribution can be characterized with this method qualitatively. An abnormality that can be found with this method is the occurrence of late components of the compound action potentials

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WILHELM J. SCHULTE-MATTLER

Relative Proportion [%]

70 60

width

50 40 30 20 10 0 0

10

20

30

40

50

60

70

Conduction Velocity [m/s]

Fig. 18.1 Conduction velocity distribution of a normal human nerve of an upper extremity. Semiquantitative estimation compiled from data collected with various methods (Dorfman, 1984; Dengler at al., 1988; Panayiotopoulos and Chroni, 1996). The upper border of the conduction velocity distribution, i.e., the position of the right column (arrow), is equal to the conventional maximal nerve conduction velocity.

(Behse and Buchthal, 1971). Late components represent subpopulations of abnormally slow conducting nerve fibers, independently of whether the conventional NCV is abnormal or not (Fig. 18.4). This serves as an example for the principle that certain determinants of the conduction velocity distribution can be derived from compound action potentials. 18.2.2. Selective nerve fiber stimulation Dengler et al. (1988) measured conduction velocities of single motor axons innervating human hand muscles by recording from single motor units with special tungsten microelectrodes. The electrodes were inserted into the muscle during steady voluntary innervation. Then the position was adjusted until action potentials of a single motor unit could be recorded optimally. This position of the recording electrode was carefully maintained during subsequent electrical nerve stimulation. Stimulus intensity and position of the stimulus electrode that was positioned at the wrist, were manipulated until action potentials of the previously identified motor unit could be recorded and their latencies measured. Thereafter, the stimulation procedure was repeated with the stimulus electrode at the elbow. The axonal conduction velocity was calculated from the distance between both stimulation sites and the difference of the latencies. The axons of 94 motor units from 9 muscles could be studied. Their conduc-

tion velocity distribution ranged from 40 to 63 m/s, with a peak between 53 and 53 m/s. Nearly half of the axons had conduction velocities in the range from 52 to 55 m/s. Although the conduction velocity of single motor axons can be measured with this method, it should be noted that only 10 axons per muscle could be studied on average. This is a relatively small sample of the whole population of the motor axons of a muscle, which introduces the methodological issue of sampling bias. Therefore, and because of its substantial requirements to both examiner and patient, the method is not suitable for clinical routine measurements. 18.3. Methods based on F-wave recordings After supra-maximal stimulation of a motor nerve, action potentials travel in two directions: orthodromically to the muscle, causing the M-response, and antidromically to the anterior horn cells. Very few anterior horn cells react to the arrival of the action potentials by “backfiring,” i.e., by generating an action potential, which travels orthodromically back to the muscle. The muscle response to the action potentials generated by backfiring is called the F-wave (for details see Chapter 9 of this volume). Its latency represents the fastest conducting axon among those contributing to the F-wave. The conduction velocity (V) of this axon can be calculated from the M-latency, the F-latency and the distance (d) between the stimulation site and the motor neurons (V = 2*d/(F − M − 1 ms)). Because F-waves following successive stimuli are generated by different motor neurons, it makes sense to measure the F-wave conduction velocity distribution after a series of successive stimuli (Fig. 18.5). It was used as representative of the conduction velocity distribution of the entire nerve (Panayiotopoulos, 1979; Panayiotopoulos and Chroni, 1996). The usefulness of this method for basic research is compromised by findings of Guiloff and ModarresSadeghi (1991), which were consistent with preferential generation of F-responses by larger motor units. This caused a shifting of the F-wave conduction velocity distributions towards faster values than expected. Moreover, Tsai et al. (2003) found significant differences of F-wave conduction velocity distributions between patients with spinal cord injury and controls, showing that F-wave conduction velocity distribution does not reflect motor properties exclusively. For clinical purposes, the F-wave dispersion was used to characterize abnormal conduction velocity

CONDUCTION VELOCITY DISTRIBUTION

407 Fig. 18.2 Three types of motor conduction velocity distributions (CVD) in a motor nerve (left column) and corresponding pairs of compound muscle action potentials (CMAPs, right column) upon distal (upper traces) and proximal (lower traces) nerve stimulation. Results of a computer simulation of a human posterior tibial nerve (Schulte-Mattler, 2001a). (A) Normal CVD. Normal amplitude of the CMAPs, normal nerve conduction velocity. (B) CVD as in hereditary polyneuropathy: uniform reduction of the conduction velocity of all nerve fibers causes a reduced nerve conduction velocity and a decrease of the CMAP amplitude after proximal stimulation, which is within the range of normal. (C) CVD as in an acquired polyneuropathy: nonuniform reduction of the conduction velocity of some but not all nerve fibers causes pronounced temporal dispersion with an abnormal decrease of the CMAP amplitude after proximal stimulation. The nerve conduction velocity and the difference in duration between both CMAPs are within the range of normal. Note the obvious difference in the shape of the CMAPs after proximal and after distal stimulation.

Relative Proportion [%]

70 60 50 40 30 20 10 0

A

0

10

20

30

40

50

60

70

60

70

60

70

Conduction Velocity [m/s]

Relative Proportion [%]

70 60 50 40 30 20 10 0

B

0

10

20

30

40

50

Conduction Velocity [m/s]

Relative Proportion [%]

70 60 50 40 30 20 10 0

C

0

10

20

30

40

50

Conduction Velocity [m/s] 10 ms

distributions. It is defined as the difference between the maximal and the minimal F-wave latencies (chronodispersion) or between maximal and the minimal F-wave conduction velocity (tacheodispersion) of a series of F-waves. Normative data vary considerably between different laboratories (Table 18.1), which reflects that F-wave methodology is less standardized than conventional nerve conduction studies. Moreover, the correlation between test and retest of the F-wave chronodispersion is much lower (0.8) (Puksa et al., 2003). Nonetheless, in a retrospective analysis of 1520

patients, an increased F-wave chronodispersion was the only electrodiagnostic abnormality in 22% of the peroneal nerves and in 10% of the posterior tibial nerves of the patients with neurogenic lesions but normal conventional nerve conduction studies (Weber, 1998). However, this diagnostic sensitivity was not reproduced by Nobrega et al. (2001) who compared Fwave parameters for diagnostic sensitivity in diabetic patients. The most frequently abnormal parameter in their 27 patients was the maximal F-wave latency (44%). As this parameter also indicates an abnormal conduction velocity distribution, it can be argued that

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Fig. 18.3 Construction of a compound sensory action potential by the summation of three sensory nerve fiber action potentials (computer simulation, surface electrodes). Left column: action potentials immediately upon nerve stimulation. Right: action potentials after propagation through a 15-cm nerve segment (d). Different arrival times at the recording electrode due to different conduction velocities of the fibers. The conventional NCV is 45 m/s.

d 45m/s

40m/s

35m/s

Σ

Σ

2 ms

F-waves are useful to demonstrate abnormal conduction velocity distributions in patients, but methodological issues are critical. 18.4. Methods based on collision testing Collision testing (Chapter 16 of this volume) was suggested by Thomas et al. (1959) and fully developed by Hopf (1962) to measure the conduction velocity distributions of peripheral motor nerves. In this method, a distal supra-maximal stimulus is combined with a delayed proximal supra-maximal stimulus. The distal stimulus elicits two volleys of action potentials in the nerve. One volley travels orthodromically to the muscle where it evokes a compound muscle action potential (CMAP). The other volley travels antidromically towards the proximal stimulation site. If the delay Fig. 18.4 Construction of a compound sensory action potential by the summation of three sensory nerve fiber action potentials (computer simulation, needle electrodes). Left column: action potentials immediately upon nerve stimulation. Right: action potentials after propagation through a 15 cm nerve segment (d). Different arrival times at the recording electrode due to different conduction velocities of the fibers. The conventional NCV is 45 m/s but a late component with a NCV of 35 m/s can be identified (arrow).

between distal and the proximal stimulus is less than the time necessary for the antidromic volley to reach the proximal site, the volley collides with and extinguishes the orthodromic volley elicited by the proximal stimulus. In this case, the proximal stimulus does not evoke a CMAP (Fig. 18.6A). If the delay between both stimuli is larger than the time necessary for the whole distal volley to pass the proximal site (plus the refractory period of the nerve fibers), a normal CMAP is evoked by the proximal stimulus (Fig. 18.6D). If the delay is as long as necessary for the antidromic action potentials of the fastest conducting fibers to pass the proximal site, the action potentials of slower conducting fibers collide, and a submaximal CMAP is evoked by the proximal stimulus (Fig. 18.6B, C). The area of this CMAP is assumed to be proportional to the number of nerve fibers that passed the proximal site and,

d

45m/s 40m/s 35m/s

Σ

Σ

2 ms

CONDUCTION VELOCITY DISTRIBUTION

409

12

Number of Fibers

10 8 6 4 2 0 200μV

36 38 40 42 44 46 48 50 Conduction Velocity [m/s]

2mV 10ms

Fig. 18.5 Abnormal F-wave dispersion. Left: Recording of 20 F-waves (arrows) from an abductor hallucis muscle of a 50year-old woman suffering from a mild diabetic polyneuropathy. Note the presence of multiple A-waves (dashed lines) indicating demyelination (Bischoff et al., 1996). Right: Conduction velocity distribution of the F-waves of the left side. It is shifted towards lower values.

thus, contributed to the CMAP. In this situation, a slight increase in the delay results in a corresponding slight increase in the area of the CMAP because some action potentials are able to pass the proximal site, which collide at the shorter delay (the relationship between the delay and the area of the CMAP evoked by the proximal stimulus is called the cumulative

Table 18.1 F-wave chronodispersion: Upper limits (95%) of normal

Nerve Median Ulnar

Tibial Peroneal

Upper limit [ms]

N

8.9 4.1 8.7 6.7 3.9 9.5 5.9 7.5 10.6 6.9

10 20 10 64 20 10 20 20 10 20

Weber, 1998 Puksa et al., 2003 Weber, 1998 Nobrega et al., 2001 Puksa et al., 2003 Weber, 1998 Puksa et al., 2003 Panayiotopoulos, 1979 Weber, 1998 Puksa et al., 2003

N, Number of F-waves from which the chronodispersion was calculated.

density function, see Fig. 18.6E). Thus, the increase in area is proportional to the number of nerve fibers conducting at a velocity that can be calculated from the delay between the stimuli and the distance between the sites of stimulation. Figure 18.6 illustrates this principle and how it can be used to measure the conduction velocity distribution of a peripheral nerve segment. Caccia et al. (1992b) demonstrated that the applicability of the method is not restricted to motor nerves but can be also used to estimate the conduction velocity distribution of sensory nerves. In the ulnar nerves of the 20 normal subjects studied by Hopf (1962) with this method, the difference in conduction velocity between the fastest and the slowest fibers, i.e., the width of the conduction velocity distribution, was between 4 and 7 m/s. Ingram et al. (1987) modified Hopf’s method by introducing a third stimulus and by using a computer to permit accurate measurements of the slowest 1% of motor nerve fibers. As expected, they found a greater width of the conduction velocity distribution, namely 3.6–9.2 in 20 median nerves, 3.9–13.5 in six ulnar nerves, and 5.3–17.6 in four peroneal nerves of their control subjects. However, as Rossi et al. (1981) and Ruijten et al. (1993) reported similar results obtained with the original method in the peroneal nerves of healthy subjects,

410

1.0

D

Relative Area

0.8

C

0.6

0.4 B 0.2

A

0.0

E

A 5

10 Inter Stimulus Interval [ms]

1

1.0

Relative Area

0.8

B

0.6

0.4

0.2

0.0

F

25 30 35 40 45 50 55 Conduction Velocity [m/s]

100

C

45 m/s 40 m/s 40 m/s 35 m/s

Relative Proportion [%]

Fig. 18.6 Measurement of a conduction velocity distribution by collision testing. (A) to (D): Construction of a compound muscle action potentials by summation of the action potentials of 4 motor units (computer simulation, surface electrodes) upon combined distal and proximal stimulation. Horizontal bar: time between the first, distal stimulus and the second, proximal stimulus. Distance between stimulation sites: D = 0.3 m. (A) The interstimulus interval (ISI) is less than the time necessary for action potentials to travel from the distal to the proximal stimulation site. The proximally elicited action potentials are extinguished because of collision. (B) The ISI is as long as necessary for the antidromic action potential of the fastest conducting fiber (45 m/s) to pass the proximal site before the proximal stimulus is given, which, thus, evokes a CMAP generated by this fiber only (arrow). (C) Same as (B) with an ISI long enough for the action potentials of the 40 m/s fibers to pass the proximal site before the proximal stimulus is given. The proximal CMAP is generated by three fibers. (D) The ISI is large enough for the antidromic action potentials of all fibers to pass the proximal site. The proximal CMAP is generated by all fibers. (E) Relationship between the area of the CMAP evoked by the proximal stimulus and the ISI (cumulative density function). CMAP area is percentage of CMAP area upon supra-maximal stimulation. (F) Same as (E), but ISI transformed to conduction velocity CV= D / ISI. (G) The conduction velocity distribution is derived from (F) by the subtraction of successive data points.

WILHELM J. SCHULTE-MATTLER

10 ms

80

60

40

20

0

D

it is not clear to what extent the methodological changes suggested by Ingram et al. (1987) improved the accuracy of the original method. Leifer et al. (1977) carried out a thorough mathematical analysis of the method and suggested a sophisticated algorithm to calculate the conduction velocity distribution from the CMAPs upon stimuli of varied delay. They found the width of the conduction velocity distribution ranging from 8.5 to 16.5 m/s in the ulnar nerves of 16 healthy controls. This suggests that their algorithm is particularly sensitive in detecting small numbers of slowly conducting axons. However,

G

25 30 35 40 45 50 55 Conduction Velocity [m/s]

no clinical data are available to compare this method with others. The potential diagnostic superiority of collision testing to conventional nerve conduction studies in demyelinating neuropathies was systematically studied in 138 diabetic patients without overt polyneuropathy (Bertora et al., 1998). Both motor and sensory fibers were studied conventionally and with Hopf’s method. A computer program was used to derive the cumulative density function from the CMAP amplitudes (Caccia et al., 1992a, 1992b). A reduced motor NCV in at least one nerve segment was found in 67%

CONDUCTION VELOCITY DISTRIBUTION

of the patients, sensory NCV was abnormal in 28%. An abnormal motor conduction velocity distribution was found in 82%, and an abnormal sensory conduction velocity distribution in 58% of the patients. The conduction velocity distribution was abnormal in 18% of the nerve segments in which the NCV was normal. This demonstrates a superior diagnostic sensitivity of conduction velocity distribution measurement to conventional nerve conduction studies. However, as the exact number of demyelinated nerves in study population is not known, absolute values of diagnostic sensitivities cannot be calculated. 18.5. Methods based on the analysis of compound action potentials The methods described above have the common grounds that action potentials of subpopulations of nerve fibers are isolated by some special technique and the conduction velocities of these fiber groups are measured. In contrast, the following methods are intended to derive the conduction velocity distribution as a whole, or certain parameters of it, from compound action potentials recorded with one of the standard methods described in the previous chapters. 18.5.1. Analysis of a single compound action potential Figure 18.3 illustrates that a compound sensory nerve action potential (SNAP) is the sum of the action potentials of the single fibers of that nerve. It is obvious that the compound SNAP can be calculated from the single fiber action potentials, simply by summation. If the inverse problem was solved, namely to calculate the single fiber action potentials from the compound SNAP, the conduction velocity distribution could be measured easily. Figure 18.4 illustrates that the inverse problem can be solved if the single fiber action potentials are very short. In this case the contribution of each single potential to the compound SNAP is apparent. In general, the inverse problem can only be solved if the single fiber action potentials meet certain conditions or if certain assumptions are made about them (see the appendix for a more mathematical discussion of this topic). Cummins et al. (1979a) introduced this principle and studied how the assumptions about the single fiber action potentials influence the resulting conduction velocity distributions. As the assumptions about the single fiber action potentials are critical to the method, and as there is no universal

411

agreement upon them, the method was not widely applied in the clinical setting. 18.5.2. Comparison of two compound action potentials During the following part of this chapter “two compound action potentials” stands as a name for action potentials recorded from the same site, but upon stimulation of the same nerve at different sites. Based on a computer simulation, Lee et al. (1975) suggested that an analysis of the differences between two CMAPs might provide a method for more detailed assessment of motor nerve conduction than conventional nerve conduction studies. Figure 18.2 illustrates that these differences are related to the conduction velocity distribution of the nerve segment between the stimulation sites. 18.5.2.1. Sensory nerves Barker et al. (1979) calculated conduction velocity distributions from two compound SNAPs. They used the method of Cummins et al. (1979a) described above (18.5.1) and additionally recorded SNAPs upon a second, more distal stimulus to generate and refine the assumptions about the single fiber action potentials. Cummins et al. (1979b) found that the summation of single nerve fiber action potentials to a compound SNAPs is equivalent to a mathematical operation called convolution (equation 3; see appendix) and used this principle to compute the conduction velocity distribution from two compound SNAPs. They studied median nerves of four healthy controls and found the conduction velocity distribution ranging from 35 to 75 m/s with a peak between 58 and 62 m/s. They compared this normative data with data from a median nerve of a patient with juvenile diabetes mellitus. Its maximal NCV was normal while its conduction velocity distribution was shifted towards lower values. Hirose et al. (1986) elegantly showed that to estimate the conduction velocity distribution by comparing two compound SNAPs is equivalent to solving a Fourier transformed mathematical equation (equation 4; see appendix). The mathematical background is called deconvolution. They provided a numerical algorithm for that purpose and studied its performance in median nerve SNAPs of ten healthy control subjects. They found non-Gaussian conduction velocity distributions ranging from 20 to 65 m/s and the peak between 52 and 60 m/s.

412

Gu et al. (1996) developed an alternative algorithm to solve equation (4) and compared its results with experimental animal data recorded in vitro from ten sciatic nerves. A good congruence between the computed conduction velocity distributions and the experimental data was found, but only for conduction velocities above 30 m/s. Gonzalez-Cueto and Parker (2002) also developed an alternative algorithm to solve equation (4) and used it on recordings from median nerves of 6 control subjects. Their results were similar to those of Hirose et al. (1986). To be able to study short nerve segments by a deconvolution method, Wells and Gozani (1999) recorded compound SNAPs from multiple nerve sites and also varied the stimulation site. Their results from median nerves of four control subjects were similar to the results of Hirose et al. (1986). Hirose et al. (1986) and Gonzalez-Cueto and Parker (2002) studied the test-retest reliability of their methods. Both groups found a good reproducibility of the estimated conduction velocity distributions, particularly in the range above 40 m/s, where the coefficient of variation was less than 10%. Below 40 m/s, the variability was consistently found twice as high than above 40 m/s. The method of Cummins et al. (1979b) was used in diabetic patients (Cummins and Dorfman, 1981; Dorfman et al., 1983). As intended, abnormal conduction velocity distributions could be demonstrated in the nerves of four (21%) out of 19 patients with normal conventional NCV. The clinical value of the other deconvolution methods has to be established. Dorfman (1984) already emphasized that these methods are particularly sensitive to noise and stimulus artifacts and permit estimation down to a conduction velocity of about 30 m/s, but usually not lower. Nonetheless, the results obtained with the method of Cummins et al. (1979b) suggest that the use of deconvolution methods improves the diagnostic value of nerve conduction studies. 18.5.2.2. Motor nerves Compound SNAPs can be treated as the sum of action potentials that are different in amplitude and latency, but not in shape (key assumption for equation 2; appendix). In contrast, CMAPs are the sum of action potentials that are different in shape also. Thus, deconvolution methods as described above will not necessarily produce valid results if applied to CMAPs instead of compound SNAPs. Nonetheless, this has been done by Dorfman et al. (1982). Their results cor-

WILHELM J. SCHULTE-MATTLER

responded reasonably well with results obtained with the collision method. Observations on conventional nerve conduction studies and ideas related to the aforementioned deconvolution methods led to the development of a new method to detect abnormally slow conducting fibers in a motor nerve. Conventionally, a CMAP upon proximal stimulation is lower, of longer duration, and of a different shape than the CMAP upon distal stimulation of the nerve. The differences increase with the distance between the stimulation sites and are greater in demyelinated nerves than in normal nerves (Kimura et al., 1986, 1988; Olney et al., 1987; Taylor, 1993; Schulte-Mattler et al., 2001b). Similar differences are observed when a lowpass filtered CMAP is compared with the original CMAP. Leifer et al. (1977) predicted and explained this phenomenon when they provided the theoretical background for their method of collision testing. Schulte-Mattler et al. (1999) thus compared Fourierspectra of CMAPs. The above-mentioned shape differences were quantitatively expressed as the high-frequency attenuation (HFA). The measurement of the HFA is based on off-line analysis of CMAPs, which are recorded following the standard motor nerve conduction methods (Chapter 6 of this volume). Routine equipment can be used, provided it has built-in artifact removal and Fourier analysis, or it supports some kind of waveform data export for waveform analysis by third-party software. A step-by-step description of the method follows: (1) Select a nerve for the study from Table 18.2. Place the recording surface electrodes over belly and tendon of the corresponding muscle. Place the ground electrode between the distal stimulation site (Table 18.2) and the recording electrodes. Set the amplifier gain to 5 mV/V and the filters to 2 Hz–5 kHz. Note that the filter setting may not be changed as the subsequent signal analysis takes places in the frequency domain. It may be necessary to adjust the amplifier gain to surely avoid clipping of the recorded waveforms, which makes them appear flat-topped in the display. (2) Place the stimulus electrode over the distal stimulation site (Table 18.2) and stimulate the nerve with increasing intensity until supra-maximal stimulus intensity is reached. The stimulation parameters are not critical to the method; the pulse width should suffice to later allow proximal supra-maximal

CONDUCTION VELOCITY DISTRIBUTION

413

Table 18.2 High frequency attenuation: Upper limits (99%) of normal Upper limit [%]

Stimulation sites

Recording site

Median nerve, wrist–elbow Ulnar nerve, wrist–elbow–Erb’s point Tibial nerve, ankle–knee

Thenar eminence Abductor digiti minimi Abductor hallucis

16 15 40

Upper limit [%] (length dependence taken into account) 13 + 0.22 * length 13 + 0.16 * length 29 + 0.4 * length

length: length of the nerve segment studied [cm].

stimulation. Make sure that the stimulus artifact is not excessive. Especially its slow (positive) afterwave should be less pronounced than the one shown in Fig. 18.7A. (3) Store the waveform (distal CMAP). (4) Place the stimulus electrode over the proximal stimulation site (Table 18.2) and stimulate the nerve with supra-maximal intensity. Although not mandatory for this method, the supramaximal intensity should be pursued, because otherwise, certain waveform characteristics, such as amplitude and area, cannot be measured validly. (5) Store the waveform (proximal CMAP). The further steps describe the digital processing of stored waveforms. Software to perform this task is freely distributed by the author ([email protected], to date, the software processes output file formats of systems of nicolet biomedical, Madison, Wisconsin, and Toennies, Hoechberg, Germany) to stimulate research on the measurements of conduction velocity distributions by post-processing of waveforms obtained during routine nerve conduction studies. (6) Remove the stimulus artifact from the CMAPs as shown in Fig. 18.7B, C. (7) Compute the Fourier-spectra of both CMAPs. Note that this is not the same as the “power spectrum,” but the square root of it. (8) In the Fourier-spectrum of each CMAP, determine the voltage at the cut-off frequency of 49 Hz and the area above 49 Hz, and divide the area by the voltage to get the sharpness of the CMAP (Fig. 18.7D). Note that with certain equipment it may happen that the cut-off frequency cannot be set to 49 Hz. The nearest of the possible value should be chosen in this case. However, the exact value is not critical.

(9) HFA =

sharpness distal − sharpness proximal sharpness distal

The example (Fig. 18.7) also illustrates that the artifact removal is critical to the method, as the HFA was 30 versus 60% without removal of the stimulus artifact. The theoretical reasoning, namely that an increased high-frequency attenuation indicates an increased percentage of abnormally slow conducting fibers in a nerve, was supported by a close correlation between high-frequency attenuation and changes in CMAP duration (Schulte-Mattler et al., 1999, 2001b). As the method was intended to sensitively detect conduction abnormalities (Fig. 18.8), its diagnostic sensitivity was studied in 20 patients with a polyneuropathy and a conventional motor NCV between 29 and 40 m/s, and in 21 patients with a polyneuropathy but normal conventional motor NCV. Abnormal highfrequency attenuation was found in eight (40%) of the patients with a reduced NCV and in nine (43%) of the patients with normal NCV (Schulte-Mattler et al., 1999). It was concluded that this method improves detection and characterization of demyelination, although it does not provide the full conduction velocity distribution of a nerve segment. An advantage of the method is that it can easily be applied to CMAPs recorded during routine nerve conduction studies if sufficient software is built into to the recording equipment or is available as an add-on. 18.6. Clinical implications For clinical purposes, the discomfort and the cost of a diagnostic method must be balanced against its diagnostic sensitivity and specificity. In the current context, demyelination is the target with respect to which diagnostic sensitivity and specificity are discussed.

414 Fig. 18.7 Measurement of the high-frequency attenuation (HFA) of a motor nerve segment. (A) Compound muscle action potentials (CMAPs) recorded from an abductor hallucis muscle of a healthy person. Electrical stimulation of the posterior tibial nerve at the ankle (distal) and at the knee (proximal). The large stimulus artifact was produced purposefully to demonstrate the artifact removal. (B) To eliminate the stimulus artifact, all waveform data before a certain time (T0, vertical dotted line) are replaced by the same value, i.e., the value measured at T0. Dashed oblique line: linear interpolation (LI) between the first and the last data point of the distal CMAP. (C) The LI is subtracted from the distal CMAP to eliminate the vertical gap between its first and its last data point, because such gaps cause large artifacts in Fourier-spectra. (D) Fourier-spectra of the CMAPs in (C). The baseline shift due to the subtraction of the LI appears as a peak at 0 Hz (arrow). Hatched: area above 49 Hz of the spectrum of the CMAP upon proximal stimulation. The sharpness value (= area above 49 Hz / amplitude at 49 Hz) of this CMAP is 292 Hz. Note the difference between both spectra in the area above 49 Hz. The sharpness value of the distal CMAP is 418 Hz. Thus, the high-frequency attenuation (= 1 − proximal sharpness/distal sharpness) of the nerve segment is 30% (upper limit of normal, 40%).

WILHELM J. SCHULTE-MATTLER

A distal proximal T0

4mV

B

5ms

C

D distal proximal

50 Hz

18.6.1. Diagnostic sensitivity A method’s diagnostic sensitivity for demyelination cannot be determined as usual by dividing the number of the detected by the number of the affected, because there is no gold standard method by which the number of the affected could be validly determined. However, the diagnostic sensitivities of methods can be com-

pared by counting the number of pathological findings in a group of patients that contains at least a certain number of affected individuals. In this case, the superiority of a method to a reference method can be expressed as that method’s percentage of abnormal findings in the subgroup of patients classified as normal by the reference method. This approach was chosen to compare the diagnostic sensitivities of the

CONDUCTION VELOCITY DISTRIBUTION

415

distal

proximal

4mV

50Hz

5ms

Fig. 18.8 Left: Compound muscle action potentials (CMAPs) recorded from an abductor hallucis muscle of a patient with a mild diabetic polyneuropathy. Same muscle as in Fig. 18.5. Nerve conduction velocity is 46 m/s. The differences in amplitude, area, and duration between both CMAPs are within the range of normal. Note the different shape of the CMAPs. Right: Fourier-spectra of the CMAPs. Hatched: area above 49 Hz of the spectrum of the CMAP upon proximal stimulation. Note the marked difference between both spectra in the area above 49 Hz. The high-frequency attenuation of the nerve segment is 46% (upper limit of normal, 40%).

methods discussed in this chapter. The conventional NCV served as the reference method to compile Table 18.3. In summary, it is well supported by the results of the clinical studies that the measurement of conduction velocity distributions increases the diagnostic yield of electrodiagnostic testing. However, a definite ranking of the methods according to their diagnostic sensitivity is not possible, because the structure of the groups of patients was different among the studies done so far. Moreover, several deconvolution methods call for their clinical evaluation. 18.6.2. Diagnostic specificity Demyelination cannot be characterized by only one parameter, as it is variable in both degree and distribution. For instance, inflammatory polyneuropathies cause a nonuniform degree of demyelination among the various individual nerve fibers comprising a peripheral nerve trunk. In contrast, a more diffuse and uniform demyelination is found in hereditary neuropathies, such as Charcot–Marie–Tooth, Type 1. Theoretically, each of both kinds of demyelination may well be characterized by the conduction velocity distribution of the affected nerve segment (Fig. 18.2). The conventional NCV is typically reduced in uniform demyelination, while the NCV may be normal in nonuniform demyelination. Especially in the latter case, the propagation of synchronously evoked action potentials from the stimulation site to the recording electrode is desynchronized. Called temporal dispersion, this is assessed with routine methods by compar-

ing amplitude, area, and duration of compound action potentials after proximal versus distal nerve stimulation (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force, 1991; Oh et al., 1994). However, the diagnostic sensitivity of this approach is limited (Weber, 1998). In the current context, the diagnostic specificity of a method would be maximal if an abnormal conduction velocity distribution obtained with this method was caused by uniform or nonuniform demyelination and not by some other underlying pathophysiological condition or an artifact. Moreover, the conduction velocity distribution should indicate whether the abnormality was caused by uniform or nonuniform demyelination. It is not clear at all how well this is the case in the reality. Only very few data on this topic were available when it was reviewed by Dorfman (1984). Since then, investigators have focused on the diagnostic sensitivity of the methods, so newer data on the diagnostic specificity are not available. However, according to our experience with the HFA method, it is likely that an increased HFA in a nerve segment with normal NCV specifically indicates nonuniform demyelination. A special pathophysiological state that challenges the diagnostic specificity of a method to estimate a conduction velocity distribution is conduction block, which is a segmental loss of the ability of axons to conduct action potentials. Kimura (1997) pointed out that demyelination may cause coexistence of both, temporal dispersion and conduction block in the same nerve segment, and that it may be impossible to

416

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Table 18.3 Overview of methods to characterize nerve conduction velocity distribution

Method

Fiber type

CVD

Gain in diagnostic sensitivity*

Pain**

Time***

Skills****

Remarks

Near nerve recording Nerve fiber stimulation F-wave dispersion

s, x m

p p

11% (Oh et al., 2001) n. d.

> 50 > 60

1h

yes yes

Invasive method Invasive method

m

f

20

0

no

Nerve segments cannot be studied

Collision testing

m, s

f

0–22% (Chroni and Panayiotopoulos, 1993; Weber, 1998; Nobrega et al., 2001) 18% (Bertora et al., 1998)

> 20

< 0.5 h

yes

Deconvolution of compound SNAPs

s, x

f 0 (< 0.5 h)

0

no

Special software needed

Deconvolution of CMAPs High frequency attenuation

m

f

7%–21% (Cummins and Dorfman, 1981, Dorfman et al., 1983) n. d.

0

0

no

m

p

0

0

no

Special software needed Special software needed

43% (SchulteMattler et al., 1999)

n.d., not determined; m, motor; s, sensory; x, mixed. CVD, Result of the method is a full conduction velocity distribution (f) or parameter(s) of it (p). * percentage of abnormal findings in a group of patients with (suspected) polyneuropathy but normal NCV. It should be noted that the structure of the groups of patients varies between studies. ** estimated number of electrical stimuli exceeding those required for a conventional nerve conduction study (NCS). *** time required in addition to what is necessary to do a conventional NCS. **** special training required in addition to what is necessary to do a conventional NCS.

distinguish between both conditions with conventional methods (Fig. 18.2C is an example). Conduction block may also be caused by channelblocking molecules (Brinkmeier et al., 2000) and thus occur independently from demyelination. Both causes of conduction block could be distinguished if the conduction velocity distribution in the nerve segment was known. However, no reports on the validity of the available methods in nerves with conduction block exist, except for the high-frequency attenuation method. When a partial conduction block was simulated by comparing CMAPs upon an inframaximal proximal stimulus with CMAPs upon a distal supramaximal stimulus, the high-frequency attenuation value was found independent of the intensity of the proximal stimulus (Schulte-Mattler et al., 1999). This suggests that demyelination and conduction block

may be assessed independently from each other, but further studies are necessary to confirm these results. 18.6.3. Suitability for clinical use All methods discussed in this chapter have the potential to provide more information about the pathophysiological state of a nerve or a nerve segment than current routine methods. However, each method has specific shortcomings, which may have hindered its widespread use in electrodiagnostic laboratories. The shortcomings are obvious with near nerve recording or with collision testing. The patient’s discomfort is definitely higher upon one of these studies than upon a routine nerve conduction study. Moreover, both methods are more time consuming than routine studies (Table 18.3). The time consumption especially

CONDUCTION VELOCITY DISTRIBUTION

417

has led to a gradual decrease in the number of studies done. However, the collision methods are particularly valuable for basic research, because they are the most reliable methods to determine the full conduction velocity distribution of a motor nerve. Some of the methods described here essentially are nothing else as numerical post-processing of waveforms obtained during routine nerve conduction studies, namely the F-wave dispersion, the deconvolution, and the HFA methods. The F-wave dispersion has the advantage that it can be measured without sophisticated computer programs but has the disadvantage of low test-retest reliability. The opposite is the case in the deconvolution and the HFA methods, which have high test-retest reliability but require specialized computer programs. If the computer programs were implemented into a routine laboratory, the diagnostic information that can be obtained with these methods would be available at no cost in time or patient’s discomfort. The use of these computer programs does not require a thorough understanding of the mathematical operations employed, which by the way are less complex than those required for computerized tomography. Thus, these methods are most suitable for clinical use. Moreover, a superior diagnostic sensitivity of one of the deconvolution methods and of the HFA method compared to conventional nerve conduction studies has been demonstrated (Table 18.3). A more widespread clinical use and further studies on their usefulness for clinical problem solving are therefore recommended.

N

CAP (ti) = ∑ FAPj (ti–l j)

with i running from 1 to the number of data points (D). Due to digitization, the number of different values of lj is limited to L, and may be limited to a lower value for the purpose of putting conduction velocities into classes. So (1c) is the same as: L

CAP (ti) = ∑ nj • FGAPj(ti–l j)

Mathematical formulation of the analysis of compound action potentials The summation of nerve fiber action potentials (FAPj) to a compound action potential is written as (N = number of nerve fibers, lj = latency of FAPj, vj = conduction velocities of the nerve fibers, d = distance between stimulation site and recording site): N

CAP (t) = ∑ FAPj(t –l j) with lj = d/vj

(1)

j=1

In reality, measurements and calculations are done with computers. Due to digitization, waveforms and latency values are represented as discrete data points, sampled at individual moments ti determined by the sampling rate sr = 1 / (ti+1 − ti). For computation (1) is written as

(ld)

j=1

In this equation, nj is the number of fibers in latency class lj (note the conduction velocity in each latency class is known by vj = d/lj, and that the pairs of nj and vj are the conduction velocity distribution). FGAPj are the action potentials generated by the fibers in latency class lj. If the FGAPj are given, (1d) is a system of linear equations that determines the nj if D > L (Cummins et al., 1979a). With the assumption that the action potentials of the single nerve fibers are different only in amplitude and latency, but are similar in shape, (1d) can be written as L

L

j=1

j=1

CAP(ti) = ∑ nj • aj NFAP (ti–lj ) = ∑ pj • NFAP (ti–lj) with NFAP

(2)

being the normalized single fiber action potential, aj the amplitude of FGAPj. Note that the information about the conduction velocity distribution is in the pj = nj • aj. For continuous instead of digitized data, equation (2) is equivalent to: ∞

CAP(t) = Appendix

(lc)

j=1

∫0 p(l ) • NFAP(t–l )dl = p(t) * NFAP(t)

(3)

where * denotes the convolution operation. Nerve stimulation at two different sites results in two different action potentials: CAPprox(t) = pprox(t)*NFAP(t) and CAPdist(t) = pdist (t) * NFAP(t) which can be written after Fourier transformation as ftCAPprox(w) = ftPprox(w) • ftNFAP (w) and ftCAPdist(w) = ftPdist(w) • ftNFAP(w) where ftXX represents the Fourier transformed term XX and w an angular frequency. These equations result in: ftCAPprox(w) ftCAPdist(w)

=

ftPprox(w) ftPdist(w)

(4)

418

This equation eliminates the necessity to know NFAP(t). Basically, the methods by researchers (Hirose et al., 1986; Gu et al., 1996; Wells and Gozani, 1999; and Gonzalez-Cueto and Parker, 2002) are different approaches to solve this equation for the P(w) numerically. References Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force (1991) Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology, 41: 617–618. Barker, AT, Brown, BH and Freeston, IL (1979) Determination of the distribution of conduction velocities in human nerve trunks. IEEE Trans. Biomed. Eng., 26: 76–81. Behse, F and Buchthal, F (1971) Normal sensory conduction in the nerves of the leg in man. J. Neurol. Neurosurg. Psychiatry, 34: 404–414. Bertora, P, Valla, P, Dezuanni, E, Osio, M, Mantica, D, Bevilacqua, M, Norbiato, G, Caccia, MR and Mangoni, A (1998) Prevalence of subclinical neuropathy in diabetic patients: assessment by study of conduction velocity distribution within motor and sensory nerve fibres. J. Neurol., 245: 81–86. Bischoff, C, Stalberg, E, Falck, B and Puksa, L (1996) Significance of A-waves recorded in routine motor nerve conduction studies. Electroencephalogr. Clin. Neurophysiol., 101: 528–533. Brinkmeier, H, Aulkemeyer, P, Wollinsky, KH and Rudel, R (2000) An endogenous pentapeptide acting as a sodium channel blocker in inflammatory autoimmune disorders of the central nervous system. Nat. Med., 6: 808–811. Caccia, MR, Osio, M, Dezuanni, E, Bevilacqua, M, Bertora, PL, Salvaggio, A, Mangoni, A, and Norbiato, G (1992a) Nerve conduction velocity distribution in normal subjects and in diabetic patients without clinical neuropathy. I. Motor nerve. Electromyogr. Clin. Neurophysiol., 32: 403–409. Caccia, MR, Osio, M, Dezuanni, E, Bevilacqua, M, Bertora, PL, Salvaggio, A, Mangoni, A and Norbiato, G (1992b) Nerve conduction velocity distribution in normal subjects and in diabetic patients without clinical signs of neuropathy. II. Sensory nerve. Electromyogr. Clin. Neurophysiol., 32: 411–416. Chroni, E and Panayiotopoulos, CP (1993) F tacheodispersion: quantitative analysis of motor

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fiber conduction velocities in patients with polyneuropathy. Muscle Nerve, 16: 1302–1309. Cummins, KL, Perkel, DH and Dorfman, LJ (1979a) Nerve fiber conduction-velocity distributions. I. Estimation based on single-fiber and compound action potentials. Electroencephalogr. Clin. Neurophysiol., 46: 634–646. Cummins, KL, Dorfman, LJ and Perkel, DH (1979b) Nerve fiber conduction-velocity distributions. II. Estimation based on two compound action potentials. Electroencephalogr. Clin. Neurophysiol., 46: 634–646. Cummins, KL and Dorfman, LJ (1981) Nerve fiber conduction velocity distributions: studies of normal and diabetic human nerves. Ann. Neurol., 9: 67–74. Dengler, R, Stein, RB and Thomas, CK (1988) Axonal conduction velocity and force of single human motor units. Muscle Nerve, 11: 136–145. Dorfman, LJ, Cummins, KL and Abraham, GS (1982) Conduction velocity distributions of the human median nerve: comparison of methods. Muscle Nerve, 5: S148–153. Dorfman, LJ, Cummins, KL, Reaven, GM, Ceranski, J, Greenfield, MS and Doberne L (1983) Studies of diabetic polyneuropathy using conduction velocity distribution (DCV) analysis. Neurology, 33: 773–779. Dorfman, LJ (1984) The distribution of conduction velocities (DCV) in peripheral nerves: a review. Muscle Nerve, 7: 2–11. Gonzalez-Cueto, JA and Parker, PA (2002) Deconvolution estimation of nerve conduction velocity distribution. IEEE Trans. Biomed. Eng., 49: 140–151. Gu, D, Gander, RE and Crichlow, EC (1996) Determination of nerve conduction velocity distribution from sampled compound action potential signals. IEEE Trans. Biomed Eng., 43: 829–838. Guiloff, RJ and Modarres-Sadeghi, H (1991) Preferential generation of recurrent responses by groups of motor neurons in man. Conventional and single unit F wave studies. Brain, 114: 1771–1801. Hirose, G, Tsuchitani, Y and Huang, J (1986) A new method for estimation of nerve conduction velocity distribution in the frequency domain. Electroencephalogr. Clin. Neurophysiol., 63: 192–202. Hopf, HC (1962) Untersuchungen über die Unterschiede in der Leitgeschwindigkeit motorischer Nervenfasern beim Menschen. Dtsch. Z. Nervenheilk, 183: 579–588.

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Ingram, DA, Davis, GR and Swash, M (1987) Motor nerve conduction velocity distributions in man: results of a new computer-based collision technique. Electroencephalogr. Clin. Neurophysiol., 66: 235–243. Kimura, J, Machida, M, Ishida, T, Yamada, T, Rodnitzky, RL, Kudo, Y and Suzuki, S (1986) Relation between size of compound sensory or muscle action potentials, and length of nerve segment. Neurology, 36: 647–652. Kimura, J, Sakimura, Y, Machida, M, Fuchigami, Y, Ishida, T, Claus, D, Kameyama, S, Nakazumi, Y, Wang, J and Yamada, T (1988) Effect of desynchronized inputs on compound sensory and muscle action potentials. Muscle Nerve, 11: 694–702. Kimura, J (1997) Facts, fallacies, and fancies of nerve conduction studies: twenty-first annual Edward H Lambert Lecture. Muscle Nerve, 20: 777–787. Lee, RG, Ashby, P, White, DG and Aguayo, AJ (1975) Analysis of motor conduction velocity in the human median nerve by computer simulation of compound muscle action potentials. Electroencephalogr. Clin. Neurophysiol., 39: 225–237. Leifer, L, Meyer, M, Morf, M and Petrig, B (1977) Nerve bundle conduction velocity distribution measurement and transfer function analysis. Proc. IEEE, 65: 747–755. Nobrega, JA, Manzano, GM and Monteagudo, PT (2001) A comparison between different parameters in F-wave studies. Clin. Neurophysiol., 112: 866–868. Oh, SJ, Kim, DE and Kuruoglu, HR (1994) What is the best diagnostic index of conduction block and temporal dispersion. Muscle Nerve, 17: 489–493. Oh, SJ, Melo, AC, Lee, DK, Cichy, SW, Kim, DS, Demerci, M, Seo, JH and Claussen GC (2001) Large-fiber neuropathy in distal sensory neuropathy with normal routine nerve conduction. Neurology, 56: 1570–1572. Olney, RK, Büdingen, HJ and Miller, RG (1987) The effect of temporal dispersion on compound action potential area in human peripheral nerve. Muscle Nerve, 10: 728–733. Panayiotopoulos, CP (1979) F chronodispersion: a new electrophysiologic method. Muscle Nerve, 2: 68–72. Panayiotopoulos, CP and Chroni, E (1996) F-waves in clinical neurophysiology: a review, methodological issues and overall value in peripheral neuropathies.

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Electroencephalogr. Clin. Neurophysiol., 101: 365–374. Puksa, L, Stalberg, E and Falck, B (2003) Reference values of F wave parameters in healthy subjects. Clin. Neurophysiol., 114: 1079–1090. Rossi, B, Sartucci, F and Stefanini, A (1981) Measurement of motor conduction velocity with Hopf’s technique in the diagnosis of mild polyneuropathies. J. Neurol. Neurosurg. Psychiatry, 44, 168–170. Ruijten, MW, Salle, HJ and Kingma, R (1993) Comparison of two techniques to measure the motor nerve conduction velocity distribution. Electroencephalogr. Clin. Neurophysiol., 89: 375–381. Schulte-Mattler, WJ, Jakob, M and Zierz, S (1999) Assessment of temporal dispersion in motor nerves with normal conduction velocity. Clin. Neurophysiol., 110: 740–747. Schulte-Mattler, WJ (2001a) Zeitliche Dispersion Und Leitungsblock In Menschlichen Motorischen Nerven: Ein Computermodell. Klin. Neurophysiol., 32: 196. Schulte-Mattler, WJ, Müller, T, Georgiadis, D, Kornhuber, ME and Zierz, S (2001b) Length dependence of variables associated with temporal dispersion in human motor nerves. Muscle Nerve, 24: 527–533. Taylor, PK (1993) CMAP dispersion, amplitude decay and area decay in a normal population. Muscle Nerve, 16: 1181–1187. Thomas, PK, Sears, TA and Gilliatt, RW (1959) The range of conduction velocity in normal motor nerve fibers to the small muscles of the hand and foot. J. Neurol. Neurosurg. Psychiatry, 22: 175–181. Tsai, CT, Chen, HW and Chang, CW (2003) Assessments of chronodispersion and tacheodispersion of F waves in patients with spinal cord injury. Am. J. Phys. Med. Rehabil., 82: 498–503. Weber, F (1998) The diagnostic sensitivity of different F wave parameters. J. Neurol. Neurosurg. Psychiatry, 65: 535–540. Wells, MD and Gozani, SN (1999) A method to improve the estimation of conduction velocity distributions over a short segment of nerve. IEEE Trans. Biomed Eng., 46: 1107–1120.

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CHAPTER 19

Magnetic stimulation Malcolm Yeh*, Jun Kimura and Thoru Yamada Department of Neurology, University of Iowa Hospital and Clinics, IA, USA

19.1. Introduction In early studies to map the motor cortex in animals and humans (Horsley, 1909; Leyton and Sherrington, 1917; Penfield and Boldrey, 1937), muscle twitches were elicited by electrical currents passed through the exposed brain. A modern electric stimulator allows excitation of the motor cortex transcutaneously with the use of high-intensity shocks (Merton and Morton, 1980). Electrical stimuli applied over the cervical spine can also activate C-8 and T-1 motor roots in the region of the intervertebral foramina (Merton et al., 1982). It takes much stronger stimuli to excite the descending tracts at the level of the pyramidal decussation (Ugawa et al., 1991, 1992, 1995a) or the spinal cord (Marsden et al., 1982; Snooks and Swash, 1985; Mills and Murray, 1986). Electrical stimulation has played an important role in elucidating motor physiology and pathophysiology (Cowan et al., 1984; Mills and Murray, 1985a; Eisen and Shtybel, 1990; Rossini et al., 1994), but discomfort associated with shocks applied at the scalp limits its practical application (Rossini et al., 1985b). In contrast, painless transcranial magnetic stimulation that relies on induced eddy-current stimulation has gained wider acceptance and has generally replaced electric shock in the clinical study of the motor evoked potential (MEP) (Barker et al., 1985c). The term “magnetic stimulation” has come to mean electrical stimulation from magnetic field induced eddy-currents rather than from direct stimulation by the magnetic field. Current induced from magnetic stimulation can excite not only the motor cortex but also the motor roots in the region of the intervertebral

*Correspondence to: Malcolm Yeh, MD, Department of Neurology, University of Iowa Health Care, Iowa City, IA 52242, USA. E-mail address: [email protected] Fax: +1-319-384-5195.

foramina, as well as peripheral nerves and plexuses (Smith and Murray, 1986; Chokroverty et al., 1989; Evans et al., 1990). With the use of a specially constructed coil, magnetic stimulation can activate the pyramidal decussations (Ugawa et al., 1994a, 1994b, 1995b, 1996; Werhahn et al., 1996) but not the spinal cord (Ugawa et al., 1989b). This technique has limited application in the assessment of the peripheral nerve for two reasons: (1) the inability to pinpoint the exact activation site; and (2) difficulty to stimulate selectively a specific nerve under consideration (Evans et al., 1988; Britton et al., 1990; Olney et al., 1990). Advances in coil design may further improve the technical precision and clinical utility of transcranial magnetic stimulation in the study and diagnosis of the peripheral nerve diseases. 19.2. Electrical stimulation of the brain and spinal cord 19.2.1. Animal experiments A brief low-intensity anodal electrical stimulus delivered to the exposed motor cortex induces a single descending volley (Amassian et al., 1987; Cracco, 1987; Inghilleri et al., 1989). This is called the direct wave (D-wave) because it results from direct activation of pyramidal tract neurons in the region of the axon hillock (Patton and Amassian, 1954). With a stimulation of higher intensities, a series of descending volleys follow the D-wave at intervals of about 2 ms. These subsequent waves are called indirect waves (I-waves) because they result from transynaptic activation of the same corticospinal neurons through interneurons (Kernell and Chien-Ping, 1967). Removal of the cortex abolishes the I-waves, which depend on cortical interneurons, though the D-wave persists and does not require any synaptic activation. A single high-intensity anodal shock to the contralateral scalp causes repetitive firing of the anterior horn cells, producing a muscle twitch that greatly exceeds

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the force produced by supramaximal stimulation of the peripheral nerves (Day et al., 1987a). 19.2.2. D-wave and I-waves Anodal current, applied on the motor cortex, hyperpolarizes dendrites near the surface and depolarizes the axon and cell body in the depth more effectively than the cathodal current (Hern et al., 1962). In the anodal case, the dendrites serve as the current source where the current flows out. The axon at the hillock, the site of the current sink where the current enters, depolarizes the first internode and produces a D-wave. Activation of interneurons with stimulation of higher intensities leads to trans-synaptic excitation of the pyramidal output neurons and I-waves. In reverse, cathodal stimulation over the surface hyperpolarizes the axon hillock, raising the threshold for D-wave acti-

vation which, in turn, enhances the indirect transsynaptic excitation of I-waves (Day et al., 1987a; Rothwell et al., 1987). Randomly timed low-intensity cortical shocks alter the firing probability of a voluntarily activated motor unit (Boyd et al., 1986). A single peak in the peristimulus time histogram produced by this means corresponds to a D-wave volley. When recorded from the cervicomedullary junction during surgery, the D-wave has a latency of about 2 ms after cortical stimulation. Higher electrical stimulus intensities induce both D-waves and a series of I-waves volleys in the pyramidal tract. (Fig. 19.1) 19.2.3. Technical considerations Using a specially made electrical stimulator capable of delivering a high-voltage (2000 V) pulse of short duration (10 μs), a single-scalp stimulus with an anode

Electrical stimulation Cervical-medullary recording

Isoflurane 0.5 % Stim intensity 10 V 50 V 125 V 200 V 300 V

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Fig. 19.1 The comparison of D-waves and I-waves. The arrows show an increasing amplitude of the D-wave response with progressively shorter latencies as the cortical electrical stimulation increases. Note that I-waves appear at higher stimulation intensities and is are more prominent in the absence of anesthesia.

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over the motor cortex and a cathode at the vertex (Cowan et al., 1984; Mills and Murray, 1985a) elicits a submaximal MEP of 1 mV or more. Moderate voluntary contraction facilitates the muscle response elicited by a stimulus not much above threshold, yielding a muscle action potential of near maximal amplitude. A modified monopolar stimulation utilizes a flat anode (4.8 cm2) placed on the scalp over the motor cortex, and a flexible stainless steel belt cathode wrapped around the head 2–3 cm above the nasioninion plane. Unifocal stimulation tends to concentrate the electrical field on the anode over the motor cortex with the field spreading to the circumferential cathode, allowing the motor cortex to be stimulated with a fraction of the shock intensities employed by the conventional bipolar stimulator (Rossini et al., 1985b). High-voltage electrical stimulation applied over the mastoid process at the base of the skull can activate the descending motor tracts at the level of cervicomedullary junction. A small voluntary contraction of the target muscle tends to facilitate an evoked muscle response with no change in latency. In one study (Ugawa et al., 1991), the latency difference for the first dorsal interosseous averaged 1.5 ms between cortical and brainstem stimulation, and 3.9 ms between cortical and cervical stimulation. Thus, this method seems to stimulate the pyramidal decussation at a point midway between the cortex and the cervical enlargement. Unlike cortical stimulation that elicits multiple descending volleys, brainstem stimulation probably evokes a single impulse. The facilitation of cortical stimulation by the subject’s voluntary contraction of the muscle is not present for transcutaneous stimulation of the spinal cord and requires a very large electrical stimulus (1500 V) making it impractical for clinical use (Marsden et al., 1982; Snooks and Swash, 1985). 19.2.4. Clinical studies and limitations Transcranial electrical stimulation of the cortex provides a means to monitor spinal cord function during surgery (Levy, 1987; Edmonds et al., 1989; Zentner, 1989). Stimulation of the spinal cord with needle electrodes inserted into the spinous processes also elicits, via descending impulses to the anterior horn cells, a peripheral nerve potential that may be recorded at the popliteal fossa if neuromuscular transmission is blocked with muscle relaxants (Owen, 1993; Phillips et al., 1995). Spinal-evoked potentials recorded by epidural electrodes also serve as a monitor for spinal cord surgeries (Kitagawa

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et al., 1989; Shinomiya et al., 1990). Anesthesia, with inhalational agents such as nitrous oxide, halothane, enflurane, and isoflurane suppresses the descending impulse at the level of the spinal interneuronal or motor neuronal systems (Zentner and Ebner, 1989; Zentner et al., 1992). An electrical shock using smaller stimulating electrodes is better suited for surgical monitoring than magnetic stimulation because a more focal activation overcomes the effect of anesthetic agents. Also, under the influence of anesthesia, patients perceive no discomfort associated with contraction of the scalp and facial muscles, induced by high-intensity stimulation. Certain physiologic studies still require deliveries of single electrical stimuli of very high intensities with a half-decay time for discharge of 50 or 100 μs (Rothwell et al., 1987; Benecke et al., 1988; Robinson et al., 1988). Electrical shock therapies, that produce convulsions, use the intensities far exceeding those required for MEP. Kindling typically develops only after trains of long-duration stimuli of about 1.0 ms, not by single stimuli of short duration. Thus, despite initial considerable concerns, the delivery of single stimuli of very short duration (50 μs) will produce few side effects if any at all. Nevertheless, one must seek unequivocal evidence that no permanent adverse changes result before embarking on new specific modes of cortical stimulation. 19.3. Transcranial magnetic stimulation 19.3.1. Design of the magnetic coil Magnetic coil stimuli can excite the motor cortex through the intact scalp and skull in conscious, alert subjects to elicit a motor evoked potential (Barker et al., 1985a; Hess et al., 1987a). Stimulation with a circular coil may fail to evoke detectable responses in the lower limb in 10% of normal subjects. The figureof-eight coil with precise placement, has a better yield providing a more focal excitation under the site of intersection (Eisen and Shtybel, 1990; Jalinous, 1991). This type of coil is also used to activate the bulbocavernosus, sphincter, and pelvic floor muscles (Opsomer et al., 1989; Ertekin et al., 1990). Magnetic stimulation induces sensation described as tingling descending along the leg, usually accompanied by responses evoked in the leg muscles (Cohen et al., 1991d). The coil can activate the cortex, peripheral nerves, and roots but, for some unknown reason, not the spinal cord (Ugawa et al., 1989b).

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Based on Faraday’s principle, an electric current in a conducting coil forms the primary circuit that will induce a time-varying magnetic field that, in turn, induces an electric current in tissue adjacent to the coil (Gualtierotti and Paterson, 1954). This induced tissue current represents the secondary circuit. This technique, although first applied in peripheral nerve stimulation is now used mostly in studies of the motor cortex (Barker et al., 1987; Bickford et al., 1987; Durand et al., 1992). In contrast to direct electrical stimulation applied to the cortex that excites the corticospinal axons directly, magnetic stimulation activates both the axon hillocks of the output neurons and a presynaptic site (Mills and Kimiskidis, 1996a). Based on the analysis of the electric field, the site of maximal intensity is localized to the level of the gray-white junction, resulting in activation of layer VI of the cerebral cortex (Epstein et al., 1990). With magnetic coil stimulation, discharging a capacitor charged to 4 kV generates a brief but intense magnetic field of up to 2 tesla. This magnetic field induced by the coil placed over the scalp penetrates unattenuated through the skull and induces a secondary current inside the skull (Reutens et al., 1993). This induced current exceeds the threshold to excite the motor cortex although the low current density at the surface causes no pain. Variations of coil shapes include, in addition to the original circular form, the figure-of-eight or “butterfly,” “four-leaf,” “slinky” (Zimmermann and Simpson, 1996), and “double cone” configuration (Ugawa et al., 1994b, 1996). 19.3.2. Discharge pattern of motor neurons The intensity of stimuli, orientation of the coil, and excitability of neural elements dictate the size of the MEP (Mills and Nithi, 1997b; Nakatoh et al., 1998). A stimulus with intensity 20% above the threshold stimulus is required to evoke a reproducible response in the intrinsic hand muscles with latencies consistent with conduction from fast central pathways. Higher intensities are required to activate the proximal muscles in the upper limbs. The responses evoked by magnetic stimuli have a longer latency by about 2 ms compared to those elicited electrically (Hess et al., 1986a). This latency difference shift corresponds to the delay of the first I-wave after the D-wave, as might be expected from preferential excitation of interneurons from magnetic stimulation as opposed to selective motor neuron excitation from electric stimulation (Day et al., 1987b).

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Figures 19.1 and 19.2 show the D-wave and I-wave responses to electrical and magnetic stimulation, respectively. It is of note that electrical stimulation can preferentially stimulate D-waves in isolation whereas magnetic stimulation cannot due to the inherent nature of the diffuse sites that magnetic pulses stimulate. The direction of current flow in the magnetic coil determine the efficacy of cortical current in exciting the interneurons and motor neurons (Day et al., 1989; Wilson et al., 1996). A circular coil centered at the vertex tends to activate the left hemisphere and the intrinsic hand muscles on the right, if the inducing current is directed anticlockwise when viewed from above. Turning the coil over reverses the direction of the current, thus stimulating the right hemisphere. In one study, it took less intensity to stimulate the left hemisphere than the right to minimally activate the contralateral abductor digiti minimi (Macdonell et al., 1991). During voluntary muscle contraction, small slowconducting cortical motor neurons fire before the larger, faster-conducting neurons. This size principle (Henneman et al., 1965) also applies to magnetic stimulation that activates the cortical motor neurons in the same order, recruiting the long-latency motor units first using intensities at threshold to just begin to stimulate the brain (Hess et al., 1987a). With stronger stimuli capable of inducing the D-wave, the initially activated motor units with the lowest threshold shorten in latency as other motor units are recruited. Multiple firing at the level of the anterior horn cell occurs after single electrical or magnetic stimuli. This multiple firing contributes to the complexity of the MEP waveform when greater stimulus intensities are used. For the same reason, the twitch forces produced by a single maximal cortical stimulus may exceed those elicited by supramaximal excitation of the peripheral nerve. The use of collision studies can help document repetitive firing of alpha motor neurons with a single cortical stimulus (Day et al., 1987a; Hess et al., 1987a; Rothwell et al., 1987). In this technique, stimulation at the wrist sets up an antidromic volley, which eliminates the first of the orthodromic volley of the spinal motor neurons induced by either electric or magnetic brain stimulation (Day et al., 1987a). If the anterior horn cells fire more than once, however, the second orthodromic volleys meet no antidromic impulse, giving rise to a corresponding muscle response. Voluntary background contraction enhances the recorded response not only by recruitment of additional motor units but also by repetitive firing of the same motor units.

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A Magnetic stimulation Cervical-medullary recording Isoflurane Off Stim intensity 50 %

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Fig. 19.2 (A) Magnetic stimulation shows the onset of I-waves with smaller amplitude D-waves when compared to electrical stimulation with increasing stimulation intensity. (B) Increasing intensities of magnetic stimulation shows more robust CMAP amplitudes at shorter latencies.

As mentioned earlier, transcranial magnetic stimuli modulate the firing pattern of voluntarily discharging motor units. Superimposing many such trials while maintaining steady voluntary contraction reveals a firing probability for a motor unit when viewed in a peristimulus time histogram (Hess et al., 1986b; Mills, 1991; Mills et al., 1991; Boniface et al., 1994; Garland and Miles, 1997). The primary peak, seen at approximately 20 ms after stimulus, corresponds to the latency of the corticospinal pathway. Thus, this peak reflects the excitatory postsynaptic potentials (EPSP) arriving at the anterior horns cell of the peripheral motor neurons following cortical activation. The peristimulus time histogram shows an abnormal corticospinal excitability in amyotrophic lateral scle-

rosis but not in Kennedy’s diseases, which involves only the lower motor neuron (Eisen et al., 1996; Kohara et al., 1996; Mills and Nithi, 1997a; EnterzariTaher et al., 1997; Kohara et al., 1999; Weber and Eisen, 1999). The same technique applied to the corticobulbar tract revealed a short latency activation of EPSP to the orbicularis oris, consistent with a direct monosynaptic projection (Liscic et al., 1998). 19.3.3. Facilitation and inhibition Spontaneous fluctuations in corticospinal excitability (Ellaway et al, 1998) probably account for a high degree of variability in the amplitude of MEP on repeated trials (Kiers et al., 1993; Nielsen, 1997).

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When using conditioning stimuli, the cortical excitability has been shown to have an initial facilitation at intervals of 1–2.5 ms and a period of suppression of up to 20 ms, before a gradual recovery to the baseline (Inghilleri et al., 1990; Rossini et al., 1996; Schafer et al., 1997). Similar studies recording the corticospinal volleys show a triphasic change of excitability that includes inhibition at 2.5 ms, facilitation at 25 ms, and a second inhibition at 100–200 ms (Kaneko et al., 1996a, 1996b; Nakamura et al., 1997). An actual or imaginary contraction of the target muscle (Kiers et al., 1997) enhances MEPs elicited by cortical stimulation (Hess et al., 1987a). In this type of facilitation, lowering the motor neuron threshold probably involves both the motor cortex and the spinal cord. An additional peripheral mechanism may or may not play a role (Macdonell et al., 1992; Shafiq and Macdonell, 1994; Shefner et al., 1995). With electric stimulation, voluntary contraction reduces the onset latency of the recorded response by 2 to 4 ms and increases its amplitude approximately linearly with the degree of effort. With magnetic stimulation, a small voluntary contraction reaching only 5% of maximum is sufficient to markedly enhance the amplitude (Helmers et al., 1989) and shorten the onset latency by about 3 ms. This is probably a result of spinal summation (Kaneko et al., 1996a, 1996b). Post-exercise facilitation, induced by mild nonfatiguing exercise of the target muscle, decays to baseline over 2–4 min, whereas post-exercise depression caused by fatiguing exercise returns to baseline after about 12 min (Brasil-Neto et al., 1993, 1994; Samii et al., 1997b). In contrast, voluntary contraction of the contralateral muscle produces neither post-exercise facilitation nor depression (Samii et al., 1997a). Vibration of the target muscle increases the excitability of the alpha motor neurons which, in turn, enhances a cortically activated MEP response (Claus et al., 1988b; Kossev et al., 1999; Siggelkow et al., 1999). Motor-threshold stimulation of the median nerve at the wrist enhances the cortically activated MEP response, which is probably on the basis of muscle afferent input from the peripheral nerve stimulation (Komori et al., 1992). Other inputs such as cutaneous afferent activities (Deletis et al., 1992; Rossini et al., 1996) and speech (Tokimura et al., 1996) also affect cortical excitability. Likewise, a magnetic stimulus over the cerebellum reduces the size of cortical activated MEP responses evoked by magnetic stimulation given 5–7 ms later (Ugawa et al., 1997a).

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Transcranial magnetic stimulation induces a silent period for the voluntarily contracted target muscle, which probably results from intracortical inhibition (Uozumi et al., 1991, 1992; Wilson et al., 1993a; McKay et al., 1996; Odergren and Rimpilainen, 1996; Cruccu et al., 1997; Fritz et al., 1997; Sacco et al., 1997; Leis et al., 1998). Transcranial magnetic stimulation also inhibits brainstem motor neurons (Leis et al., 1993; Cruccu et al., 1997). A transcallosal inhibition, which develops after the age of 5 years, accounts for suppression of voluntary muscle contraction ipsilateral to the transcranial magnetic stimulation (Davey et al., 1994; Heinen et al., 1998). 19.3.4. Practice and safety consideration Magnetic stimulation applied to the cortex transcranially can produce a motor evoked potential that can be recorded with a pair of surface electrodes placed conventionally over the target muscle (Dunnewold et al., 1998). The muscle modestly facilitated with voluntary contraction in the range of 10–20% of full capacity yields the best response. With stronger effort, excessive noise makes latency measurement difficult, whereas with weaker effort, responses become inconsistent. Moderate contraction of the contralateral homologous muscle shows a similar effect, reducing latency and increasing amplitude without the obscuring noise. With a slightly contracted muscle, the onset latency remains the same over a wide range of stimulus intensity regardless of the coil location within an area of 6 cm2 over the vertex. The shortest onset latency is measured from the largest response after a series of four or five consecutive trials and the amplitude is expressed as a percentage of the maximal muscle response evoked by stimulation of the peripheral nerve (Hess et al., 1986a). Transcranially induced MEP responses have a greater physiologic temporal dispersion and phase cancellation than peripherally evoked MEP responses, reflecting a longer pathway. An additional startle effect from the loud snapping sound of the discharging magnetic coil may give rise to late muscle responses sometimes recorded after the cortically evoked short-latency primary potential (Holmgren et al., 1990). Some investigators also measure waveform complexity, and trial-to-trial variability (Britton et al., 1991a, 1991b; Mills and Nithi, 1997a). Abnormalities may result from different pathophysiologic processes, such as a block or degeneration of corticospinal fibers or a dispersion of the response, depressed excitability of spinal motor neurons or presynaptic inhibition of corticospinal terminals.

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Rate-dependent conduction failure characteristic of demyelination may block trains of I-waves, which, in turn, would prevent discharges of otherwise normal spinal motor neurons. For these reasons, changes seen in a wide range of neurologic disorders imply no single disease process, although some findings are considered more typical of one than another. A few milliseconds’ delay in the central conduction time also have limited specificity, because a number of physiologic variables affect the propagation of the descending volley in the corticospinal tract. Despite this nonspecific nature, the technique helps confirm motor system abnormalities suspected on clinical ground and demonstrate subclinical motor abnormalities. Its role for quantification and follow-up purposes, however, remains ill defined. Magnetic stimulation, if conducted judiciously, is safe in the clinical domain (Cowan et al., 1984; Mills and Murray, 1985a; Hess et al., 1986b). In one series of 30 healthy subjects, studies of EEG and cognitive and motor functions remained normal before and after transcranial magnetic stimulation. Biochemical studies detected a slight decline in serum prolactin level, but the test results showed an absence of correlation to the extent of stimulation (Bridgers and Delaney, 1989). A repeated series of high-intensity stimuli in the cat caused no adverse effects on cortical electrical

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activity and blood flow, blood pressure, and heart rate (Eyre et al., 1990). During rapid repetition of magnetic stimulation, the heating of metal electrodes can cause surface temperature increases, but not to the extent to induce a skin burn or other possible safety hazard (Roth et al., 1992). Despite initial concerns, single or repetitive stimuli now in use pose no risk of kindling, which require a train of high-frequency stimuli at a rate of 3 Hz or higher (Jahanshahi et al., 1997). Only isolated reports of focal seizures have appeared associated with the procedure out of many thousands of patients tested with cortical stimulation (Homberg and Netz, 1989; Kandler, 1990). One study looks at the acoustic noise levels generated by magnetic coils as shown in Fig. 19.3 (Counter and Borg, 1992). The maximum peak energy in the acoustic spectrum of the noise from the magnetic coil had maximum energy in the frequency range of 2 to 5 kHz. This is the range of highest sensitivity in the human ear. Ear protectors were recommended as a result of this study. However, these results were obtained on earlier magnetic coil designs and may not be applicable to the newer coils used today, though a follow-up studies on the newer coils is yet to be done. Other possible adverse effects, although unlikely, would include dislodging of intracranial metallic objects such as aneurysm clips and shunts, and disrupting implanted electronic

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0.1

0.5

1.0

5.0

10.0

Frequency (kHz)

Fig. 19.3 The wave form and spectral characteristics (A,B) of the MCAA (Magnetic Coil Acoustic Artifact) at 70% EMS (extracranial magnetic stimulation) generated by the 5-cm coil of the Cadwell MES 10 and recorded in the sound field with a microphone positioned 10 cm from the coil in place of the head, and at the vertex position on the manikin (C,D), all in an anechoic chamber with a 0.5 ms delay before onset of wave form trace. (Reprinted from Counter, SA and Borg, E (1992) Analysis of the coil generated impulse noise in extracranial magnetic stimulation. Electroencephalogr. Clin. Neurophysiol., 85: 280–288. Reprinted with permission from International federation of Clinical Neurophysiology.)

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hardware such as a cardiac pacemaker. A published guideline describes the recommended application and safety precautions for the use of repetitive transcranial magnetic stimulation in the US (Wassermann et al., 1996; Chen et al., 1997). 19.4. Studies of the peripheral nerve Magnetic stimulation began with studies of the peripheral nervous system in 1959, using a frog nervemuscle preparation (Kolin et al., 1959). Later attempts with a mixed human nerve produced visible muscle contractions (Bickford et al., 1987). A single-pulsed magnetic stimulator was then introduced to elicit compound muscle action potentials (Barker et al., 1987). Its clinical utility is still limited to the study of the proximal nerve segments not easily accessible to conventional electrical stimulation (Evans et al., 1988; Maccabee et al., 1988a). 19.4.1. Stimulator characteristics Magnetic coil stimulation, in general, fails to excite various nerves focally at different definable points along their course, although optimal coil orientation helps activate the nerve at the stimulator position. A longitudinal current depolarizes the axons more effectively than transverse-fields (Ruohonen et al., 1996). Thus, the nerve fibers oriented perpendicular to the coil surface receive less current than those lying parallel to the rim. Results may vary, depending on soft tissue heterogeneity, which determines current flow (Kobayashi et al., 1997). A clockwise and counterclockwise current flow are equally effective though lifting the stimulator coil off the skin surface markedly reduces the stimulus effect because induced tissue current declines with the distance from the stimulating induction coil. Submaximal nerve activation renders the estimation of the stimulus point less accurate. The degree of selective excitation of the peripheral nerve depends on the type of coil employed and its orientation to the nerve. With the use of a round coil, for example, supramaximal stimulation of the median nerve at the wrist tended to concomitantly activate the ulnar nerve (Evans et al., 1988). Others, however, reported success in focally exciting some peripheral nerves using a different type of round coil (Maccabee et al., 1988a). Round coils may deliver supramaximal stimulation in a tangentialedge orientation at some selective sites (Olney et al.,

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1990) but they usually do not fulfill the stimulation requirements for the peripheral nerve. Even butterfly coils that provide more selective stimulation with improved focus cannot match the precision afforded by electrical stimulators. Reproducibility studies of magnetic stimulation using round coils on the same subjects on two separate occasions, revealed dramatic variability in conduction velocities ranging from 5 to 11 m/s for motor fibers (Halar and Venkatesh, 1976) and up to 14 m/s for antidromic sensory fibers. This is compared to the use of a butterfly coil, which showed velocity differences of less than 7 m/s for sensory and motor conduction in most segments. Magnetic stimulation proved less accurate than electrical stimulation for calculation of conduction velocities, especially for the short segment of the ulnar nerve across the elbow (Olney et al., 1990). The preferential activation of sensory axons over motor axons seen with electric stimulation does not hold with magnetic stimuli, which excite both fiber populations equally. Thus, electrical stimulation suits better for the study of H-reflexes, which is best elicited by selective activation of the sensory axons (Olney et al., 1990). Magnetic stimulation, if applied directly over the skeletal muscle, excites the nerve terminal at the motor point leading to a muscle contraction (Machetanz et al., 1994; Ellaway et al., 1997). Motor point stimulation also evokes cerebral potentials (Tsuji et al., 1988) through the activation of terminal afferents independent of muscle contraction (Zhu et al., 1996). Based on the results of collision experiments, magnetic stimulation shows a greater current dispersion longitudinally compared to electric shocks (Cros et al., 1990). Distal sensory nerve action potentials cannot be reliably recorded with magnetic stimulation because there is interference from muscle response and stimulus artifact. (Lotz et al., 1989). All the above data justify the conclusion that the use of a magnetic coil stimulator is not warranted in the routine clinical practice of peripheral electrodiagnosis. As a test for a commonly studied peripheral nerve, round magnetic stimulators provide no real advantages over conventional bipolar electrical stimulation (Evans et al., 1988). The technique generally fails the minimal requirement met by electrical stimulation for low intertrial variability of latencies, localization of the stimulation point, and reproducibility of the evoked waveform. The lack of supramaximal intensity poses further problems in assessing the exact

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site of nerve activation (Evans et al., 1988; Maccabee et al., 1988a; Olney et al., 1990). Consideration for future devices should include smaller stimulator heads, improved coil configuration, and higher power output (Binkofski et al., 1999). 19.4.2. Stimulation of deep structure Conventional electrical stimulation has better precision than magnetic stimulation in peripheral nerve studies. However, the use of magnetic fields, which attenuate very little through the bone, provides a useful addition when studying deeply located nerve (Cros et al., 1992). Magnetic stimulation given over the spinal column activates the nerve roots or spinal nerve and elicits the potentials in limb muscles with little pain. Although a flat 12 cm coil design fails to produce supramaximal responses, preferential activation of the largest diameter axons makes the onset latency stable for clinical use (Britton et al., 1990). Highvoltage electrical stimulation over the spinal column, though painful, has the advantage of evoking supramaximal motor responses (Mills and Murray, 1986; Maertens de Noordhout et al., 1988). Magnetic or electrical stimulation applied near the C6 spinous process elicits muscle action potentials in the upper limbs. Unlike cortical stimulation, voluntary contraction does not appreciably influence the responses elicited by cervical stimulation. Based on the latency comparison with the F-wave, cervical excitation, either electric or magnetic, activates the spinal nerve 2–4 cm distal to the motor neuron (Mills and Murray, 1986; Schmid et al., 1990). The exact site of activation is determined by the degree of nerve excitability and the electric field within the heterogeneous volume conductors, but depolarization probably originates in the axon hillock known to have the lowest threshold (Maccabee et al., 1991). Thus, shifting the coil position induces little change in latency of the evoked response. With a coil is placed over the appropriate nerve roots the clockwise current, as viewed from behind, activates a greater response in the right arm, and vice versa (Schmid et al., 1990). Excitation of the sensory axons near the spinal foramina by magnetic stimulation placed over the cervical spine elicits sensory potentials around the fingers (Zwarts, 1993). Somatosensory cortical potentials evoked by magnetic stimulation over the T10, T12 and L5 vertebral levels show a correlation between the body height and the latency of the N2 component (Tsuji and Murai, 1991).

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Stimulation over the lumbosacral region evokes muscle action potentials in the lower limbs (Markand et al., 1984). Stimuli applied over the conus medullaris at the T12 spinous process elicit a response more effectively than those delivered over the cauda equina more distally (Ugawa et al., 1990). A round coil placed over the lumbar spinal column tends to activate the spinal nerve some 3.0 ms or 15 cm distal to the motor neuron (Britton et al., 1990). Consequently, the peripheral conduction time measured by this means relates to the nerve segment distal to the radicular portion. This MEP latency often decreases further with the spread of effective current distally with the use of greater supramaximal stimuli (Plassman and Gandevia, 1989). Muscle responses elicited by proximal stimuli, vary in waveform from one trial to the next partly because of overlapping, intermittently generated F-waves. Consecutive subtraction of sequentially elicited muscle responses, therefore, reveals proximally activated F-waves, which appears only intermittently. Concomitantly applied distal stimulation can also elucidate the F-wave by eliminating orthodromic impulses responsible for the M-response. The F-waves recorded by these means provide a measure of the nerve conduction time for the most proximal parts of the motor axons. Application of a figure-eight coil over the distal cauda equina, tend to excites the lumbar roots if the junction is oriented horizontally, and the sacral roots if the junction is oriented vertically (Maccabee et al., 1996; Maegaki et al., 1997). A figure-eight coil oriented with the junction vertically, that yields a cranially directed induced current, can also excite the cauda equina proximally near or at the root exit zone (Maccabee et al., 1996). The latency difference between this proximal response and distal response elicited by lumbar or sacral root stimulation near the foramina yields a cauda equina conduction time. Careful stimulation of the sacral roots allows simultaneous recording of M- and H- waves in one trace. The latency difference between these two responses relates to the cauda equina conduction time along the short proximal reflex pathway or the central loop, eliminating the much longer distal components of the afferent and efferent arc. (Troni et al., 1996; Zhu et al., 1998). The magnetic coil has been used to stimulate the deeply located nerves such as the intracranial portion of the cranial nerves (Schmid et al., 1995; Ghezzi and Baldini, 1998), phrenic nerve (Garland

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et al., 1996; Zifko et al., 1996a), femoral nerve (Polkey et al., 1996), and thoracic spinal nerve (Chokroverty et al., 1995). In one study, transcranial magnetic stimulation activated the facial nerve approximately 6.5 cm proximal to the usual site of electric stimulation near the stylomastoid foramen (Maccabee et al., 1988b). In another study, the impulse was generated in the proximal part of the facial canal to yield a transosseal conduction time of 1.2 ms (Rosler et al., 1989). When placing the magnetic coil tangentially over the T5 or T6 electrode position (using the International 10–20 EEG System nomenclature), compound muscle action potentials can be recorded from the ipsilateral nasalis muscle with onset latencies of 4.5 ± 0.5 ms (mean ± SD) (Seki et al., 1990). These values are compared to the onset latencies of 3.2 ± 0.4 ms obtained by electrical stimulation applied 1 cm below the anterior tragus. Calculations based on extracranial facial nerve conduction velocity of 59.6 ± 4.5 m/s localized the point of magnetic activation to the brainstem root exit zone of the facial

C3

nerve, which is 79.0 ± 8.6 mm proximal to the point of extracranial electrical stimulation. Intraoperative stimulation of the facial nerve at this point indeed elicits a response with the same latency as transcranial magnetic stimulation (Tokimura et al., 1993). Magnetic stimulation of the facial nerve has been used in the studies of Bell’s palsy (Maccabee et al., 1988b; Rosler et al., 1989; Seki et al., 1990; Tokimura et al., 1993; Rosler et al., 1994), facial myokymia (Oge et al., 1996) and other disorders of the facial nerve (Glocker et al., 1999a, 1999b). A magnetic coil placed below the zygomatic arch can activate the trigeminal nerve to elicit a masseter response that is recorded with an electrode inserted into the pterygomandibular plica over the belly of the muscle (Turk et al., 1994). Figure 19.4 shows another study investigating facial nerve CMAPs elicited by magnetic coil placed at different sites over the scalp. Onset and peak latencies were the same, irrespective of the coil location, but the highest amplitude was obtained when the coil was centered at T5 (Seki et al., 1990).

P3

C3

T3 C3/T3

T5

M

O1

P3/T5 M

T3

P3

T5

pM

pM

T5/O1

O1

1 mV 1 ms

Fig. 19.4 CMAPs elicited by magnetic coil placed at different sites over the scalp. Onset and peak latencies were the same, irrespective of the coil location, but the highest amplitude was obtained when the coil was centered at T5. C3/T3, P3/T5, and T5/O1 indicate the midpoints between C3 and T3, P3 and T5, and T5 and O1, respectively. M, mastoid tip; pM, 4 cm under T5. Twenty percent of maximum magnetic output (5% supramaximal intensity of this subject) was applied. In all traces, the sweep began 1 ms after stimulus. (with permission: Seki, Y et al. (1990) Transcranial magnetic stimulation of the facial nerve: recording technique and estimation of the stimulated site. Neurosurgery, 26: 286–290 with permission from Lippincott Williams and Wilkins.)

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19.5. Central conduction time 19.5.1. Method and normal values The onset latencies of the motor evoked potential (MEP) elicited by transcranial cortical stimulation relate to the entire motor system from the cortex to the muscle, including the corticospinal pathway to the spinal motor neurons. Cervical stimulation with the cathode over the C7 and T1 spinous processes excites the motor roots at the foramina where they leave the spinal canal (Mills and Murray, 1986). The central conduction time calculated as the latency difference between the two, therefore, includes a small radicular component. In a typical case, the total motor conduction time of about 20 ms comprises a peripheral latency of 13 ms, synaptic and root delay of 1.5 ms, and central motor conduction time of 5.5 ms. Some researchers advocate the use of F-waves (Rossini et al., 1985b; Samii et al., 1998) elicited from magnetic coil stimulation over Erb’s point to estimate the peripheral latency for calculation of the central conduction time. 19.5.2. Use of root stimulation Root stimulation by magnetic or high-voltage electrical stimulation over the spinal process provides a means of measuring peripheral conduction time (Mills and Murray, 1986). A magnetic coil centered over the spinal column with the inducing current flowing clockwise, as viewed from behind, excites the cervical motor roots on the right (Schmid et al., 1990). An alternative method uses needle stimulation of the lower cervical roots with the cathode placed near the C7 to T1 interspinous space and the anode 6 cm rostrally or laterally. Muscle responses evoked by cervical magnetic stimulation nearly, though not completely, match in amplitude those elicited by electrical stimulation of the peripheral nerve at the wrist or elbow. Thus, in addition to latency measures, the technique can be used to determine proximal conduction block in the motor roots (Mills and Murray, 1985b). High-voltage electrical stimuli, though associated with moderate local discomfort, works best to elicit a reproducible muscle response to assess the waveform. The central conduction time is calculated by subtracting the CMAP latency of root stimulation from the CMAP latency of cortical motor neuron stimulation. Of these, the root conduction time covering the 1 to 2 cm distance varies, depending on peripheral motor

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conduction velocities from a normal 0.4 ms at 50 m/s to 0.46 ms at 30 m/s and 0.89 ms at 20 m/s (Claus et al., 1990). The use of a higher stimulus intensity to elicit a larger response will activate the root more distally, shortening the peripheral latency which, in turn, increases calculated central conduction time. For the lower limb study, the stimulating cathode or the magnetic coil is placed over the conus medullaris to excite the intradural motor roots close to the cord (Maertens de Noordhout et al., 1988; Ugawa et al., 1989b). Thus, the central conduction time determined by this method includes the short radicular latency. The cathode or coil may be placed more caudally to stimulate the motor roots distally near the intervertebral foramina. The latency difference between the two yields a measure of conduction along the cauda equina. 19.5.3. Calculation based on the F-wave In contrast to root stimulation, the use of F-waves enables the determination of the total peripheral motor conduction time, thus eliminating a small radicular component from the calculated central conduction time. The F-wave latencies vary with a small change in the stimulation point along the nerve, posing a particular problem with the poorly localized activation site after magnetic coil stimulation. Irrespective of the site of nerve activation, however, the sum of the M- and Flatencies remain the same because the increase or decreased in F-wave latency precisely compensates for the opposite change in M-response latency. Thus, the conduction time along the entire length of the peripheral motor pathway calculated by the following formula holds, regardless of the site of nerve excitation. Assuming 1 ms for the turnaround time at the cell body, Total peripheral conduction time =

( F + M −1) 2

where M and F represent the latencies of the Mresponse and F-wave. 19.6. Clinical application 19.6.1. Normal values Magnetic stimulation has found a wide application in the evaluation of the motor system and higher brain functions (Cracco, 1987; Rossini and Rossi, 1998). Various factors influence the normative data for motor evoked potential and central motor conduction studies when using either electrical or magnetic stimulation.

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These include the subject’s age and height, target muscle, degree of voluntary contraction, coil position, coil size, direction of current flow, stimulus intensity and the method for estimating peripheral conduction time. The formula for the calculation of central conduction time assumes the activation of the same group of motor fibers from both cortical and spinal stimulation. If the large fast-conducting spinal motor neurons are recruited from cervical stimulation but not cortical stimulation, for example, this discrepancy will lead to an erroneous increase in calculated central conduction time (Thompson et al., 1987a). In one study of 40 normal subjects, body height showed a linear correlation to both cortical and spinal latencies when using electrical stimulation. The central conduction time calculated as the difference between the two, however, remained the same (Ugawa et al., 1989a). Infants have a high threshold for cortical magnetic stimulation, decreasing to the adult level at about age of eight years (Koh and Eyre, 1988). The onset latency shows a progressive increase from childhood to adolescence reaching adult values at about 11 years of age. A further increase with age reflects slowing of conduction in both the central and peripheral motor pathways associated with decline in amplitude (Eisen and Shtybel, 1990). Magnetic stimulation, with an intensity 20% above the threshold at rest, evokes a response in an weakly contracted muscle of at least 18% of the maximal response elicited by peripheral electrical stimulation. Therefore, an amplitude reduction to a level below 15% of the maximum response suggests a conduction block along the motor pathways. In one study (MilnerBrown et al., 1975), MEP latency of 22.5 ms obtained by transcranial magnetic stimulation slightly exceeded that of 18–21 ms obtained after stimulation of the exposed human cortex. Transcranial magnetic stimulation elicited a response in the voluntarily contracted tibialis anterior with an average central motor conduction latency of 12.5 ms in healthy subjects (Claus, 1990). Either demyelination or degeneration of fast-conducting corticospinal fibers delays the central motor conduction. The impulses are transmitted by the affected fibers or small intact myelinated fibers, or by other physiologically slower indirect pathways. Any reduction in the descending volley by loss of fibers or conduction block will diminish the central drive on the alpha motor neurons, delaying their excitation. Thus, the correlation between the central motor conduction time and the degree of phasic and twitch force gener-

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ated with muscle contraction reflects the conduction block and temporal dispersion of descending impulse rather than delayed conduction per se (van der Kamp et al., 1991). 19.6.2. Neuropathies and radiculopathies Magnetic stimulation shows normal central conduction times if corrected for slowing of the proximal motor roots in Charcot–Marie–Tooth disease (CMT) types 1 and 2 and multifocal motor neuropathy (Molinuevo et al., 1999). This stands in contrast to delayed central conduction in CMT type 5 with pyramidal features such as extensor plantar responses (Claus et al., 1990), and in some cases of acute or chronic inflammatory demyelinating polyneuropathy (Ormerod et al., 1990; Wohrle et al., 1995). The use of magnetic stimulation in the diagnosis of lumbosacral radiculopathy has inherent limitation associated with the inability to localize the exact site of activation (Chokroverty et al., 1989; Bischoff et al., 1993b; Ertekin et al., 1994a; Linden and Berlit, 1995). Recording from the external anal sphincter, magnetic stimulation of the cauda equina at the L1 revealed a greater pudendal nerve latency in patients with idiopathic neurogenic fecal incontinence (7.3 ± 0.7 ms mean ± SD) compared to normal subjects (5.6 ± 0.6 ms) (Swash and Snooks, 1986). The two groups, however, showed no difference in the proximal conduction time of the cauda equina between the L1 and L4 vertebral levels (Swash and Snooks, 1986), demonstrating the clinical utility of evaluating the efferent system in this condition. 19.6.3. Other applications Normal motor-evoked potential studies support, but do not necessarily prove a functional basis of apparent weakness. For example, patients with chronic “post viral” fatigue syndrome have normal central motor conduction studies both at rest and after a prolonged muscle contraction. Conversely, an absent or delayed MEP tends to rule out an entirely functional weakness, if suspected on clinical grounds (Schriefer et al., 1987). Other areas of peripheral nerve function or related fields evaluated by transcranial magnetic stimulation include reciprocal inhibition (Mercuri et al., 1997), motor control (Tarkka et al., 1995; Hoshiyama et al., 1996), tremor resetting (Pascual-Leone et al., 1994b), the effect of limb immobilization (Zanette et al.,

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1997), effects of digital nerve stimulation (Manganotti et al., 1997), sympathetic skin responses (Linden et al., 1996; Matsunaga et al., 1998; Niehaus et al., 1998), brachial plexus injury (Oge et al., 1997), mitochondrial disorders (Di Lazzaro et al., 1997), and tetanus (Warren et al., 1999). References Amassian, VE, Stewart, M, Quirk, GJ and Rosenthal, JL (1987) Physiological basis of motor effects of a transient stimulus to cerebral cortex. Neurosurgery, 20: 74–93. Barker, AT, Freeston, IL, Jalinous, R and Jarratt, JA (1985a) Motor responses to non-invasive brain stimulation in clinical practice. Electroencephalogr. Clin. Neurophysiol., 61: S70. Barker, AT, Freeston, IL, Jalinous, R and Jarratt, JA (1987) Magnetic stimulation of the human brain and peripheral nervous system: an introduction and the results of an initial clinical evaluation. Neurosurgery, 20: 100–109. Barker, AT, Jalinous, R and Freeston, IL (1985c) Noninvasive magnetic stimulation of human motor cortex. Lancet, 1: 1106–1107. Benecke, R, Meyer, BU, Gohmann, M and Conrad, B (1988) Analysis of muscle responses elicited by transcranial stimulation of the cortico-spinal system in man. Electroencephalogr. Clin. Neurophysiol., 69: 412–422. Bickford, RG, Guidi, M, Fortesque, P and Swenson, M (1987) Magnetic stimulation of human peripheral nerve and brain: response enhancement by combined magnetoelectrical technique. Neurosurgery, 20: 110–116. Binkofski, F, Classen, J and Benecke, R (1999) Stimulation of peripheral nerves using a novel magnetic coil. Muscle Nerve, 22: 751–757. Bischoff, C, Meyer, BU, Machetanz, J and Conrad, B (1993b) The value of magnetic stimulation in the diagnosis of radiculopathies. Muscle Nerve, 16: 154–161. Boniface, SJ, Schubert, M and Mills, KR (1994) Suppression and long latency excitation of single spinal motoneurons by transcranial magnetic stimulation in health, multiple sclerosis, and stroke. Muscle Nerve, 17: 642–646. Boyd, SG, Rothwell, JC, Cowan, JM, Webb, PJ, Morley, T, Asselman, P and Marsden, CD (1986) A method of monitoring function in corticospinal pathways during scoliosis surgery with a note on

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Deletis, V, Schild, JH, Beric, A and Dimitrijevic, MR (1992) Facilitation of motor evoked potentials by somatosensory afferent stimulation. Electroencephalogr. Clin. Neurophysiol., 85: 302–310. Di Lazzaro, V, Restuccia, D, Servidei, S, Valeriani, M, Nardone, R, Manfredi, G., Silvestri, G, Ricci, E and Tonali, P (1997) Functional involvement of central nervous system in mitochondrial disorders. Electroencephalogr. Clin. Neurophysiol., 105: 171–180. Dunnewold, RJ, van der Kamp, W, van den Brink, AM, Stijl, M and van Dijk, JG (1998) Influence of electrode site and size on variability of magnetic evoked potentials. Muscle Nerve, 21: 1779–1782. Durand, D, Ferguson, AS and Dalbasti, T (1992) Effect of surface boundary on neuronal magnetic stimulation. IEEE Trans. Biomed. Eng., 39: 58–64. Edmonds, HL, Jr., Paloheimo, MP, Backman, MH, Johnson, JR, Holt, RT and Shields, CB (1989) Transcranial magnetic motor evoked potentials (tcMMEP) for functional monitoring of motor pathways during scoliosis surgery. Spine, 14: 683–686. Eisen, A, Entezari-Taher, M and Stewart, H (1996) Cortical projections to spinal motoneurons: changes with aging and amyotrophic lateral sclerosis. Neurology, 46: 1396–1404. Eisen, AA and Shtybel, W (1990) AAEM minimonograph #35: Clinical experience with transcranial magnetic stimulation.[see comment]. Muscle Nerve, 13: 995–1011. Ellaway, PH, Davey, NJ, Maskill, DW, Rawlinson, SR, Lewis, HS and Anissimova, NP (1998) Variability in the amplitude of skeletal muscle responses to magnetic stimulation of the motor cortex in man. Electroencephalogr. Clin. Neurophysiol., 109: 104–113. Ellaway, PH, Rawlinson, SR, Lewis, HS, Davey, NJ and Maskill, DW (1997) Magnetic stimulation excites skeletal muscle via motor nerve axons in the cat. Muscle Nerve, 20: 1108–1114. Enterzari-Taher, M, Eisen, A, Stewart, H and Nakajima, M (1997) Abnormalities of cortical inhibitory neurons in amyotrophic lateral sclerosis. Muscle Nerve, 20: 65–71. Epstein, CM, Schwartzberg, DG, Davey, KR and Sudderth, DB (1990) Localizing the site of magnetic brain stimulation in humans.[see comment]. Neurology, 40: 666–670. Ertekin, C, Hansen, MV, Larsson, LE and Sjodahl, R (1990) Examination of the descending pathway

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patients with ataxia. Electroencephalogr. Clin. Neurophysiol., 104: 453–458. Ugawa, Y, Terao, Y, Nagai, C, Nakamura, K and Kanazawa, I (1995b) Electrical stimulation of the cerebellum normally suppresses motor cortical excitability in a patient with ataxia due to a lesion of the middle cerebellar peduncle. Eur. Neurol., 35: 243–244. Ugawa, Y, Uesaka, Y, Terao, Y, Hanajima, R and Kanazawa, I (1994b) Magnetic stimulation of corticospinal pathways at the foramen magnum level in humans. Ann. Neurol., 36: 618–624. Ugawa, Y, Uesaka, Y, Terao, Y, Suzuki, M, Sakai, K, Hanajima, R and Kanazawa, I (1996) Clinical utility of magnetic corticospinal tract stimulation at the foramen magnum level. Electroencephalogr. Clin. Neurophysiol., 101: 247–254. Uozumi, T, Ito, Y, Tsuji, S and Murai, Y (1992) Inhibitory period following motor potentials evoked by magnetic cortical stimulation. Electroencephalogr. Clin. Neurophysiol., 85: 273–279. Uozumi, T, Tsuji, S and Murai, Y (1991) Motor potentials evoked by magnetic stimulation of the motor cortex in normal subjects and patients with motor disorders. Electroencephalogr. Clin. Neurophysiol., 81: 251–256. van der Kamp, W, Maertens de Noordhout, A, Thompson, PD, Rothwell, JC, Day, BL and Marsden, CD (1991) Correlation of phasic muscle strength and corticomotoneuron conduction time in multiple sclerosis. Ann. Neurol., 29: 6–12. Warren, JD, Kimber, TE and Thompson, PD (1999) The silent period after magnetic brain stimulation in generalized tetanus. Muscle Nerve, 22: 1590–1592. Wassermann, EM, Grafman, J, Berry, C, Hollnagel, C, Wild, K, Clark, K and Hallett, M (1996) Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr. Clin. Neurophysiol., 101: 412–417. Weber, M and Eisen, A (1999) Assessment of upper and lower motor neurons in Kennedy’s disease: implications for corticomotoneuronal PSTH studies.[see comment]. Muscle Nerve, 22: 299–306. Werhahn, KJ, Taylor, J, Ridding, M, Meyer, BU and Rothwell, JC (1996) Effect of transcranial magnetic stimulation over the cerebellum on the excitability of human motor cortex. Electroencephalogr. Clin. Neurophysiol., 101: 58–66.

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Wilson, SA, Day, BL, Thickbroom, GW and Mastaglia, FL (1996) Spatial differences in the sites of direct and indirect activation of corticospinal neurones by magnetic stimulation. Electroencephalogr. Clin. Neurophysiol., 101: 255–261. Wilson, SA, Lockwood, RJ, Thickbroom, GW and Mastaglia, FL (1993a) The muscle silent period following transcranial magnetic cortical stimulation. J. Neurol. Sci., 114: 216–222. Wohrle, JC, Kammer, T, Steinke, W and Hennerici, M (1995) Motor evoked potentials to magnetic stimulation in chronic and acute inflammatory demyelinating polyneuropathy. Muscle Nerve, 18: 904–906. Zanette, G, Tinazzi, M, Bonato, C, di Summa, A, Manganotti, P, Polo, A and Fiaschi, A (1997) Reversible changes of motor cortical outputs following immobilization of the upper limb. Electroencephalogr. Clin. Neurophysiol., 105: 269–279. Zentner, J, Albrecht, T and Heuser, D (1992) Influence of halothane, enflurane, and isoflurane on motor evoked potentials.[see comment]. Neurosurgery, 31: 298–305. Zentner, J and Ebner, A (1989) Nitrous oxide suppresses the electromyographic response evoked by electrical stimulation of the motor cortex. Neurosurgery, 24: 60–62. Zhu, Y, Starr, A, Haldeman, S, Chu, JK and Sugerman, RA (1998) Soleus H-reflex to S1 nerve root stimulation. Electroencephalogr. Clin. Neurophysiol., 109: 10–14. Zhu, Y, Starr, A, Haldeman, S, Fu, H, Liu, J and Wu, P (1996) Magnetic stimulation of muscle evokes cerebral potentials by direct activation of nerve afferents: a study during muscle paralysis. Muscle Nerve, 19: 1570–1575. Zifko, U, Remtulla, H, Power, K, Harker, L and Bolton, CF (1996a) Transcortical and cervical magnetic stimulation with recording of the diaphragm. Muscle Nerve, 19: 614–620. Zimmermann, KP and Simpson, RK (1996) “Slinky” coils for neuromagnetic stimulation. Electroencephalogr. Clin. Neurophysiol., 101: 145–152. Zwarts, MJ (1993) Sensory potentials evoked by magnetic stimulation of the cervical spine. Muscle Nerve, 16: 289–293.

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CHAPTER 20

Applications of SSEP recordings in the evaluation of the peripheral nervous system Malcolm Yeh*, Thoru Yamada and Jun Kimura Department of Neurology, University of Iowa Hospital and Clinics, IA, USA

20.1. Introduction The somatosensory evoked potential (SSEP) obtained from transcutaneous electrical stimulation of superficial nerves has been used in clinical medicine for well over 30 years because of the ease and availability of portable electronic systems that provide both stimulus and recording in one unit. Transcutaneous electrical stimulation has the advantage of being a very brief and accurately timed stimulus. This is required to capture time-locked SSEPs that have amplitudes well below the average amplitude of ongoing EEG activity. The time-locked acquisition of the SSEP improves the signal-to-noise ratio by averaging techniques and thus resolves the SSEP signal from the background electrical activity. Following stimulation of a peripheral nerve, SSEPs are recorded from the surface electrodes placed over the scalp, spine, and peripheral nerves along the anatomical course of the sensory pathway. SSEPs have been used for diagnostic assessment of sensory pathways in the brain, brain stem, spinal cord, and peripheral nerves. Electrical stimulation of peripheral nerves can also generate compound muscle action potentials (CMAPs) and peripheral nerve action potential (PNAPs); these action potentials have large-amplitude responses in the range of milli-volts (mV) and are readily elicited by a single electric shock. In contrast, SSEPs have much smaller amplitude responses, in the range of microvolts (μV), and are commonly amplified by signal averaging over a sufficient number of responses recorded from timelocked stimulation. Signal averaging elevates the

* Correspondence to: Malcolm Yeh MD, Department of Neurology, University of Iowa Hospital and Clinics, Iowa City, IA 52242, USA. E-mail address: [email protected] Tel.: +1-319-356-2695; fax: +1-319-384-5195.

amplitude of the SSEP signal over that of the background because averaging eliminates random noise. The smaller the amplitude of the response, the greater the number of replicate responses that must be averaged to yield a measurable and meaningful significant response. The standard error of the mean amplitude is inversely proportional to the square root of the number of measurements. Because SSEPs track the functional integrity of the peripheral and central nervous system, a lesion affecting any part of somatosensory pathway can alter the recorded SSEP. SSEP components, especially far-field potentials of short latency, prove useful in localizing lesions that affect the spinal cord, brainstem, subcortical, and cortical regions. Details of far-field potentials are beyond the scope of this chapter; the reader is referred to references (Cracco and Cracco, 1976; Jones, 1977; Yamada et al., 1980; Kimura and Yamada, 1990) for further information. To evaluate the peripheral nerves, electromyography (EMG) and nerve conduction studies (NCS) are the primary diagnostic tools, but SSEPs also play an important role. SSEPs may be especially useful in examining proximal segments of peripheral nerves (i.e., plexus or root lesions), where EMG and/or NCS are difficult to apply. SSEPs are conventionally elicited by electrical stimulation of either mixed or cutaneous nerves. Although more natural stimulations, such as pain, temperature, and pressure, can elicit SSEPs (Pratt and Starr, 1986), the early responses are much smaller than those of electrically elicited SSEPs, because the onset and offset of natural stimuli are more gradual, and the natural stimulus devices are more complicated. Thus, the use of SSEP studies to evaluate pain and temperature function have not been popularized as clinical diagnostic tests. Electrical stimulation activates the large and fast-conducting group IA muscle afferent nerves and group II cutaneous afferent fibers. The slow conduction of myelinated and unmyelinated

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fibers carrying pain and temperature information does not contribute signals in the same domain as those evoked electrically. However, high-intensity electrical stimulation or CO2 laser stimulation can elicit longlatency SSEPs, which have been termed as “painrelated SSEPs.” To evaluate pain fiber conduction and pain-perception, CO2 laser pulses have become a more common mode of stimulation because the laser pulse selectively activates pain (nociceptive) fibers, without concomitant activation of cutaneous mechano-receptors such as tactile, pressure, and proprioceptive receptors. In this chapter, we shall present various methods of SSEP recordings using electrical as well as various natural stimuli and discuss the usefulness and limitations of various modes of stimulation used to evaluate the central sensory pathways and function of peripheral nerves. 20.2. Somatosensory evoked potentials from transcutaneous electrical stimulation 20.2.1. Somatosensory evoked potentials methods using transcutaneous electrical stimulation The following section describes electrode placement and transcutaneous electrical stimulation parameters for SSEP recordings that specifically select for the fastest-conducting fibers in the peripheral nervous system. 20.2.1.1. Recording electrodes For upper extremity SSEPs, electrodes are placed in the left and right supraclavicular fossas (known as Erb’s points or Ep), Cv5 (cervical spine at the level of C5), and over the scalp located in the frontal (F3, F4 in accordance to 10–20 International System) and parietal areas (CP3, CP4 which are situated in-between C3 and P3, C4 and P4, respectively). Additional electrodes that may be used as reference electrodes, include A1 and A2 as references for scalp electrodes, and anterior-neck as references for the Cv5 cervical electrode. Representative derivations have been shown in Fig. 20.1. In montage A (recommended by the American Clinical Neurophysiology Society, formerly the American EEG Society; Anonymous, 1994), the CPi–Epi derivation (“c” indicates contra- and “i” indicates ipsilateral electrode to the side of stimulation) registers the far-field potentials of P9, P11, P13 and P14 and N18 (Fig. 20.1A). The CPc–CPi derivation

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records near-field potential N20 selectively, with all the above far-field potentials cancelled because such potentials are distributed bilaterally with equi-potentiality at both (CPc, CPi) electrodes. The Cv5–Epc derivation yields the N13 cervical potential and the Epc–Epi derivation records the Erb’s near-field potential. In montage B, the Fc–Ai derivation records the P13–P14 and N18 potentials and the CPc–Ai derivation yields the P13 and P14 far-field potentials along with the N20 near-field potential (Fig. 20.1B). These two derivations help to identify the far-field potentials, P13/P14, because P13/P14 are present on both (Fc and CPc) electrodes. Further, the N20 near-field potential that appears shortly after the N18 potential, has a near phase-reversal relationship with frontal P22. The Cv5–anterior neck derivation registers the N9, N11 and N13 potentials, of which “N9” is the inverse of the P9 far-field potential. This P9 potential becomes N9, a negative peak in the Cv5–anterior neck derivation because the potential is more positive at the anterior neck electrode relative to the Cv5 electrode. To record the lower extremity SSEP, the electrodes are placed at the popliteal fossa, T12 spine, and scalp. Because the cortical representation for the lower extremity is situated close to the interhemispheric fissure, the electrodes are placed closer to midline using CPz (in-between Cz and Pz electrodes), CP1, and CP2 electrodes (in-between CP3 and CPz, and CP4 and CPz, respectively). Electrodes Fpz, linked-ears, or neck can be used as a reference for scalp electrodes and the iliac crest (IC) location can be used as a reference for the T12 spine electrode. In montage A (recommended by American Clinical Neurophysiology Society), the CPi–Fpz and CPz–Fpz derivations record the P37 (P40) cortical potential (Fig. 20.2A). In contrast to SSEP recordings of the upper extremity (which show the first cortical potential, N20, recorded at parietal electrode contralateral to the side of stimuli), the first cortical potential, P37 (P40), is maximally distributed over the ipsilateral hemisphere close to the midline (CP) region, which is designated as a “paradoxical” lateralization (Seyal et al., 1983; Kakigi and Shibasaki, 1983; Yamada et al., 1996). The Fpz–Cv5 derivation records the P31 and N34 far-field potentials for the lower extremity, which corresponds to the P14 and N18 potentials for upper extremity SSEPs, respectively (Urasaki et al., 1993). The P31 and N34 potentials are derived predominantly from the FPz electrode with little activity contributed from the Cv5

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Right Median Nerve Stimulation Montage A N20

CP3(c)-CP4(i)

N18

CP4(i)-Ep(Lt)

P9

P11 P13

P14

N13

Cv5-Ep(Lt)

Ep(Rt)-Ep(Lt)

3 ms 5 ms

2.5 μV 32 ms

Fig. 20.1 (A) CP3 (c )–CP4 (i) registers near field potential (the first cortical potential) of N20 selectively, canceling all far-field potentials, which are common in both electrodes. CP4 (i)–Ep (Lt) is for far-field potential recording, registering P9, P11, P13, P14 and N18. Note the close latency relationship between P9 and Erb’s potential and between cervical N13 and scalp P13. P14, identified as the onset peak of N18, occurs slightly later than the cervical N13 peak. (In this and subsequent figures, “i” indicates ipsilateral and “c” indicates contralateral electrodes in relationship to the side of the body stimulated). Continued

electrode. The T12–IC derivation registers only the N24 spinal potential. In montage B, the CPz–FPz derivation records only the P37 (P40) near-field potential; however when CPz, CP1, or CP2 is referenced to the ear electrode, then both the P31 far-field potential and P37 (P40) nearfield potential can be recorded (Fig. 20.2B). The popliteal electrodes record the near-field peripheral nerve potential with a latency of about 8 msec (N8). 20.2.1.2. Stimulus parameters The stimulus electrodes are placed on the skin overlying the nerve to be stimulated, with the cathode proximal to the anode by 2–3 cm. For upper extremity SSEPs, the ulnar or median nerve is stimulated at the

wrist. To obtain adequate SSEP responses, the stimulation intensity required for a mixed nerve is usually 1.3–1.5 times the motor threshold, which generally ranges from 10 to 25 mA. The stimulus pulse duration typically ranges between 0.1 and 0.2 msec. The median nerve is the most commonly used site because it yields the most robust responses. The median nerve stimulation activates the C6 and C7 cutaneous afferents, whereas ulnar nerve stimulation activates the C8 and T1 afferents. The choice of nerve to stimulate is dependent on the anatomical level of interest at the nerve root or cord level. To evaluate of root lesions that have more segmental specificity, cutaneous nerve stimulation is preferred over median nerve stimulation. Cutaneous nerve stimulation using ring

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Right Median Nerve Stimulation Montage B N30 N18

F3(c)-A2(i)

P13 P14 P22

N32

N20

CP3(c)-A2(i) P13 P14 N9 N11 N13

P26

Cv5-Ant.Neck

Ep(Rt)-Ep(Lt)

3 ms 5 ms

2.5 μV 32 ms

Fig. 20.1, Cont’d (B) The derivations F3 (c)–A2 (i) and CP3 (c) -A2 (i) register the P13/P14 far-field potentials. Subsequent peaks have different latencies between F3 and CP3 electrodes: The N18–P22–N30 potential complex is noted in the frontal electrode and the N20–P26–N32 potential complex occurs at the parietal electrodes. With the non-cephalic derivation, CV5–anterior neck, N9 and N11 potentials are registered, which correspond to P9 and P11, respectively, recorded from the scalp-non cephalic derivation (CP4–EP in Fig. 20.1A). The P14 potential, identified as the onset peak of N18 or N20, consistently occurs slightly later than the cervical N13 peak.

electrodes to stimulate cutaneous nerves in the fingers can be performed at the thumb for C6, middle finger for C7, and little finger for C8 root assessments. The SSEP response is much smaller in amplitude from digit stimulation than from mixed nerve stimulation and, therefore, requires a greater number of trials for averaging to yield a measurable response. The stimulus intensity for these cutaneous nerves is usually two to three times the sensory threshold using the same stimulus pulse duration of 0.1–0.2 ms. The stimulus rate is usually 3–5 Hz but can be as fast as 8 Hz without significant deterioration in the response (Tsuji et al., 1984; Shiga et al., 2001).

For the lower extremity SSEP, the posterior tibial nerve at the ankle is the most common site stimulated. The peroneal nerve can be stimulated at the popliteal fossa, but this induces large leg movements that may interfere with the recording. Both sites stimulate a mixed nerve and evaluate spinal roots at the level of L5 and S1. For more specific segmental stimulation, cutaneous nerves in the lower extremity can be stimulated. This includes the sural nerve on the dorsum of foot for root S1, the superficial peroneal nerve located above the ankle for root L5, the saphenus nerve located at the knee and ankle for roots L3 and L4, respectively, and the lateral

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Right Tibial Nerve Stimulation Montage A N50

CP2(i)-Fpz

P40

P60 N50

CPz-Fpz

P60

P40

Fpz-Cv5

N34

P31

T12Sp.-lliac crest N24

2.5 μV

10 ms

5 ms 55 ms

Fig. 20.2 (A) The derivations CP2 (i)–FPz and CPz–FPz register the P40–N50–P60 cortical potentials, which are paradoxically lateralized to the ipsilateral (to the side of stimulation) hemisphere and vertex region. The FPz–CV5 derivation shows the far-field potentials P31 and N34, which are primarily derived from the FPz electrode with little contribution from the Cv5 electrode. P31 and N34 of lower extremity SSEPs are equivalent potentials to P14 and N18, respectively, of upper extremity SSEPs. Unlike P14 and N18, P31 and N34 may not be present in some normal subjects. The (T12Sp–Iliac Crest) derivation registers the N24 potential, corresponding to cervical N13 for the upper extremity SSEP. Unlike N13, however, N24 may not be present in some normal subjects. Continued

femoral cutaneous nerve located at the inguinal region for root L2. The pudendal nerve at the penis or clitoris can be stimulated for evaluation of the S3 root. Similar to upper extremity SSEPs, SSEPs obtained from pure sensory cutaneous nerve are much smaller than those obtained from mixed nerves. Thus, a large number of samples (>2000) must be averaged to yield a reliably measured response. The stimulus intensity and rates are the same as for upper extremity SSEPs.

20.2.2. Upper extremity somatosensory evoked potential components 20.2.2.1. N9, N11 and N13 potentials recorded from posterior neck–anterior neck derivation The N9 potential is a far-field potential recorded in the Cv5–anterior neck derivation. N9 becomes inverted to P9 when the individual electrodes at Cv5 and anterior neck are referenced to distant reference electrode (Fig. 20.1A). It appears as a “negative” potential in the Cv5–anterior neck derivation because the potential

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Right Tibial Nerve Stimulation Montage B N50

CPz-A1+A2

N34

P31

P60

P40 N50

CP2(i)-Fpz

T12Sp.-lliac crest

P60

P40 N24

Popliteal fossa

5 ms

10 ms

2.5 μV

55 ms

Fig. 20.2, Cont’d (B) The CPz–(A1 + A2) derivation registers the far-field potentials P31–N34 complex and the near field cortical potentials of P40–N50–N60, whereas the CP2 (i)–FPz derivation only shows the P40–N50–P60 near field (cortical) potentials. In this montage, the interpeak latency between the popliteal potential and N24 represents the peripheral nerve conduction time, including the proximal segment of the peripheral nerve, while the interpeak latency between N24 and P31 represents spinal cord conduction time.

over the anterior neck is more positive relative to the posterior neck and N9 is the potential difference between the posterior and anterior positions (Fig. 20.1B). N9 arises from the distal portion of brachial plexus (Yamada et al., 1980; Desmedt et al., 1983b) and its latency is slightly shorter than the negative peak of Erb’s potential (Fig. 20.1B). N11 that corresponds to the P11 far-field potential in the scalp–noncephalic derivation (Fig. 20.1A) appears as the notched peak in the rising phase of the cervical N13 peak. N11 has a latency that is slightly longer than the negative peak of Erb’s potential. The N11 peak is generated at the cervical root entry zone (Jones, 1977; Yamada et al., 1980; Lueders et al.,

1983). Theoretically, N11 or P11 would be a useful potential in the assessment of the very proximal portions of the peripheral nerves but N11 or P11 is not consistently present in all normal subjects. Previously, the N13 cervical potential was commonly recorded using either an ear or scalp (Fpz) reference electrode. However, this derivation is no longer recommended because both ear and scalp electrodes are coupled to the P13/P14 far-field potentials. P13/P14 are of brainstem origin and, therefore, the neck—ear and neck—scalp derivations create an amalgam of two different anatomical origins. Because the cervical N13 potential represents a horizontally oriented dipole with the positive end of the dipole

APPLICATIONS OF SSEP RECORDINGS IN THE EVALUATION OF THE PERIPHERAL NERVOUS SYSTEM

20.2.2.2. P13/P14, N18–P22, N20–P26 components The P13/P14 far-field potentials, recorded from scalp electrodes, are often double-notched positive peaks that occur at the onset of the N18 or N20 peaks (Fig. 20.1A and B). Because the P13/P14 potential peaks are diffusely distributed, they are registered at both frontal and parietal electrodes (Fig. 20.1B). The P13/P14 potentials arise from brainstem, possibly at the level of medial lemniscus (Lueders et al., 1983; Yamada et al., 1986), though P13 and P14 may have separate generators (Restuccia, 2000). The N18 potential is also considered to be a farfield potential and is the first negative potential recorded from the scalp electrodes. (Desmedt and Cheron, 1981a; Mauguiere et al., 1983; Yamada et al., 1984; Sonoo, 2000) This potential is widely distributed over the scalp and can be recorded from the bifrontal and ipsilateral parietal electrodes (Fig. 20.1A and B). N18 can appear as a notched peak over the rising phase of N20 at the contralateral parietal electrode. Earlier studies proposed a thalamic origin for N18 (Yamada et al., 1984, 1985), however later studies have suggested that N18 may arise from the rostral brainstem. (Mauguiere et al., 1983; Sonoo, 2000).

The first negative peak at the parietal electrode is N20, which has a close latency relationship with frontal P22. N20 appears as a horizontally oriented dipole created from the tangential input entering into area 3b of primary sensory cortex. (Allison, 1982; Desmedt and Bourguet, 1985) Because N20 is the first cortically generated potential, it is commonly used to assess both the central and peripheral sensory pathways. Here is the logic. Inter-peak latency difference between either cervical N13 or scalp P13/14 and N20 are reported as central conduction times. Interpeak latency differences between Erb’s potential and N20 represent conduction times of the proximal peripheral nerve segments plus the central pathway. Finally, interpeak latency differences between Erb’s potential (N9) and cervical N13 represent conduction times in the proximal segment of the peripheral nerve. Reference ranges in normal adult subjects with various arm lengths for the early latency SSEP peaks are shown in Figs. 20.3–20.8. Figure 20.9 shows the range of interpeak latencies (N13 to N20) that represents central conduction time in normal subjects and demonstrates that the interpeak latency does not depend on arm length. 20.2.2.3. N32, P40, and N60 components N32, P40, and N60 peak potentials are defined as medium latency SSEP peaks and are distributed over the contralateral parietal region (Yamada et al., 1984) (Fig. 20.10). In contrast to the short latency SSEP peaks, these medium latency components have not been popularized for clinical diagnostic testing, primarily because the anatomical origins of these Erb's Potential Latency to Arm Length

latency (ms)

pointing toward the anterior neck region (Beall et al., 1977; Desmedt and Cheron, 1981b), it is appropriate to record N13 from posterior neck–anterior neck derivation (Fig. 20.1B), which potentiates the cervical N13 amplitude. Alternatively, N13 can be recorded from the posterior neck–ipsilateral Erb’s point derivation (Fig. 20.1A). Earlier studies suggested that N13 was generated from the dorsal column, dorsal root or cuneate nucleus (Cracco and Cracco, 1976; Jones, 1977; Yamada et al., 1980; Kimura and Yamada, 1990). More recent studies, however, indicate that N13 reflects the activation of the dorsal horn interneurons situated close to central gray matter (Austin and McCouch, 1955; Beall et al., 1977; Desmedt and Cheron, 1981b; Urasaki et al., 1988; Restuccia and Mauguiere, 1991; Mauguiere, 2000). Unlike other SSEP components that are mediated through the dorsal column–medial lemniscus system, N13 appears independent of this pathway. Supporting this notion is the observed absence of N13 in patients with a syrinx affecting the central gray matter, though the P13/P14 and N20 potentials are preserved (Urasaki et al., 1988; Restuccia and Mauguiere, 1991). The result is a sensory disassociation where there is impaired pain sensation with a normal proprioceptive sense.

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15 14 13 12 11 10 9 8 7 6 5 50

55

60

65

70

arm length (cm) N = 40

Linear +/− 3 s.d.

y = 0.2241 x −3.05 R2 = 0.8271

Fig. 20.3 Upper extremity Erb’s SEP reference ranges for adult subjects. Erb’s peak latency is graphed in relation to the arm’s length.

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14 13 12 11 10 9 8 7 6 5 50

19

55

60 65 arm length (cm)

15 13

9

70

50

y = 0.2107 x − 3.2406 R2 =0.7559

Linear +/− 3 s.d.

Fig. 20.4 Upper extremity N9 SEP reference ranges for adult subjects. N9 peak latency is graphed in relation to the arm’s length.

55

N = 40

60 arm length (cm)

Linear +/− 3 s.d.

65

70

y = 0.2791 x −1.491 R2 = 0.846

Fig. 20.6 Upper extremity P14 SEP reference ranges for adult subjects. P14 peak latency is graphed in relation to the arm’s length.

N13 Potential Latency to Arm Length

19

N18 Potential Latency to Arm Length 23

17

21

15

latency (ms)

latency (ms)

17

11

N = 40

13 11 9 7

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21

latency (ms)

latency (ms)

N9 Potential Latency to Arm Length

19 17 15 13

50

55

N = 40

60 arm length (cm) Linear +/− 3 s.d.

65

70

11 50

y = 0.2678 x −2.4649 R2 = 0.8231

Fig. 20.5 Upper extremity N13 SEP reference ranges for adult subjects. N13 peak latency is graphed in relation to the arm’s length.

components have not been elucidated. Also, the clinical application is complicated by the tendency toward prolonging the latency and decreasing the amplitude in sleep. Medium latency components can also be affected by the higher cognitive functions of the subject, such as distraction, attention, or expectation to the stimulus (Desmedt et al., 1983a; Desmedt and Tomberg, 1989; Tomberg et al., 1989). Cortically mediated SSEP components may be present in severe peripheral neuropathies when conventional nerve conduction studies fail to elicit sensory nerve action potentials (SNAP). In these cases, medium latency components such as N30, P40 and N60 may be preserved despite the absence of shorter latency peaks of P14–N20, including Erb’s potential

N = 40

55

60 arm length (cm)

Linear +/− 3 s.d.

65

70

y = 0.2798x + 0.4396 R2 = 0.6534

Fig. 20.7 Upper extremity N18 SEP reference ranges for adult subjects. N18 peak latency is graphed in relation to the arm’s length.

(Fig. 20.11). Using the techniques of conventional nerve conduction studies, peripheral nerve conduction velocity can be roughly estimated from the latency differences from a medium latency component when two different stimulation sites of known inter-site distance are compared (Parry and Aminoff, 1987). A dissociation of short and medium latency SSEP components (i.e., loss of the fast cortical potential, N20, in association with preserved N30, P40 and N60 components) can be produced experimentally as was noted in our previous studies (Yamada et al., 1981). In these experiments, the arm was made ischemic by blood pressure cuff inflation above the systolic pressure and maintained for about 20–30 min. There was a progressive latency prolongation and amplitude

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Fig. 20.9 Upper extremity N13–N20 interpeak latency reference ranges for adult subjects. N13–N20 interpeak latency peak latency is graphed in relation to the arm’s length. Note that the low correlation coefficient (R2 = 0.0006) shows the interpeak latency is not dependent on height, which is generally true for most interpeak latency measurements.

Fig. 20.8 Upper extremity N20 SEP reference ranges for adult subjects. N20 peak latency is graphed in relation to the arm’s length.

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Fig. 20.10 Short and medium latency SSEP components include the N20–P26–N32–P40–N60 potential complex occurring on the contralateral parietal electrode. Note the latency differences between the frontal and parietal responses after the P13/P14 far-field potential.

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Fig. 20.11 Medium and short SSEP recordings are shown in a patient with severe polyneuropathy secondary to arsenic poisoning. Note the absence of the Erb’s potential, the cervical potential and the P14–N20 short latency subcortical–cortical potentials. However, the medium latency potentials of the N32–P40–N60 potential complex are preserved.

reduction of Erb’s potential, with similar changes for the N20 component. When Erb’s potential was no longer elicited, N20 also disappeared whereas well defined N30, P40 and N60 were still obtainable. 20.2.2.4. P90, N140, and P200 components In contrast to the early and medium latency SSEP cortical peaks that are predominately distributed over the contralateral parietal region, there are longer latency peaks that are distributed more toward the midline vertex region (Desmedt et al., 1983a; Desmedt and Tomberg, 1989). These peaks are highly variable components of the SSEP and are closely

related to cognitive functions. These components are best elicited by randomly delivered stimuli at a very slow rate of less than 1 Hz (Tomberg et al., 1989). Faster or repetitive stimulation tends to cause habituation that will result in significant amplitude reduction of the SSEP (Fig. 20.12). The potentials are enhanced when the subject attends to the stimulus and are attenuated when the subject is distracted from the stimulus. Of these, the P200 potential has been referenced as a “pain” related potential because there is a graded response of this component to the intensity of the painful stimulus (Katayama et al., 1985; Kakigi et al., 2000).

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Fig. 20.12 The long latency potentials P90, N140, P200 and N350 are distributed close to the midline (Cz) electrode. The short- and medium-latency potentials are relatively stable with increases in the stimulus rate, whereas long-latency potentials are much more attenuated with an increasing stimulus rate. Conversely, these long-latency peaks are enhanced by slow and irregularly paced stimulation or when the subject has increased vigilance or attention to the stimulus. (With permission Yamada, T, Yeh, M and Kimura, J (2004). Fundamental principles of somatosensory evoked potentials. Physical Medicine and Rehabilitation Clinics of North America, 15: 19–42).

20.2.3. Lower extremity Somatosensory evoked potential components 20.2.3.1. P31, N34, N37, P37(P40), P50, N60 components The P31 far-field potential is the initial positive peak recorded from the scalp–ear or scalp–neck derivations. The P31 potential is distributed bilaterally (Fig. 20.2A and B) and arises from the brainstem. It is considered to be analogous to the P14 potential in upper extremity SSEP (Urasaki et al., 1993; Kakigi and Shibasaki, 1983; Yamada et al., 1996). However, P31 may not be present in some normal subjects, unlike P14, which is consistently present. Subsequent negative–positive

peaks have different latencies among different electrodes; the first negative peak has slightly shorter latency at ipsilateral (N34) than that of contralateral (N37) electrode (Fig. 20.13). Similar to N18 in the upper extremity SSEP, N34 is widely distributed over the bifrontal and ipsilateral parietal regions. This is considered to be analogous to the N18 far-field potential (Urasaki et al., 1993; Yamada et al., 1996). The derivation Fpz–Cv5 in montage A (Fig. 20.2A) records the N34 peak primarily at the Fpz electrode with little contribution from Cv5 electrode. The contralateral N37 is similar to N20 in the upper extremity SSEP and distributed over the contralateral parietal region, but it is not clear if N37 is equivalent to N20. Unfortunately,

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Fig. 20.13 “Paradoxical” lateralization of the P40 component is shown with a dominant P40 occurring on the ipsilateral (to the side of stimulation) and vertex regions. On the contralateral side, the peak latencies are slightly delayed (N37–P40c) when compared to the N34–P40 on the ipsilateral side.

both N34 and N37 are usually small potentials that may not always be recognized in normal subjects. Thus, they have been rarely used for routine clinical application. A large positive potential, designated as either P37 or P40, has a slightly shorter latency and larger amplitude over the scalp ipsilateral to the vertex region than that of contralateral scalp (P40(c)). This ipsilateral dominant positive potential has been termed “paradoxical lateralization” and is attributed to electrical activity projected to the scalp from the mesial hemisphere, which is the anatomical site for cortical representation of lower extremity (Cruse et al., 1982; Yamada et al., 1996; Yamada, 2000). The P40 (P37) peak is the first cortical potential for the lower extremity SSEP and is very useful from a clinical application standpoint because of its consistency and large amplitude. Subsequent negative–positive peaks, generally referred as N50 and P60 that are also dominant over the ipsilateral hemisphere (Yamada et al., 1996; Yamada, 2000), are rarely used for clinical application because of the variability of these peaks with cognitive functions and level of consciousness.

20.2.3.2. N21, N24 recorded from L4, T12 spine with iliac crest reference The spinal potential recorded at the L1 or T12 level of the spine is likely to be the analogue of the N13 cervical potential of upper extremity SSEP (Yamada et al., 1982; Seyal et al., 1983; Desmedt and Cheron, 1983; Seyal and Gabor, 1985). It is thought to be a postsynaptic potential at the conus medullaris generated by dorsal horn interneurons. Like N13 that has positive counter field in the anterior neck region, the positive counter field (P24) for spinal N24 exists over the abdominal surface (Desmedt and Cheron, 1983). Thus, in theory, the T12/L1 electrode can be referenced to abdominal surface. However, it is usually referenced to iliac crest simply because of easier electrode application. On the rising phase of the N24 potential, there may appear a small-notched peak in some subjects, designated as N21. N21 is best recorded at the L4 spinal level, suggesting that this potential arises from the cauda equina and is likely to represent a pre-synaptic nerve volley (Seyal and Gabor, 1985; Yamada et al., 1996). This would be equivalent to the N11 cervical potential of the upper extremity SSEP. Measuring latency difference between N24 and N21 would be useful to assess the proximal segment of peripheral conduction; however, N21 or N24 may not be present is some normal subjects, thus its clinical utilization is limited. Further N21 and N24 cannot be recorded in most subjects when a cutaneous nerve is used for stimulation. The latency values for N24, P31 and P37 are linearly correlated with the height of the subject. Therefore, the individual’s height must be taken into account when assessing absolute peak latencies of a lower extremity SSEP. The interpeak latency of N24–P31, representing the spinal cord conduction time, and the interpeak latency of N24–P37, representing central conduction time, are not significantly dependent on the subject’s height. Reference ranges within three standard deviations in normal adult subjects of various heights are shown for the early latency SSEP peaks in Figs. 20.14–20.17. Figure 20.18 shows the interpeak latencies of N24–P31 that represent spinal cord conduction times. Like the interpeak latencies of the upper extremity, the interpeak latencies of the lower extremity do no depend on height or leg length. Pediatric reference ranges for the P28 potential (which is equivalent to the P40 potential for adults) have been reported previously in relation to height and age by Gilmore and is shown in Figs. 20.19 and 20.20 (Gilmore et al., 1985).

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Fig. 20.14 Lower extremity popliteal potential SEP reference ranges for adult subjects. Popliteal peak latency is graphed in relation to height.

Fig. 20.15 Lower extremity N24 SEP reference ranges for adult subjects. N24 peak latency is graphed in relation to height.

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20.3. Somatosensory evoked potentials from alternative stimulation methods Transcutaneous electrical stimulation of superficial peripheral nerves has been the most common stimulus mode in SSEP recordings. However, this type of stimulation has a number of limitations that must be kept in mind. These include the following: (1) The recording is limited to only the fastest conducting myelinated-nerve fibers, which include the group IA muscle and group II cutaneous afferent fibers (Halonen et al., 1988). These potentials, in turn, tend to drown out the

response of the slower-conducting fibers due to the greater time dispersion of potentials arising from the slower fibers. (2) Electrical stimulation is noted to be unnatural and bypasses the peripheral receptor at the most distal portion of the nerve. (3) SSEPs from electrical stimulation of a major nerve do not evaluate the distal portions of the nerve fibers and therefore, are not well suited to evaluate small fiber neuropathies. Alternative methods of time-locked stimulation specifically aimed at the peripheral nerve receptors have been developed to provide stimulation directly from the receptor end of the nerve as opposed to

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Fig. 20.16 Lower extremity P31 SEP reference ranges for adult subjects. P31 peak latency is graphed in relation to height.

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Fig. 20.17 Lower extremity P40 SEP reference ranges for adult subjects. P40 peak latency is graphed in relation to height.

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electrically stimulating the axon of the nerve. Methods have included air puffs for stimulating the mechanoreceptors (Schimsheimer et al., 1995; Hashimoto, 1999). A variety of articles in pain research report the use of thermal stimulation from laser pulses that selectively stimulate the distal ends of small pain fibers. There is one method that even reports use of pinpoint electrical stimulation to the skin that directly stimulates small nerve fibers (Inui et al., 2002).

Linear +/− 3 s.d.

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20.3.1. Somatosensory evoked potentials from laser stimulation Laser stimulation was first proposed by Mor and Carmon in 1975 as an alternative to heat stimulators in assessing nociceptive pain pathways (Mor and Carmon, 1975). Shortly thereafter, this method was shown to generate a well-defined cerebral evoked potential and subsequently have been labeled laser-evoked potentials

APPLICATIONS OF SSEP RECORDINGS IN THE EVALUATION OF THE PERIPHERAL NERVOUS SYSTEM

Fig. 20.18 Lower extremity N24–P31 interpeak latency reference ranges for adult subjects. N24–P31 interpeak latency peak latency is graphed in relation to height. Note the low correlation coefficient (R2 = 0.0436) shows the interpeak latency is not dependent on height, which is generally true for most interpeak latency measurements.

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Fig. 20.19 Effect on height on the cortical evoked potential (P28 in children and P 40 in adults). A, during growth and development (1–8-years-old). B, during adulthood (18–40-years-old). Note that the P28 peak latency has less correlation (r = 0.50) with height compared to adult values (r = 0.81). (Modified from Gilmore, RL et al. (1985) Developmental assessment of spinal cord and cortical evoked potentials after tibial nerve stimulation: effects of age and stature on normative data during childhood. Electroencephalogr.Clin. Neurophysiol. 62(4): 241–251, with permission from Elsevier).

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(LEP) to differentiate them from SSEPs produced from electrical stimulation (Carmon et al., 1976). Like electrical stimulation, the use of lasers to stimulate pain fibers allows an extremely precise onset and offset of the stimulus. Unlike electrical stimulation that stimulates the fast conducting myelinated fibers peripherally and the dorsal spinal columns centrally, laser stimulation has the advantage of stimulating the most superficial pain fibers at the receptor level. Also, laser stimulation elicits the normal double pain response, which was first postulated to be due to slow and fast conducting pain fibers by Lewis in 1937 (Lewis and Pochin, 1937). The slow conducting nerve fibers were later classified into two types of pain fibers called A-δ and C-fibers. The laser stimulus is able to assess slow pain fibers of the peripheral nervous system, which

subsequently project to the spinal thalamic tracts of the spinal cord. This is in contrast to SSEPs, where fastmyelinated nerves of the peripheral nervous system are assessed which, in turn, project to dorsal columns of the spinal cord. Aδ- fibers are thin myelinated pain fibers with an estimated conduction velocity between 10 and 20 m/s. C-fibers are unmyelinated pain fibers with a much slower conduction velocity around 1 m/s (Bromm and Treede, 1987). When these fibers are stimulated, potentials can be recorded from the vertex of the scalp and are sometimes referred to as vertex potentials (Arendt-Nielsen and Chen, 1999). Depending on how the laser stimulus is applied, the vertex potential can have either a late or an ultra-late component with latencies that are in the range of 150–400 ms for the late component and 500–1200 ms

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Fig. 20.20 (Left) Relationship between stature and absolute latency of N5 (N9 in adult) in children with height ranging 82 to 130 cm: y = −1.021 + 0.056 (height). (Right) Relationship between age and absolute latency of N5 in children aged 1 to 8 years: y = 3.23 + 0.38 (age) The solid line is the line of regression and the dotted lines represent ± 3 S.D. (with permission from Gilmore, RL, Bass, NH et al. (1985) Developmental assessment of spinal cord and cortical evoked potentials after tibial nerve stimulation: effects of age and stature on normative data during childhood. Electroencephalogr. Clin. Neurophysiol. 62(4): 241–251.)

for the ultra-late component. It is also of note that neither component can exist in the presence of the other; that is, when one component is present, the other is absent. The precise reason for this is still conjectural. The LEP latencies are in the range of event-relatedpotentials (ERPs), which are potentials that likely represent secondary or tertiary processing of the sensory stimulus. This is different from the early potentials obtained in electrically elicited SSEPs that have components with a latency range of 5–40 ms. Early potentials represent the primary processing of the sensory signal that take place before total awareness of the sensation has occurred and have the unique characteristic of being resistant to change with varying levels of consciousness. On the other hand, LEP potentials are very sensitive to levels of consciousness and even different levels of attentiveness. Maintaining the subjects attentiveness is a requirement during LEP recordings to ensure a reproducible response. The late vertex potentials with latencies in the range of 150–400 ms are thought to represent the response from Aδ pain fibers and the ultra-late potentials occur-

ring between 500 and 1200 ms are attributed to the slower conducting C pain fibers. The latencies of these vertex waves have some variance in the literature but will mainly depend on where the stimulation was performed, i.e., shorter latencies will be observed when stimulating the skin over the proximal spinal areas and longer latencies are observed when stimulating the distal areas of the extremities. (As a general rule, the ultralate potential latencies tend to be 2–3.5 times longer than late potentials.) Estimates of the peripheral conduction times for Aδ- and C-fibers have been calculated indirectly from noted changes in the latency of the vertex potential when different sites of the extremity or spine are stimulated. Using such techniques, Aδfibers have been estimated to conduct at about 16 m/s and C-fibers to be about 1 m/s (Bromm and Treede, 1987). However, approximations made in this method could present significant limitations. First, it is assumed that stimulating two different sites along an extremity to calculate velocity is a good estimate of nerve conduction in a pain fiber. However, it is unlikely that the same small pain fiber will be stimulated at both sites. Second, a significant amount of jitter has been reported with the ultra-late potential, which may also be due to factors of secondary and tertiary processing within the central nervous system. Third, it had been previously questioned whether there was any relationship between the interpeak LEP latency differences and peripheral pain fiber conduction because one could as easily argue that the late and ultra-late potentials represented the secondary and tertiary processing of sensory input and therefore the latency differences may be significantly influenced by central nervous system processing. To address this last question first hand, a recent experiment that directly measures pain fiber conduction velocity from laser stimulation employed microneurography techniques. From direct pain fiber measurements, the reported conduction velocities are 1.1 ± 0.3 m/s for C-fibers and 11.7–14.1 m/s for Aδfibers (Qiu et al., 2003) (Fig. 20.21). This closely matches nerve conduction velocities estimated by LEP interpeak latency measurements. 20.3.1.1. Methodology The recording of the late and ultra-late potentials from laser-evoked potentials (LEPs) depends on many factors that require monitoring. These factors include specific stimulus variables and conditions (wavelength of the laser, beam size, duration, intensity, inter-stimulus interval (ISI), skin temperature, skin characteristics, and angle of incidence of pulse to

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Fig. 20.21 Direct measurement of peripheral C pain fiber responses using microneurography techniques of the peroneal nerve recorded in the popliteal fossa. C-fiber responses are displayed for electrical stimulation and laser stimulation in the dotted circles. Based upon the latency and the measured distance from stimulus site to the recording area, the peripheral C-fiber conduction velocity is calculated as 1.1 ± 0.3 m/s. (With permission from Qiu, Y et al. (2003) Microneurographic study of C fiber discharges induced by CO2 laser stimulation in humans. Neurosci. Lett., 353(1): 25–28 with permission from Elsevier.)

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skin), the recording conditions (electrode montage, bandwidth, calibration, reference electrode, and artifact rejection), and the condition of the subject (vigilance, habituation, arousal, attention, anticipation, and action). 20.3.1.2. Stimulus parameters The wavelength of the laser light determines how much energy will be absorbed by the skin minus the energy that is reflected from the skin. When comparing the SEP responses from different lasers, there do not appear to be dramatic differences between, say, a Thulium laser (2.01 μm wavelength) and a CO2 laser (10.6 μm wavelength). Superficial burns as a side effect of laser stimulation can occur with the Thulium laser as well as the CO2 laser, although slightly more power is required from the Thulium laser to cause this side effect because it does not raise the skin temperature as much (Spiegel et al., 2000). The superficial first-degree erythema burn reported is self-limited and usually resolves itself in a few days. The stimulus can be controlled by either adjusting the power of the stimulus or by the duration. The objective is to raise the skin temperature to between 39 and 48˚ C with the lower temperature stimulation activating the C-fibers and the higher temperature stimulation activating the Aδ- fibers. The beam size can also be selective in pain fiber type activation. Use of small beam area of 0.15–0.25 mm2 tends to selectively activate the ultra-late potentials, suggesting activation mainly of C-fibers nociceptors. This is attributed to the higher density of the

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C-pain fiber population as opposed to other nerve fiber populations (Bragard et al., 1996; Dotson, 1997; Opsommer et al., 1999). Intensity of the stimulus can be varied by adjusting the power of the light pulse (upto the maximum power of the laser) and the duration of the pulse by either mechanical means (as was done in early laser studies using mechanical shutters) or by electronic switching as more recent advances in the technology occurred. Pulse durations range between 10 and 50 ms. Adjusting the pulse duration is used to fine-tune the amount of energy delivered. Intensity will determine the degree to which the skin temperature is raised. Using intensities that raise the skin temperature to about 39˚ C will preferentially stimulate C-fiber nociceptors resulting in an ultra-late vertex potential whereas, raising the skin temperature to a range of 48˚ C will stimulate both Aδ- and C-fibers, though only the late vertex potential is recordable and it is not entirely known at this point why disappearance of the ultra-late vertex occurs when the Aδ- fibers are activated (Iannetti et al., 2003) (Fig. 20.22). The laser pulse intensity is usually expressed in milli-Joules/millimeter squared (mJ/mm2). A CO2 laser intensity of 10–14 mJ/mm2 is usually required for the threshold for pain. It is of note that the window between the pain threshold and the onset of tactile perception (a slight tactile tapping sensation) is quite small with the onset of detection occurring at a stimulus intensity of 70% of the pain threshold (Bromm and Treede, 1991). The inter-stimulus interval is usually randomized. It is recommended that the ISI for LEPs be no less

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Fig. 20.22 The left hand side of the figure shows the laser intensity is enough to raise the skin temperature to 39˚C to evoke only ultra-late responses representing C pain fiber stimulation. The right hand side of the figure shows the laser intensity adjusted to raise the skin a higher temperature of 48˚ C, which evokes late peak responses representing thin myelinated Aδ- pain fiber stimulation. (Reproduced from Iannetti, GD et al. (2003) Evidence of a specific spinal pathway for the sense of warmth in humans. J. Neurophysiol., 89(1): 562–570 with permission from The American Physiological Society.)

than 4–5 seconds for optimum signal-to-noise ratio (Raij et al., 2003). In addition, the laser pulse site of stimulation is slightly changed for each stimulus to reduce habituation and to reduce the side effect of first-degree burns to the skin. In an attempt to obtain the most robust vertex response, the skin temperature is usually controlled by allowing the subject to come to thermal equilibrium with the room so as to maintain a constant temperature over the entire body surface. In experiments of significant temperature difference across the body surface, amplitudes were attenuated, even if the temperature difference occurred in an area of the body not being stimulated (Watanabe et al., 1996). If the change in skin temperature with thermal stimulation is to be monitored, then very thin thermocouple wires have

been used on the skin at the center of the pulse to obtain peak temperature readings. Skin thickness is an important factor in laser stimulation. Hairy non-glabrous skin is optimal for laser stimulation because it has a thickness of 50–100 micrometers (μm). Glabrous skin is found over the palms and soles of the extremities and can be as thick as 1 mm or 1000 μm (Bromm and Treede, 1991). Skin pigment and angle of incidence of the laser pulse have been reported as theoretical factors to consider. However, because almost all studies using laser stimulation apply the pulse perpendicular to the skin and because no studies have attempted to grade the amount of pigment, it is not known to what extent these factors come into play. The determination of stimulus threshold for bare perception of touch and for sharp pain is likely to take these factors into account. It is very interesting to note that laser stimuli can be very precise in the heating only the most superficial layers of the skin. In 1983, Bromm and Treede measured the thermal depth of heating within the skin and found a very steep temperature gradient localizing most of the heating to the skin surface. Skin depths of 0.5 mm showed no significant heating (Bromm and Treede, 1983). 20.3.1.3. Recording parameters The late and ultra-late vertex potentials are most reliably recorded off the scalp at the Cz electrode (hence, the name “vertex potential”). However, if more detailed analyses are to be done using computational methods, then the number of electrodes will be determined by the spatial resolution required by the analysis method. For the purposes of clinical practice, it may be useful to start with Cz with addition of a few other electrodes that are symmetrically placed about Cz (C4, C3, T4, T3, Pz, and Fz), according to the international 10–20 system. Linked-ears is the usual chosen reference. A ground electrode is used to reduce overall noise recorded within the system. An electrode impedance of less than 5 Kohms is required unless methods are employed that can accurately maintain all electrodes at another impedance. Attempting to maintain electrodes at a specific impedance is usually impractical, especially if numerous electrodes are employed because the conditions of electrode contact are continually changing with drying of the electrolyte gel under the electrodes. The recording band pass for the amplifiers is 0.1–70 Hz and the signal is usually sampled at a rate of 200 Hz, which is the current recommended standard for clinical EEG recordings. Finally, artifact rejection, an important aspect of the recording, selec-

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tively eliminates those trials with either known noise or signals with amplitudes above the expected amplitude range. Known artifacts that can interfere with the record include intrinsic biologic signals such as eye movements and rhythmic EKG signals. Monitoring biologic activity with channels that monitor eye movements and EKG can assist in eliminating those trials when these signals contaminate the record. The recording analysis window (or time-base of recording) is usually 1.5–2.5 seconds with 20–50 trials usually averaged to resolve the late and ultra-late potentials. These potentials will usually have amplitudes ranging between 10 and 50 μV. If small beams of 0.15–0.25 mm2 are used, then more trials are recommended for each average (Bragard et al., 1996). 20.3.1.4. Subject parameters Factors endogenous to the subject that affect the vertex potential include the level of consciousness, attention, expectation, habituation, and age. Because the late and ultra-late potentials represent secondary or tertiary processing of the sensory stimulus, level of consciousness has a profound effect on the absence or presence of these potentials. A difference in the vertex potential response is commonly noted in attention with expectation as opposed to just attention. Habituation of the stimulus is frequently affected by the ISI, temporal regularity and predictability of the stimulus, spatial regularity, and fatigue with repetitive recordings (Arendt-Nielsen and Chen, 1999). Finally, increasing age has a noted increase in pain thresholds (Bromm and Treede, 1991). These factors are likely the cause of the large intra-session and inter-subject variability. Laser-evoked potentials have a promising application to clinical medicine since it has been demonstrated that this stimulus modality effectively stimulates the pain receptors most superficial in the skin without concomitant stimulation of thermal receptors and mechano-receptors in the deeper areas of the skin. There has also been research in the clinical setting using laser stimulation. When studying patients with a dissociated sensory loss, Bromm (1991) noted a dissociation between LEPs and electrical SSEPs, i.e., when SSEP response is present, the LEP response may be absent (Bromm and Treede, 1991). Polyneuropathies are usually conditions with a dissociated sensory loss, depending on whether it involves the large myelinated fibers or the small unmyelinated fibers. Kakigi has reported a dissociation between LEP and electrical SSEP responses in correlation with the type of polyneuropathy present

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histologically (Kakigi et al., 1991). When polyneuropathy has a predominant loss of large fibers, as in demyelinating conditions, the SSEPs are absent or attenuated in the presence of normal LEPs. In contrast, abnormal LEP responses in the presence of normal SSEPs have been reported by Rossi and others in their investigation of LEP responses in Type I diabetic patients (Rossi et al., 2002). In this case, diabetic polyneuropathy primarily involves small nerve fibers. From these observations, one can conclude that LEPs are more sensitive in identifying small fiber neuropathies and that electrical SSEPs are more sensitive in identifying large fiber neuropathies. Because small as well as large fiber polyneuropathies can be identified with the combined use of LEP and electrical SSEP, this may reduce the need to perform nerve biopsies if the major question is whether the polyneuropathy involves small or large fibers. The major clinical disadvantage at this time is the lack of a clinical system, which incorporates laser stimulation and recording into one unit. It would be even better to have laser stimulation incorporated with electrical stimulation so that one unit can compare both stimulation modalities at once. At present, setting up a laser stimulator is just not convenient from a clinical testing standpoint. The other disadvantages of LEPs are the number of variables one has to pay attention to when applying the laser stimulus, although these variables probably will not present many problems with adequate testing protocols. 20.3.2. Somatosensory evoked potentials from air puff stimulation Evoked potentials from air puffs to the cornea and mucosa of the nares was introduced by Matsumiya in 1972 (Matsumiya and Mostofsky, 1972). However, air puff stimulation has not been widely adopted as a clinical test and only a few groups have evaluated this technique further. In 1999, Hashimoto published a thorough review of the peripheral SNAP and somatosensory evoked potentials recorded from air-puff stimuli (Hashimoto, 1999). 20.3.2.1 Methodology The evoked potentials from air puffs can be recorded from stimulation of any dermatome with a short jet pulse of air of durations ranging between 15 and 50 ms at varying pressures. This type of stimulus is very focal and constant over a 1-mm diameter area. The evoked cerebral response is recorded from the scalp using AgCl

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electrodes placed at Cz and referenced to Fz with a ground electrode place on the leg. Impedances are kept below 5 Kohms. A total of 500 time-locked averages are recorded with a time-base recording window of 100 ms and a band pass of 30–3000 Hz. The evoked responses usually consist of two negative and two positive peaks that are similar to electrical SSEPs. Because the first negative peak, N1, is not always clear, the second negative peak, N2 is the easier potential measured and has a latency of 67.1 ± 3.3 ms for L1 dermatomal stimulation. In 1995, Schimsheimer compared responses from electrical stimulation of the same dermatome to air puff stimulation and found the responses to be comparable in morphology (Schimsheimer et al., 1995). The N2 peak latencies for the air puffs are 5–6 ms longer than the corresponding N2 peaks from electrical stimulation (commonly known as N60 by other groups). The latency difference was proposed to be due to a slower rise time of the air-puff stimulus that may excite receptors of different thresholds. It is of note that the N2 responses are in the middle latency response ranges (early response potentials are 5–40 ms, middle response potentials are 50–100 ms, late response potentials are 100–500 ms). Unlike early potential responses that are relatively stable regardless of the subjects level of consciousness, the middle latency responses require the subject to remain alert and attentive. Skin indentation and receptor transduction are additional variables. The advantage of using air pulse stimulation is that it activates sensory nerves at the receptor level rather than at the axon of the nerve beyond the receptor. Another advantage is the electrical stimulus artifact common in standard SSEPs is eliminated, which can be a very cumbersome problem, especially when stimulation is applied close to the recording electrodes as in trigeminal stimulation. Finally, the equipment needed is usually not very complicated. However, mechanical devices are used to deliver the air pulse stimulus, which could vary over time and require additional steps in the recording to allow for calibration. The current disadvantages for use of air pulses in clinical medicine are the lack of standard norms, methodologies, and the paucity of clinical research in pathological settings. 20.3.3. Somatosensory evoked potentials using distal electrical stimulation of pain fiber receptors A novel way of assessing the terminal pain fibers by using an electric intra-epidermal needle stimulator has been described by Inui in 2001. This study compares vertex potentials of the intra-epidermal needle stimu-

M. YEH ET AL.

lator to conventional SSEP and LEP and appears to be a simple method to selectively stimulate Aδ- fibers. The intra-epidermal needle stimulator is a less complicated set-up as compared to the laser stimulators described above. The stimulator is a specially designed needle electrode mounted on a holding plate. When placed against the skin, the needle electrode will protrude 0.2 mm into the epidermis to reach the superficial pain fibers. Because electrical stimulation is employed, there is a selection for stimulating the myelinated Aδ- pain fibers (Inui et al., 2002). When using this method, the vertex potential that is recorded has a N1–P1 response with the P1 response having less inter-individual variability of amplitude. When comparing vertex potentials from laser stimulation and transcutaneous electrical stimulation to epidermal electrical stimulation, the morphology of each vertex potential was strikingly similar in amplitude and shape. The only significant difference between each modality of stimulation was the latency of the response. The P1 response for hand stimulation was longest for laser pulses at 341 ± 21.2 ms and shortest for transcutaneous electrical stimulation at 245 ± 21.8 ms. The epidermal needle stimulator produced a P1 latency response at 302 ± 17.4 ms, which is in between the LEP and SSEP. 20.3.3.1. Stimulus parameters A needle electrode mounted on a pushpin-like plate is pressed gently against the skin. This allows contact of the needle cathode to a depth of 0.2 mm into the epidermis. A 1 cm surface electrode placed 4 cm from the stimulation site serves as the anode. A constant current stimulus at an intensity high enough to provoke pain is used (0.19 mA for the hand and 0.22 mA for the arm). The stimulus duration is 1 ms with a stimulation rate of 0.1 to 0.3 Hz. It is noted that no evidence of C pain fiber activation occurs (i.e., no flare reactions of the skin are noted with needle stimulation), which is attributed to the higher electrical threshold of C-fibers to Aδ- fibers. 20.3.3.2. Recording parameters Vertex potentials are maximal at the Cz electrode referred to linked ears (A1+A2) in accordance to the International 10–20 system. Electrodes over the supra- and infra-orbital areas are used to reject trials with eye movements present. Also, epochs larger than 80 μV were rejected from averages. Only 10 responses are needed for each average, and a few minute interval of rest is allowed to reduce

APPLICATIONS OF SSEP RECORDINGS IN THE EVALUATION OF THE PERIPHERAL NERVOUS SYSTEM

habituation. A 600-ms analysis time was used in the original study; therefore, no comments can be made about an ultra-late potential. Use of the electric intra-epidermal needle stimulator has the appeal of being simple to apply with few stimulus variables to monitor. The only disadvantage at this time is the paucity of clinical research in patients that would validate the test. 20.4. Summary In summary, electrically induced SSEPs may have a role in the clinical assessment of the peripheral nervous system when conventional nerve conduction studies cannot assess proximal nerve lesions in the limb. It is useful in the intra-operative setting during plexus surgery to identify functionally intact components by having SSEP responses recorded from the scalp as various sites of the plexus are directly stimulated by the surgeon. However, use of SSEP for diagnosis of thoracic outlet syndrome, spinal stenosis, and radiculopathy should be considered a supplemental test to support clinical suspicion for these diagnoses because the literature is quite variable on the specificity and sensitivity of this test. Use of non-electric stimulation applied to various dermatomes evoke robust cerebral responses though the latencies of these responses are usually beyond the short latency responses of SSEPs and have additional factors endogenous to the subject that could affect the response (i.e., level of consciousness, attention, habituation, and expectation). Despite this, these alternative methods have the ability to assess the peripheral nervous system right at the receptor level and have the potential to be a useful diagnostic tool for small fiber disorders. Some of the problems with electrical stimulus artifact found with SSEPs (especially when the stimulation is close to the recording electrodes as in trigeminal nerve stimulation) are completely avoided. The sensitivity of laser stimulation has even been demonstrated to detect subclinical disease. However, the current limitation with the alternative methods (with the exception of the electric needle electrode stimulation) is the complexity of the stimulators and the lack of standard norms in the methodologies. References Allison, T (1982) Scalp and cortical recordings of initial somatosensory cortex activity to median nerve stimulation in man. Ann. N Y Acad. Sci., 388: 671–678.

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Anonymous (1994) Guideline nine: guidelines on evoked potentials. American Electroencephalographic Society. J. Clin. Neurophysiol., 11: 40–73. Arendt-Nielsen, L and Chen, AC (1999) Evoked potentials to painful laser stimulation. Electroencephalogr. Clin. Neurophysiol. Suppl., 50: 311–327. Austin, G and McCouch, G (1955) Presynaptic component of intermediary cord potential. J. Neurophysiol., 441–451. Beall, JE, Applebaum, AE, Foreman, RD and Willis, WD (1977) Spinal cord potentials evoked by cutaneous afferents in the monkey. J. Neurophysiol, 40: 199–211. Bragard, D, Chen, AC and Plaghki, L (1996) Direct isolation of ultra-late (C-fiber) evoked brain potentials by CO2 laser stimulation of tiny cutaneous surface areas in man. Neurosci. Lett., 209: 81–84. Bromm, B and Treede, RD (1983) CO2 laser radiant heat pulses activate C nociceptors in man. Pflugers Arch., 399: 155–156. Bromm, B and Treede, RD (1987) Pain related cerebral potentials: late and ultralate components. Int. J. Neurosci., 33: 15–23. Bromm, B and Treede, RD (1991) Laser-evoked cerebral potentials in the assessment of cutaneous pain sensitivity in normal subjects and patients. Rev. Neurol. (Paris), 147: 625–643. Carmon, A, Mor, J and Goldberg, J (1976) Evoked cerebral responses to noxious thermal stimuli in humans. Exp. Brain Res., 25: 103–107. Cracco, RQ and Cracco, JB (1976) Somatosensory evoked potential in man: far field potentials. Electroencephalogr. Clin. Neurophysiol., 41: 460–466. Cruse, R, Klem, G, Lesser, RP and Leuders, H (1982) Paradoxical lateralization of cortical potentials evoked by stimulation of posterior tibial nerve. Arch. Neurol., 39: 222–225. Desmedt, JE and Bourguet, M (1985) Color imaging of parietal and frontal somatosensory potential fields evoked by stimulation of median or posterior tibial nerve in man. Electroencephalogr. Clin. Neurophysiol., 62: 1–17. Desmedt, JE and Cheron, G (1981a) Non-cephalic reference recording of early somatosensory potentials to finger stimulation in adult or aging normal man: differentiation of widespread N18 and contralateral N20 from the prerolandic P22 and N30 components. Electroencephalogr. Clin. Neurophysiol., 52: 553–570.

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Desmedt, JE and Cheron, G (1981b) Prevertebral (oesophageal) recording of subcortical somatosensory evoked potentials in man: the spinal P13 component and the dual nature of the spinal generators. Electroencephalogr. Clin. Neurophysiol., 52: 257–275. Desmedt, JE and Cheron, G (1983) Spinal and farfield components of human somatosensory evoked potentials to posterior tibial nerve stimulation analysed with oesophageal derivations and noncephalic reference recording. Electroencephalogr. Clin. Neurophysiol., 56: 635–651. Desmedt, JE, Huy, NT and Bourguet, M (1983a) The cognitive P40, N60 and P100 components of somatosensory evoked potentials and the earliest electrical signs of sensory processing in man. Electroencephalogr. Clin. Neurophysiol., 56: 272–282. Desmedt, JE, Nguyen, TH and Carmeliet, J (1983b) Unexpected latency shifts of the stationary P9 somatosensory evoked potential far field with changes in shoulder position. Electroencephalogr. Clin. Neurophysiol., 56: 628–634. Desmedt, JE and Tomberg, C (1989) Mapping early somatosensory evoked potentials in selective attention: critical evaluation of control conditions used for titrating by difference the cognitive P30, P40, P100 and N140. Electroencephalogr. Clin. Neurophysiol., 74: 321–346. Dotson, RM (1997) Clinical neurophysiology laboratory tests to assess the nociceptive system in humans. J. Clin. Neurophysiol., 14: 32–45. Gilmore, RL, Bass, NH, Wright, EA, Greathouse, D, Stanback, K and Norvell, E (1985) Developmental assessment of spinal cord and cortical evoked potentials after tibial nerve stimulation: effects of age and stature on normative data during childhood. Electroencephalogr. Clin. Neurophysiol., 62: 241–251. Halonen, JP, Jones, S and Shawkat, F (1988) Contribution of cutaneous and muscle afferent fibers to cortical SEPs following median and radial nerve stimulation in man. Electroencephalogr. Clin. Neurophysiol., 71: 331–335. Hashimoto, I. (1999) From input to output in the somatosensory system for natural air-puff stimulation of the skin. Electroencephalogr. Clin. Neurophysiol. Suppl., 49: 269–283. Iannetti, GD, Truini, A, Romaniello, A, Galeotti, F, Rizzo, C, Manfredi, M and Cruccu, G (2003) Evidence of a specific spinal pathway for the sense

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of warmth in humans. J. Neurophysiol., 89: 562–570. Inui, K, Tran, TD, Hoshiyama, M and Kakigi, R (2002) Preferential stimulation of Adelta fibers by intra-epidermal needle electrode in humans. Pain, 96: 247–252. Jones, SJ (1977) Short latency potentials recorded from the neck and scalp following median nerve stimulation in man. Electroencephalogr. Clin. Neurophysiol., 43: 853–863. Kakigi, R and Shibasaki, H (1983) Scalp topography of the short latency somatosensory evoked potentials following posterior tibial nerve stimulation in man. Electroencephalogr. Clin. Neurophysiol., 56: 430–437. Kakigi, R, Shibasaki, H, Tanaka, K, Ikeda, T, Oda, K, Endo, C, Ikeda, A, Neshige, R, Kuroda, Y, Miyata, K et al. (1991) CO2 laser-induced pain-related somatosensory evoked potentials in peripheral neuropathies: correlation between electrophysiological and histopathological findings. Muscle Nerve, 14: 441–450. Kakigi, R, Watanabe, S and Yamasaki, H (2000) PainRelated somatosensory evoked potentials. J. Clin. Neurophysiol., 17: 295–308. Katayama, Y, Tsubokawa, T, Harano, S and Tsukiyama, T (1985) Dissociation of subjective pain report and pain-related late positive components of cerebral evoked potentials in subjects with brain lesions. Brain Res. Bull., 14: 423–426. Kimura, J and Yamada, T (1990) Physiologic mechanisms underlying the generation of far-field potentials. Electroencephalogr. Clin. Neurophysiol. Suppl., 41: 13–21. Lewis, T and Pochin, EE (1937) The double pain response of the human skin to a single stimulus. Clin. Sci., 3: 67–76. Lueders, H, Lesser, R, Hahn, J, Little, J and Klem, G (1983) Subcortical somatosensory evoked potentials to median nerve stimulation. Brain, 106: 341–72. Matsumiya, Y and Mostofsky, DI (1972) Somatosensory evoked responses elicited by corneal and nostril air puff stimulation. Electroencephalogr. Clin. Neurophysiol., 33: 225–227. Mauguiere, F (2000) Anatomic origin of the cervical N13 potential evoked by upper extremity stimulation. J. Clin. Neurophysiol., 17: 236–245. Mauguiere, F, Desmedt, JE and Courjon, J (1983) Neural generators of N18 and P14 far-field somatosensory evoked potentials studied in patients with lesion of thalamus or thalamo-cortical radia-

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tions. Electroencephalogr. Clin. Neurophysiol., 56: 283–292. Mor, J and Carmon, A (1975) Laser emitted radiant heat for pain research. Pain, 1: 233–237. Opsommer, E, Masquelier, E and Plaghki, L (1999) Determination of nerve conduction velocity of Cfibers in humans from thermal thresholds to contact heat (thermode) and from evoked brain potentials to radiant heat (CO2 laser). Neurophysiol. Clin., 29: 411–322. Parry, GJ and Aminoff, MJ (1987) Somatosensory evoked potentials in chronic acquired demyelinating peripheral neuropathy. Neurology, 37: 313–316. Pratt, H and Starr, A (1986) In RQ, C and I, B-W (Eds.), Evoked Potential Frontier’s of Clinical Neuroscience. Alan R Liss Inc, New York, Vol. 3, pp. 28–34. Qiu, Y, Fu, Q, Wang, X, Tran, TD, Inui, K, Iwase, S and Kakigi, R (2003) Microneurographic study of C fiber discharges induced by CO2 laser stimulation in humans. Neurosci. Lett., 353: 25–28. Raij, TT, Vartiainen, NV, Jousmaki, V and Hari, R (2003) Effects of interstimulus interval on cortical responses to painful laser stimulation. J. Clin. Neurophysiol., 20: 73–79. Restuccia, D (2000) Anatomic origin of P13 and P14 scalp far-field potentials. J. Clin. Neurophysiol., 17: 246–257. Restuccia, D and Mauguiere, F (1991) The contribution of median nerve SEPs in the functional assessment of the cervical spinal cord in syringomyelia. A study of 24 patients. Brain, 114: 361–379. Rossi, P, Morano, S, Serrao, M, Gabriele, A, Di Mario, U, Morocutti, C and Pozzessere, G (2002) Pre-perceptual pain sensory responses (N1 component) in type 1 diabetes mellitus. Neuroreport, 13: 1009–1012. Schimsheimer, RJ, Boejharat, KR., van der Sluijs, JC, Stijnen, T and Gryz, E (1995) Cortical somatosensory evoked potentials from lumbosacral dermatomes: airpuff versus electrical stimulation. Electromyogr. Clin. Neurophysiol., 35: 5–10. Seyal, M, Emerson, RG and Pedley, TA (1983) Spinal and early scalp-recorded components of the somatosensory evoked potential following stimulation of the posterior tibial nerve. Electroencephalogr. Clin. Neurophysiol., 55: 320–330. Seyal, M and Gabor, AJ (1985) The human posterior tibial somatosensory evoked potential: synapse dependent and synapse independent spinal components.

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Electroencephalogr. Clin. Neurophysiol., 62: 323–331. Shiga, Y, Yamada, T, Ofuji, A, Fujita, Y, Kawamura, T, Inoue, K, Hada, Y, Yamazaki, H, Cheng, MH and Yeh, MH (2001) Effects of stimulus intensity on latency and conduction time of shortlatency somatosensory evoked potentials. Clin. Electroencephalogr., 32: 75–81. Sonoo, M (2000) Anatomic origin and clinical application of the widespread N18 potential in median nerve somatosensory evoked potentials. J. Clin. Neurophysiol., 17: 258–268. Spiegel, J, Hansen, C and Treede, RD (2000) Clinical evaluation criteria for the assessment of impaired pain sensitivity by thulium-laser evoked potentials. Clin. Neurophysiol., 111: 725–735. Tomberg, C, Desmedt, JE, Ozaki, I, Nguyen, TH and Chalklin, V (1989) Mapping somatosensory evoked potentials to finger stimulation at intervals of 450 to 4000 msec and the issue of habituation when assessing early cognitive components. Electroencephalogr. Clin. Neurophysiol., 74: 347–358. Tsuji, S, Luders, H, Dinner, DS, Lesser, RP and Klem, G (1984) Effect of stimulus intensity on subcortical and cortical somatosensory evoked potentials by posterior tibial nerve stimulation. Electroencephalogr. Clin. Neurophysiol., 59: 229–237. Urasaki, E, Tokimura, T, Yasukouchi, H, Wada, S and Yokota, A (1993) P30 and N33 of posterior tibial nerve SSEPs are analogous to P14 and N18 of median nerve SSEPs. Electroencephalogr. Clin. Neurophysiol., 88: 525–529. Urasaki, E, Wada, S, Kadoya, C, Matsuzaki, H, Yokota, A and Matsuoka, S (1988) Absence of spinal N13-P13 and normal scalp far-field P14 in a patient with syringomyelia. Electroencephalogr. Clin. Neurophysiol., 71: 400–404. Watanabe, S, Kakigi, R, Hoshiyama, M, Kitamura, Y, Koyama, S and Shimojo, M (1996) Effects of noxious cooling of the skin on pain perception in man. J. Neurol. Sci., 135: 68–73. Yamada, T (2000) Neuroanatomic substrates of lower extremity somatosensory evoked potentials. J. Clin. Neurophysiol., 17: 269–279. Yamada, T, Graff-Radford, NR, Kimura, J, Dickins, QS and Adams, HP, Jr. (1985) Topographic analysis of somatosensory evoked potentials in patients with well-localized thalamic infarctions. J. Neurol. Sci., 68: 31–46.

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Yamada, T, Ishida, T, Kudo, Y, Rodnitzky, RL and Kimura, J (1986) Clinical correlates of abnormal P14 in median SEPs. Neurology, 36: 765–771. Yamada, T, Kayamori, R, Kimura, J and Beck, DO (1984) Topography of somatosensory evoked potentials after stimulation of the median nerve. Electroencephalogr. Clin. Neurophysiol., 59: 29–43. Yamada, T, Kimura, J and Nitz, DM (1980) Short latency somatosensory evoked potentials following median nerve stimulation in man. Electroencephalogr.Clin. Neurophysiol., 48: 367–376.

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Yamada, T, Machida, M and Kimura, J (1982) Far-field somatosensory evoked potentials after stimulation of the tibial nerve. Neurology, 32: 1151–1158. Yamada, T, Matsubara, M, Shiraishi, G, Yeh, M and Kawasaki, M (1996) Topographic analyses of somatosensory evoked potentials following stimulation of tibial, sural and lateral femoral cutaneous nerves. Electroencephalogr. Clin. Neurophysiol., 100: 33–43. Yamada, T, Muroga, T and Kimura, J (1981) Tourniquet-induced ischemia and somatosensory evoked potentials. Neurology, 31: 1524–1529.

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CHAPTER 21

Electromyographic assessment of peripheral nerve diseases: an overview Janice M. Massey* Box 3403, Duke South Clinic 1L, Room 1255, Duke University Medical Center, NC USA

21.1. Introduction The technique of conventional EMG originated in 1929, when Adrian and Bronk developed a concentric needle electrode capable of recording extracellular muscle action potentials and spontaneous electrical signals arising from the muscle membrane in humans. (Adrian and Bronk, 1929) Variations on the technique were developed: single-fiber EMG (SFEMG) to select a smaller sample of the motor unit and Macro EMG to assess a larger area of the motor unit territory. These EMG techniques have proved to be valuable clinical aids in the diagnosis and prognosis of nerve, muscle, and neuromuscular junction diseases. As research tools, these techniques furnish a greater understanding of physiology, pathophysiology, disease progression, and response to treatment. A number of excellent texts and manuals provide in-depth information about each technique (Daube, 1991; Stålberg and Trontelj, 1994; Preston and Shapiro, 1998; Kimura, 2001; Dumitru et al., 2002). A review of the motor unit (MU) and the changes that occur with denervation is useful in understanding the utility and interpretation of various EMG techniques. The MU consists of an anterior horn cell, its myelinated axon, and all the individual muscle fibers it innervates along with their neuromuscular junctions. A MU in normal human limb muscle consists of approximately 200–350 muscle fibers lying within an area of 5–10 mm diameter that are supplied by a single anterior horn cell (Buchthal and Schmalbruch, 1980). These muscle fibers are interspersed with those supplied by other anterior horn cells. The muscle

* Correspndence to : Janice M. Massey, M.D., Professor of Neurology, Box 3403, Duke South Clinic 1L, Room 1255, Duke University Medical Center, Durham, NC, 27710. E-mail address: [email protected] Tel.: +919-684-5196; fax: +919-660-3853.

fibers are randomly distributed in a territory resembling a mosaic or checkerboard fashion as seen in histochemical examination of the normal muscle. When there is axonal or anterior horn cell injury, muscle fibers are denervated and no longer able to contract, producing weakness. With partial denervation, the muscle is proportionately weak; with complete denervation, the muscle is paralyzed. Following denervation, muscle fibers that have lost their neuronal supply undergo physiologic changes: they become sensitized to acetylcholine, fire spontaneously and atrophy. When denervation within a muscle is incomplete, soon there are attempts to reestablish innervation. If there are nearby surviving axons, they produce collateral sprouts directed toward the denervated or “orphaned” muscle fibers. These sprouts are capable of reestablishing a neuromuscular junction with the denervated muscle fiber. As these neuromuscular junctions become competent, weakness improves. Following sprouting, the motor unit territory of the reinnervating motor unit increases and muscle histochemistry demonstrates type grouping. Early in this process, the newly established neuromuscular junctions are immature and neuromuscular transmission is not constant. However, as they mature, neuromuscular transmission becomes dependable. If the injured neuron undergoes repair and regrowth, it can reestablish innervation with previously denervated muscle fibers and the collateral sprouts from nearby axons recede. Axon regrowth is estimated to occur at 1–3 mm/day (Sunderland, 1978). In instances where the injured neuron is incapable of regrowth, the surviving axons maintain control of the previously denervated muscle fibers, but over time, reorganization or remodeling occurs with replacement of sprouts to distant muscle fibers by the sprouts from closer axons. If all denervated muscle fibers are reinnervated, the muscle regains full strength. In contrast, when the degree of denervation is greater than the capacity of the surviving axons to reinnervate, some muscle fibers remain

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denervated and proportional weakness persists. Whereas, if the denervating process is continuous, increasing demand on the surviving axons will outstrip their capacity to sprout further and reinnervate “orphaned” muscle fibers and weakness increases. In addition, weakness occurs with demyelination of the peripheral nerve or root. Due to loss of the insulating effect of myelin, axonal current is dissipated and either propagated at a slow rate along the peripheral nerve or blocked. With axonal blocking, no electrical impulse reaches the neuromuscular junction and no muscle fiber contraction occurs. With demyelination, however, there is no loss of the integrity of the neuromuscular junction and individual muscle fibers are not denervated. The dynamic, physiologic changes that occur in the motor unit with denervation and subsequent reinnervation and the pattern seen with demyelination of the peripheral nerve can be demonstrated in vivo using electromyographic techniques. This chapter provides an overview of three electromyographic techniques useful in the evaluation of disorders of the peripheral motor nerve: conventional needle electromyography (EMG), single fiber electromyography and Macro EMG. 21.2. EMG technique 21.2.1. Equipment requirements Distinguishing features of EMG techniques lie in the unique characteristics of the recording electrodes and filtering techniques (Table 21.1). Recorded EMG signal voltages range from a few microvolts to more than 15 mV and must be amplified and displayed for analysis. The amplifier must have an adequate response to display the signals without distortion. Current amplifiers are of high quality and allow small potentials to be seen with little interference from background noise. The ear can discern certain features of the EMG signal more readily than the eye; so a simultaneous auditory output is essential. A variety of EMG equipment is available with single or multichannel display, audio monitor, adjustable sweep speed, amplification and filters. Options for selection of motor unit action potentials (MUAPs) using an amplitude trigger, and dual time base display are preferable. Permanent records of data and study reports may be stored on the computer hard disc, paper, or magnetic tape. Software programs for SFEMG analysis, MUAP analysis, Interference Pattern analysis and Macro analysis are available for many machines.

JANICE M. MASSEY

The degree of selectivity of EMG recordings depends on several factors, including: the size and configuration of the recording area of the EMG electrode; the filtering techniques; the conductive properties of nearby tissue; and the strength of the generated electrical signal. The size of the recording electrode port distinguishes the various EMG techniques, allowing recording from a large, nonselective area of the motor unit (Macro EMG) to a small and selective area assessing single muscle fibers (Single fiber EMG). Table 21.1 provides a comparison of the characteristics of EMG electrodes (Nandedkar and Sanders, 1991; Nandedkar et al., 1990; Stålberg and Trontelj, 1994; Ekstedt and Stålberg, 1973; Stålberg, 1980; Dorfman et al., 1985). 21.2.2. Filter setting options Variable high and low band pass filters limit the physiologic frequency responses for recording. For conventional EMG studies, filter settings of 2 Hz–10 kHz allow all prominent muscle action potential frequencies to be recorded. Occasionally, a band pass of 20 Hz–5 kHz may be necessary in the presence of interfering electrical noise. 21.2.3. Conventional EMG needle electrodes Conventional EMG recordings are made with either a concentric or monopolar needle electrode, the electrodes most widely employed in clinical electromyography (Table 21.1). The coaxial, bipolar, concentric needle electrode consists of a stainless steel cannula with an insulated wire in the lumen. The active (recording) electrode area is the exposed surface of the inner wire at the beveled tip; the outer conducting shaft (the cannula) serves as the reference and voltage differences are measured between the two. The concentric electrode has a unidirectional recording area as half of the electrical field is partially shielded from the active electrode by the steel bevel. The uptake area is about 1 mm. Recording characteristics show little variability with slight electrode movement; thus concentric electrodes are a good choice for quantitative EMG studies where reproducibility is important (Nandedkar et al., 1990, 1997). The monopolar needle electrode has a Tefloncoated wire with only a bare, conical tip. Voltage differences are measured between the unshielded tip of the needle and a separate reference electrode placed

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Table 21.1 Comparison of EMG electrode characteristics

Concentric

Monopolar

Single fiber

Recording surface

Smaller (fixed) 0.07 mm2

Smaller (variable) 0.17 mm2

Smallest 25 μm2

Uptake area

1 mm

1 mm

300 μm

Macro (Dual Recording) 1. Macro (Cannula) 2. Single fiber port 1. Large (from Cannula) 2. Smallest 25 μm2 (from SF port) 1. Several mm 2. 300 μm

Recording properties Amplitude and effect of needle movement

Background

Reference electrode

Motor unit potentials

Quantitative techniques

Disadvantages

Disposable Cost

Moderate, minimal Higher than concentric, Highest but marked 1. Low amplitude but amplitude change some effect with change with relatively with small electrode small electrode electrode movement unaffected by movements movement electrode movement 2. Same as single fiber Less noise (better Noise from surrounding Requires minimum 1. May distort macro common mode muscles more notable activation MUAP rejection) 2. Same as single fiber Needle shaft Separate reference Needle shaft 1. Separate surface or electrode intramuscular electrode 2. Needle shaft Basis for reference Greater area, Measures single 1. Larger, phases less values amplitude and muscle fiber detectable number of phases potentials 2. Single fiber potentials Most reliable for Less reference data Standard for Jitter 1. Reference data for MU quantitation for MU quantitation and fiber density many muscles 2. Can measure fiber density More painful than Recording area Difficult to perform, Most painful, requires Monopolar more variable requires unique skill, unique skill, amplitude trigger dual channel and SFEMG recording analysis program and macro analysis program Yes Yes No No Low Low High High

elsewhere in or on the tested muscle. The recording characteristics from the spherical uptake area are slightly different from those of concentric electrodes (Nandedkar et al., 1990; Nandedkar and Sanders, 1991). In general, MUAPs recorded from monopolar electrodes are slightly more polyphasic, the amplitude of EMG signals recorded are higher (Kohara et al.,

1993) and the duration longer (Dumitru et al., 1997). However, they record similar area: amplitude ratio as concentric electrodes. Inexpensive, disposable concentric and monopolar electrodes are available, provide reliable recordings, and are preferable due to the concern about transmissible infectious agents.

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21.3. General principles of needle examination The patient should be instructed and reassured about the procedure, its potential risks and discomfort. The patient is best studied in a gown, in a warm, comfortable room. 21.3.1. Study design In preparation for an EMG examination, consideration must be given to which muscles should be chosen for study. Muscles found weak on examination or muscles suspected of being involved should be selected. When possible, one should examine superficial muscles that are less painful, can be selectively activated and are familiar to the examiner. The timing of the study will depend on the information needed from the EMG. Following acute denervation, the earliest abnormality is reduced recruitment of MUAPs. Signs of denervation occur at 7–21 days, while evidence of reinnervation evolves over several weeks to months. Remodeling occurs in the motor unit over years. 21.3.2. Pattern bracketing Once abnormality is found, it is important to determine whether the changes represent a focal pattern as in individual nerve lesions or radiculopathy or are widespread as in peripheral neuropathy or motor neuron disease. Thus, by appropriate choice of muscles for EMG study, one may “bracket” the area of abnormality. 21.3.3. Special issues in needle electromyography The electromyographer is frequently confronted by special problems presented by patients with underlying medical diseases. The following are guidelines in the management of the most common of these problems (Kimura, 2002; AAEM, 1999; AANEM Professional Practice Committee, 2005). 21.3.3.1. Accessibility Areas of interest for study are occasionally difficult to access. Local infection or cellulitis, edema, or lymphedema, sutured wounds, casting, IV catheter, or shunt sites may prevent study in a specific area of interest. Immobilized patients may be unable to move to expose such areas as the paraspinal musculature. 21.3.3.2. Special precautions Safety precautions are needed in the use of needle electrodes in patients who are demented and have a

JANICE M. MASSEY

history of known viral hepatitis, HIV, or other potentially transmittable diseases. These needles should be carefully discarded after use. ●

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●

All patients with these disorders should be examined with a disposable concentric needle or Teflon-coated, monopolar electrode. If a nondisposable needle is inadvertently used on a demented patient, it must be set aside until there is full assurance that the patient does not have JacobCreutzfeldt disease. If not forthcoming, it should be discarded. Electrodes used with the other viral disorders should be sterilized appropriately. Use of gloves by the physician is strongly recommended for all studies and it is necessary when performing needle examination on patients who have a potentially transmissible disease.

21.3.3.3. Bleeding disorders Patients with a variety of bleeding disorders or those receiving anticoagulant therapy (heparin, coumadin, lovenox, and aspirin) may be referred for electromyography. The electromyographer must examine each case individually, carefully weighing the potential risks and benefits. Specific muscle areas may show more potential for complication because of inability to assess for bleeding (e.g., deep muscles, paraspinal muscles) or potential for a compartment syndrome (e.g., anterior tibialis). In thrombocytopenia, an increased potential from bleeding may be expected in patients with a platelet count of less than 50 000/mm3. However, additionally prolonged local pressure will usually be sufficient to induce hemostasis in patients with thrombocytopenia, other coagulopathies or who are receiving anticoagulants. Needle examination should be avoided in patients with hemophilia who have Factor VIII or IX inhibitors (Scranton et al., 1979). 21.3.3.4. Cardiac valvular disease Patients with rheumatic or other types of cardiac valvular disease and patients with prosthetic valves are at risk for developing endocarditis as a result of transient bacteremias. However, the risk from needle electromyography is similar to the risk from repeated venipunctures in which prophylactic antibiotics are not used. Prophylactic antibiotics for such patients undergoing EMG are therefore not recommended. 21.3.3.5. Analgesia for patients Adult patients or young children may have difficulty tolerating the discomfort of the EMG needle examination. Under most circumstances, thorough explanation

ELECTROMYOGRAPHIC ASSESSMENT OF PERIPHERAL NERVE DISEASES: AN OVERVIEW

of the procedure and a kind, sympathetic demeanor with adult patients will be sufficient to complete the needle examination. However, on rare occasions, it may be necessary to use a short-term analgesic. For this purpose, Fentanyl can be used with appropriate precautions. For children, the sedative chloral hydrate can be used. Topical lidocaine is often of limited value, as it must be applied to the skin at the site of needle insertion an hour prior to the procedure. Also in the pediatric population, most hospitals have a conscious sedation policy that requires anesthesia support during the procedure. 21.3.3.6. Serum creatine kinase level In patients with myopathy and rarely in normal individuals, mild elevation of serum creatine kinase (CK) may occur following extensive EMG of several muscles. Such elevation is mild and transient. To avoid misinterpretation of CK results, it should be obtained prior to EMG. 21.3.4. Muscle identification and needle insertion 21.3.4.1. Muscle identification A thorough knowledge of anatomy and surface landmarks of commonly studied muscles is necessary. A number of texts are available for this purpose (Geiringer, 1994; Perotto, 1994). 21.3.4.2. Needle insertion A surface ground electrode is placed on a nearby inactive surface. The muscle of interest is palpated while having the patient contract the muscle. The patient is asked to relax the muscle and needle insertion through the skin is made with a rapid smooth movement. Throughout the examination, the patient is both instructed in their role and reassured regarding the discomfort. Once the needle is in muscle, it is important to confirm the proper location by selective activation of the muscle and identification of motor unit potentials with rapid rise time of less than 500 ms. 21.4. Potentials recorded by conventional electromyography 21.4.1. Recordings from relaxed muscle 21.4.1.1. Technique With an amplification of 50–100 mV/cm and a sweep speed of 10 and/or 50 ms/cm, 2–4 rapid passes of about 1 mm each are made through the relaxed

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muscle. This movement is repeated by withdrawing the needle to the surface of the muscle and advancing in a different quadrant somewhat resembling the edges of a pyramid such that four quadrants are examined. Once the movement ceases and the needle lies still within the muscle, any form of spontaneous activity is assessed. 21.4.1.2. Insertional activity The activity of the muscle following each needle movement is assessed and termed insertional activity. Normal: At rest, the concentric or monopolar EMG needle electrode records no electrical activity in a normal muscle, other than that stimulated by insertion and movement of the needle (insertion activity) and endplate noise. Needle movement produces repetitive high-frequency spikes that persist 100 Hz) repetitive irregular discharges, similar to tetany, which are seen in a variety of conditions (Newsom-Davis and Mills, 1993). They may produce a high-pitched, “pinging” sound. These spontaneously occurring discharges are produced by instability of the peripheral nerve fibers. They may occur at rest but are exaggerated or have onset after voluntary or electrically-stimulated nerve activity and may coexist with myokymia.

Fig. 21.5 Myokymic discharges.

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21.4.2. Evaluation of voluntary motor unit activity Concentric or monopolar EMG electrodes inserted and repositioned into the muscle record signals generated from only a portion of muscle fibers within a 5–10 mm diameter. MUAPs measured by these electrodes are markedly affected by changes of the position of the electrode within the MU territory. 21.4.2.1. Technique Following assessment of insertional and spontaneous activity, the patient is asked to voluntarily activate the muscle at a low level of activity. During this period, MUAP morphology is evaluated. With minimal contraction of the muscle, the needle electrode is passed slowly through the muscle with rotational movements to optimize the view of MUAPs recorded. ●

●

Amplification: 100 μV/cm (range of 100– 1000 μV/cm) Sweep speeds: 5, 10, and 50 ms/cm (total sweep of 50, 100, and 1000 ms)

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●

●

●

●

Pass through muscle slowly in short steps during maintained minimal contraction (2–5 MUAPs on screen) Assess only MUAPs with rise time of 500 ms or less Comment on recruitment, duration, number of phases (turns), amplitude compared to normal values for that muscle (Buchthal and Rosenfalck, 1955; Sacco et al., 1962) Assess at least 20 MUAPs per muscle

21.4.2.2. Motor unit morphology Voluntary contraction of the muscle produces MUAPs, each of which results from the temporal and spatial summation of the electrical activity produced by all of the muscle fibers in a single motor unit within the recording area of the electrode (Fig. 21.6 A). The duration and amplitude of the MUAP reflect the number and local concentration of muscle fibers comprising that particular motor unit. Important characteristics of the MUAP include rise time, amplitude, and duration,

Fig. 21.6 Normal, neuropathic, and myopathic motor unit potentials recorded with a concentric EMG electrode.

ELECTROMYOGRAPHIC ASSESSMENT OF PERIPHERAL NERVE DISEASES: AN OVERVIEW

number of phases, turns, and stability. The rise time is short for nearby motor unit potentials so only those with a rise time of 500 ms or less are assessed. The amplitude of the MUAP is measured as the maximum peak-to-peak waveform. The maximum spike component is determined by a limited number of muscle fibers located within 500 μm of the tip of the recording electrode (Nandedkar et al., 2002). Amplitudes normally range from several hundred microvolts to a few millivolts. Amplitude measurements are sensitive to even slight electrode displacement. The motor unit duration is defined as time from initial takeoff of the waveform to return to the baseline. Duration reflects the contribution of muscle fibers belonging to the motor unit both near and those at the outer limit of the

477

recording area. In contrast to amplitude measurements, needle movement has less effect on duration. The waveform has phases, defined by each takeoff and return to baseline. If the waveform changes direction but does not return to the baseline, the term turn is used. MUAPs from normal muscles have four phases or less. An increase in phases, or polyphasia, indicates desynchronization of the individual single muscle fiber action potentials either due to spatial or temporal displacement. Variability in neuromuscular transmission produces a characteristic sound and can be seen in a triggered potential as variability of the amplitude and position of components of the MUAP. This is termed jiggle (Fig. 21.7) (Stålberg and Sonoo, 1994). Late components, often termed satellite potentials, may be

Fig. 21.7 Jiggle. Motor unit potentials recorded during slight voluntary contraction of the biceps muscle in a patient with motor neuron disease. Variability in the waveform (“jiggle”) is seen among the discharges. At a slower oscilloscope sweep speed, this variability would appear as fluctuations in amplitude and has a distinctive sound. Unstable, “jiggling” MUAPs are also seen in myasthenia gravis and in neuropathic diseases, especially motor neuron disease, and are thus not specific for MG. When seen without other evidence of neuronal disease, unstable MUAPS should lead to an assessment for MG or other disease of neuromuscular transmission

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present; these arise from fibers that are distant or separated by connective tissue. 21.4.2.3. Recruitment and interference pattern The firing rate of early recruited MUAPs is 5–10 MUAP discharges per second in normal muscles. As the force of contraction increases, recruited MUAPs fire faster and additional large and small MUAPs are recruited (Ertas et al., 1995). At maximum forced contraction, the interference pattern is full and individual MUAPs cannot be distinguished. While the largest MUs are recruited last based on the size principle (Henneman et al., 1965), the size of the MUAP depends more on electrode position than the MU size. A reduced interference pattern is seen in: ●

●

● ●

Denervated muscle (e.g., from nerve, root, or anterior horn cell disease or injury) Demyelinating processes (neuropathies, nerve compression or conduction block) Upper motor neuron processes Inadequate voluntary effort

21.4.2.4. Quantitative EMG techniques The concept of quantitative motor unit analysis was pioneered by Buchthal and Rosenfalck (Buchthal and Rosenfalck, 1955; Sacco et al., 1962), who recorded individual motor unit potentials and manually assessed duration and amplitude; these values are currently accepted as reference values. This technique is so time consuming that it is impractical in the clinical setting and most clinical electromyographers assess MUAP morphology and recruitment subjectively. In contrast to subjective analysis of EMG signal, a means of quantitative analysis is desirable, particularly for the inexperienced examiner. Motor unit potential signals acquired under reproducible standard conditions lend themselves well to automated computer assessment. Automated computerized programs are able to perform assessments based on specific parameters such as measurement of number of phases, duration, amplitude, area, rise time, firing rate, and fullness on the interference pattern. Signal is acquired using a standard type of electrode, recording settings, type of signal acquisition, processing and analysis. A number of computer-based software algorithms are available and are discussed fully elsewhere (Nandedkar et al., 2002; Stålberg, 2003). Either the mean value of 20 samples or individual parameters of a single MUAP can be compared to reference values acquired from a normal population. Quantitative analysis of motor unit potentials can be valuable as a clinical and educational tool for the

JANICE M. MASSEY

inexperienced electromyographer in defining the presence and type of abnormality on EMG; for followup comparisons following the evolution of a disease process or monitoring EMG changes in response to therapy. 21.4.2.5. Scanning EMG Scanning-EMG, in which a concentric EMG needle electrode is moved through the motor unit by steps, has been used to gain information about the configuration of the MU and is complementary to the information provided by Macro EMG studies as discussed below. It proves that temporally separated portions of the motor unit arise from muscle fibers each innervated by a nerve branch from the motor unit (Stålberg and Antoni, 1980). 21.4.2.6. Clinical utility in neuropathic disease Conventional EMG techniques are the mainstay for the diagnosis of disorders of the peripheral nerve and anterior horn cell. With denervation, spontaneous activity in the form of fibrillations and positive waves is seen early, between 7 and 21 days, and persists until reinnervation occurs. If reinnervation is incomplete, fibrillations may persist indefinitely. In the time prior to development of spontaneous activity, the only abnormality seen may be reduced numbers of normal appearing MUAPs; if the examined muscle is completely paralyzed, no MUAPs may be recruited. If the lesion is severe, early reinnervation may only occur with a few muscle fibers and the sparsely recruited MUAPs may be small, of short duration, and extremely polyphasic with much jiggle. With partial denervation, reinnervation begins with collateral sprouting, and the resultant MUAPs are very polyphasic, have long duration, increased amplitude, jiggle and recruit in an incomplete pattern proportionate to the weakness (Figs. 21.6C and 21.7). Over months, if regrowth of the injured or diseased axon occurs, the MUAPs become less polyphasic or even normal as collateral sprouts recede and the muscle fiber is innervated by its original axon. Likewise, recruitment and interference pattern approach normal. In chronic neuropathic conditions, depending on the degree and balance of denervation and reinnervation, spontaneous activity may disappear if all muscle fibers are reinnervated and the MUAP remodels into waveforms that are quite long in duration, with high amplitude but may be simple in configuration. In demyelinating neuropathies or demyelination of an isolated peripheral nerve, the EMG in the weak

ELECTROMYOGRAPHIC ASSESSMENT OF PERIPHERAL NERVE DISEASES: AN OVERVIEW

muscles does not demonstrate spontaneous activity but will be notable for a reduction of the interference pattern that parallels the weakness. Nerve conduction study in these patients should also demonstrate the findings of demyelination. When demyelination is severe or chronic, some evidence of axonal involvement may be present, with reinnervation MUAPs or even mild spontaneous activity. Serial EMG studies are useful in assessing the progression or response to therapy of certain neuropathic conditions such as ALS or immune mediated neuropathies and aid in predicting prognosis as in peripheral nerve injury. 21.5. Single fiber and macro electromyography 21.5.1. Selective recording: single fiber electromyography Ekstedt and Stalberg (1963) developed the technique of single fiber electromyography (SFEMG) in 1963. Action potentials from single muscle fibers are selected using a small electrode recording surface and selective filter settings. Two types of measurements, Fiber Density (FD) estimates and Jitter measurements each provide unique information about the function and microarchitecture of the motor unit. With reinnervation, both muscle fibers originally and now those recently innervated by a single anterior horn cell are close together and are seen as type grouping on muscle histopathology. SFEMG FD estimates allow counting of action potentials from muscle fibers in the recording area innervated by individual motor neurons, providing an electrophysiologic correlate of type grouping. Increased FD estimates signify reinnervation and may offer evidence of a neuropathic process before typical changes are seen on conventional EMG. Early in reinnervation, newly formed neuromuscular junctions and distal nerve twigs do not function reliably and jitter measurements are abnormal. Jitter measurements allow assessment of the integrity of the neuromuscular junction and, thus, it has become a valuable tool in the diagnosis of neuromuscular transmission disorders but also for better understanding the pathophysiology of a variety of disorders of nerve and muscle (Stålberg and Trontelj, 1994). 21.5.1.1. Single fiber EMG needle electrode The single fiber EMG needle electrode is a variant of the concentric needle, with a steel shaft and an inner insulated wire that terminates as a small (25–30 μm)

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active recording port on the side of the shaft 3 mm proximal to its tip. Because of its high input impedance and small recording surface, directional recordings are made from a selected uptake area, a hemicircle of about 300 μm (Ekstedt and Stålberg, 1973). Single fiber EMG and Macro electrodes are handmade and therefore, expensive. They are reusable, require sterilization after each use and periodically need sharpening. 21.5.1.2. Filters Within the small recording area of the SFEMG electrode, distant high-frequency components of the signal are lost or reduced by the muscle tissue, which acts as a low pass filter. Thus, only low frequency signals from distant muscle fibers are recordable with the SFEMG electrode. By using a high pass filter of 500–800 Hz, the low frequency signals from distant muscle are eliminated. Nearby fibers have readily recordable high-frequency components. The combination of the small, selective recording surface of the SFEMG electrode and the use of filters allows for recording of only those nearby single muscle fiber signals. Electrical signals recorded from concentric or monopolar electrodes record from a larger area and these electrodes are not as selective. Single muscle action potentials (APs) from two nearby fibers may be seen as one spike with these electrodes. Use of these electrodes underestimates neuromuscular jitter and fiber density measurements 21.5.1.3. Technique While the patient maintains slight contraction of the tested muscle, a SFEMG needle electrode is inserted and advanced until action potentials (AP) acceptable for analysis are displayed. An amplitude or peak trigger with a delay line is required. Slight rotation and depth adjustments are necessary to optimize the single fiber recording site. Acceptable APs should have amplitudes of 200 μV or greater and a fast rise time of < 300 μs. ●

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Amplification: 200 μV/cm (range of 200– 1000 μV/cm) Sweep speeds: 0.5 ms/cm—total sweep of 5 ms (range of 0.5–20 ms/cm) Pass through muscle slowly in short steps during maintained minimal contraction (2–5 APs on screen). Assess 20 sites in each muscle for fiber density measurements Assess jitter in 20 pairs of APs

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21.5.1.3.1. Fiber density estimates. The techniques of Fiber Density and Jitter measurements are slightly different. By measuring the number of time-locked action potentials (APs) that have the above characteristics, an estimation of FD of a motor unit is determined. The AP of interest is triggered and for FD estimates, the amplitude of the AP is maximized by slight adjustments of the electrode position. If the AP is time-locked to another AP, all spikes are counted; if the AP is not time-locked to another AP, it is counted as one AP. Time-locked APs are muscle fibers from a single motor unit. The needle is then repositioned and other APs are counted in a similar manner. Most sites in normal muscle have a fiber density of one or two, occasionally 3 and almost never greater. By sampling 20 sites from two to four separate needle insertions, a mean fiber density estimate is calculated and compared to normative data (Gilchrist and Ad hoc Committee, 1992). Fiber density estimation provides information about the configuration of the motor units and increased fiber density is an electrophysiologic counterpart of fiber-type grouping seen in muscle following reinnervation. 21.5.1.3.2. Neuromuscular jitter measurements. The technique for jitter measurements is similar to that for FD estimate although it is not necessary to maximize the amplitude of the triggered AP if the amplitude and rise time are adequate. Sites must be found where two or more time-locked APs are recorded. The time interval between the APs of two or more muscle fibers in the same motor unit is variable with consecutive discharges of the motor neuron. This variability primarily arises at the synapse with minimal contribution by the muscle fiber conduction. The variability of synaptic transmission time is recognized as changes in rise time of the end-plate potentials and is called neuromuscular jitter. Jitter is calculated as the mean difference between consecutive interpotential intervals (MCD) (Stålberg and Trontelj, 1994; Sanders and Stålberg, 1996; Sanders and Howard, Jr., 1986). The details of this statistical tool have been described elsewhere (Stålberg and Trontelj, 1994). Other statistical measures of jitter do not minimize physiologic influences such as slowing of the propagation velocity along two muscle fibers during continuous activity or technical influences such as changes in action potential shape as a result of minor movement of the recording electrode. In addition, the MCD allows ease of use in designing automated jitter calculation software. A small amount of variability is present in

JANICE M. MASSEY

normal muscles and the jitter ranges from 10 to 50 μs (Fig. 21.8A). When neuromuscular transmission is severely impaired, with jitter values around 100 μs or greater, neuromuscular block may occur as end-plate potentials fail to reach adequate threshold to generate APs (Fig. 21.8C). Thus, recordings from 20 pairs of single muscle fiber action potentials are necessary to document abnormality in mild disease and to quantify results. Results are expressed as the percentage of pairs of single muscle fiber APs with normal jitter, increased jitter without blocking and those with blocking. In normal studies, 18 or more of 20 potential pairs are normal. In addition, the mean jitter for all potential pairs is calculated and there are established normal values for many muscles (Stålberg and Trontelj, 1994; Gilchrist and Ad hoc Committee, 1992; Bromberg and Scott, 1994). In the majority of abnormal studies, both the overall mean jitter is abnormal and 10% or more of fiber pairs show jitter that exceeds the upper limit of normal. Jitter may be rate-dependent. In acquired myasthenia gravis (MG), a postsynaptic disorder, some potential fiber pairs with abnormal jitter show increased abnormality at higher firing rates. In presynaptic disorders such as Lambert–Eaton syndrome (LEMS), botulism and neuropathic disorders, some potential fiber pairs demonstrate increased jitter at lower firing rates. These findings are not present in all muscle fiber pairs in any type of disorder. Concomitant blocking is recognized as a distinct pattern where two or more APs from the same motor unit block simultaneously and have similar increased jitter values. These APs are often late components of a complex MUAP with increased jitter in several of the earlier components. Jitter between the blocking potentials should be >5 μs to exclude the possibility of their originating from a single endplate from a split muscle fiber. Concomitant blocking is presumed to arise during reinnervation when an immature nerve twig innervating two or more muscle fibers does not conduct an impulse consistently or from a conduction block with demyelination. 21.5.1.4. Clinical utility in neuropathic disease Because the great utility of jitter measurements in disorders of neuromuscular transmission is often emphasized, the value of SFEMG in neuropathic disease may be underappreciated. Jitter may be abnormal in any disorder in which neuromuscular transmission is impaired, including neuropathies and some myopathies (Stålberg and

ELECTROMYOGRAPHIC ASSESSMENT OF PERIPHERAL NERVE DISEASES: AN OVERVIEW

481

Fig. 21.8 Single fiber EMG recordings of: (A) Normal Jitter, (B) increased Jitter and (C) increased Jitter with neuromuscular blocking.

Trontelj, 1994). When Jitter is abnormal, it is necessary to perform other electromyographic techniques, including SFEMG FD estimates in order to assess the presence of primary nerve or muscle diseases. The temporal profile and distribution of electrophysiologic abnormality vary in different diseases (Table 21.2). In neuropathic processes, FD is increased and jitter is more abnormal in limb muscles than in facial muscles, while in myasthenia gravis (MG), facial muscles usually demonstrate more severe abnormality than limb muscles and FD estimates are normal. Increased FD and abnormal jitter may occur even in clinically normal muscles in amyotrophic lateral sclerosis (ALS); such muscles may show no

abnormality with conventional EMG (Massey and Sanders, 1985). In ALS, FD increases to a maximum in early to mid disease, but in the terminal stages rapidly decreases as remaining, diseased axons lose their capacity to innervate a large MU territory. Early in acute partial nerve injury with muscle paralysis, jitter increases before FD. Jitter improves as FD peaks, which parallels early muscle contraction. Both jitter and FD fall dramatically after 10 weeks corresponding with resolving weakness (Massey and Sanders, 1991). 21.5.1.5. Stimulation single fiber EMG (S-SFEMG) A similar technique, stimulation SFEMG (Trontelj et al., 1992; Trontelj and Stålberg, 1992), can be used

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Table 21.2 Comparison of EMG results in disorders of nerve and muscle Conventional EMG

Neuropathic

Myopathy (nondisfigurative)

Myopathy (disfigurative)

Myasthenia gravis

Insertional activity Normal

Increased

Normal

Spontaneous activity

Fibrillations, positive waves, CRDs

None

Increased, may have myotonia Fibrillations, Positive waves, CRDs, possible myotonia

Normal, rarely increased Normal, rarely increased

Variable, often low, simple to polyphasic Normal early, then PP may increase frequent PP, Later with chronic stable disorders, PP decreases Increased Normal Decreased Increased Increased Decreased Rapid firing Increased, despite weak muscle contraction

Variable, low to high

Normal to low

Increased PP

Usually normal, rarely slight PP

Rarely increased Increased Decreased Increased, despite weak muscle contraction

Increased Normal Normal to short Normal, rarely increased

Incomplete, with maximum muscle contraction

Full with weak muscle contraction

Full with weak muscle contraction

Normal but may not be sustained

Normal to Normal Increased Normal, rarely Increased, often slightly increased with blocking

Normal

None

Motor unit potential Amplitude

200 μV to 3 mV

Polyphasia (PP)

10–15% PP

Jiggle (instability) turns/amplitude duration recruitment

Normal Normal 5–15 ms Increases with strong contraction of muscle Complete with strong contraction

Interference pattern

Enlarged

Single-fiber EMG Fiber density

Normal

Increased

Usually normal

Jitter

Normal

Increased, frequent blocking

Macro EMG MU size

Normal

Increased

Usually normal, may have pairs with reduced Jitter Decreased or normal

in patients with tremor and in children or other patients unable to cooperate for voluntarily evoked muscle action potentials. The motor nerve proximal to its entry into the muscle or the intramuscular nerve is stimulated while recording from individual muscle fibers. Normal values for this technique differ since the jitter from only one end-plate is measured. This technique has limited application in neuropathic disorders as FD estimation cannot be performed using this technique.

Decreased Normal (except Duchenne Dystrophy, FSH)

21.5.2. Nonselective recordings: macro electromyography While the single fiber EMG needle electrode allows for examination of individual muscle fibers within a small recording area, and conventional EMG assesses summated firing of muscle fibers from a larger but still restricted area, at the end of the spectrum is Macro EMG. Macro EMG was created as a complementary

ELECTROMYOGRAPHIC ASSESSMENT OF PERIPHERAL NERVE DISEASES: AN OVERVIEW

EMG technique to assess a larger recording area of the motor unit and estimate the entire motor unit size. Assessment of a larger area is more likely to reveal nonuniform abnormalities, which are characteristic of some disease processes such as motor neuron disease and certain myopathies. In Macro EMG, two signals are acquired (Fig. 21.9). SFEMG is recorded from the side port and the Macro (cannula) signal is recorded from the

7.5 mm

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unshielded distal portion of the Macro electrode. Dual-channel recording is required: The SFEMG signal identifies individual motor unit activity, triggers the sweep that starts the averager and allows monitoring of the needle electrode position. Signals from the cannula are delayed and averaged for the Macro EMG MUAP. All cannula APs time-locked with the sentinel SFEMG signal, are averaged and represent muscle fibers from a single motor unit. The Macro EMG

40 mm

A

SFEMG

Cannula 10 ms

Averaged response (Macro MUP)

B

100

100 μV 10 ms

Fig. 21.9 Macro EMG assessment of fibers from one motor unit. (A) Macro-EMG is recorded on two channels: one SFEMG channel, derived between the SFEMG surface and the cannula and one cannula signal derived between the cannula and a remote surface electrode as reference. (B) 1: The SFEMG potential is used to trigger the display sweep and the averager. 2: The cannula signal is delayed (about 40 ms) and fed to the averager. 3: The contribution from the fibers in a motor unit is extracted after averaging: the macro-MUP. (Reproduced from Stalberg E (2003). Handbook of Clinical Neurophysiology, Vol. 2).

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MUAP amplitude and area sampled from 20 sites provide information about the size of the MU, the MU architecture and its territory. Because of its large recording area, the Macro recording is nonselective. Macro MUAP configuration remains relatively constant even with needle position changes within a given motor unit territory. Normal values change with age and vary with level of contraction (Stålberg and Fawcett, 1982). Fiber density measurements can be made from the single fiber EMG signal, allowing comparison to the Macro MUAP amplitude and area. 21.5.2.1. Macro electrode The Macro needle electrode is similar to the SFEMG electrode except the 26 μm2 recording port is 7.5 mm proximal to the tip and the steel shaft is insulated with Teflon except for the distal 15 mm. The side recording port is used for SFEMG signal, which serves as the trigger, while the Macro signal is recorded from the un-insulated distal cannula. This electrode is used solely for Macro EMG recordings; it is handmade, expensive and nondisposable. 21.5.2.2. Filters The large recording area of the Macro electrode serves as a low pass filter favoring the low-frequency components from distant fibers. For the cannula Macro signal 5–10 000 Hz filter and for the SFEMG signal, 500–10 000 Hz filter settings are used. 21.5.2.3. Technique Recordings are made on two channels. The SFEMG signal is recorded on one channel, which is used to trigger the oscilloscope sweep and the averager. With partial muscle activation, the electrode is positioned to maximize the amplitude of a SFEMG signal; this position is maintained throughout the acquisition of the Macro recording. The Macro MUAP, the signal from the cannula with a remote surface or monopolar reference electrode, is averaged and recorded on a second channel, which is best visualized with a 40 ms delay. The Macro MUAP peak-to-peak amplitude, area of the rectified waveform correlate with the size and number of muscle fibers in the motor unit (Stålberg, 1990). ●

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Channel 1 recording—Cannula to surface reference (5–10 000 Hz filter) for averaged Macro MUAP. Channel 2 recording—SFEMG to Cannula reference (500–10 000 Hz filter) for the SFEMG trigger & FD measurements 20 Macro MUAPs are measured from different sites within the muscle.

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FD is measured from 20 different sites within the muscle for an averaged FD measurement.

21.5.2.4. Macro EMG in normal and neuropathic disorders 21.5.2.4.1. Normal subjects. Studies in muscles of healthy subjects provide reference values for several muscles (Stålberg and Fawcett, 1982). Abnormality is defined by values outside the limits for either individual Macro MUAP amplitudes or Median Macro EMG MUAP amplitude and area values for 20 recordings. Macro MUAP values change with age, particularly after the age of 60 and reference values are stratified by decade ranging from 100 to 350 μV (Stålberg, 1990; Stålberg and Fawcett, 1982). In normal muscle, the largest Macro MUAP amplitude may be greater than the smallest by a factor of 10 before the age of 60 and increase to a factor of 20 after age 60 (Stålberg and Fawcett, 1982). 21.5.2.4.2. Macro EMG in neuropathic disorders. In neuropathic processes with reinnervation, the MacroMUAP amplitude and area are typically increased, reflecting a larger motor unit territory. In long standing, chronic neuropathic disorders, such as after poliomyelitis, the Macro MUAP is quite high. In dynamic motor unit disorders such as amyotrophic lateral sclerosis, the Macro MUAP evolves; often increasing markedly in the earlier stages but decreasing late in the disease. Serial Macro EMG studies allow quantitative assessment of reinnervation processes. 21.6. Applications in neuropathic disease EMG provides information about the function of the motor unit and is particularly useful in assessing weakness from disorders of the lower motor neuron. On a more limited basis, EMG studies can also give information about the central nervous system function. The pattern of electromyographic abnormality depends on the site of the underlying disorder, which may be localized or broadly distributed. Using techniques of nerve conduction study and electromyography, a skilled examiner can determine if a disorder involves the peripheral nerve, plexus, root, anterior horn cell, neuromuscular junction or muscle. In neuropathic disorders, distinction between axonal and demyelinating processes is usually possible. Additional evidence of the presence of reinnervation and changes in the MU may be obtained from complementary techniques including SFEMG FD estimates, jitter measurements and Macro EMG.

ELECTROMYOGRAPHIC ASSESSMENT OF PERIPHERAL NERVE DISEASES: AN OVERVIEW

Results from all needle EMG techniques must be considered along with those of motor and sensory nerve conduction studies and interpreted in the context of the clinical setting. In addition to providing diagnostic information, EMG studies often provide information about prognosis, disease progression or response to therapy, particularly when performed serially over a period of time. References AAEM (1999) AAEM guideliness in electrodiagnostic medicine. Muscle Nerve 22: Supplement 8. AANEM Professional Practice Committee (2005) Needle EMG in certain uncommon clinical contexts. Muscle Nerve, 31: 398–399. Adrian, ED and Bronk, DW (1929) The discharge of impulses in motor nerve fibres. Part II. The frequency of discharge in reflex and voluntary contractions. J. Physiol., 67: 119–151. Albers, JW, Allen, AA, Bastron, JA and Daube, JR (1981) Limb myokymia. Muscle Nerve, 4: 494–504. Allen, AA, Albers, JW, Bastron, JA and Daube, JR (1976) Myokymic discharges following radiotherapy for malignancy. Arch. Phy. Med. Rehabil., 57: 595. Bromberg, MB and Scott, DM (1994) Single fiber EMG reference values: reformatted in tabular form. Muscle Nerve, 17: 820–821. Brown, WF and Varkey, GP (1981) The origin of spontaneous electrical activity at the endplate zone. Ann. Neurol., 10: 557–560. Brumback, RA, Bertorini, T, Engel, WK, Trotter, J, Oliver, KL and Zirzow, GC (2004) The effect of pharmacologic acetylcholine receptor of fibrillations and myotonia in rat skeletal muscle. Arch. Neurol., 35 (1): 8–10. Bryant, SH (1973) The electrophysiology of myotonia, with a review of congenital myotonia of goats. In: J.E. Desmedt (Ed.) New Develop. Electromyogr. and Clin. Neurophysio., Karger, Basel, pp. 420–450. Buchthal, F and Rosenfalck, P (1955) Action potential parameters in different human muscles. Acta Psychiatrica Scandinavica, 30: 125–131. Buchthal, F and Rosenfalck, P (1966) Spontaneous electrical activity of human muscle. Electroencephalogr. Clin. Neurophysiol., 20: 321. Buchthal, F and Schmalbruch, H (1980) Motor unit of mammalian muscle. Physiol. Rev., 60: 90–142. Daube, JR (1991) AAEM minimonograph #11: needle examination in clinical electromyography. Muscle Nerve, 14: 685–700.

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Daube, JR, Kelly, JJ, Jr. and Martin, RA (1979) Facial myokymia with polyradiculopathy. Neurology, 29: 662–669. Denny-Brown, D and Pennypacker, JB (1938) Fibrillation and fasciculation in voluntary muscle. Brain, 61: 311–334. Dorfman, LJ, McGill, KC and Cummins, KL (1985) Electrical properties of commercial concentric EMG electrodes. Muscle Nerve, 8: 1–8. Dumitru,D., Amato,A.A. and Zwarts,M.J. (2002) Electrodiagnostic Medicine, Hanley & Belfus, Philadelphia, 2nd edition. Dumitru, D and King, JC (2000) Hybrid fibrillation potentials and positive sharp waves. Muscle Nerve, 23: 1234–1242. Dumitru, D, King, JC and Nandedkar, SD (1997) Motor unit action potential duration recorded by monopolar and concentric needle electrodes. Physiologic implications. Am. J. Phys. Med. Rehabil., 76: 488–493. Ekstedt, J and Stålberg, E (1963) A method of recording extracellular action potentials of single muscle fibres and measuring their propagation velocity in voluntarily activated human muscle. Bull. Amer. Ass. EMG Electrodiagn., 10: 16. Ekstedt, J and Stålberg, E (1973) How the size of the needle electrode leading-off surface influences the shape of the single muscle fibre action potential in EMG. Comput. Programs Biomed., 3: 204–212. Ertas, M, Stålberg, E and Falck, B (1995) Can the size principle be detected in conventional EMG recordings? Muscle Nerve, 18: 435–439. Falk, G and Landa, JF (1960) Effects of potassium on frog skeletal muscle in a chloride-deficient medium. Am. J. Physiol., 198: 1225–1231. Geiringer SR (1994) Anatomic Localization for Needle Electromyography. Hanley & Belfus, Philadelphia. Gilchrist, JM and Ad hoc Committee (1992) Single fiber EMG reference values: a collaborative effort. Muscle Nerve, 15: 151–161. Henneman, E, Somjen, G and Carpenter, DO (1965) Excitability and inhibitibility of motoneurons of different sizes. J. Neurophysiol., 28: 599–620. Isaacs, H (1961) A syndrome of continuous musclefibre activity. J. Neurol. Neurosurg. Psychiatry, 24: 319–325. Kimura, J (2001) Electrodiagnosis in Diseases of Nerve & Muscle. Oxford, New York, 3rd edition. Kimura, J (2002) Routine needle electromyography. In: T. Bertorini (Ed.), Clinical Evaluation and Diagnostic Tests for Neuromuscular Disorders, Butterworth Heinemann, Woburn, MA, pp. 331–364.

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Kohara, N, Kaji, R and Kimura, J (1993) Comparison of recording characteristics of monopolar and concentric needle electrodes. Electroencephalogr. Clin. Neurophysiol., 89: 242–246. Layzer, RB (1994) The origin of muscle fasciculations and cramps. Muscle Nerve, 17: 1243–1249. Layzer, RB and Rowland, LP (1971) Cramps. N. Engl. J. Med., 285: 31–40. Massey, JM and Sanders, DB (1985) Sensitivity of various EMG techniques in motor neurone disease. Electroencephalogr. Clin. Neurophysiol., 61: 574–575 (Abstract). Massey, JM and Sanders, DB (1991) Single-fiber EMG demonstrates reinnervation dynamics after nerve injury. Neurology, 41: 1150–1151. Mateer, JE, Gutmann, L and McComas, CF (1983) Myokymia in Guillain–Barré syndrome. Neurology, 33: 374–376. Nandedkar, SD, Barkhaus, PE, Sanders, DB and Stålberg, EV (2000) Some observations on fibrillations and positive waves. Muscle Nerve, 23: 888–894. Nandedkar, SD, Dumitru, D and King, JC (1997) Concentric needle electrode duration measurement and uptake area. Muscle Nerve, 20: 1225–1228. Nandedkar, SD and Sanders, DB (1991) Recording characteristics of monopolar EMG electrodes. Muscle Nerve, 14: 106–112. Nandedkar, SD, Stalberg, E and Sanders, DB (2002) Quantitative EMG. In: D. Dumitru, A.A. Amato and M.J. Zwarts (Eds.), Electrodiagn. Med., Hanley & Belfus, Inc, Philadephia, 2nd edition., pp. 293–356. Nandedkar, SD, Tedman, B and Sanders, DB (1990) Recording and physical characteristics of disposable concentric needle EMG electrodes. Muscle Nerve, 13: 909–914. Newsom-Davis, J and Mills, KR (1993) Immunological associations of acquired neuromyotonia (Isaacs’ syndrome). Report of five cases and literature review. Brain, 116: 453–469. Perotto, AO (1994) Anatomical Guide for the Electromyographer. Charles C. Thomas, Springfield, Illinois, 3rd edition. Preston, DC and Shapiro, BE (1998) Electromyography and Neuromuscular Disorders: ClinicalElectrophysiologic Correlations. ButterworthHeinemann. Purves, D and Sakmann, B (1974) Membrane properties underlying spontaneous activity of denervated muscle fibers. J. Physiol., 239: 125–153.

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Sacco, G, Buchthal, F and Rosenfalck, P (1962) Motor unit potentials at different ages. Arch. Neurol., 6: 366–373. Sanders, DB and Howard, JF, Jr. (1986) Single-fiber electromyography in myasthenia gravis. Muscle Nerve, 9: 809–819. Sanders, DB and Stålberg, EV (1996) AAEM Minimonograph #25: single-fiber electromyography. Muscle Nerve, 19: 1069–1083. Scranton, PE Jr., Hasiba, U and Gorenc, TJ (1979) Intramuscular hemorrhage in hemophiliacs with inhibitors. A medical emergency. JAMA, 241 (19): 2028–2030. Stålberg, E (1980) Macro EMG, a new recording technique. J. Neurol. Neurosurg. Psychiatry, 43(6): 475–482. Stålberg, E (1990) Macro EMG. Methods in Clin. Neurophysio., 1: 1–14. Stålberg, E (2003) Methods for quantitation of conventional EMG. In: E. Stålberg (Ed.), Clinical Neurophysiology of Disorders of Muscle and Neuromuscular Junction, Including Fatigue, Elsevier, Amsterdam, pp. 213–244. Stålberg, E and Antoni, L (1980) Electrophysiological cross section of the motor unit. J. Neurol. Neurosurg. Psychiatry, 43(6): 469–474. Stålberg, E and Fawcett PR (1982) Macro EMG in healthy subjects of different ages. J. Neurol. Neurosurg. Psychiatry, 45(10): 870–878. Stålberg, E and Sonoo, M (1994) Assessment of variability in the shape of the motor unit action potential, the “jiggle,” at consecutive discharges. Muscle Nerve, 17: 1135–1144. Stålberg, E and Trontelj, JV (1994) Single Fiber Electromyography. Studies in Healthy and Diseased Muscle. Raven Press, New York, 2nd edition. Sunderland, S (1978) Regeneration of the axon and associated changes. In: Nerve and Nerve Injuries, Churchill Livingstone, Edinburgh, 2nd edition. pp. 108–132. Trontelj, J and Stålberg, E (1983) Bizarre repetitive discharges recorded with single fibre EMG. J. Neurol. Neurosurg. Psychiatry, 46: 310–316. Trontelj, JV and Stålberg, E (1992) Jitter measurements by axonal micro-stimulation: guidelines and technical notes. Electroencephalogr. Clin. Neurophysiol., 85: 30–37. Trontelj, JV, Stålberg, E, Mihelin, M and Khuraibet, A (1992) Jitter of the stimulated motor axon. Muscle Nerve, 15: 449–454. Wettstein, A (1979) The origin of fasciculations in motoneuron disease. Ann. Neurol., 5: 295.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 22

Autonomic testing Francis O. Walker* Department of Neurology, Wake Forest University School of Medicine, NC, USA

22.1. Introduction Evaluating the autonomic nervous system (ANS) presents unique challenges that distinguish it from the more traditional evaluation of classical sensory and motor pathways. The ANS comprises primarily small myelinated or unmyelinated fibers, which conduct slower and generate lower amplitude potentials than those studies in the peripheral nervous system (PNS). Unlike the skeletal muscles innervated by efferent peripheral nervous system fibers, efferent end organs in the ANS do not generate large, easily recorded signals. Further, if denervated, autonomic end organs often continue to function. ANS afferents on the other hand, generate no discrete perceptual modality nor do they localize in the way that large myelinated afferent sensory fibers do. Organized differently than the PNS, the ANS is often redundant, providing dual innervation to structures with both excitatory and inhibitory effects and as such, baseline ANS activity is influenced by a variety of internal states including arousal and mood. Further, autonomic end organs can also be influenced by a variety of non-neurogenic local or systemic influences, and these can be difficult to control for when attempting to measure ANS effects. Anatomically, the PNS and ANS differ as well. Autonomic nerve plexuses are typically located deep within visceral or somatic structures and are not readily amenable to surface stimulation or recording. Furthermore, autonomic innervation often involves complex networks of fibers, making it difficult to selectively isolate or activate individual

* Correspondence to: Francis O. Walker MD, Professor, Department of Neurology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1078, USA. E-mail address: [email protected]. Tel.:+1-336-716-7548-Office; fax: +1-336-716-7794.

units. Finally, the diversity of efferent end organs in the ANS is remarkable, ranging from lacrimal glands to erector pili muscles and afferent ANS endings can be found in a similar diversity of structures. As such, identifying, recording, and interpreting ANS signals require technical and clinical sophistication beyond those required for routine nerve conduction studies and electromyography. It is simpler to assess large myelinated peripheral nerve fibers that have discrete functions and are unitary than small autonomic fibers that have protean functions and are diffuse. Most current tests of autonomic function record the activity of end organ structures innervated by the ANS and analyze variations in this activity in response to controlled stimuli. Therefore, unlike nerve conduction studies and electromyography, autonomic testing often relies on indirect measures of nerve activity and must be interpreted accordingly. There is no simple physiologic test that directly measures ANS function. The current understanding of the clinical relevance of autonomic dysfunction followed the development of autonomic testing and its application to clinical populations. It is now apparent that autonomic testing predicts prognosis in patients with diabetes, identifies some patients with asymptomatic myocardial ischemia, and correlates with fatigue and impaired exertional capacity in a variety of medical and neurological disorders (Clark et al., 1998; Low et al., 2003; Vinik et al., 2003). It, therefore, seems likely that further advances in techniques to study autonomic function will have tangible clinical benefits for patients. This chapter will review a variety of available approaches for testing the autonomic nervous system and their technical and methodological limitations. The discussion is complete but not exhaustive and focuses on techniques that have been used in clinical contexts or show particular promise for clinical use.

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22.2. Neurophysiologic recordings of secretory glands 22.2.1. Sympathetic skin response The oldest and simplest indicator of sweat gland function is the sympathetic skin response. However, unlike the more conceptually straightforward measurements of sweat gland secretion described in Section 22.4, the origins of the sympathetic skin response remains a subject of active investigation. The latest studies suggest that sympathetic skin responses are electrical potentials that reflect changes in sodium concentration gradients with the sweat gland canal, in response to sweat gland activation (Mitani et al., 2003; Toyokura, 2003). Obtaining sympathetic skin responses is quite simple. A recording electrode is placed over an area of high sweat gland density, and a reference electrode is placed close by over an area of lower sweat gland density. Most commonly, the palm and dorsum of the hand are used (Fig. 22.1), but any area of the palmar or plantar skin surface, including digits serves well as the active recording site. Some investigators prefer referencing this to either a site over the knuckles on the dorsum of the hand (or foot), where the sweat gland density is particularly low, or over the nail bed. The

Fig. 22.1 This is a recording of the sympathetic skin response from four adjacent electrodes in the palm, each with a different filter setting: the top trace 0.2 Hz/30 Hz (Low-frequency filter/high-frequency filter); the second trace, 0.5 Hz/30Hz; the third trace 2 Hz/30 Hz, and the bottom trace 2 Hz/10 000 Hz. Note the marked attenuation in amplitude with increases in the low-frequency filter. The bottom trace shows the muscle artifact, which is otherwise filtered out with the lower high frequency filter settings. The arrow marks the onset of a deep aspiratory gasp; a small movement artifact is detected here.

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response can be elicited by any number of stimuli, ranging from an electrical shock anywhere on the body, to a loud noise, a bright light, unexpected tactile stimulation, or a host of novel verbal or non verbal stimuli. Due to habituation to many of these responses, however, a sudden single cough or deep inspiration are sometimes used instead. Recently, magnetic stimulation of the cortex has been found to elicit responses with little habituation (Toyokura et al., 2003). Marking the onset of stimuli can be easiest with electrical stimulation, but a variety of devices (accelerometers, pneumatic belts, microphones, etc.) can be used to mark the onset of other maneuvers. Stimulating and recording parameters, however, are critical. Because of habituation, certain stimuli may fail to elicit a response. As such, when attempting to identify whether a patient has an absent response, it is critical to use multiple types of stimulation, including loud noises, surprise, or deep breathing and sudden gasp. Patients may not fully cooperate with respiratory activation maneuvers, so encouragement is sometimes indicated. In terms of recording, sympathetic skin responses are of extremely low-frequency, and as such, the low-frequency filter is best set at 0.5 Hz or lower. Small variations in the low-frequency filter can significantly affect the amplitude of the recorded response (Fig. 22.1). A setting of 30 Hz for the high-frequency filter can screen out unwanted muscle artifact. The sweep speed needs to be slow, since responses typically occur between 1 and 2 seconds after a stimulus, and last for at least several seconds. With DC recordings, the response duration is significantly longer. The effects of age, skin temperature, and recent caffeine or smoking on the sympathetic skin response have not been widely studied. It seems advisable to control for these effects in clinical investigations. The sympathetic skin response seems to be larger in small children, possibly because the number of sweat glands on the hand is constant, with a reduction in density with growth of hand size. The prolonged latency of the response does not reflect the afferent limb of the response, as active stimuli are probably relayed centrally by large myelinated fibers. The efferent post ganglionic transit subsumes most of the latency of the response. The sympathetic cholinergic postganglionic fibers that mediate sweat gland activation have their cell bodies in the para-thoracic sympathetic trunk ganglia. From here, the unmyelinated C-fiber axons carry the responses along a route that typically accompanies the large myelinated fiber nerve pathways to the sweat glands. Traveling at

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1 meter per second, these action potentials spend approximately 800 ms in transit prior to synapsing with the sweat gland. Here, the neuro-glandular delay subsumes additional latency prior to the generation of the sympathetic skin response. Based on microelectrode recordings of sympathetic nerve activity, it is likely that the efferent axons carry a stream of successive impulses down innervating axons, explaining why single or even limited trains of repetitive stimulation do not reliably elicit direct sympathetic skin responses. The amplitude of sympathetic skin responses varies considerably, and some individuals have particularly large response amplitudes not unlike those seen for axon reflex sweating (Low et al., 1990). As a result, the distribution of response amplitudes (typically measured from positive to negative peak) do not describe the typical bell shaped curve in that the results are skewed by a disproportionate number of particularly large amplitude responses. The traditional cut-off value of two or three standard deviations below the mean to distinguish normal from abnormal cannot be used. Instead, only absent responses have been considered to be abnormal. More sophisticated statistical approaches to calculate lower limits of normal for a skewed distribution of normal values, have never been applied. Absent sympathetic skin responses, however, have shown consistent correlation with other measures of autonomic dysfunction in multiple clinical trials (Ravits, 1997). The latency of sympathetic skin responses also shows considerable variation. It is unclear why this is the case, but latency variation occurs even in subjects receiving stimuli of identical intensity and location. Bedside observation suggests that arousal, readiness, distractions and habituation probably influence the latency of these responses, but formal studies have yet to be published. It is possible to estimate C-fiber conduction velocities of autonomic sudomotor fibers using the sympathetic response. Latency differences between responses on the sole and palm in the same subject in part reflect differences in the length of the post ganglionic axon based on measurements of upper and lower extremity length (Parisi, 2001). Although useful for estimating C-fiber conduction time in a large population of subjects, the variation in individuals may limit its use in single patient studies. Further studies of this approach are needed to determine its clinical relevance. Simple latency measurements of sympathetic skin responses in response to single electrical stimuli are too variable and do not correlate well with other tests of autonomic function. At this time,

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latency measurements are not being used for diagnostic purposes. Normal values for the sympathetic skin response are sensitive to the technique used and the low-frequency filter selected. Several recent studies nicely demonstrate the variability of the response and how subtle changes in positioning along the palm can significantly (Cariga et al., 2001; Donadio et al., 2002; Toyokura 2003) affect the amplitude of the recorded response. Typically responses are in the 0.5–2 mV, with a high coefficient of variation across subjects. However, when averaged across even a small number of subjects, the mean sympathetic skin response amplitude is fairly constant over time making it useful for serial studies or in tests of drug effects (Walker and Lewis, 1990). 22.2.2. Sympathetic skin response testing; comments The most established test of sweat gland activity is the sympathetic skin response. It has applications in behavioral studies and provides a unique technique for investigating phenomena such as habituation, cognition, and arousal (Tranel and Damasio, 1985; Donadio et al., 2002). It can be recorded by the equipment available to all clinical neurophysiologists, and can be set up and performed in a matter of a few minutes. A number of methods are available to standardize the response, and continued study and experience with the technique may yet yield further improvements in its reliability and sensitivity. Its ease of use makes it more prone to misinterpretation by those lacking sophistication in autonomic testing, and its physiologic basis is not well understood; further studies are needed to clarify its role in autonomic evaluation. However, it correlates well with other tests of autonomic function, and is valuable as a screening tool (Vetrugna et al., 2003). What it lacks in precision and specificity is addressed in part by other available tests of sweat function discussed in Section 22.4. For example, although sympathetic skin responses can be recorded from several areas other than the hands and feet, including forehead, perineal areas, and lips, they cannot be used over large parts of the body (Ravits, 1997; Matsunaga et al., 1998; Zhu and Shen, 2001). Other sweat test methods provide a variety of alternatives. 22.3. Heart rate testing One of the critical roles of the autonomic nervous system is the regulation of cardiac pacemaker activity.

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Parasympathetic (vagal) input tends to slow heart rate, and sympathetic activity tends to increase it. Although capable of responding to neurohumoral substances and maintaining activity despite complete denervation, the heart is able to function at peak efficiency when autonomic integrity is preserved. Even simple maneuvers, such as standing up, require rapid adjustments in the heart rate (discussed in Section 22.4.1), and denervation impairs normal homeostatic mechanisms. 22.3.1. Heart rate variation to deep breathing Normally, the heart rate varies with breathing. This effect, called sinus arrythmnia, is a result of autonomic reflexes. The effect is amplified by slow deep breathing and is maximal at a rate of 6 per minute. Using this rate and depth significantly enhances the specificity and sensitivity of cardiac testing (Fig. 22.2 A and B). A variety of protocols can be used to study heart rate variation with deep breathing. The simplest is to use a strip chart EKG tracing and, with careful observation and a brief instruction period, have the subject inhale steadily to a maximum over 5 seconds and exhale steadily over 5 seconds to a maximum. The maneuver is repeated through at least three cycles, and interbeat intervals are measured. Any number of statistical analyses can be performed once this information is gathered. The simplest, but not the most sensitive or specific, is to subtract the fastest single heart rate from the slowest, for a maximal minimal

FRANCIS O. WALKER

heart rate difference. Calculating the coefficient of variation may be the conceptually simplest and valid statistical test to perform, but a number of other approaches have advantages and disadvantages as well. For electromyographers, the beat to beat variation can be displayed using a trigger and delay line and the result, although manifest in seconds instead of microseconds, is analogous to jitter analysis in single fiber EMG studies (Fig. 22.2 A–C). Heart rate analysis, however, needs to be monitored carefully. Patients, particularly older patients or those with pulmonary disease, are often poorly cooperative with the technique and either fail to achieve maximal inspiratory or expiratory volumes or reach them to suddenly and end up with more breath-holding than appropriate. The use of a pneumatic belt or respirometer can help control for such variation, but there is no substitute for training or enthusiastic oversight. Further complications result from premature atrial or ventricular heartbeats, which can significantly skew results. Such beats should be excluded from any mathematical calculations. The effect of age is rather striking, however, and any use of the technique must control for this. An additional factor that influences the test is the nature of the resting heart rate. Variability decreases in normals with higher resting heart rates (Piha et al., 1991) and this can limit the usefulness of the test. Placement of the leads for recording an EKG signal is of some importance as well. With deep breathing, the heart undergoes significant changes in positioning

Fig. 22.2 These are recordings of EKG signals at rest (A), during slow deep breathing (B), and during a Valsalva’s maneuver (C). The top trace in each image is a superimposition of seven consecutive heartbeats during each of these maneuvers demonstrating a small segment of the overall recording captured in the graphs below (Nicolet Viking, Madison WI). Note the somewhat irregular nature heart rate fluctuations during all of the maneuvers but the significant increase in variation with both deep breathing and Valsalva’s maneuver. The arrows in Fig. 22.2 C mark the onset and offset of the maneuver.

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within the chest and chest well and diaphragm muscles are activated. As such, it helps to set the highfrequency filter quite low (100 Hz or lower) to minimize unwanted skeletal muscle artifact, If a program is being used that is based on a QRS response amplitude, it needs to be adjusted so that it can detect all variations in the amplitude of the QRS with inspiration and expiration. The normal value of the test for maximumminimum difference is 27 if for those who are age 20, but 8 for those who are age 70; the decrease is virtually linear, with a loss of two beats every 5 years. The lower limit of normal (0.05% limit) at age 20 is 13, and this decreases linearly by about 1 beat very 5 years based on a large sample of 143 patients (Piha et al., 1991). By the age of 70 about 5% of normals show no variation with deep breathing, so the usefulness of the test is quite limited in the elderly. A maximum to minimum ratio can also be calculated, which tends to be more uniform; it shows a similar profound change with age, however it does not appear to be that much more sensitive than the absolute difference. Men and women have equivalent responses. These findings have been reported in other studies (Vita et al., 1986; Kuroda et al., 1990; Ziegler et al., 1991). Low et al., (1990) described such findings from 157 normals, and compared the same with previously published values, and demonstrated the correlation of this measure with several other tests of autonomic function. A variety of instruments and modifications have been developed to enhance the analysis of cardiac variation with deep breathing. These include sophisticated devices that can detect premature atrial and ventricular beats, analyze each inter-beat interval automatically and provide power spectral analysis of electrical signals. Higher-frequency components are indicators of parasympathetic function, and lower-frequency components are more indicative of sympathetic function (Freeman et al., 1991; Blaber et al., 1996; Ravits, 1997; Vinik et al., 2003. These advances make the technique more reliable and may enhance the ability to analyze information from individual patients. 22.3.2. Heart rate variation to the Valsalva’s maneuver and the Valsalva ratio Valsalva’s maneuver has characteristic effects on the heart rate that are easy to monitor. The maneuver, by increasing thoracic pressure, decreases cardiac venous return and output, leading to a decrease in blood pressure. This leads to activation of the barore-

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flex receptors and induces a compensatory tachycardia. With release of the maneuver, venous return is accentuated, leading to an increase in blood pressure which, through the baroreflex receptors, induces a reflex bradycardia. Assessment of the variation of heart rate during the Valsalva’s maneuver, therefore, provides an assessment of cardiac autonomic innervation (Fig. 22.2 A–C). The blood pressure changes in Valsalva’s maneuver have been divided into four phases, but this is still a bit of a simplification (Ravits, 1997). At the onset of strain (phase 1), there is actually a brief period of increased venous return and enhanced arterial output. After this, the blood pressure falls secondary to decreased venous returns, and then it slowly increases as compensatory mechanisms takeover (phase 2). The blood pressure, in a reversal of phase 1, then drops briefly due to the release of pressure in the chest (phase 3), and then increases significantly as venous return increases and then slowly returns to normal (phase 4). All in all, there are six changes in blood pressure and heart rate that occur. Pharmacologic tests indicate that the phase 2 recovery of blood pressure is mediated by sympathetically mediated vasoconstriction (Fig. 22.3), and that heart rate changes are mediated by both parasympathetic and sympathetic mechanisms. Blood pressure changes in the Valsalva’s maneuver are rarely used in routine evaluation of individual patients. However, elegant work by Goldstein (2003) has shown how the pattern of blood pressure changes in patients can be used to carefully map different aspects of autonomic function. These correlate well with recordings of muscle sympathetic activity obtained by inserting a tungsten microelectrode into the peroneal nerve. Although a highly specialized example of autonomic investigation, this type of study provides insight into what can be currently done with existing technology. To test the effects of Valsalva’s maneuver on heart rate, a Valsalva ratio is calculated. The patient is asked to strain against a closed glottis for 15 seconds, followed by relaxation for 20 seconds. The longest inter-beat interval (during post-valsalva relaxation) is then divided by the shortest inter-beat interval (during Valsalva’s maneuver) to generate a ratio. The degree of strain can be monitored by having the patient blow into the recording tube of a sphygmomanometer to a set pressure (40 mm HG). To prevent malingering and placement of the tongue over the tube to maintain the pressure with straining, a bleeder connection can be used. A section of a cut foley catheter works well in this regard. The large opening is fitted

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Fig. 22.3 This is a pulsed Doppler ultrasound recording (7.5 mHz probe, Phillips 5500, Bothel WA) of the radial artery in a normal subject at rest (top trace), during a Valsalva’s maneuver (middle trace), and immediately following release of the Valsalva’s maneuver (bottom trace). Note the prompt reduction in peak systolic and diastolic flow at A, most marked at B with prompt recovery beginning at the bottom trace. These changes reflect alterations in peripheral resistance to blood flow and demonstrate heart rate changes as seen in Fig 22.2. Similar studies can be performed in more distal or proximal locations or in the splanchnic vascular bed (superior mesenteric artery) to determine autonomically mediated changes in blood flow. RI is a calculated resistivity index, which is a mathematical approximation of resistance to flow.

over the sphygmomanometer, as the patient maintains the pressure the small opening in the wall of the tube (the portion used to inflate the anchoring balloon) allows for a small quantity of air to escape at a pitch audibly detectable to the investigator. The same caveats regarding QRS complex amplitude changes and detection of premature beats as in the deep breathing exercise apply. Normal values for the Valsalva ratio need to be adjusted for age. A normal value at age 20 is 1.9 and this decreases by 0.01 per year until the age of 70, when the value is 1.44. The lower limit of normal (0.05% limit) at the age of 20 is 1.25 and this value decreases by 0.03 units every 5 years. By 60 years, the lower limit of normal is 1.01, and in older ages, the lower limit falls below 1.0, which is of uncertain significance (Phia, 1991). Other studies show similar results and changes with age, but slight variations in technique and study populations are noted (Low, 1990; Kuroda et al., 1990; Ziegler et al., 1991; Vita et al., 1986). Blood pressure should not fall more than 20 mm HG during the maneuver, and failure for blood pressure to increase following a drop is also abnormal (Ravits, 1997), but standardized values for normal pressor responses have been less well studied than for heart rate changes. Further, normative

findings for these pressor changes with age have not been established. It is not known as to how much more information is provided by performing multiple tests of cardiac function, or how differentially sensitive these tests are to different kinds of autonomic dysfunction. Furthermore, it should be noted that the autonomic innervation of cardiac pacemaker activity may be a highly specialized autonomic function that may not reflect the activity of autonomic innervation of other end organs. For patients with significant metabolic disorders such as diabetic polyneuropathy, both tests of cardiac variation correlate well with abnormalities of other autonomic measures. As with other studies of blood pressure or heart rate, recent ingestion of caffeine or hot beverages may influence the results of the study and should be avoided before testing (Quinlan et al., 1997). 22.4. Testing secretory gland output 22.4.1. Lacrimal glands Perhaps the conceptually simplest tests of autonomic function involve the measurement of the secretion

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of autonomically innervated glands. Tests of tear production, for example, provide some estimate of autonomic function of the lacrimal gland. The Schirmer test, in which a filter paper strip of standard shape and manufacture (e.g., 0.5 × 30 mm; Color Bar; Schirmer tear test standardized sterile strips: Eagle vison, Memphis Tenn) is placed between the medial and lateral third of the lower fornix of the eyelid (Vissink et al., 2003). After 5 min, the amount of wetting is measured from the extrafornicieal position of the strip. A value of 5 mm or less is considered abnormal, but recent studies suggest that there is considerable variation in this measurement in normal subjects. (Haldenberg and Berens, 1961; Vissink et al., 2003). The Schirmer test, however, turns out to be somewhat more complicated that it first appears. The tear volume in the eye is an equilibrium determined by the production of tears minus tear drainage and the typically minor factor of evaporation. The insertion of a small strip of filter paper in the eye removes a significant volume of tear fluid, and such drainage may induce reflex tearing. This may obscure results of the test if it is being used simply to detect steady state conditions (Yokoi et al., 2000). From an autonomic testing standpoint, however, it may be more meaningful to test for reflex activation of the gland, than to simply assess baseline function. Autonomic contributions can perhaps be determined by performing the study before and after anesthetizing the eye (Yokoi et al., 2000), but this seems inordinately invasive, and prone to other unwanted affects. A simpler approach is the cotton thread test, in which the same principle of capillary diffusion is used to estimate tear volume, but the effect of fluid loss is minimized by the use of a thread (Yokoi et al., 2000), thus allowing better measurement of the baseline state. Other tests of lacrimal production include a clinical rating of the distribution of dye instilled into the eye after one or two blinks (the rose bengal score), the tear breakup time following fluorescein dye instillation, in which the time between the last blink and the first break in the tear film is measured, and the tear meniscus height, as measured by specialized video equipment (Yokoi et al., 2000; Vissink et al., 2003). Abnormalities in any of these tests need to be interpreted carefully, however. In addition to autonomic dysfunction, primary lacrimal failure, lacrimal duct obstruction, excessive evaporation, lid malfunction, or excessive tear duct drainage could all lead to abnormal results.

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22.4.2. Salivary glands Salivary gland secretion is somewhat easier to measure than lacrimal gland secretion, because evaporation is insignificant and drainage by swallowing is subject to voluntary control. The simplest techniques for measuring output involves dependent drooling of saliva into a cup for 15 min. Somewhat more complex is stimulating salivary secretion by basting the lateral borders of the tongue every 30 seconds with a cotton swab dipped in a 2% wt/vol citric acid solution, and collecting saliva for 10 min by asking the patient to spit in a cup (Vissink et al., 2003). In one study, normal subjects produced 0.023 ± 0.15 (SD) ml/min at rest and 1.58 ± 0.46 ml/min of saliva with stimulation (Vissink et al., 2003). Alternatively, a standardized piece of paraffin wax or cotton dental pads (e.g., Absorb-its, All Dental ProdX Solutions, Gig Harbor, WA) (Chancellor et al., 2001) can be chewed for set periods of time and saliva measured by spitting into a cup or weighing the absorbents (Racette et al., 2003). These techniques can yield similar flow rates but there is greater variability on using shorter time epochs. Both measures of salivary output demonstrated the impact of therapy (oral anticholinergic medication and injected botulinum B toxin), suggesting that a change in salivary output can be a practical measure of autonomic activity. In addition to medication effects, cigarette smoking, time of day, and caffeine exposure should be controlled for in salivary testing as these can all influence salivary output. 22.4.3. Sweat glands Unlike lacrimal and salivary gland activity that is mediated by parasympathetic nerves, sweat gland activity is mediated by sympathetic nerves. Further, sweat glands are widely distributed over the body and, therefore, more suitable for evaluating local or length dependent disruptions of autonomic activity. However, sweat gland output is more difficult to assess since the output of any individual gland is small, and evaporation is a critical problem. 22.4.3.1. Gross sweat measurement The simplest test of sweat function is simple inspection. Sweating can be observed with the naked eye or a magnifying glass, and side-to-side comparisons, sometimes using touch to confirm, can demonstrate gross differences in regional sweat activity. Simple inspection, for example, is sufficient for targeting sites

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of botulinum toxin injection for axillary hyperhydrosis. Microscopic evaluation of sweat activity is also possible (Kamei et al., 1997; Tsuda et al., 2000a) for more precise delineation of sweat output and documentation; however, additional steps are required. 22.4.3.2. Thermoregulatory sweat test The thermoregulatory sweat test provides a precise anatomic record of the distribution of sweating on the body and provides some degree of qualitative information regarding the density of sweating in these areas. The patient is dusted with a moisture-indicating powder, heated in a controlled environment to induce thermoregulatory sweating, and examined and photographed after a suitable warming period has elapsed. Several powders change color when moist, including quinizarin, which can be irritating, iodinated cornstarch, and other iodine solutions. A preferred mixture currently is alizarin red (50 g) mixed with cornstarch (100 g) and sodium carbonate (50 g) (Fealey et al., 1989). The heating method ideally involves a special chamber that can maintain temperatures at 45–50°c and 45–50% humidity, sometimes with infrared warmers to help maintain skin temperature. A variety of studies, however, have used other techniques to raise body temperature, for example, immersion in a hot tub can be effective in inducing thermoregulatory sweating in the face or upper extremities (Allison and Reger, 1998; Gass et al., 2002). The key is to measure both core and surface body temperature so that conditions can be replicated. Raising the core body temperature 1.4°c or to 38° centigrade appears optimal. Because of the substantial body areas involved, it is difficult to provide quantitative descriptions of normal, but clinical scoring of the patient in terms of focal, segmental, regional, distal or generalized anhydrosis is fairly straightforward given.s suitable experience with normal studies (Fealey et al., 1989). The effects of aging in thermoregulatory control may be significant (Grassi et al., 2003) and should be controlled in comparative studies. Although conceptually elegant, in practice the technique is untidy. It is time consuming, requires dedicated space, equipment, and materials not readily available in most clinical settings, and should not be used to study patients who have multiple sclerosis to avoid heat induced worsening of their condition. The test also poses risks for those prone to orthostatic hypotension. It is most useful for addressing questions regarding changes in sweat distribution in patients.

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The informativeness of the technique is nicely illustrated in a report of changes in sweat distribution following surgical sympathectomy for hyperhydrosis (Atkinson and Fealey, 2003). 22.4.3.3. Sweat drop imprint testing An approach that further modifies sweat testing involves mapping the distribution of individual sweat glands in particular areas of the body. The technique involves the induction of local sweating, followed by applying an indicator dye, bond paper, or plastic or silicone imprints of the skin (Vilches et al., 2002). Using these techniques, the single tiny droplets of sweat formed by individual sweat glands can be imaged, displayed, and scored in terms of size and counted (Stewart et al., 1994). These tests provide a degree of quantitative measurement lacking in the thermoregulatory sweat test. For example, the hand has 311 ± 38 sweat glands per cm sq in the hand compared to 281 ± 38 in the feet, and droplet size is equivalent in both areas, with a coefficient of variation of approximately 25% (Stewart et al., 1994). The sensitivity of the test appears greatest in terms of sweat gland counts as opposed to estimates of drop size (Kennedy and Navarro, 1993; Ravits, 1997). 22.4.3.4. Quantitative sudorometry Sweat gland secretion can, of course, be more accurately measured. Simple techniques can involve weighing filter paper before and after exposure to the skin (Baser et al., 1991; Ravits, 1997), but such simple approaches have not been well standardized. Other methods, involving taped patches of absorbent chemicals with water-tight seals or sophisticated methods for measuring sweat content following collection by exposure to 1% ethanol (Tsuda, 2000b), may eventually be useful for measuring sweat production. Currently, sweat production can be most accurately measured using small airtight chambers placed on the skin with intake and exhaust tubes; dry nitrogen gas is blown through the chamber and collected and the evaporative moisture is measured. The simplest use of sweat capsule testing is the measurement of baseline sweat production. However, as can be deduced from observations of thermoregulatory sweat testing diagrams (Fealey et al., 1989), sweat production is variable from subject to subject and from site to site. Furthermore, activities, such as body temperature, smoking alcohol or caffeine intake,

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age, and psychological responsiveness, may influence recordings. Exercise training also significantly influence sweat production (Roberts et al., 1977). 22.4.3.5. Axon reflex testing with quantitative sudorometry More specific analysis of the innervation of sweat glands can be evaluated by activation of the axon reflex. This is a phenomenon in any branched axon, in which the excitement of any one branch leads to activation of all others through antidromic and orthodromic conduction. The classic example of an axon reflex is the histamine flare response. Histamine, when injected into the skin, directly excites the C-fiber nociceptors that it contacts. This causes axon reflex excitation of multiple C-fiber terminals and these release vasodilatory substances that induce a red flare in an area exceeding the histamine permeated area by several square centimeters. The sympathetic fibers that innervate sweat glands branch extensively; therefore, excitation of sweat gland fibers in a small area of skin lead to axon reflex activation of sweat glands in a larger surround area. A dual chamber capsule allows for measurement of axon reflex-mediated sweating. In the surround chamber, the iontophoresis of acetylcholine activates axon reflexes. It also directly activates sweat glands in the surround area, so measurement of sweat output here is uninformative with regard to neurogenic sweating. However, in the central chamber, the output of sweat glands occurs in response only to axon reflex activation, a true measure of neurally mediated sweat output. A solution of 10% acetylcholine is iontophoresed over a small area of skin delimited by the surround chamber using a constant current generator and a stimulus of 2 mA for 5 min. Sweat is collected in the central chamber for 10–15 min after iontophoresis (Fig. 22.4). Sweat output is expressed as uL/cm2, and men (3.10 uL/cm2) produce about twice as much axon reflex sweat as women (1.15 uL/cm2) at the forearm and over the foot (2.65 ± 1.65 uL/cm2, versus 1.15 ± 1.14 uL/cm2) (Low, 1990). The coefficient of variation over the feet of 62% for men and 99% for women indicates that the test has considerable variation. Although not statistically significant, there appears to be some regression in sweat output with age (Low, 1990), and age-matched controls might be a consideration when using the technique. Other techniques for eliciting axon reflexes, such as simple electrical stimulation of the skin (Lewis and Walker, 1988) have not been tested in this fashion. A

Fig. 22.4 This tracing, from the right forearm, shows sweat production in the right forearm (Q-SweatTM WR Medical Stillwater, MN). The bottom units are in minutes. Baseline sweat production is 0.46 nanoliters of sweat per minute. At one minute acetylcholine is iontopheresed and there is a 1 min and 45 second delay before a steady increase in sweat production is seen. A total of 0.829 ml of sweat are produced during the 10 min recording.

reduction in sweat output is seen with age. Complex temporal patterns of sweating in response to axon reflex activation have been described, and involve changes in latency and persistence of sweat production, but these have not been extensively characterized. Further research and clinical use of these techniques should be informative. 22.4.3.6. Comments on sweat testing techniques Thermoregulatory sweat testing provides an objective means of mapping sweat activity over the body, and tests far more surface area than sudorometery or sympathetic skin response testing. Sudorometry and sweat imprint testing measure direct sweat gland activity or viability in focal areas and as such are more sensitive and specific for these functions than the sympathetic skin response. In addition, different tests evaluate different aspects of sweating: the thermoregulatory sweat test assesses the afferent limb of heat sensation and thermodynamic control mechanisms of sweat activity; sweat imprint testing assesses the function and viability of individual sweat glands, and sudorometry can specifically quantify postganglionic axonal activity. Further clinical studies using multiple techniques should be helpful in determining how to best use tests of sweating. One area of parallel technologic development that may enhance research in this area is the development of sophisticated sweat assays for biological and pharmacological compounds (Samyn and van Haeren, 2000; Tsuda et al., 2000b; Moody and Cheever, 2001; Naitoh et al., 2002).

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22.4.4. Tests of other secretory glands

22.5.1. Blood flow: measurements

A variety of neurophysiologically mediated stimuli can induce secretion of endocrine or exocrine glands (Holzer et al., 2001). It is clear that autonomic activity mediates much of this activity, but specific pathways and mechanisms, and the role of other humoral agents in mediating this activity are not well understood. Currently, sophisticated assays are available that can detect subtle variations in the levels of a variety of biological compounds in blood, saliva, gastric secretions, tracheal aspirates and sweat (Tsuda et al., 2000b). Endocrine secretion of norepinephrine, epinephrine, glucagon, vasopressin, insulin, vasoactive intestinal peptide, oxytocin and other agents in response to neural or psychophysiological stimuli are well known, but have not been studied in sufficient detail to use them as sensitive tests of autonomic function (Steffens et al., 1990; Yamaguchi 1992; Wood et al., 1999; Gimpl and Fahrenholz, 2001; Holzer et al., 2001; Hansen, 2003). Even phenomenon such as mast cell degranulation and other inflammatory or immunologic mechanisms may be related to autonomic activity (Wood et al., 1999). Plasma levels of norepinephrine have been used in the study of patients with orthostatic hypotension, but these have not been particularly helpful in terms of clinical management (Goldstein et al., 2003). Exocrine secretions, from vasomotor rhinitis to gastric release of hydrochloric acid are influenced by autonomic nervous system activation. Quantitative measures of these changes in response to standardized maneuvers have not been used as autonomic indicators. Approaches of this type may be useful in the future.

Like sweating, the simplest measures of blood flow involve inspection. Peripheral vasodilation is associated with redness and warmth from the hemoglobin that is shunted through the skin when superficial arterioles dilate. However, the relationship between redness and blood flow is variable. Skin blood flow, measured by laser, doppler, may need to increase fourfold for their to be apparent erythema, and redness may appear without changes in blood flow (Berardesca et al., 2002). Similarly, red cheeks may be normal for an individual, or a sign of intoxication with alcohol or carbon monoxide.

22.5. Tests of smooth muscle function Much of the autonomic nervous system is devoted to the control of smooth muscles. The most superficially located of these muscles are those that have been studied in terms of autonomic control. These include the arteriolar smooth muscle of the dermal vascular bed, the pupils, and to a limited extent the behavior of the smooth muscle components of the anal and urinary sphincters. Autonomic testing of deeper structures such as the uterus, ureters, and gall bladder, structures of intense clinical interest when active or obstructed, has not been developed. Autonomic activity of the gut is being evaluated by surface electrogastrograms, but outside of simple manometry, the extensive autonomic innervation of enteric smooth muscle is not routinely tested.

22.5.1.1. Skin wrinkling The simplest measure of blood flow is digital skin wrinkling in response to immersion in warm water. The test involves the immersion of the hand to mid forearm in a water bath that is kept at 40°c for 30 min. The number of skin ridges is counted per fingertip after immersion and typically three ridges develop per finger (Djaldetti et al., 2001). Alternatively, blood flow measures by ultrasound-based Doppler can be used following the procedure (Wilder-Smith and Chow, 2003). The physiology of skin wrinkling results from the high concentration of arteriovenous vessels in the distal digit pulp, the so-called “Hoyer-Grosser’s” or glomus organs. These structures are anchored to the epidermis and with vasoconstriction, these structures shrink. Due to the rigid anchoring points, however, the skin cannot uniformly depress, but rather folds inward between anchoring points (Wilder-Smith and Chow, 2003). This creates ridges, which are easily counted on each digit. A decrease or absence of fingertip wrinkling after hot water immersion appears to be a fairly sensitive test of autonomic function that correlates well with other clinical measures (Vasudevan et al., 2000; Djaldetti et al., 2001). EMLA cream is able to induce similar wrinkling (Wilder-Smith and Chow, 2003). 22.5.1.2. Capillaroscopy A conceptually simple technique is capillaroscopy, the direct visualization of capillary flow using microscopy or lenses with direct contact with an oil drop on the surface of the skin to minimize reflected light. This technique allows visualization of only the most superficial structures, primarily capillaries, but this can reveal changes, such as loss of density and enhanced irregularity with ageing. Computer-based image analysis coupled with fluorescein dye further enhances

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capillaroscopy. Several recent studies demonstrate the power of this approach in terms of viewing the microcirculation, and it adaptability. The vasculature of the oral mucosa is amenable to study, and imaging capillaries in the nail bed can be done quickly and non-invasively using a handheld lens (Bergman et al., 2003; Newell et al., 2003; Scardina and Messina, 2003). Adaptation of the technique to study the autonomic nervous system, however, has been limited. 22.5.1.3.1. Skin temperature measurements: Thermometry. Skin temperature largely reflects underlying blood flow and can sometimes be used as a surrogate marker of underlying vascular activity. One variation of skin temperature measurements is the measurement of thermal conductivity. In this case, the ability of the skin to remove heat from an area heated by an external probe is measured; this is primarily due to local blood flow (Dittmar, 1989; Beradesca et al., 2002). The technique is time consuming and site dependent, so control values need to be collected carefully. This area is one of renewed interest, however, in attempts to find more efficient ways to cool the skin following laser therapy. More direct measurements of skin temperature can be made with electric thermometers. These can measure subtle and rapid variations in skin temperature (Allen et al., 2002). After a deep inspiratory gasp, for example, digital skin temperature falls by 0.089°c, a change that reflects almost complete shutdown of blood flow by laser doppler. Although less sensitive than individual measures made by electronic thermometers, whole body imaging can be used to map skin temperature. Thermography can be done with flexible contact plates using liquid crystal technology (Stuttgen and Flesch, 1985), or by remote infra red thermal photographic detectors. Infrared radiation, however, can be reflected so it is important to control for any potential incident sources of warmth. 22.5.1.3.2. Skin temperature measurements: thermography. The basic technique of thermography is simple. Patients are seated or standing upright with a constant distance from the camera (this is to simplify comparison of serial images). A series of successive images at 10-second intervals are obtained and averaged for analysis (Schick et al., 2003). A variety of additional maneuvers, such as cooling and rewarming can be performed as well. Patients need to be acclimatized to ambient room conditions, which need to be

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specified prior to imaging. Prior activity, including strenuous exercise, smoking, caffeine intake, and time of the day can influence imaging. Further, patients can intentionally alter the results of testing by a variety of maneuvers such as scratching, rubbing, use of vasoactive topical agents, or even straining, and careful clinical pre-screening is warranted. Side to side symmetry of thermographic images is known to be robust. On the forehead, a difference of 0.5° centigrade and on the foot of 1° centigrade represent significant differences (more than two standard deviations from the mean) (Uematsu et al., 1988). Striking and anatomically consistent changes can be documented with thermography following procedures such as lumbar sympathetic block (Kim et al., 2003). However, the interpretation of thermography in diagnostically ambiguous situations is far from simple. For example, in Raynaud’s syndrome, thermography showed a poor correlation with blood flow as measured by laser doppler technique (Clark et al., 2003). Thermography cannot measure blood flow directly and represents a thermal average of locally conducted heat, and reflects a balance of heating, cooling, and compensatory mechanisms. Even when used following a definitive procedure such as sympathectomy, the results of thermography are variable, difficult to explain, and fail to correlate with reduction in sweat production. In patients with radiculopathy, the findings are insensitive and of no apparent clinical value (Harper et al., 1991). Although thermography is a reliable and physiologically valid technique, its relationship to innervation patterns of the dermal vasculature and peripheral and autonomic nervous system dysfunction is poorly understood. Used in appropriately controlled conditions, thermography is a useful technology for studying temperature control mechanisms but further studies are needed before it can be considered appropriate for diagnostic purposes. 22.5.1.4. Laser doppler flowmetry Fortunately, there are more direct techniques for measuring skin blood flow than temperature. Laser doppler flowmetry technique is based on the ability to detect Doppler shifts in light reflected from moving red blood cells. Since stationary objects do not create Doppler shifts when reflecting light, an analysis of Doppler frequency shifting provides an estimate of blood movement in vascular tissues (Beradesca et al., 2002). The physics of the relationship between laser doppler output signals is complex, but other techniques for measuring blood

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flow show a fairly good correlation, although at low and high rates of flow, the correlation weakens somewhat. Since no definitive test perfectly measures blood flow, however, it is difficult to say whether laser Doppler flowmetry is less or more accurate than any other technique. Further, because of significant variation in local factors, skin pigmentation, skin depth, and variability of structure, laser doppler can only be used to measure relative changes in blood flow and cannot be used to calculate absolute flow (Berardesca et al., 2002). Current instruments can use a probe placed directly on the skin, which can influence local blood flow, or use a light source held at a fixed distance (Wardell et al., 1993; Berardesca et al., 2002). An optical detector system is used to analyze the doppler shift, and is connected to a computer that calculates local blood flow. A variety of factors affect readings, and need to be controlled. In increasing order of importance these are circadian rhythm, age and race, menstrual cycle, anatomical site, mental activity, physical activity, body position, drugs and foods, ambient skin temperature and if relevant, probe pressure (Berardesca et al., 2002). The recordings in response to maneuvers such as a deep inspiratory gasp have an appearance not dissimilar from those of sympathetic skin responses (Fig. 22.5). 22.5.1.4.1. Laser doppler perfusion imaging. One technique that enhances laser Doppler flowmetry is perfusion imaging. Here, the external laser beam, using

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stepper motors, is scanned across the surface of the tissue of interest, typically the hand. It records up to 4,096 points to assess perfusion up to an area of 12 × 12 cm (Laser Doppler perfusion imager, Lisca, Linkoping, Sweden) (Ruch et al., 2003). The scanning process requires 4–5 min, and provides a snapshot of local perfusion patterns, all based on laser Doppler flowmetry principles (Fig. 22.6). The technique demonstrates a significant loss of perfusion in the territory of transected peripheral nerves (Ruch et al., 2003). 22.5.1.5. Photoplethysmography Photoplethysmography is a subtraction technique for measuring blood flow. A light source and light detector are used, either adjacent to each other (reflection photoplethysmography) or situated facing each other across an imaged structure, for example a digit or earlobe (transillumination plethysmography). The greater the presence of hemoglobin, the greater the amount of light that is absorbed, and the difference provides and estimate of blood volume and flow (Berardesca et al., 2002). Modifications of the technique using wavelengths of light that can penetrate deeper into tissue, have been used to study muscle blood flow in human anterior tibialis. Such surface recordings provide good correlation with invasive single-fiber laser doppler flowmetry, a technique that involves inserting a small optical fiber within the muscle (Zhang et al., 2001) to measure blood flow.

Fig. 22.5 This is a tracing of laser Doppler flowmetry from a small probe taped to the pulp of the index finger (top trace) and great toe (bottom trace). Note the variation in flow as synchronized with the pulse. The arrow marks a cough, and initially, due to enhanced expulsion of thoracic blood there is a transient, mechanical increase in blood flow, followed by a slow, autonomic nervous system mediated reduction in blood flow that recovers after approximately 20 seconds, with what appears to be mild rebound. Finger blood flow is significantly greater than toe blood flow (study courtesy of Thomas Smith PhD).

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Fig. 22.6 This is an image of laser Doppler perfusion imaging (Laser Doppler perfusion imager, Lisca, Linkoping, Sweden) of the palmar aspect of the right hand before and immediately after the left hand is immersed in a bucket of ice water. Note the prominent loss of flow in all digits, most marked in digits 3 and 4. Overall blood flow decreased 37% during the maneuver. The blood pressure increased from 98/72 pre-immersion to 116/82 during the maneuver. As in Fig. 22.3., this tracing provides graphic evidence of local, autonomically mediated changes in vascular resistance in response to distant stimuli. (Study courtesy of Tom Smith PhD).

22.5.1.6. Ultrasound based doppler Conventional ultrasound instruments can calculate blood flow in small arteries using doppler shift analysis. The sensitivity and resolution of ultrasound instruments continues to improve over time and recent studies with ultrasound have shown it to be a fairly sensitive indicator of blood flow in digital arteries (Wilder-Smith and Chow, 2003). Ultrasound can also be used to calculate flow in large arteries, and as such, has the potential to be informative in investigating autonomic control of blood pressure and hemodynamics as well (Fig. 22.3). Blood flow in the superior mesenteric artery may be a particularly relevant measurement of the control of blood flow specific to the enteric nervous system (Perko, 2001). The imaging technique is challenging in that it involves imaging through the abdominal wall, and an 8-h fast and 24-h avoidance of flatogens helps minimize imaging distortions. The transducer (typically 2.5–3 Mhz to achieve depth) is placed just below the xiphoid process and the superior mesenteric artery if found by scanning to the left and caudad. The angle of insonation should be kept between 60 and 90°. A variety of maneuvers affect flow (Perko, 2001), some neurally mediated. For example, head up tilt to 50° causes a reflex decrease in both blood flow and peak systolic pressures of approximately 50% (Perko at al., 1996). Further studies of this technique as a test

of autonomic function are needed, but this technology shows promise for non-invasive monitoring of enteric blood flow. 22.5.1.7. Blood flow measurements, comments A variety of technologies exist to measure blood flow. The most direct measurements involve reflected or absorbed light from superficial vascular beds, such as in the skin. However, the complexity of the local vasculature is such that even these tests are indirect measures of sympathetic activation of arteriolar smooth muscle. They cannot discriminate between changes in blood flow due to local inflammation, use of certain active topical agents, nor do they address factors that can influence steady state activity of circulation, such as recent exertion or caffeine/nicotine intake. Furthermore, the anatomy of the circulation, in part, determines light absorption and reflection; so even in ideal controlled conditions, blood flow measures are at best close estimates of true blood flow. Indirect tests of blood flow, thermography and thermal conductivity, both are significantly influenced by the thermal properties of skin, its ability to retain and conduct heat and mechanisms of evaporative cooling superimposed on these mechanisms. All of these tests are based on sound physics and physiological principles, but the interpretation of the findings is complex and must take into account technical and biological

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factors that influence findings. Simpler techniques for measuring blood flow, such as fingertip wrinkling, should be included, when appropriate, in clinical investigations in order to put the cost-effectiveness of the other technologies in perspective. 22.5.2. Pupillometry The iris contains the only observable contracting smooth muscle in the body and provides a window on baseline activation and function of the autonomic nervous system. Pupillary testing, like other autonomic tests, however, yields highly variable results. Simple inspection of the pupil reveals hippus, a cyclic variation in pupil size in the resting state. It varies considerably from individual to individual, and can be measured as an indicator of autonomic function. Most often, however, pupillary function is tested by provocative maneuvers, light and convergence being the most common. A number of factors influence pupil size and response to these simple maneuvers. From a clinical standpoint, absence of these responses is abnormal, but the preservation of even minimal responsiveness may be normal. Side-to-side asymmetry, however, is of importance, and a great deal of clinical neurology deals with such findings. Partial or patchy contraction of the iris, however, is a sign of autonomic dysfunction, and can be seen following partial denervation, or complete denervation with partial reinnervation. Although conceptually simple, quantitative pupillary studies have rarely been performed as part of screening tests for autonomic function. Two studies, however, indicate their potential value. The technique involves photographing the pupil from a set camera distance, and measuring its size at baseline and after different types of maneuvers. By using a variety of pharmacologically active agents, parasympathetic and sympathetic functions of the pupil can be analyzed separately; further they can provide evidence of denervation supersensitivity. In diabetics, the mean-dark adapted pupillary size was significantly smaller than in controls. However, the difference between diabetics and controls was less than the effect of age, in that young controls (age 5–14) had a mean dark-adapted pupil diameter of 6.7 versus 6.3 mm in diabetics; in older controls (70 years or older) it was 4.96 versus 4.50 mm in diabetics. Duration of diabetes had a significant impact on pupillary sensitivity to dilute (0.1%) pilocarpine, with advanced patients showing constriction of 15% or greater to this agent, suggesting

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denervation supersensitivity. The response to 4% cocaine was not different between diabetics and controls. These findings indicate that the smaller pupils in diabetics are unlikely to result from sympathetic denervation, parasympathetic pupillary dysfunction predates sympathetic dysfunction in diabetics, and the dilute pilocarpine test may be a useful indicator of early autonomic abnormalities (Cahill et al., 2001). Pupillometry can also use the ciliospinal reflex. An adequate stimulus is the sudden removal of a standardized adhesive strip from the back of the neck (Havelius et al., 1997); in normal eye sight the pupil dilates approximately 11% with this degree of stimulation. Pupillary studies have largely been restricted to evaluating neurophthalmologic problems, but these studies suggest that further studies of pupillary function in patients with generalized autonomic dysfunction will be informative. 22.5.3. Smooth muscle in bladder and pelvic sphincter muscles The autonomic nervous system innervates the bladder and pelvic sphincter muscles. These can be studied by balloon manometry, and simple reflex responses analyzed. Cystometrograms provide objective information regarding overactive or underactive reflexes to filling. Similarly, pressure dynamics can be used to quantitate sphincter function. In one study of diabetic cystopathy, cystometry revealed loss of sensation, increased capacity and decreased contractility (Ueda et al., 1997). Residual volume and decreased detrusor contraction could also be identified in patients with other evidence of autonomic neuropathy. The authors noted the difficulty in defining strict objective criteria of autonomic dysfunction, and it is clear that further studies are needed to determine the value of cystometry as a measure of autonomic bladder dysfunction. Further discussion of testing of pelvic floor muscles can be found in Chapter 13 of this text by Vodusek, which includes a thorough discussion of testing bowel and bladder function. 22.5.4. Smooth muscle in the gut The autonomic innervation of the gut is extensive, and the vagal contributions to gut motility are of particular interest to those interested in autonomic neuropathy because of its length. Taken as an entire system, however, the autonomic innervation of the gut is distinctly unique and is perhaps best classified separately from

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the parasympathetic and sympathetic nervous system as the enteric nervous system. Autonomic testing of the enteric nervous system, however, has been limited by the inaccessibility of gut structures to non-invasive techniques. Balloon manometry and imaging of swallowed media, such as barium, represent the two traditional avenues of approach to evaluating GI autonomic function. These tools provide pressure recordings and estimates of gastric transit time. 22.5.4.1. Transit time A simple transit time test uses a radiolabeled charcoal capsule and follows them with scintigraphy. Solid material passes through the stomach after about 3 h, the small intestine after 6 h , the colon after 24 h and the sigmoid rectum after 30–32 h (Hansen, 2002). Hourly scans for the first 6 h are informative about stomach/small intestine; fluids pass slightly faster. Significant stasis can be evidence of autonomic dysmotility. Further tests can help clarify the usefulness of transit time studies as a measure of autonomic activity. 22.3.4.2. Manometry Manometery is done by positioning pressor monitors throughout specific areas in the esophagus, stomach or small intestine via endoscopy. Pressure waves are readily recorded and a variety of distinct esphogeal, gastric, and small intestine patterns have been described (Camilleri et al., 1998; Spechler and Castell, 2001; Hansen, 2002). Experimental techniques for evaluating colonic contractions by manometry have been developed (Spencer et al., 2001; Smith et al., 2003) but work in humans has largely been confined to the distal sphincter areas. Inspection from within the gut walls with scopes or from without with laparoscopic tools can provide limited qualitative information about function, but all these techniques are invasive to some degree and can interfere with the functions they are intended to observe. 22.5.4.3. Electrogastrography (EGG) Over the last two decades, pioneered by physiological psychologists, the electrogastrogram has proven to be a useful device for studying the smooth muscle of the stomach (Walker et al., 1978; Stern et al., 1987; Koch, 1997, 2003). Subsequent work has indicated its value in assessing autonomically mediated changes in gut function. The technique involves the placement of four silverchloride electrodes on slightly abraded skin over the abdomen, one below the left rib margin in the

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midclavicular line, one equidistant between the xiphoid process and the umbilicus, one between these two, and a reference electrode placed in the right upper quadrant. The high frequency filter is set at 0.3Hz and low frequency filter at 0.16 H z . At these settings, the instrument is highly sensitive to movement artifacts, but with a proper positioning, high amplitude, sinusoidal, 0.05 Hz (3 per minute) waves are seen with an amplitude of approximately 500 μV. (Branza and Koch, 1997, 1998). Power spectral analysis provides more quantitative information regarding the gastric activity. These waves can be inhibited with maneuvers ranging from immersing the hand in ice water, or eating unappetizing food (Thompson et al., 1983; Stern et al, 2001). The amplitude and consistency of the waves increases significantly in patients with outlet obstruction, and are significantly diminished or absent in patients with gastroparesis. Motion sickness nausea, as induced by sitting in a rotating opticokinetic drum, induces a tachygastria, with frequent waves of 0.1 Hz (6 per minute) or greater. Significant changes also follow vagotomy (Koch, 2003). EGG can be seen as a useful tool for investigating gastric function. Similar waveforms occur in small intestine, but these occur at higher frequencies and have been less well studied (Koch, 2002). Further studies using this technique may provide useful ways for evaluating the enteric nervous system, which has up until now been a difficult area to assess. 22.5.5. Other smooth muscles A series of reports over the last decade have indicated that the smooth muscle of the corpora cavernosa can be studied with electromyography (Stief et al., 1997; Yarnitsky et al., 1995; Sasso et al., 1996; Baser et al., 1998). The technique involves inserting a concentric EMG needle, mid shaft, into the body of the cavernosa approximately 2–4 mm in depth. The responses are of low-frequency, and the low-frequency filter setting is 0.1 Hz and the high-frequency setting 37 Hz (Yarnitsky, 1995). The recorded potentials have a configuration not unlike that of sympathetic skin responses, and they are reduced in the erect state or when papaverine is injected. Further studies are needed, however, to identify the specific generator site of these responses and their significance. Their occurrence may explain why sympathetic skin response type patterns can be obtained in the penis, even though there are no sweat glands in this structure (Yarnitsky et al., 1995; Lefaucheur et al., 2001).

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22.6. Cardiovascular and pressor responses Perhaps the most therapeutically significant relationship of the autonomic nervous system to the health of a large community is its control of the cardiovascular system and blood pressure. It is not surprising to find that these are perhaps the systems in which autonomic control has been most studied both in terms of basic mechanisms and clinical investigation. The pressor responses to Valsalva’s maneuver have been discussed in Section 22.3 on heart rate responses. 22.6.1. Orthostatic pressor responses The act of standing requires significant alterations in vascular tone and cardiovascular effort to maintain the blood pressure. Failure in this system causes orthostatic tachycardia and/or orthostatic hypotension often with associated symptoms of light headedness that can be followed by falls or syncope. However, not all patients with orthostatic hypotension perceive the prodromal symptom. Assessment of orthostatic reflexes is, therefore, part of the work up of unexplained falls or syncope, particularly in the elderly. The simplest way to perform the test is to have the patient supine and relaxed for 5 min; in this time, blood pressure and pulse are recorded. The patient is then asked to stand, and the blood pressure and pulse are recorded immediately and several minutes later; it may be checked at subsequent intervals as well. Normally, the blood pressure does not drop more than 10 mm Hg diastolic or 20 mm HG systolic. Changes greater than this magnitude qualify as orthostatic hypotension (Ravits, 1997). It the pulse rate increases more than 25 beats per minute, or 20 beats per minute in patients with a resting tachycardia (>110), or if it increases above 140 beats per minute, this is considered abnormal (Ravits, 1997). Other approaches to measuring heart rate changes can be used as well. The maximal heart rate within 15–20 seconds after standing can be compared to the minimal heart rate while supine. This test, though not used as frequently, yields results similar to other cardiac tests of autonomic function discussed in Section 22.3 and has been standardized and corrected for age (Piha, 1991). If the blood pressure falls and no increase in heart rate is seen, this is more suggestive of primary autonomic failure; prolonged bedrest or dehydration are associated with orthostatic hypotension, but compensatory tachycardia is expected. Orthostatic blood pressure testing is one of the simplest and most clinically relevant of the available

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autonomic tests and it is probably also the one that is most often overlooked in the bedside evaluation of patients. Proper interpretation requires the ability to identify other causes of orthostasis, including those above as well as heart failure, blood loss, vomiting, overmedication, adrenal insufficiency, and septic shock. For patients with severe symptoms, the blood pressure from supine to sitting is informative and avoids the risk of falling. Should symptoms develop during testing patients need to be able to resume the recumbent position. 22.6.1.1. Tilt table testing A variation on orthostatic testing is the tilt table test in which EKG and blood pressure are monitored, often with beat-to-beat systems that can record blood pressure automatically. It is somewhat more standardized than having the patient stand, in the sense that the stress is more postural and less exertional. It is also safer, as the patient cannot fall, and the monitoring can identify arrythmnias immediately. However, variations in the duration the patient is supine before tilting, the degree of tilt, and the use of provocative infusions of drugs such as isoproterenol are common, and these significantly influence normal values and outcomes of the study. Typically the tilt is 60–80°, and the supine period is 20 min. The changes in blood pressure and heart rate previously identified are significant, but some laboratories have more precise sets of normal values for the specific populations that they see. Provocative tests enhance the sensitivity of tilt table testing but may reduce its specificity. Normative data is required for proper interpretation. Other factors such as temperature, diet, nicotine and caffeine intake, dehydration, etc., can influence the outcome of tilt table tests. Furthermore, the interactions of blood pressure and pulse can be complex, making it difficult to define exactly what constitutes an abnormal pattern. Tilt table testing is particularly helpful in identifying hyperactive autonomic reflexes as in neurocardiogenic (vasovagal) syncope. 22.6.2. Pressor responses to handgrip, mental stress, and cold Other tests of pressor function include changes in blood pressure to handgrip dynamometry, mental stress, and ice-water immersion of the hand. The patient is asked to sustain a handgrip of 30% maximal effort for up to 5 min, and an increase in diastolic blood pressure of more than 15 mm HG is considered normal, and 11–15 mm HG borderline. The sustained handgrip test

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is a simple one, and recent studies suggest that it can be modified in a variety of ways, and used consistently in patients despite age, bedrest or spinal cord injury (Goldstraw and Marren, 1985; Spaak et al., 2001; Petrofsky and Laymon, 2002). Changes in blood pressure also routinely occur in response to mental stress. A variety of protocols for stress induction have been described (Weidner et al., 2001; Arminario et al., 2003; Falaschi et al., 2003; Rutledge and Linden, 2003), ranging from stressful interviews to public speaking. Typically, mental arithmetic is used, for example, in serial subtraction of 13 from random four-digit numbers, which change every minute. Healthy young adults will develop an increase of about 20 mm HG systolic and 10 mm HG diastolic with these maneuvers (Dishman et al., 2002; Falaschi et al., 2003) but the effects of age on the upper and lower limits of normal for individuals have not been widely studied. It is difficult to quantitate the stress experienced by the individual by a given mental task and this test is, therefore, subject to somewhat greater variability than the handgrip or ice-water test. Ice-water immersion of the hand is painful, it differs from other tests of pain in the sense that it poses no risk of structural damage to the subject, and the subject has second-to-second control over the discomfort, as he or she can remove their hand from the ice-water bath at any time. Rare individuals who do not feel pain as the result of central alterations may have a pressor response despite the absence of the perception of discomfort (Walker et al., 1982, 1985). Typical subjects have an elevation in blood pressure on the order of 20 mm HG systolic and 10 mm HG diastolic (Schindler et al., 2003), but responses vary (Dishman et al., 2002). Subtle variations in technique may be responsible, where simple factors such as the extent to which the hand and forearm are submerged, stirring the ice water regularly, the duration of immersion, and the extent of finger spreading, all can significantly affect the discomfort and stress of the procedure. Foot immersion can be used as can an ice bag to the forehead; the response seems fairly stable in an individual over a decade ( Sherwood et al., 1997; Dishman et al., 2002), but the effects of vast age differences has not been well studied. Surprisingly, pet ownership, but not marital status, seems to predict a lower magnitude of response (Allen et al., 2002).

additional avenue for autonomic assessment. The most informative use of the technique to date has involved positron emission tomography (PET) imaging of 6-[18F] fluorodopamine uptake in cardiac sympathetic nerve terminals. Following injection of the compound into normal subjects, high density radioactive fluorine can be seen around the heart. This is because it is actively taken up by sympathetic nerve terminals, converted to 18F-fluoronorepinepherine, and stored in synaptic vesicles. In patients with loss of cardiac sympathetic neurons, a marked reduction in 6[18F]-fluorodopamine-derived radioactivity is seen (Carrio, 2001). Of interest, such changes occur in Parkinson’s Disease-related orthostatic hypotension, but their axon reflex sweating, mediated by sympathetic cholinergic nerve terminals is preserved (Sharabi, 2003). The study nicely demonstrated the selective loss of a subgroup of sympathetic adrenergic but not cholinergic terminals in a disease where neurodegenerative changes preferentially occur in adrenergic neurons. It is noted that control subjects for the study were matched for sex but not age. 123 I-metaiodobenzylguanidine is another radiopharmaceutical that can be used to image sympathetic nervous system activity, and this can be imaged both with PET and SPECT. Imaging with this compound has shown the slow but gradual process of cardiac reinnervation following transplantation (Di Carli, 1997; Estorch, 1999). A variety of other radiolabeled compounds are available to study autonomic activity, including 18F-fluorocarazolol, which binds to postsynaptic adrenoceptors and 11C-methylquinuclidinyl benzylate that binds to post-synaptic muscarinic receptors (Carrio, 2001). Imaging techniques show considerable promise for assessment of autonomic function. At this time, the technology is limited primarily to research studies, and although powerful has not been widely used in the routine evaluation of patients with autonomic dysfunction. Like other tests of autonomic function, however, the time-consuming process of establishing normative data for large populations of subjects differentiated by age, sex, and other factors will be required to make the tests suitable for routine diagnostic use.

22.7. Imaging the autonomic nervous system

This chapter has reviewed a number of autonomic tests that range in complexity and require instrumentation. The challenge of the clinician-investigator is to determine how to best develop and then use these tools

More direct methods for imaging neurotransmitter activity are becoming available and are providing an

22.8. Conclusions

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in the study of their patients. From the standpoint of utility, several autonomic tests are easily performed in any electrodiagnostic laboratory. The first is the sympathetic skin response. Not only is this test of use in assessing autonomic function, but it can differentiate selective autonomic involvement of different digits, for example, following local anesthetic blocks (Czop et al., 1997; Butterworth et al., 1998). Next in ease of use are the various tests of heart rate variation. Almost all EMG instruments can be adapted to analyze heart rate and quantitative information can be derived from simple maneuvers. Several simple clinical tests can also be performed in the EMG laboratory. Simply measuring the blood pressure response to sitting and standing is perhaps the most informative clinical test of autonomic function. Skin wrinkling and pressor response to ice water immersion or handgrip are other simple tests that can provide a rapid screening of autonomic function as well. Of the other more specialized tests, quantitative sudorometery, laser Doppler flowmetry or perfusion imaging, ultrasound Doppler blood flow measurements, and EGG can be performed with instruments that are in the cost range of high end EMG instruments or sometimes available in other departments in large medical centers. A few final conclusions regarding autonomic tests are appropriate: (1) Simpler tests are not necessarily inferior to those that require more sophisticated instrumentation. A number of the simpler autonomic tests are well suited to screening large populations of patients and have selected uses in the evaluation of individual patients as well. (2) Descriptive studies, particularly those that identify common sources of variation in autonomic tests such as age are critical for making them useful for diagnosis. Studies without well-defined norms need to be interpreted with caution, no matter how elegant the technology. (3) A number of autonomic test results exibit wide variation even in controlled populations. The use of more sophisticated statistical analyses or mathematical models may enhance their yield. (4) Interdisciplinary work in autonomic testing has been limited. As a result, simple questions regarding the selectivity of autonomic disorders with respect to nerve fiber length, nerve fiber size, or nerve fiber function have sometimes been overlooked because subspecialists tend to restrict their investigations to single organs and single measure-

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ments. Collaborative work (Shirabi et al., 2003) illustrates the value of combined approaches. (5) Quantitative or imaging analysis of drug effects and secretory mechanisms in blood, saliva, sweat, and gastric contents may lead to useful, routine, techniques for measuring autonomic function. The rate of publication of articles on autonomic testing has expanded one hundred fold since 1970. As the field continues to expand it will likely be shaped by new technology and improved understanding of the autonomic nervous system. The ability to more sensitively detect autonomic dysfunction and its recovery will enhance the testing and discovery of new therapeutic interventions for autonomic disorders. References Allen, K, Blascovich, J and Mendes, WB (2002) Cardiovascular reactivity and the presence of pets, friends, and spouses: the truth about cats and dogs. Psychoso. Med., 64(5): 727–739. Allen, J, Frame, JR and Murray A (2002). Microvascular blood flow and skin temperature changes in the fingers following a deep nspiratory gasp. Physiol. Measures, 23(2): 365–373. Allison, TG and Reger, WE (1998) Comparison of responses of me to immersion in circulating water at 40.0 and 41.5 degrees C. Aviat. Space. Environ. Med., 69(9): 845–850. Arminario, P, del Rey, RH, Martin-Baranera, M, Almendros, MC, Ceresuela, LM and Pardell, H (2003) Blood Pressure reactivity to mental stress task as a determinant of sustained hypertension after 5 years of follow-up. J. Hum. Hypertension, 17(3):181–186. Atkinson, J and Fealey, R (2003) Sympathotomy instead of sympathectomy for palmar hyperhidrosis: minimizing posterative compensatory hyperhidrosis. Mayo Clini. Proc., 78: 167–172. Baser, SM, Meer, J, Polinsky, RJ and Hallett, M (1991) Sudomotor function in autonomic failure. Neurology, 41(10): 1564–1566. Berardesca, E, Leveque, J, Masson, P and the EEMCO Group (2002) EEMCO guidance for the skin measurement of skin microcirculation. Skin Pharmacol. Appl. Skin. Physiol., 15:442–456. Bergman, R, Sharony, L, Schapira, D, Nahir, MA and Balbir-Gurman, A (2003) The handheld dermatoscope as a nail fold capillaroscopic instrument. Arch. Dermatol., 139(8): 1027–1030.

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 23

Reference value determination Lawrence R. Robinson* Department of Rehabilitation Medicine, University of Washington,WA 98195, USA

This chapter addresses the methodology to determine normal or reference values for electrodiagnostic studies. It will review the purpose of establishing reference values, terminology, selecting a population to study, data collection, and data analysis. It will also provide examples using these methodologies. Becoming familiar with the statistical theory and methodology for establishing reference values in electrophysiology is critical to providing an accurate determination of abnormalities. 23.1. Purpose of reference value determination In electrodiagnostic medicine, a major goal is to distinguish between those subjects with peripheral nerve disease and those with healthy nerves. To achieve this goal, the clinical neurophysiologist can employ a variety of quantitative measures. One of these measures is the nerve conduction study (NCS); the same principles apply to motor unit potential quantification, motor unit number estimation, autonomic quantitation, and other quantitative measures. Typically, when evaluating a patient with possible disease, the results of studies in individual patients are compared to results from a group of asymptomatic healthy subjects to determine whether the individual patient is likely to have an abnormality or not. Usually, a reference value has been derived beforehand from a study of the healthy subjects. Individual patient values outside this reference range are considered abnormal, while those within the reference range are considered “normal.” An understanding of the methods for deriving reference values, as well as of the pitfalls in deriving

*(Correspondence to: Lawrence R. Robinson MD, Depart-ment of Rehabilitation Medicine, Harborview Medical Center, 325 Ninth Avenue, Box 359740, Seattle, WA 98104, USA. E-mail address: [email protected] Tel.: +1-206-731-3167; fax: +1-206-731-6554.

and using the reference values is important to allow our electrodiagnostic tests to maintain high specificity and sensitivity. 23.2. Terminology and basic statistical concepts A variety of terms are used to discuss the statistical concepts behind reference value determination. More complete discussion of these terms can be found in other sources (Benson, 1972; Elveback, 1973; Dorfman and Robinson, 1997; Wang and Robinson, 1998; Buschbacher, 2000). Normal values and reference values are two terms that are sometimes used interchangeably but have different meanings that are important to appreciate. Normal values are generally considered to be measures derived from disease-free healthy asymptomatic individuals (Dorfman and Robinson, 1997). Reference values, on the other hand, are values often derived from the healthy population but are used to provide information as to the probability or likelihood that a given result either came from a healthy person or from a diseased individual (Campbell and Robinson, 1993; Eisen et al., 1994). Due to the statistical methodology employed in deriving reference values, healthy (normal) individuals, sometimes by chance fall in the “diseased” reference range, while those with disease sometimes fall into the “normal” reference range. Thus, since our reference values are not perfect in determining health versus disease, we will use the term reference value rather than normal value, as no cutoff number can definitively convey whether a subject is normal or abnormal. The difference in these two terms is seen in other laboratory methodology as well. In clinical chemistry for example, the term “normal” became criticized because of its ambiguous meaning and the term reference value has been adopted instead (Benson, 1972). The measurements we take on individual subjects or patients are variables. A variable can be defined as a property sampled in individuals that differs in some

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ascertainable way. There are generally five types of variables: ratio, interval, ordinal, nominal, and derived. Ratio variables are the most common type that we work with in nerve conduction studies. These variables are linear, they have a clear zero point, and the usual rules of arithmetic apply. An example is amplitude, which cannot extend below zero but which can be averaged, added, or subtracted. Interval variables are similar to ratio variables in the sense that they have a constant interval size, but they do not have a true zero. The Fahrenheit temperature scale is an example, since temperatures can extend below zero. Ordinal variables are also used in electrophysiology such as needle EMG. These variables display relative magnitude but not on a linear scale (Zar, 1984). For example, the scoring of fibrillation potentials ranges from zero to 4+. We know that 4+ represents more fibrillations than 2+ but not necessarily twice as many or twice as much denervation as 2+. The usual rules of arithmetic cannot be applied to ordinal variables as they would be with ratio variables. An average of fibrillation scores across muscles, for example, would not be arithmetically meaningful. Manual muscle testing is another example of an ordinal variable; here too, the usual rules of arithmetic cannot be used. Nominal variables cannot be quantitatively measured but represent various categories such as gender or race. Finally, derived variables are generally dependant on several independently measured ratio or interval variables. For example, nerve conduction velocity is based on two independent measures, namely latency and distance. Derived variables, when obtained from ratio variables, can be arithmetically manipulated. However, as the error of multiple independently measured variables are added together, a derived variable can lose accuracy and may not have the same distribution as the original measured variables (Sokal and Rohlf, 1987). There are several terms with which the reader should be familiar that describe the distribution of variables within a population. These terms are generally used to describe either the central tendency (i.e., “middle”) of the population or the edges of the population. Percentile refers to the number of individuals below a given value within a population. A 5 percentile (5 %ile) value, for instance, indicates that 5% of the population would fall below the value and 95% would be above. Percentile values do not depend on the distribution of the population but do require a relatively large population to determine reliable percentile values that can be extrapolated to

LAWRENCE R. ROBINSON

the population as a whole, particularly at the edges of the population (e.g., 2.5 %ile). The range refers to the highest and lowest values in a distribution. The concept of the normal distribution, also referred to as the Gaussian bell curve distribution, is commonly used in statistical analysis. The concept of the normal distribution was initially proposed by Abraham de Moivre, a French mathematician who lived from 1667 to 1754 (Munro, 1986). He developed the idea of a “normal” curve based on his observations of games of chance. Later, Gauss developed the concept of “laws of errors,” which states that if repeated measures are made of the same physical object, the distribution of the random component of the errors, can be approximated by the Gaussian or normal distribution (Elveback et al., 1970). An analogy often used to describe the concept behind the Gaussian distribution is the following: If measurements of a large brick to the nearest millimeter were obtained daily for a year, the distribution of measurements would approximate a normal distribution. If an infinite number of measurements were made, a smooth bell curve would eventually be produced. Most of the measurements would be near the mean, fewer would be either shorter or longer than the mean. The reader should keep in mind, however, that this is different than the way the Gaussian distribution is commonly used for deriving reference values today. In deriving reference values, single measurements are made on many different subjects rather than having multiple measurements made on a single subject (i.e., measuring many different bricks once each rather than measuring the same brick many times). Consequently, measurement of biologic variables across multiple individuals do not always or even commonly follow a Gaussian distribution (Owen and Campbell, 1968; O’Halloran et al., 1970; Boulat et al., 1993; Jonetz-Mentzel and Wiedmann, 1993). Nevertheless, the Gaussian distribution is very important in statistics and, because of the powerful inferences that can be made from it, is commonly used to derive reference values. The distribution is usually defined by two variables, the arithmetic mean and the standard deviation. The Gaussian distribution has an unusual quality, which is the ability to predict the relative frequency of variables. Within one standard deviation of the arithmetic mean, 68% of the distribution can be found. Within two standard deviations 95% can be found, and within three standard deviations 99% can be located (Fig. 23.1) (Dorfman, 1997). As a result, if a distribution closely approximates a Gaussian one, conclusions about the frequency

REFERENCE VALUE DETERMINATION

513 Fig. 23.1 The normal or Gaussian distribution. Dotted lines indicate 1, 2, or 3 standard deviations from the mean.

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distribution can be made with relative ease. Hence reference values can be estimated by statistical methods of relatively smaller sample size (Elveback et al., 1970). There are, however, problems that occur when a distribution is assumed to be Gaussian but is not so, particularly as inferences are made about the edges or extremes of the population. There are two common deviations from the normal distribution that are seen in analysis of biologic variables. Kurtosis refers to the “peakedness” of the distribution. A distribution with a high kurtosis would have a sharp peak, and thus, may deviate from the normal distribution, with more individuals in the center of the distribution and fewer at the edges. More common in collections of biologic variables however, is skewness (Fig. 23.2). Skewness refers to the shift of the peak of the distribution to the left or the right, with a positive skew causing a peak to the left of the mean and a tail extending out to the right of the mean. Skewness has several potential causes in NCS (Robinson et al., 1991). First, since most NCS variables are ratio variables, they have a true zero and cannot extend below zero. With no limit to higher numbers, the tail can extend to the right but not to the left. Amplitude, for example, cannot be below zero but there is no absolute mathematical limit to the right (higher value), hence most amplitudes are positively skewed. Moreover, disease (either clinical or subclinical) can produce a tail on one end of the distribution. For example, when collecting median nerve latencies, the latency can be only so short physiologically, but

inclusion of a few people with median nerve slowing can produce a tail to the right (longer latencies). If one is to use parametric statistics (i.e., statistics depending on a normal or Gaussian distribution) to develop reference values an evaluation of the distribution should be performed first. The validity of the assumption that one has a Gaussian distribution can be checked with several methods including G-statistics, goodness of fit testing, graphical methods, and other methods. G-statistics involve measuring the coefficients of skewness or kurtosis (Solberg, 1981). In a perfect distribution, the coefficients are zero; if absolute values of one or both coefficients are greater than 2.6 times the corresponding coefficient of variation (SD/mean), the hypothesis of a Gaussian distribution can be rejected (Solberg, 1981). Goodness of fit tests that can be used to test for a Gaussian distribution are chi-square analysis and Kolmogorov–Sminov procedure. Graphical methods are often a good starting point. By examining a histogram of the collected data, one can often see whether or not the data approximately follows a bell-shaped Gaussian distribution. There are several additional terms and concepts the clinical neurophysiologist should be aware of, which are used to describe the merit of a test or particular reference value. Conceptually, any time we perform quantitative diagnostic testing, we imagine two groups of individuals, the healthy asymptomatic control group, and the diseased group. In the ideal world, these two groups would not overlap and an individual test could completely distinguish all members of each

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LAWRENCE R. ROBINSON Fig. 23.2 A positively skewed distribution with tail to the right.

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group (Fig. 23.3). It is rare that a test will completely distinguish between healthy and control groups, and it is more typical for there to be some overlap between the two groups (Fig. 23.4). If the overlap is excessive, the test will not be useful (Fig. 23.5). Thus, while the use of a test and a particular reference value can identify some people with abnormal tests and presence of disease (true positives) and some healthy individuals with a normal test (true negatives), classification errors will inevitably occur. False positives represent those people who are healthy but have a test result outside the reference range (“abnormal”), while false negatives represents those individuals with disease who have tests within the reference range (“normal”) (Fig. 23.6). Another way to describe the situation is through the terms sensitivity and specificity (Leaverton, 1995). Sensitivity is a measure of the ability of a test to detect disease when the disease is present. Specificity is the ability of a test to classify healthy subjects correctly. Sensitivity can also can be described as the probability of a positive test in a patient with disease and sensitivity as the likelihood of negative test in a patient without the disease (Fig. 23.6). While sensitivity (the ability to detect disease) is an important feature of a test, and is commonly focused on in the electrodiagnostic literature, specificity (detecting lack of disease) is equally or more important (Robinson, 1999). Particularly when one is assessing for a condition that may be treated surgically or with other treatments that carry significant risk, it is critical to maintain a high specificity. Studies that report comparisons among different tests on sensitivity, but do not also measure specificity at the same time are of limited use.

A common example of this concept is evaluation for possible radiculopathy. While MRI is sensitive for picking up abnormalities of the spine, it is a relatively nonspecific test since roughly half of healthy individuals have lumbar disk bulges and nearly a third have disk protrusions (Jensen et al., 1994). EMG, in contrast, is likely to have a lower sensitivity but carries a high specificity since there are few false positives (i.e., abnormal EMGs in healthy asymptomatic individuals) (Robinson, 1999). When developing reference values for electrodiagnostic studies, it is generally wise to sacrifice some measure of sensitivity when needed to assure a high level of specificity, i.e., to keep the likelihood of false positive results low. Analysis of receiver operator characteristic curves (ROC) provides another method to quantify the value of a particular test. In this analysis, sensitivity is plotted against 1-specificity. A perfect test would have an area under the curve of 1.0, while a test with an area of 0.5 would be useless (Fig. 23.7). While this method has been primarily used to compare statistical regression models, some have advocated its use in comparing electrodiagnostic tests (Eisen et al., 1994). An additional concept to keep in mind when establishing reference values is the idea of reliability. Reliability reflects the likelihood that an examiner testing a patient at two different times will obtain the same results (intrarater reliability) or that two different examiners examining the patient would obtain the same results (interrater reliability). Reliability is seldom reported in the electrodiagnostic literature, but becomes important when one is studying the same individual repeatedly over time, or if multiple

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individuals examine the same patient over some time. Reliability is often measured as a correlation coefficient (Spearman’s Rho, Pearson correlation coefficient, intra-class correlation coefficient); a coefficient of one indicates perfect reliability and zero indicates one would get randomly different results on two different tests. There are significant differences between using the Spearman’s Rho or Pearson correlation

coefficients versus using the intraclass correlation coefficient (ICC). The first two tests simply indicate that Test A and Test B are related to each other. However, if Test B were always twice the value of Test A, then these correlation coefficients would be high. The ICC, on the other hand, is a better measure of whether Test B gives a similar result to Test A, without any biased offset (see example in Fig. 23.8).

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Fig. 23.8 Comparison of methods for judging reliability. In the upper left plot of hypothetical data, the Pearson Correlation Coefficient (r) and Spearman rho (rho) are high, as is the Intraclass Correlation Coefficient (ICC). In the plot to the upper right, the results of Test B are roughly twice those of Test A. While r and rho are high, the ICC is low, indicating that Test B is often different from Test A. The comparisons between Test B and Test A are best illustrated using the methods of Bland and Altman (Bland, 1986) on the corresponding plots below each upper plot.

While the intraclass correlation coefficient is probably the most commonly used and is the best out of the correlation coefficients (Shrout and Fleiss, 1979), especially if the data follows a normal distribution, there are superior methods for measuring test-retest reliability. Bland and Altman have reported on plotting the difference between Test B and Test A versus the average results of the two tests (Bland and Altman, 1986). This methodology not only allows one to see how closely the two tests are correlated, but also allows for examination of any offset between Test B and Test A, as well as examining the reliability of the two tests over the full range of measured values. The method also allows one to examine the mean and

standard deviation of the differences between Test A and Test B, thus allowing determination of what represents a significant difference between tests. 23.3. Population sampling When collecting data from a healthy control population to develop reference values, just who one samples for the reference data will have marked influence on the results (Hulley et al., 1988). A number of individual attributes are known to affect electrophysiologic data, particularly nerve conduction studies. For example, age, temperature, finger circumference, and height are all reported to significantly alter nerve conduction results

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(Wang and Robinson, 1998). While temperature can be addressed through warming the limbs, the other factors need to be controlled for or in some way considered when developing reference values for one’s laboratory. The individual attributes can be controlled in using multiple linear regressions equations, although this can be cumbersome to institute clinically. As an alternative, the reference data can be stratified by age and height, e.g., provide reference values for those over 50 and under 50, or those over or under 170 cm (Buschbacher, 2000). However, as more stratification into smaller groups is performed, greater total numbers of healthy individuals are required, since each group requires its own sufficient sample size. In addition to measuring the attributes that we know influence the nerve conduction studies, there may be other attributes that we do not yet know of or for which we are unable to completely control. In an idealized world, every person without any known disease would undergo testing and contribute to an overall data set. Since this is not possible, a sample is obtained from the population of healthy individuals with the intent to reliably represent the population who does not have disease. When doing this, however, the population studied should be as close as possible to the overall population to which the generalizations are being made or at least as close as possible to those will be studied in the electrodiagnostic laboratory. Specifically, one wants a population similar to that referred to the electrodiagnostic laboratory, but without disease (Feinstein, 1985; Gerr and Letz, 1998). Sampling can be performed with two general methodologies, probability and nonprobability sampling. Probability sampling relies upon a random process to select individuals who are representative of the population, while nonprobability sampling attempts to approximate a probability sample using more practical methodology. Probability sampling uses a random selection process to assure that each subject in the population has an equal opportunity to be selected for sampling. The random selection can be either simple (every individual has an equal probability), stratified sampling (when the population is segregated by characteristics such as age or gender), or cluster sampling (when a random sample of groups of individuals are obtained). Nonprobability sampling tends to be more practical for collection of reference data from healthy individuals. The costs and effort are much less involved, although there is a potential bias involved in how subjects are selected. Consecutive sampling is one method of non-probability sampling, which involves

LAWRENCE R. ROBINSON

examining every individual who meets the criteria during a specific time period or over a number of subjects. Convenience sampling is a methodology that examines the most easily available members (often residents, hospital staff, or medical students). Judgmental sampling, on the other hand, involves picking the individuals deemed most appropriate for the study. The above nonprobability sampling methods are the most commonly used ones for electrophysiologic reference value studies. Whichever method is used, the clinical neurophysiologist should be aware of possible bias introduced by the selection of individuals. Applying reference values from young healthy medical residents to the elderly could, for example, be problematic. While some authors have advocated using asymptomatic limbs of patients referred for clinical testing to derive reference values, there are significant problems with this approach. First, even if those with obvious disease are excluded, the remaining patients with a mild disease may be included in the reference group and shift the distribution toward the abnormal range. Moreover, some individuals referred for testing in one symptomatic limb could have diffuse problems such as polyneuropathy that would affect results in other limbs. On the other hand, some authors have advocated obtaining reference values not from completely healthy asymptomatic individuals but from individuals with symptoms or signs in their limb that may resemble or come close to the signs and symptoms of the disease being studied (Feinstein, 1985; Gerr and Letz, 1998). For example, one could use subjects with non-specific limb pain but no numbness as a control group when collecting reference ranges for median NCS across the wrist. The rationale for this is that in the electrodiagnostic laboratory, one is not trying to separate people with disease from healthy individuals, but rather one is trying to distinguish between those symptomatic individuals who have potentially confusing a particular disease versus those who have symptoms but are without the disease under study. This latter point is still controversial, since in some cases, one does not have an alternative gold standard to differentiate those with symptoms who truly have the disease versus those who do not. If some of the control group actually have the disease under study, reference value determination would be problematic. 23.4. Logistics of data collection Once a population sampling method has been selected, a number of logistics of data collection need to be considered as one collects a sample of reference

REFERENCE VALUE DETERMINATION

However, this argument does not address the above point. At the same time, it can be very useful to collect data on both sides in order to look for side-to-side differences in patients being assessed in the laboratory. Side to side differences may be more sensitive at detecting abnormalities as opposed to comparing results to reference values alone. This has been noted for some time in measurements of the H-wave that side to side differences of as little as 1.2 ms are significant, but measurements need to be over 5.5 ms from the expected mean value for age and leg length to be considered abnormal (Braddom and Johnson, 1974). This concept is also illustrated in Fig. 23.9 from our dermatomal SEP data. Here, side-to-side differences of 10 ms would be clearly abnormal when comparing sides; however, values of 45 ms and 55 ms are both within the normal range. Although not commonly performed, if one measures repeatability, it is important to do repeat studies

Count

S1 dermatomal SEP 18 16 14 12 10 8 6 4 2 0 30

35

40

45

50

55

60

65

70

L P1 lat

S1 dermatomal SEP 30 25 20 Count

values. First, particularly if a publication is being considered or if a novel technique is being used, human subjects’ (institutional review board) review should be accomplished prior to starting the study. Even if publication is not a consideration, one may want to contact the hospital risk management office to be sure proper procedures are in place. In addition, one should carefully consider which variables will be collected. It is especially important to collect information about symptoms of peripheral nerve disease, and any potentially influential attributes that might be controlled for or segregated for in the nerve conduction studies such as height, age, temperature, finger circumference, etc. It is generally helpful to develop a form for data collection well before the study starts. The size of the sample to be collected should be estimated a priori (i.e., before this sample is collected). The required sample size will be determined by the expected variability, how the data will be analyzed, and how subjects will be aggregated. Generally, if one has a normally distributed variable (or can transform to a normally distributed variable; see below) one can collect fewer subjects than if nonparametric methods are being used. While 30–50 subjects may be sufficient to determine two standard deviation levels for a variable with a Gaussian distribution, for example, nonparametric analyses (i.e., using 2.5 percentile values) would require that 100– 120 subjects should be studied (Owen and Campbell, 1968; Mainland, 1971). If subjects will be segregated according to height or age, for example, then a sufficient number of subjects will need to be collected for each subgroup. While it is tempting to collect data from two sides in each individual and count each as a separate study, collecting left and right sides from one subject is not the same as collecting information from one limb in two different individuals. Intraindividual variability (i.e., left versus right) is smaller than inter-individual variability (between individuals). If the left and right sides are grouped together amongst all the individuals, then the standard deviation of the sample will be less than a study of all one side and reference values will be erroneously too close to the mean. Thus, one should ideally include in reference values only one side for each individual. One may separately wish to study the other side and look at side-to-side variability, but it is inappropriate to include both sides together counting each one as a separate limb. Some authors have justified grouping the two sides based on the argument that they did not significantly differ.

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15 10 5 0 −15

−10

−5

0

5

10

15

L−R lat diff

Fig. 23.9 Example of normative data for S1 dermatomal SEPs. In this example the distribution of the first positive deflection (P1) is plotted in the upper figure. In the lower figure, side-to-side differences are plotted. If a patient had a P1 latency of 45 ms on one side and 55 ms on the other side, both would be within reference values. Sensitivity is improved by examining side-to-side differences, where a 10 ms difference would exceed reference values.

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Median palmar amplitude 8 7 6 5 Count

on the same individual, making sure there is no bias between studies. For example, the individual performing the second study should not know or remember the results of the first study, all electrodes and markings should be removed before the second study, and both subject and examiner should be blinded to the first study results. It is also helpful to include patients with disease in repeatability studies, to ascertain whether repeatability is similar across the range of possible values.

LAWRENCE R. ROBINSON

4 3 2

23.5. Analysis of reference data Once an appropriate number of healthy control subjects have been studied, the clinical neurophysiologist will want to enter the data into a computer and perform the analyses. There will be usually two issues that come up during data entry. First, how many decimal places should be retained during data entry? This will depend upon the particular study being evaluated and the accuracy of the data being recorded. Generally, three significant digits are sufficient. Carrying latencies or amplitudes to four or five digits suggests an accuracy and precision beyond the error inherent in the measurements. If rounding is to occur, one should be careful to alternate rounding of fives with half rounding up and half rounding down. A bigger problem in data entry and subsequently the analysis is what to do with missing values. Missing values can occur if the subject refused the particular study being performed, if there were technical problems with performing a study, or if the response was simply absent. If the study cannot be performed adequately, it is best to leave these entries blank and simply record how many subjects could not have the test completed. If, however, the test was completed but the response was absent, then one could enter a zero for amplitude of the response or enter a code to separately identify absence versus inability to test. Entries for latency and conduction velocity when responses are absent are more difficult. An entry of zero into one of these categories would be inappropriate and offset the data set as a whole. Thus, these should likely be coded separately and not analyzed together with the other data. Once the data is entered into the computer, the first step is to do a graphical analysis such as examining histograms. Figure 23.10 demonstrates an example of this for the median sensory amplitude recorded at the wrist with stimulation 8 cm proximally at the palm in 27 subjects. It is also appropriate at this time to measure the coefficient of skewness. One can see in the histogram

1 0 0

20 40 60 80 100 120 140 160 180 200 220 ampl μV

Fig. 23.10 Histogram of median palmar amplitude. Skew = 0.79

(Fig. 23.10) a skew with central tendency to the left and tail to the right. Coefficient of skewness is 0.79. After plotting the data graphically, one can then decide whether to establish reference values using parametric statistics or nonparametric methodology. Generally, nonparametric methodology has the advantage of not being dependant upon the distribution of data. However, establishing percentile values at the ends of the distribution requires a larger N than the use of parametric methods. In the example shown, since there are only 27 subjects, it is not possible to accurately calculate the 2.5 percentile value which is normally used for a reference value. The second value from the bottom (in this case 30 μV) would represent the 3.5 percentile value and the second value from the top (178 μV) would represent the 96 percentile value. At least 40 cases are required to calculate a 2.5 percentile value, with 100–120 cases required to provide a reliable value. Another alternative to analyzing the attached data is to use parametric statistics, relying upon the mean and standard deviation to find the reference values at the ends of the graph. In this case, it is preferable to use a Gaussian distribution, or a distribution that is as close to Gaussian as possible (Robinson et al., 1991). In Fig. 23.11, the data from the prior figure has been transformed by taking the square root of each raw value. When plotted in this new histogram, the skew is reduced to −0.13 indicating the distribution is closer to Gaussian. Using this transformed distribution, we can now take the mean and two standard deviations to find the central 95% of the distribution. These end points (which are in units of square root of amplitude) are

REFERENCE VALUE DETERMINATION

521

Median palmar amplitude

Median palmar amplitude (transformed) 8

8

7

7

6

6

5 Count

Count

9

5 4

4 3

3

2

2

1

1 0

0 2

3

4

5

6

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8

9

10 11 12 13 15

0

then squared to return to the original units of microvolts. Using the transformation does produce a significant alteration in the reference values (Solberg and Grasbeck, 1989). If the original data were simply used to calculate a mean + − 2 SD, the lower reference value would be 4 μV. After transformation, selection of reference points, and then retransformation back to original units, the lower reference value becomes 21 μV (Fig. 23.11). Even if a distribution is not statistically significantly skewed, transformation to achieve a lower coefficient of skewness may be beneficial. It is somewhat arbitrary as to how many standard deviations are used when setting reference values. The use of two standard deviations is common. This includes 95% of the population within the reference values. Generally, in clinical neurophysiology, however, we are only concerned about one side of the distribution. For example, we are not likely make a diagnosis on too large an amplitude, too short an latency, or too fast a conduction velocity. Thus, when looking at only one tail of the distribution, mean ± 2 SD would include 97.5% of the healthy population within the reference values (Fig. 23.12). Different numbers of standard deviations can be used with some authors recommending 2.5 or 3 standard deviations from the mean. Going from 2 to 3 standard deviations would be expected to increase the specificity of the test (the false positive rate would theoretically drop from 2.5 to 0.5%) but would also likely reduce the sensitivity of the test for detecting disease. Whichever number is chosen, the clinical neurophysiologist should always keep in mind that the tests are not perfect, they only make a statement about likelihood of

Fig. 23.12 Histogram median palmar amplitude, as in Fig. 7. Dotted lines represent mean ± 2 SD of raw data, solid lines represent mean ± 2 SD of transformed data.

disease, and that there will be some false positives and some false negatives regardless of the level chosen. In some cases, the clinical neurophysiologist will be interested in the repeatability of the study and will have data from two separate testing sessions to analyze. In this case, it is often useful to plot the results from Test A and Test B (Fig. 23.13). While this gives a general sense of repeatability (there is an overall correlation between A and B), it does not tell how much of a difference between Test A and Test B would be significant, nor does it tell whether the difference between A and B varies across the range. It is more useful to plot the difference between Test B and Test A versus the average value as seen in Fig. 23.14 (Bland Median palmar latency 3.4 3.2 3.0 2.8 Test B (ms)

Fig. 23.11 Histogram of data in Fig. 7 plotted as square not of amplitude. Skew = −0.13

20 40 60 80 100 120 140 160 180 200 220 ampl μV

Square root of ampl

2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20 3.40 Test A (ms)

Fig. 23.13 Repeatability studies of median palmar latency performed on two different days in 32 subjects.

522

LAWRENCE R. ROBINSON

Median palmar latency 0.4

B−A difference (ms)

0.3 0.2 0.1 0.0 −0.1 −0.2 −0.3 1.4

1.6

1.8

2

2.2

2.4

2.6

2.8

3

3.2

3.4

Average latency (ms)

Fig. 23.14 Plot of differences between Test B and Test A versus average data from Fig. 23.12. Dotted lines represent mean ± 2 SD.

and Altman, 1986). This demonstrates that the amount of variation across the range of latencies observed is fairly constant and is not, for instance, more variable at the high end of the latencies. Moreover, it now allows us to see how much of a difference between Test A and Test B would be significant. Using the mean and standard deviation of the differences, one can see that a 0.3 ms difference between Test A and Test B would be a significant change (i.e., this would exceed mean ± 2 SD). Applying this to the clinical situation, if a patient came in with a median palmar latency today that varied by 0.3 ms or more than that seen on a prior visit, we would say that this represents a significant change, while a difference of 0.2 ms is not likely significant. It is not unusual for the clinical neurophysiologist to perform more than one test on a patient who comes into the electrodiagnostic laboratory. Rather, there are multiple tests that will be performed and the consultant’s job is to interpret these multiple tests into a cohesive impression whenever possible. At the same time, one needs to be prepared for the fact that the more tests that are performed, the greater the likelihood of abnormal results occuring by chance alone. Table 23.1 indicates the number of abnormalities expected according to the number of variables examined in a given patient (Robinson et al., 1991). This Table assumes that each test carries a 2.5% false positive rate (i.e., using two standard deviations) and assumes that the tests are relatively independent. One can see from this table that if one relies on a single

abnormality to make a diagnosis, that the false positive rate goes up quickly as more variables are being studied (Table 23.1) (Rivner, 1994). There are two general ways to address the concern of having multiple tests and the increasing likelihood of abnormality by chance alone. One approach is to require that multiple tests be abnormal before making a diagnosis. For instance, if one looks at ten different variables (which may include latencies, amplitudes, and conduction velocities), there would be a 22% chance of making a false positive diagnosis when relying on a single abnormality. However, if one relied on two abnormalities to make a diagnosis, there would be only a 2.5% chance of false positive results. By requiring multiple consistent abnormalities before making a diagnosis, one reduces the false positive rate and enhances the specificity of the test. This approach does reduce the sensitivity of the test, since some patients may have only one abnormality or could have multiple trends toward abnormality, none of which exceeds the reference value on an individual test. Another approach one may take is to create a summary variable based on the multiple test results (Robinson et al., 1998; Rondinelli et al., 1994). This has the advantage of allowing us to look at only one variable, hence there is only a 2.5% false positive rate regardless of how many test results go into the single summary variable. It also enhances sensitivity since patients or subjects who tend to be toward the abnorTable 23.1 Probability of abnormal results by chance alone Number of abnormalities Number of variables examined 1 2 3 4 5 6 7 8 9 10

≤1 (%)

≥2 (%)

≥3 (%)

2.5 4.9 7.3 9.6 11.9 14 16.2 18.3 20.4 22.4

– 0.1 0.2 0.4 0.6 0.9 1.2 1.6 2 2.5

– – < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.2

The probability of finding an abnormal result by chance alone according to the number of parameters studied. These calculations assume that 2.5% of an asymptomatic control population fall into the “abnormal” range for each parameter studied, and that each parameter is independent.

REFERENCE VALUE DETERMINATION

mal end of the distribution but do not exceed the reference value on individual tests will, when their values become added together, then exceed the threshold for the summary index. Moreover, reliability of a summary variable appears to be greater than simple studies, as small variations in simple tests get evened out as they incorporate into a summary score (Lew et al., 2000). There are two potential disadvantages to using summary variables. First, the concept of adding variables that mean different things such as latency and amplitude to form a summary variable is problematic (Robinson and Micklesen, 2002). There may be some diseases that affect latency but not the amplitude or visa versa, hence, pathophysiologically it may not make sense to add these variables together into a summary score. Secondly, there are logistical problems with adding or averaging different variables in different units of measurement. When the variables are in different units (e.g., μV and ms), or even sometimes in the same units, one needs to convert each value into a Z-score (i.e., the number of standard deviations the value is from the mean of the control group) and add or average the Z-scores. While not challenging computationally with a computer, this is not easily amenable to clinical practice. Finally, if one or more of the contributing variables to the summary index is missing or if the response is absent, one cannot calculate a summary index easily. Nevertheless, there are cases where a summary index can be calculated easily. An example is the combined sensory index which has been studied in the evaluation of carpal tunnel syndrome (Robinson et al., 1998). In this case, three latency differences between sensory nerves (all in units of milliseconds) are added together to provide a single variable reflecting median nerve slowing (compared to ulnar and radial nerves). Recent publications have demonstrated that this approach enhances the sensitivity and reliability of the test without losing specificity. The number is also easily calculated since it involves only addition of three latency differences, and does not require calculations of Z-scores. Another example of combining has been described by Dyck and colleagues. These authors have combined multiple nerve conduction scores in diabetic patients to arrive at a composite score (Dyck et al., 1997, 2003). This composite has been found to be more sensitive and reproducible than individual nerve conduction results when specificity remains fixed at 97%. Moreover, the scores correlate well with inde-

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pendent measures of neurologic impairment (Dyck et al., 2003), making this an attractive measure to follow over time, particularly in clinical trials. Whatever approach is taken to the problem of multiple test results, the clinical neurophysiologist needs to think through this issue before starting the test so that he or she will know how to handle multiple and sometimes conflicting data in a consistent manner. Table 23.2 illustrates our experience with using three different tests in the evaluation of carpal tunnel syndrome. While performing three tests and making a diagram based on a single abnormality produced the highest sensitivity (85%), it also resulted in poor specificity (92%). The summary index was the best approach. 23.6. Assessing published values In many cases, the clinical neurophysiologist will not be able to collect his/her own reference data and will rely upon published values. In such an event, one should evaluate the methods of data collection and assess how well they can be generalized to one’s own laboratory. It is preferable to examine original articles

Table 23.2 Sensitivity and specificity using Alternate Approaches

Test Med-Uln palmar Med-Uln ring finger Med-Rad thumb One of three tests abnormal Two of three tests abnormal Three of these tests abnormal Combined sensory index Combined sensory index

Reference value

Sensitivity (%)

Specificity (%)

≤ 0.3

70

97

≤ 0.4

74

97

≤ 0.5

76

97

85

92

74

99

56

100

≤ 0.9

83

95

≤ 1.1

82

100

Sensitivity and specificity of three tests for carpal tunnel syndrome. Results are presented for each test, allowing a diagnosis based on one, two, or three abnormalities, or using a summary variable (Robinson, et al, 1998).

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than summaries in textbooks whenever possible. Questions that one should ask include: ●

●

● ● ●

What population was studied? Was it similar to the population to be studied in the clinical testing laboratory, or did it at least span a wide range of individuals? What was the sample size? Was it sufficient for the statistical tests applied? How were left and right sides handled? How were missing values handled? Were the data normally distributed? If not, were the data transformed or were nonparametric statistics used?

If the study methodology is acceptable, and the methods applied in one’s clinical testing laboratory are very close to those used in reference data collection, then one can use the published reference values. However, the clinical neurophysiologist should be aware that deviations from the methods used in reference value collection will introduce errors and hence it is often preferable to collect one’s own reference data. 23.7. Summary The clinical neurophysiologist needs a working knowledge of how reference values are determined and how they should best be used. He or she also needs to know the concepts of sensitivity and specificity. For individuals interested in collecting reference data, the difficulties described may seem either overwhelming or trivial. However, since decisions to provide or withhold sometimes risky treatment are often based on electrophysiologic data, the clinical neurophysiologist does need to have a working knowledge of reference value determination. For those clinicians, performing and interpreting nerve conduction studies, but not necessarily collecting reference data themselves, over-reliance on published reference values should be cautioned against. Not all published reference values have been developed with the above notions in mind. Even for those reference values that are determined perfectly, there will be a small but not insignificant percentage of patients who have “abnormal” values but do not have disease. It is important to remember that the reference values are not definitive diagnostic decision limits, but only provide a guide as to the likelihood of a diagnosis. References Benson, ES (1972) The concept of the normal range. Hum. Pathol., 3: 152–155.

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Bland, JM, and Altman, DG (1986) Statistical methods for assessing agreement between two methods of clinical measurement. Lancet, 1: 307–310. Boulat, O, Janin, B et al. (1993) Plasma carnitines: reference values in an ambulatory population. Eur. J. Clin. Chem. Clin. Biochem., 31: 585–589. Braddom, RL and Johnson, EW (1974) Standardization of H reflex and diagnostic use in S1 radiculopathy. Arch. Phys. Med. Rehabil., 55: 161–166. Buschbacher, RM (2000) Manual of Nerve Conduction Studies. Demos Medical Publishing, Inc., New York, NY. Campbell, WW and Robinson, LR (1993) Deriving reference values in electrodiagnostic medicine. Muscle Nerve, 16: 424–428. Dorfman, LJ and Robinson, LR (1997) AAEM minimonograph #47 normative data in electrodiagnostic medicine. Muscle Nerve, 20: 4–14. Dyck, PJ, Davies, JL, Litchy, WJ and O’Brien, PC (1997) Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort. Neurology, 49 (1): 229–239. Dyck, PJ, Litchy, WJ, Daube, JR, Harper, CM, Dyck, PJ, Davies, J and O’Brien, PC (2003) Individual attributes versus composite scores of nerve conduction abnormality: sensitivity, reproducibility, and concordance with impairment. Muscle Nerve, 27 (2): 202–210. Eisen, A, Schulzer, M, Pant, B, MacNeil, M, Stewart, H, Trueman, S, Mak, E (1994) Receiver operating characteristic curve analysis in the prediction of carpal tunnel syndrome: a model for reporting electrophysiological data. Muscle Nerve, 17: 704–705. Elveback, LE (1973) The population of healthy persons as a source of reference information. Hum. Pathol., 4: 9–16. Elveback, LR, Guillier, CL and Keating, FR (1970) Health, normality, and the ghost of gauss. JAMA, 211: 69–75. Feinstein, AR (1985) Clinical epidemiology. Sanders, 177–182. Gerr, F and Letz, R (1998) J. Hand. Surg., 23B: 151–155. Hulley, SB, Gove, S and Browner, WS (1988) Choosing the study subjects: Specification and sampling. In: SB Hulley and SR Cummings (Eds.), Designing Clinical Research. Williams and Wilkins, Baltimore. Jensen, MC, Brant, Zawadzki, MN, Obuchowski, N, Modic, MT, Malkasian, D and Ross, JS (1994)

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Magnetic resoncance imaging of the lumbar spine in people without back pain. N. Engl. J. Med., 331: 69–73. Jonetz-Mentzel, L and Wiedmann, G (1993) Establishment of reference ranges for cortisol in neonates, infants, children, and adolescents. Eur. J. Clin. Chem. Clin. Biochem., 31: 525–529. Leaverton, PE (1995) Descriptive Statistics. In a Review of Biostatistics. Little Brown and Company, Boston, Vth ed., pp 7. Lew, HL, Wang, L and Robinson, LR (2000) Testretest reliability of the combined sensory index: implications for diagnosing carpal tunnel syndrome. Muscle Nerve, 23: 1261–1264. Mainland, D (1971) Remarks on clinical norms. Clin. Chem., 17: 267–274. Munro, BH (1986) Distributions. In: BH Munro, MA Visintainer and EB Page (Eds.), Statistical Methods for Health Care Research. JB Lippincott Co., Philadelphia. O’Halloran, MW, Studley-Ruxton, J and Wellby, ML (1970) A comparison of conventionally derived normal ranges with those obtained from patients’ results. Clinica. Chimica. Acta, 27: 35–46. Owen, JA and Campbell, DG (1968) A comparison of plasma electrolyte and urea values in healthy persons and in hospital patients. Clinica. Chimica. Acta, 22: 611–618. Reed, AH, Henry, RJ and Mason, WB (1971) Influence of statistical method used on the resulting estimate of normal range. Clin. Chem., 17: 275–284. Rivner, MH (1994) Statistical errors and their effect on electrodiagnostic medicine. Muscle Nerve, 17: 811–814. Robinson, LR (1999) Electromyography, magnetic resources imaging, and radiculopathy: It’s time to focus on specificity. Muscle Nerve, 22: 151–152.

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Robinson, LR, Micklesen, P and Wang, L (1998) Strategies for analyzing nerve conduction data: superiority of a summary index over single tests. Muscle Nerve, 21: 116–1171. Robinson, LR and Micklesen, PJ (2002) Expression of nerve conduction test results. Muscle Nerve, 25: 123–25. Robinson, LR, Temkin, NR, Fujimoto, WY and Stolov, WC (1991) Effect of statistical methodology on normal limits in nerve conduction studies. Muscle Nerve, 14: 1084–1090. Rondinelli, RD, Robinson, LR, Hassanein, KM, Stolov, WC, Fujimoto, WY and Rubner, DE (1994) Further studies on the electrodiagnosis of diabetic peripheral polyneuropathy using discriminant function analysis. Am. J. Phys. Med. Rehabil., 73: 116–123. Sokal, RR and Rohlf, FJ (1987) Data in Biostatistics. In Introduction to Biostatistics. WH Freeman and Company, New York, pp. 7–8. Solberg, HE and Grasbeck, R (1989) Reference Values. Ad. Clin. Chem., 27: 1–79. Solberg, HE (1981) Statistical Treatment of Collected Reference Values and Determination of Reference Limits. In: R Grasbeck and T Alstrom (Eds.), In Reference Values in Laboratory Medicine: The Current State of the Art. John Wiley and Sons, Chichester. Shrout, PR and Fleiss, JL (1979) Intraclass correlations: uses in assessing rater reliability. Psychol. Bull., 86: 420–428. Wang, SH and Robinson, LR (1998) Considerations in reference values for nerve conduction studies. Phys. Med. Rehabil. Clin. N. Am., 9: 907–923. Zar, JH (1984) Introduction. In Biostatistical Analysis, Englewood Cliffs, Prenctice Hall Inc., NJ, IInd ed.

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CHAPTER 24

Commonly tested nerves of the head and upper cervical region Edward A. Aul* University of Iowa, Roy J. and Lucille A. Carver College of Medicine, IA, USA

24.1. Introduction This chapter reviews the various nerve conduction techniques available to evaluate cranial and cervical nerves. The first part (Sections 24.2 and 24.3) involves examination of the facial and trigeminal nerves. The facial motor conduction study and blink reflex are the most widely practiced of these methods, and are discussed in great detail. Other strategies practiced with less regularity are also introduced. The second part (Sections 24.4–24.6) deals with evaluation of the spinal accessory, greater auricular and phrenic nerves, all of which are of upper cervical origin. Several phrenic nerve conduction methods are described, as is electromyography of the diaphragm. Evoked potentials are another useful tool to assess cranial nerve function. They will be addressed in another chapter of this text. As with all electrodiagnostic methods, evaluation of cranial and cervical nerves is most effective when interpreted as an adjunct to clinical history and neurologic examination. 24.2. The facial nerve The facial nerve (cranial nerve VII) is a mixed nerve consisting of branchial motor, visceral motor, general sensory, and special sensory components. The branchial motor (special visceral efferent) fibers, that constitute the largest part of the facial nerve, supply the muscles of facial expression, among others. The facial nerve is involved in a number of pathological conditions, including Bell’s palsy and other facial neuropathies, lesions of the cerebellopontine angle, and

* Correspondence to: Edward A. Aul, MD, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Department of Neurology, 200 Hawkins Drive, Iowa City, IA 52242, USA. E-mail address: [email protected] Tel.: +1-319-356-7235; fax: +1-319-356-4505.

axonal and demyelinating polyneuropathies. To assist evaluation of these disorders, several electrodiagnostic studies have been developed to assess the function of the motor component of the facial nerve. 24.2.1. Facial motor conduction study (direct response) 24.2.1.1. Background Electrical stimulation of the facial nerve to evaluate facial weakness was first described in the late 19th century, but did not become a part of routine clinical practice until recent years. In 1958, a method to determine conduction latency in facial nerve fibers was first described (Desmedt, 1958). The facial motor conduction study was subsequently adapted to examine individuals with Bell’s palsy and various other neuropathies (Waylonis and Johnson, 1964). While a number of techniques have been practiced since that time, the facial motor conduction study continues to be an important means to assess conditions associated with facial weakness. 24.2.1.2. Methods 24.2.1.2.1. Examination technique. Stimulation of the facial nerve allows one to assess distal nerve excitability. Single electric shocks may be applied with a bipolar stimulating electrode to the facial nerve at the anterior tragus, directly in front of the lower ear (Preston and Shapiro, 1998); just below the ear, anterior to the mastoid process (Waylonis and Johnson, 1964); or directly over the stylomastoid foramen (Taylor et al., 1970). In normal individuals, the threshold at which a muscle twitch can be provoked is usually between 3.0 and 8.0 mA; and the difference between right and left should not exceed 2.0 mA (Kimura, 2001). When surface stimulation is impaired by anatomical factors such as local edema or fat, needle electrode or magnetic stimulation of the facial nerve may be considered. Compound muscle action potentials (CMAPs) may be recorded from a number of the muscles of

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facial expression following supramaximal electrical stimulation of the facial nerve. These include the nasalis, orbicularis oculi and orbicularis oris muscles. Surface recording electrodes are most common. The active electrode (E1) is generally placed over the belly of the muscle, while a reference electrode (E2) is placed over the same muscle on the opposite side or on the nose. Based on initial negative deflection and maximal amplitude of motor responses, optimal recording electrode placement on several facial muscles supplied by different branches of the facial nerve has been investigated (Han et al., 1998). The results are summarized in Table 24.1. Alternatively, facial CMAPs may be recorded from a coaxial needle electrode placed in the orbicularis oris muscle superior to the corner of the mouth (Taylor et al., 1970). The technique utilized in our laboratory at the University of Iowa is demonstrated. Stimulation is applied to the facial nerve anterior to the tragus. The recording electrodes are placed on the nasalis muscle, lateral to the midnose. The active electrode (E1) is situated on the side of stimulation, and the reference electrode (E2) is situated contralaterally. A ground electrode is placed on the chin (Figs 24.1 and 24.2 and Table 24.2). 24.2.1.2.2. Response characteristics. The facial motor conduction study can be performed easily. The reproducibility of facial compound muscle action potentials (CMAPs) is similar to that of motor nerves in the limbs (Di Bella et al., 1997). The latency of the facial CMAPs, typically about 3–4 ms, is a measure of

the distal conduction of the fastest nerve fibers. Facial response latencies are more prolonged in the neonate, though relatively constant above two years of age (Waylonis and Johnson, 1964). The amplitude of the facial CMAPs, usually greater than 1 mV, reflects the number of functional motor axons. The amplitude of facial motor responses is variable, necessitating comparison between the right and left sides or assessment by serial examinations. A reduction of response amplitude to one half that of the unaffected side is considered to indicate distal degeneration (Kimura, 2001). Of note, the facial motor conduction study is limited to evaluation of only the distal portion of the facial nerve. Proximal lesions not associated with distal axonal degeneration may not be detected by this method. In addition, electrical changes may not be evident for up to 4–6 days, even after section of the facial nerve (Gilliatt and Taylor, 1959). 24.2.1.3. Normal values In reviews of 83 pediatric to adult subjects (mean age 37 years) and 30 neonates who underwent facial motor conduction studies at the University of Iowa, normal values for facial motor latency have been reported (Kimura et al., 1976, 1977). The study method consisted of recording from the orbicularis oculi muscle and stimulating the facial nerve anterior to the mastoid. For the adults, the mean facial motor latency was 2.9 ± 0.4 ms with an upper limit of normal (mean + 3 SD) of 4.1 ms. For the neonates, the mean facial motor latency was 3.3 ± 0.4 ms with an upper limit of normal of 4.5 ms. The results are summarized in Table 24.2.

Table 24.1 Optimal electrode placement in facial nerve conduction studies Muscle

Facial nerve branch

Active electrode placement

Frontalis

Temporal

Nasalis Orbicularis Oculi

Buccal Zygomatic

Orbicularis Oris

Buccal, Mandibular, Zygomatic

Triangularis

Mandibular

Midway between the hairline and the eyebrow, on a line running vertically through the pupil On the muscle belly at the midnose At the medial quarter, between the medial and lateral canthus 2 mm below the lower lip, midway between the midline and the corner of the mouth 15 mm lateral and 25 mm below the corner of the mouth

Results are based on maximal amplitude obtained for compound muscle action potentials. Assessment of individual branches of the facial nerve may be accomplished by recording from the appropriate muscles (Han et al., 1998).

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION

529

Fig. 24.1 Facial motor conduction study: recording electrode placement. The active electrode (E1) is applied on the nasalis muscle, ipsilateral to the side of stimulation. The reference electrode (E2) is applied contralaterally.

Fig. 24.2 Facial motor conduction study: stimulation technique. Stimulation of the facial nerve is accomplished with a bipolar electrode placed anterior to the tragus of the ear.

24.2.2. Blink reflex (indirect response)

found to be associated with two separate bursts of electromyographic activity (Kugelberg, 1952). The first component (R1) was characterized by a shorter latency, more synchronized response, while the second component (R2) was manifested by a longer latency, less synchronized and more prolonged response. The blink reflex produced by electrical stimulation of the

24.2.2.1. Background In 1896 the blink response, a reflex contraction of the orbicularis oculi muscles in response to a gentle tap on the forehead, was first characterized as a cranial reflex (Overend, 1896). This blink reflex was subsequently

Table 24.2 Facial motor conduction studies Stimulation site

Anterior to mastoid

Anterior to tragus of ear

Recording site(s)

E1—lower orbicularis oculi m. E2—about 2 cm laterally 2.9 ± 0.4 ms (4.1 ms)

E1—ipsilateral nasalis m. E2—contralateral nasalis m.

Normal latency

Facial motor conduction studies (from data in Kimura et al., 1976).

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supra-orbital nerve was later applied to the evaluation of individuals with unilateral facial paresis (Kimura et al., 1969) and other disorders of cranial nerves (Bender et al., 1969). The electrically stimulated blink reflex remains an important diagnostic tool today. The blink reflex is mediated by a complex anatomical circuit (Fig. 24.3). The afferent pathway consists of sensory fibers of the supraorbital branch of the ophthalmic division of the trigeminal nerve (cranial nerve V1), which synapse with both the ipsilateral main sensory nucleus of the trigeminal nerve in the mid pons, as well as the ipsilateral spinal trigeminal nucleus in the lower pons and medulla. The efferent pathway consists of motor fibers of the facial nerve (cranial nerve VII), which originate in the ipsilateral facial motor nucleus of the pons. The R1 response is thought to be mediated by a disynaptic (at least) pathway between the main sensory nucleus of the trigeminal nerve and the ipsilateral facial motor nucleus (Trontelj and Trontelj, 1978). The R2 responses are mediated by polysynaptic pathways between the spinal trigeminal nucleus and both the ipsilateral and contralateral facial motor nuclei (Kimura and Lyon, 1972). Thus, the electrically stimulated blink reflex reflects the functional integrity

Fig. 24.3 Anatomy of the blink reflex. The afferent component of the blink reflex consists of sensory fibers of the ophthalmic division (V1) of the trigeminal nerve, which synapse with the ipsilateral main sensory trigeminal nucleus (VM) in the mid pons, as well as the ipsilateral spinal trigeminal nucleus (VS) in the mid and lower pons. The efferent component consists of motor fibers of the facial nerve (VII), which originate in the facial motor nucleus (VII) in the pons. The R1 response of the blink reflex is mediated by a disynaptic pathway between the main sensory trigeminal nucleus (VM) and the ipsilateral facial motor nucleus (VII). The R2 responses are mediated by a polysynaptic pathway between the spinal trigeminal nucleus (VS) and bilateral facial motor nuclei (VII). Modified, Preston and Shapiro, 1998 with permission.

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of the entire facial nerve, as well as the trigeminal nerve and associated brainstem pathways. 24.2.2.2. Methods 24.2.2.2.1. Examination technique. The subject should be relaxed, lying supine on an examination table in a warm room. The eyes should be open or gently closed. A pair of surface recording electrodes is placed on the inferior aspect of the orbicularis oculi muscles, bilaterally. The active electrodes (E1) are applied inferior and slightly lateral to the pupil (at midline) on each side, and the reference electrodes (E2) are applied about 2 cm laterally. A ground electrode is usually placed on the chin, but may also be situated on the forehead or arm (Figs 24.4 and 24.5). Single electric shocks of 0.1 ms duration and appropriate intensity, usually ranging from 50 to 100 V or 5 to 10 mA, are applied with a bipolar stimulating electrode to the supra-orbital nerve as it exits the supra-orbital

Fig. 24.4 Blink reflex: recording electrode placement. Pairs of recording electrodes are placed on the orbicularis oculi muscles, bilaterally. The active electrodes (E1) are applied inferior to the pupil. The reference electrodes (E2) are applied 2 cm laterally.

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION

531

per division. Filter settings of 20 Hz low frequency and 10 kHz high frequency are generally sufficient for recording both the R1 and R2 components. 24.2.2.2.2. Response characteristics. In normal subjects, supramaximal electrical stimulation of the supraorbital nerve elicits two distinct responses in the orbicularis oculi muscles, the early ipsilateral R1 component and late bilateral R2 components (Kimura et al, 1969). A stimulus of greater intensity may yield more complex late responses, consisting of bilateral R2 and R3 components (Rossi et al., 1989) (Figs 24.6 and 24.7). The R1 latency reflects the conduction time of the blink reflex circuit. Thus, an abnormal R1 response

Fig. 24.5 Blink reflex: stimulation technique. Electrical stimulation is applied to the supraorbital nerve with a bipolar electrode. Mild voluntary contraction of the orbicularis oculi muscles may facilitate the R1 response.

foramen. Electrical responses are recorded bilaterally. A relatively stable R1 response is typically generated with repeated trials. In roughly 5–10% of normal individuals, single shocks may be insufficient to produce a stable R1 response (Kimura, 2001). In these individuals, mild voluntary contraction of the orbicularis oculi muscles may help facilitate the response. Additionally, paired stimuli, the first subthreshold and the second supramaximal, with an interstimulus interval of 3–5 ms are usually sufficient to produce an acceptable blink response. Electrical stimulation may alternatively be applied to the infraorbital or mental nerves, though the R1 responses are elicited less consistently in these studies. The R1 and R2 response latencies are typically 10–12 ms and 30–40 ms, respectively. Response amplitudes are variable, though usually measure a few hundred microvolts. For best results, recording apparatus settings should include a sweep speed of 5–10 ms per division and sensitivity of 100–200 μV

Fig. 24.6 Blink reflex: R1 and R2 responses. A normal blink reflex consists of an early, ipsilateral R1 response and late, long duration, bilateral R2 responses. In the diagram, the top two tracings reflect the blink responses associated with stimulation of the right supraorbital nerve, while the bottom two tracings reflect the responses associated with stimulation of the left. Key: iR2 = ipsilateral R2, cR2 = contralateral R2, O–Oc = orbicularis oculi muscles.

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Fig. 24.7 Blink reflex: R3 response. The tracing demonstrates normal blink reflex responses (R1, R2 and R3). Electrical stimulation intensity is suprathreshold for pain sensation (Rossi and Vignocchi, 1993 with permission from Springer-Verlag).

may reflect pathology of the trigeminal nerve, facial nerve, and/or brainstem pathways. The latency ratio of R1 to the direct response (R/D Ratio) allows one to compare the conduction time of the entire reflex arc with that of the distal segment of the facial nerve. The R2 responses correlate with the clinically observed blink response, and are most useful to localize the site of pathology along the reflex arc, as will be discussed later (Section 24.2.2.4.). The R1 latency is relatively fixed with repeated trials, though R2 latencies vary from one trial to the next. In addition, the R2 responses have a tendency to habituate with repeated trials in normal subjects (Kimura, 1973). Bilateral R3 responses can be induced by electrical or mechanical stimulation that approximates the pain threshold (Rossi et al., 1989; Beise et al., 1999). The R3 response latencies are about 70–80 ms in normal individuals. The R3 components readily habituate, and may be attenuated by attention and enhanced by distraction (Rossi and Vignocchi, 1993). Painful laser stimulation may also evoke late bilateral responses of about 130 ms latency (Ellrich et al., 1997). Evaluation of these different types of late responses may serve as a means to study nociceptive mechanisms. 24.2.2.2.3. Technical considerations. There are certain situations in which the blink reflex may yield responses that vary from normal. Unilateral stimulation of the supraorbital nerve occasionally produces

bilateral R1 responses. This effect may occur with priming in normal individuals (Willer et al., 1984) or after facial nerve palsy (Nacimiento et al., 1992), suggesting the activation of a preexisting crossed reflex pathway. Both R1 and R2 responses are normally recorded in the orbicularis oculi muscles. The blink reflex may sometimes be recorded in other muscles innervated by the facial nerve, such as the orbicularis oris muscle or platysma. This electrical evidence of synkinesis may be observed with aberrant regeneration after facial nerve paralysis (Kimura et al., 1975) or in the setting of hemifacial spasm (Auger, 1979) (See Fig. 24.8). In addition to electrical and mechanical stimulation, the blink reflex may be elicited by magnetic coil stimulation. The R1 and R2 response latencies recorded with magnetic stimulation are essentially the same as those recorded with electrical stimulation (Bischoff et al., 1993). While magnetic stimulation tends to be less uncomfortable and causes no shock artifacts, electrical stimulation of the supraorbital nerve remains the preferred method of assessing the blink reflex. 24.2.2.3. Normal values For the electrically elicited blink reflex, the normal ranges of latency of R1 and R2 responses were established in 83 healthy subjects, 7–86 years of age (mean 37 years), as well as 30 full-term neonates, at the

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION

Fig. 24.8 Blink reflex: recording of synkinesis. Pairs of recording electrodes (E1 and E2) are placed on the orbicularis oculi and platysma muscles. The supraorbital nerve is stimulated, as with routine blink reflex examination. Electrical evidence of synkinesis consists of blink reflex responses (R1 and R2) recorded in other facial muscles in addition to the orbicularis oculi muscles (i.e., the platysma in this situation).

University of Iowa (Kimura, 1975; Kimura et al., 1977). The upper limits of normal (mean + 3 SD) for the adults were as follows: R1 response 13.0 ms, ipsilateral R2 response 41 ms, and contralateral R2 response 44 ms. The upper limits of normal (mean

533

+ 3 SD) for the neonates were as follows: R1 response 15.0 ms and ipsilateral R2 response 43 ms. Findings are summarized in Table 24.3. For the mechanically elicited blink reflex, the normal range of latency of R1 was recorded in 21 healthy subjects, also at the University of Iowa (Kimura et al., 1985). The upper limit of normal (mean + 3 SD) for the R1 response was 16.7 ms. In general, the difference between the two sides should not exceed 1.2 ms for the electrically stimulated R1 response or 1.6 ms for the mechanically evoked R1 response. The direct and consensual R2 response latencies induced by a unilateral electrical stimulus should not differ by more than 5 ms, and the direct and consensual R2 response latencies on one side should not differ by more than 7ms when elicited by ipsilateral versus contralateral stimulation. In a study of 51 healthy subjects, 12–77 years of age (mean 40 years), reflex responses from the orbicularis oculi muscles elicited by electrical stimulation of the supra-orbital, infraorbital and mental nerves were compared (Kimura, 1999). Stimulation of the infraorbital nerve yielded R1 and R2 responses comparable to stimulation of the supraorbital nerve. While R2 responses were obtained in all subjects with infraorbital stimulation, the R1 responses were elicited in less than half of these individuals. In addition, stimulation of the mental nerve produced R1 responses in few subjects and R2 responses somewhat inconsistently (Table 24.4). 24.2.2.4. Abnormalities Disorders of the cranial nerves will be discussed at length in Chapter 39. However, certain basic patterns of abnormality of the blink reflex will be reviewed in the present text. 24.2.2.4.1. Afferent defect. Unilateral lesions of the trigeminal nerve result in an afferent pattern of abnormality. Electrical stimulation of the supraorbital nerve

Table 24.3 Blink reflex in adults and neonates

Adults upper limit Neonates upper limit

n

M

R1

iR1

cR2

R/D Ratio

166

2.9 ± 0.4 4.1 3.3 ± 0.4 4.5

10.5 ± 0.8 13.0 12.1 ± 1.0 15.0

30.5 ± 3.4 41 35.9 ± 2.5 43

30.5 ± 4.4 44 often absent

3.6 ± 0.5

60

Blink reflex in adults and neonates (from data in Kimura, 1975; Kimura et al., 1977).

3.7 ± 0.4

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Table 24.4 Blink reflex stimulation methods Mode

Site

n

R1

iR2

cR2

Mechanical Electrical Electrical Electrical

Glabella Supraorbital n. Infraorbital n. Mental n.

21 51 51 51

12.5 ± 1.4 (21) 10.1 ± 0.9 (51) 10.3 ± 1.2 (23) 10.6 ± 3.4 (5)

28.8 ± 3.6 (51) 27.9 ± 4.2 (51) 33.3 ± 5.6 (43)

29.9 ± 3.4 (51) 29.9 ± 4.0 (51) 34.9 ± 5.2 (44)

Blink reflex stimulation methods (from data in Kimura et al., 1985; Kimura, 1999).

summary, when considering lesions of the efferent arc, the blink reflex reveals abnormal R1 and R2 responses on the affected side, regardless of the side or method of stimulation.

on the affected side yields a delayed or absent R1 response ipsilaterally, and delayed or absent R2 responses bilaterally. Stimulation on the unaffected side produces a normal R1 ipsilaterally, and normal R2 responses bilaterally (Fig. 24.9). Mechanical stimulation activates bilateral afferent pathways. Therefore, a glabellar tap provokes a delayed or absent R1 response on the affected side and normal R1 response on the unaffected side. The R2 responses are normal bilaterally, owing to crossed input from the intact trigeminal nerve.

24.2.2.4.3. Other abnormalities. In addition to unilateral lesions of the facial or trigeminal nerves, the blink reflex may be affected by lesions of the brainstem involving the afferent or efferent pathways. For example, a mid-pontine lesion involving the main sensory nucleus of the trigeminal nerve may result in a unilaterally delayed or absent R1 response, but normal direct and consensual R2 responses, when the supraorbital nerve is stimulated on the affected side. In addition, a lateral medullary lesion involving the spinal nucleus of the trigeminal nerve may be associated with a delayed or absent R2 response on the side of the lesion, regardless of the side of stimulation, while other components of the blink reflex remain normal (Kimura and Lyon, 1972; See Fig. 24.11). The blink reflex may also be influenced by more diffuse processes. Demyelinating polyneuropathies may be associated with notably delayed R1 and R2

24.2.2.4.2. Efferent defect. Unilateral lesions of the facial nerve result in an efferent pattern of abnormality. Electrical stimulation of the supraorbital nerve on the affected side yields delayed or absent R1 and R2 responses ipsilaterally, and a normal R2 response contralaterally. Stimulation on the unaffected side produces normal R1 and R2 responses ipsilaterally, but a delayed or absent R2 response contralaterally (See Fig. 24.10). Similarly, a glabellar tap provokes delayed or absent R1 and R2 responses on the affected side, but normal R1 and R2 responses on the unaffected side. In

V1 Stimulation site Right

Fig. 24.9 Afferent blink reflex abnormalities. (A) Normal blink reflex: Stimulating the supraorbital nerve on each side yields an ipsilateral R1 response and bilateral R2 responses. (B) Partial right trigeminal lesion: Stimulation on the affected side results in delayed ipsilateral R1 and bilateral R2 responses, while stimulation of the unaffected side yields normal responses. (C) Complete right trigeminal lesion: Stimulation on the affected side results absent responses, while stimulation of the unaffected side yields normal responses. Modified from Preston and Shapiro, 1998 with permission.

A

B

C

Left

R

R

L

L

R

R

L

L

R

R

L

L

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION V1 stimulation site Right

A

B

C

Left

R

R

L

L

R

R

L

L

R

R

L

L

V1 stimulation site Right

A

B

C

D

Left

R

R

L

L

R

R

L

L

R

R

L

L

R

R

L

L

responses bilaterally, even in the absence of detectable facial weakness (Kimura, 1971). There may be temporal dispersion of the early (R1) response or merging of the early (R1) and late (R2) responses in the setting of demyelination. In contrast, axonal polyneuropathies demonstrate a much lower incidence of blink reflex abnormality (Fig. 24.11). 24.2.3. Electroneurography Electroneurography (ENoG) is another method to assess the physiologic status of the facial nerve. The procedure is a variation of the standard facial motor conduction study. The purpose of ENoG is to quantify

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Fig. 24.10 Efferent blink reflex abnormalities. (A) Normal blink reflex: stimulating the supraorbital nerve on each side yields an ipsilateral R1 response and bilateral R2 responses. (B) Partial right facial lesion: Stimulation on the affected side results in delayed R1 and R2 responses on the affected side and normal R2 response on the unaffected side, while stimulation on the unaffected side yields normal R1 and R2 responses on the unaffected side and delayed R2 response on the affected side. (C) Complete right facial lesion: Stimulation on either side results in absent responses on the affected side but normal responses on the unaffected side. Modified from Preston and Shapiro, 1998 with permission.

Fig. 24.11 Other blink reflex abnormalities. (A) Normal blink reflex: stimulating the supraorbital nerve on each side yields an ipsilateral R1 response and bilateral R2 responses. (B) Right pontine lesion, involving the main sensory nucleus of the trigeminal nerve: Stimulation on the affected side results in a delayed or absent ipsilateral R1 response but normal bilateral R2 responses, while stimulation on the unaffected side yields normal responses. (C) Right medullary lesion, involving the spinal nucleus of the trigeminal nerve: stimulation on either side results in a delayed or absent R2 response on the affected side, while other responses are normal. (D) Demyelinating polyneuropathy: All responses of the blink reflex may be delayed or absent. Modified from Preston and Shapiro, 1998 with permission.

the percentage of facial nerve fibers that are responsive to electrical stimulation (Beck and Benecke, 1993). ENoG is most commonly utilized to assess unilateral facial nerve lesions, such as Bell’s palsy. 24.2.3.1. Examination technique Similar to the facial motor conduction study, single electric shocks of supramaximal intensity are applied with a bipolar stimulating electrode to the facial nerve anterior to the tragus of the ear. Compound muscle action potentials are recorded from the ipsilateral nasolabial fold using a pair of exploring electrodes, which are manipulated to yield the response of greatest amplitude (Gantz et al., 1999; see Fig. 24.12 and Table 24.5).

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24.2.3.2. Response characteristics In contrast to the facial motor conduction study, electroneurography (ENoG) yields an electrical potential that reflects the summation of activity of many facial muscles lateral to the nose (Thomander and Stahlberg, 1981). The peak-to-peak amplitude is measured from the early positive peak to the subsequent negative peak. The amplitude of responses from the symptomatic and normal sides are compared, allowing one to approximate the percentage of functioning motor fibers in the facial nerve on the affected side. The latency of the recorded responses has not proven to be a reliable indicator of facial nerve status (Beck and Benecke, 1993). As with the facial motor conduction study, ENoG provides an assessment of distal facial nerve function. The timing of the test relative to the onset of facial weakness is important. If ENoG is performed prior to completion of Wallerian degeneration, the degree of facial nerve injury may be underestimated.

Table 24.5 Electroneurography Nerve Stimulation site Recording site(s)

Response

Facial nerve Anterior to tragus of ear Ipsilateral nasolabial fold, position adjusted to maximal response amplitude Summated compound muscle Action potential (CMAP)

24.3. The trigeminal nerve The trigeminal nerve (cranial nerve V) is a mixed nerve consisting of branchial motor and general sensory components. As with the facial nerve, the trigeminal nerve may be affected by focal processes or more generalized neuropathies. Although practiced less commonly than studies of facial nerve function, several electrodiagnostic methods have been developed to examine both the motor and sensory components of the trigeminal nerve. 24.3.1. Trigeminal sensory conduction study A method to record sensory nerve action potentials from the ophthalmic branch of the trigeminal nerve has been described (Raffaele et al., 1987).

24.3.1.1. Examination technique Electrical stimulation of the ophthalmic division of the trigeminal nerve is achieved by placing a bipolar stimulating electrode on the lateral aspect of the forehead, a few centimeters superior to the zygomatic process of the frontal bone. Surface recording electrodes are placed on the supra-orbital nerve as it exits the supraorbital foramen. Single electric shocks of less than 100 V intensity and 0.05–0.1 ms duration are sufficient to yield orthodromic sensory nerve action potentials. Filter settings of 1.6 Hz low frequency and 3.2 kHz high frequency were utilized in the initial study (Fig. 24.13).

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION

537

recording distances and small sensory response amplitudes. Nevertheless, this method may be used to help confirm lesions involving the ophthalmic branch of the trigeminal nerve (Table 24.6). 24.3.2. Trigeminal motor conduction studies 24.3.2.1. Background The trigeminal nerve is composed of three main divisions: the ophthalmic nerve, the maxillary nerve and the mandibular nerve. The ophthalmic and maxillary divisions are purely sensory in function. The mandibular nerve is the largest of the three divisions and consists of sensory and motor fibers. The mylohyoid nerve and the deep temporal nerve are both terminal branches of the mandibular nerve. Techniques to record motor responses from these braches of the trigeminal nerve have been described (Dillingham et al., 1996).

Fig. 24.13 Trigeminal sensory conduction studies. The ophthalmic division of the trigeminal nerve is stimulated with a bipolar electrode placed on the lateral forehead, superior to the zygomatic process of the frontal bone. Recording electrodes are placed on the supraorbital nerve, arising from the supraorbital foramen, the active electrode (E1) situated superiorly and the reference electrode (E2) situated inferiorly (Raffaele et al., 1987).

24.3.1.2. Response characteristics Normal parameters for trigeminal sensory nerve action potentials were established in a group of 10 individuals, 5 men and 5 women, age 18–54 years (Raffaele et al., 1987). Mean peak response latency was 0.81 ± 0.11 ms. Mean amplitude was 32.8 ± 2.77 μV. Mean nerve conduction velocity was 59.1 ± 8.92 m/s. Latency was measured at the negative peak of the sensory response due to difficulty differentiating response onset from stimulus artifact. Similar results were obtained across all age groups. There was no significant difference between male and female subjects. However, the study group was small. In addition, the study is limited by potential error related to short

24.3.2.2. Mylohyoid motor conduction study 24.3.2.2.1. Examination technique. The mylohyoid nerve is stimulated intraorally. A bite block is used to hold the mouth open. A bipolar pediatric nerve stimulator is placed against the medial mandibular ramus with the cathode in the small depression of the pterygomandibular fossa. Compound muscle action potentials are recorded from the mylohyoid muscle at the floor of the oral cavity. The active electrode (E1) is placed over the belly of the mylohyoid muscle under the chin. A reference electrode (E2) is placed over the mental protuberance. A ground electrode may be situated over the ipsilateral cheek. Supra-maximal electric shocks of 0.1–0.5 ms duration are applied to the mylohyoid nerve to produce the motor responses. Filter settings of 2 Hz to 10 KHz, sweep speed of 2 ms/division and sensitivity of 1–2 mV/division are adequate to capture these responses (Fig. 24.14).

Table 24.6 Trigeminal sensory nerve conduction study Stimulation site Recording site(s) Normal Values

Lateral forehead, above zygomatic process of frontal bone Supraorbital nerve at supraorbital foramen Latency: 0.81 ± 0.11 ms Amplitude: 32.8 ± 2.77 μV Velocity: 59.1 ± 8.92 m/s

Trigeminal sensory conduction studies (from data in Raffaele et al., 1987).

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2.2 mV. Subject age was not a significant factor. This method enables one to determine if there is a conduction delay along the distal course of the trigeminal nerve. Side-to-side comparison of motor response amplitudes may reveal whether substantial axonal loss has occurred (Table 24.7). 24.3.2.3. Deep temporal motor conduction study 24.3.2.3.1. Examination technique. The deep temporal nerve is also stimulated intraorally. The stimulating electrode, however, is placed more cranially, near the upper rear molar, with the cathode angled posteriorly. Compound muscle action potentials are recorded from the temporalis muscle. The active electrode (E1) is placed over the middle aspect of the temporalis muscle, and a reference electrode (E2) is placed on the forehead. A ground electrode is positioned on the cheek. Stimulus and equipment settings are similar to those described for the mylohyoid nerve conduction study (Refer to Fig. 24.15). Fig. 24.14 Mylohyoid motor conduction technique: recording electrode placement. The active electrode (E1) is attached to the mylohyoid muscle under the chin. The reference electrode (E2) is placed on the mental protuberance. The trigeminal nerve is stimulated intraorally (Dillingham et al., 1996).

24.3.2.2.2. Response characteristics. Results were obtained in 42 healthy adult subjects of mean age 47 ± 17.4 years (Dillingham et al., 1996). Mylohyoid compound muscle action potentials were elicited bilaterally in all cases. Mean response latency was 1.9 ± 0.2 ms with an upper limit of normal (mean + 2 SD) of 2.3 ms and maximal right-to-left difference of 0.4 ms. Mean baseline-to-peak response amplitude was 4.9 ± 1.8 mV with a lower limit of normal of 1.3 mV and maximal right-to-left difference of

24.3.2.3.2. Response characteristics. Results were obtained in the same 42 adult subjects (Dillingham et al., 1996). Deep temporal compound muscle action potentials were elicited bilaterally in only 25 subjects. Responses were absent on one or both sides in the remaining 17 individuals. Mean response latency was 2.1 ± 0.3 ms with an upper limit of normal (mean + 2 SD) of 2.7 ms and maximal right-to-left difference of 0.6 ms. Mean baseline to peak response amplitude was 4.3 ± 2.0 mV with a lower limit of normal of 0.3 mV and maximal right-to-left difference of 3.0 mV. The standard deviations for the motor response latency, amplitude and side-to-side differences for the deep temporal motor conduction study are higher than that for the mylohyoid motor conduction study. Thus, the deep temporal method is a less sensitive means to

Table 24.7 Trigeminal motor conduction studies

Stimulation site Recording site(s) Normal values

Mylohyoid nerve

Deep temporal nerve

Intraoral—medial mandible at pterygomandibular fossa E1—mylohyoid m. under chin E2—mental protuberance Latency: 1.9 ± 0.2 ms Amplitude: 4.9 ± 1.8 mV

Intraoral—medial mandible by Upper rear molar E1—mid temporalis m. E2—forehead Latency: 2.1 ± 0.3 ms Amplitude: 4.3 ± 2.0 mV

Trigeminal motor conduction studies (from data in Dillingham et al., 1996).

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which activates and triggers the oscilloscope to begin recording. Simultaneous responses are recorded from bilateral masseter muscles. The active electrodes (E1) are placed over the belly of each masseter muscle, and the reference electrodes (E2) are placed laterally on the chin. A ground electrode is usually used under the chin (Fig. 24.16).

Fig. 24.15 Deep temporal motor conduction technique: recording electrode placement. The active electrode (E1) is attached to middle of the temporalis muscle. The reference electrode (E2) is placed at the center of the forehead. The trigeminal nerve is stimulated intraorally (Dillingham et al., 1996).

detect abnormality in the trigeminal nerve. Furthermore, higher stimulation levels are required to produce responses in the deep temporal nerve, making the procedure more uncomfortable to the subject and yielding greater stimulus artifact in the recording (Table 24.7).

24.3.3.1.2. Response characteristics. Typical findings for the masseter reflex were reported in study of 23 healthy volunteers, age of 13–60 years (Kimura et al., 1970). Mean response latency, combining both right and left recordings, was 7.08 ± 0.62 ms with a maximal side-to-side difference of 0.8 ms. Mean response amplitude was 0.22 ± 0.24 mV with a maximal side-to-side difference of 2.7 mV. Successive unilateral recordings reveal significant variations in masseter reflex latency and amplitude, particularly the latter (Kimura et al., 1970). Comparison of bilateral reflex responses, recorded simultaneously is, therefore, most practical. Unilateral absence of the masseter reflex, bilateral absence of the reflex in individuals less than 70 years of age, or a right-to-left latency difference of greater than 0.5 ms is considered pathological (Goor and Ongerboer de Visser, 1976). Unilateral abnormality of the masseter reflex may be

24.3.3. Trigeminal reflexes Various strategies have been employed to assess the reflexes mediated by the trigeminal nerve. As previously discussed, the blink reflex involves both trigeminal afferent and facial efferent mechanisms. Other methods have been applied to evaluate trigeminal afferent and trigeminal efferent pathways. 24.3.3.1. Masseter reflex The masseter or jaw reflex consists of a brief contraction of the masseter muscle in response to mechanical stretch of its muscle spindles, such as may be produced by a tap on the mandible. The reflex is mediated by trigeminal sensory (afferent) and trigeminal motor (efferent) fibers, via the mesencephalic nucleus of the trigeminal nerve. 24.3.3.1.1. Examination technique. To elicit the masseter reflex, a mechanical tap is applied to the mandible with a percussion hammer possessing a microswitch,

Fig. 24.16 Masseter reflex. Stimulation consists of a mechanical tap applied to the mandible, which triggers recording. The active recording electrodes (E1) are placed on bilateral masseter muscles, while the reference electrodes (E2) are placed on the lateral aspects of the chin.

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indicative a lesion of the trigeminal nerve or brainstem pathways (Refer to Table 24.8). 24.3.3.2. Corneal reflex The corneal reflex is a nociceptive response, characterized by a blink of the eyelids, typically provoked by mechanical stimulation of the cornea. The reflex is mediated by trigeminal sensory (afferent) and facial motor (efferent) fibers, via the spinal nucleus of the trigeminal nerve and bilateral facial motor nuclei. 24.3.3.2.1. Examination technique. The corneal reflex may be elicited by electrical stimulation of the cornea. A method to record the electrically stimulated corneal reflex has been reported (Accornero et al., 1980). Corneal stimulation is accomplished with a thin cotton thread emerging from the tip of a glass pipette, which is filled with gauze soaked with saline solution and connected to the cathode of an electrical stimulator. A reference electrode is placed on the earlobe or forearm. The thread is touched to the cornea, and stimuli of 1ms duration and 50–2000 μA intensity are delivered. Reflex responses are recorded from bilateral orbicularis oris muscles. The active electrodes (E1) are applied to the inferior eyelids over the palpebral portion of the muscles on both sides. A common reference electrode (E2) is placed on the glabella. Filter settings of 0.1–3 kHz, sweep speed of 10 ms/division, and gain of 0.1 mV/division are endorsed. 24.3.3.2.2. Response characteristics. Testing was conducted on 30 subjects, age 20–70 years (mean age 42.7 ± 16.7 years). Electrical stimulation of the cornea yielded twitch responses in bilateral orbicularis oculi muscles, with latencies similar to the second (R2) component of the blink reflex. These responses were not preceded by an early ipsilateral (R1) component, unlike the blink reflex. The threshold for response Table 24.8 Masseter reflex Stimulation site Recording site(s) Normal values

Mandible (mechanical tap) E1—bilateral masseter m. E2—bilateral chin Latency: 7.08 ± 0.62 ms Amplitude: 0.22 ± 0.24 mV

Masseter reflex (from data in Kimura et al., 1970).

activation was achieved with corneal stimuli of 50–350 μA intensity (mean 200 ± 90 μA). Tolerance level intensity was 1000–2500 μA (mean 1850 ± 500 μA). At tolerance level, the mean latency for the direct response was 40.65 ± 2.54 ms. The mean latency for the consensual response was 42.50 ± 2.61 ms. The latency difference between the direct and consensual responses recorded simultaneously from both sides was 1.50 ± 1.50 ms. The latency difference for direct and consensual responses recorded sequentially from the same side was 1.90 ± 1.23 ms. Threshold stimulation levels above 500 μA were invariably pathologic, felt to be indicative of an afferent block. At tolerance level, afferent defect may be demonstrated by reflex response latencies of greater than 50 ms in both orbicularis oculi muscles elicited by unilateral stimulation, and a latency difference exceeding 8 ms between the direct responses elicited from both corneas. Efferent defect may be demonstrated by a latency difference of greater than 5 ms between the direct and consensual reflex responses. In this fashion, findings resemble those of the R2 component of the blink reflex. However, the latency and duration of the corneal reflex tend to be longer than those of the R2 response. Furthermore, the corneal reflex may still be evoked after the R2 response of the blink reflex has habituated. These findings suggest that the corneal reflex and the blink reflex do not follow identical neural pathways (Berardelli et al., 1985). 24.4. The spinal accessory nerve The accessory nerve (C1–C5; cranial nerve XI) is a pure motor nerve that supplies the sternocleidomastoid and trapezius muscles. The nerve originates in the anterior horn of the upper cervical spinal cord. The motor fibers ascend into the cranium through the foramen magnum, and the accessory nerve exits the cranium through the jugular foramen. The accessory nerve then passes inferiorly through the posterior triangle of the neck, where it follows a relatively superficial course, allowing easy accessibility for nerve stimulation techniques. The accessory nerve may be involved in several disease processes, including trauma, neoplasm and surgical manipulation. Nerve conduction data may be of benefit in these situations. Furthermore, repetitive stimulation of the spinal accessory nerve may be useful in the evaluation of disorders of neuromuscular transmission.

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION

24.4.1. Spinal accessory motor conduction study 24.4.1.1. Examination technique The spinal accessory nerve may be electrically stimulated with a bipolar electrode placed in the middle of the posterior triangle of the neck, the boundaries of which are the sternocleidomastoid muscle, the trapezius muscle and the clavicle. Surface recording electrodes are applied to the upper trapezius muscle, approximately 5 cm lateral to the spinous process of the C7 vertebra (Cherington, 1968). Compound muscle action potentials are easily recorded with supramaximal stimulation. Abnormality is determined by comparing the response latency and amplitude of the affected and unaffected sides (Fig. 24.17). As an alternative to electrical stimulation, magnetic stimulation of the spinal accessory nerve can be achieved by applying the stimulator to the base of the skull, below the lower border of the mastoid process and posterior to the occipital insertion of the sternocleidomastoid muscle (Pelliccioni et al., 1995). In addition to the upper trapezius muscle, motor responses may be recorded from the middle and lower trapezius muscles (Fahrer et al., 1974) or the sternocleidomastoid muscle (Pelliccioni et al., 1995). 24.4.1.2. Response characteristics Normal latency values for compound muscle action potentials in the upper trapezius muscle evoked by electrical stimulation of the spinal accessory nerve were demonstrated in 25 normal individuals, age 10–60 years (Cherington, 1968). The range of normal latencies was 1.8–3.0 ms for distances of 5.0–8.0 cm.

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Normal values have also been reported for magnetic stimulation of the accessory nerve in 10 subjects, age 28–74 years (Pelliccioni et al., 1995). Recording from the sternocleidomastoid muscle, mean latency was 2.1 ± 0.5 ms and mean amplitude was 4.8 ± 2.6 mV. Recording from the trapezius muscle, mean latency was 3.7 ± 0.6 ms and mean amplitude was 7.5 ± 2.9 mV (Table 24.9). 24.5. The greater auricular nerve The greater auricular nerve (C2–C3) is a pure sensory nerve originating in the cervical plexus. Its anterior branch supplies the skin over the mastoid and the back of the lower part of the auricle. The greater auricular nerve is susceptible to injury related to neck trauma or surgery. It may also be affected in leprosy and inherited and non-inherited hypertrophic neuropathies. Thus, electrodiagnostic study of the greater auricular nerve may be useful in evaluating these conditions. 24.5.1. Greater auricular sensory conduction study A simple technique to record sensory nerve action potentials from the greater auricular nerve has been reported (Palliyath, 1984). 24.5.1.1. Examination technique The greater auricular nerve can be stimulated as it courses superficially in the neck. A pair of surface recording electrodes is placed on the posterior aspect of the ear lobe. The active electrode (E1) is situated inferiorly and the reference electrode (E2) about 2 cm

Fig. 24.17 Spinal accessory nerve conduction technique. Stimulation is applied to the accessory nerve in the middle of the posterior triangle of the neck. Recording electrodes (E1 and E2) are placed on the trapezius muscle (Cherington, 1968).

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Table 24.9 Spinal accessory motor conduction study Stimulation site Recording site(s)

Normal values

Middle of posterior triangle of neck E1 – upper trapezius m. (about 5 cm lateral to C7 process) E2 – about 2 cm laterally Latency: 1.8–3.0 ms Distance: 5.0–8.0 cm

Spinal accessory nerve conduction studies (from data in Cherington, 1968).

distally. Electrical stimulation is applied to the greater auricular nerve on the lateral aspect of the sternocleidomastoid muscle, at a point 8 cm proximal to the active electrode. The ground electrode may be placed on the back of the neck. Single electric shocks of 0.1 ms duration and 10–12 mA intensity are typically sufficient to yield reproducible responses. A sweep speed of 1 ms per division and gain of 20 μV per division are appropriate recording apparatus settings (See Fig. 24.18). 24.5.1.2. Response characteristics Normal results for greater auricular sensory nerve action potentials were determined from 35 nerves, studied in 20 healthy volunteers, age 21–66 years (Palliyath, 1984). Mean peak latency was 1.7 ± 0.2 ms. Mean baseline to peak amplitude was 12.7 ± 4.1 μV. Mean nerve conduction velocity was 46.8 ± 6.6 m/s. There was no significant difference between right and left recordings. A subsequent study employing similar technique and measuring peak-to-peak amplitudes (Kimura et al., 1987) reported a linear correlation between the amplitude of greater auricular sensory nerve action potentials and age, as well as a linear correlation between the amplitude of greater auricular and median sensory nerve action potentials. This technique provides a simple and reliable means of evaluating conduction in the greater auricular nerve (Table 24.10). Given the occasional anatomic variability of the greater auricular nerve, stimulation may be applied at multiple sites on the lateral aspect of the sternocleidomastoid muscle of varying distance from the recording electrodes, selecting the point at which sensory nerve action potentials of maximal amplitude are achieved (Sand and Becser, 1998). This approach should be

Fig. 24.18 Greater auricular nerve conduction technique. Stimulation is applied to the greater auricular nerve at the lateral border of the sternocleidomastoid muscle. Recording electrodes (E1 and E2) are placed on the back of the ear lobe at a distance of 8 cm from the site of stimulation (Palliyath, 1984).

considered with caution. If the stimulating site is too proximal, the spinal accessory or phrenic nerves may be stimulated. In addition, a greater degree of error may be introduced with shorter distances between stimulating and recording electrodes.

Table 24.10 Greater auricular sensory conduction study Stimulation site Recording site(s) Normal values

Lateral border sternocleidomastoid m. (distance 8 cm) E1—posterior ear lobe (proximal) E2—posterior ear lobe (2cm distal) Latency: 1.7 ± 0.2 ms

Greater auricular nerve conduction studies (from data in Palliyath, 1984).

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION

24.6. The phrenic nerve The phrenic nerve (C3–C5) is a mixed motor and sensory nerve arising from the cervical plexus. The efferent fibers are the sole nerve supply to the muscle of the diaphragm. The afferent fibers transmit sensory information from the pericardium, as well as the pleural and peritoneal surfaces associated with the diaphragm. The roots of the phrenic nerve unite in the neck on each side lateral to the anterior scalene muscle at the level of the cricoid cartilage. The nerve then runs vertically downward in front of the anterior scalene muscle and passes into the thorax, passing anterior to the subclavian artery. The phrenic nerve may be involved in traumatic injuries, neoplasms and more generalized neuropathies. Several methods have been developed to evaluate phrenic motor function. 24.6.1. Phrenic motor conduction study 24.6.1.1. Surface electrode stimulation 24.6.1.1.1. Lateral recording technique. Early methods of evaluating phrenic motor conduction involved recording diaphragmatic compound muscle action potentials from the lateral chest wall. One of the earliest of these accounts reported results from 22 phrenic nerves in 18 normal subjects, age 20–61 years (Newsom Davis, 1967). Supra-maximal electrical stimulation was applied to the phrenic nerve with an electrode placed on the posterior border of the sternocleidomastoid muscle at the level of the thyroid cartilage, delivering pulses of 0.2–1.0 ms duration. Surface recording electrodes were situated on the lateral chest wall. The active electrode (E1) was placed at the eighth intercostal space in the anterior axillary line. The reference electrode (E2) was place 3.5–5.0 cm laterally.

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A ground electrode was applied to the chest. Normal parameters for diaphragmatic compound muscle action potentials were obtained. Mean onset latency was 7.7 ± 0.80 ms with a range of 6.1–9.2 ms. Amplitude range was 160–500 μV (Table 24.11). Several observations were made in this initial study (Newsom Davis, 1967). First, there was a good correlation between the latency of phrenic motor responses recorded with surface electrodes and those recorded with surgically implanted electrodes. The technique provided a way to document phrenic neuropathy. Furthermore, the degree of latency delay in the phrenic nerves of patients with polyneuropathies was shown to be similar to the degree of slowing in proximal segments of the median and ulnar nerves in these same individuals. A variation of this technique has been employed in our laboratory at the University of Iowa. Electrical stimulation is applied at the posterior border of the sternocleidomastoid muscle, as described. The active electrode (E1) is again placed at the eighth intercostal space in the anterior axillary line. However, the reference electrode (E2) is placed above the xiphoid process. Technically, both active and reference electrodes are electrically “active”, though diaphragmatic compound muscle action potentials are usually well delineated. Waveforms may have a predominantly positive or negative deflection (Fig. 24.19). 24.6.1.1.2. Midline recording technique. Other studies of phrenic motor conduction have measured diaphragmatic compound muscle action potentials near midline. One such technique was described in an analysis of the phrenic nerves in 50 patients, age 31–72 years, one to two days prior to cardiothoracic surgery (Markand et al., 1984). Electrical stimulation

Table 24.11 Phrenic motor conduction studies

Stimulation site Recording site(s)

Normal values

Lateral recording

Midline recording

posterior border of sternocleidomastoid m. at level of thyroid cartilage E1—eighth intercostals space, anterior axillary line E2—3.5 to 5.0 cm laterally latency: 7.7 ± 0.80 ms amplitude: 160 to 500 μV

posterior border of sternocleidomastoid m. in supraclavicular fossa E1—xiphoid process, about 5 cm superior to tip E2—costal margin, 16 cm laterally latency: 6.54 ± 0.77 ms amplitude: 660 ± 201 μV

Phrenic motor conduction studies (from data in Newsom Davis, 1967; Chen et al., 1995).

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EDWARD A. AUL Fig. 24.19 Phrenic nerve conduction technique. Electrical stimulation is applied to the phrenic nerve at the posterior border of the sternocleidomastoid muscle at the level of the thyroid cartilage. The active recording electrode (E1) is placed at the eighth intercostal space in the anterior axillary line. The reference electrode (E2) is placed at the xiphoid process.

of the phrenic nerve was achieved with a bipolar electrode placed at the posterior border of the sternocleidomastoid muscle at the level of the upper edge of the thyroid cartilage. Stimuli of 0.1–0.5 ms duration, 1 Hz frequency and 100–250 V intensity were utilized. The active recording electrode (E1) was applied at the xiphoid process, and the reference electrode (E2) was applied at the seventh intercostal space above the costochondral junction. In a comparison with other recording electrode combinations, this montage was shown to produce the most reliable positive motor potentials. A ground electrode was placed on the upper chest. Appropriate stimulation of the phrenic nerve was associated with a “hiccup,” as has been observed in other studies. Diaphragmatic compound muscle action potentials recorded by this method were characterized by monophasic or biphasic positive waveforms. The findings of the phrenic nerve conduction studies in these 50 control subjects were reported (Markand et al., 1984). Mean onset latency was 7.77 ± 0.77 ms on the right and 7.74 ± 0.76 ms on the left. Response duration was 18.08 ± 3.06 ms on the right and 16.89 ± 2.94 ms on the left. Mean baselineto-peak amplitude was 0.79 ± 0.19 mV on the right and 0.77 ± 0.22 mV on the left. There was no significant difference between results on the right and left for any of these parameters. 24.6.1.1.3. Subcostal recording method. In an effort to simplify the recording procedure, a technique to measure diaphragmatic compound muscle action potentials using a relatively large fixed distance

between the active and reference recording electrodes was developed (Bolton, 1993). This approach eliminated the inaccuracy of rib counting encountered in other methods. Electrical stimulation was applied to the phrenic nerve at the posterior border of the sternocleidomastoid muscle in the supraclavicular fossa, just above the clavicle. Supra-maximal stimulation was achieved with a pulse duration of 0.1 ms and intensity less than 90 mA. Midline recording electrode placement was utilized. The active electrode (E1) was placed on the xiphoid process, 5 cm superior to the tip. The reference electrode (E2) was placed at the costal margin, at a distance of 16 cm from the active electrode. This location corresponded roughly to the seventh intercostal space. The position of the stimulating electrode was adjusted slightly as necessary to assure selective stimulation of the phrenic nerve and production of a “hiccup”, while preventing inadvertent stimulation of the brachial plexus and associated arm movement (Refer to Fig. 24.20). Results of phrenic nerve conduction studies employing this technique were established in the examination of 50 nerves in 25 normal subjects, 14 men and 11 women, age 22–80 years (Chen et al., 1995). Mean onset latency was 6.54 ± 0.77 ms with an upper limit (mean + 2 SD) of 8.1 ms. Mean duration was 19.4 ± 2.7 ms. Mean amplitude was 660 ± 201 μV. Mean area was 7.28 ± 2.09 μVms. Results remained stable with serial testing. There was no significant difference related to the side of recording. Findings were not influenced by the sex, weight, height, or percentage body fat of the subjects. Conversely, there were direct correlations between response latency

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Fig. 24.20 Phrenic nerve conduction technique: subcostal recording: Electrical stimulation is applied to the phrenic nerve at the posterior border of the sternocleidomastoid muscle in the supra-clavicular fossa. The active recording electrode (G1) is placed at the xiphoid process. The reference electrode (G2) is placed at the costal margin at a fixed distance of 16 cm from the active electrode. Modified (Bolton, 1993 with permission from John Wiley and Sons, Inc.).

S

G1

G2

G2

and age, as well as response amplitude and chest circumference (Table 24.11). 24.6.1.2. Needle electrode stimulation In addition to surface stimulation techniques, needle electrode stimulation of the phrenic nerve has also been reported (MacLean and Mattioni, 1981). The stimulating cathode consisted of a monopolar needle electrode, inserted at the posterior margin of the sternocleidomastoid muscle at the level of the cricoid cartilage. The electrode was angled anteriorly and advanced to a depth of 15–25 mm (Fig. 24.21). The anode was a surface electrode applied at the manubrium sterni. Recording was accomplished with a midline recording montage. The active electrode (E1) was placed at the xiphoid process, and the reference electrode was placed at the eighth intercostal space. Findings were demonstrated for the assessment of 60 phrenic nerves in 30 subjects, age 18–74 years (MacLean and Mattioni, 1981). Mean latency was 7.44 ± 0.59 ms with a range of 6.0–9.5 ms. Average duration was 48.1 ± 12.2 ms. Mean amplitude was 845 ± 405 μV with a range of 200–2000 μV. There was no significant between right and left recordings. There was a trend for latency to increase with age, though not statistically significant in this study. 24.6.1.3. Magnetic stimulation More recent efforts have described cervical magnetic stimulation as a means to assess phrenic nerve conduction (Similowski et al., 1989). Activation of the

phrenic nerve is accomplished by placing a magnetic stimulator behind the neck with the coil centered over the spinous process of the C7 vertebra and the handle directed caudally either parallel to the vertebral column or at a 45º angle. In a comparison of magnetic and electrical phrenic nerve stimulation, similar latency values for the diaphragmatic compound muscle action potential were obtained with both methods when threshold magnetic stimulation was employed; but shorter latencies were obtained when maximal magnetic stimulation was applied (Similowski et al., 1997). This observation suggests more distal phrenic nerve activation with maximal magnetic stimulation. In contrast to electrical stimulation, magnetic stimulation of the phrenic nerve is usually painless. Bilateral phrenic nerves can be examined simultaneously. While electrical stimulation of the phrenic nerve may be impaired by inability to accurately locate the nerve, this is not generally the case for magnetic stimulation. Refer to Chapter 19 of this text for further discussion of magnetic stimulation. 24.6.1.4. Technical considerations Several methods to evaluate phrenic nerve conduction have been described. Unfortunately, there are several potential limitations to these techniques. Adequate stimulation of the phrenic nerve may be difficult to achieve, particularly when the examiner must deal with edema, excessive body fat, catheters, cervical collars or other anatomic or medical factors. Nevertheless, in a study of 110 individuals, diaphragmatic compound

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EDWARD A. AUL Fig. 24.21 Needle electrode stimulation of the phrenic nerve. A monopolar needle electrode is inserted at the posterior margin of the sternocleidomastoid muscle at the level of the cricoid cartilage and angled anteriorly as shown. Modified (MacLean and Mattioni, 1981 with permission from American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation).

Int. jugular v. Carotid a.

Sternocleido mastoid m.

Phrenic n. Ant. scalene m.

muscle action potentials were obtained bilaterally with surface stimulation of the phrenic nerve in 95% of all subjects, 99% of normal controls and 81% of patients with diaphragmatic weakness (Mier et al., 1987). These observations suggest that phrenic nerve conduction studies can be performed successfully in most individuals. Across techniques, results for response latencies are fairly uniform and reliable. However, there is a high degree of error in measures of response amplitude and duration. For this reason, only measures of latency and the presence or absence of diaphragmatic compound muscle action potentials should be considered when reviewing phrenic nerve conduction studies. As discussed, a number of methods to stimulate and record responses from the phrenic nerve have been described, and as many arguments to support their usage. No single technique has gained widespread practice. It has been argued that the lateral recording method with the active electrode in the anterior axillary line actually measures evoked responses from the serratus anterior muscle rather than the

diaphragm (Raimondo et al., 1983). On the other hand, differing reports have not shown an advantage of midline over lateral recording techniques (Swenson and Rubenstein, 1992). Electrical stimulation of the phrenic nerve with surface electrodes is often painful for the examinee. Needle electrode and magnetic stimulation are reportedly more comfortable. With all the stimulating methods, inadvertent stimulation of the brachial plexus may occur, introducing movement artifact that can interfere with correct interpretation of recorded waveforms. The technique of midline recording with a fixed distance between the active and reference recording electrodes (Bolton, 1993) is relatively simple and yields reliable results (Chen et al., 1995). This approach deserves further attention. Phrenic nerve conduction studies are useful in evaluating phrenic nerve function in the setting of trauma, neoplasm or other focal processes. Involvement of the phrenic nerve in more generalized polyneuropathies may also be demonstrated (Newsom Davis, 1967). In patients considering diaphragmatic pacing due to quadriplegia associated with cranio-cervical trauma,

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION

these studies can assess the viability of the phrenic nerves (Lieberman et al., 1980). Information gained about general pulmonary status, however, is somewhat limited. In an evaluation of phrenic nerve conduction in patients with hereditary motor and sensory neuropathy, type 1 (CMT–1), prolonged compound muscle action potential latency did not correlate with other indices of pulmonary function, such as forced vital capacity or maximal inspiratory and expiratory pressures, or with clinical signs and symptoms of respiratory insufficiency (Carter et al., 1992). 24.6.2. Diaphragmatic electromyography The function of the phrenic nerve can also be ascertained by electromyography of the diaphragm. Respiration will demonstrate bursts of electrical activity (motor unit potentials) during inspiration, alternating with periods of electrical silence during expiration. Spontaneous electrical activity, such as fibrillation potentials and/or positive sharp waves, may be evident with phrenic nerve injuries associated with axonal degeneration. One method involves approaching the diaphragm from an insertion site below the costal margin (Saadeh, 1993). Examination is performed with the patient lying in a supine position. A 50 mm monopolar or bipolar recording electrode is used. The insertion site is determined by marking the intersection of the costal margin and the paramedial clavicular line, which is a vertical line originating at the clavicle, midway between its lateral edge and the sternal notch. This location corresponds to the cartilage of the ninth

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rib. The examiner depresses the abdomen inferior to the costal margin, and the needle electrode is introduced in a direction parallel to the posterior aspect of the chest wall (Fig. 24.22). The electrode is then advanced to the diaphragm. If inserted too deeply, the needle may penetrate the pleural cavity. If inserted too superficially, the electrode may remain in abdominal musculature and record its activity rather than respiratory function. Finally, if a parallel approach cannot be achieved, the abdominal cavity may be entered. Correct needle placement in the diaphragm should be associated with electrical bursts during inspiration, as noted. Another technique for diaphragmatic electromyography involves needle electrode insertion above the costal margin (Bolton, 1993). The electrode can be introduced horizontally through any of the interspaces between the medial clavicular and anterior axillary lines, just above the costal margin (Fig. 24.23). At this point, there is a roughly 1.5 cm distance between the pleural reflection and the lower costal cartilage, where the diaphragm inserts. The electrode will pass through the external oblique, rectus abdominus, and external and internal intercostal muscles before reaching the diaphragm. If inserted too deeply, the needle may enter the peritoneum. There is little risk of entering the pleura. Again, correct needle placement in the diaphragm is associated with inspiratory bursts of electrical activity. The procedure can be performed safely. In a survey of 1000 subjects undergoing this technique, only two patients were reported to have pneumothorax as a complication of diaphragmatic electromyography (Bolton, 1993). Fig. 24.22 Diaphragmatic electromyography: vertical insertion of the needle recording electrode inferior to the costal margin and parallel to the chest wall (Saadeh et al., 1993).

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Lung

External oblique muscle Seventh rib Pleure

Diaphragm

Peritoneum Monopolar needle

Skin

Liver Lower costal margin

Subcutaneous tissue

Fig. 24.23 Diaphragmatic electromyography: horizontal insertion of the needle recording electrode superior to the costal margin and perpendicular to the chest wall (Bolton, 1993 with permission from John Wiley and Sons, Inc.).

24.7. Conclusions Disorders involving the cranial and cervical nerves are encountered regularly by neurologists and neurophysiologists. Among those affecting the cranial nerves are Bell’s palsy and other cranial neuropathies, various polyneuropathies, and lesions of the brainstem or cerebellopontine angle. This chapter has demonstrated several methods to evaluate the cranial nerves. The facial motor conduction study and blink reflex have proved to be reproducible and reliable and, consequently, are practiced fairly routinely. Electroneurography has gained acceptance as a tool to evaluate and assist management of Bell’s palsy. With the exception of the blink reflex, the approaches described to assess trigeminal sensory, motor and reflex pathways have been utilized less consistently, in part due to the complexity of some of these procedures. Examination of nerves of upper cervical origin that may be involved in focal or more diffuse processes, has also been addressed. Spinal accessory and greater auricular nerve conduction

studies are simple and reliable procedures. There continues to be some debate about which method of assessing phrenic nerve conduction is most reliable. Nevertheless, several of these procedures, published findings and associated technical considerations have been reviewed. In general, the nerve conduction techniques reported in this chapter can assist the clinician by confirming localization, assessing the degree of involvement, indicating prognosis, and/or guiding therapy for conditions affecting the cranial or cervical nerves. References Accornero, N, Berardelli, A, Bini, G, Cruccu, G and Manfredi, M (1980) Corneal reflex elicited by electrical stimulation of the human cornea. Neurology, 30: 782–785. Auger, RG (1979) Hemifacial spasm: clinical and electrophysiologic observations. Neurology, 29: 1261–1272.

COMMONLY TESTED NERVES OF THE HEAD AND UPPER CERVICAL REGION

Beck, DL and Benecke, JE (1993) Electroneurography: electrical evaluation of the facial nerve. J. Am. Acad. Audiol., 4: 109–115. Beise, RD, Kohlloffel, LUE and Claus, D (1999) Blink reflex induced by controlled, ballistic mechanical impacts. Muscle Nerve, 22: 443–448. Bender, LF, Maynard, FM and Hastings, SV (1969) The blink reflex as a diagnostic procedure. Arch. Phys. Med. Rehabil., 50: 27–31. Berardelli, A, Cruccu, G, Manfredi, M, Rothwell, JC, Day, BL and Marsdens, CD (1985) The corneal reflex and the R2 component of the blink reflex. Neurology 35: 797–801. Bischoff, C, Liscic, R, Meyer, B-U, Machetanz, J and Conrad, B (1993) Magnetically elicited blink reflex: an alternative to conventional electrical stimulation. Electromyogr. Clin. Neurophysiol., 33: 265–269. Bolton, CF (1993) AAEM minimonograph #40: clinical neurophysiology of the respiratory system. Muscle Nerve, 16: 809–181. Carter, GT, Kilmer, DD, Bonekat, HW, Lieberman, JS and Fowler, WM (1992) Evaluation of phrenic nerve and pulmonary function in hereditary motor and sensory neuropathy, type I. Muscle Nerve, 15: 459–462. Chen, R, Collins, S, Remtulla, H, Parkes, A and Bolton, CF (1995) Phrenic nerve conduction study in normal subjects. Muscle Nerve, 18: 330–335. Cherington, M (1968) Accessory nerve conduction studies. Arch. Neurol., 18: 708–709. Desmedt, JE (1958) Methods of studying the neuromuscular function of man. Acta. Neurol. Belg., 58: 977–1017. Di Bella, P, Logullo, F, Lagalla, G, Sirolla, C and Provinciali, L (1997) Reproducibility of normal facial motor conduction studies and their relevance in the electrophysiological assessment of peripheral facial paralysis. Neurophysiol. Clin., 27: 300–308. Dillingham, TR, Spellman, NT and Chang, AS (1996) Trigeminal motor nerve conduction: deep temporal and mylohyoid nerves. Muscle Nerve, 19: 277–284. Ellrich, J, Bromm, B and Hopf, HC (1997) Painevoked blink reflex. Muscle Nerve, 20: 265–270. Fahrer, H, Ludin, HP, Mumenthaler, M and Neiger, M (1974) The innervation of the trapezius muscle: an electrophysiologic study. J. Neurol., 207: 183–188. Gantz, BJ, Rubenstein, JT, Gidley, P and Woodwoth, GG (1999) Surgical management of Bell’s palsy. Laryngoscope, 109: 177–1188.

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Gilliatt, RW and Taylor, JC (1959) Electrical changes following section of the facial nerve. Proc. R. Soc. Med., 52: 1080–1083. Goor, C and Ongerboer de Visser, BW (1976) Jaw and blink reflexes in trigeminal nerve lesions: an electrodiagnostic study. Neurology, 26: 95–97. Han, TR, Chung, SG and Kwon, YW (1998) Optimal electrode placement in facial nerve conduction study. Electromyogr. Clin. Neurophysiol., 38: 279–284. Kimura, I, Seki, H, Sasao, S and Ayyar, DR (1987) The great auricular nerve conduction study: a technique, normative data and clinical usefulness. Electromyogr. Clin. Neurophysiol., 27: 39–43. Kimura, J (1971) An evaluation of the facial and trigeminal nerves in polyneuropathy: electrodiagnostic study in Charcot–Marie–Tooth disease, Guillain–Barré syndrome and diabetic neuropathy. Neurology, 21: 745–752. Kimura, J (1973) Disorder of interneurons in parkinsonism: the orbicularis oculi reflex to paired stimuli. Brain, 96: 87–96. Kimura, J (1975) Electrically elicited blink reflex in diagnosis of multiple sclerosis. Review of 260 patients over a seven year period. Brain, 98: 413–426. Kimura, J (1999) The blink reflex as a clinical test. In: MJ Aminoff (Ed.), Electrodiagnosis in Clinical Neurology. Churchill Livingstone, New York, IVth ed., pp. 337–363. Kimura, J (2001) Electrodiagnosis is diseases of nerve and muscle, principles and practice. Oxford University Press, New York, IIIrd ed., pp. 409–438, 474–478. Kimura, J, Bodensteiner, J and Yamada, T (1977) Electrically elicited blink reflex in normal neonates. Arch. Neurol., 34: 246–249. Kimura, J, Giron, LT Jr and Young, SM (1976) Electrically elicited blink reflex in assessment of prognosis. Arch. Otolaryngol., 102: 140–143. Kimura, J and Lyon, LW (1972) Orbicularis oculi reflex in the Wallenberg syndrome: alteration of the late reflex by lesions of the spinal tract and nucleus of the trigeminal nerve. J. Neurol. Neurosurg. Psychiatry, 35: 228–233. Kimura, J, Powers, JM and Van Allen, MW (1969) Reflex response of orbicularis oculi muscle to supraorbital nerve stimulation: study in normal subjects and in peripheral facial paresis. Arch. Neurol., 21: 193–199.

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Kimura, J, Rodnitzky, RL and Okawara, S (1975) Electrophysiologic analysis of aberrant regeneration after facial nerves paralysis. Neurology, 25: 989–993. Kimura, J, Rodnitzky, RL and Van Allen, MW (1970) Electrodiagnostic study of trigeminal nerve. Orbicularis oculi reflex and masseter reflex in trigeminal neuralgia, paratrigeminal syndrome other lesions of the trigeminal nerve. Neurology, 20: 574–583. Kimura, J, Wilkinson, JT, Damasio, H, Adams, H Jr, Shivapour, E and Yamada, T (1985) Blink reflex in patients with hemispheric cerebrovascular accident (CVA). J. Neurol. Sci., 67: 15–28. Kugelberg, E (1952) Facial reflexes. Brain, 75: 385–396. Lieberman, JS, Corkill, G, Nayak, NN, French, BN and Taylor, RG (1980) Serial phrenic nerve conduction studies in candidates for diaphragm pacing. Arch. Phys. Med. Rehabil., 61: 528–531. MacLean, IC and Mattioni, TA (1981) Phrenic nerve conduction studies: a new technique and its application in quadriplegic patients. Arch. Phys. Med. Rehabil., 62: 70–73. Markand, ON, Kincaid, JC, Pourmand, RA, Moorthy, SS, King, RD, Mahomed, Y and Brown, JW (1984) Electrophysiologic evaluation of diaphragm by transcutaneous phrenic nerve stimulation. Neurology, 34: 604–614. Mier, A, Brophy, C, Moxham, J and Green, M (1987) Phrenic nerve stimulation in normal subjects and in patients with diaphragmatic weakness. Thorax, 42: 885–888. Nacimiento, W, Podoll, K, Graeber, MB, Topper, R and Mobius (1992) Contralateral early blink reflex in patients with facial nerve palsy: indication for synaptic reorganization in the facial nucleus during regeneration. J. Neurol. Sci., 109: 148–155. Newsom Davis, J (1967) Phrenic nerve conduction in man. J. Neurol. Neurosurg. Psychiatry, 30: 420–426. Overend, W (1896) Preliminary note on a new cranial reflex. Lancet, 1: 619. Palliyath, SK (1984) A technique for studying the greater auricular nerve conduction velocity. Muscle Nerve, 7: 232–234. Pelliccioni, G, Scarpino, O and Guidi (1995) Magnetic stimulation of the spinal accessory nerve: normative data and clinical utility in an isolated stretchinduced palsy. J. Neurol. Sci., 132: 84–88. Preston, DC and Shapiro, BE (1998) Electromyography and Neuromuscular Disorders, ClinicalElectrophysiologic Correlations. ButterworthHeinemann, Boston, pp. 57–62. Raffaele, R, Emery, P, Palmeri, A, Ricca, G and Perciavalle, V (1987) Sensory nerve conduction

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velocity of the trigeminal nerve. Electromyogr. Clin. Neurphysiol., 27: 115–117. Raimondo, D, Bennici, S, Lima, J and Fierro, B (1983) Considerations on the technique of phrenic nerve conduction measurement. Acta. Neurologica., 5(5): 346–350. Rossi, B, Risaliti, R and Rossi, A (1989) The R3 component of the blink reflex in man: a reflex response induced by activation of high threshold cutaneous afferents. Electroencephalogr. Clin. Neurophysiol., 73: 334–340. Rossi, B and Vignocchi, MG (1993) Methodological considerations on the use of the blink reflex R3 component in the assessment of pain in man. Ital. J. Neurol. Sci., 14: 217–224. Saadeh, PB, Crisafulli, CF, Bosner, J and Wolf, E (1993) Needle electromyography of the diaphragm: a new technique. Muscle Nerve, 16: 15–20. Sand, T and Becser, N (1998) Neurophysiological and anatomical variability of the greater auricular nerve. Acta. Neurol. Scand., 98: 333–339. Similowski, T, Fleury, B, Launois, S, Cathala, HP, Bouche, P and Derenne, JP (1989) Cervical magnetic stimulation: a new painless method for bilateral phrenic nerve stimulation in conscious humans. J. Appl. Physiol., 67: 1311–1318. Similowski, T, Mehiri, S, Duguet, A, Attali, V, Straus, C and Derenne, JP (1997) Comparison of magnetic and electrical phrenic nerve stimulation in assessment of phrenic nerve conduction time. J. Appl. Physiol., 82(4): 1190–1199. Swenson, MR and Rubenstein, RS (1992) Phrenic nerve conduction studies. Muscle Nerve, 15: 597–603. Taylor, N, Jebsen, RH and Tenckoff, HA (1970) Facial nerve conduction latency in chronic renal insufficiency. Arch. Phys. Med. Rehabil., 51: 259–261. Thomander, L and Stalberg, E (1981) Electroneurography in the prognostication of Bell’s palsy. Acta. Otolaryngol., 92: 221–237. Trontelj, MA and Trontelj, JV (1978) Reflex arc of the first component of the human blink reflex: a single motoneurone study. J. Neurol. Neurosurg. Psychiatry, 41: 538–547. Waylonis, GW and Johnson, EW (1964) Facial nerve conduction delay. Arch. Phys. Med. Rehabil., 45: 539–541. Willer, JC, Boulu, P and Bratzlavsky, M (1984) Electrophysiological evidence for crossed oligosynaptic trigemino-facial connections in normal man. J. Neurol. Neurosurg. Psychiatry, 47: 87–90.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 25

Commonly tested nerves in the shoulder girdle and upper limb S. Veronica Tan and Nicholas M.F. Murray* The National Hospital for Neurology and Neurosurgery, UK

25.1. Introduction In this chapter, the methods of studying commonly tested nerves in the shoulder girdle and upper limb are described. The brachial plexus, median, ulnar, and radial nerves are described in turn, preceded by a brief outline of the anatomy with the emphasis on the clinically relevant features. The usefulness of comparative studies and common pitfalls are outlined in the “comments” section following each method described. The methods described are those routinely used in adults; nerve conduction in children requires a different– approach and often, different recording electrodes and techniques. Normative data varies according to the technique and the age of the child (Rabben, 1995; Royden Jones et al., 2003). For a detailed review, we refer the readers to the authoritative text by Royden Jones et al. (2003). The normal values given are for testing at a skin temperature of 32º unless otherwise stated. Where it is not possible to warm the limb adequately, an approximate correction of velocities and latencies for temperature can be made (Liveson and Ma, 1992); please see chapter 15. Distances are measured with a tape measure, except where stated otherwise (see sections on Brachial plexus and Radial nerve, where obstetric callipers should preferably be used for certain segments). Sensory amplitudes are measured peak-to-peak and motor amplitudes are measured from baseline to the negative peak unless otherwise stated. Typical machine settings are as listed in Table 25.1.

* Correspondence to: Nicholas M.F. Murray, MB, FRCP, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. E-mail address: [email protected] Tel.: + 44-20-7829-8752; fax: + 44-20-7713-7743.

25.2. The brachial plexus 25.2.1. Anatomy The brachial plexus is formed by the union of the ventral rami of the C5–8, and T1 roots; with variable contributions from the C4 root (larger contribution in prefixed plexus) and T2 root (larger in postfixed plexus). Nerves arising directly from the roots include the dorsal scapular nerve to the rhomboids (C5), the long thoracic nerve to serratus anterior (C5–7), the nerves to the scaleni and longus colli (C5–8) and the C5 contribution to the phrenic nerve. Behind the scalene muscles, the C5 and C6 roots unite to form the upper trunk, C8 and T1 unite to form the lower trunk, with the C7 root itself constituting the middle trunk. The upper trunk gives rise to the suprascapular nerve (to the spinati) and the nerve to subclavius. Just above or behind the clavicle, each trunk splits into an anterior and posterior division. The anterior divisions of the upper and middle trunks unite to form the lateral cord, the anterior division of the lower trunk forms the medial cord, and the posterior divisions of all three trunks units to form the posterior cord. The lateral cord gives rise to the lateral pectoral nerve and the musculocutaneous nerve to biceps. The medial cord gives rise to the medial pectoral nerve, the medial cutaneous nerve of the forearm and the medial cutaneous nerve of the arm. The posterior cord gives rise to the upper and lower subscapular nerves, the thoracodorsal nerve to latissimus dorsi, and the axillary nerve to teres minor and deltoid. In the region of the third part of the axillary artery, the lateral cord and part of the medial cord unite to form the median nerve, the remainder of the medial cord continues as the ulnar nerve and the posterior cord forms the radial nerve.

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Table 25.1 Typical machine settings for motor studies, sensory studies and mixed nerve studies, unless otherwise stated in the text

Study

Sweep velocity (ms/div)

Motor nerve conduction Sensory nerve conduction Mixed nerve studies Short segment Forearm segment F wave studies

Sensitivity (per division)

High frequency filter (kHz)

Low frequency filter (Hz)

Stimulus duration (ms)

2

2 mV

10

2

0.1–0.2

1

10 μV

2

20

0.1

10 μV

2

20

0.1

200 μV

10

20

0.1–0.2

1 2 5/10

Modified from Sethi et al., 1989.

25.2.2. Clinical applications Brachial neuritis and traumatic brachial plexus and root injuries are commonly encountered problems. In traumatic injuries, upper plexus lesions are the most common, frequently as a result of a closed traction injury as in motorcycle accidents, “burner syndrome” or rucksack paralysis or, in obstetric practice, in the brachial plexopathy associated with an Erb’s palsy. Lower trunk lesions are seen in neurogenic thoracic outlet syndromes and in malignant infiltration (such as Pancoast tumors); Klumpke’s palsy is rare. In radiation plexopathies, the emphasis is commonly on the lateral cord/upper plexus distribution (Ferrante, 2004), possibly because of the shielding effect of the clavicle. Unilateral proximal demyelination may occur in multifocal CIDP and in multifocal motor neuropathy with conduction block. 25.2.3. Motor studies 25.2.3.1. Nerve root stimulation (Fig. 25.1) Stimulation of the nerve roots allows the evaluation of conduction in the most proximal segments of the brachial

Fig. 25.1 Nerve root stimulation. Site of stimulation for C8 root: between C7 and T1 spinous processes(black: cathode, white: anode).

plexus. This can be performed either electrically (with monopolar needle electrodes, or by high voltage transcutaneous electrical stimulation), or magnetically (with a coil over the skin). Magnetic stimulation that, as for electrical stimulation, excites the roots at the exit foramina, is useful for assessing motor latencies, but cannot be used for detecting proximal conduction block, since supramaximal stimulation cannot be guaranteed. Where proximal conduction block is suspected, electrical stimulation is required. For details of these techniques, please see Mills and Murray, 1986 and Schmid et al. 1990. Distal motor latencies to serratus anterior, the rhomboids, the spinati, deltoid, biceps, and triceps can be obtained, recording with concentric needle electrodes or, for some muscles, surface electrodes (see below). In unilateral lesions, a side-to-side latency difference exceeding 1 ms may be more sensitive than absolute latencies, provided the distances between stimulating and recording electrodes are identical (Berger et al., 1987). In routine practice, however, root stimulation is most commonly used for detecting proximal conduction block to the biceps (C5, 6), triceps (C6–8) and abductor digiti minimi (C8, T1). For routine assessment of conduction in the proximal branches of the plexus, surface stimulation over Erb’s point is usually sufficient. 25.2.3.2. Erb’s point stimulation (Fig. 25.2) Erb’s point is located in the angle between the posterior edge of the clavicular head of the sternocleidomastoid and the clavicle. In most individuals, a supramaximal stimulus delivered over Erb’s point is capable of exciting the whole plexus (duration

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Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode over Erb’s point, the anode is located above and medially Normal values: Latency: 5.2 ± 0.7 ms, Distance: 19.9 cm (range 16.5–21.5), measured using obstetric callipers. (N = 21, age: 19–73 year) (Lo Monaco et al., 1983).

Fig. 25.2 Erb’s point stimulation (black: cathode, white: anode).

required 0.2–1 ms); it is a convenient point of stimulation for the following nerves 25.2.3.2.1. Long thoracic nerve C5, C6, C7 roots Recording electrodes Active electrode (A): over serratus anterior in the midaxillary line over the 5th or 6th rib (CNE in serratus anterior may be used if only distal motor latency (DML) required) Reference electrode (R): over the same rib, 3 cm anterior to (A) Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode: over Erb’s point, the anode is located above and medially Normal values: (Patient age 36–50 years) Latency (ms): 3.3 ± 0.3 (mean ± SD) Amplitude (mV) 3.8 ± 2.4 (mean ± SD) (Alfonsi et al., 1986; DeLisa et al., 1994) Comments: This nerve is frequently involved in brachial neuritis and, together with the trapezius, is a common neurological cause of a winged scapula. Comparison of the CMAP with the contralateral side is a useful guide to the degree of axonal loss present in unilateral lesions. 25.2.3.2.2. Dorsal scapular nerve C5 root Recording electrodes Active electrode (A): CNE in rhomboid major at the medial edge of the scapula midway between the spine and the inferior angle of the scapula

25.2.3.2.3. Suprascapular nerve C5, C6 roots, Upper trunk Recording electrodes Active electrode (A1), Supraspinatus: CNE, inserted into the supraspinatus muscle just above and medial to the midpoint of the spine of the scapula. Active electrode (A2), Infraspinatus: CNE, inserted into the Infraspinatus muscle in the infraspinous fossa, two fingerbreadths below the medial portion of the spine of the scapula. Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode over Erb’s point, the anode is located above and medially Normal values: Supraspinatus: Latency: 2.7 ± 0.5 ms (range 1.7–3.7 ms) (Kraft, 1972). Infraspinatus: Latency: 3.3 ± 0.5 ms (range 2.4– 4.2 ms) (Kraft, 1972). Some authors suggest that monopolar needle recordings provide a more accurate measurement of latency (Casazza et al., 1998), with a side to side latency difference of 0.4 ms being the upper limit of normal. 25.2.3.2.4. Axillary nerve C5, C6 roots, upper trunk, posterior division, posterior cord Recording electrodes Active electrode (A): over the most prominent part of the middle fibres of the deltoid, midway between the acromion and the deltoid tubercle Reference electrode (R): over the its tendon, where it inserts into the deltoid tubercle Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode over Erb’s point, the anode is located above and medially Normal values: (N = 62) Latency 3.9 = −0.5 ms (range 2.8–5.0 ms) (Kraft, 1972).

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25.2.3.2.5. Musculocutaneous nerve C5, C6 roots, upper trunk, anterior division, lateral cord Recording electrodes Active electrode (A): just distal to the midpoint of the biceps brachii muscle Reference electrode (R): proximal to the antecubital fossa over the biceps tendon Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode positions (1) Over the musculocutaneous nerve in the anterior aspect of the axilla (Trojaborg, 1976) (2) Over Erb’s point, the anode is located above and medially (3) Over the C5 root, the cathode is placed between the C5 and C6 spines and the anode 6 cm laterally on the side being examined using a high voltage transcutaneous stimulator (Digitimer 180, time constant of decay 0.05–0.1 ms, typically corresponding to 40–60% of the stimulator’s maximal output [1500 V]) Normal values: Stimulation in the axilla: Latency 1.3–3.6 ms (recording distances 7–13 cm) (Trojaborg, 1976) Stimulation at Erbs: Latency 4.5 ± 0.6 (range 3.3–5.7) (Kraft, 1972). Stimulation over C5, C6 roots: Latency 5.3 ± 0.4 (MacLean, 1980) Comments: Assessment of proximal conduction looking for block or slowing of conduction is useful in suspected inflammatory neuropathies, focal CIDP and multifocal motor neuropathy. 25.2.3.2.6. Thoracodorsal nerve C6, C7, C8 roots, upper, middle and lower trunks, posterior division, posterior cord Recording electrodes Active electrode (A): CNE in latissimus dorsi, three fingerbreadths distal to and along the posterior axillary fold Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode over Erb’s point, the anode is located above and medially Normal values: Latency 3.9 ± 0.4 ms, distance 17–21 cm (Lo Monaco et al., 1983). 25.2.3.2.7. Radial nerve C6, C7, C8 roots, upper, middle and lower trunks, posterior divisions, posterior cord

S V TAN AND NMF MURRAY

Recording electrodes Active electrode (A1): CNE in long head of triceps, four fingerbreadths distal to the posterior axillary fold Active electrode (A2): surface electrode over the long head of triceps, four fingerbreadths distal to the posterior axillary fold Reference electrode (R): surface electrode over the triceps tendon at the elbow Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode (1) High voltage surface stimulation over the C6, C7 and C8 roots, cathode over the C7 spine and anode 6 cm laterally (2) Over Erb’s point, the anode is located above and medially Normal values: Latency from roots: 5.4 ± 0.4 ms (MacLean, 1980), Latency from Erb’s point: 4.9 ± 0.45 ms, distance 26.5 cm (Gassel, 1964) 25.2.4. Sensory studies When present, the demonstration of postganglionic sensory involvement in the form of reduced SNAPs is useful in differentiating plexus from root lesions. In C5, C6 or upper trunk injuries, this may be difficult because of the lack of a reliable C5 sensory potential; in these cases demonstration of asymmetrical lateral cutaneous SNAPs (C5, C6) may be helpful. 25.2.4.1. Lateral cutaneous nerve of the forearm (C5,C6) (Fig. 25.3) This nerve is the cutaneous sensory termination of the musculocutaneous nerve. Recording electrodes Active electrode (A): 12 cm from the cathode, along a line drawn between the stimulation point and the radial artery at the wrist Reference electrode (R): 4 cm distal to (A) Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode in the elbow crease just lateral to the biceps tendon (antidromic stimulation) Normal values: Amplitude (μV) (peak to peak): 24 ± 7.2 (mean ± 1 SD), range 12–50 Conduction velocity: 65 ± 3.6 ms (mean ± 1 SD) (Spindler and Felsenthal, 1978)

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555

Fig. 25.3 Lateral cutaneous nerve of the forearm. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

25.2.4.2. Medial cutaneous nerve of the forearm (C8, T1) (Fig. 25.4) This nerve originates from the medial cord or rarely the lower trunk. It becomes subcutaneous just proximal to the medial epicondyle. Recording electrodes Active electrode (A): 10 cm distal to the cathode along a line connecting the cathode to the pisiform bone at the wrist. Reference electrode (R): 4 cm distal to (A) Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode. The cathode is placed medial to the biceps tendon at the junction of the medial third and lateral two thirds of a line connecting the biceps tendon to the medial epicondyle. The anode is proximal. Normal values: Onset latency: 1.54 ± 0.17 ms (mean ± 1SD) Amplitude (μV) (peak to peak): 18.8 ± 7.1 (mean ± 1SD), range 6–40 (Kimura and Ayyar, 1984) Comments: This sensory potential is useful in differentiating lower trunk/medial cord lesions (as in thoracic outlet syndrome) from ulnar nerve neuropathies.

25.2.4.3. Posterior cutaneous nerve of the forearm (C5, 6, 7, 8) (Fig. 25.5) This nerve arises from the radial nerve in the arm, usually proximal to the spiral groove. It accompanies the radial nerve through the groove, perforates the lateral head of the triceps and descends along the lateral side of the arm, and then along the dorsum of the forearm to the wrist. It supplies the lateral and dorsolateral aspect of the upper arm and forearm. Recording electrodes Active electrode (A): 12 cm distal to the cathode along a line from the cathode to the mid-dorsum of the wrist. Reference electrode (R): 4 cm distal to (A) Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode just above the lateral epicondyle, between the brachioradialis and triceps, at the border of the lateral head of the triceps Normal values: Onset latency: 1.9 ± 0.3 ms (mean ± 1SD) Amplitude (μV) (peak to peak): 8.6 ± 3.9 (mean ± 1SD), range 5–20 (Ma and Liveson, 1983). A correlation between subject age and amplitude has been noted by some authors (Prakash et al., 2004).

Fig. 25.4 Medial cutaneous nerve of the forearm. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

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S V TAN AND NMF MURRAY Fig. 25.5 Posterior cutaneous nerve of the forearm. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

Comments: This nerve may be affected in a radial nerve lesion at or proximal to its origin in the spiral groove. Isolated lesions of this nerve are uncommon, but it may be injured following trauma, surgical procedures or injections in the arm. It may also be involved in brachial neuritis and may be helpful when attempting to distinguish pre- and postganglionic lesions. 25.3. Median nerve 25.3.1. Anatomy The nerve fibers in the median nerve originate from the C6, 7, 8 and T1 roots, and pass through the upper, middle and lower trunks, and the lateral and medial cords of the brachial plexus. At a variable distance proximal to the elbow joint, the branch(es) to pronator teres is given off before the nerve enters the forearm between the two heads of this muscle and supplies, flexor carpi radialis, palmaris longus (absent in 13% of the normal population) and flexor digitorum superficialis. There are usually multiple branches to the pronator teres muscle, with the more proximal ones innervating the superficial head while the distal branches supply the deep head (Dumitru and Zwarts, 2002). The anterior interosseous nerve is a purely motor branch arising from the posterior aspect of the median nerve between the two heads of pronator teres just distal to the branches to the forearm flexors described above. It supplies the lateral half of flexor digitorum profundus, flexor pollicis longus and pronator quadratus. The palmar cutaneous branch originates proximal to the wrist and supplies the skin over the thenar eminence. The median nerve enters the hand through the carpal tunnel under the flexor retinaculum and emerges to supply the lateral two lumbricals, opponens pollicis, abductor pollicis brevis and, in some cases, flexor pollicis brevis (LOAF), as well as sensory branches to the volar aspect of the thumb, index, middle and lateral half of the ring finger and the dorsal

aspect the their terminal phalanges (although variations to this pattern are common). In many individuals, flexor pollicis brevis is innervated wholly or in part by the ulnar nerve (see below). 25.3.2. Clinical applications Median nerve entrapment at the carpal tunnel is the most common entrapment neuropathy. Less common median nerve entrapment neuropathies include: (a) ligament of Struther’s syndrome, at the distal humerus and (b) compression by the bicipital aponeurosis (lacertus fibrosus), both causing a high median nerve lesion, and, more controversially, (c) pronator teres syndrome, with entrapment of the nerve in the region of this muscle either by a fibrous band, a fibrous edge of a forearm flexor or hypertrophied pronator teres (usually sparing the branch(es) to this muscle) (Stewart, 2000). Isolated lesions of the anterior interosseous nerve are probably most commonly inflammatory in nature (as a variant of brachial neuritis), although compression by fibrous bands or an aberrant vessel has been described (Dawson et al., 1983; Seror, 1999; Stewart, 2000). The Martin–Gruber anastomoses. In 10–44% of normal individuals, nerve fibre bundles cross over from the median nerve to the ulnar nerve in the forearm. It is transmitted as an autosomal dominant trait and, in over 60% of patients, is bilateral. The commonest fibres involved are those supplying the normally ulnar innervated intrinsic hand muscles, causing a median motor response that is larger (but with initial positivity) at the elbow than at the wrist, and an ulnar motor response that mimics conduction block at the elbow. Other patterns have been described but are less common (Leibovic and Hastings, 1992). Another cause of anomalous innervation of the intrinsic hand muscles is communication in the hand between the deep motor branch of the ulnar nerve and the median nerve (Riche–Cannieu anastomosis) (Harness and Sekeles, 1971) leading to small median CMAPs with-

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Fig. 25.6 Median motor study to abductor pollicis brevis. Active recording electrode marked with a dot. Position of stimulating electrodes at proximal and distal sites marked with dots (black: cathode, white: anode).

out wasting or denervation. Although largely ignored compared with the Martin–Gruber anastomosis, the Riche–Cannieu anastomosis is anatomically present in approximately 77% of hands, although the exact percentage of either median or ulnar muscle fibres innervated through this anastomosis is unknown. It is the most likely explanation for the rare cases of the “all ulnar” hand (Dumitru et al., 2002). Thenar wasting is also seen in T1 or lower trunk lesions (as in thoracic outlet syndrome, where thenar wasting is seen in association with normal median but small ulnar SNAPs). 25.3.3. Motor studies 25.3.3.1. Median motor study to abductor pollicis brevis (Figs. 25.6 and 25.7) (C8, T 1 roots, lower trunk, medial cord) Recording electrodes Active electrode (A): over the motor point of abductor pollicis brevis Reference electrode (R): over the proximal phalanx of the thumb Ground electrode (G): over the dorsum of the hand

Stimulating electrode (1) Palm: the cathode is placed at the point in the palm located by flexing the fourth finger onto the palm. The anode is distal. A transcarpal velocity can be obtained by stimulating the recurrent thenar branch in the palm and the median nerve at the wrist (2) Wrist: between the tendons of flexor carpi radialis and palmaris longus, 8 cm proximal to the active electrode. (3) Elbow: just lateral to the brachial artery pulse (4) Axilla: over the axillary artery, in the groove between the coracobrachialis and triceps muscles (5) Erb’s point (see above) Normal values: On stimulation at the wrist and elbow Distal motor latency (DML): 3.7 ± 0.3 ms (mean ± 1SD) (range 3.2–4.2 ms) Maximal conduction velocity (MCV): 56.7 ± 3.8 ms (mean ± 1SD) (range 50–67.3 ms) Amplitude (baseline to negative peak): 13.2 ± 5 mV (mean ± 1SD) (range 5–25 mV) (DeLisa et al., 1994). On stimulation in the palm

Fig. 25.7 Median nerve: Recurrent thenar branch. Active recording electrode marked with a dot. Position of stimulating electrodes in the palm marked with dots (black: cathode, white: anode). Position of routine stimulation at the wrist also marked.

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Amplitude (mV): 7.1 (mean); ratio of palm evoked to wrist evoked CMAP 1.0 (SD = 0.2, range = 0.8–1.1) Velocity across the carpal tunnel: 54.6 ± 7 (mean ± SE) Difference between forearm and transcarpal velocities (ms): 0.3 ± 4.8 (mean ± SE) (Walters and Murray, 2001). Comments: In median nerve lesions where APB is severely wasted, current spread to the ulnar nerve at the wrist may result in a volume-conducted response from ulnar innervated thenar muscles. Care should, therefore, be taken to increase the stimulation current in small increments, noting sudden changes in the configuration and latency of the response that may suggest activation of ulnar innervated muscles. In cases of suspected Martin–Gruber anastomosis, it is often helpful to record the response to stimulation of both the median and ulnar nerves at the wrist and at the elbow (four sites) whilst recording first from APB and then from ADM. Care should taking to distinguish a true Martin–Gruber anastomosis from understimulation of the median nerve at the wrist, or overstimulation of the median nerve at the elbow resulting in current spread to the ulnar nerve (especially in cases where the stimulus duration has been increased). Co-stimulation of the ulnar nerve is difficult to avoid when stimulating the median nerve at sites proximal to the elbow; proximal conduction block is, therefore, difficult to demonstrate in the median nerve with routine recordings over APB; collision techniques may be necessary for reliable interpretation. “Inching” studies by stimulating at 1 cm increments across the wrist and into the hand may be helpful in demonstrating focal slowing or conduction block across the carpal tunnel.

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Transcarpal motor conduction to APB is comparable in sensitivity with transcarpal sensory conduction and the second lumbrical-interosseous latency difference in carpal tunnel syndrome. The recurrent thenar branch is sometimes damaged in isolation in the palm, either by local trauma or following surgery (especially keyhole) for carpal tunnel syndrome. F-wave studies Recording electrodes (as for routine motor conduction studies above) Active electrode (A): over the motor point of abductor pollicis brevis Reference electrode (R): over the proximal phalanx of the thumb Ground electrode (G): over the dorsum of the hand Stimulating electrode The cathode is placed proximal to the anode over the median nerve at the wrist. Normal values: Minimum latency (10 or more F-waves): 26.4 ms (mean), range 22–31 ms. (Sethi and Thompson, 1989) For correction tables of F-waves for arm length and height see chapter 9. Comment Prolonged F wave latencies or absent F-waves may be seen in proximal demyelinating lesions such as Guillain–Barré syndrome or CIDP. F-wave persistence may be reduced in radiculopathies or in some neuropathies. 25.3.3.2. Second lumbrical (Fig. 25.8) Comparison of the DMLs of the median innervated second lumbrical and the ulnar innervated underlying interosseous muscle is a useful means of demonstrating

Fig. 25.8 Median motor study to second lumbrical. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode) for median and ulnar stimulation sites.

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differential median motor slowing across the wrist in carpal tunnel syndrome. Recording from the second lumbrical is a useful alternative for obtaining median forearm motor conduction velocities in severe carpal tunnel syndrome if a CMAP is unrecordable from APB. Recording electrodes Active electrode (A): on the palm, slightly radial to the midpoint of the third metacarpal Reference electrode (R): over the bony prominence of the second proximal interphalangeal joint. Ground electrode (G): over dorsum of the hand Stimulating electrode At the wrist between the tendons of flexor carpi radialis and palmaris longus. Distance to active recording electrode should be identical to that used for ulnar nerve stimulation to the interosseous muscle (recording electrodes unchanged) (see ulnar nerve section below). Normal values: DML to second Lumbrical—DML to interosseous ≤ 0.4 ms (Buschbacher, 2000)

Reference electrode (R): over the ulnar styloid; alternatively the reference may be placed over the volar aspect of the forearm opposite the active electrode Ground electrode (G): over the dorsal forearm, between the stimulating and recording electrodes Stimulating electrode The cathode is placed over the median nerve at the elbow, the cathode is proximal Normal values: Onset latency: 3.6 ± 0.4 ms (mean ± 1SD) (range 2.9–4.4) Amplitude: 3.2 ± 0.8 mV (mean ± 1SD) (range 2.0–5.2) (Buschbacher, 2000) Comment Side–side comparisons of the DML and CMAP may be useful in lesions of the anterior interosseous nerve (see also flexor pollicis longus above).

25.3.3.3. Flexor pollicis longus Recording electrodes Active electrode (A): on the lateral forearm over the radius, approximately 40% of the distance from the distal volar crease of the wrist to the antecubital crease of the elbow Reference electrode (R): over the tendon of flexor pollicis longus at the wrist Ground electrode (G): on the radius, between the stimulating and recording electrodes Stimulating electrode Just medial to the biceps tendon at the elbow, just proximal to the antecubital crease Normal values: Onset latency: 2.6 ± 0.43 ms (mean ± 1SD) (range 1.8–3.6), upper normal limit 4.0 ms. Amplitude: 5.6 ± 1.16 mV (mean ± 1SD) (range 3.8–7.5), lower normal limit : 2.5 mV (Craft et al., 1977) Comment Together with pronator quadratus, this muscle is useful to assess the severity of proximal lesions of the median nerve or anterior interosseous nerve.

25.3.4.1. Median sensory nerve conduction from the second and third digits (Fig. 25.9) (Orthodromic method) Recording electrodes A 4 cm bar electrode is placed over the median nerve at the wrist between the tendons of flexor carpi ulnaris and palmaris longus with the active electrode (A) 14 cm proximal to the cathode. The reference electrode (R) is proximal. Ground electrode (G): over the dorsum of the hand Stimulating electrode Recordings can be made from either the index (F2) or middle (F3) fingers. Cathode: A ring cathode is placed over the proximal interphalangeal joint Anode: A ring anode is placed over the distal interphalangeal joint Normal values: Amplitude: 41.6 ± 25uV (mean ± 1SD) (range 10–90 uV) Sensory conduction velocity: 56.9 ± 4 ms (mean ± 1SD) (range 48–64.9 ms) (DeLisa et al., 1994)) Comment Comparison of median (F2-wrist, F3-wrist) and ulnar (F5-wrist) sensory conduction velocities may be useful in carpal tunnel syndrome (Normal: ulnar sensory velocity-median sensory velocity = 10 m/s being abnormal. In carpal tunnel syndrome, the median palm-wrist segment velocities are slower than the F2- or F3-wrist velocities (normally, the palm-wrist segment being warmer, the sensory velocities would be similar or faster than the finger-wrist segment).

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25.3.5.2. Wrist-elbow segment Recording electrodes With a bar electrode with the active electrode (A) over the median nerve at the elbow, just medial to the brachial artery pulse and the reference electrode (R) 3 cm proximally Ground electrode (G): in the forearm between the stimulating and recording electrodes Stimulating electrode Over the median nerve at the wrist Normal-values: Amplitude (peak-to-peak): 32.1 ± 16.3 μV (mean ± SD) (lower limit of normal >10) Onset conduction velocity: 64.5 ± 4.3 m/s (mean ± SD) (lower limit of normal >55.9) (Oh, 1984) Comment The median mixed nerve study is useful in the localization of more proximal median nerve lesions. Where motor conduction block has been demonstrated in the forearm segment of the median nerve, a normal median mixed nerve potential would favour multifocal motor neuropathy (MMN) over CIDP, and an abnormal median mixed nerve potential would be against MMN. 25.4. Ulnar nerve 25.4.1. Anatomy The ulnar nerve is derived mainly from the C8 and T1 roots (with a variable contribution from C7), the lower trunk and medial cord. It runs through the axilla and arm on the medial side of the axillary and brachial arteries respectively, and in front of the medial head of

Fig. 25.10 Median palm-wrist segment. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

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the triceps to the ulnar groove/sulcus where it is palpable behind the medial epicondyle. About 1.5–4 cm distally, it enters the cubital tunnel between the two heads of flexor carpi ulnaris and eventually becomes superficial again at the wrist, where it lies just medial to the flexor carpi ulnaris tendon. In the mid-forearm, it releases the palmar cutaneous branch that travels into the hand (without passing through Guyon’s canal [see below]) and innervates a small patch of the skin over the proximal hypothenar eminence. This branch is rather inconstant and is often replaced by terminal ulnar sensory fibres. About 5 cm above the wrist, it gives off a dorsal cutaneous branch that supplies sensation to the dorsal aspects of the medial part of the hand and the proximal portions of the dorsum of the little and medial half of the ring fingers; rarely this nerve may arise anomalously from the superficial radial nerve. The nerve enters the hand superficial to the flexor retinaculum between the pisiform bone and the hook of the hamate (the canal of Guyon) where it divides into a superficial sensory and deep motor branch. The terminal sensory branches supply the distal hypothenar eminence and the little and medial half of the ring fingers, and the dorsal terminal portions of the same digits. In the forearm the ulnar nerve supplies first the flexor carpi ulnaris and then the ulnar half of flexor digitorum profundus. The branches to flexor carpi ulnaris usually arise within the first 10 cm below the epicondyle, but occasionally a branch to this muscle arises proximal to the medial epicondyle (Campbell et al., 1989; Stewart, 2000). In the hand the ulnar nerve supplies the adductor, flexor and opponens digiti minimi, the interossei, the third and fourth lumbricals, adductor pollicis and the (in most cases) flexor pollicis brevis. Clinical applications Ulnar nerve lesions are the second commonest upper limb entrapment/pressure neuropathy and most frequently occur either in the ulnar groove or at the cubital tunnel. Less commonly, the nerve may be com-

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promized in the hand at the canal or Guyon, or more distally by focal pressure/trauma or a ganglion. Demonstrating conduction block across the elbow on mixed nerve studies is useful in confirming mild ulnar nerve lesions at the elbow, and axonal involvement of the dorsal ulnar cutaneous nerve is helpful for localizing the lesion proximal to the wrist; it is also accessible for a biopsy if involved as part of a mononeuritis multiplex. In multifocal motor neuropathy, the ulnar nerve is useful when attempting to demonstrate proximal motor conduction block, since it is easily accessible at various segments up to the C8 root and, unlike recordings over the thenar eminence (for the median nerve) and forearm (for the radial nerve), recordings from the hypothenar eminence are generally not complicated by volume conduction from non-ulnar innervated muscles. If motor conduction block is demonstrated in the forearm, mixed nerve studies that show preservation of sensory conduction are diagnostically helpful. 25.4.2. Motor studies 25.4.2.1. Ulnar motor studies to adductor digiti minimi (Fig. 25.11) Recording electrodes Active electrode (A): over the midpoint of abductor digiti minimi Reference electrode (R): over the proximal phalanx of the fifth digit Ground electrode (G): over the dorsum of the hand Stimulating electrode (1) Wrist: the cathode is placed 8 cm from (A) just radial to the flexor carpi ulnaris tendon, the anode is proximal. (2) Below elbow: 3–5 cm distal to the ulnar groove. (3) Above elbow: 6–7 cm proximal to the ulnar groove (the distance between stimulation points below and above the elbow should not

Fig. 25.11 Ulnar motor studies to adductor digit minimi. Active recording electrode marked with a dot. Position of stimulating electrodes at proximal and distal sites marked with dots (black: cathode, white: anode).

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be less than 10 cm; measurement across the elbow is made with the elbow flexed to 70˚). (4) Axilla: over the axillary artery, in the groove between the coracobrachialis and triceps muscles (5) Erb’s point: (see above) (6) C8, T1 roots: with 6 cm bar placed horizontally over the back, 1 cm caudal to the C7 spine, with the cathode in the interspace between the C7 and T1 vertebral processes and the anode distally, using a high voltage transcutaneous stimulator (Digitimer 180, time constant of decay 0.05–0.1 ms, typically at intensity corresponding to 40–60% of the stimulator’s maximal output [1500 V]). Normal values DML to ADM: 3.0 ± 0.3 ms (mean ± 1 SD) Amplitude: 11.6 ± 2.1 mV (mean ± 1 SD) Maximum conduction velocity (MCV) (wrist-below elbow segment): 61 ± 5 m/s (mean ± 1SD) (range 53–73) MCV (across elbow segment): 62.7 ± 5.5 m/s (mean ± 1SD) (range 52–74) MCV (above-elbow-axilla): >56 m/s MCV (axilla-Erb’s point): >55 m/s (Sethi and Thompson, 1989; DeLisa et al., 1994; Buschbacher, 2000) Comment Slowing of motor conduction of >10 m/s around the elbow compared with the forearm velocity is a useful indicator of an ulnar nerve lesion at the elbow, but should not be used as the sole criterion for the diagnosis. Inching studies may be performed across the elbow to look for focal slowing or conduction block. Proximal stimulation is usually of value in suspected proximal demyelination causing focal conduction block or slowing as in focal CIDP, multifocal

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motor neuropathy with conduction block, brachial plexopathy related to hereditary neuropathy with liability to pressure palsies (HNPP), or in unusual cases of Guillain–Barré syndrome. In conjunction with magnetic stimulation of the motor cortex, it may be used instead of F-waves to separate central and peripheral conduction times. 25.4.2.2. First dorsal interosseous (1DIO) Similar ulnar motor studies can be performed recording from the first dorsal interosseous muscle. Recording electrodes Active electrode (A): over the first dorsal interosseous at the proximal edge of the muscle between the first and second carpometacarpal joints Reference electrode (R): over the metacarpophalangeal joint of the thumb or index finger Ground electrode (G): over the dorsum of the hand Stimulating electrode (As described for adductor digiti minimi) Normal values DML: mean 3.4 ms (range 2.3–4.5) Amplitude: 13 mV (range 6–24) The DML to the 1DIO should not exceed the DML to the contralateral 1DIO by >1.3 ms, and should not exceed the DML to the ipsilateral ADM by >2 ms. (Simplified from Olney and Wilbourn, 1985) Comment Comparison of the CMAPs and DMLs between the 1DIO and the ipsilateral ADM is useful in ulnar nerve lesions in the hand. 25.4.2.3. Second interosseous (palmar) (Fig. 25.12) Comparison of the DMLs of the median innervated second lumbrical and the ulnar innervated underlying

Fig. 25.12 Ulnar motor to second interosseous. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black:cathode, white:anode) for median and ulnar stimulation sites.

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interosseous muscle is a useful means of demonstrating differential median motor slowing across the wrist in carpal tunnel syndrome. Recording electrodes Active electrode (A): on the palm, slightly radial to the midpoint of the third metacarpal Reference electrode (R): over the bony prominence of the second proximal interphalangeal joint. Ground electrode (G): over dorsum of the hand Stimulating electrode Over the ulnar nerve at the wrist, at the same distance from (A) as when stimulating the median nerve to the lumbrical. Normal values DML to second Lumbrical—DML to interosseous ≤ 0.4 ms (Buschbacher, 2000) 25.4.3. Sensory studies 25.4.3.1. Ulnar sensory studies from the fifth finger [F5-wrist] (orthodromic sensory) (Fig. 25.13) Recording electrodes A 4-cm bar recording electrode is placed over the ulnar nerve at the wrist with the active electrode (A) 10–14 cm proximal to the cathode. The reference electrode (R) is proximal. The ground electrode (G) is placed over the dorsum of the hand. Stimulating electrode Ring electrodes are placed with the cathode near the fifth metacarpophalangeal joint and the anode over the distal interphalangeal joint.

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Normal values Amplitude: 13.7 ± 6.4 μV (mean ± 1SD) (lower limit of normal >5 μV) Onset conduction velocity: 60.9 ms ± 5.2 (mean ± 1SD) (lower limit of normal >50.6 ms) (Sethi and Thompson, 1989) 25.4.3.2. Ulnar palm-wrist segment (see under mixed nerve studies) 25.4.3.3. Ulnar sensory studies from the fifth finger [F5-above elbow] (orthodromic sensory) (Fig. 25.14) Recording electrodes A 4-cm bar recording electrode is placed over the ulnar nerve at the elbow with the active electrode (A) in the ulnar groove just proximal to the medial epicondyle. The reference electrode (R) is proximal. The ground electrode (G) is placed between the stimulating and recording electrodes Stimulating electrode Ring electrodes are placed with the cathode near the fifth metacarpophalangeal joint and the anode over the distal interphalangeal joint. Normal values and comment The amplitude of the F5-above elbow sensory potential is usually 30–50% that of the F5-wrist sensory potential. Comparison of the ratio of these amplitudes when the finger-wrist SNAP is of reduced amplitude, may be helpful in differentiating lower trunk/medial cord lesions (normal ratio preserved) from ulnar nerve lesions at the elbow (F5-above elbow SNAP either absent or Ⰶ30% of the distal ulnar SNAP) (Gilliatt et al., 1978).

Fig. 25.13 Ulnar sensory studies from the fifth finger (F5-wrist). Active recording electrode marked with a dot. Stimulation is via ring electrodes (black: cathode) over F5.

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Fig. 25.14 Ulnar sensory studies from the fifth finger (F5-above elbow). Active recording electrode marked with a dot. Stimulation is via ring electrodes (black: cathode) over F5.

25.4.3.4. Dorsal ulnar cutaneous nerve (antidromic sensory) (Fig. 25.15) Recording electrodes Active electrode (A): at the apex of the V between the fourth and fifth metacarpal bones or on the dorsum of the fifth metacarpal bone Reference electrode (R): on the base of the fifth digit at the level of the metacarpophalangeal joint Ground electrode (G): on the dorsum of the hand between the stimulating and r recording electrodes Stimulating electrode The cathode is placed 8–10 cm proximal to the ulnar styloid between the ulna and the tendon of the flexor carpi ulnaris (although in some cases, it may be helpful to stimulate more distally [up to 2 cm proximal to the ulnar styloid]. The anode is proximal. The forearm is pronated. The distance from the stimulating to the recording electrodes is approximately 11–12 cm. Normal values Peak latency: 2.1 ± 0.3 ms (mean ± 1SD) Amplitude: 24.2 ± 10.8 μV (mean ± 1SD) (Kim et al., 1981)

Comment This nerve is spared in ulnar nerve lesions in the hand. Isolated lesions of the nerve may occur as a result of tight wrist bands, watch straps or handcuffs, or as part of a mononeuritis multiplex. 25.5. Mixed nerve studies 25.5.1. Ulnar palm-wrist segment (Fig. 25.16) Recording electrodes A 4 cm bar electrode is placed with the active electrode (A) over the proximal wrist crease just radial to the tendon of flexor carpi ulnaris. The reference electrode (R) is proximal. Ground electrode (G): over the dorsum of the hand Stimulating electrode The cathode is placed in the mid-palm, between the fourth and fifth metacarpals 8 cm distal to (A). The anode is distal. Normal values: Onset latencies: 1.6 ± 0.2 ms (mean ± 1SD)

Fig. 25.15 Dorsal ulnar cutaneous nerve. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

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S V TAN AND NMF MURRAY Fig. 25.16 Ulnar palm-wrist segment. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

Fig. 25.17 Ulnar mixed nerve study (wrist elbow segment). Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

Acceptable difference between median and ulnar onset latencies: 0.3 ms (Buschbacher, 2000; Dumitru and Zwarts, 2002) Comment Comparison of the median and ulnar palm-wrist mixed-nerve velocities is helpful in carpal tunnel syndrome, with a median-ulnar difference of >10 ms being abnormal. In carpal tunnel syndrome, the median palm-wrist segment velocities are slower than the F2- or F3-wrist velocities (normally, the palm-wrist segment being warmer, the sensory velocities would be similar or faster than the finger-wrist segment).

Onset conduction velocity: 68.4 ± 4.6 ms (mean ± 1SD) (lower limit of normal >59.3) (Oh, 1984) Comment The ulnar mixed nerve potential is helpful in localizing proximal lesions of the ulnar nerve and, in the case of ulnar nerve entrapment at the elbow, is more sensitive than the distal ulnar sensory potentials, which will not be affected by mild purely demyelinating focal lesions at the elbow. If conduction block is demonstrated in the forearm segment of the ulnar nerve, the preservation of the ulnar mixed nerve potential would favor MMN, whereas a small mixed nerve potential would exclude MMN and favor CIDP.

25.5.2. Ulnar wrist-elbow segment (Fig. 25.17) Recording electrodes A 4-cm bar electrode is placed over the ulnar nerve at the elbow with the active electrode (A) over the ulnar groove and the reference electrode (R) proximally. The ground electrode (G) is placed in the forearm between the stimulating the recording electrodes. Stimulating electrode The ulnar nerve is stimulated at the wrist, just radial to the flexor carpi ulnaris tendon, with the cathode proximal to the anode. Normal values Amplitude: 33.2 ± 14.8 μV (mean ± 1SD) (lower limit of normal >10)

25.6. Radial nerve 25.6.1. Anatomy The radial nerve arises from the posterior cord of the brachial plexus, which is formed from the posterior divisions of the upper, middle and lower trunks (C5, C6, C7, C8, and occasionally T1). It courses down the lateral wall of the axilla on the medial side of the humerus and supplies the medial, lateral and long heads of the triceps and anconeus before traversing the spiral groove of the humerus. On the lateral side of the humerus it enters the anterior compartment of the arm immediately below the insertion of the deltoid. It then courses

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between the biceps and brachioradialis muscles supplying motor branches to brachioradialis, extensor carpi radialis longus and brevis before dividing into a deep motor branch (the posterior interosseous nerve) and a superficial sensory branch (superficial radial nerve). The posterior interosseous nerve enters the supinator muscle through the arcade of Frohse, formed by the edge of the proximal border of the superficial head of the muscle, and innervates the muscle on its way through it. It then innervates the remaining forearm and wrist extensors, terminating in the extensor indicis proprius. Two sensory branches arise above the elbow: the posterior cutaneous nerve of the arm, which arises in the axilla and supplies a small area of skin on the dorsum of the upper arm and the posterior cutaneous nerve of the forearm, which usually arises proximal to the spiral groove, accompanies the radial nerve through the groove, and supplies the lateral and dorsolateral aspect of the upper arm and forearm. The superficial radial nerve, arising proximal to the posterior interosseous nerve supplies the dorsolateral aspect of the hand and dorsal aspect of the first three digits. 25.6.2. Clinical applications Injury to the radial nerve around the midshaft of the humerus may occur due to compression of the radial nerve against the humerus in or around the spiral groove (“Saturday night palsy”) or in fractures of the humerus. Less commonly, the radial nerve may be damaged in the axilla by the incorrect use of crutches, or by dislocations of the shoulder. The posterior interosseous syndrome is an uncommon neuropathy, resulting in weakness of the finger extensors and extensor carpi ulnaris. It is often associated with fractures or dislocations of the radius because of its close anatomic relationship with the head and proximal shaft of the radius. Compression by a variety of soft tissue masses and tumours has been described, such as lipomas (most frequent), ganglia arising from the elbow joint, neurofibromas, schwannomas, chondromas, haemangiomas or, in rheumatoid arthritis, hypertrophied synovium or dislocation of the head of the radius. It may, however, develop without obvious cause or may follow strenuous use of the arm, particularly excessive pronation-supination movements of the arm. In some such cases surgical exploration has shown compression of the nerve by the fibrous edge of the arcade of Frohse, fibrous bands or an apparently tight passageway through the supinator muscle (“supinator syndrome”). In some cases, asso-

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ciated with an acute and painful onset, the possibility of an isolated posterior interosseous nerve lesion representing a form of acute brachial neuritis has been suspected, but this remains controversial and is much less common than lesions of the anterior interosseous nerve (Stewart, 2000). Radial neuropathies occur fairly frequently in patients with HNPP, with the site of the nerve damage varying from one episode to another and among patients. There is also a predilection for the radial nerve and posterior interosseous nerve in MMN; some patients having exclusively or predominantly a radial neuropathy (Stewart, 2000). 25.6.3 Motor studies 25.6.3.1. Extensor indicis proprius (Fig. 25.18) Recording electrodes Active electrode (A): over extensor indices proprius, 4–6 cm proximal to the ulnar styloid and just radial to the ulna Reference electrode (R): over the ulnar styloid Ground electrode (G): on the forearm between the stimulating and recording electrodes Stimulating electrode (1) Forearm: approximately 8 cm proximal to the ulnar styloid just ulnar to the extensor carpi ulnaris muscle. (2) Elbow/antecubital fossa: in the groove between the brachioradialis muscle and the biceps tendon, about 6 cm proximal to the lateral epicondyle of the humerus. (3) Spiral groove: just posterior and inferior to the insertion of the deltoid. (4) Axilla: just posterior to the axillary artery in the groove between the coracobrachialis and triceps muscles. (5) Erb’s point: in the supraclavicular fossa in the angle between the posterior edge of the clavicular head of the sternocleidomastoid and the clavicle; the anode is located above and medially. At this point, a pulse duration of 0.5–1.0 ms may be required to completely activate the posterior cord. Normal values Forearm to EIP: DML: 2.4 ± 0.5 (mean ± 1SD) Amplitude: 14 ± 8.8 (mean ± 1SD) Conduction velocities: Elbow to forearm: 62 ± 5.1 ms (lower limit of normal > 51.8 ms)

568

S V TAN AND NMF MURRAY Fig. 25.18 Radial motor study to extensor indices proprius. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

Axilla to elbow : 69 ± 5.6 ms (lower limit of normal > 57.8 ms) Erb’s point-elbow: 72 ± 6.3 ms (range 56–93 ms) Distance measurements for Erb’s-axilla and axillaelbow segments are made using obstetric callipers. The elbow-forearm segment is measured using a tape measure. (Trojaborg and Sindrup, 1969; Sethi, 1989; DeLisa et al., 1994). Some authors recommend examination of the radial nerve with the elbow in full extension, with stimulation in the forearm and in the radial groove, the distance between the sites being measured using a tape measure running just lateral to the biceps tendon at the elbow (Date et al., 2002). Conduction velocities at 0˚ elbow flexion (SE on EIP) Forearm-radial groove: 71.7 ± 4.7 ms (range 60.2–79.2 ms). Minimum F-wave latency: 19.8 ± 3.7 ms (Date et al., 2002) Comment Stimulation at sites more proximal than the spiral groove often results in co-stimulation of the median and ulnar nerves, making it difficult to demonstrate conduction block at these more proximal sites when recording from EIP because of volume conducted response from other forearm muscles. Care should be taken to use the minimum stimulus necessary to produce a wave form similar in appearance to that on distal stimulation. If proximal block is suspected, recording from triceps is recommended.

25.6.3.2. Extensor digitorum communis Recording electrodes Active electrode (A): over the muscle 8 cm from the stimulation point in the antecubital fossa Reference electrode (R): over the ulnar styloid

Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode At the elbow, spiral groove, axilla and Erb’s point as above. Normal values (stimulation at the elbow) DML (ms): 2.6 ± 0.44 (mean ± SD) Conduction velocity (ms): 68 ± 7 (mean ± SD) Amplitude (mV): 11.24 ± 3.5 (mean ± SD) (Young et al., 1990) Comment As for EIP above, similar precautions to avoid volume conducted potentials with proximal stimulation apply. 25.6.3.3. Brachioradialis Recording electrodes Active electrode (A): on the belly of the muscle, 3 cm distal to the elbow Reference electrode (R): over the radial styloid or thumb. Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode The cathode is a monopolar needle electrode inserted 5–6 cm proximal to the lateral epicondyle on the lateral upper arm. The anode is a subcutaneous needle electrode located 2 cm proximally. [N.B. Stimulation can also be performed in the spiral groove, axilla and Erb’s point (as described above). The authors’ preference is for the surface stimulation method]. Normal values DML (ms): 2.66 ± 0.32 (mean ± SD) (range 1.8–3.5). Upper limit of normal for side-side difference: 0.4 ms. (Buschbacher, 2000) Comment Being predominantly innervated by the C6 root, this muscle (together with extensor carpi radialis

COMMONLY TESTED NERVES IN THE SHOULDER GIRDLE AND UPPER LIMB

longus and brevis) is largely spared (unlike the other radial innervated muscles) in C7 root lesions. It is involved in ‘Saturday night palsy’ and spared in lesions of the posterior interosseous nerve. 25.6.3.4. Triceps Recording electrodes A concentric needle electrode (A and R) is placed in the long head of triceps. Ground electrode (G): is placed between the stimulating and recording electrodes. Stimulating electrode In the axilla and at Erb’s point (see above). Normal values Stimulation at Erb’s point, distance 20–30 cm: DML (ms): 4.5 ± 0.1 (Dumitru et al., 2002) Comment The triceps muscle is spared in lesions of the radial nerve at, or distal to, the spiral groove. High voltage stimulation of the roots, and recording with surface electrodes (see section on Brachial plexus) may be useful in suspected proximal block or demyelination. 25.7. Sensory 25.7.1. Superficial radial nerve sensory potential (Fig. 25.19) Recording electrodes Active electrode (A): over the superficial radial nerve where it can be palpated crossing over the tendon of extensor pollicis longus at the wrist

569

Reference electrode (R): slightly proximal to the second metacarpal head in the first web space. Ground electrode (G): between the stimulating and recording electrodes Stimulating electrode The cathode is placed on the radial side of the forearm 10 cm proximal to the active electrode. The anode is proximal. Normal values Onset latency (ms): 1.8 ± 0.3 (mean ± SD) Amplitude (uV): 31 ± 20 (mean ± SD) (range 13–60) (Mackenzie and DeLisa, 1981). The forearm segment of the superficial radial nerve can be examined by stimulation of the nerve 3 cm above the line of the cubital crease and near the lateral border of the biceps brachii tendon and recording 4–6 cm proximal to the radial styloid (Chang and Oh, 1990). Normal values: amplitude (μV) 15.2 ± 9.8 (range 5–56); velocity (ms): 53.3 ± 3.6 (range 42.2–65.3). Comment The superficial radial nerve is usually preserved till late in generalised large fibre neuropathies. Asymmetry of the radials may be a useful pointer in inflammatory or vasculitic neuropathies, and disproportionately small radials (compared with the sural SNAPs) may suggest an inflammatory neuropathy or a sensory neuronopathy. Isolated lesions may occur at the wrist where it lies close to the distal end of the radius where it may be compressed by tight bands around the wrist such as watchstraps, handcuffs, bracelets, rubber gloves or tight plaster casts. Lacerations of the nerve may occur in conjunction with a fracture of the distal radius. It may

Fig. 25.19 Superficial radial nerve sensory potential. Active recording electrode marked with a dot. Position of stimulating electrodes marked with dots (black: cathode, white: anode).

570

S V TAN AND NMF MURRAY

also be damaged by an intravenous cannula aimed at the vein that lies close to the nerve (Stewart, 2000). 25.7.2. Wrist-F1 antidromic sensory (more distal lesions) Recording electrodes Active electrode (A): a ring electrode is placed over the first metacarpophalangeal joint Reference electrode (R): a ring electrode is placed over the interphalangeal joint Ground electrode (G): over the dorsum of the hand Stimulating electrode Radial nerve: The cathode(C) is placed over the radial nerve as it is palpated on the lateral radius 10 cm proximal to the active electrode. The anode (A) is proximal. Normal values Peak latency (ms)

Mean

SD

Range

2.4

0.2

1.9–2.8

Baseline to peak

Mean

SD

amplitude (μV)

12

1

(Buschbacher, 2000) Comment This method, preferably using the contralateral hand as control, is useful in lesions of the superficial radial nerve occurring distal to the wrist. 25.7.3. Posterior cutaneous nerve of the forearm See description of method under section on Brachial Plexus above. References Alfonsi, E, Moglia, A, Sandrini, G and Pisoni, MR, Arrigo (1986) Electrophysiological study of the long thoracic nerve conduction in normal subjects. Electromyogr. Clin. Neurophysiol., 26: 63–67. Arunachalam, R, Osei-Lah, A and Mills, KR (2003) Transcutaneous cervical root stimulation in the diagnosis of multifocal motor neuropathy with conduction block. J. Neurol. Neurosurg. Psychiatry, 74: 1329–1331. Berger, AR, Busis, NA, Logigian, EL, Wierzbicka, M and Shahani, BT (1987) Cervical root stimulation in the diagnosis of radiculopathy. Neurology (Minneap.), 37: 329–332.

Buschbacher, RM (2000) Manual of Nerve Conduction Studies. Demos Medical Publishing, New York, pp. 1–281. Campbell, WW, Pridgeon, RM, Riaz, G, Astruc, J, Leahy, M and Crostic, EG (1989) Sparing of the flexor carpi ulnaris in ulnar neuropathy at the elbow. Muscle Nerve, 12: 965–967. Casazza, BA, Young, JL, Press, JP and Heinemann, AW (1998) Suprascapular nerve conduction: a comparative analysis in normal subjects. Electromyogr. Clin. Neurophysiol., 38(3): 153–160. Chang, CW and Oh, SJ (1990) Sensory nerve conduction study in forearm segment of superficial radial nerve: standardization of technique. Electromyogr. Clin. Neurophysiol., 30(6): 349–351. Craft, S, Currier, DP and Nelson, RM (1977). Motor conduction of the anterior interosseous nerve. Phys. Ther., 57: 1143–1147. Date, ES, Teraoka, JK, Chan, J, Kingery, WS (2002) Effects of elbow flexion on radial nerve motor conduction velocity. Electromyogr. Clin. Neurophysiol., 42(1): 51–56. Dawson, DM, Hallett, M and Millender, LH (1983) Entrapment Neuropathies. Little, Brown, Boston. DeLisa, JA, Lee, HJ, Baran, EM, Lai, K-S, Spielholz, N and Mackenzie, K (1994) Manual of Nerve Conduction Velocity and Clinical Neurophysiology. Lippincott Williams and Wilkins, USA, IIIrd ed., pp 1–479. Dumitru, D, Amato, AA and Zwarts, M (2002). Nerve conduction studies. In D Dumitru, AA Amato, MJ Zwarts (Eds.), Electrodiagnostic Medicine, Hanley & Belfus. Inc. Philadelphia, IInd ed., pp. 159–224. Dumitru, D and Zwarts, MJ (2002). Focal peripheral neuropathies. In D Dumitru, AA Amato, MJ Zwarts (Eds.), Electrodiagnostic Medicine. Hanley & Belfus. Inc., Philadelphia, IInd ed., pp. 1043–1126. Ferrante, MA (2004). Brachial plexopathies: classification, causes, and consequences. Muscle Nerve, 30: 547–568. Gassel, MM (1964) A test of nerve conduction to the muscles of the shoulder girdle in the diagnosis of proximal neurogenic and muscular disease. J. Neurol. Neurosurg. Psychiatry, 27: 200–205. Gilliatt, RW, Willison, RG, Dietz, V and Williams, IR (1978) Peripheral nerve conduction in patients with a cervical rib and band. Arch. Neurol., 4(2): 124–129. Harness, D and Sekeles, E (1971) The double anastomotic innervation of thenar muscles. J. Anat., 109: 461–466.

COMMONLY TESTED NERVES IN THE SHOULDER GIRDLE AND UPPER LIMB

Kim, DJ, Kalantri, A, Guha, S and Wainapel, SF (1981) Dorsal cutaneous ulnar nerve conduction. Arch. Neurol., 38: 321–322. Kimura, J and Ayyar, DR (1984) Sensory nerve conduction study in the medial antebrachial cutaneous nerve. Tohoku J. Exp. Med., 142: 461–466 Kraft, GH (1972) Axillary, musculocutaneous and suprascapular nerve latency studies. Arch. Phys. Med. Rehabil., 53: 383–387. Leibovic, SJ and Hasting, H (1992) Martin-Gruber revisited. J. Hand. Surg. (Am), 17: 47–53. Liveson, JA and Ma, DM (1992) Laboratory Reference for Clinical Neurophysiology. Oxford University Press, New York, pp. 11–12. Lo Monaco, M, Di Pasqua, PG and Tonali, P (1983) Conduction studies along the accessory, long thoracic, dorsal scapular, and thoracodorsal nerves. Acta Neurol. Scand., 68: 171–176. Ma, DM and Liveson, JA (1983) Nerve Conduction Handbook. FA Davis, Philadelphia. MacLean, IC (1980) Nerve root stimulation to evaluate conduction across the brachial and lumbosacral plexuses. Third Annual Continuing Education Course, American Association of Electromyography and Electrodiagnosis, Philadelphia, PA. Mackenzie, K and DeLisa, JA (1981) Distal sensory latency measurement of the superficial radial nerve in normal adult subjects. Arch. Phys. Med. Rehabil., 62: 31–34. Mills, KR and Murray, NMF (1986) Electrical stimulation over the human vertebral column: which neural elements are excited? Electroenceph. Clin. Neurophys., 63: 582–589. Oh, SJ (1984). Clinical Electromyography: Nerve Conduction Studies. University Park Press, Baltimore. Olney, RK and Wilbourn, AJ (1985). Ulnar nerve conduction study of the first dorsal interosseous muscle. Arch. Phys. Med. Rehabil., 66: 16–18. Prakash, KM, Leoh, TH, Dan, YF, Nurjannah, S, Tan, YE, Xu, LQ and Lo, YL (2004) Posterior antebrachial cutaneous nerve conduction studies in

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normal subjects. Clin. Neurophysiol., 115(4): 752–754. Rabben, OK (1995). Sensory nerve conduction studies in children. Age-related changes of conduction velocities. Neuropediatrics, 26(1): 26–32. Royden Jones, H, De Vivo, D, Darras, B (Eds.) (2003) Neuromuscular Disorders of Infancy, Childhood, and Adolescence. Butterworth Heinemann Health, Philadelphia, pp. 1–1323. Schmid, UD, Walker, G, Hess, CW, Schmid, J (1990) Magnetic and electrical stimulation of cervical motor roots: technique, site, and mechanisms of excitation on J. Neurol Neurosurg. Psychiatry, 53: 770–777. Seror, P (1999) Electrodiagnostic examination of the anterior interosseous nerve. Normal and pathologic data (21 cases). Electromyogr. Clin. Neurophysiol., 39(3): 183–189. Sethi, RK, and Thompson, LL (1989) The Electromyographer’s Handbook, Little, Brown and Company, Boston/Toronto, IInd ed., pp. 1–199. Spindler, HA and Felsenthal, G (1978) Sensory conduction in the musculocutaneous nerve. Arch. Phys. Med. Rehabil., 59: 20–23. Stewart, JD (2000) Focal Peripheral Neuropathies, Lippincott Williams and Wilkins, IIIrd ed., pp. 1–580. Trojaborg, W (1976) Motor and sensory conduction in the musculocutaneous nerve. J. Neurol. Neurosurg. Psychiatry., 39: 890–899 Trojaborg, W and Sindrup, GH (1969) Motor and sensory conduction in different segments of the radial nerve in normal subjects. J. Neurol. Neurosurg. Psychiatry, 32: 354. Uncini, A, Lange, DJ, Solomon ,M, Soliven, B, Meer, J and Lovelace, RE (1989) Ring finger testing in carpal tunnel syndrome: a comparative study of diagnostic utility. Muscle Nerve, 12: 735–741. Walters, RJ and Murray, NMF (2001) Transcarpal motor conduction velocity in carpal tunnel syndrome. Muscle and Nerve, 24: 966–968. Young, AW, Redmond, MD, Hemler, DE and Belandres, PV (1990) Radial motor nerve conduction studies. Arch. Phys. Med. Rehabil., 71: 399–402.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 26

Commonly tested nerves of the pelvic girdle William J. Litchy* Department of Neurology, Mayo Clinic, MN, USA

26.1. Introduction This chapter is intended to present techniques for the electrophysiologic evaluation of nerves of the pelvic girdle. The pelvic girdle is an anatomical structure composed of the sacrum joined to the two coxal (hip) bones. The pelvic girdle nerves are anatomically related to the pelvis as they traverse to their terminal branches. The following nerves will be discussed in this chapter: femoral, lateral femoral cutaneous, medial femoral cutaneous, and posterior femoral cutaneous. The evaluation of the proximal portion of nerves as they course through the pelvic girdle, with lumbo-sacral root stimulation will also be reviewed. The reader is referred to Chapter 13 for the techniques associated with the evaluation of the nerves innervating the pelvic floor. Here we shall discuss the other nerves traversing the pelvis and ending in the distal part of the lower limb. A description of the anatomy emphasizing the pertinent information required to perform the nerve conduction studies is followed by a description of the more common approaches to study the nerves is the format for this chapter. Although the nerves originate in the pelvic girdle, often making their evaluation difficult because they are relatively inaccessible, it is still important to follow the principles of nerve conduction studies in selecting nerves to be studied and the methodology used to study them. In selecting a nerve for evaluation, it should be clinically relevant and provide clinically meaningful physiological data helpful for understand the etiology of patient’s clinical symptoms. The technique employed to study the nerve must be reliable, able to truly provide information about the function of

* Correspondence to: William J Litchy MD, Consultant in Neurology, Department of Neurology, Mayo Clinic, Rochester, MN 55101, USA. E-mai address: [email protected] Tel.: +507-538-501; fax: +507-538-5036.

the nerve of interest and not confounding information resulting in difficult or inaccurate making of the acquired data. The technique must be reproducible providing the same information each time the study is performed. Reference data must be available for the technique so the clinical neurophysiologist can determine if the results are normal or abnormal. For the nerves described in this chapter the reference data available for each technique is not robust as desired. When reference data is lacking it has been the practice to compare the data of the affected side with the asymptomatic side. Although this is often necessary, reference data controlled for the relevant variables (e.g., age, height, weight) would be better. And finally, the nerve studied and the techniques used must be reasonable. Reasonable meaning the nerve can be studied safely, with the least amount of discomfort to the patient, and with a technique able to be performed by a clinical neurophysiologist or technologist. The sensory nerve studies described in this chapter, lateral femoral cutaneous nerve, medial femoral cutaneous nerve, and the posterior femoral cutaneous nerve normally have low sensory nerve action potentials. They also have variable anatomical courses and are often not associated with prominent anatomical landmarks. These nerves are cutaneous nerves, penetrating the fascia to innervate the skin at variable locations and ending at variable locations. All of these factors make the evaluation of these nerves and the interpretation on data acquired a challenge for the clinical neurophysiologist. The femoral motor nerve, while generating a large compound muscle action potential, is often injured along the intrapelvic portion of the nerve. This makes the evaluation of the nerve to obtain clinically relevant information more difficult. On the other hand, the study of the femoral nerve for neuromuscular junction disorders like myasthenia gravis and Lambert Eaton Myasthenic Syndrome is very useful. Using repetitive stimulation techniques, it is not unusual to observe the most severe pathophysiologic changes in the neuromuscular junction of this nerve. The techniques for

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repetitive stimulation will not be presented in this chapter as they are covered elsewhere. 26.2 Anatomy The detailed anatomy of the lumbosacral plexus and the nerves, the structure responsible for the formation of the nerves in the pelvic girdle, can be found in a standard anatomy text (Stewart, 2000). Knowledge of the anatomical structures and the common variations is essential for the practicing clinical neurophysiologist to perform reliable nerve conduction studies producing clinically meaningful results. The following anatomical description focuses on the pertinent information required to perform, and interpret the nerve conduction studies described in this chapter. 26.3. Lumbar plexus The lumbar plexus originates from the ventral rami of L1 through L4 roots (Fig. 26.1). These rami pass laterally through the psoas major muscle forming the lumbar plexus within the muscle before emerging. The major nerves emerging from the plexus are the T12 Subcostal n. T1

Iliohypogastric n.

T2

Ilioinguinal

Genitofemoral n.

T3

Lateral femoral cutaneous n. T4

Femoral n.

T5

Accessory obturator n. Obturator n. Lumbo-sacral trunk (Furcal n.)

Fig. 26.1 Lumbar plexus. A diagram of the lumbar plexus with posterior (black) and anterior (white) divisions.

femoral nerve and the obturator nerve. The obturator nerve is derived from the anterior division of the L2 through L4 roots, while the femoral nerve is a posterior division of the same roots. The obturator nerve innervates thigh adductor muscles. The femoral nerve descends laterally to the psoas muscle and enters the thigh under the inguinal ligament lateral to the femoral artery and vein. A common misperception of the course of the femoral nerve is that it enters the thigh deep into the inguinal ligament and is difficult to activate with surface stimulation. In most individuals, the nerve is shallow enough and can be easily activated with low current from a surface stimulator. In heavy individuals, however, this may not be true and stimulation with a needle inserted near the nerve may be more comfortable for the patient and also produce more reliable results. The terminal branches of the femoral nerve include both sensory and motor nerves. The motor nerve innervates the quadriceps femoris muscles of the thigh. The sensory branches of the femoral nerve include the anterior femoral nerve(s) of which the most medial branch is referred to as the medial femoral cutaneous nerve. These nerves penetrate the fascia in the thigh and innervate the skin of the anterior and medial thigh. Because of the variability of where these nerves become more superficial, the challenge of performing reliable and reproducible nerve conduction studies on these nerves is increased. The saphenous nerve, the final termination of the femoral nerve, extends down the medial aspect of the leg to the ankle. The lateral femoral cutaneous nerve is derived from the L2 and LS roots and emerges from the plexus just below the anterior iliac spine, coursing under the inguinal ligament to innervate the skin of the anterolateral thigh as distal as the knee. The course of this nerve is also variable and in obese people it lies deep in the subcutaneous tissue. Both of these factors contribute to the difficulty of developing reliable and reproducible nerve conduction techniques for studying this nerve. The frustration of not being able to obtain a response in asymtomatic people has resulted in this nerve not being used frequently for the evaluation of sensory abnormalities of the thigh. A frequently occurring disorder, meralgia paresthetic, is the result of injury to the lateral forearm cutaneous nerve around the site of its exit from the pelvis. A lumbar radiculopathy is often considered when a patient has these symptoms so the ability to evaluate this nerve reliably would be useful.

COMMONLY TESTED NERVES OF THE PELVIC GIRDLE

26.4. Sacral plexus The sacral plexus is formed by the joining of the lumbosacral trunk, the furcal nerve, and the ventral rami of the sacral roots S1 through S4 (Fig. 26.2). Like the lumbar plexus, the sacral plexus also divides into anterior and posterior divisions. The two divisions form the sciatic nerve and then at a widely variable distance, divides into the tibial nerve (anterior division, L4–S3) and the peroneal (common fibular) nerve (posterior division, L4–S2). Abnormalities of the proximal portion of the sciatic nerve occur. Intramuscular injections, hip fracture, compression by a muscle or a ligamentous band, can all produce a lesion of the sciatic nerve difficult assess by conventional nerve conduction studies. Because of the proximal, intrapelvic location of some lesions, root stimulation, combined with standard tibial or peroneal nerve conduction studies is useful in evaluating the more proximal portion of the sciatic nerve. Other major nerves formed by the sacral plexus include the pudendal nerve and the posterior cutaneous nerve of thigh (posterior femoral cutaneous nerve). The pudendal nerve is formed by the S2 through S4 rami. As it reaches the posterior edge of the posterior triangle it divides into its terminal bracnches: inferior rectal nerve supplying the external anal sphincter muscles, the perineal nerve innervating the

575

deep and superficial muscles of the perineum, and the dorsal nerve of the penis (clitoris). These nerves have been more thoroughly reviewed in Chapter 13. The posterior femoral cutaneous nerve arises from S2 to S3 roots. Emerging from the sacral plexus, it enters the posterior thigh medial to the sciatic nerve. This nerve gives off several small branches, innervating the skin of the buttock, the medial side of the thigh, and the perineum. The largest branch the posterior femoral cutaneous nerve runs down the posterior midline and supplies the skin of the posterior thigh often as distal as the posterior potion of the leg to the calcaneal bone. Abnormalities of this nerve are uncommon or at least infrequently recognized. Gluteal injections, prolonged bicycle riding, and compression may produce sympotoms of neuropathy including sensory changes in the posterior thigh and leg. One is unlikely to mistake this mononeruopathy for a sacral radiculopathy but this may be considered in the appropriate clinical setting. 26.5. Femoral nerve The femoral nerve enters the thigh under the inginual ligament, dividing into an anterior division, ending as cutaneous nerve and a posterior division, innervating the quadricpes muscles and forming the saphenous nerve as its termination. Most lesions of the femoral

L4

L5 Lumbosacral trunk

Superior gluteal n.

S1

Inferior gluteal n.

S2

S3 Posterior femoral cutaneous n. Peroneal n. Tibial n. Pudendal n.

S4

Fig. 26.2 Sacral plexus. A diagram of the sacral plexus with posterior (black) and anterior (white) divisions.

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WILLIAM J. LITCHY

nerve occur at, or proximal to the inguinal ligament, making it difficult to stimulate the nerve proximal to a lesion. Neoplasm can compress the nerve, hematomas like a retroperitoneal hematoma, and tumors can injure the nerve in the plexus or the nerve more distally. Blunt and sharp trauma injuries have been reported to damage the nerve at all levels. The femoral nerve can be evaluated with stimulation of the nerve distal and proximal to the inguinal ligament (Johnson et al., 1968; Echternach and Hayden 1969). Because of proximal intrapelvic lesions, root stimulation along with distal stimulation of the femoral nerve can be useful in evaluation of the nerve (Uludag et al., 2000). This nerve is excellent for evaluating patients with disorders of the neuromuscular junction, particularly Lambert Eaton Myasthenia Syndrome. The largest changes of all nerves evaluated are often noted with repetitive stimulation. When repetitive stimulation is performed on this nerve needle stimulation and immobilization of the entire lower limb will make the study more comfortable for the patient as also the results more reliable. 26.5.1. Origin: L2, L3, L4 roots, ventral rami (posterior division) 26.5.1.1. Electrode placement (Echternach and Hayden 1969) (Mayo Clinic, unpublished data) (See Table 26.1 for normal values) (See also Fig. 26.3) Active electrode (input 1): mid-way between the inguinal ligament and the upper border of the patella over the belly of the Rectus femoris muscle (14 cm distal to cathode of stimulator). Reference electrode (input 2): over the tendon of the Rectus femoris muscle just proximal to the patella. Ground electrode: proximal to the active electrode over the Rectus femoris.

(Johnson et al., 1968) Active electrode (input 1): over the center of the vastus medialis muscle. Reference electrode (input 2): over the tendon of the vastus medialis muscle just proximal to the patella. Ground electrode: between the active electrode and the stimulator cathode. 26.5.1.2. Stimulation (Echternach and Hayden 1969) (Mayo Clinic, unpublished data) Distal to the inguinal ligament lateral to the femoral artery. (Johnson et. al., 1968) Above the inguinal ligament lateral to the femoral artery. Below the inguinal ligament lateral to the femoral artery. 26.5.1.3. Errors Incorrect placement of the stimulator cathode resulting in excess current needed to stimulate the nerve. Submaximal stimulation resulting in a low compound muscle action potential (CMAP). Needle stimulation may be necessary to stimulate the nerve. Incorrect placement of the active electrode resulting in an initial positivity of the CMAP as well as a low. Variable CMAP response due to movement of the stimulator during testing. Inadequate mobilization of the lower limb resulting in movement artifact. 26.6. Lateral femoral cutaneous nerve The lateral femoral cutaneous nerve enters the thigh through a tunnel in the inguinal ligament. However, the course of this nerve is variable, passing above or below the anterior iliac spine. The course of the nerve

Table 26.1 Femoral motor nerve conduction: normal values Author Echternach (1969) Johnson (1968) Above inguinal ligament Below inguinal ligament Across inguinal ligament

N 51

Latency (ms)

Conduction velocity (m/s)

Amplitude (mV)

5.7 ± 2.6 (4.3–8.3)

69.4 ± 0.5 (57.6–91.3)

(0.2–11)

7.1 ± 0.7 (6.1–8.4) 6.0 ± 0.7 (5.5–7.5) 1.1 ± 0.4 (0.8–1.8)

(4.2 cm–6.6 cm)

100

COMMONLY TESTED NERVES OF THE PELVIC GIRDLE

577 Fig. 26.3 Femoral Motor Nerve Conduction Study. The active electrode is placed over the rectus femoris muscle and the reference electrode is placed over the muscle tendon proximal to the patella. The cathode of the stimulator is placed lateral to the femoral artery below the inguinal ligament. To stimulate the nerve more proximally, the cathode is moved above the inguinal ligament.

Active electrode

Reference electrode

in the thigh is also variable but most often it passes over the origin of the sartorius muscle. The variability is one reason evaluating this nerve can be difficult and frustrating. Injury to this nerve, often as a result of compression at the inguinal ligament or in the thigh, results in abnormal sensation in the distribution of the nerve in the lateral thigh. This is referred to as meralgia paresthetica. Blunt and sharp trauma to this nerve also produces similar symptoms. Because of the variable distribution of the branches of the lateral femoral cutaneous nerve and because it is often deeply embedded in subcutaneous tissue of heavy individuals it is difficult to evaluate. Nerve conduction studies (Butler et al., 1974; Sarala et al., 1979; Karandeas et al., 1995; Spevak and Prevec 1995; Laroy et al., 1999) as well as somatosensory evoked potentials (Cordato et al., 2004; Seror, 2004) have been used to evaluate the lateral femoral cutaneous nerve in patients with symptoms of meralgia paresthetica. In one study comparing the two techniques directly (Seror, 1999), nerve conduction studies were reported to be more reliable and useful. The results of the nerve conduction studies, especially when a response can not be obtained on an asymptomatic side as a comparison, need to be interpreted with caution.

Reference electrode (input 2): 4 cm distal to the active electrode along the line between the iliac spine and the patella. Ground electrode: between the active electrode and the stimulator cathode. (Laroy et al., 1999) (antidromic) Active electrode (input 1): 10 cm distal to stimulating cathode along a line connecting the anterior superior iliac spine and the lateral border of the patella. The nerve is located with submaximal stimulation and the response of the patient. Reference electrode (input 2): 4 cm distal to the active electrode along the line connecting the anterior superior iliac spine and the lateral border of the patella. Ground electrode: between the active electrode and the stimulator cathode. Ground electrode: between the active electrode and the stimulator cathode. Sarala et al. (1979) (Orthodromic) Active electrode (input 1): 1 cm medial to the anterior superior iliac spine. Reference electrode (input 2): 3 cm proximal to the active electrode. Ground electrode: between the active electrode and the stimulator cathode. 26.6.2. Stimulation

26.6.1. Origin: L2, L3 roots, ventral rami, dorsal divisions 26.6.1.1. Electrode placement (Butler et al., 1974) (antidromic) (See Table 26.2 for normal values) (See also Fig. 26.4) Active electrode (input 1): 16 cm distal to the anterior iliac spine along a line between the anterior iliac spine and the patella.

(Butler et al., 1974) 1.0 cm medial to the anterior iliac spine distal to the inguinal ligament (Laroy et al., 1999) 4.0 cm distal to the anterior superior iliac spine on a vertical line connecting the anterior superior iliac spine and the lateral border of the patella (Sarala et al., 1979). 11.0 to 16.0 cm distal and directly inferior to the anterior superior iliac spine.

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Table 26.2 Lateral femoral cutaneous nerve: normal values Author

N

Latency (ms) peak

Conduction velocity (m/s)

Amplitude (μV)

Butler et al. (1974) Laroy et al. (1999) Age 22–39 40–59 60–79 Sarala et al. (1979)

24

2.6 ± 0.2 (2.3–3.1)

47.9 ± 3.7 (43–55)

no average (10–25)

24 18 16 20

1.6 ± 0.2 1.7 ± 0.2 1.9 ± 0.3 –

61.5 ± 7.4 60.9 ± 7.6 53.6 ± 9.2 57.5 ± 8.6

11.7 ± 4.3 11.9 ± 5.4 7.1 ± 2.4 no average (2–10)

26.6.3. Errors Excessive shock artifact due to inadequate skin preparation. Excessive shock artifact due to excessive stimulation. Muscle artifact mistaken for a sensory nerve action potential. No response obtained because of incorrect placement of recording electrodes. No response obtained because of inadequate stimulation. 26.7. Medial femoral cutaneous nerve The medial femoral cutaneous nerve is the most medial branch of the anterior femoral cutaneous nerve. Where this nerve pierces the fascia of the thigh is variable and the course of the nerve, although on the medial aspect of the thigh, is also variable. Just like the lateral femoral cutaneous nerve, the variability of this nerve makes the electrophysiological study of this nerve a challenge. Abnormalities of this nerve branch are most often associated with an abnormality of the femoral nerve. A mononeuropathy of the medial femoral cutaneous nerve is rare and may be misconstrued as an

Active electrode

impingement of the L3 or L4 root. The nerve is one of the terminal sensory branches of the femoral nerve on the thigh. The saphenous nerve is the terminal sensory branch of the femoral nerve in the calf. 26.7.1. Origin: L2, L3, L4, dorsal primary rami, femoral nerve 26.7.1.1. Electrode placement (Lee et al., 1995) (See Table 26.3 for normal values) (See also Fig. 26.5) Active electrode (input 1): 14 cm distal to the inguinal ligament along a line from the palpable femoral pulse to the patella. Reference electrode (input 2): 4 cm distal to the active electrode along the line from the femoral artery to the patella. Ground electrode: between the active electrode and the cathode of the stimulator on the lateral thigh. 26.7.2. Stimulation (Lee et al., 1995) Cathode placed lateral to the femoral artery over the femoral nerve just distal to the inguinal ligament.

Reference electrode

Fig. 26.4 Lateral Femoral Cutaneous Nerve Conduction Study. The active electrode is placed 16 cm distal to the anterior iliac spine and the reference electrode 4 cm distal along the course of the nerve. The stimulator cathode below (and/or above) the inguinal ligament lateral to the femoral artery.

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Table 26.3 Medial femoral cutaneous nerve conduction: normal value (Lee et al., 1995) Side

N

Right

32

Left

32

Latency (ms) Onset

Peak

2.4 ± 0.2 (2.0–2.9) 2.3 ± 0.2 (1.9–2.8)

2.9 ± 0.3 (2.3–3.5) 2.9 ± 0.2 (2.5–3.2)

26.7.3. Errors Excessive shock artifact due to inadequate skin preparation. Excessive shock artifact due to poor alignment of the cathode and anode. Corrected by rotating the anode around the cathode. Low amplitude sensory nerve action potential due to inadequate stimulation. The cathode should be moved laterally/medially across the femoral triangle to locate the nerve. Low amplitude or absent sensory nerve action potential because of incorrect recording electrode placement. 26.8. Posterior femoral cutaneous nerve The posterior femoral nerve originates directly from the sacral plexus, passing anterior to the piriformis muscle and posteromedial to the sciatic nerve entering the thigh in the groove between the biceps femoris and semi-membrabousu muscles. The nerve terminates in the calf sometime as distal as the calcaneus. The posterior femoral cutaneous nerve supplies more skin than any other cutaneous nerve (Moore, 1992). Surprisingly, mononeuropathies of the posterior

Active electrode

Conduction velocity (m/s)

Amplitude (μV)

59 ± 5 (48–70)

4.8 ± 1.0 (3.8–7.9)

61 ± 5 (50–74)

4.9 ± 1.0 (3.4–7.4)

femoral cutaneous nerve are infrequent or at least not frequently reported. Iatrogenic injuries as a result of injections near the gluteal fold have been reported (Tong and Haag, 2000) as well as injury in bicycle riders. 26.8.1. Origin: S1, S2, S3, posterior rami, anterior (S2 and S3) and posterior divisions (S1 and S2) 26.8.1.1. Electrode placement Dumitru and Nelson (1990) (See Table 26.4 for normal values) (See also Fig. 26.6) Active electrode (input 1): 6 cm proximal to the mid popliteal area along a line from the gluteal fold to the popliteal fossa bisecting the posterior thigh. Reference electrode (input 2): 4 cm distal to the active electrode along the mid thigh line. Ground electrode: just proximal to the active electrode. 26.8.2. Stimulation Dumitru and Nelson (1990) Cathode place in the groove between the biceps femoris and semimembranosus muscles 12 cm proximal to the active electrode.

Reference electrode

Fig. 26.5 Medial Femoral Cutaneous Nerve Conduction Study. The active electrode is placed and the reference electrode is placed 4 cm distal along the course of the nerve. The cathode of the stimulator is placed over the femoral nerve located lateral to the femoral artery.

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Table 26.4

26.10. Lumbar plexus: root stimulation

Posterior femoral cutaneous nerve: normal values (Dumitru, 1990)

26.10.1. Electrode placement

Side

N

Left

40

Right

40

Bilateral

80

Peak latency (ms)

Amplitude (μV)

2.8 ± 0.2 (2.4–3.2) 2.8 ± 0.2 (2.3–3.3) 2.8 ± 0.2 (2.4–3.2)

6.6 ± 1.7 (4.6–12) 6.4 ± 1.5 (4.1–10) 6.5 ± 1.5 (4.4–11)

26.8.3. Errors Excessive shock artifact due to excessive stimulation. Excessive shock artifact due to inadequate skin preparation. Excessive stimulation activating the tibial and/or peroneal nerves producing a volume conducted motor response mistaken for a sensory nerve action potential. Stimulation of muscle creating an artifact mistaken for a sensory nerve action potential. No response obtained because of incorrect placement of recording electrodes. No response obtained because of inadequate stimulation.

(MacLean, 1988); Table 26.5 Active electrode (input 1): over the center of the vastus medialis muscle. Reference electrode (input 2): over the tendon of the vastus medialis muscle just proximal to the patella. Ground electrode: between the active electrode and the stimulator cathode. (MacDonell, 1992) Active electrode (input 1): over the tibialis anterior muscle 1/3 the distance between the patella and the bimalleolar line. Reference electrode (input 2): on the dorsum of the ankle at the bi-malleolar line. Ground electrode: between the active electrode and the stimulator cathode. 26.10.2. Stimulation (MacLean, 1988; MacDonell, 1992) Monopolar needle is used as the cathode. It is inserted through the skin 2–2.5 cm lateral to the spinous process of the L4 vertebral body and positioned near the periosteum of the vertebral arch overlying the L4 nerve root. The anode is a surface electrode placed in the same location on the coontralateral side.

26.9. Lumbosacral plexus: root stimulation Abnormalities of the proximal portion of a nerve, as well as abnormalities of the plexus, are difficult to evaluate using conventional nerve conduction techniques. One electrophysiological technique for assessing this portion of the nerve is direct stimulation of the nerve root(s). There are several concerns when using these techniques. Root stimulation usually requires the use of a needle inserted to the lamina of the vertebral body. However, Ogura et al. (2003) have reported a technique using transcutaneous electrical stimulation to stimulate single lumbosacral roots. The current required to maximally activate the root is more uncomfortable then more distal stimulation sites. It may be difficult to identify the root stimulated and for these studies to be clinically meaningful and reliable it is important to know that the root stimulated is the correct one.

Active electrode

Reference electrode

Fig. 26.6 Posterior Femoral Nerve Conduction Study. The active electrode is placed 6 cm proximal to the mid-popliteal area and the reference electrode 4 cm distally along the course of the nerve. The cathode is placed in the groove between the internal and external hamstring muscles 12 cm proximal to the active electrode. The stimulator should be moved laterally and medially while stimulating to locate the nerve.

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Table 26.5 Root stimulation Author

N

MacLean (1988) Lumbar Root Sacral Root MacDonell et al. (1992) Lumbar Root Sacral Root

Latency (ms)

Amplitude

3.4 ± 0.6 (2.0–4.0)^ 3.94 ± 0.7 (2.5–4.9)^ 12 14

13.54 ± 1.2* (11.4–15.9) 254 ± 2.0* (21.7–29.7)

664 ± 31** (7–100) 644 ± 19** (25–100)

^The time across the plexus with femoral or sciatic nerve conventional nerve conduction studies latencies subtracted from the absolute nerve root latencies. * The time from site of stimulation to the muscle. ** The amplitude is expressed as a percentage of the response from distal stimulation.

26.10.3. Errors Incorrect placement of the stimulator cathode (needle) requiring excess current to maximally stimulate the root. Incorrect placement of the stimulator anode. Not doing routine nerve conduction studies to evaluate the entire length of the nerve. 26.11. Sacral plexus: root stimulation 26.11.1. Electrode placement (MacLean, 1988) Active electrode (input 1): over the center of the adductor hallucis muscle. Reference electrode (input 2): over the metatarsal—phalangeal joint of the large toe. Ground electrode: between the active electrode and the stimulator cathode. (MacDonell, 1992) Active electrode (input 1): over the center of the flexor hallucis brevis muscle. Reference electrode (input 2): over the metatarsal— phalangeal joint of the large toe. Ground electrode: between the active electrode and the stimulator cathode. 26.11.2. Stimulation (MacLean, 1988; McDonell, 1992) Monopolar needle is used as the cathode. It is inserted through the skin medial and just caudal to the posterior iliac spine 2–2.5 cm lateral to the spinous process of the S1 vertebral body and positioned near the periosteum of the vertebral arch overlying the S1 nerve root.

The anode is a surface electrode placed in the same location on the contralateral side. References Butler, ET, Johnson, EW and Kaye, ZW (1974) Normal Conduction Velocity in the lateral femoral cutaneous nerve. Arch. Phys. Med. Rehabil., 55: 31–31. Cordatao, DJ, Yiannikas, C, Stroud, J, Halpern, JP, Schwartz, RS, Akbunar, M and Cook, M (2004) Evoked potentials elicited by stimulation of the lateral and anterior femroal cuntaneous nerve in meralgia paresthetica. Muscle Nerve, 29: 139–142. Dumitru, D and Nelson, MR (1990) Posterior femoral cutaneous nerve conduction. Arch. Phys. Med. Rehabil., 71: 979–982. Echternach, JL and Hayden, JB (1969) Motor nerve conduction velocities of the femoral nerve. Phys. Ther., 65: 33–35. Johnson, EW, Wood, PK and Powers, JJ (1968) Femoral nerve conduction studies. Arch. Phys. Med. Rehabil., 49: 528–531. Karandeas, N, Papatheodorou, A, Triantaphilos, I, Mavridis, M and Lygidakis, C (1995) Sensory nerve conduction studies of the less frequently examined nerves. 35: 169–173. Laroy, V, Knoops, P and Semoulin, P (1999) The lateral femoral cutaneous nerve: nerve conduction technique. J. Clin. Neuro., 16: 161–163. Lee, HJ, Bach, JR and DeLisa, JA (1995) Medial femoral cutaneous nerve conduction. Am. J. Rhys. Med. Rehabil., 74(4): 305–307. Moore, KL (1992) Clinically Oriented Anatomy. Williams and Wilkins, Philadelphia, IIIrd ed., p. 413.

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MacLean, IC (1988) Spinal nerve stimulation, In AAEM Course B: Nerve Conduction Studies—A Review. MacDonell, RAL, Cros, D and Shahani, BT (1992) Lumbosacral nerve root stimulation comparing electrical with surface magnetic coil techniques. Muscle Nerve, 15: 885–890. Ogura, T, Shikata, H, Hase, H, Mori, M, Hayashida, T, Osawa, T, Mikami, Y and Kubo, T (2003) Electrophysiological evaluation of lumbosacral single nerve roots using compound muscle action potentials. J. Spinal. Disord. Tech., 16: 487–492. Sarala, PK, Nishihara, T and Oh, SJ (1979) Meralgia paresthetica: electrophysiologic study. Arch. Phys. Med. Rehabil., 60: 30–31. Seror, P (1999) Lateral femoral cutaneous nerve conduction versus somatosensory evoked potentials

WILLIAM J. LITCHY

for electrodiagnostic of meralgia paresthetica. Am. J. Phys. Med. Rehab., 78: 313–316. Seror, P (2004) Somatosensory evoked potentials for the electrodiagnosis of meralgia paresthetica. 29: 309–312. Spevak, MK and Prevec, TS (1995) A noninvasive method of neurography in meralgia paresthetica. Muscle Nerve, 18: 601–605. Stewart, JD (2000) Focal Peripheral Neuropathies. Lippincott Williams and Wilcons, Philadelphia, IIIrd ed. Tong, HC and Haag, AJ (2000) Posterior femoral cutaneous mononeuropathy; a case report. Arch. Phys. Med. Rehabil., 81: 1117–1118. Uludag, B, Ertekin, C, Turman, AB, Demir, D and Kiylioglu, N (2000) Proximal and distal motor nerve conduction in obturator and femoral nerves. Arch. Phys. Med. Rehabil., 81: 1166–1170.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 27

Commonly tested nerves in the lower limb Daniel Larriviere* and Lawrence H. Phillips Department of Neurology, University of Virginia, VA, USA

27.1. Introduction This chapter provides the readers with some of the more common methods for testing nerves in the lower extremities. It begins with a summary of the relevant anatomy (Kimura, 2001) followed by descriptions of conduction study techniques. The methods presented here have gained general acceptance for reliability and reproducibility. Conduction techniques are listed for each nerve in an outline format. Each section begins with a brief description of the most common clinical problem encountered in association with the nerve presented. Then, the spinal root origin and peripheral course of the nerve in question is described. Next, a listing of recording, reference and ground electrode placements are provided. This is followed by directions for placment of the stimulating electrodes. For some nerves, more than one reliable technique exists. Where this is the case, the different methods, along with their normal values and references have been provided. Common errors or comments about particular aspects of the nerve in question are listed at the end. Finally, tables of normal values are provided for all studies have been outlined. Nerve conduction studies of the lower extremities are subject to several limitations. Sensory studies, valuable in the upper extremities to help distinguish between pre- and postganglionic lesions, present some unique problems in the lower extremities. Although several sensory nerves can be studied, only the sural and superficial peroneal sensory nerves are considered to be reliable for routine study. Either may be affected in lumbar plexus pathology. Studies have been performed in an attempt to determine the most reliable methods for testing the lateral femoral cutaneous and *Correspondence to: Daniel Larriviere MD, JD Box 800394 Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA. E-mail address: [email protected] Tel: +1-434-982-0293; fax: 1-434-982-1850.

saphenous sensory nerves (both derived from the lumbar plexus), and the saphenous methods are included in this chapter (methods for testing the femoral cutaneous nerves are presented in Chapter 25). However, saphenous sensory nerve action potentials (SNAPs) tend to be low amplitude or unrecordable, even in young, healthy patients. This limits their utility in routine studies. The tibial and peroneal motor nerve studies are most commonly used for evaluating sacral plexus lesions. In situations where no response can be recorded from the extensor digitorum brevis muscle in response to peroneal nerve stimulation, recordings can be made from the tibialis anterior muscle. 27.2. The lumbar plexus The anterior primary rami of spinal roots L1, L2, L3 and part of L4 unite to form the lumbar plexus within the posterior upper and middle portions of the psoas major muscle. The superior branch of the L1 anterior primary ramus terminates by dividing into the iliohypogastric and ilioinguinal nerves. These nerves supply the skin of the hypogastric area and medial thigh, respectively. The inferior branch of the L1 anterior primary ramus joins with the superior branch of the L2 primary ramus to form the genitofemoral nerve, which innervates the cremasteric muscle and skin of the scrotum or labia major. The rami from L2, L3 and L4 fuse to form anterior and posterior divisions, which then form the obturator and femoral nerves, respectively. The obturator nerve emerges from the medial aspect of the psoas muscle and exits the pelvis via the obturator canal. As it passes through the canal, it gives off an anterior branch to the adductor longus and brevis and gracilis muscles. In addition, it gives off a posterior branch to innervate the obturator externus and half of the adductor magnus muscles. The femoral nerve exits the lateral aspect of the psoas muscle to supply the iliopsoas and iliacus muscles. From

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DANIEL LARRIVIERE AND LAWRENCE H. PHILLIPS

there, it exits the pelvis under the inguinal ligament lateral to the femoral artery and vein and provides innervation to the sartorius and quadriceps muscles. The femoral nerve also gives rise to a sensory branch, the saphenous nerve, which is derived primarily from the L3 and L4 spinal roots. This nerve supplies the skin over the medial aspects of the thigh, lower leg and foot. After entering the femoral triangle, it descends medially into the sartorius muscle and thereafter gives off the infrapatellar branch, which provides sensation to the medial aspect of the knee. The saphenous nerve continues along the medial aspect of the leg below the knee and passes just anterior to the medial malleolus to supply the medial aspect of the foot. Lesions of the femoral nerve can occur with pelvic or hip fractures, pelvic or abdominal surgery, difficult deliveries, psoas abscesses, and hip replacements. Ruptured abdominal aortic aneurysms and hemorrhage into the iliacus or psoas muscle in anticoagulated patients can also give rise to a femoral neuropathy. Femoral motor and sensory nerve conduction techniques are described in Chapter 25, but saphenous sensory nerve conduction studies are detailed in this chapter. The L2 and L3 rami give rise to posterior divisions that fuse together to become the lateral femoral cutaneous nerve. This nerve travels along the lateral border of the psoas muscle and exits the pelvis under the inguinal ligament at its junction with the anterior superior iliac spine. It divides into an anterior branch that supplies the skin of the anterior and lateral surface of the thigh, as well as a posterior branch, which innervates the lateral and posterior portions of the thigh. The term meralgia paresthetica is given to an isolated neuropathy of this nerve. The nerve is usually compressed where it pierces the fascia in the upper thigh, but can be injured anywhere along its course. Common causes include tight-fitting clothes, other forms of prolonged compression (e.g., leaning against a counter), and obesity.

gluteus maximus muscle. The posterior divisions of S1 and S2, as well as the anterior divisions of S2 and S3 give rise to the posterior femoral cutaneous nerve, which supplies the skin of posterior thigh. The sciatic nerve is also derived from the sacral plexus and has two distinct components: the tibial and peroneal divisions. The tibial division is derived from fusion of the anterior divisions of L4 through S1 and the peroneal division is derived from the posterior divisions of L4 through S2. Although both of these nerves run together in a common connective tissue sheath, they remain distinct entities throughout their course in the leg. The tibial division gives off several branches in the thigh to supply most of the hamstring muscles—the long head of the biceps femoris, semitendinosus and semimembranosus. The short head of the biceps femoris is supplied by a branch of the peroneal division. This is the only muscle proximal to the knee that derives innervation from the peroneal division of the sciatic nerve. It is a useful muscle to study for localizing lesions in patients with foot drop. The sciatic nerve separates into the tibial and common peroneal nerves in the lower third of the thigh most commonly, but the level of the separation varies considerably between individuals. The tibial nerve arises in the popliteal fossa. It gives off branches to the medial and lateral heads of the gastrocnemius and soleus muscles. Thereafter, it innervates the tibialis posterior, flexor digitorum longus, and flexor hallucis longus muscles in the leg. The nerve then passes posterior to the medial malleolus under the flexor retinaculum and splits into medial and lateral plantar nerves to the forefoot, and a calcaneal nerve branch to the heel. The motor portions of the medial plantar nerve innervate the abductor hallucis, flexor digitorum brevis, and flexor hallucis brevis muscles. The sensory portion supplies the medial anterior two thirds of the sole and the plantar skin of the first three toes and medial portion of the fourth toe. The lateral plantar nerve innervates the abductor digiti minimi, flexor digiti minimi, abductor hallucis and the interosseus muscles. It provides sensory innervation to the fifth toe, the lateral half of the fourth toe, and the lateral aspect of the sole. As a branch of the sciatic nerve, the tibial nerve can be injured at several levels. These include pelvic fractures, hip dislocation, femur or tibial fractures and tumors. The tibial nerve can be entrapped in the popliteal fossa by a band connecting the gastrocnemius heads or by a tendinous arch associated with the origin of the soleus. The tarsal tunnel syndrome (TTS) is an entrapment of the tibial nerve at

27.3. The sacral plexus The sacral plexus is located on the anterior surface of the piriformis muscle and is formed from L4, L5, S1, S2 and S3 nerve roots. Axons from these roots combine and divide to form anterior and posterior divisions, which in turn give rise to four nerve trunks. The posterior divisions of L4–S1 give rise to the superior gluteal nerve. This nerve innervates the gluteus medius, gluteus minimus, and tensor fascia lata muscles. The posterior divisions of L5 through S2 give rise to the inferior gluteal nerve, which supplies the

COMMONLY TESTED NERVES IN THE LOWER LIMB

585

the ankle behind the medial malleolus, where it is covered by the flexor retinaculum. Motor studies can be performed on the tibial nerve, and both motor and sensory conduction studies can be performed on the medial and lateral plantar nerves. Techniques for studying these nerves are included in this chapter. The common peroneal nerve branches off laterally from the sciatic nerve in the popliteal fossa. From there, it courses superficially and laterally to wind around the head of the fibula. Thereafter, it gives off a sensory branch to the lateral patella, and it then divides into the superficial and deep peroneal nerves. The superficial peroneal nerve innervates the peroneus longus and brevis muscles and supplies the skin of the anterolateral aspect of the lower half of the leg and dorsum of the foot and toes. The deep peroneal nerve innervates the tibialis anterior, extensor digitorum longus, extensor hallucis longus, peroneus tertius and extensor digitorum brevis muscles. It also supplies a small area of skin between the first and second toes. An anomalous branch, the accessory deep peroneal nerve, may arise from the superficial peroneal nerve at the knee and go on to innervate the lateral portion of the extensor digitorum brevis. The peroneal nerve is particularly susceptible to trauma at the fibular head and as it passes through a fibrous arch connecting the peroneus longus and soleus muscles, just distal to the fibular head. Risk factors for peroneal neuropathies at the fibular head include habitual leg crossing, recent significant weight loss, repeated squatting, or prolonged sitting with the feet under the buttocks. The nerve can be stimulated above and below the fibular head to assess for focal lesions at the most common site of abnormality. The sural nerve arises from the medial branches of the tibial and peroneal nerves, just below the popliteal fossa. It travels between the heads of the gastrocnemius muscle, courses posterior to the lateral malleolus and terminates at the dorsum of the fifth toe. It supplies the skin over the posterolateral aspect of the distal leg and the lateral aspect of the foot. As a distal lower extremity nerve, it is often affected early in the course in sensory neuropathies. This fact, coupled with its fairly superficial location, has made it a commonly studied nerve in the evaluation of patients with possible sensory neuropathies.

occur in L5-S1 radiculopathy, lumbosacral plexopathy and sciatic neuropathy. The electrodiagnostic evaluation for tarsal tunnel syndrome includes nerve conduction studies of both the medial and lateral plantar divisions of the tibial nerve. Origin: L4, L5, S1 roots, ventral rami, sciatic nerve Electrode Placement: (Daube, 1996) (See Table 27.1 for normal values)(See also Fig. 27.1) Active electrode (input 1): 1 cm proximal and 1cm inferior to navicular prominence, over abuctor hallucis brevis muscle (AHB). Reference electrode (input 2): over metatarsal-phalangeal joint of great toe. Ground electrode: anterior to medial malleolus Stimulation: (Daube, 1996) Medial ankle, above and posterior to medial malleolus Popliteal fossa, midposterior knee over popliteal pulse. Errors: Low foot temperature, resulting in slowed CV and/or prolonged distal latency. Diagnosing conduction block when the finding is really pseudo-conduction block due to inadequate stimulation at the knee. Ankle to knee difference should be greater than 50% in order to constitute a conduction block. Submaximal stimulation of the nerve at the knee resulting in a low compound muscle action potential (CMAP) amplitude. Co-stimulation of the peroneal nerve at the knee if the stimulating electrode is too far lateral. Invalid comparison with opposite distal latency when distal distances differ.

27.4. Tibial motor nerve study

27.5. Medial and lateral plantar motor nerve study

The tibial nerve may be compressed under the flexor retinaculum at the ankle (tarsal tunnel syndrome), and abnormality in tibial motor nerve conduction can

It is useful to study of these nerves when a patient is suspected to have tibial neuropathy at the ankle. It is important to compare the results with study of the same

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Table 27.1 Normal values: tibial motor nerve (Daube, 1996)

16–65 Years

Amplitude (mV)

Conduction velocity (m/s)

Distal latency (ms)

F-latency (ms)

Range 2 S.D. Mean

4–25 4–19 10.1

40–58 41–58 49.0

3.0–6.0 3.0–5.8 4.2

41–57 41–56 48.6

nerves on the asymptomatic side, if possible. Responses may be absent in otherwise normal individuals. Origin: L4, L5, S1 roots, ventral rami, sciatic nerve, tibial nerve, medial and lateral plantar nerves. Tibial nerve divides into two branches within 1 cm of the malleolar-calcaneal axis in 90% of feet (Dellon and Mackinnon, 1984). Electrode Placement: Mayo (unpublished, 2000) (Table 27.2) Medial plantar motor nerve: Active electrode (input 1): 1 cm proximal and 1 cm inferior to navicular prominence, over AHB Lateral plantar motor nerve: Active electrode (input 1): 3 cm proximal to head of fifth metatarsal on lateral aspect of foot over ADMP. Reference electrode (input 2): placed over metatarsalphalangeal joint of first toe for medial plantar nerve and over metatarsal-phalangeal joint of fifth toe for lateral plantar nerve. Ground electrode anterior to medial malleolus Table 27.2 Normal values: medial and lateral plantar motor nerves: (Source Mayo, unpublished, 2000) 16–65 years

Amplitude (mV)

CV (m/s)

Distal latency (ms)

AHB range 2 S.D. Mean ADQP (19 cm)

4–25 4–19 10.1 1.4–15.6

40–58 41–58 49.0 41–53

3.0–6.0 3.0–5.8 4.2 4.6–7.3

Fig. 27.1 Tibial motor study.

Irani et al. (1982) (medial and lateral plantar nerves) (Table 27.3) Active electrode (input 1) (medial): 1 cm behind and below the navicular tubercle Active electrode (input 1) (lateral): over ADQP at midpoint of the fifth metatarsal Reference electrode (input 2): just proximal to the first metatarsal head for medial nerve and over the fifth metatarsal head for lateral nerve. Ground electrode: under the heel. Stimulation: Mayo (unpublished, 2000) Cathode is behind and 1–2 cm above medial malleolus Irani et al. (1982) Medial: 12 cm proximal to input 1, measured along the course of the nerve with the ankle flexed 90°. Lateral: 20 cm from input 1 measured diagonally across the sole of the foot with the ankle flexed to 90°. Note: One study describes a technique for stimulating across the tunnel. (Felsenthal et al., 1992) One study provides corrections for temperature (Fu et al., 1980) Errors: Failure to make side to side comparisons of amplitude and latency. Side-to-side comparisons invalid due to different distal distances. Low foot temperature resulting in prolonged distal latency.

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Table 27.3 Normal values: medial and lateral plantar motor nerves

Author

Tibial NCV (m/s)

Medial plantar latency (ms)

Lateral plantar latency (ms)

Distance to AHB/ADQP (cm)

Irani et al. (1982) Fu et al. (1980) Goodgold et al. (1965) Johnson and Ortiz (1966) Mayor and Atcheson (1966)

52.08 ± 5.40 54.9 ± 7.6 49.9 ± 5.1 50.89 ± 7.16 48.7 ± 3.5

4.87 ± 0.56 3.8 ± 0.5 4.4 ± 0.9 5.32 ± 0.82 5.0 ± 0.7

6.04 ± 0.71 3.9 ± 0.5 4.7 ± 1.0 5.86 ± 0.84

12/20 10/NA NA NA

27.6. Medial and lateral plantar sensory nerves This study is useful to evaluate patients who are referred for possible tarsal tunnel syndrome. The same caveats apply to this study as applied to the plantar motor study. Abnormalities in studies of these nerves may also be found as the earliest sign of lengthdependent peripheral neuropathy. Origin: L4, L5, and S1 nerve roots, sciatic nerve, tibial nerve, medial and lateral plantar nerves. Electrode Placement: (Mayo, unpublished, 2000) (Table 27.4) (Fig. 27.2) Active electrode (input 1): 1 cm proximal to the prominence of the medial malleolus over the pulse of the posterior tibial artery at the ankle, using a bar electrode. Reference electrode (input 2): 3 cm proximal to input 1 Ground electrode: On sole of foot between input 1 and the stimulator (Ponsford, 1988) (Tables 27.5 and 27.6) Active electrode (input 1): Posterior to medial malleolus over the posterior tibial artery. Reference electrode (input 2): Not mentioned Ground electrode: On dorsum of foot between stimulator and input 1 Stimulation: (Mayo, unpublished, 2000) Medial plantar: On medial edge of plantar fascia with anode immedi-

ately proximal to the metatarsal head. Cathode should be 12–14 cm from input 1. Lateral plantar: 2.5–3.0 cm lateral to site used for medial plantar stimulation. Cathode should be 14–16 cm from input 1 (Ponsford, 1988) Medial plantar: Lateral to the first metatarsal head, the anode level with the metatarsophalangeal joint. Lateral plantar: Between the fourth and fifth metatarsals, the anode level with the metatarsophalangeal joint. Advantages: Because it records more proximally, the Mayo technique will produce larger-amplitude SNAPs. These are more easily reproduced when comparing one side to the other. The Ponsford technique ensures a pure sensory nerve recording. Errors: Low response due to incorrect recording electrode position. Low amplitude or absent response because of incorrect cathode placement. Excessive shock artifact due to electrode orientation. This can be corrected by rotating the stimulator around the cathode. Incorrect distal latency due to long or short distance between cathode and input 1 electrode. Invalid comparison of opposite foot distal latencies because of different input 1-cathode distances on the two sides. Low foot temperature resulting in slowed conduction velocity and/or prolonged distal latency.

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DANIEL LARRIVIERE AND LAWRENCE H. PHILLIPS

Table 27.4 Plantar sensory nerves: normal values (Source: Mayo 2000,unpublished)

Age

Amplitude (μV)

Conduction velocity (m/s)

Medial plantar sensory nerve 20–54 19.6 ± 8.3 53.4 ± 3.3 Range (7–44) (47–60) >54 5.7 ± 3.8 Range (0–16) Lateral plantar sensory nerve 20–54 9.3 ± 3.9 53.4 ± 3.3 Range (3–19) >54 3.7 ± 2.5 3.5 ± 0.5 Range (0–12)

Peak distal latency (ms)

3.2 ± 0.3 (2.4–3.9) 3.0 ± 0.3 (2.6–3.6) 3.5 ± 0.5 (2.4–4.5) 3.5 ± 0.5 (2.8–4.7)

27.7. Peroneal motor nerve study A peroneal mononeuropathy is quite common. It occurs most often when the peroneal nerve is compressed against the fibular head. Patients commonly present with a foot drop and sensory loss on the dorsum of the foot. These same symptoms can also be

Fig. 27.2 Plantar sensory study.

seen in patients who have sciatic neuropathy, lumbosacral plexopathy or L5 radiculopathy and it is the job of the neurophysiologist to localize the lesion. Peroneal nerve lesions at the fibular head can be localized to that segment by stimulating at the knees and below the head of the fibula to demonstrate evidence of conduction block.

Table 27.5 Medial plantar sensory nerve: normal values Age

Number of nerves

10–19

14

20–29

13

30–39

16

40–49

18

50–59

11

60–69

11

70–79

10

> 80

7

Total

100

Amplitude (mV)

Peak latency (ms)

CV (m/s)

18.78 ± 4.57 (10–26) 17.85 ± 7.22 (10–30) 11.75 ± 3.73 (7–20) 9.55 ± 4.37 (5–20) 8.18 ± 3.43 (3–15) 6.01 ± 1.46 (4.0–8.0) 3.74 ± 1.51 (2.0–5.0) 3.64 ± 1.70 (2.0–7.0) 9.94 ± 3.5 (2.0–3.0)

3.29 ± 0.32 (2.5–3.7) 3.12 ± 0.24 (2.7–3.4) 3.16 ± 0.36 (2.8–3.9) 3.36 ± 0.64 (2.6–5.5) 3.62 ± 0.88 (2.8–5.2) 3.39 ± 0.40 (2.8–3.9) 4.23 ± 1.39 (2.5–6.0) 4.80 ± 1.08 (3.8–7.0) 3.62–0.66 (2.5–7.0)

49.43 ± 4.79 (41–57) 54.23 ± 4.36 (50–62) 54.12 ± 4.11 (50–64) 52.16 ± 5.10 (45–61) 52.27 ± 3.47 (48–60) 48.73 ± 5.68 (41–59) 49.40 ± 13.21 (33–65) 40.57 ± 5.76 (30–47) 50.11 ± 5.81 (30–65)

Reproduced from Ponsford, 1988 with permission from the BMJ Publishing group.

COMMONLY TESTED NERVES IN THE LOWER LIMB

589

Table 27.6 Lateral plantar sensory nerve: normal values Age

Number of nerves

10–19

14

20–29

13

30–39

16

40–49

14

50–59

10

60–69

11

70–79

10

≥ 80

7

Total

95

Amplitude (mV)

Peak latency (ms)

CV (m/s)

8.71 ± 3.91 (4.0–16) 7.53 ± 2.00 (5.0–12) 5.56 ± 2.50 (2.0–10.0) 4.32 ± 1.17 (3.0–6.0) 3.79 ± 1.71 (1.0–6.0) 1.0 + 1.48 (0–4.0) 0.55 ± 0.76 (0–2.0) 0.14 ± 0.38 (0–1.0) 3.94 ± 1.74 (0–16)

3.35 ± 0.40 (2.4–3.7) 3.21 ± 0.23 (2.8–3.5) 3.29 ± 0.36 (2.9–3.9) 3.46 ± 0.56 (2.8–5.0) 3.72 ± 0.92 (3.2–6.3) 3.73 ± 0.81 (0–4.8) 4.73 ± 2.17 (0–6.7) N/A

49.78 ± 6.21 (38–63) 53.85 ± 3.78 (50–62) 54.18 ± 4.18 (50–64) 51.57 ± 6.09 (40–61) 51.30 ± 2.87 (45–56) 47.25 ± 7.80 (0–54) 47.50 ± 13.28 (0–59) N/A

3.64 ± 0.78 (0–6.7)

50.78 ± 6.32 (0–6.7)

Reproduced from Ponsford, 1988 with permission from the BMJ Publishing group.

Origin: Posterior division of ventral rami of L4, L5, S1 and S2 nerves, lateral trunk of sciatic nerve. Electrode Placement: (Daube, 1996) (Table 27.7) (Fig. 27.3) Active electrode (input 1): Dorsal lateral foot over extensor digitorum brevis (EDB) muscle Reference electrode (input 2): Metatarsalphalangeal joint of the fifth toe Ground electrode: Proximal to lateral malleolus Stimulation: (Daube, 1996) Ankle: anterior ankle, 2–5 cm lateral to tibialis anterior tendon, 8.5 cm from G1. Below fibular head: lateral calf, 1–2 finger breadths distal to fibular head (at least 10 cm from popliteal stimulation site). Popliteal fossa: lateral popliteal fossa, adjacent to external hamstring tendons, at a distance of 10–12 cm from below-fibular head site.

Inching techniques for lesions at the fibular head have been described. (Kanakamedala and Hong, 1989). Errors: Failure to achieve supra-maximal stimulation at below-fibular head site. Excessive stimulation at popliteal fossa leading to co-stimulation of the tibial nerve. This can be detected by observing plantar flexion of the ankle in response to stimulation at the knee. Failure to recognize the presence of an accessory peroneal nerve when the CMAP amplitudes are larger in response to stimulation at the knee and fibular head sites than the amplitude in response to stimulation at the ankle. Low foot temperature resulting in slowed conduction velocity and prolonged distal latency. Initial positive deflection of the action potential due to incorrect position of input 1 electrode. Less than 10 cm between popliteal and below-fibular head sites leading to inaccurate calculation of conduction velocity of this segment.

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DANIEL LARRIVIERE AND LAWRENCE H. PHILLIPS

Table 27.7 Normal values: common and deep peroneal motor nerve studies (Daube, 1996)

Range 2 S.D. Mean

Amplitude (mV)

CV (m/s)

Distal latency (ms)

F-Wave latency (ms)

2.2–14.6 2–12 7.3

41–59 44–57 50.7

2.4–7.0 3.3–6.5 4.9

38–57 38–57 47.4

Fig. 27.3 Peroneal motor study.

Reference electrode (input 2): 4cm distal to input 1 Ground electrode: Distal to input 2 (Mayo, unpublished, 2000) (Fig. 27.4): Active electrode (input 1): Over tibialis anterior muscle 3/8 of the distance between the tibial tubercle and the lateral malleolus , immediately lateral to the tibial plateau. Reference electrode (input 2): On anterior surface of ankle at the level of the medial malleolus.

27.8. Peroneal motor nerve conduction study recording from tibialis anterior muscle This is a particularly useful technique in patients who are suspected of having a proximal lesion, with a generalized neuropathy which results in a very low amplitude or absent CMAP from the EDB muscle. Origin: Posterior division of ventral rami of L4, L5, S1 and S2 nerves, lateral trunk of sciatic nerve. Electrode Placement: Four Methods (Table 27.8): (Buschbacher, 2003): Active electrode (input 1): Junction of upper 1/3 of line between tibial tuberosity and tip of lateral malleolus.

Table 27.8 Peroneal motor study to the tibialis anterior muscle

Buschbacher Mayo Lee et al. Devi et al.

Mean Range Mean Range Mean Range Mean Avg. Range

Amplitude (mV)

Conduction velocity (m/s)

Distal latency (ms)

3.8 ± 2.0 1.1–20.1 7.8 5.1–10.6 6.2 ± 1.3 3.6–9.3

62 ± 10 30–89 65 44–82

3.6 ± 0.6 2.2–5.4 5.1 4.0–6.7 2.5 ± 0.3 2.0–3.0

66.3 ± 12.9 3.9 ± 1.2

4.7 ± 0.5 3.4–6.0

COMMONLY TESTED NERVES IN THE LOWER LIMB

Fig. 27.4 Peroneal motor study recording tibialis anterior.

Ground electrode: Proximal to input 1 electrode. Lee et al. (1997): Active electrode (input 1): 8 cm from cathode on a 45˚ angle anterior to cathode Reference electrode (input 2): Tibialis anterior tendon at ankle Ground electrode: Proximal to input 1 electrode Devi et al. (1977): Active electrode (input 1): Junction of upper 1/3 of line between tibial tuberosity and tip of lateral malleolus. Reference electrode (input 2): 4 cm distal to input 1 Ground electrode: Distal to input 2 Stimulation: (Buschbacher, 2003) Proximal: 10 cm proximal to belowfibular head site, slightly medial to biceps femoris tendon. Distal: posterior and inferior to fibular head (Mayo, unpublished, 2000) Below the fibular head: over the lateral calf, 1–2 fingerbreadths inferior to fibular head. Popliteal fossa: lateral popliteal fossa, adjacent to external hamstring tendons, 10–12 cm from below fibular head site. (Lee et al., 1997) Posterior-lateral aspect of fibular neck. (Devi et al., 1977) Proximal: midpatella, just inside lateral border of popliteal space

591

Distal: 10 cm from proximal site Advantages: The Mayo technique produces larger (and more easily reproducible) CMAPs, has a narrower range of normal, and is easier to use. Errors: Failure to achieve supramaximal stimulation at below-fibular head site. Excessive stimulation at popliteal fossa site, leading to co-stimulation of the tibial nerve. This can be detected by observing plantar flexion of the ankle in response to stimulation at the knee. 27.9. Superficial peroneal sensory nerve Study of this nerve will produce normal responses when there is a purely demyelinating lesion of the peroneal nerve at the fibular head, and thus it is an important part of any study in a patient with a foot drop. Origin: L5 root, originating below fibular head as a branch of the common peroneal nerve. Electrode Placement: 4 methods (Table 27.9): (Oh et al., 2001) Antidromic (reverse /input 1 and 2 electrodes for orthodromic conduction study) Active electrode (input 1): 10 cm on a line from stimulation site to midportion of great toe, or to interdigital spaces of other toes, depending upon which branch is studied. Reference electrode (input 2): Not mentioned Ground electrode: Not mentioned (Mayo, unpublished, 2000) (Fig. 27.5): Active electrode (input 1): 3 cm proximal to the midpoint between lateral malleolus and tibialis anterior tendon along the bimalleolar line. Reference electrode (input 2): 3.5–4.0 cm distal to the input 1 electrode Ground electrode: proximal to input 1 (Levin et al., 1986) See Mayo, supra

592

DANIEL LARRIVIERE AND LAWRENCE H. PHILLIPS

Table 27.9 Normal values, superficial peroneal sensory nerve, intermediate dorsal cutaneous branch

Oh Mayo Levin Izzo Jabre

Mean Mean ± SD Range Mean Range Mean Range Mean ± SD

Amplitude (μV)

Peak latency (ms)

Conduction velocity (m/s)

9.99 13.6 ± 9.1 0–45 13.8 0–45 15.1 4–40 20.5 ± 6.1

3.08 3.4 ± 0.3 2.9–4.0 3.4 2.9–4.0 3.4 2.8–4.6 2.9 ± 0.3

43.13 N/A

(Izzo et al., 1981) Active electrode (input 1): Placed over the medial and intermediate dorsal cutaneous branches after palpation of nerves. Reference electrode (input 2): 3 cm distal to input 1 Ground electrode: Proximal to input 1 (Jabre, 1981) Active electrode (input 1): one fingerbreadth medial to the lateral malleolus. Reference electrode (input 2): 3 cm proximal to input 1 Ground electrode: Proximal to input 2 Stimulation: 4 methods: (Oh et al., 2001) Midpoint between medial and lateral malleolus for the medial dorsal cutaneous nerve and a point one quarter of the distance from the lateral to the

N/A 51.3 38.8–63.6 65.7 ± 3.7

medial malleolus for the intermediate dorsal cutaneous nerve. (Mayo, unpublished, 2000) 14 cm proximal to input 1 (Levin et al., 1986): See Mayo, supra. Izzo et al. (1981) 14 cm proximal to input 1 on anterolateral aspect of the leg. (Jabre, 1981) Anterior edge of fibula, 12 cm from input 1, and 8–9 cm more proximal calculation of nerve conduction velocity. Advantages: Either the Mayo or Jabre techniques will provide the clinical neurophysiologist with larger SNAPs since the nerve is being recorded more proximally. The disadvantage with either technique is the risk of co-stimulation of the motor nerve. Errors: Activation of motor fibers to EDB by stimulation of the deep peroneal nerve. Excessively cool leg and foot temperatures Excess shock artifact due to stimulating electrode orientation. 27.10. Sural sensory nerve

Fig. 27.5 Superficial peroneal nerve study.

This nerve is affected relatively early in most lengthdependent peripheral neuropathies. This fact, coupled with its superficial, distal location, makes it an excellent nerve to study to find early evidence for peripheral neuropathy. In addition, the demonstration of a normal value reduces the likely presence of a postganglionic sacral plexus lesion.

COMMONLY TESTED NERVES IN THE LOWER LIMB

593

Origin: L5–S1 nerve roots, sciatic nerve, tibial and peroneal nerves, medial and lateral sural cutaneous nerves, sural sensory nerve. Electrode Placement: (Killian and Foreman, 2001): Dorsal cutaneous branch (Table 27.10) Active electrode (input 1): Bar electrode placed at origin of digits 4 and 5 with input 1 proximal to input 2 Reference electrode (input 2): At origin of digits 4 and 5 Ground electrode: Dorsum of foot between stimulation point and input 1 (Mayo, unpublished, 2000): Antidromic (Table 27.11) (Fig. 27.6) Active electrode (input 1): Immediately behind lateral malleolus Reference electrode (input 2): 4.0 cm distal to input 1 along the course of the nerve Ground electrode: Proximal to input 1 (Lee et al., 1992): Dorsal cutaneous branch (Table 27.12) Active electrode (input 1): Dorsolateral surface at midpoint of fifth metatarsal just

lateral to EDB tendon of fifth toe Reference electrode (input 2): Distal to active electrode Ground electrode: Dorsum of foot between cathode and input 1 Stimulation: (Killian and Foreman, 2001): Dorsal cutaneous branch Posterior to lateral malleolus (Mayo, unpublished, 2000) On posterior surface of leg, 1–3 cm lateral of the midline Point A: 7 cm proximal to input 1 Point B: 14 cm proximal to input 1 Point C: 21 cm proximal to input 1 (Lee et al., 1992) 12 cm proximal to input 1 posterior to lateral malleolus Advantages: The proximal stimulation called for in the Mayo technique will produce larger and more easily-reproducible SNAPs. Errors: Failure to rotate anode off the nerve to reduce shock artifact Insufficient pressure when leg is fat or edematous. Low foot temperature resulting in slowed NCV and/or prolonged distal latency. Recording CMAP instead of sural SNAP. Comments: Calculate conduction velocity between points A and C (Mayo, unpublished, 2000).

Table 27.10 Dorsal cutaneous sensory nerve branch: normal values Age (years)

N

Distal latency (ms)

Amplitude (μV)

Conduction velocity (m/s)

< 46

19

4.0 (3.4–4.5) 4.0 (3.5–4.7) 3.9 (3.2–4.6) 4.0 (3.7–4.5) 3.9 4.0 (3.2–4.7)

7.8 (5–15) 9.5 (7–14) 10.0 (7–13) 10.7 (10–13) 10.0 8.9 (5–15)

34.8 (31–41) 35.1 (30–40) 36.1 (30–44) 36.1 (31–38) 35.9 34.8 (30–44)

46–55

6

56–65

6

65–75

6

>75 Mean (range)

1

Reproduced from Kiilian and Foreman, 2001 with permission from John Wiley & Sons Inc.

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Table 27.11 Sural sensory normal values (Mayo, unpublished, 2000): 20–40 years

20–40 years Point B (14cm) Point A-C Point A (7cm) 40–60 years Point B (14cm) Over 60 years Point B (14cm)

Amplitude (μv)

Peak latency (ms)

Conduction velocity (m/s)

Range Mean Range Mean Range Mean

6–47 19 N/A

3.2–4.0 3.7 N/A

N/A N/A 43–59 50

15–62 30

1.4–1.7 N/A

Range Mean

6–25 12

3.2–4.4 3.8

Range Mean

0–11 6.2

3.3–4.4 3.8

When performing a dorsal cutaneous nerve study, averaging may be necessary. Dorsal sural nerve studies may be a sensitive marker for mild or early peripheral neuropathy. Sural to radial amplitude ratio may serve as a sensitive, age-independent measure of early polyneuropathy (Rutkove et al., 1997). 27.11. Saphenous sensory nerve This nerve is the distal cutaneous sensory branch of the femoral nerve. Study of this nerve can be useful in the evaluation of possible upper lumbar radiculopathies and lumbar plexus lesions. Origin: L2–L4, posterior rami, femoral nerve, posterior division of femoral nerve, saphenous nerve.

Electrode Placement: (Mayo unpublished, 2000): Antidromic (Table 27.13) (Fig. 27.7) Distal Method Active electrode (input 1): Immediately anterior to anterior border of medial malleolus, between medial malleolus and medial border of tibialis anterior tendon. Reference electrode (input 2): 3.5–4.0 cm distal to input 1 electrode Proximal Method Active electrode (input 1): bipolar surface electrode

Table 27.12 Lateral dorsal cutaneous branch of sural sensory nerve: normal values

N

Peak latency (ms)

Conduction velocity Amplitude (m/s) (μv)

12 cm 40 Range 3.0–4.9 24–36 Mean ± SD 3.9 ± 0.5 30.7 ± 3.7 Fig. 27.6 Sural sensory study.

3.0–11.0 5.8 ± 2.1

Reproduced from Lee et al., 1992 with permission from Lippincott Williams & Wilkins.

COMMONLY TESTED NERVES IN THE LOWER LIMB

595

Table 27.13 Saphenous sensory nerve: normal values. (Source Mayo unpublished, 2000 (From Kimura et al., 1983))

Distal Method

Proximal Method

N

Mean age

Peak latency (ms)

Amplitude (μV)

40

42.2 (19–79)

2.9 ± 0.3

10.7 ± 4.3

N

Mean age

Onset latency (ms)

Amplitude (μV)

28

35 (20–56)

2.5 ± 0.19 (2.2–2.8)

10.23 ± 2.05 (7.0–5.0)

strapped to leg on medial border of tibia 14 cm distal to stimulation site. Reference electrode (input 2): 3.5–4.0 cm distal to input 1 electrode Ground electrode: surface electrode between input 1 and cathode (Wainapel et al., 1978): Antidromic (Table 27.14) Active electrode (input 1): 3 cm proximal to highest prominence of the

Fig. 27.7 Saphenous sensory study.

medial malleolus, on a line halfway between the medial malleolus and the tibialis anterior tendon. Reference electrode (input 2): 3 cm distal to input 1 electrode Ground electrode: between input 1 and stimulation point. (Ertekin, 1969): Orthodromic (Table 27.15) Active electrode (input 1): Concentric needle electrode

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DANIEL LARRIVIERE AND LAWRENCE H. PHILLIPS

Table 27.14

mius muscleand the tibia. Cathode is distal. Proximal method: Cathode distal, on medial side of slightly flexed knee between gracilis and sartorius tendons about 1.0 cm above inferior border of patella. (Wainapel et al., 1978) 14 cm proximal to input 1, with cathode pressed firmly between medial gastrocnemius muscle and medial border of tibia. (Ertekin, 1969) Medial aspect of the knee Immediately proximal to the medial malleolus Advantages: The Ertekin method is more likely to produce larger SNAPs. The disadvantage of the technique is that it mandates the use of needle electrodes. Errors: Failure to compare one leg to the other. Failure to press the stimulating electrode firmly enough. Limb temperature not maintained or unequal between limbs.

Saphenous sensory nerve: normal values

N

Conduction velocity (m/s)

Latency (ms)

Amplitude (μV)

40

41.7 ± 3.4

3.6 ± 0.4

9.0 ± 3.4

Reproduced from Wainapel, 1978 with permission from Elsevier.

placed 0.5–1.5 cm lateral to the maximal pulse of the femoral artery Reference electrode (input 2): 1.5–3.0 cm lateral to input 1 electrode Ground electrode: surface electrode between and input 2 electrode Stimulation: (Mayo unpublished, 2000) Distal method: 10 cm proximal to input 1 electrode along medial border of the tibia, pushing electrodes between medial head of gastrocneTable 27.15 Saphenous sensory nerve: normal values

Knee-inguinal ligament Knee-inguinal ligament Knee-inguinal ligament Ankle-knee Ankle-inguinal ligament

Age

Mean age

Nerves examined

Conduction velocity (m/s)

Amplitude (μV)

Distance (cm)

17–38

26

33

59.6 ± 2.3

4.2 ± 1.8

42.2 ± 2.3

41–63

51

20

57.1 ± 2.3

3.6 ± 2.4

41.4 ± 3.1

17–36

25

10

59.4 ± 2.8

4.8 ± 2.4

42 ± 1.2

17–36 17–36

25 25

10 10

52.3 ± 2.3 56.6 ± 2.0

26.6 ± 3.8 68.8 ± 3.8

Reproduced from Ertekin, 1969 with permission from the BMJ Publishing group.

References Buschbacher, RM (2003) Reference values for peroneal motor conduction to the tibialis anterior and for peroneal vs. tibial latencies. Am. J. Phys. Med. Rehabil., 82: 296–301.

Daube, J (1996) Compound muscle action potentials. In J Daube (Ed.), Clinical Neurophysiology. F.A. Davis, Philadelphia, pp. 199–234. Dellon, AL and Mackinnon, SE (1984) Tibial nerve branching in the tarsal tunnel. Arch. Neurol., 41: 645–646.

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Devi, S, Lovelace, RE and Duarte, N (1977) Proximal peroneal nerve conduction velocity: recording from anterior tibial and peroneus brevis muscles. Ann. Neurol., 2: 116–119. Ertekin, C (1969) Saphenous nerve conduction in man. J. Neurol. Neurosurg. Psychiatry, 32: 530–540. Felsenthal, G, Butler, DH and Shear, MS (1992) Across-tarsal-tunnel motor-nerve conduction technique. Arch. Phys. Med. Rehabil., 73: 64–69. Fu, R, DeLisa, J and Kraft, G (1980) Motor nerve latencies through the tarsal tunnel in normal adult subjects: standard determinations corrected for temperature and distance. Arch. Phys. Med. Rehabil., 61: 243–248. Goodgold, J, Kopell, HP and Spielholz, NI (1965) The tarsal tunnel syndrome: objective diagnostic criteria. N. Engl. J. Med., 273: 742–745. Irani, KD, Grabois, M and Harvey, SC (1982) Standardized technique for diagnosis of tarsal tunnel syndrome. Am. J. Phys. Med., 61: 26–31. Izzo, KL, et al. (1981) Sensory conduction studies of the branches of the superficial peroneal nerve. Arch. Phys. Med. Rehabil., 62: 24–27. Jabre, JF (1981) The superficial peroneal sensory nerve revisited. Arch. Neurol., 38: 666–667. Johnson, E and Ortiz, P (1966) Electrodiagnosis of tarsal tunnel syndrome. Arch. Phys. Med. Rehabil., 47: 776–780. Kanakamedala, RV and Hong, CZ (1989) Peroneal nerve entrapment at the knee localized by short segment stimulation. Am. J. Phys. Med. Rehabil., 68: 116–122. Killian, JM and Foreman, PJ (2001) Clinical utility of dorsal sural nerve conduction studies. Muscle Nerve, 24: 817–820.

Kimura, I, Ayyar, DR and McVeety, JC (1983) Saphenous nerve conduction in healthy subjects. Tohoku J. Exp. Med., 140, 67–71. Kimura, J (2001) Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice, Oxford University Press, New York, IIIrd ed., 991 pp. Lee, HJ, Bach, JR and DeLisa, JA (1992) Lateral dorsal cutaneous branch of the sural nerve: standardization in nerve conduction study. Am. J. Phys. Med. Rehabil., 71: 318–320. Lee, HJ, Bach, JR and DeLisa, JA (1997) Peroneal nerve motor conduction to the proximal muscles: an alternative approach to conventional methods. Am. J. Phys. Med. Rehabil., 76: 197–199. Levin, KH, Stevens, JC and Daube, JR (1986) Superficial peroneal nerve conduction studies for electromyographic diagnosis. Muscle Nerve, 9: 322–326. Mayor, H and Atcheson, JB (1966) Posterior tibial nerve conduction: velocity of sensory and motor fibers. Arch. Neurol., 14: 661–669. Oh, SJ, Demirci, M, Dajani, B, Melo, AC and Claussen, GC (2001) Distal sensory nerve conduction of the superficial peroneal nerve: new method and its clinical application. Muscle Nerve, 24: 689–694. Ponsford, SN (1988) Sensory conduction in medial and lateral plantar nerves. J. Neurol. Neurosurg. Psychiatry, 51, 188–191. Rutkove, SB, Kothari, MJ, Raynor, EM, Levy, ML, Fadic, R and Nardin, RA (1997) Sural/radial amplitude ratio in the diagnosis of mild axonal polyneuropathy. Muscle Nerve, 20: 1236–1241. Wainapel, SF, Kim, DJ and Ebel, A (1978) Conduction studies of the saphenous nerve in healthy subjects. Arch. Phys. Med. Rehabil., 59: 316–319.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 28

Cervical and thoracic radiculopathies Elaine S. Datea,* and Byung Jo Kimb a

Department of Orthopedic Surgery, Stanford University Medical Center, CA, USA b Department of Neurology, Korea University Medical Center, Seoul, Korea

28.1. Cervical radiculopathies

brachial plexus, which is composed of spinal roots C5-T1.

28.1.1. Introduction The lifetime prevalence of spinal pain has been reported as 65–80% in the neck and low back (Bovim et al., 1994; Cote et al., 1998; Linton et al., 1998). Lintone et al. (1998) have reported a 44% prevalence of cervical region pain in the general population. Some authors have reported that the prevalence of neck pain is the same or even higher than low back pain (Ylinen and Ruuska, 1994; Hellsing and Bryngelsson, 2000). Cervical radiculopathy is among the most common causes of neck pain. A thorough history, physical examination, and testing that includes electrodiagnostic examination and imaging studies may distinguish radiculopathy from other pain sources (e.g., soft tissue pathology). Differential diagnoses for neck, shoulder, and arm pain are given in Table 28.1. 28.1.2. Anatomy The eights pairs of cervical nerves are attached to the spinal cord by dorsal and ventral roots. The first cervical root exits the neural foramen between the occiput and atlas. All cervical roots except C8 exit via the neural foramen above correspondingly numbered cervical vertebrae. The eighth cervical root exits between the C7 and T1 vertebrae. The ventral rami of C1 through C4 innervate the muscles of head and neck while C5 through C8 supply the upper extremity through the

*Correspondence to: Elaine S. Date, MD, Associate Professor and Division Head, Division of Physical Medicine & Rehabilitation, Department of Orthopedic Surgery, Stanford University Medical Center, 300 Pasteur Dr., R105B, Stanford, 94305, CA, USA. E-mail address: [email protected].

28.1.3. Clinical symptoms and signs Classic symptoms of cervical radiculopathy include pain and tingling in the neck and/or upper extremity, numbness, and eventually weakness. In rare cases, cervical radiculopathy may present as shoulder pain and may be misdiagnosed as shoulder impingement syndrome (Date and Gray, 1996). Potential causes of cervical radiculopathy are listed in Table 28.2. Degenerative spine disease causing narrowing of the neuroforamen and radicular compression (e.g., disc herniation and spondylosis) is the most common cause. An epidemiological study (Radhakrishnan et al., 1994) showed that 68.4% of cases were related to spondylosis, disc herniation or both. In 21.9% of the cases, disc protrusion was confirmed. A C7 nerve root monoradiculopathy is typically involved, followed by C6, C8 and C5, in descending order. Neurological findings may include weakness on manual muscle testing, decreased sensation in dermatomal distributions, and diminished or absent muscle stretch reflexes (biceps—C5, brachioradialis—C6, triceps— C7). Spurling’s test (Spurling and Scoville, 1944), involving lateral neck bending and extension while applying pressure to the spine, is not particularly sensitive, but specific for cervical radiculopathy diagnosed by electromyography (EMG) (Tong et al., 2002). Wainner et al. (2003) found that upper limb tension testing (utilizing scapular depression, shoulder abduction, forearm supination, wrist and finger extension, shoulder lateral rotation, elbow extension, and neck contralateral and ipsilateral side bending) was useful in ruling out cervical radiculopathy. Evaluation of potential radiculopathy is one of the most common referrals to the electrodiagnostic laboratory. Lauder et al. (2000) showed that medical history and physical examination may not accurately

602 Table 28.1 Differential diagnoses for neck and shoulder pain Neurological Cervical myelopathy Cervical radiculopathy Thoracic outlet syndrome Diabetic amyotrophy Peripheral neuropathy Peripheral nerve entrapment Brachial plexopathy Musculoskeletal/Rheumatologic Shoulder impingement syndrome Rotator cuff tear Adhesive capsulitis Osteoarthritis Shoulder instability Osteoid tumor Polymyalgia rheumatica Polymyositis Reflex sympathetic dystrophy Pancoast tumor Other Spine Cervical degenerative disc disease Spinal tumor Vascular Deep vein thrombosis Peripheral vascular disease

Table 28.2 Etiologies for cervical radiculopathy Degenerative Cervical disc herniation Cervical spondylosis Traumatic Infection Osteomyelitis Epidural or Paravertebral abscess Herpes zoster Neoplastic Amyloidosis

predict electrodiagnostic outcome. In a study of 183 subjects with suspected radiculopathy, almost 50% of patients with normal physical examination showed abnormal EMG results. Electrodiagnosis can help distinguish cervical radiculopathy from other neck and shoulder pain etiology (Hunt and Miller, 1986; Manifold and McCann, 1999). Determining the involved spinal nerve root levels and correlating those

E.S. DATE AND B.J. KIM

levels with current symptoms are paramount in evaluating radiculopathy and planning future treatment. Electrodiagnostic findings in cervical radiculopathies are discussed below. 28.1.4. Needle examination Needle EMG is the most important, sensitive, and specific component of electrodiagnostic examination for axonal loss radiculopathy (Levin, 2002). Sufficiently severe nerve root lesions may cause axonal loss, detected as abnormal spontaneous activity in involved musculature innervated by the nerve root (Wilbourn and Aminoff, 1988). There are limitations to needle studies, as abnormalities occur only when there is sufficient injury to produce motor axon loss and/or conduction block. The lesion level is determined by the abnormal findings in a specific myotomal pattern. It is important to study muscles from different peripheral nerve innervations and establish that proximal and distal muscles are both affected so that a diagnosis of peripheral polyneuropathy may be excluded. American Association of Electrodiagnostic Medicine (AAEM) guidelines suggest that a “minimum evaluation for a radiculopathy should include needle EMG examination of a sufficient number of muscles to adequately screen each major myotome in the symptomatic limb (AAEM, 1999).” The guidelines also suggest bilateral studies to rule out spinal stenosis or bilateral radiculopathies. It is rare to have abnormal findings in the entire myotome, due to: (1) individual variations in muscle innervation; (2) incomplete root compromise; and (3) re-innervation of the more proximal muscles prior to EMG (Wilbourn and Aminoff, 1988). In a retrospective study of 175 patients screened for cervical radiculopathy, Lauder and Dillingham (1996) concluded that a seven-muscle screen, including paraspinal muscles, provided optimal EMG examination for cervical radiculopathy. The seven-muscle screen, including paraspinals, identified 93–98% of electrodiagnostically confirmable cervical radiculopathies. Examining additional muscles did not substantially improve results. In a later prospective multicenter study, Dillingham et al. (2001) recommended a six-muscle screen including paraspinals. Using this approach, 94–99% of cervical radiculopathies were identified. Table 28.3 outlines needle EMG screens suggested for nonspecific arm symptoms (Dumitru and Zwarts, 2002; Levin, 2002). Paraspinal EMG can help distinguish radiculopathy and plexopathy (Aminoff, 2002), since paraspinals

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603

Table 28.3 Screening needle EMG examination for putative cervical radiculopathy Muscle

Root level

Levin’s suggestion

Dumitru’s suggestion

Cervical paraspinal muscles Deltoid Biceps Triceps Extensor carpi radialis Flexor carpi radialis Pronator teres Flexor pollicis longus Extensor indicis proprius Thenar muscles First dorsal interossei Hypothenar muscles

C4–T2 C5–6 C5–6 C6–7 C6–8 C6–8 C6–7 C8 C8 C8–T1 C8–T1 C8–T1

O O O O × × O O O × O ×

O O O O O O O × × O O O

Dumitru, D and Zwarts, MJ (2002) Radiculopathies. In: D Dumitru , AA Amato , MJ Zwarts, (Eds.), Electrodiagnostic medicine, Hanley and Belfus, Philadelphia, IInd ed., pp 713–776; and Levin, KH (2002) Electrodiagnostic approach to the patient with suspected radiculopathy. Neurol. Clin., 20(2): 397–421.

are supplied by the dorsal primary rami proximal to the dorsal root ganglion. Care should be taken to study the deep paraspinal layers, which have the highest specificity (Gough and Koepke, 1966). Czerny and Lawrence (1996) showed that of 49 patients diagnosed with cervical radiculopathy, 20 (40.8%) had only paraspinal muscle abnormalities, 5 (10.2%) had only limb abnormalities, and 24 (49.0%) had both paraspinal and limb muscle abnormalities. In a study of surgical and EMG localization of cervical radiculopathies, Levin et al. (1996) reported that 22 of 50 subjects (44%) with cervical radiculopathies showed fibrillations or positive sharp waves in the paraspinal muscles. Dillingham et al. (2001) recommended including paraspinals in cervical screening, since abnormal findings (e.g., positive sharp waves, fibrillations, and complex repetitive discharges) increase radiculopathy detection. Studying six muscles, including paraspinals, yielded high recognition rates for cervical radiculopathy. When paraspinals were not included, as in cases of previous neck surgery, eight distal limb muscles identified 92–95% of cervical radiculopathies. Caution should be taken in attributing radiculopathy as the etiology of neck pain when EMG cervical paraspinal abnormalities are the only positive findings. In the authors’ experience, cervical paraspinal EMG can reveal abnormal spontaneous activity in normal asymptomatic subjects. Similar findings have been previously reported for lumbar paraspinal EMG

(Date et al., 1996; Nardin et al., 1998). Additionally, pacemaker artifact may be recorded and confused with spontaneous activity at lower cervical paraspinal needle EMG. The regularity, frequency, and its correlation with the peripheral pulse can help to differentiate this artifact from abnormal spontaneous activity. It is widely believed that abnormal spontaneous activity in the paraspinals may be detected within 7–10 days of injury, with spontaneous activity occurring in limb muscles after 3–6 weeks (Levin et al., 1996). Re-innervation is thought to progress distally, occurring first in the paraspinals after 6–9 weeks, progressing to proximal limb muscles (2–5 months) and finally to distal muscles (3–7 months) (Eisen, 1985). However, a wide range of spontaneous activity findings in cervical paraspinals and varied symptom duration has been reported (Dillingham et al., 1998). The mean duration of symptoms was 17.2 weeks in patients with abnormal cervical paraspinal findings. In a prospective multicenter study, Pezzin et al. (1999) found no correlation between symptom duration and spontaneous activity in the paraspinals and eight of the nine upper limb muscles. Although the authors caution against interpreting electrodiagnostic findings based on symptom duration, the evolution of EMG findings may generally correlate the time after injury and the severity of axonal damage. The earliest finding after root injury is reduced recruitment before spontaneous activity, including fibrillation potentials. With re-innervation, the motor-unit potential becomes

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polyphasic and unstable in a few weeks. Polyphasic, unstable motor-unit potentials remain as denervation continues. After the completion of axonal destruction, large, stable motor-unit potentials develop. While a relatively mild, persistent motor-unit potential develops in proximal muscles, more prominent changes occur in distal muscles as residual of radiculopathy. Persistent fibrillation potentials in distal muscles can be observed years after axonal damage when severe radiculopathy destroys so many axons that full reinnervation is not possible. Table 28.4 outlines electrodiagnostic findings relative to the time after injury. 28.1.5. Sensory nerve conduction studies Peripheral sensory nerve studies are usually unaffected by lesions proximal to the dorsal root ganglion (Benecke and Conrad, 1980). In addition, acute early radiculopathy is usually presents as pain and altered sensory perception, primarily due to involvement of C-type sensory fiber. The relatively small size of these fibers precludes routine electrodiagnosis techniques. However, in cases of intraspinal lesion extending into the neuroforamen (e.g., tumor), the dorsal root ganglion is damaged. Wallerian degeneration of sensory axons may result, and the sensory nerve action potential amplitude may be affected (Levin, 2002). Median wrist mononeuropathy (carpal tunnel syndrome) may present as hand, forearm, elbow and shoulder pain (Cherington, 1974), and thus present clinically similar to a cervical radiculopathy. Therefore, routine peripheral sensory nerve studies are helpful in these cases. Occult peripheral nerve lesions distal to the root may be overt due to axoplasmic damage induced by root

lesion; such patients are frequently referred for electromyography to rule out multilevel cervical radiculopathy. In these cases, sensory nerve studies are helpful. 28.1.6. Motor conduction studies As with sensory nerve studies, motor conduction studies may assist to exclude peripheral nerve lesions. However, results are often normal in radiculopathy (Aminoff, 2002). External root compression by disc herniation or spondylosis, common in radiculopathies, usually damages only a fraction of nerve root fibers, reducing the sensitivity of motor conduction studies (Levin, 2002). The amplitude of the compound muscle action potential (CMAP) may be affected when the root lesion causes axonal degeneration. A ≥50% reduction of CMAP in studies performed 1 month after injury indicates axonal degeneration and a poorer prognosis (Wilbourn and Aminoff, 1988; Aminoff, 2002). 28.1.7. H-reflexes The H-reflex was introduced by Paul Hoffman in 1918 to describe the calf muscle response to tibial nerve stimulation (Hoffman, 1918). The impulse is conducted in Ia afferent fibers, activating (possibly monosynaptically) motor neurons in the anterior horn of the spinal cord and is then conducted in efferent alpha fibers. The H-reflex can be reliably obtained from the flexor carpi radialis (FCR) muscle recording (Jabre, 1981; Fisher, 2002b). The surface electrode is placed over the FCR muscle at the junction of the upper onethird and lower two-thirds of the distance between the

Table 28.4 Evolution of electrodiagnostic findings relative to the time of injury

CMAP Motor NCV Motor DL F wave Fibrillation Fasciculation MUP

Acute (< 7 Days)

Subacute (weeks)

Progressive

Residual

Normal Normal Normal Prolonged or absent None Rare Reduced recruitment Polyphasic, may vary

Low if severe < 30% slow if severe < 30% long if severe Absent or prolonged Proximal, brief Rare Reduced recruitment Long duration

Low if severe < 30% slow if severe < 30% long if severe Absent or prolonged Proximal and distal Contraction fasciculation Reduced recruitment Long duration, high amplitude polyphasic, may vary

Low if severe < 30% slow if severe < 30% long if severe Prolonged or absent Distal, small, few Contraction fasciculation Reduced recruitment High amplitude distal > proximal

CMAP, compound muscle action potential; NCV, nerve conduction velocity; DL, distal latency; MUP, motor unit potential.

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medial epicondyle and radial styloid. Facilitation increases the likelihood of response. The H-reflex response was recorded from the FCR in 100% of normal subjects with facilitation and 74% of subjects with the muscle at rest in one study (Paik et al., 2001). Delayed or absent FCR H-response has been seen in patients with C6 or C7 radiculopathy. Schimsheimer et al. (1985) performed FCR H-reflexes in 143 normal subjects and 32 subjects with cervical radiculopathy. Of the seven patients with C5 and C8 radiculopathies, the H-reflex could be elicited bilaterally without significant differences in latencies. Of the 25 patients with C6 or C7 radiculopathies, the H-reflex was absent in 11 patients on the affected side and prolonged in six of the remaining 14 patients. Nomograms using arm length were useful for defining normal latencies in this study. The upper limit of normal has been reported as 21 msec. A side-to-side difference limit of 1.5 msec maximum has been suggested (Fisher, 2002b). It has been found that head/neck posture can affect reflex amplitude but not the latency (Sabbahi and Abdulwahab, 1999). Head extension, lateral bending, and rotation toward the side of the lesion was found to facilitate the H-reflex response. While not used routinely in clinical practice, techniques for monosynaptic recordings have been reported from the biceps brachii (to study C5/6 nerve roots) (Miller et al., 1995a), extensor carpi radialis (C6/7) (Miller et al., 1995b), and abductor pollicis brevis (APB) (Miller et al., 1995b). Miller et al. (1999) showed that the various H-reflexes afforded a sensitivity of 72% and specificity of 85% for the detection of cervical radiculopathy and concluded that specialized segmental H-reflex studies of the upper extremity were as sensitive and specific as magnetic resonance imaging. 28.1.8. F-wave The F-waves are small, late responses recorded by an antidromic stimulus of motor efferent fibers. A group of anterior horn cells are activated, causing orthodromic impulses to be conducted by efferent fibers. Unlike the H-reflex, the F-wave can be recorded more readily from any muscle. The F-wave was initially proposed to be helpful in the electrodiagnostic evaluation of cervical radiculopathy (Fisher et al., 1979). More recent studies have shown that the F-wave has limited clinical utility for radiculopathies. This remains a controversial issue. Rivner (1998) recorded F-wave latencies in 2,093 patients with clinical radicu-

605

lopathy symptoms. Abnormal F-waves were found in 201 patients (9.6%). Eighty patients (6.7%) showed abnormal F-wave findings and normal needle EMG. Among patients with abnormal needle EMG findings consistent with cervical radiculopathy, only 121 patients (13.5%) had abnormal median or ulnar Fwaves. Reasons proposed for the limited utility of Fwaves for radiculopathy workup include: (1) only a portion of the group of nerves are recorded with each stimulation; (2) latency delays can be diluted by the long course of the F-wave; and (3) abnormalities can be masked by normal fibers (Fisher, 2002b). Studies on the sensitivity and specificity of F-waves in cervical radiculopathy have been limited. Further study should be conducted in this area. 28.1.9. Cervical root stimulation The technique of cervical nerve root stimulation involves placing the stimulating needle in the cervical paraspinals and recording over a peripheral muscle (e.g., biceps, triceps, abductor digiti minimi) (MackLean and Taylor, 1975; Berger et al., 1987; Tsai et al., 1994). A few studies have reported higher sensitivity relative to other techniques, including needle EMG. Berger et al. (1987) reported that cervical root stimulation and needle EMG detected abnormal findings in 100 and 61% of patients with clinical evidence of radiculopathy, respectively. In 32 patients with clinical symptoms and signs of cervical radiculopathy, Tsai et al. (1994) reported that 25 patients showed abnormal cervical root stimulation versus 18 patients who showed abnormal EMG. The group concluded that cervical root stimulation provides sensitive, direct evaluation of proximal root conduction and is valuable for presurgical radiculopathy evaluation. Despite promising results, popular use of the technique has been limited due to uncomfortable electrical stimulation and uncertainty regarding the precise stimulation site (Aminoff, 2002). In addition, there are limitations in patients with primarily sensory fiber or bilateral root involvement. Further investigation is needed to establish this technique as a routine test for evaluating cervical radiculopathy. 28.1.10. Somatosensory evoked potential In earlier literature, it was proposed that somatosensory evoked potentials (SEP) may be another useful tool for the early diagnosis of cervical radiculopathy, particularly when sensory signs or symptoms predominate. The cervical spinal response is sizable and easily elicited by

606

median nerve stimulation (Matthews et al., 1974). Prolonged conduction time between the spinal response and Erb’s point response is considered to reflect slowing through the root or plexus. Eisen (1985) suggested that the diagnostic power of SEPs in radiculopathy will improve if amplitude and dispersion become more exactly defined, coupled with delayed latency for more precise criteria. Nerve trunk stimulation may yield abnormal SEPs in patients with cervical radiculopathy (Yiannikas et al., 1986). Cutaneous sensory nerve stimulated SEPs are characterized by more specific, isolated root innervations. Scalp-recorded SEPs from cutaneous sensory nerve stimulation were abnormal in 57% of the patients, including cervical radiculopathy, based on findings of abnormal amplitude and waveform configuration (Eisen et al., 1983). However, several limitations diminish the value of SEP for cervical radiculopathy assessment: (1) excessively variable normal amplitude; (2) dilution of focal root slowing by normal conduction along the rest of the sensory pathway; and (3) masking of abnormality by simultaneous stimulation of fibers belonging to more than one root segment (Wilbourn and Aminoff, 1993). An SEP approach using dermatomal territory skin stimulation has been introduced (Eisen, 1985), but the technique failed to exibit high yield. Use of SEP has not been sufficiently validated for routine radiculopathy diagnosis. 28.1.11. Motor-evoked potential Motor-evoked potential (MEP) recorded from muscles supplied by specific nerve roots via magnetic stimulation of the spinal nerve root has been described. The MEP shows increased motor root conduction times in radiculopathies (Chokroverty et al., 1991; Chistyakov et al., 1995; Wehling et al., 1995). Some reports have suggested a correlation with clinical patterns and an ability to distinguish between medial and lateral root compressive disc herniation (Buchthal, 1977; Levin, 2002). The MEP may provide valuable information in patients with radiculopathy, especially when electromyographic results are negative or equivocal. However, the technique remains investigational due to uncertainty regarding the stimulation site and uncomfortable stimulation (Aminoff, 2002). 28.1.12. Specific clinical considerations 28.1.12.1. C5/C6 Radiculopathy Due to the similarity of clinical and electrodiagnostic findings, these two root lesions should be considered

E.S. DATE AND B.J. KIM

together. Abnormal needle EMG findings from the supra- and infraspinatus, deltoid, and biceps brachii are consistent with C5 radiculopathy, but the C6 nerve root involvement also can show abnormal findings in the above muscles. Abnormal findings from the pronator teres, flexor carpi radialis, or extensor carpi radialis in addition to the muscles listed above are consistent with C6 radiculopathy. The pronator teres muscle is particularly useful in distinguishing a C6 radiculopathy from that of C5 (Levin et al., 1996). Similarly, the rhomboid muscle distinguishes a C5 radiculopathy from that of C6. Normal needle EMG does not rule out a C5 radiculopathy due to the technical difficulty of placing the needle into the rhomboideus. A unilateral flexor carpi radialis H-reflex abnormality can assist in the diagnosis of a C6 radiculopathy. Partial upper trunk plexopathy, the most common type of brachial plexopathy, should be considered in the differential diagnosis with C5/C6 radiculopathy. Assessment of plexopathy typically utilizes axillary and musculocutaneous motor nerve conduction studies and lateral and median antebrachial cutaneous sensory nerve conduction studies. 28.1.12.2. C7 Radiculopathy The C7 radiculopathy is easy to distinguish relative to other root involvement. Typically, the anconeus, triceps, extensor digitorum communis and pronator teres show abnormal findings. If the triceps is not involved, other lesion sites or disease should be considered (Levin et al., 1996). The extensor carpi radialis is unreliably affected in most C7 radiculopathies and is not a routine needle EMG survey muscle. H-reflex study from the flexor carpi radialis can help evaluate patients when C7 radiculopathy is suspected. No reliable motor nerve conduction studies generate compound muscle action potentials from muscles innervated by the C7 root (Levin, 2002). 28.1.12.3. C8/ T1 Radiculopathy Although T1 root involvement is rare, C8 should be considered with T1 due to similar clinical and electrophysiological characteristics. Detailed clinical differences are discussed in the thoracic radiculopathy section of this chapter. Due to myotome commonality, the distribution of abnormal needle EMG findings usually cannot differentiate involvement of these roots. Although controversial, the abductor pollicis brevis may permit differentiation due to some evidence that the muscle is primarily innervated by T1 (Levin et al., 1996). Severe C8 root involvement may afford loss of the amplitude of ulnar compound

CERVICAL AND THORACIC RADICULOPATHIES

muscle action potentials recorded from the abductor digiti minimi or first dorsal interossei. In addition, the mild slowing that occurs with moderate to severe axonal loss in a C8 radiculopathy is easily mistaken for an ulnar neuropathy. Inching and sensory studies are required for differential diagnosis. The C8 and T1 roots are often avulsed from the spinal cord via closed traction susceptibility. If the compound muscle action potential is not elicited, and a sensory nerve action potential assessing the same root elements is present, intraspinal canal lesion including avulsion should be considered as a differential diagnosis. 28.1.12.4. Cervical spondylosis Discs between the third and seventh cervical vertebra are commonly affected in cervical spondylosis. Radiculopathy induced by cervical spondylosis is typically manifested as bilateral multiple radiculopathies involving C6 and C7. When combined with myelopathy, clinical findings may be confused with motor neuron disease. Needle EMG from muscles innervated by cranial nerves and cervical spine imaging studies may help distinguish these two diseases. 28.1.12.5. Root avulsion Traumatic injury may cause pre- or post-ganglionic avulsion to the roots, plexus, or both. Myelographic findings can facilitate diagnosis, but structural abnormal findings do not necessarily coincide with functional abnormality. To evaluate functional deficits secondary to neural damage, electrodiagnostic study is ideal. The presence of sensory nerve action potentials in a completely denervated dermatome is consistent with preganglionic lesion. Precise delineation of the lesion site is confounded by controversy concerning the roots responsible for sensory innervation. Intraoperative root stimulation has been recommended for unambiguous evaluation. 28.1.12.6. Noncompressive radiculopathies Diabetes mellitus is a common cause of noncompressive lumbosacral radiculopathies. Cervical root involvement has been rarely reported, although some investigator suggested that diabetic radiculoplexopathy may involve the cervical region before, after, or simultaneously with the lumbosacral syndrome (Katz et al., 2001). Clinical findings are similar to those of the legs, with subacutely progressive weakness and pain followed by spontaneous recovery. Electrodiagnostic findings in the arms usually show complicated multifocal involvement of the roots, plexus, or peripheral

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nerves in the cervical, thoracic, and lumbosacral areas. Another type of noncompressive radiculopathy is chemical radiculitis, an inflammatory condition of the nerve root due to annulus fibrosus rupture and dissemination of disc fluid along the nerve root sheath. Clinical history and imaging studies can help diagnose chemical radiculitis in patients with typical electrodiagnostic findings of cervical root involvement. 28.1.13. Conclusion Cervical radiculopathy may have various etiologies. The most common causes are cervical disc herniation and cervical spondylosis. Diagnosis is usually possible using clinical symptoms/signs and electrophysiologic examination. Although various electrodiagnostic examinations may help evaluate cervical radiculopathy, needle EMG is the most important, sensitive, and specific method. Involved muscles show various needle EMG findings, such as reduced recruitment, spontaneous activity, high amplitude, and long duration polyphasic motor unit potentials. These findings may be generally related to the time after root insult and the severity of damage. Nerve conduction studies often fail to reveal substantial abnormalities. A unilateral flexor carpi radialis H-reflex abnormality can assist in the diagnosis of C6 or C7 radiculopathy. Although electrical or magnetic cervical root stimulation may reveal root conduction abnormalities, further investigation is required to establish this technique as a routine test. 28.2. Thoracic radiculopathy 28.2.1. Introduction Clinically, thoracic radiculopathies may be confused with intra-abdominal disorders. Since symptomatic thoracic disc herniations comprise 10 μV). (e) An ulnar lesion at the elbow causing (b) and (c) would not allow these normal motor findings. (The ulnar mixed nerve AP and the comparison of evoked CMAPs give the highest yield of abnormality in ulnar lesions at the elbow.) (f) The thenar CMAP is always recorded because nerve damage at the thoracic outlet commonly reduces its amplitude. The thenar eminence, especially its lateral part, can be grossly wasted, but the hypothenar eminence is rarely affected to the same extent. The thenar latency is normal in this case, but can be increased through loss of large diameter fibres. The thenar F-wave latency is significantly longer than on the left, where it is

The abductor pollicis brevis (APB) was of normal bulk and strength in this patient. As is usually the case, there was no fibrillation, but needle sampling revealed a severely reduced pattern with simple unstable MUAPs of up to 18 mV. The same picture was present in the normally strong first dorsal interosseous, with MUAPs to 15 mV. Forearm flexors did not need to be investigated given the findings in APB, but a C7 muscle, extensor digitorum communis, was normal. Severe partial denervation due to loss of C8 (and presumably T1) motor fibres had evidently been exceptionally well compensated by collateral nerve fiber sprouting, preserving both strength and bulk. This illustrates the practical importance of sampling these muscles even if they are clinically normal. It also suggests that the parallel processes of denervation and reinnervation had been going on for years rather than months. Perhaps it is physical growth and the demands of an active adult life which lead to the condition becoming apparent for the first time. EMG report: “The electrophysiological findings are typical of chronic damage to the medial cord of the brachial plexus. A cervical rib or fibrous band may be assumed to be present.” Radiology report: “Prominent transverse process of seventh cervical vertebra or truncated cervical rib.” At operation: “Brachial plexus and brachial artery passed across a prominent band running from cervical rib to first rib. Hard, tight, and sharp as a fine wire. Table 29.2

Table 29.1 Sensory nerve conduction parameters in a patient with thoracic outlet syndrome

Motor nerve conduction parameters in a patient with thoracic outlet syndrome Right

(a) digit III–wrist (b) digit V–wrist (c) wrist–sulcus* (d) mcnf *

Right

Left

Right

Amplitude μV

Amplitude μV

CV m/s

40 absent 18 absent

Mixed nerve mcnf = medial cutaneous nerve of forearm.

60 25 95 15

CMAP (e) wrhypothen. (e) aehypothen (f) wr-thenar

Left

Right

Left

Amplitude Amplitude F latency F latency mV mV ms ms 4.0

25.0

3.5 6.5

8.0

29.0

wr = wrist ae = above elbow (a–f) = points for discussion above NB Only measurements necessary to the diagnosis are given.

25.5

616

Across it the medial cord was flattened and took a sharp turn through nearly 90˚. Brachial artery embarrassed when shoulder depressed and pushed posteriorly.” 29.4.3. Other means of investigation General acceptance of the simple and effective investigation described has not discouraged attempts to find other electrophysiological approaches. These have included Erb’s point stimulation with ulnar conduction studies across the thoracic outlet (Urschell et al., 1971), F-wave studies (Eisen et al., 1977), somatosensory evoked potential studies using conduction time between plexus and cord (Jerrett et al., 1984) and C8 root stimulation with needles (Felice et al., 1999). Each has its proponents but none has become widely used, presumably because none has achieved a reliable and worthwhile increase in diagnostic accuracy. After a comparison of different methods, Aminoff and his colleagues (1988) concluded: “Newer techniques for which we anticipated a useful role in the evaluation of plexopathies have proved disappointing.” This accords with the observations of Veilleux et al. (1988) and Passero et al. (1994). 29.4.4. The Importance of correct diagnosis The scheme presented above stems from the work of Gilliatt and his colleagues, who in 1977, rescued the true neurological lesion at the thoracic outlet from a morass of ill-defined conditions causing upper limb symptoms unaccompanied by neurological deficit. It is in fact rare, and requires surgical management, unlike non-neurological conditions for which many patients have undergone unnecessary removal of the first rib (Wilbourn, 1988). 29.5. Traumatic brachial neuropathy The main purpose of electrophysiological study in this field, typified by the motor cycle accident or birth palsy resulting in a flail arm, is to distinguish between avulsion of roots, with its serious prognostic implications, and injury distal to the dorsal root ganglion. The damage can range from neurapraxia of limited extent, which recovers in a few weeks, to neuronotmesis due to root avulsion or rupture; all the degrees can be present in the same plexus. The clinical distinction between neurapraxia, axonotmesis, and neuronotmesis is impossible at the outset and needle EMG is indispensable. Investigation conducted less than three weeks after injury is almost certain to be misleading.

W. TROJABORG AND J. PAYAN

Avulsion interrupts the sensory pathway proximal to the dorsal root ganglion. This leaves the ganglion cell and its peripheral process intact, so that a normal CSNAP can be recorded even though the area is insensible. Axonal loss distal to the ganglion results in a reduced or absent CSNAP. If there are lesions both proximal and distal to the ganglion, evidence of avulsion is masked (Fig. 29.1). It may, nevertheless, be detected if there is denervation activity in posterior cervical muscles, but overlap between different spinal segments reduces the usefulness of this test. Absence of fibrillation does not exclude avulsion with certainty. Bufalini and Pescatori, (1969) discuss this test. An indication of what the traditional electrophysiological approach can achieve is provided by Trojaborg (1991) and Vredeveld and his colleagues (2001), who studied 184 patients and compared the results of their electrophysiological investigation with final diagnoses based on radiographic and surgical findings. Their standard protocol of EMG and nerve conduction studies proved reliable in 84% of cases. It includes radial, median (to digits I and III), ulnar, and if necessary lateral antebrachial CSNAPs. The latter, as shown by Ferrante and Wilbourn (1995) in their study of pathways traversed by fibres contributing to individual CSNAPs, passes through lateral cord and upper trunk to C6. Two muscles innervated by different nerves were sampled for each root. In the majority of cases, therefore, the necessary information is obtainable by conventional EMG, but the usefulness of peripheral, spinal, and cortical SEPs has been investigated by a number of workers (Jones, 1979; Jones et al., 1981; Yiannikas et al., 1983; Aminoff et al., 1988). In one of Aminoff’s patients: “SEPs were particularly helpful because the presence of small potentials over Erb’s point with absence of any responses over the cervical spine or scalp suggested the possibility of concomitant multiple root avulsions,” subsequently shows to be the case. Yiannikas makes the point that this technique “provides a non-invasive test for the follow-up of patients, particularly after surgical intervention, to assess the progress of nerve regeneration.” Clearly, the study of SEP’s is useful as an occasional adjunct rather than a routine procedure. 29.5.1. Obstetric palsy Brachial plexus injury during birth deserves mention in the present context. If within a month of birth voluntary movement is detected in each myotome, recovery

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Cortical sep's

Mw Left

Uw

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Fig. 29.1 Twenty-one-years-old male motorcyclist hit by car. Flaccid paralysis of right upper limb. Traumatic meningocele corresponding to C8 and T1. Neurophysiological investigation at one month. Top: Cortical somatosensory evoked potentials (SEP) recorded over contralateral hand area on stimulation of left and right median (Mw) and ulnar (Uw) nerves. Note normal responses recorded over right hemisphere, absent over left. This implies discontinuity of sensory path proximal to dorsal root ganglia. Bottom: Sensory potentials recorded at elbow (E) and spinal SEPs at C7 on stimulation of left and right median and ulnar nerves, respectively. Note the normal sensory potentials and SEPs after stimulation on the left. Stimulation of nerves on the right results in small sensory potentials; spinal SEPs are absent. The implication is that there is damage both distal and proximal to the dorsal root ganglia; avulsion is masked by the presence of peripheral potentials. These results illustrate the value of using nerve conduction studies in conjunction with SEP.

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will occur and there is no need for EMG. The extensive investigation which would be employed in an older patient is not always possible, and it may be sufficient to concentrate on the area most involved. Thus, if the infant reflexly grips a finger placed in its palm but shows no inclination to extend the elbow, deltoid, biceps, and triceps should be sampled. Voluntary MUAPS may be present even when no movement is seen. Such an infant falls into the largest group, in which a mixture of neurapraxia and axonotmesis present in the C5, C6, and perhaps C7 distributions is likely to recover spontaneously. If EMG reveals no function in biceps at three months, surgical intervention is likely to be considered. EMG can show that apparent recovery is actually due to the development of trick movements, but it can also show that a reinnervated muscle is not being used properly due to the infant’s neglect of the limb during the period of paralysis, an observation made by McComas and his colleagues, (1993). The same group has found that motor unit estimation (MUNE) may give a more accurate picture of motor axon regeneration in obstetric palsy than conventional M wave studies (Scarfone et al., 1999). In one subject studied serially, reinnervation of hypothenar muscles first examined at the age of 10 months continued for the next 6 years. In one subject studied serially, MUNE and sensory studies revealed trauma to the supposedly unaffected arm. A poor prognosis can be proved wrong: a girl first seen at the age of 10 weeks had total plexus palsy complicated by paralysis of the hemidiaphragm. Radial and ulnar CSNAPs were each 1 μV, the median absent. Thenar and hypothenar CMAPs were absent. Discrete unstable 2 mV MUAPs were found in biceps and deltoid but were rare in triceps. In EDC, APB, and first dorsal interosseous, there was no voluntary activity. Five years later, the radial CSNAP was 20 μV, the median 10 μV and the ulnar 12 μV. The thenar CMAP was 5.3 mV, with a F-latency of 19 ms. The deltoid showed discrete unstable MUAPs of 10 mV and EDC a similar picture of 6 mV. Grip was strong, as was elbow flexion. Residual weakness in arm abduction and wrist extension indicated that the posterior cord had recovered least well from a major and widespread injury.

W. TROJABORG AND J. PAYAN

culty in deciding whether upper limb symptoms after irradiation for cancer are due to malignant infiltration or the effect of irradiation is notorious. Patients with a neoplastic plexopathy tend to feel pain more often as the first and most pronounced symptom, a shorter duration of symptoms before diagnosis and a higher incidence of Horner’s syndrome (Harper et al., 1989), but none of these pointers has the diagnostic value of the finding of myokymia after irradiation. In the present context, local myokymia signifies irradiation plexopathy with a high, though not absolute, degree of certainty (Harper et al., 1989; Gutmann, 1991). Albers and his colleagues, (1981) studied 38 patients with limb myokymia, of whom 27 had received radiation for malignancy and three had known metastasis to the region. A variety of acute and chronic neurological complaints was responsible for the other 11. There was no major difference in the quality of the myokymia between the two groups. Of the 27 patients with myokymia following radiation therapy, 25 had a plexopathy. Standard investigation showed small CSNAPs (eight patients), small CMAPs (five patients), or a combination of both (six patients). Partial block of conduction or focal slowing across the plexus was shown to be present in 7 of 18 patients. Only one of eight patients in whom F-wave latencies were measured showed an increase. All 25 had chronic neurogenic changes on needle EMG confined to a distribution consistent with a plexus lesion. Conduction block within the plexus was regarded by the Harper group as favoring radiation plexopathy, and has been studied by Esteban and Traba, (1993). A correlation between persistent block and intensity of “fasciculation-myokymic type activities” was thought to suggest a causal connection. This association had already been noted by Roth and Magistris, (1987) in conditions other than radiation plexopathy. Of 25 patients with irradiation plexopathy, the flexor carpi radialis H-reflex was absent in 9 and delayed in 16 (Ongerboer De Visser et al., 1984), the authors concluding that this test “affords a useful tool in demonstrating a proximal lesion of the median nerve in the plexus region as a complication of radiation therapy.”

29.6. Post-irradiation and neoplastic brachial plexopathy

References

These conditions are better considered together, because the only purpose of electrophysiology is to distinguish them from each other. The clinical diffi-

Abbruzzese, G, Morena, M, Caponetto, C, Trompetto, C, Abbruzzese, M and Favale, E (1993) Motor evoked potentials following cervical electrical

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stimulation in brachial plexus lesions. J. Neurol., 241: 63–67. Airaksinen, EM, Livanainen, M, Karli, P, Saino, K and Haltia, M (1985) Hereditary recurrent brachial plexus neuropathy with dysmorphic features. Acta Neurol. Scand., 71: 309–316. Albers, JW, Allen, AA, Bastron, JA and Daube, JR (1981) Limb myokymia. Muscle Nerve, 4: 494–504. Arts, WFM, Busch, HFM, Van den Brand, HJ, Jennekens, FGI, Frants, RR and Stefanko, SZ (1983) Hereditary neuralgic amyotrophy. J. Neurol. Sci., 62: 261–279. Aminoff, MJ, Olney, RK, Parry, GJ and Raskin, NH (1988) Relative utility of different electrophysiologic techniques in the evaluation of brachial plexopathies. Neurology, 38: 546–550. Buffalini, C and Pescatori, G (1969) Posterior cervical electromyography in the diagnosis and prognosis of brachial plexus injuries. J. Bone Joint Surg., 51-B: 627–631. Dunn, HG, Daube, JR and Gomez, MR (1978) Heredofamilial brachial plexus neuropathy (hereditary neuralgic amyotrophy with brachial predilection) in childhood. Dev. Med. Child Neurol., 20: 28–46. Eisen, A, Schomert, D and Melmed, C (1977) The application of F-wave measurements in the differentiation of proximal and distal upper limb entrapments. Neurology, 27: 662–668. Esteban, A and Traba, A (1993) Fasciculationmyokymic activity and prolonged nerve conduction block. A physiopathological relationship in radiation-induced brachial plexopathy. Electroenceph. clin. Neurophysiol., 89(6): 382–391. Felice, KJ, Butler, KB and Druckemiller, WH (1999) Cervical root stimulation in a case of classic neurogenic thoracic outlet syndrome. Muscle Nerve, 22: 1287–1292. Ferrante, MA and Wilbourn, AJ (1995) The utility of various sensory nerve conduction responses in assessing brachial plexopathies. Muscle Nerve, 18: 879–889. Flagmann, PD and Kelly, JJ (1980) Brachial plexus neuropathy. An electrophysiologic evaluation. Arch. Neurol., 37: 160–164. Gilliatt, RW, Le Quesne, PL, Logue, V and Sumner, AJ (1977) Wasting of the hand associated with a cervical rib or band. J. Neurol. Neurosurg. Psychiatry, 33: 615–624. Gregory, RP, Loh, L and Newsom-Davis, J (1990). Recurrent isolated alternating phrenic nerve

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palsies: a variant of brachial neuritis? Thorax, 45: 420–421. Gutman, L (1991) AAEM minimonograph #37: facial and limb myokymia. Muscle Nerve, 14: 1043–1049. Harper, C, Thomas, JE, Cascino, TL and Litchy, WJ (1989) Distinction between neoplastic and radiation-induced brachial plexopathy, with emphasis on the role of EMG. Neurology, 39: 502–506. Jerrett, SA, Cuzzone, LJ and Pasternak, BM (1984) Thoracic outlet syndrome. lectrophysiologic reappraisal. Arch. Neurol., 41: 960–963. Jones, SJ (1979) Investigation of brachial plexus traction lesions by peripheral and spinal somatosensory evoked potentials. J. Neurol. Neurosurg. Psychiatry, 42: 107–116. Jones, SJ, Wynn Parry, CB and Landi, A (1981) Diagnosis of brachial plexus traction lesions by sensory nerve action potentials and somatosensory evoked potentials. Injury, 12: 376–382. Kothari, MJ, Macintosh, K, Heistand, M and Loggian, EL (1998) Medial antebrachial cutaneous sensory studies in the evaluation of the neurogenic thoracic outlet syndrome. Muscle Nerve, 21: 647–649. Lo, Y-L and Mills, KR (1999) Motor root concuction in neuralgic amyotrophy: evidence of proximal conduction block. J. Neurol. Neurosurg. Psychiatry, 66: 586–590. McComas, AJ, Pape, K and Kirsch, S (1993) Apraxia in congenital brachial palsy. Can. J. Neurol. Sci., 20: 362. Mills, KR and Murray, NMF (1986) Electrical stimulation over the human vertebral column: which neural elements are excited? Electroenceph. Clin. Neurophysiol., 63: 582–589. Nishida, T, Price, SJ and Minieka, MM (1993) Medial antebrachial cutaneous nerve conduction in true neurogenic thoracic outlet syndrome. Electromyogr. Clin. Neurophysiol., 33: 285–288. O’Brien, M and Payan, J (1980) Neuralgic amyotrophy (letter), Lancet, 975. Ongerboer De Visser, BW, Schimsheimer, RJ and Hart, AAM (1984) The H-reflex of the flexor carpi radialis muscle: a study in controls and radiationinduced brachial plexus lesions. J. Neurol. Neurosurg. Psychiatry, 47: 1098–1101. Passero, S, Paradiso, C, Giannini, C, Cioni, R, Burgalassi, L and Battistini, N (1994) Diagnosis of thoracic outlet syndrome. Relative value of electrophysiological studies. Acta Neurol. Scand., 90: 179–185.

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Petrera JE (1991) Neuralgic amyotrophy. A Clinical and Electrophysiological Study. Thesis, University of Copenhagen, 163 pp. Rennels, GD and Ochoa, J (1980) Neuralgic amyotrophy manifesting as anterior interosseus nerve palsy. Muscle Nerve, 3: 160–164. Roth, G and Magistris, MR (1987) Neuropathies with prolonged conduction block, single and grouped fasciculation, localized limb myokymia. Electroenceph. Clin. Neurophysiol., 67: 428–438. Rubin, M and Lange, DJ (1992) Sensory nerve abnormalities in brachial plexopathy. Eur. Neurol., 32: 245–247. Scarfone, H, McComas, AJ, Pape, K and Newberry, R (1999) Denervation and reinnervation in congenital brachial palsy. Muscle Nerve, 22: 600–607. Seror, P, Kuntz, PP, Maisonobe, T, Le Forestier, N and Bouche, P (2002) Sensory nerve action potential abnormalities in neuralgic amyotrophy: a report of 18 cases. J. Clin. Neuromusc. Dis., 2: 45–49. Seror, P (2004) Isolated sensory manifestations in neuralgic amyotrophy: report of eight cases. Muscle Nerve, 29: 134–138. Trojaborg, W (1991) Electrophysiological diagnosis of neural injuries. In: MS Watson (Ed.), Surgical

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Disorders of the Shoulder, Churchill Livingstone, pp. 617–625. Urschel, HC, Razzuk, MA, Wood, RE, Parekh, M and Paulson, DL (1971) Objective diagnosis (ulnar nerve conduction velocity) and current therapy of the thoracic outlet syndrome. Ann. Thoracic Surgery, 12: 608–620. Veilleux, M, Stevens, JC and Campbell, JK (1988) Somatosensory evoked potentials: lack of value for diagnosis of thoracic outlet syndrome. Muscle Nerve, 11: 571–575. Vredeveld, JW, Slooff, BCJ, Blaauw, G and Richards, R (2001) Validation of an electromyographic and nerve conduction study protocol for analysis of brachial plexus lesions in 184 consecutive patients with traumatic lesions. J. Clin. Neuromusc. Dis., 2: 123–128. Wilbourn, AJ (1988) Thoracic outlet syndrome surgery causing severe brachial plexopathy. Muscle Nerve, 11: 66–74. Yiannikas, C, Shahani, BT and Young, RR (1983) The investigation of traumatic lesions of the brachial plexus by electromyography and short latency somatosensory potentials evoked by stimulation of multiple peripheral nerves. J. Neurol. Neurosurg. Psychiatry, 46: 1014–1022.

Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006, Elsevier B.V. All rights reserved

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CHAPTER 30

Lumbosacral radiculopathies Michael J. Aminoff* School of Medicine, University of California, CA, USA

30.1. Introduction Low back pain is one of the most common causes of disability, and a major reason for medical consultation and specialist referral. It may be accompanied by clinical evidence of lumbosacral radiculopathy involving most commonly the L5 or S1 root, or both. Regardless of any clinical signs of root involvement, patients are commonly evaluated by imaging procedures such as computed tomography or magnetic resonance imaging. However, the findings from such studies are often difficult to interpret, because anatomical abnormalities become increasingly common with advancing age (Jensen et al., 1994), so that their presence may be unrelated to the symptoms for which the patient is seeking medical attention. Moreover, noncompressive causes of radiculopathy are usually not visualized by imaging studies. Electrophysiological studies are helpful as a means of detecting abnormalities of function in lumbosacral nerve roots, determining which root is involved, and indicating the functional relevance of any imaging abnormalities that are found. Thus, they should be regarded as complementary to imaging studies whereas, all too often, they are taken to be redundant because anatomical abnormalities have been found. In addition to their role in helping to establish the presence of a lumbosacral radiculopathy, electrophysiological studies are helpful in determining the severity and prognosis of root lesions and therefore have a role in guiding management. Abnormal findings also suggest that vague symptoms have an organic basis although the converse—that normal findings indicate a nonorganic basis—is not necessarily true at all. * Correspondence to: Michael J. Aminoff*, M.D., D.Sc., F.R.C.P, Professor of Neurology, School of Medicine, University of California, San Francisco, California, USA. E-mail adddress: [email protected] Tel.: +1-415-353-1986 fax: +1-415-353-8578.

Electrophysiological studies have certain limitations. In particular, the findings depend on the timing of the examination after onset of a radiculopathy, as well as on the underlying pathophysiology and its chronicity. Furthermore, interpretation of the needle examination is subjective and it is not possible to corroborate or refute the reported findings except by repeating the study. Nerve conduction and other studies are generally not standardized, which may confound attempts to compare studies from different laboratories. Moreover, there is no simple way to test the functional integrity of small-diameter nerve fibers, even though it is likely that pain fibers are affected early in compressive root lesions. Finally, the electrophysiological findings may indicate the presence of a radiculopathy but provide no clue as to its cause or even to the site of involvement of the individual root, which may be anywhere in the cauda equina or at the exit foramina in patients with lumbosacral radiculopathies. In assessing the utility of electrophysiological techniques for evaluating root function, certain methodological difficulties merit consideration. There is no “gold standard” against which to compare different investigative techniques that have been used for the diagnosis of radiculopathies. Except in advanced cases with segmental sensory loss and reflex changes, clinical criteria are notoriously unreliable diagnostically. Even the occurrence of low back pain that radiates into the leg cannot be taken as unequivocal evidence of a radiculopathy, as it may relate, for example, to sacroiliac disease. As mentioned earlier, the imaging findings are also of no help in this regard because abnormalities are common in asymptomatic middle-aged or elderly subjects. These considerations make it difficult to establish the utility of a particular test in the diagnosis of lumbosacral radiculopathy, and perhaps account for the wide variety of tests for which utility has been claimed over the years.

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There are five lumbar and five sacral pairs of nerve roots, which descend in the cauda equina below the inferior portion of the spinal cord (which ends at about the L1 level) to exit immediately below the correspondingly numbered vertebrae. The nerve roots may be affected at their exit foramina or within the cauda equina, where a lesion at one level may produce multilevel functional deficits. Particularly in this latter circumstance, clinical or electrophysiological abnormalities may be bilateral (Chu, 1981; Wilbourn, 1982; Grana and Kraft, 1995). Accordingly, in patients with unilateral clinical deficits in whom electrophysiological abnormalities are found on the symptomatic side, the other side should also be examined electrophysiologically. 30.2. Needle electromyography Needle electromyography is not only the oldest electrophysiological technique for evaluating root function, it is also the most useful. The presence of abnormalities in at least two muscles innervated by the same root but by different peripheral nerves is indicative of a root lesion, and, if abnormalities are not present in muscles supplied by the adjacent roots, a diagnosis of isolated radiculopathy can be made. An adequate examination thus requires the examination of muscles from all of the myotomes in the limb, but with emphasis especially on the root in question and on the immediately adjacent roots. If abnormalities are found in a particular muscle, another muscle supplied by the same nerve but different roots—as well as muscles supplied by the same root but a different nerve— should also be examined to exclude peripheral nerve pathology (Fig. 30.1). The muscles that are best examined in individual radiculopathies are summarized in a later section in this chapter. Electromyographers have generally used myotomal charts to identify the involved nerve root, although such charts have generally been derived from anatomical or clinical studies rather than electrodiagnostic examinations. A recent study by Tsao et al. (2003) correlating the electrodiagnostic findings with the surgical and operative findings in patients with single-level lumbosacral radiculopathies is, therefore, particularly helpful. The number of muscles to be examined depends upon the findings and must therefore be determined on an individual basis. In most instances, between 5 and 10 muscles are examined, including the paraspinal muscles. Sampling of the paraspinal muscles is important in distinguishing a radiculopathy, in which abnormalities

Fig. 30.1 Myotomal chart of the lower extremity (From Wilbourn and Aminoff (1998) with permission).

may be found, from a plexopathy, in which abnormalities should not be present. In patients with an unequivocal radiculopathy, however, the findings in the paraspinal muscles may be normal if these muscles were spared or have come to be reinnervated. A radiculopathy should not be diagnosed solely on the presence of paraspinal abnormalities because such abnormalities may be found in asymptomatic normal subjects or in patients with a variety of other disorders including amyotrophic lateral sclerosis, diabetes, metastatic disease, trauma, or polymyositis and other inflammatory myopathies. Paraspinal abnormalities should not be used to localize the lesion to any specific segmental level, because of the marked segmental overlap in the innervation to these muscles. In patients who have undergone previous back surgery, the paraspinal findings may have to be neglected if they could have resulted from the surgery itself. The electromyographic (EMG) findings will depend upon the severity of the root lesion. In particular, they depend upon whether neurapraxia or axonal loss characterizes the underlying pathological process. With

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neurapraxia, the prognosis for recovery is good and improvement may occur rapidly, in contrast to axonloss lesions in which recovery may be prolonged and incomplete. 30.2.1. Neurapraxia In neurapraxic lesions, the only electrophysiological abnormality is likely to be a disturbance of recruitment of motor unit potentials, so that the number of motor units firing for a given degree of voluntary activity is reduced. Motor units normally fire at about 5–10 Hz, but may have faster firing rates when the number of active motor units is reduced. Although an increased firing rate of motor units may be an early feature of a radiculopathy, in many instances the number of motor axons affected is not sufficient to alter the firing frequency of motor units. When changes do occur, not all of the muscles in the myotome are affected. As indicated by Wilbourn and Aminoff (1998), the tibialis anterior muscle may, for example, be the only one affected in an L5 root lesion. Unfortunately, it requires considerable experience to recognize changes in firing pattern, which are important particularly in distinguishing a lower motor neuron disturbance from poorly sustained voluntary effort. Such a finding is likely to be encountered as soon as the radiculopathy develops, when it is not possible to distinguish between neurapraxia and axonloss lesions on purely electrophysiological grounds, as there will not have been time for the development of any changes of denervation. 30.2.2. Axon-loss radiculopathies The earliest abnormality in axon-loss lesions is reduced recruitment of motor unit potentials. In addition, however, abnormal spontaneous and insertion activity develop at a variable time, depending on the muscle that is examined. Such abnormal spontaneous activity develops soonest in the most proximal muscles and only later in distal muscles following an acute lesion. With time, as reinnervation occurs, it may only be found in distal muscles. A diagnosis of axon-loss radiculopathy should not be made solely on the basis of increased insertion activity; rather, the examination should be repeated after two or three weeks, at which time additional abnormalities will have developed if there has, indeed, been loss of axons. Later examination will not only permit the development of more definite signs of denervation and thus a more secure

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diagnosis, but will also allow the distribution of abnormalities to be determined more definitively and thus facilitate localization of the lesion. In addition to increased insertion activity, abnormal spontaneous activity is present in axon-loss radiculopathies. Such activity may, however, take between four to six weeks to develop in the distal muscles of the limbs and thus become widespread. The temporal sequence in which changes of denervation develop is reflected by the sequence in which reinnervation occurs, so that the proximal muscles, in which abnormal spontaneous activity is detected first, are also the muscles in which such activity first disappears as reinnervation occurs. Thus, abnormalities may be missed because they have not had time to develop if the examination is performed too early, or because they have now disappeared if the examination is performed too late. It is important to bear this in mind as patients with radiculopathy are evaluated electrophysiologically, so that the findings can be interpreted correctly. In severe axon-loss lesions, abnormal spontaneous activity may persist indefinitely in distal muscles either because of ongoing axon loss or because reinnervation is incomplete. The abnormal spontaneous activity most commonly consists of fibrillation potentials and positive sharp waves. Complex repetitive discharges occur rarely as an isolated phenomenon and, when present, are often found in just a few of the muscles of the myotome; they are held to indicate chronicity of the pathological process. They have been reported as an isolated phenomenon in the iliacus muscle of normal subjects, so that their presence in that muscle should not be used to support a diagnosis of L2 or L3 radiculopathy (Wilbourn, 1982). Occasional patients show fasciculation potentials, but if these are the sole abnormality, the possibility that they are either benign in nature or relate to disease of the anterior horn cells should be borne in mind and lead to a more extensive examination. Abnormal spontaneous activity may be present in only a few of the muscles in a myotome, and this does not exclude the diagnosis of radiculopathy if the definition provided earlier is met. Such selectivity in the distribution of fibrillation potentials and positive sharp waves may relate simply to the time at which the examination is performed or result from involvement of only a limited number of fibers in the nerve root. Axon-loss radiculopathies lead to a reduction in the number of motor units activated with voluntary effort, and a consequent increase in their firing rate.

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This contrasts to the findings in patients with poorly sustained voluntary effort, such as may occur because of pain or for other reasons, in whom the reduced number of activated motor units is not accompanied by an increase in firing rate. As denervated muscle fibers come to be reinnervated by collateral sprouting from surviving nerve fibers, motor unit potentials will come to have an abnormal configuration, so that there is an excessive number of polyphasic potentials. These potentials may initially show instability, i.e., variation in size and configuration because of insecure neuromuscular transmission. With time, they become more stable but show configurational changes, becoming larger in amplitude and longer in duration. Such configurational changes will persist indefinitely. As reinnervation continues, abnormal spontaneous activity diminishes and, in some instances, disappears completely; its persistence implies either on-going axon loss or, especially when confined to distal muscles, a failure of complete reinnervation. In very mild axon-loss radiculopathies, no abnormalities of motor unit potentials may be present, and this should not exclude the diagnosis. In occasional instances, the only EMG abnormality is an excessive number of polyphasic motor unit potentials, and if these are of normal architecture and dimensions (amplitude and duration), a definite diagnosis of radiculopathy should be avoided. 30.3. Other electrophysiological abnormalities of the motor system 30.3.1. Motor conduction studies Motor conduction studies are likely to be normal if the muscle from which recordings are made is not supplied predominantly or exclusively by the affected root. Thus, they are generally normal in patients with isolated radiculopathies because the limb muscles generally are innervated by at least two nerve roots. Motor conduction studies will also be normal if the pathophysiology is purely demyelinative. When axonloss is the primary pathological process and is severe enough to cause weakness and wasting of muscles, however, the size of the compound muscle action potential (CMAP) elicited from affected muscles is often reduced, provided that sufficient time is allowed for significant Wallerian degeneration to occur; conduction velocity is typically normal. An attenuated CMAP compared either to normal laboratory standards or the corresponding muscle on the unaffected,

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contralateral side thus suggests a poorer prognosis than otherwise. Because radiculopathy and neuropathy are sometimes difficult to distinguish, e.g., because both may cause foot drop, nerve conduction studies are an important part in the evaluation of patients. 30.3.2. F-wave studies In patients with a compressive root lesion, conventional nerve conduction studies should be normal because of the proximal site of the pathology. Conduction through the site of pathological involvement, however, may be abnormal. Thus, abnormal F-wave studies, and in particular a prolongation of the F-wave minimal latency or abnormalities of such other parameters as mean latency, chronodispersion, and size and persistence of F-waves, might be expected in patients with a radiculopathy (Eisen et al., 1977; Fisher et al., 1979; Tonzola et al., 1981; Eisen, 1985; Fisher, 1992). Eisen and associates (1977) found delayed F-waves in 65% of patients with myelographically confirmed disk disease causing lumbar or sacral root compression. However, the yield has proven to be disappointingly low in patients with suspected root involvement, usually being in the order of 10–20% (18% in the series of the Aminoff et al., 1985b), perhaps because motor fibers are often involved later than sensory fibers in compressive root lesions. Furthermore, even when motor fibers are involved, the region with abnormal conduction is likely to be very small compared with respect to the length of the pathway under test (from the site of stimulation to the anterior horn cells and then back to the muscle from which the recording is made), so that abnormalities of conduction may be “masked.” Abnormalities may also be missed because of the normal function in the stimulated peripheral nerve of other fibers that traverse unaffected nerve roots. Abnormal F-wave studies are, furthermore, of little localizing value, showing only that an abnormality exists at some point along the pathway tested; the lesion could be anywhere between the anterior horn cells and the muscle under study, and could be in any of the roots supplying the affected muscle. Finally, even when F-wave abnormalities are encountered, they are usually of no practical consequence because the needle examination has already provided evidence of pathological involvement of the roots (Aminoff et al., 1985b; Wilbourn and Aminoff, 1998). Abnormalities may also be missed because of the normal function in the stimulated

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peripheral nerve of other fibers that traverse unaffected nerve roots. 30.3.3. Proximal stimulation of motor fibers Attempts have been made to stimulate motor nerve fibers proximally by either electrical or magnetic stimulation. In case of electrical stimulation, a monopolar needle electrode is placed close to the nerve roots by insertion through the paraspinal muscles, and the response to nerve root stimulation is then recorded from representative muscles in the limbs. Chang and Lien (1990) suggested that this technique may be more sensitive than the needle examination in showing evidence of lumbosacral root involvement, finding abnormalities in 16 of the 17 patients by this approach, compared to only 10 by needle examination. The technique has not, however, gained widespread acceptance. It is uncomfortable for patients, and the site of stimulation is uncertain. An alternative approach has been with magnetic stimulation, in which a rapidly changing magnetic field is used to induce an electric current in the subjacent tissues (Eisen and Shtybel, 1990). Technical details are provided elsewhere in this volume. Chokroverty et al. (1989) evaluated the utility of magnetic stimulation over the lumbar spine in patients with lumbosacral radiculopathies, recording the responses of different muscles in the symptomatic and asymptomatic limbs. They found abnormalities in amplitude and latency of such motor-evoked potentials (MEPs) on the symptomatic side in their patients. Again, however, there remains uncertainty about the precise site of stimulation and, because the definition of abnormality is based primarily on interside comparison, the approach is likely to be unhelpful in patients with bilateral disease. Furthermore, several authors have reported only a low yield of MEP studies in patients with lumbosacral root disease (Ertekin et al., 1994; Linden et al., 1995). Accordingly, the technique has not gained wide acceptance as a means of diagnosing lumbosacral radiculopathy and remains primarily of academic interest. 30.4. Electrophysiological investigation of sensory function 30.4.1. Sensory conduction studies Sensory conduction (superficial peroneal and sural) studies are usually normal in patients with an isolated lumbosacral radiculopathy but are, nevertheless, helpful

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in distinguishing a root lesion from a plexus or more peripheral lesion, which may be difficult clinically. The size of the sensory nerve action potential (SNAP) is normal in patients with a radiculopathy, because the lesion is proximal to the dorsal root ganglia, whereas it is likely to be reduced in patients with a plexopathy or peripheral neuropathy because sensory fibers degenerate distally from the site of the lesion. Thus, the presence of normal SNAPs in patients with sensory complaints indicative of a root lesion provides support for the radicular location of the underlying pathology (Benecke and Conrad, 1982; Brandstater and Fullerton, 1983). However, in elderly patients, the peripheral SNAPs may be attenuated due to age, and this must be borne in mind when patients are evaluated. In addition, in rare instances an L5 radiculopathy may be associated with an attenuated superficial peroneal SNAP if the L5 dorsal root ganglion is located intraspinally and a compressive lesion affects it or the postganglionic sensory fibers (Levin, 1998). 30.4.2. H-reflex studies H-reflex studies have been used to evaluate both sensory (Ia afferent) and motor fibers and can be used to assess the function of the S1 root, but none of the other lumbosacral roots. They can be easily elicited from the gastrocnemius-soleus complex in normal subjects, but may be absent bilaterally in the elderly or in patients with pathology at any point in the reflex arc, affecting either sensory or motor fibers, or both. Thus, H-reflex abnormalities do not localize the lesion, which may be anywhere along the pathway subserving the reflex; similarly, they provide no information about the age of the underlying lesion. Abnormalities in response amplitude or latency compared to laboratory reference values or the asymptomatic side in an individual patient have been used for recognizing abnormalities in the pathway under test, but it remains unclear whether amplitude or latency changes are more useful (Wilbourn and Aminoff, 1993; Nishida et al., 1996). In this author’s experience, amplitude is the more helpful criterion, an interside asymmetry exceeding 50% or loss of the response signifying pathology. Others have relied more on latency changes, using either absolute latency value (with values exceeding those predicted by a nomogram being taken as abnormal) or interside differences. However, a focal compressive lesion at the root level is likely to produce little slowing in conduction (or prolongation in latency) because of the

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long length of the pathway under test in which conduction will be unaffected. This may explain why the findings are sometimes normal in patients with definite S1 root involvement, as also may sparing of some of the fibers subserving the reflex. Even when the findings are abnormal in patients with suspected S1 radiculopathies, they need to be interpreted in the context in which they are obtained, recognizing the limitations and low specificity mentioned above. An H-reflex abnormality that is the sole electrophysiological abnormality is insufficient to establish the diagnosis of an S1 root lesion with confidence, at least in this author’s opinion. One approach to improving the utility of H-reflex studies has been to elicit them by stimulation at several different sites in order to distinguish between proximal and distal involvement of the reflex pathway. Zhu and colleagues (1998) elicited H-reflexes and CMAPs in normal subjects by electrical and magnetic stimulation of the S1 nerve root at the S1 foramen and at different levels of the cauda equina as well as more distally. Such an approach, by reducing the conduction distance (and thereby reducing any “masking” of latency abnormalities in patients with focal lesions) and localizing the likely site of pathology to a proximal or distal site, may be more helpful in the evaluation of patients with suspected S1 root lesions. Further evaluation in a group of patients with S1 radiculopathies therefore seems warranted. 30.4.3. Somatosensory evoked potentials Somatosensory evoked potentials (SEPs) have also been used to evaluate patients with suspected lumbosacral root disease. They were performed in the belief that involvement of sensory fibers occurs early but at a proximal site that will not lead to abnormalities of conventional nerve conduction studies. The initial approach was to record the SEP over the scalp to stimulation of a nerve trunk in the leg. Given the polysegmental nature of the nerve trunks, it is not surprising that SEPs are always normal in this author’s experience in patients with isolated radiculopathies. Indeed, it is hard to understand how any abnormality could be expected, although claims have been made for the utility of the technique in this context. Again, given the length of the pathway from the site of stimulation at the knee (peroneal nerve) or ankle (tibial nerve) to the site of recording (the scalp), any slowing of conduction from root involvement would likely be masked by the extensive pathway with normal conduction. Indeed, for

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conduction slowing to be identified, despite the dilutional effect of normal conduction along most of the pathway under test, slowing would have to be so extreme that conduction will fail altogether. Even with polyradiculopathies, the scalp-recorded SEP to nerve trunk stimulation is likely to be of normal latency if just a few fibers remain unaffected, and amplitude changes are usually of little help because intersubject and interside variability is normally so marked. An attempt has been made to increase the segmental specificity of the test by stimulating cutaneous nerves or in specific dermatomal territories, rather than mixed nerve trunks. The cutaneous nerves are segmentally more specific than the nerve trunks, but they are also not derived solely from a single segment. This may account for the disappointing yield obtained by Eisen and colleagues (1983) who found that in only 56% of patients with a cervical or lumbar root lesion did the cutaneous-derived SEPs reveal abnormalities, in contrast to simple clinical examination, which revealed a sensory deficit far more commonly. Although others have subsequently claimed that the SEPs to cutaneous nerve stimulation are very useful in detecting root involvement, often at a time when clinical signs are minimal or absent (Perlik et al., 1986; Walk et al., 1992), this has not been the general experience (Seyal et al., 1989; Dumitru and Dreyfuss, 1996). Attempts to record the responses over the spine rather than the scalp at least reduce the conduction distance and, as shown by Seyal et al. (1989), increase the diagnostic yield, although to no more than approximately 50%. Early studies suggested that dermatomal stimulation, in either the L5 or S1 territory, was helpful in the recognition of isolated lumbosacral root lesions (Scarff et al., 1981). However, subsequent studies, with a clearly defined group of normal subjects serving as controls (Aminoff et al., 1985a), indicated that in patients with clinically unequivocal L5 or S1 root lesions, dermatomal SEPs were abnormal (Fig. 30.2) in only 25% of cases (Aminoff et al., 1985b), a yield that is not likely to be helpful. Somewhat surprisingly, Katifi and Sedgwick (1987) reported a 95% yield for dermatomal SEPs in 21 patients studied. However, they had a very generous definition of abnormality (a latency or interside latency value that exceeded the normal yield by only two standard deviations), made multiple statistical comparisons, and evaluated patients who had disease at more than one level. Reanalysis of their data in relation to their own gold standard, which was the operative findings, reveals that the dermatomal SEPs were abnormal for 12 roots

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that were not affected at operation, and that in only 4 of the 21 patients did the dermatomal SEPs accurately and completely predict the extent of root involvement, (Aminoff and Goodin, 1988; Aminoff, 1998). The utility of SEPs elicited by dermatomal and cutaneous nerve stimulation was re-explored by Dumitru and Dreyfuss (1996) in 20 patients who met strict clinical criteria for probably lumbosacral radiculopathy based on the history and physical findings and who had an abnormal CT scan or MRI that was clearly consistent with a unilateral/unilevel nerve root encroachment and deflection of the L5 or S1 root due to a laterally herniated disk. Forty-three healthy men and women served as the control group. Regression equation analysis for the first major positive and subsequent negative components of the scalp-recorded response based on height and age-height relationships was performed. They found that it impossible to achieve both a high sensitivity and high specificity, and concluded that there was, therefore, little clinical utility of the techniques.

Kraft and associates in Seattle have suggested that dermatomal SEPs may be more useful than any other electrophysiological technique in the evaluation of patients with spinal stenosis, providing a more complete picture of the extent of involvement in that disorder. They have not yet published a detailed account of their findings, although they have been presented in abstract form (Qureshi et al., 1999; Hillman et al., 2000; Kraft, 2003). There are several reasons that dermatomal or cutaneous-derived SEPs have failed to live up to the expectations of them. As indicated previously, conduction disturbances in a small region of a long pathway may be masked by normal conduction in other parts of the pathway under test. Furthermore, slowed conduction in some afferent fibers may have been masked by normal conduction in uninvolved fibers in the same root. In addition, cutaneous nerves are not completely specific segmentally, having minor contributions from other nerve roots; in addition, there is

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greater segmental overlap in the dermatomal territories than is suggested by the published dermatomal maps encountered in standard textbooks. Finally, the intersubject and intrasubject (interside) variability of SEPs amplitudes in the normal population make it difficult to use amplitude as a criterion for abnormality. 30.5. Electrophysiological findings in various clinical contexts 30.5.1. Upper lumbar radiculopathies Upper lumbar radiculopathies (L2,3,4) are uncommon, typically presenting with weakness of the quadriceps femoris and adductors of the thigh that may masquerade as a femoral or obturator neuropathy, or a lumbar plexopathy. The distribution of abnormalities on needle electromyography, particularly the presence of paraspinal abnormalities, help to establish the radicular location of the pathological process, but precise localization is sometimes impossible. Nerve conduction studies are not helpful in this context. 30.5.2. L5 radiculopathies In both an L5 radiculopathy and a peroneal neuropathy, the needle examination of muscles below the knee shows abnormalities in tibialis anterior, extensors hallucis and digitorum brevis, and peroneus longus, but with the radiculopathy changes are also found in tibialis posterior and flexor digitorum longus, which should therefore be sampled. A peroneal neuropathy can also be excluded by finding abnormalities in above-knee muscles supplied by L5 but not the peroneal nerve, such as tensor fascia lata, gluteus medius, and the hamstrings. The paraspinal muscles are also commonly involved. In rare instances of L5 radiculopathy, the superficial peroneal SNAP is attenuated or lost, presumably because of the intraspinal location of the dorsal root ganglion (Levin, 1998). 30.5.3. S1 radiculopathies With S1 radiculopathies, needle examination may reveal abnormalities in the glutei, both heads of biceps femoris, gastrocnemius-soleus, flexor digitorum longus, and abductors hallucis and digiti quinti; they are sometimes also found in extensor digitorum brevis. Paraspinal changes may also be found, but are less common than with L5 lesions (Tsao et al., 2003). The H-reflex is often absent, attenuated, or delayed in

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latency. When an S1 radiculopathy is identified, the contralateral limb should be examined even if asymptomatic because S1 root involvement is commonly bilateral due to the medial location of the sacral roots in the cauda equina (Wall et al., 1990). 30.5.4. Lower sacral radiculopathies Combined involvement of S2, 3, and 4 may occur bilaterally as a consequence of a lesion of the cauda equina, sometimes as part of even more extensive root involvement. Electrodiagnostic studies are of only limited value, but changes may be found in a few muscles in the limbs, such as the abductor hallucis and abductor digiti quinti. Sphincteric EMG may be abnormal, with evidence of denervation. The H-reflex may be abnormal if the S1 root has been affected. 30.5.5. Multiple lumbosacral radiculopathies The electrophysiological definition of an isolated radiculopathy was provided earlier. In many patients, multiple roots are involved, either because of a lesion affecting the cauda equina or because degenerative changes in the spine are diffuse. In some instances, lumbar stenosis is responsible. Most commonly, there is bilateral but asymmetrical involvement of the L5, S1, and S2 roots. In such circumstances, needle examination reveals abnormalities that are most conspicuous distally in the legs (below the knees) and also in the paraspinal muscles. The abductor hallucis CMAPs to tibial nerve stimulation are small or attenuated with S1 and S2 involvement, and the CMAPs recorded from tibialis anterior or extensor digitorum brevis with peroneal nerve stimulation are similarly attenuated when L5 is affected. Sensory nerve action potentials (sural or superficial peroneal) are normal, but the H-reflex is lost with S1 lesions. 30.5.6. Lumbar spinal stenosis Patients with lumbar spinal stenosis may have electrophysiological changes of multiple lumbosacral radiculopathies, as described above. In other instances, changes indicative of an isolated radiculopathy or of two or more discrete radiculopathies are encountered. Any abnormalities may be unilateral or bilateral, and symmetrical or asymmetrical. Claims for the utility of dermatomal SEP studies are hard to validate in the absence of a peerreviewed report of the findings in a group of patients with lumbar spinal stenosis. In many patients with spinal stenosis, the electrophysiological findings are normal.

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References Aminoff, MJ (1998) Electromyography in Clinical Practice. Churchill Livingstone: New York, 3rd ed. Aminoff, MJ and Goodin, DS (1988) Dermatomal somatosensory evoked potentials in lumbosacral root compression. J. Neurol. Neurosurg. Psychiatry, 51: 740–741. Aminoff, MJ, Goodin, DS, Barbaro, NM, Weinstein, PR and Rosenblum, ML (1985a) Dermatomal somatosensory evoked potentials in unilateral lumbosacral radiculopathy. Ann. Neurol., 17: 171–176. Aminoff, MJ, Goodin, DS, Parry, GJ, Barbaro, NM, Weinstein, PR and Rosenblum, ML (1985b) Electrophysiological evaluation of lumbosacral radiculopathies: electromyography, late responses and somatosensory evoked potentials. Neurology, 35: 1514–1518. Benecke, R and Conrad, B (1980) The distal sensory nerve action potential as a diagnostic tool for the differentiation of lesions in dorsal roots and peripheral nerves. J. Neurol., 223: 231–239. Brandstater, ME and Fullerton, M (1983) Sensory nerve conduction studies in cervical root lesions. Can. J. Neurol. Sci., 10: 152. Chang, CW and Lien, IN (1990) Spinal nerve stimulation in the diagnosis of lumbosacral radiculopathy. Am. J. Phys. Med. Rehabil., 69: 318–322. Chokroverty, S, Sachdeo, R, DiLullo, J and Duvoisin, RC (1989) Magnetic stimulation in the diagnosis of lumbosacral radiculopathy. J. Neurol. Neurosurg. Psychiatry, 52: 767–772. Chu, J (1981) Lumbosacral radicular symptoms: importance of bilateral electrodiagnostic studies. Arch. Phys. Med. Rehabil., 62: 522. Dumitru, D and Dreyfuss, P (1996) Dermatomal/segmental somatosensory evoked potential evaluation of L5/S1 unilateral/unilevel radiculopathies. Muscle Nerve, 19: 442–449. Eisen, A (1985) Electrodiagnosis of radiculopathies. Neurol. Clin., 3: 495–510. Eisen, A, Hoirch, M and Moll, A (1983) Evaluation of radiculopathies by segmental stimulation and somatosensory evoked potentials. Can. J. Neurol. Sci., 10: 178–182. Eisen, A, Schomer, D and Melmed, C (1977) An electrophysiological method for examining lumbosacral root compression. Can. J. Neurol. Sci., 4: 117–123. Eisen, AA and Shtybel, W (1990) Clinical experience with transcranial magnetic stimulation. Muscle Nerve, 13: 995–1011.

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Ertekin, C, Nejat, RS, Sirin, H, Selcuki, D, Arac, N and Ertas, M (1994) Comparison of magnetic coil and needle-electrical stimulation in diagnosis of lumbosacral radiculopathy. Muscle Nerve, 17: 685–686. Fisher, MA (1992) H-reflexes and F-waves: Physiology and clinical indications. Muscle Nerve, 15: 1223–1233. Fisher, MA, Shidive, AJ, Teixera, C and Grainer, LS (1979) The F-response: A clinically useful physiological parameter for the evaluation of radicular injury. Electromyogr. Clin. Neurophysiol., 19: 65–75. Grana, EA and Kraft, GH (1995) Lumbosacral radiculopathies: Distribution of electromyographic findings. Muscle Nerve, 15: 1204. Hillman, L, Kraft, GH and Massagli, T (2000) Lumbosacral stenosis: dermatomal somatosensory evoked potentials versus imaging and clinical outcomes after surgery. Muscle Nerve, 23: 1630. Jensen, MC, Brant-Zawadski, MN, Obuchowski, N, Medic, MT, Malkasian, D and Ross, JS (1994) Magnetic resonance imaging of the lumbar spine in people without back pain. N. Engl. J. Med., 331: 69–73. Katifi, HA and Sedgwick, EM (1987) Evaluation of the dermatomal somatosensory evoked potential in the diagnosis of lumbosacral root compression. J. Neurol. Neurosurg. Psychiatry, 50: 1204–1210. Kraft, GH (2003) Dermatomal somatosensory-evoked potentials in the evaluation of lumbosacral spinal stenosis. Phys. Med. Rehabil. Clin. North Am., 14: 71–75. Levin, KH (1998) L5 radiculopathy with reduced superficial peroneal sensory responses: intraspinal and extraspinal causes. Muscle Nerve, 21: 3–7. Linden, D and Berlit, P (1995) Comparison of late responses, EMG studies and motor evoked potentials (MEPs) in acute lumbosacral radiculopathies. Muscle Nerve, 18: 1205–1207. Nishida, T, Kompoliti, A, Janssen, I and Levin, KF (1996) H reflex in S-1 radiculopathy: latency versus amplitude controversy revisited. Muscle Nerve, 19: 915–917. Perlik, S, Fisher, MA, Patel, DV and Slack, C (1986) On the usefulness of somatosensory evoked responses for the evaluation of lower back pain. Arch. Neurol., 43: 907–913. Qureshi, AA, Hillman, L and Kraft, GH (1999) Dermatomal somatosensory evoked potentials predict surgery for lumbosacral spinal stenosis better than magnetic resonance imaging. Muscle Nerve, 22: 1322–1323.

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Scarff, TB, Dallman, DE, Toleikis, JR and Bunch, WH (1981) Dermatomal somatosensory evoked potentials in the diagnosis of lumbar root entrapment. Surg. Forum, 32: 489–491. Seyal, M, Sandhu, LS and Mack, YP (1989) Spinal segmental somatosensory evoked potentials in lumbosacral radiculopathies. Neurology, 39: 801–805. Tonzola, RF, Ackil, AA, Shahani, BT and Young, RR (1981) Usefulness of electrophysiological studies in the diagnosis of lumbosacral root disease. Ann. Neurol., 9: 305–308. Tsao, BE, Levin, KH and Bodner, RA (2003) Comparison of surgical and electrodiagnostic findings in single root lumbosacral radiculopathies. Muscle Nerve, 27: 60–64. Walk, D, Fisher, MA, Doundoulakis, SH and Hemmati, M (1992) Somatosensory evoked potentials in the evaluation of lumbosacral radiculopathy. Neurology, 42: 1197–1202.

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Wall, EJ, Cohen, MS, Massie, JB, et al. (1990) Cauda equina anatomy: I: Intrathecal nerve root organization. Spine, 15: 1244–1247. Wilbourn, AJ and Aminoff, MJ (1998) The electrodiagnostic examination in patients with radiculopathies. Muscle Nerve, 21: 1612–1631. Wilbourn, AJ and Aminoff, MJ (1993) Radiculopathies. In: WF Brown, CF Bolton (Eds.), Clinical Electromyography. Butterworth-Heinemann, Boston, IInd ed., pp. 177–209. Wilbourn, AJ (1982) The value and limitations of electromyographic examination in the diagnosis of lumbosacral radiculopathy. In: RW Hardy (Ed.), Lumbar Disc Disease. Raven Press, New York, pp. 65–109. Zhu, Y, Starr, A, Haldeman, S, Chu, JK and Sugerman, RA (1998) Soleus H-reflex to S1 nerve root stimulation. Electroencephalogr. Clin. Neurophysiol., 109: 10–14.

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CHAPTER 31

Lumbosacral plexopathies Asa J. Wilbourn* EMG Laboratory, The Cleveland Clinic Foundation, OH, USA

31.1. Introduction The lumbar plexus and the sacral plexus provide innervation for the lower limb, hip girdle, and much of the pelvic floor. When these two plexuses, and the lumbosacral trunk that links them, are considered as a single entity, the resulting lumbosacral plexus (or pelvic plexus) is probably the largest peripheral nervous system (PNS) structure (Fig. 31.1). Electrophysiologic assessments of the lumbosacral plexus often are performed, but these have limitations which are not encountered on similar assessments of the brachial plexus (the second largest PNS structure). (Eisen 1993, Weber 2002) Among these are the following: First, virtually every element of the brachial plexus can be assessed with nerve conduction studies (NCSs) except the sensory fibers derived from the C5 root (Wilbourn, 2004). In contrast, no reliable sensory NCS is available to assess the lumbar plexus (L2–L4 root origin), and the sensory NCSs that assess the superior half of the sacral plexus (L5, S1 root origin) frequently are compromised by various factors. Moreover, the inferior half of the sacral plexus (S2–S4 root origin) has almost no limb or girdle representation. Rather, it essentially provides innervation to pelvic floor structures. Consequently, for the most part, it is not evaluated by any of the standard electrodiagnostic (EDX) procedures. Instead, special techniques, and often special equipment, are required for its electrophysiologic assessment, which is still suboptimal (Fowler, 1995; Roberts and Park, 1998; Wilbourn and Ferrante, 2001). Second, the majority of the brachial plexus can be assessed with percutaneous stimulation, i.e., the axons in the mid to upper portions of the trunks can be acti* Correspondence to: Asa J. Wilbourn, M.D., Director, EMG Laboratory, The Cleveland Clinic Foundation, Cleveland, OH, USA. E-mail address: [email protected] Tel.: +1-216-444-5548; fax: +1-212-658-9035.

vated by supraclavicular percutaneous stimulation (Wilbourn and Ferrante, 2001). In contrast, no portion of the lumbosacral plexus can be stimulated percutaneously, unless special procedures are used. Consequently, focal demyelinating lesions affecting the lumbosacral plexus generally must be diagnosed inferentially, rather than directly. Fortunately, such disorders are relatively uncommon. Third, brachial plexopathies usually are readily distinguished from focal lesions of other nearby PNS structures, – e.g., cervical radiculopathies and proximal peripheral nerve injuries – by both the clinical situation and the EDX findings. In contrast, very often the PNS disorders with which lumbosacral plexopathies are confused – e.g., L2–L4 radiculopathies and femoral neuropathies with lumbar plexopathies; L5, S1 radiculopathies and high sciatic neuropathies with sacral (superior aspect) plexopathies—commonly occur under the same clinical circumstances, and frequently the EDX examination differentiation rests on a single, often somewhat unreliable, finding (e.g., the presence or absence of paraspinal fibrillation potentials). Thus, in one recent report of 152 patients in whom a lumbosacral plexopathy was considered in the EDX differential diagnosis, in only 49 (32%) was unequivocal localization to that PNS structure possible. Of the remaining 103 patients, the diagnosis was either a root or plexus lesion in 48, a plexus or peripheral nerve lesion in 28, and either a root, plexus or peripheral nerve lesion in 27 (Tavee et al., 2003). Fourth, unlike many brachial plexopathies (e.g., post-medial sternotomy plexopathy; true neurologic TOS) (Wilbourn, 2004), few lumbosacral plexopathies have distinctive presentations. Instead, most have a rather generic EDX appearance, and their etiology cannot be predicted by their EDX manifestations. Because of the above and other confusing factors that will be discussed, the only portion of the lumbosacral plexus that can be assessed with somewhat the same degree of thoroughness as the brachial plexus is the superior portion of the sacral plexus, and

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Fig. 31.1 The lumbar and sacral plexuses and their link, the lumbosacral trunk. Supplied by Cleveland Clinic Foundation.

then only in certain patients; the electrophysiologic assessment of the lumbar plexus, and particularly the inferior portion of the sacral plexus, are suboptimal. In the following discussion, the electrophysiologic evaluation of the lumbosacral plexus will be considered under three categories, depending upon the nerve fibers affected: (1) the lumbar plexus (L2–L4); (2) the superior half of the sacral plexus (L4–S1 (S2)); (3) the inferior half of the sacral plexus (S2–S4). The last named, for the most part, cannot be assessed by EDX procedures considered “routine” in most laboratories. The EDX procedures available for assessing the lumbar plexus and the superior portion of the sacral plexus not only will be detailed, but also their limitations; the “typical” EDX findings with certain of these plexopathies will be described as well. Although the lumbar and superior sacral plexuses are separate structures, and combined lesions of them are no more common than lesions of each one separately, they are usually discussed as a single entity. Moreover, the information in many reports concerned with them is provided in such a manner that the data

regarding each separate one often cannot be extracted. Consequently, it is important to note that with many lumbosacral plexopathies, only the lumbar or the superior sacral plexus is involved, whereas with others, combined lesions of them exist (Wilbourn and Ferrante, 2001). Unlike brachial plexopathies, a significant number of lumbosacral plexopathies are bilateral, including those due to neoplasms (estimated to be bilateral in 25% of cases), radiation, and diabetic amyotrophy (Rutkove and Sax, 2002; Wilbourn and Ferrante, 2001). In part, this is due to the fact that violent trauma, which is one of the prime causes of brachial plexopathies and which almost never causes bilateral lesions, is responsible for only a small proportion of lumbosacral plexopathies (6%). In contrast, neoplastic plexopathies, which occur in less than 1% of patients with known neoplasms and which are responsible for only a small percentage of brachial plexus lesions, probably comprise slightly more than half of all lumbosacral plexopathies (Mumenthaler and Schliack, 1991; Rutkove and Sax, 2002; Wilbourn, 2004).

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31.2. Electrophysiological assessment 31.2.1. Procedures available and general principles Various portions of the lumbar and the superior portion of the sacral plexus can be assessed with motor NCSs, sensory NCSs, mixed NCSs, F-waves, motor-evoked potentials, reflex testing (i.e., H-responses), needle electrode examination (needle EMG), and somatosensory evoked potentials (SEPs). Even though the inferior portion of the sacral plexus is assessed with NCSs, needle EMG, reflex testing, motor-evoked potentials, and SEPs, the procedures used to assess this portion of the lumbosacral plexus are highly specialized, and often technically difficult to perform (Ferrante and Wilbourn, 2001; Fowler, 1995). In regard to physiologic evaluation of the lumbar plexus and the superior sacral plexus, the following two facts are pertinent. (1) Because the most proximal stimulation points for all the standard lower limb NCSs are quite distal to the lumbosacral plexus (i.e., in the popliteal fossa), lesions of the latter will only alter the NCSs responses when the underlying pathophysiology is axon loss caused by conduction failure. For this reason, only the amplitudes of the NCS responses are significant. (2) Whether a given recorded amplitude is normal or abnormal can be determined by comparing it either to normal laboratory values or to the amplitude of the response obtained when the same NCS is performed on the contralateral, normal limb. In our experience, the latter is more reliable, and, consequently, whenever there is a question of a lumbosacral plexopathy being present, NCSs always are performed bilaterally, for comparison purposes (Wilbourn and Ferrante, 2001). 31.2.2. Motor axon evaluation 31.2.2.1. Motor nerve conduction studies The compound muscle action potential (CMAP) responses obtained during lower limb motor NCSs will be low in amplitude or unelicitable whenever a substantial number of the nerve fibers assessed have undergone wallerian degeneration as a result of a lumbosacral plexopathy. However, such changes do not permit localization of the lesion, because these NCS amplitudes are equally altered whenever axon loss affects the same number of motor fibers at the level of the L3–S1 spinal cord segments, the L3–S1 roots, the femoral nerve, or the sciatic nerve. Although the CMAP amplitude changes do not localize the lesion they are, nonetheless, helpful for two reasons. First,

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they can establish the pathophysiology responsible for the weakness of a recorded muscle (e.g., the tibialis anterior): axon loss, demyelinating conduction block, or a combination of the two. With axon loss lesions assessed one week or more after onset, typically the amplitude of the CMAP recorded from a muscle, and the amount of reduced motor unit potential (MUP) recruitment seen on needle EMG of it, are concordant. Thus, whenever a foot drop is present clinically because of a sacral plexopathy, not only is the peroneal motor CMAP, recording tibialis anterior, quite low in amplitude, but also needle EMG of that muscle reveals a substantial dropout of MUPs on maximal effort. Conversely, if demyelinating conduction block is responsible for the foot dorsiflexor weakness, although the reduced MUP recruitment will be identical, the CMAP amplitude recorded from the tibialis anterior will be unaffected. Such incongruence permits a demyelinating conduction block lesion to be inferentially diagnosed. This is important with the relatively few lumbosacral plexopathies in which demyelinating conduction block is the predominant pathophysiology. For this combination of findings to be reliable, the assessment must be performed after the CMAP amplitudes have had time to reach their nadir, if an axon loss lesion is present (i.e., 7 days after onset). Second, with axon loss lumbosacral plexopathies, the CMAP amplitudes can provide a semiquantitative measure of the number of nerve fibers that have degenerated if, with abrupt onset lesions, they are performed after the CMAP amplitudes have reached their nadir (7 days) and before they may have increased substantially because of collateral sprouting from unaffected motor axons (beginning at three to four months post injury) (Ferrante and Wilbourn, 2001; Wilbourn, 2002). 31.2.2.2. F-waves Similar to motor NCSs, F-waves are another EDX procedure that solely assesses motor fibers. Although they are considered useful for diagnosing certain PNS disorders, most particularly in identifying pathophysiology (i.e., demyelinating conduction slowing) along the proximal segments of many of the major limb nerves with generalized polyneuropathies, for various reasons discussed below, they have no demonstrated utility in the evaluation of lumbosacral plexopathies. 31.2.2.3. Motor-evoked potentials The motor axons that compose the lumbosacral plexuses can be stimulated at the cortical level, and at

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or near the root level, both electrically and magnetically, and with both surface and needle electrodes; the recording electrodes can be placed over various lower limb muscles. However, in the relatively few reports dealing with these techniques, most of the investigators were attempting to assess the lumbar and superior sacral roots, and were seeking to diagnose lumbosacral radiculopathies, rather than lumbosacral plexopathies. Nonetheless, such proximal stimulation may reveal abnormalities with lumbosacral plexopathies if they are causing demyelination (either conduction slowing or conduction block) or if the procedure is performed so early with axon loss lesions that the distal stump is still capable of conducting impulses (i.e., less than five to six days after onset). An example of the latter will be demonstrated. It is pertinent to note that none of the techniques used to assess the lumbar or superior sacral plexus has achieved wide acceptance, even though the first description of them appeared more than a quarter century ago (MacLean, 1980; Chokroverty et al., 1988, 1989; Chang and Lein, 1990; MacDonell et al., 1992; Eisen, 1993). In regard to inferior sacral plexus assessment, motor potentials have been evoked by both cortical and spinal percutaneous stimulation, employing both electrical and magnetic stimulation. Apparently, the motor-evoked studies performed on this portion of the lumbosacral plexus have proven more informative than those done on the other two portions (Fowler, 1995). 31.2.2.4. Needle electrode examination The needle EMG is one of the most potent tools available in the EDX laboratory for identifying lumbosacral plexopathies. However, its value varies with the specific portion of the pelvic plexus affected and often, because of various factors, its reliability for localization is questionable. In general, the needle EMG with suspected lumbosacral plexopathies must be extensive if it is to provide maximal benefit. 31.2.3. Sensory axon evaluation 31.2.3.1. Sensory nerve conduction studies This type of testing is indispensable for localizing proximal axon loss PNS lesions to the plexus, as opposed to the intraspinal canal (i.e., spinal cord or roots). With plexopathies, the sensory cell bodies in the dorsal root ganglia (DRG) are separated from their peripheral sensory axons. As a result, the latter, which are assessed during sensory NCSs, degenerative, and the amplitudes of the sensory nerve action potentials

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(SNAPs) are reduced. In contrast, root lesions typically affect the sensory fibers proximal to their DRG. Consequently, the peripheral sensory components are usually not affected, so sensory NCSs performed on them yield normal results. Sensory NCSs, moreover, are of particular assistance in identifying axon loss lesions because, for uncertain reasons, the SNAP amplitudes are more affected by incomplete axon loss lesions than are the CMAP amplitudes that assess motor fibers traveling over the same pathway. Accordingly, with moderate axon loss, characteristically the only components of the NCSs that are abnormal are the SNAP amplitudes; the CMAP amplitudes are still within the normal range (Ferrante and Wilbourn, 2001). 31.2.3.2. Somatosensory evoked potentials (SEPs) Stimulation of mixed nerves or cutaneous nerves, or stimulation in a specific dermatomal territory, can all be used to elicit SEPs. However, as judged by the literature, the only focal PNS lesions for which these procedures are performed for diagnostic purposes are radiculopathies, and even with them their value has been seriously questioned in recent years. There are several reasons why SEPs contribute very little to the assessment of the lumbar and superior sacral plexus. In regard to mixed nerve stimulation, the long pathways involved and the inaccessibility of the lumbosacral plexus means that, even if the responses were delayed, the localization would be over such an extensive length of nerve (e.g., between the lumbar spine and either the inguinal ligament or the popliteal fossa) as to be essentially meaningless. Moreover, unless nearly all of the sensory nerve fibers were affected, the normal conduction along the remaining ones could obscure any focal abnormality. In regard to segmental or dermatomal SEPs, recording reproducible potentials from the lumbar spine is extremely difficult in unsedated patients. This leaves only the cortical potentials, and if they were abnormal, the lesion could be situated at any point between the stimulation site and the cortex, which is of no practical value (Dumitru et al., 2002). Cutaneous SEPs may be helpful, however, in limited situations. These will be discussed below under the appropriate headings. Only one SEP is available for assessing the inferior sacral plexus: the pudendal SEP. Stimulation can be applied to the pudendal nerve in both men and women while recording from the upper (L1) spine or the sensory cortex (midline). The latter are easier to obtain (Fowler, 1995).

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31.2.4. Combined motor and sensory axon evaluation 31.2.4.1. Reflex testing Various procedures that access reflex activity can be performed on both the superior and inferior portions of the sacral plexus. The standard lower limb H-reflex test consists of stimulating the tibial nerve in the popliteal fossa, while recording from the gastrocnemius/soleus muscle group. Thus, it essentially assesses S1-fibers that traverse the superior sacral plexus, sciatic nerve, and tibial nerve. Several “sacral reflex tests” are available for assessing the inferior portion of the sacral plexus. These consist of eliciting contractions of various pelvic floor muscles by applying electrical stimuli to the skin or mucosa of the urethra, perineum, or anus. The sacral reflexes that can be performed include the bulbocavernosus reflex in the male and the clitoral anal reflex in the female, as well as the urethral anal reflex and the bladder anal reflex (i.e., the vesico-anal reflexes and the anal reflex) in both sexes (Fowler, 1995; Roberts and Park, 1998; Wilbourn and Aminoff, 1998). 31.2.4.2. Plantar nerve conduction studies The medial and lateral plantar nerves can be assessed with NCSs. Because these are mixed nerves, plantar NCSs share with the H-wave test the fact that they evaluate sensory and motor fibers; moreover they assess axons derived from the same root (the S1 root). Hence, they assess the anterior component of the superior portion of the sacral plexus. 31.3. Electrophysiologic findings with lumbosacral plexus lesions 31.3.1. Lumbar plexopathies: assessment Only one motor NCS is available for assessing the lumbar plexus fibers: The femoral motor, recording quadriceps. Unfortunately, in certain patients (e.g., those who are markedly obese), even the responses with this NCS may be technically difficult to obtain (Wilbourn, 1993). F-waves have no value in lumbar plexus assessment. Recording F-waves from proximal limb muscles, such as the quadriceps with femoral nerve stimulation, is very difficult because they are obscured by the much larger M-wave (i.e., the direct muscle response that is generated by the stimulus) (Fisher, 1992).

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Proximal motor fiber stimulation can be used to assess the lumbar plexus. A long (75 mm) stimulating needle electrode is inserted into the ipsilateral lumbar paraspinal muscles, “2–3 cm lateral and slightly cephalad to the L4 spinous process” (MacLean, 1980). No attempt is made to activate the individual lumbar roots; rather, the goal is to stimulate all three roots (L2–L4) simultaneously. The response is recorded from one of the quadriceps muscles. The latency is then compared to the latency recorded when the same procedure is performed on the contralateral limb (assuming that the lesion is unilateral). Two reports have provided normal values for latencies obtained in this manner, but they have been quite disparate, ranging from 3.4 to 8.8 ms for the mean value, and 4.4 to 12.4 ms for the upper limits of normal (MacLean, 1980; Eisen, 1993). Regardless, the latencies elicited by these methods probably are of relatively little significance, since nearly all patients referred to the EDX laboratory for lumbar plexopathy assessment have clinical weakness, and latencies measure only the speed of conduction along the fastest conducting fibers, not the number that are conducting. These motor-stimulation studies are far more useful if attention is focused on the amplitudes of the CMAPs elicited, rather than the latencies (Wilbourn, 2002). Moreover, if the CMAP amplitude obtained on root stimulation is compared of that obtained during femoral motor NCSs, a conduction block at the lumbar plexus level may be detected. To be certain that the amplitude drop on root stimulation is not simply technical in nature, the findings must be compared to those obtained on the contralateral, normal side (MacLean, 1980). The needle EMG is critical for lumbar plexopathy assessment, but still has significant shortcomings. On motor NCSs, whenever a femoral CMAP is low in amplitude or unelicitable because of axon loss, the responsible lesion could involve the L2–L4 roots, the lumbar plexus, or the femoral nerve. The needle electrode examination usually can distinguish lumbar plexopathies from femoral neuropathies. It does so by demonstrating fibrillation potentials, reduced MUP recruitment, and sometimes chronic neurogenic MUP changes, not only in various heads of the quadriceps, but also in the thigh adductor muscles (innervated by the obturator nerve), and the iliacus (which usually receives branches directly from the lumbar plexus). Unfortunately, needle EMG does not distinguish lumbar plexopathies from L2 to L4 radiculopathies with the same degree of certainty.

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With both disorders, identical needle EMG findings may be seen in the limb muscles. The only needle EMG difference between the two is the presence, in the ipsilateral lumbar paraspinal muscles, of fibrillation potentials with radiculopathies, but not with lumbar plexopathies. Thus, lumbar plexopathies are being diagnosed by negative, rather than positive, findings (i.e., with them, lumbar paraspinal fibrillation potentials are not seen) (Wilbourn, 1993). Relying on paraspinal muscle sampling either to identify a radiculopathy or to exclude a plexopathy can be treacherous. It is known, for example, that fibrillation potentials may be found in the paraspinal muscles, particularly the more caudal paraspinal muscles, with a number of disorders other than radiculopathies, as well as in an appreciable number of asymptomatic older subjects. (Date et al., 1996; Nardin et al., 1998) Consequently, their presence does not eliminate a lumbar plexopathy from consideration. Even more problematic is the practice of rejecting the diagnosis of lumbar radiculopathy—and, therefore, by default, diagnosing a lumbar plexopathy—by the absence of paraspinal fibrillation potentials. This is never a valid approach, because a radiculopathy can never be excluded by the absence of needle EMG abnormalities in any muscle, including the paraspinal muscles. There are at least two reasons why fibrillation potentials may not be found in the paraspinal muscles with radiculopathies. First, similar to all other muscles in the myotome, the paraspinal muscles being sampled may not have had the nerve fibers supplying them damaged by the compressive radiculopathy, or damaged to the point where they underwent axon loss. Second, they may have initially contained abnormalities, but then have been reinnervated before the needle EMG was performed. In this regard, much is made of the fact that the paraspinal muscles should be the first muscles of the myotome to show abnormalities, because they are the most proximally situated. However, for the same reason, they should be the first muscles of the myotome to be reinnervated (Wilbourn and Aminoff, 1998). Typically, in these situations, the results of the sensory NCSs are critical for localization. However, as will be noted, there are no dependable sensory NCSs available for assessing the lumbar plexus. Moreover, none of the other EDX procedures discussed are helpful, except in the rare instance in which qualitative data regarding the integrity of the lateral femoral cutaneous or the saphenous nerves can be obtained with cutaneous SEPs (Dumitru et al., 2002). Consequently, a lumbar plexopathy cannot be

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diagnosed with near certainty in the EDX laboratory, as can many brachial plexopathies and superior sacral plexopathies. The most defensible conclusion that can be stated, whenever motor axon loss is abundant in an L2–L4 root/lumbar plexus limb distribution and yet the lumbar paraspinal muscles are normal on needle EMG, is the following: “The findings are most suggestive of a lumbar plexopathy, but not definitely diagnostic” (Ferrante and Wilbourn, 2001). There are no sensory NCSs of consistent value for assessing the lumbar plexus (Weber, 2002). The sensory axons that comprise the lateral femoral cutaneous nerve derive from the L2 and L3 DRG, whereas those that form the sphenous nerve originate predominantly from the L4 DRG. Consequently, NCSs performed on either of these nerves evaluate lumbar plexus fibers. Unfortunately, reliable NCSs techniques have not been devised for assessing either of them, even though several have been reported for each nerve (Liveson and Ma, 1992; Oh, 2003). (This is particularly ironic in regard to the saphenous nerve, because it is the largest sensory nerve in the body). Typically, SNAPs can be consistently recorded with these two NCSs only when they are performed on young, lean persons. This is neither the age nor physiognomy of the typical patient referred for lumbar plexus assessment. The lack of a dependable sensory NCS to assess the lumbar plexus prevents definite EDX localization of a proximal axon loss lesion to the lumbar plexus, compared to the L3–L4 roots. Lacking such a NCS, localization must depend on the needle EMG findings; specifically, the presence or absence of fibrillations in the lumbar paraspinal muscles, which, as already discussed, are not reliable (Ferrante and Wilbourn, 2001). SEPs are of very limited value in lumbar plexus assessment. The reasons why SEPs elicited by mixed nerve or dermatomal stimulations are unhelpful have already been discussed. Cutaneous SEPs, however, may be of benefit in a limited way in assessing the lateral femoral cutaneous and saphenous nerves which, as noted, are difficult to evaluate with standard sensory NCSs. If the only information sought is whether or not these nerves can conduct impulses (i.e., qualitative rather than quantitative data), then stimulating them while recording from the cortex may yield definite cortical responses, thereby confirming that at least some of the nerve fibers composing them are in continuity (Dumitru et al., 2002). No reflex tests are available for assessing the lumbar plexus.

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31.3.2. Lumbar plexopathies: specific etiologies The majority of lumbar plexopathies, regardless of cause, are unilateral, axon loss in type, and rather severe in degree. Consequently, typically they present with low amplitude or unelicitable femoral CMAPs on NCSs, as well as fibrillation potentials and reduced MUP recruitment in the iliacus, quadriceps, and thigh adductor muscles on needle EMG. Examples of lumbar plexopathies that manifest electrophysiologically in this fashion include those caused by retroperitoneal hemorrhage into the psoas muscle (usually the result of therapeutic anticoagulation, clotting disorders, or pelvic trauma), large vessel disease (such as aortic aneurysms or dissection), post-operative lesions (following such surgery as radical pelvic or aortic vascular procedures) and neoplasms (Wilbourn and Ferrante, 2001; Rutkove and Sax, 2002). In one large series concerned with lumbosacral plexopathies resulting from cancer, the lumbar plexus was affected in nearly half (49%) of the patients; in 31% by itself, and in 18% with concominent involvement of the ipsilateral sacral plexus (Jaeckle et al., 1985). An example of the typical presentation with these lumbar plexopathies is as follows. A 50-year-old patient, anticoagulated because of atrial fibrillation, abruptly developed severe pain in the right groin, along with weakness of right hip flexion, knee extension, and thigh adduction, as well as a sensory deficit along the anterior and medial thigh, and the medial aspect of the leg. Computed tomography (CT) revealed a retroperitoneal mass in or near the ipsilateral psoas muscle. On EDX examination, all the motor and sensory NCSs that assess the sacral plexus were normal. However, a right femoral motor CMAP was unelicitable, while the corresponding one on the left was 7 mV in amplitude. Saphenous NCSs were attempted, but were unelicitable bilaterally. On needle EMG, abundant fibrillation potentials and absence of voluntary MUPs were noted in three of the heads of the right quadriceps, the thigh adductors, and the iliacus. Similar abnormalities were not seen in the corresponding muscles on the left, nor in many muscles assessed in the right lower limb innervated by the sacral plexus, such as the tibialis anterior, medial gastrocnemius, biceps femoris (short head), and gluteus medius. Fibrillation potentials also were not

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seen in the right mid lumbar, low lumbar, or high sacral paraspinal muscles. The absence of a normal amplitude saphenous NCS response on the left (presumably due to technical factors that were also responsible for the corresponding response being unelicitable on the right) precluded the definite diagnosis of a lumbar plexopathy. However, the absence of ipsilateral paraspinal fibrillation potentials in the presence of such severe denervation in the proximal limb and girdle muscles was more in keeping with a lumbar plexopathy than with a severe, high, multi-root (L2–L4) radiculopathy. One type of lumbar plexopathy deserves special comment: Radiation-induced lesions. These mostly are the result of prior, often quite remote, radiation directed to midline structures to treat lymphomas or, more often, carcinomas involving the cervix, uterus, ovaries, testicles, or prostate. Our experience apparently differs somewhat from other investigators (Rutkove and Sax, 2002), since we have found these plexopathies are usually bilateral, although sometimes asymmetrical. Moreover, at least initially, the weakness associated with them presumably is due to demyelinating conduction block (as it typically is with radiation-induced brachial plexopathies initially), because normal or near normal CMAP amplitudes are recorded, on femoral motor NCSs, from the obviously weak quadriceps muscles. Similarly, on needle EMG, whereas MUP dropout is observed in the appropriate muscles, fibrillation potentials are usually sparse, although myokymic discharges frequently are rather prominent. (It is our impression that myokymic discharges are seen more often with radiation-induced lumbosacral plexopathies than with radiationinduced brachial plexopathies, for unknown reasons.) (Wilbourn and Ferrante, 2001) Although diabetic amyotrophy was considered by many in the past to be a lumbar plexopathy, and is now viewed by many as being a radiculoplexoneuropathy, on EDX examination, generally it has the appearance of a severe L2, L3 radiculopathy. Thus, the CMAP on femoral motor NCS typically is quite low in amplitude or unelicitable, while fibrillation potentials and prominent MUP dropout is seen not only in the quadriceps, thigh adductors, and iliacus, but also the ipsilateral mid, and low lumbar paraspinal muscles. Often the disorder is bilateral, but asymmetrical. Rather frequently, the onset of symptoms in the two limbs was separated by several months, so the findings on EDX examination are quite different. On the side of recent

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onset (i.e., three weeks to three months or so duration), the femoral motor NCS response is quite low in amplitude, fibrillation potentials are rather abundant in an L2–L4 distribution (although often noticeably variable from one muscle to another) and, while MUP dropout is prominent, the MUPs that are present are essentially normal in configuration. Conversely, on the contralateral limb, where the lesion is of many months duration, the femoral motor CMAP often is only somewhat low in amplitude (due principally to reinnervation via collateral sprouting), while needle EMG reveals few fibrillation potentials, a dropout of MUPs, and prominent chronic neurogenic MUP changes in the L2–L4 supplied limb muscles. In the majority (approximately 70%) of patients with diabetic amyotropy, the lower limb EDX examination is confounded by the fact that an axon loss polyneuropathy co-exists. However, generally this is mild enough that the leg muscles assessed (e.g., tibialis anterior and gastrocnemei) are not substantially denervated, a fact which can be proven on both motor NCSs and needle EMG (Wilbourn, 1993). 31.3.3. Superior sacral plexopathies: assessment At least four motor NCSs are available for assessing the superior portion of the sacral plexus. Two of these represent the standard lower limb motor NCSs: Peroneal, recording extensor digitorum brevis (EDB), and posterior tibial, recording abductor hallucis (AH). In many patients, unfortunately, interpreting the results of these NCSs is problematic because of confounding factors. Thus, the EDB muscle rather frequently is denervated in isolation, even in young patients, presumably because of compromise of the distal peroneal nerve by shoe wear. As a result, low amplitude or even unelicitable CMAPs recorded from that muscle often are clinically irrelevant. Similarly, patients with pes planus, or who have undergone various foot operations, may have low amplitude or unelicitable posterior tibial CMAPs. More reliable lower limb motor NCSs, in this regard, are those recorded from leg, rather than foot, muscles: The peroneal motor, recording tibialis anterior (TA), and the posterior tibial motor, recording gastrocnemei (i.e., the direct muscle component, or M-wave, of the H response). With axon loss lesions involving the superior sacral plexus, these two motor NCSs can demonstrate the severity of the disorder, and whether the anterior or posterior portions of the plexus are affected equally, or if one is involved predominantly or solely. This is

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because the peroneal CMAP, recording TA, assesses the L5 fibers that travel through the posterior portion of the sacral plexus, whereas the posterior tibial CMAP, recording gastrocnemei, assesses principally the S1fibers that traverse the anterior portion. Although the majority of axon loss sacral plexopathies affect the anterior and posterior components about equally, whenever one is involved preferentially, usually it is the posterior component, in our experience (i.e., the peroneal CMAP amplitude is more severely affected than the posterior tibial CMAP) (Ferrante and Wilbourn, 2001; Wilbourn and Ferrante, 2001). F-waves can be recorded from both common peroneal and tibial nerve innervated muscles distal to the knees (Fisher, 1992). They have been most useful in demonstrating pathophysiology (i.e., demyelinating conduction slowing) along the proximal portions of these nerves with Guillain–Barré syndrome, because a long segment of nerve is involved. Although some investigators have advocated their use in diagnosing lumbosacral radiculopathies, their value in this regard is much more controversial (Wilbourn and Aminoff, 1998). Apparently, there are no reports of their being employed to detect sacral plexopathies. Theoretically, F-waves are more likely to be abnormal with sacral plexopathies than with L5 or S1 radiculopathies, because all the nerve fibers stimulated traverse the affect region, not just some of them (i.e., with radiculopathies, because of multi-segmental innervation of muscles, the stimulated peripheral nerve contains axons that originate from an unaffected, as well as an affected, root). Moreover, the segment of nerve fiber in which conduction is abnormal may be much longer than that typically produced by compressive radiculopathies, thereby somewhat duplicating the situation encountered with Guillain–Barré syndrome. Nonetheless, as with radiculopathies, the pathophysiology may be other than demyelinating conduction slowing, so F-waves do not necessarily have to be prolonged. Moreover, even if they are prolonged, their diagnostic contribution is minimal, because the information they provide is both redundant and of little localizing value. Thus, the fact that a lesion is present, and located proximal to the knee, usually is already evident from other portions of the EDX examination, particularly the needle EMG and the sensory NCSs (Wilbourn and Aminoff, 1998). Proximal motor fiber stimulation can be used to assess the superior sacral plexus, as well as the lumbar plexus. Techniques have been described for stimulating the L5 and S1 roots by inserting a needle electrode

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“just medial and slightly caudal to the posterior superior iliac spine” (MacLean, 1980). Curiously, both reports that mention this technique have recorded, for uncertain reasons, from S1-innervated muscles (AH and gastrocnemius) rather than L5-innervated muscles (MacLean, 1980; Eisen, 1993). If the TA (L5/peroneal nerve-innervated) and the medial gastrocnemius (S1/tibial nerve-innervated) muscles serve as recording points, and surface recording electrodes are used. Then, theoretically, conduction blocks can be detected across the sacral plexus, by combining root stimulation with supra-maximal stimulation of the ipsilateral sciatic nerve in the sciatic notch or in the popliteal fossa. To ensure that low amplitudes recorded on root stimulation are not caused by technical problems, amplitude comparisons with the corresponding responses obtained on the contralateral, normal limb, are mandatory. If this same technique is used very soon after onset of weakness, then evidence of an axon discontinuity conduction block (a conduction block resulting from the fact that the motor fibers in the distal stump of a degenerating nerve can still conduct impulses to the recorded muscle for six days after lesion onset) may be seen. This may allow for far more precise localization than is possible after all of the fibers distal to an axon loss sacral plexopathy undergo conduction failure (Wilbourn, 2002). An example of this localization follows. The patient, a 47-year-old woman with metastatic breast carcinoma, had had 10 days of right buttock pain, five days of right foot numbness, and just two days of right leg weakness in L5 and S1-innervated muscles. The right peroneal motor, tibial motor and sural NCSs were all normal at this early stage, although reduced MUP recruitment was noted on limited needle EMG of right L5 and S1 innervated muscles. While recording AH, the motor nerve fibers were stimulated at four points: (1) the L5 and S1 spinal nerves with a needle electrode; (2) the sciatic nerve at the sciatic notch with a needle electrode; (3) the tibial nerve at the popliteal fossa with a surface electrode; and (4) the posterior tibial nerve at the ankle with a surface electrode. These studies were performed bilaterally. Although the responses on the three more distal stimulation sites were quite similar in configuration and amplitude on both sides, those obtained on root stimulation were not: That on the left was 10 mV in amplitude, whereas that on the right was much lower in amplitude, and

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Fig. 31.2 The use of root stimulation (in this case, S1) to demonstrate a conduction block along the sacral plexus.

somewhat slowed (Fig. 31.2). A CT of the lumbar spine showed a large soft tissue mass in the right sacrum, extending into the paravertebral tissue (History and illustration courtesy of J. Daube). The needle EMG is critical with sacral plexopathies. Along with the sensory NCSs, it is vital for electrophysiologic diagnosis. All the muscles distal to the knee, as well as the hamstrings, glutei, and tensor fascia lata, may show abnormalities. The majority of sacral plexopathies, in contrast to typical L5 and S1 compressive radiculopathies, kill a substantial number of motor axons. Consequently, virtually all of the limb and hip girdle muscles innervated by the sacral plexus frequently exhibit prominent denervation. However, while such changes indicate that a proximal lesion is present, they do not distinguish between unusually severe L5 and S1 radiculopathies and a sacral plexopathy. The critical needle EMG finding for this differentiation is the presence or absence of lumbosacral paraspinal fibrillation potentials. However, as noted above (in regard to lumbar plexus assessment), the absence of paraspinal fibrillation potentials never excludes a radiculopathy. Accordingly, the superficial peroneal sensory and sural NCSs become indispensable for localization. As will be noted below, characteristically they are normal with radiculopathies, because the lesions along the sensory fibers are proximal to the

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L5 and S1 dorsal root ganglia (DRG), whereas they are low in amplitude or unelicitable with sacral plexopathies. However, there are limitations to this approach. Even when these SNAPs are abnormal, thereby excluding radiculopathies, the lesion could still be affecting the high sciatic nerve, rather than the sacral plexus. To distinguish between these two possibilities by EDX examination, needle EMG of the muscles innervated by the gluteal nerves, i.e., the gluteus maximus, medius, and minimus, as well as the tensor fascia lata, become critical. If fibrillation potentials and neurogenic MUP changes are found in them, then the abnormalities are in a sacral plexus, rather than a high sciatic nerve distribution. Unfortunately, this EDX distinction is not absolute, because both false negative and false positive studies for sacral plexopathies are encountered. With false negative studies, the glutei and tensor fascia lata appear normal, often because the EDX examination has been performed so long after onset of symptoms with static lesions that these very proximal muscles have been re-innervated in the interim. False positive studies are more common, i.e., changes are found in these muscles, but they are due to other than sacral plexopathies. Thus, with many iatrogenic (e.g., hip surgery) and traumatic (e.g., falls upon the buttock) lesions, the gluteal nerves or the gluteal muscles themselves are injured in concert with the high sciatic nerve. The combination of findings that results is very suggestive of a sacral plexopathy. The disorder in which coexisting, but independent, injuries of the high sciatic nerve and the gluteal nerves can perfectly mimic the needle EMG findings seen with a sacral plexopathy is gluteal compartment syndrome. Here, the gluteal nerves are compromised within the gluteal compartment by increased pressure (most often because of an expanding hematoma), whereas the proximal sciatic nerve is damaged by external pressure from the same source. The end result essentially is total denervation in the distribution of both the gluteal and sciatic nerves (i.e., in a sacral plexus distribution), although with different causes (Ferrante and Wilbourn, 2001). With a sacral plexopathy, the needle EMG findings may be uniform or nonuniform in the limb muscles. Thus, if the posterior compartment of the proximal sacral plexus is more severely affected, the needle EMG, as well as the NCS, changes will be most prominent in an L5 distribution. Conversely, if the anterior compartment of the proximal sacral plexus is more involved (which happens less often), the changes will be most prominent in an S1 distribution. Lesions of the distal sacral plexus may present with more sub-

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stantial denervation in a proximal common peroneal nerve distribution, compared to a proximal tibial distribution, or the reverse, depending on which fibers are most affected (Wilbourn and Ferrante, 2001). Three sensory NCSs are available for assessing the superior portion of the sacral plexus. The two principle ones are the superficial peroneal sensory and the sural. The superficial peroneal sensory NCS assesses axons that derive predominantly from the L5 DRG and traverse the posterior component of the sacral plexus. The sural NCS—the standard lower limb sensory NCS in most EDX laboratories—assesses nerve fibers that mainly originate in the S1 DRG and traverse the anterior compartment of the sacral plexus. One or both of these NCSs will be affected by axon loss sacral plexopathies of moderate or greater severity (i.e., their SNAPs will be low in amplitude or unelicitable). In the majority of cases, both are equally altered. However, in some instances, one portion of the sacral plexus is more affected than the other, so one or the other of these two SNAPs is disproportionately involved, most often the superficial peroneal SNAP (Wilbourn and Ferrante, 2001). Under normal circumstances, neither of these sensory NCSs will be abnormal with lumbar intraspinal canal lesions causing axon loss. A notable exception is the occasional patient with an L5 radiculopathy who has an abnormality of the ipsilateral superficial peroneal SNAP because of compression of the L5 DRG (Levin, 1998). Consequently, these sensory NCSs are indispensable for accurately localizing proximal axon loss lesions to either the root or plexus level. However, there are several limitations. First, their being abnormal does not localize to the sacral plexus, because they may be equally affected with high sciatic neuropathies (with which sacral plexopathies frequently are confused). They may also be abnormal because of independent, but coexisting PNS disorders, such as focal nerve damage from prior distal limb trauma or surgery, as well as with generalized polyneuropathies. The latter confounding factor can be particularly frustrating when patients with suspected neoplastic sacral plexopathies are assessed, because many of these patients have undergone chemotherapy that conceivably could cause a polyneuropathy. The superficial peroneal and sural SNAPs may also be unelicitable for other than PNS pathology. Thus, often, neither can be obtained in patients older than 60 years of age; unfortunately, this is the age range in which a sizeable minority, if not the majority, of patients are who have suspected sacral

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plexopathies. They may also be unelicitable because of such rather commonly encountered features as marked obesity and substantial distal lower limb edema (Wilbourn and Ferrante, 2001). The posterior femoral cutaneous NCS, similar to the superficial peroneal sensory and sural NCSs, also assesses the superior sacral plexus. In theory, it has advantages over the other two sensory NCSs for doing so, because it evaluates fibers derived from both the posterior and anterior components of the sacral plexus. Moreover, both its stimulating and recording points are proximal to the knee, rather than in the distal lower limb (where those for the superficial peroneal sensory and sural are), so it cannot be adversely affected by such confounding factors as distal limb edema or most polyneuropathies. Unfortunately, however, this particular lower limb SNAP, while more often elicitable than the lateral femoral cutaneous and saphenous SNAP, can still be quite difficult to obtain consistently, primarily for various technical reasons (e.g., shock artifacts; lack of total muscle relaxation; marked obesity). Consequently, it is seldom used, despite its apparent benefits (Dumitru et al., 2002). Lower limb SEPs, for reasons already discussed under lumbar plexus assessment, are of no material value in assessing the sacral plexus. The standard lower limb H-reflex test consists of stimulating the tibial nerve in the popliteal fossa while recording from the gastrocnemius/soleus muscle group. Thus, it essentially assesses S1-fibers that traverse the superior sacral plexus, sciatic nerve, tibial nerve, and proximal posterior tibial nerve. The Hreflex is very helpful in identifying S1-radiculopathies and generalized polyneuropathies. Similar to some of the other procedures already mentioned, however, it is not used in evaluating the superior component of the sacral plexus, because its utility in this regard is quite limited. Most of its limitations in assessing lumbosacral radiculopathies apply to lumbosacral plexopathies as well (Wilbourn and Aminoff, 1998). Of particular concern is the fact that H-responses may be unelicitable bilaterally because of prior lumbosacral root surgery, or even in patients who are greater than 60 years of age. Many patients with suspected sacral plexopathies fall into one, if not both, of these categories. Moreover, even if an abnormality of the Hwave itself—affecting either the latency, the amplitude, or both—is found, typically, it is of no practical value. This is because, in contrast to the situation with S1-radiculopathies, an H-wave abnormality is extremely unlikely to be the sole finding with a sacral

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plexopathy, and the other electrophysiologic abnormalities that accompany it are far more apt to provide an adequate diagnosis than would an abnormal Hresponse alone. The latter would merely localize the lesion to some point between the popliteal fossa and the S1 segment of the spinal cord, a much too long segment of nerve to be of any clinical value (Wilbourn and Aminoff, 1998; Wilbourn, 2002). Medial and lateral plantar NCSs assess motor and sensory fibers derived from the S1 root that reach the foot via the sciatic and tibial nerves. Hence, these NCSs assess the anterior components of the superior portion of the sacral plexus. However, only rarely are they abnormal with sacral plexopathies without sural SNAPs being equally so; consequently, the information they provide usually is redundant. Moreover, they may be unelicitable bilaterally in patients 45–50 years of age or older, i.e., the age range in which the majority of the patients who have sacral plexopathies are in. Finally, they are more difficult to perform than sural NCSs, particularly the lateral plantar NCS. For these reasons, plantar NCSs contribute very little to lumbosacral plexus assessment. 31.3.4. Superior portion sacral plexopathies: specific etiologies Most superior sacral plexopathies are axon loss in type and rather severe in degree. They may be unilateral or bilateral. Bilateral lesions are most often the result of midline abnormalities, particularly neoplasms, e.g., carcinoma of the prostate or rectum. The diagnosis of this type of lumbosacral plexopathy can be made with a reasonable degree of confidence when the following combination of EDX changes is seen: (1) Low amplitude or unelicitable peroneal and tibial CMAPs, particularly when recording from the TA and gastrocnemei muscles; (2) unelicitable (occasionally just low amplitude) superficial peroneal and sural SNAPs; (3) fibrillation potentials and MUP changes in all the muscles innervated by the sciatic nerve and gluteal nerves; (4) normal needle EMG of the ipsilateral quadriceps, low lumbar and high sacral paraspinal muscle; and (5) normal superficial peroneal and sural SNAPs in the contralateral limb. An example of this “ideal presentation” follows: A 65-year-old man, with known prostate carcinoma, had experienced progressive pain and weakness in his left lower limb for three months. On motor NCSs, the peroneal and tibial CMAPs

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were low in amplitude recording from leg muscles (TA and gastrocnemei), while unelicitable recording from foot muscles (EDB and AH). In contrast, the femoral motor CMAP was normal, as were corresponding motor NCSs performed on the contralateral limb. On sensory NCSs, both the superficial peroneal and sural SNAPs were unelicitable on the left, while normal on the right. Needle EMG revealed fibrillation potentials and rather prominent MUP drop out in all the left lower limb muscles examined distal to the knee (including the TA, medial gastrocnemius, flexor digitorum longus, peroneus longus, EDB, and AH), as well as three of the four hamstring muscles, and the gluteus maximus, medius, and tensor fascia lata. In contrast, needle EMG of the left quadriceps, iliacus, and the low lumbar and high sacral paraspinal muscles, as well as selected muscles in the right lower limb, revealed no abnormalities. In this patient, the diagnosis of a unilateral (in this case, a left) sacral plexopathy can be made with considerable assurance: the ipsilateral unelicitable SNAPs and absence of ipsilateral paraspinal fibrillation potentials both speak against left L5 and S1 radiculopathies, whereas the needle EMG changes in the left glutei and tensor fascia lata exclude a high sciatic neuropathy. Unfortunately, in many patients, the “ideal presentation” of a sacral plexopathy described above is not met, for various reasons. When pelvic carcinoma is the etiology, for example, frequently the patients are elderly, they have undergone chemotherapy, and they have bilateral, although often asymmetrical, symptoms. Thus, there are at least three reasons (advanced age; polyneuropathies; bilateral sacral plexopathy) for the lower limb SNAPs to be unelicitable bilaterally, thereby causing the EDX localization to be far more equivocal. Similarly, many patients with sacral plexopathies caused by operations in the pelvic area have had major incisions through the gluteal musculature, thus compromising the localization value of any needle EMG abnormalities found in the gluteal muscles or the tensor fascia lata. In all patients with suspected sacral plexopathies, prior lumbar laminectomies negate the value of the paraspinal needle EMG examination (Wilbourn and Ferrante, 2001). Many disorders that involve the lumbar plexus equally affect the sacral plexus, although to different degrees. Thus, neoplasms are a common cause for sacral plexopathies. The sacral plexus alone is affected by neoplasms more often than the lumbar plexus (51%

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versus 31%). Overall, the sacral plexus is involved in more than two-thirds (69%) of patients with neoplastic lumbosacral plexus lesions. Metastatic lesions are particularly likely to involve the sacral plexus (Jaeckle et al., 1985; Wilbourn and Ferrante, 2001). Large vessel disease also may affect either the lumbar or sacral plexus, or sometimes both, as the following case report illustrates. A 40-year-old man experienced an aortic dissection with right iliac artery occlusion. After undergoing a femoral-femoral bypass for right lower extremity ischemia, he complained of pain and weakness in the right lower limb, particularly the anterior thigh area. The question posed by the referring vascular surgeon was whether the patient “had a femoral neuropathy or a cauda equina lesion”. On EDX examination, the right femoral CMAP was unelicitable (compared to a 10 mV response on the left), while the right peroneal and posterior tibial CMAPs were low in amplitude, with those recorded from the leg muscles being 25–50% of those of the left, and those recorded from the foot muscles being 0.5–20% of those on the left. The superficial peroneal sensory and sural SNAPs were unelicitable on the right, while normal on the left. A saphenous SNAP could not be elicited in either lower limb. On needle EMG, abundant fibrillation potentials were noted in a lumbar plexus distribution, along with absence of voluntary MUPs, whereas fibrillation potentials were less prominent, and accompanied by a reduced number of MUPs, in all the muscles examined that were innervated by the right sacral plexus (including the gluteus medius and maximus). Needle EMG of the right L4–S1 paraspinal muscles, as well as several muscles in the left lower limb, was normal. In this instance, the EDX examination demonstrated that the patient had neither a right femoral neuropathy nor a cauda equina lesion but, rather, a diffuse right pelvic plexopathy which was particularly affecting the lumbar plexus. Nonetheless, the fact that the right saphenous NCS was unelicitable (presumably for technical reasons, because a response was equally unelicitable on the left) made localization to the lumbar plexus more problematic than the localization to the sacral plexus. Not all lumbosacral plexopathies involve both lumbar and superior plexus fibers. Some preferentially, if not solely, involve one of the other. Thus, retroperitoneal

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hemorrhage far more often involves the lumbar plexus than the sacral plexus. Moreover, when it does involve the latter, almost always it also affects the former. Similarly, diabetic amyotrophy rarely involves the axons of the sacral plexus without prior involvement of those of the lumbar plexus. Conversely, the lumbosacral plexopathies associated with childbirth (i.e., maternal lumbosacral plexopathy; maternal paralysis) and those related to paracervical block anesthesia, customarily affect solely the sacral plexus. These two sacral plexopathies are noteworthy, because their characteristically underlying pathophysiology is very predominantly demyelinating conduction block, rather than axon loss. With maternal paralysis, the lumbosacral trunk portion of the sacral plexus is compressed between the fetal head and the rim of the pelvis. These patients exhibit certain symptoms in the early postpartum period, the most evident being foot drop. On peroneal motor NCSs, performed seven or more days after onset, the CMAP recorded from the weak TA muscle typically is normal, or only slightly low in amplitude, compared to that recorded from the contralateral TA. Thus, it is evident that the major pathophysiology is demyelinating conduction block. Nonetheless, definite localization depends on finding modest amounts of axon loss, in the form of fibrillation potentials, in an L5 limb distribution, plus the gluteus medius and tensor fascia lata (Katirji et al., 2002; Wilbourn, in press). 31.3.5. Inferior sacral plexopathies (pelvic floor) assessment The inferior portion of the sacral plexus, derived from the S2 through S4 roots, essentially has no limb representation. Consequently, when this segment of the sacral plexus is solely involved, characteristically no abnormalities are seen, on either NCSs or needle EMG, during lower limb assessment, with the possible exception of a few fibrillation potentials in the AH, abductor digiti quinti pedis, or soleus muscles. Nonetheless, electrophysiologic assessment of this portion of the sacral plexus can be valuable, because an appreciable number of sexual, bladder, and bowel abnormalities are caused by damage to various nerves in the pelvic floor. The latter consists of muscles, fascia, and ligaments within the bony pelvis that provide support and maintain the proper positioning of the bladder, vagina, uterus, and rectum (Roberts and Park, 1998). In general, the various neurophysiologic tests that assess the nerve supply to the pelvic floor structures are used in the following clinical situations: Urinary

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incontinence; urinary retention; fecal incontinence; erectile failure; perineal sensory disturbances; and differentiating multiple system disorders from Parkinson’s disease (Fowler, 1995; Ismael et al., 2000). The nerve supply to the pelvis floor consists of both autonomic and somatic fibers (both afferent and efferent). The major somatic nerve supplying this region is the pudendal nerve, which derives from the S2–S4 roots, and ultimately divides into several terminal nerves, including the inferior rectal (which provides motor innervation to the external anal sphincter muscle and cutaneous innervation to the skin surrounding the anus), the perineal nerve (which provides cutaneous innervation to the posterior scrotum and labia as well as motor innervation to several muscles, including the bulbocavernosus and the external urethral sphincter), and the dorsal nerve of the penis and clitoris (which provides cutaneous innervation to the penis and clitoris) (Roberts and Park, 1998; Dumitru et al., 2002). In addition to the standard surface and needle electrodes used during NCSs and needle EMG of other portions of the body, an array of special electrodes is required for assessing the innervation of the pelvic floor. These include special skin surface, pubococcygeus, vaginal, catheter mounted ring, and anal plug electrodes (Fowler, 1995). Of all the nerves supplying the pelvic floor, the only one that is assessed in many EDX laboratories is a branch of the pudendal nerve, specifically its inferior rectal branch, by needle EMG of the external anal sphincter muscle. Examination of this muscle not only is helpful with lesions involving the inferior portion of the sacral plexus, but also with those affecting the cauda equina in which there are bowel and bladder symptoms. Moreover, this procedure can be useful in diagnosing multiple system atrophy, a disorder in which the external anal sphincter is selectively affected. This is because this muscle is innervated by a subgroup of atypical alpha motor neurons, known collectively as Onuf’s nucleus, located in an anterior lateral position within the anterior horns at the S1–S3 segments of the spinal cord. For unknown reasons, these anterior horn cells, although relatively resistant to certain motor neuronopathies such as poliomyelitis and amyotrophic lateral sclerosis, are highly susceptible to damage with multiple system atrophy (Roberts and Park, 1998). (Onuf’s nucleus also contains the cell bodies that innervate the bladder sphincter; there are direct connections between these cells and the pontine micturition center (Fowler, 1995).

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Because the external anal sphincter muscle is a tonic muscle, continuous MUP firing is seen on needle EMG of it at rest. However, whenever neurogenic abnormalities affect the pelvic floor, frequently some fibrillation potentials are seen, as is reduced MUP recruitment, and occasionally definite chronic neurogenic MUP changes. (The MUPs of the external anal sphincter muscle normally are of brief duration and low amplitude. Consequently, if the MUPs seen have the appearance of those observed in the limb muscles, then they are chronic neurogenic in nature.) A number of other procedures are available for assessing the nerves that supply the pelvic floor, including the following. First, pudendal NCSs, which consist of a pudendal nerve terminal motor latency if the recording site is the external anal sphincter, and a perineal nerve terminal motor latency if the recording site is the urethral sphincter. These studies often are abnormal (i.e., prolonged in latency) in patients with fecal or urinary incontinence, respectively. However, such slowing has no direct relationship to clinical weakness. Moreover, regardless of whether these latencies are normal or prolonged (or even if the responses are unelicitable), they have no predictive value in regard to whether surgical repair will be successful. Second, sacral reflex testing which, as noted, consists of eliciting contractions in various pelvic floor muscles by applying electrical stimuli to the skin or mucosa of the urethra, perineum, or anus. These studies typically require that the motor-evoked responses be prolonged in latency. However, for some of them, the pathways assessed are poorly defined. Moreover, all of them can be technically difficult to perform, and may yield results which are equally difficult to interpret. Third, electromyography (i.e., needle EMG) of various pelvic floor muscles. The assessment of the external anal sphincter, as already noted, is performed in many EDX laboratories. Other muscles that may be sampled are the puborectalis, the external urethral sphincter, and the bulbocavernosus. Fourth, motor-evoked potentials, recorded from the urethral sphincter, anal sphincter, or bulbocavernosus muscle, using transcortical or transcutaneous spinal (L1–L4) stimulation, generated either electrically or magnetically. Fifth, SEPs obtained by stimulating the pudendal nerve, posterior urethra, or bladder neck while recording from the cortex (Fowler, 1995; Roberts and Park, 1998; Ismael et al., 2000; Dumitru et al., 2002). With the possible exception of needle EMG of the external anal sphincter, all the various electrophysio-

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logic tests for assessing the nerve supply to the pelvic floor yield accurate, reproducible results only when they are performed, and interpreted, by highly trained and skilled practitioners. Even in these instances, problems persist, such as the absence of standardized techniques, and the lack of normal values. Nonetheless, these tests have been demonstrated to be helpful in several situations, including the following: (1) Localizing a lesion to the lower portion of the sacral plexus, or nerves derived through it, following pelvic trauma; (2) Detecting an unsuspected PNS lesion (e.g., a sacral plexopathy) in patients with presumed psychogenic voiding disorders; and (3) Differentiating between denervated and innervated muscle prior to surgical sphincter repair (Roberts and Park, 1998). Although these tests are customarily not performed in most EDX laboratories (again, with the possible exception of needle EMG of the external anal sphincter muscle), they probably will gain wider use in the future. A recent report, for example, indicates that childbirth can cause damage to the inferior portion of the sacral plexus, resulting in perineal sensory disturbances, without any accompanying abnormalities of the lower limbs (i.e., without coexisting damage to the superior portion of the sacral plexus) (Ismael et al., 2000). References Chang, CW and Lien, IN (1990) Spinal nerve stimulation in the diagnosis of lumbosacral radiculopathy. Am. J. Phys. Med. Rehabi., 69: 318–322. Chokroverty, S and DiLullo, J (1998) Magnetic coil stimulation of the lumbosacral roots and proximal nerves. Muscle Nerve, 11: 996–997. Chokroverty, S, Sachdeo, R, DiLullo, J and Duvoisin, RC (1989) Magnetic stimulation in the diagnosis of lumbosacral radiculopathy. J. Neurol. Neurosurg. Psychiatry, 52: 767–772. Date, EF, May, EY, Burgola, MR and Teraoka, JK (1996): The prevalence of lumbar paraspinal spontaneous activity in asymptomatic subjects. Muscle Nerve, 19: 350–354. Dumitru, D, Amato, T and Zwarts, MJ (2002) Electrodiagnostic Medicine. Hanley & Belfus, Philadelphia, IInd ed. Eisen, AA (1993) The electrodiagnosis of plexopathies. In: WF Brown, CF Bolton (Eds.), Clinical Electromyography, Butterworth-Heinemann, Stoneham, pp. 211–225. Ferrante, MA and Wilbourn, AJ (2001) Plexopathies, In: KH Levin, HO Lüders (Eds.), Comprehensive

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Clinical Neurophysiology, WB Saunders, Philadelphia, pp. 201–214. Fisher, MA (1992) AAEM Minimonograph #13: Hreflexes and F-waves: physiological and clinical indications. Muscle Nerve, 15: 1123–1233. Fowler, C (1995) Pelvic floor neurophysiology. In: JW Osselton (Ed.), Clinical Neurophysiology: EMG, Nerve Conductions and Evoked Potentials, Butterworth-Heinemann, Oxford, pp. 233–252. Ismael, SS, Amarenco, G, Bayle, B and Kerdraon, J (2000) Postpartum lumbosacral plexopathy limited to autonomic and perineal manifestations: Clinical and electrophysiological study of 19 patients. J. Neurol. Neurosurg. Psychiatry, 68: 71–73. Jaeckle, KA, Young, DF and Foley, KM (1985) The natural history of lumbosacral plexopathy in cancer. Neurology, 35: 8–15. Katirji, B, Wilbourn, AJ, Scarberry, JL and Preston, DC (2002) Intrapartum maternal lumbosacral plexopathy. Muscle Nerve, 28: 340–347. Levin, KH (1998) L5 radiculopathy with reduced superficial peroneal sensory responses: Intraspinal and extraspinal causes. Muscle Nerve, 21: 3–7. Liveson, JA and Ma, DM (1992) Laboratory Reference for Clinical Neurophysiology. FA Davis, Philadelphia. MacDonell, RAL, Cros, D and Shahani, BT (1992) Lumbosacral nerve root stimulation: Comparing surface with magnetic coil techniques. Muscle Nerve, 15: 885–890. MacLean, IC (1980) Nerve root stimulation to evaluate conduction across the brachial and lumbosacral plexuses, In syllabus: Recent Advances in Clinical Electromyography. American Association of Electromyography and Electrodiagnosis, Rochester (MN), pp. 51–55. Mumenthaler, M and Schliack, H (1991) Peripheral Nerve Lesions, Theme Medical, New York. Nardin, RA, Raynor, EM and Rutkove, SB (1998) Fibrillations in lumbar paraspinal muscles of normal subjects. Muscle Nerve, 21: 1347–1349.

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Oh, SJ (2003) Clinical Electromyography: Nerve Conduction Studies. Lipincott, Williams & Wilkins, Philadelphia, IIIrd ed. Roberts, MM and Park, TA (1998) Pelvic floor function/ dysfunction and electrodiagnostic evaluation. Phys. Med. Rehabil. Clin. N. Am., 9: 831–851. Rutkove, SV and Sax, TW (2002) Lumbosacral plexopathies, In: B Katurji, HJ Kaminski, DC Preston, RL Ruff, BE Shapiro (Eds.), Neuromuscular Disorders in Clinical Practice, ButterworthHeinemann, Boston, pp. 907–915. Tavee, JO, Mays, MA and Wilbourn, AJ (2003) Pitfalls in the electrodiagnostic (EDX) studies of lumbosacral plexopathies. Neurology, 60(Suppl. 1): A347. Weber, M (2002) Lumbosacral plexopathies, In: WF Brown, CF Bolton, MJ Aminoff (Eds.), Neuromuscular Function and Disease, WB Saunders, Philadelphia, Vol. 1, pp. 852–864. Wilbourn, AJ: Plexus injuries. In: Evans, RW (ed.): Neurology and trauma, 2nd ed., Oxford U. Press (in press). Wilbourn, AJ (2004) Brachial plexopathies. In: PJ Dyck, PK Thomas, Peripheral Neuropathies. WB Saunders, Philadelphia, IVth ed., in press. Wilbourn, AJ (2002) Nerve conduction studies: types, components, abnormalities, and value in localization. Neurol. Clin. N Amer., 20: 305–228. Wilbourn, AJ (1993) Diabetic Neuropathies, In: WF Brown, CF Bolton (Eds.), Clinical Electromyography, Butterworth-Heinemann, Boston, IInd ed., pp. 477–515. Wilbourn, AJ and Ferrante, MA (2001) Plexopathies, In: R Pourmand (Ed.), Neuromuscular Diseases: Expert Clinicians Views, Butterworth-Heinemann, Boston, pp. 493–527. Wilbourn, AJ and Aminoff, MJ (1998) The electrodiagnostic examination in patients with radiculopathies. Muscle Nerve, 21: 1612–1631.

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CHAPTER 32

Neuropathies associated with medical conditions James W. Teenera,* and James W. Albersb Department of Neurology, University of Michigan Health System, MI, 48109-0032, USA

32.1. Introduction This chapter will explore the most common types of polyneuropathy, those associated with general medical conditions. In the developed world, diabetes mellitus is the leading cause of neuropathy. Worldwide, the infectious disease leprosy assumes the leading role in producing neuropathy. These medical conditions, and others, will be discussed below with particular attention to the clinical neurophysiology of each condition. In some situations, the medical condition will be known and the development of a polyneuropathy is an expected potential complication. In these situations, vigilance for the presence of neuropathic signs and symptoms allows identification of the neuropathy at its earliest stages. Appropriate therapy can then be initiated. Therapy may include specific measures to treat the neuropathy, as is typical with immune mediated or infectious processes. Perhaps more commonly, the neuropathy therapy will be more supportive in nature, such as bracing for weak joints or patient education to prevent traumatic complications in an insensate foot. Further discussion of therapy for the various neuropathies which follow is beyond the scope of this volume. A larger challenge presents when a neuropathy develops de novo, without any known underlying medical condition. The differential diagnosis here obviously includes primary neuropathies such as chronic inflammatory demyelinating polyneuropathy, but more likely there is an unrecognized underlying medical condition. The search for such underlying medical conditions now assumes

* Correspondence to: James W. Teener, MD, Department of Neurology, 1C325/0032 University Hospital, University of Michigan Health System, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-0032, USA. E-mail address: [email protected]) Tel.: +1-734-936-8586; fax: +1-734-936-5185.

great importance. The challenge is to choose the appropriate diagnostic testing within the limits of patient tolerance and the economic realities of medical practice. It is simply not possible to test every patient for every possible medical condition related to neuropathy. Thankfully, such a “shotgun” approach is not only inefficient, it is unnecessary. Results from a carefully taken history and examination combined with results from nerve conduction studies and electromyography narrow the differential diagnosis. At this point, further studies can be rationally chosen to hone in upon the cause of the neuropathy. 32.2. Types of neuropathy most often associated with medical conditions Most polyneuropathies result in length-related, distal greater than proximal, sensory loss, weakness and hyporeflexia. This classic description is appropriate for the common distal symmetric polyneuropathy (DSP), but a variety of other patterns are also encountered. Patients with DSP typically report sensory disturbances involving the feet as the presenting symptom. These disturbances may be “negative” in nature, involving loss of sensation described as numbness or deadness. Even in the presence of such sensory loss, “positive,” dysesthetic sensory symptoms are common as well. These are often described as tingling or “pins and needles,” and can range from mild to very severe. Most patients will describe some degree of thermal sensation, such as “my feet are cold as ice” or “my feet feel like they are on fire.” Allodynia, the perception of severe pain following an innocuous stimulus such as light touch, is a common and very disturbing symptom. Clinically important weakness usually only develops late in the progression of the neuropathy, though signs of motor involvement such as wasting of intrinsic foot muscles are present much earlier. Neurologic examination reveals sensory abnormalities in a length-related pattern. As the sensory loss ascends to near the knees, abnormalities

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will typically be detected in the hands. A bit later, sensory impairment over the anterior chest and abdomen also can be demonstrated. Hyporeflexia is typical. Weakness may not be present in the early stages, but usually develops in the lower legs and feet as the neuropathy progresses. Further details of the clinical examination of neuropathy follow below. A second common pattern seen with neuropathies associated with medical conditions is mononeuritis multiplex, also known as mononeuropathy multiplex. This condition results from the accumulation of insults to multiple nerves. A typical mechanism involves ischemic injury to nerves. Multifocal demyelination, as can develop in chronic inflammatory demyelinating polyneuropathy, may also produce mononeuropathy multiplex pattern. Because this type of injury is more or less random, any nerve can be involved and the pattern of involvement is often asymmetric. However, because longer nerves present a greater area for potential insult, they tend to be more affected. This results in a pattern that can mimic the distal symmetric polyneuropathy. As mononeuritis multiplex becomes more widespread, the nerve involvement may become confluent, making clinical differentiation from DSP difficult, if not impossible. Both sensory and motor function is typically involved, but on occasion the deficit may be much more apparent in one modality. Pain is common with most causes of mononeuritis multiplex. Other patterns of nerve involvement are seen less frequently in association with medical conditions. Some important, if rare, patterns include purely sensory neuropathy/neuronopathy, purely motor neuropathy/neuronopathy and polyradiculopathy. While these patterns may be highly suspected based upon history and examination, neurophysiologic testing is often needed to identify these patterns of neuropathy with certainty. Because they are seen in association with only a few conditions, the identification of one of these patterns often rapidly leads to the identification of an underlying medical condition. Some examples include the pure sensory neuropathy seen in Sjögren’s syndrome and the severe polyradiculopathy caused by cytomegalovirus infection among patients with acquired immunodeficiency syndrome (AIDS). 32.3. Clinical evaluation of polyneuropathy Identification of the pattern of involvement in the peripheral nervous system is the first step toward identifying the underlying cause of the neuropathy. A variety of clinical neurophysiologic procedures help to

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define the characteristics of the neuropathy. Most clinicians find the peripheral nervous system examination less complicated than examination of the central nervous system or behavior. In the context of suspected neuropathy, the examiner looks for signs of impairment, placing greatest emphasis on the most objective signs. For example, muscle stretch reflexes are sensitive to mild levels of abnormality, yet independent of patient motivation, education, level of concentration, or effort. Subjective signs of peripheral dysfunction include most of the clinical sensory tests, making these tests more difficult to interpret. The sensory examination includes evaluation of large sensory fibers subserving vibration, joint position, and touchpressure (“fine-touch”) sensations, and evaluation of small sensory fibers subserving pin-pain and temperature sensations. Light touch is difficult to quantify but, nevertheless, frequently abnormal in large fiber neuropathies. Joint position is a relative insensitive measure of sensory function relative to vibration sensation. Joint position abnormalities do not appear until a neuropathy becomes moderately severe. In contrast, Romberg testing accentuates abnormalities of joint position sensation. Maintaining balance with the eyes closed is a functional sensory test when other problems, such as disorders of the vestibular system, are excluded. Normal balance with the eyes closed is inconsistent with other than a mild large fiber sensory neuropathy. Pin-pain sensation is a sensitive indicator of small fiber dysfunction. Small fiber dysfunction is common in neuropathies associated with medical conditions. Routine nerve conduction studies and electromyography are insensitive to small fiber dysfunction, making the clinical examination of paramount importance in evaluating small fiber dysfunction. Newer neurophysiologic techniques as discussed below promise to improve evaluation of small fiber dysfunction. Most neuropathies that involve motor fibers are most severe in the distal lower extremities. Careful examination of the feet may reveal atrophy and weakness. Severe sensory loss can produce complaints of weakness, presumably due to impairment of proprioception and afferent feedback from muscle. In this setting, the patient must be coached to produce maximal effort. Experienced clinicians can typically correctly determine that motor function is normal in this situation. Identification of high arches and hammer toe deformities raises the possibility of an inherited neuropathy or other very chronic process rather than a recently acquired neuropathy.

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Reflex abnormalities are found in most clinically significant neuropathies, most typically in the form of absent ankle reflexes. The afferent reflex arc is mediated by large sensory axons, the axons most often involved in polyneuropathies. The reflex examination results are reproducible, and absent ankle reflexes are an important sign of neuropathy. Reflexes that are easily elicited with facilitation should not be considered abnormal. The neurological examination includes substantial redundancy, increasing the overall reliability of combined findings. For example, fine touch, vibration, ankle reflexes, and balance (Romberg) are all mediated by the same large sensory axons. Therefore, a neuropathy producing loss of vibration sensation usually results in a positive Romberg sign and abnormal ankle reflexes.

to the peripheral nervous system. Additional questions addressed by the EMG evaluation include: (1) Do abnormalities involve primarily or exclusively sensory axons, motor axons, or a combination of both? (2) Are the abnormalities best explained by a polyneuropathy (diffuse involvement of nerves), a mononeuropathy multiplex (multifocal involvement of individual nerves), or a polyradiculopathy (diffuse involvement of nerve roots)? (3) Is there substantial slowing of nerve conduction to an extent greater than can be explained by loss of large caliber axons? The EMG protocol is designed to answer these questions and thereby characterize the patient’s neuropathy, using anatomical and physiological information to define the patient’s problem.

32.4. Neurophysiologic approach to neuropathies associated with medical conditions

A predominance of small nerve fiber dysfunction is seen in neuropathies associated with several common medical conditions. Because small fiber function is poorly evaluated by routine EMG studies, a variety of other techniques have been developed in an attempt to better evaluate small nerve fiber pathology. The bestevaluated procedures include the sympathetic skin response, quantitative sensory testing, the quantitative sudomotor axon reflex test (QSART) and other tests of sudomotor and autonomic function. These techniques are discussed in detail elsewhere in this volume.

32.4.1. Electromyography and nerve conduction studies Nerve conduction studies and needle electromyography are the most common neurophysiologic procedures employed in the evaluation of polyneuropathy. Few clinicians would debate the importance of the electrodiagnostic examination in the evaluation of neuropathy. These examinations are the foundation of Electrodiagnostic Medicine, and the results of these studies are used to confirm clinical signs, localize lesions to a degree not clinically possible, and identify pathophysiologic mechanisms (Albers, 1993). Nerve conduction studies play a prominent role in the evaluation of suspected neuropathy. The results are important in defining the type, distribution, and degree of peripheral involvement. Importantly, sensory conduction studies are the only non-invasive measures available to localize sensory loss to the periphery. The role of the needle EMG examination in the evaluation of neuropathy is less important than that of nerve conduction studies. The needle EMG examination is used to document the distribution of axonal lesions and identify disorders such as polyradiculopathy that may be clinically indistinguishable from neuropathy. In addition, information derived from the needle examination also addresses questions related to the duration and extent of axonal injury more readily than do the nerve conduction study results (Albers, 1993). The most fundamental question addressed by the EMG evaluation involves localization of an abnormality

32.4.2. Other tests used in evaluation of small fiber neuropathy or autonomic dysfunction

32.4.3. Histopathology Even though electrophysiologic evaluation plays the primary role in the evaluation of neuropathy, it often does not provide a definitive diagnosis. If the combination of clinical examination, electrophysiology and selected laboratory evaluation does not reveal a satisfactory explanation for the neuropathy, nerve biopsy should be performed. Nerve biopsy may provide evidence of the precise underlying pathology, as is typical the case with vasculitic neuropathies. The nerve most commonly biopsied is the sural sensory nerve. Other nerves commonly biopsied include the superficial peroneal sensory branch and the superficial radial sensory branch. It is extremely unusual to biopsy nerves containing motor axons, although in select circumstances a biopsy of a small motor fascicle may be performed. Obviously, there is likely to be some degree of motor dysfunction caused by this procedure. Most nerve biopsy specimens are processed for routine light microscopy. In special instances, electron

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microscopy may provide additional information, particularly in the evaluation of neuropathic processes involving small nerve fibers which may be difficult to accurately quantitate on light microscopy. Small fiber histopathology may also be assessed via the evaluation of epidermal nerve fiber density in very small skin “punch” biopsies (Kennedy et al., 1996). This technique was made possible by the identification of an antibody against protein gene product 9.5 which binds to all axons in the peripheral nervous system. Prior to the development of this antibody, nerve fibers were treated to highlight myelin, and most small nerve fibers are unmyelinated, and thus go unstained on traditional studies. The antibody vividly identifies small nerve fibers present in the epidermis. Current techniques rely predominantly on quantitative measurement of the fiber density, and morphologic analysis of the fibers is limited. The technique does not allow the detection of processes such as vasculitis or amyloidosis beyond identifying the axonal loss. Despite these limitations, evaluation of epidermal nerve fiber density is increasingly recognized as a valuable tool in the investigation of small fiber neuropathies and has been reported to be a sensitive measure of pathology in neuropathies associated with medical conditions, particularly diabetes and HIV infection. 32.4.4. Other testing A variety of other laboratory and pathologic studies are often required to complete the investigation of medical conditions that may be causing neuropathy. These tests will be presented where applicable in the following sections devoted to specific medical conditions. 32.5. Medical conditions frequently associated with neuropathy 32.5.1. Diabetes mellitus

JAMES W. TEENER AND JAMES W. ALBERS Table 32.1 Diabetic neuropathies Polyneuropathies

● ● ●

●

Focal / Multifocal neuropathies

●

●

● ●

Distal symmetric polyneuropathy Autonomic neuropathy Acute painful diabetic neuropathy Treatment induced (insulin) neuropathy Diabetic lumbosacral radiculoneuropathy (Diabetic amyotrophy, proximal motor neuropathy) Diabetic thoracolumbar radiculoneuropathy Mononeuropathies Cranial neuropathies

most forms of diabetic neuropathy, a variety of palliative therapies are available. It is critical to implement appropriate palliative therapies in order to minimize complications of neuropathy such as diabetic foot ulcer. In addition, tight and consistent control of serum glucose levels slows the progression of diabetic neuropathy (DCCT, 1993, 1995). In many patients, the appearance of neuropathic symptoms will lead to the diagnosis of diabetes or glucose intolerance. The American Diabetes Association definitions for conditions of abnormal glucose metabolism are listed in Table 32.2. All persons presenting signs or symptoms of unexplained neuropathy should be screened for diabetes. Studies have indicated that even impaired glucose tolerance is associated with neuropathy, particularly painful small fiber distal symmetric neuropathy (Novella et al., 2001; Russell and Feldman, 2001; Singleton et al., 2001). For this reason, a glucose tolerance test is recommended as a Table 32.2 ADA definitions of abnormal glucose metabolism

Diabetes is the leading cause of neuropathy in North American and likely most of the developed world. The term “diabetic neuropathy” is something of a misnomer, given the diverse nature and number of different neuropathic syndromes which are associated with diabetes. (Table 32.1) Some degree of neuropathy is present in most patients who have lived with diabetes for years (Dyck, 1993). In patients with known diabetes, the clinician’s focus should be on early identification of neuropathy. Although there is no specific treatment at present for

Diabetes

Impaired glucose tolerance Impaired fasting glucose

Symptoms of diabetes associated with random glucose >200 mg/dl or a fasting glucose >126 mg/dl or 2 hr postprandial glucose >200 mg/dl during oral 75g glucose tolerance test 2 hr postprandial glucose 140–200 mg/dl Fasting glucose 110–126 mg/dl

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screening mechanism because glucose intolerance is often identified even in the presence of normal hemoglobin A1C levels and random glucose levels (Simmons and Feldman, 2002). 32.5.1.1. Distal symmetric polyneuropathy A distal predominantly sensory polyneuropathy (DSP) is the most common neuropathy associated with diabetes. This is a classic length-related neuropathy with initial involvement of the toes. It shows a slow evolution to involve first the lower legs, and then the fingers and hands, in the so-called “stocking-glove” distribution. The loss of sensation in the feet, along with associated autonomic changes, contributes directly to the very dangerous development of diabetic foot ulcers and Charcot joints (Most and Sinnock, 1983; Reiber et al., 1999; Report, Department et al., 1999; Simmons and Feldman, 2002; Perkins and Bril, 2003). Motor involvement is relatively minimal, although denervation changes are demonstrable on needle examination of the distal foot muscles of most patients with diabetic DSP. Autonomic neuropathy frequently, though not always, accompanies the DSP (Low et al., 2003). The severity of the neuropathy is often associated with poor control and longstanding diabetes, although DSP is not infrequently the presenting manifestation of diabetes mellitus. Two related polyneuropathy syndromes have been well described in diabetic patients but occur less commonly. A severely painful condition associated with rapid weight loss in diabetic patients has been called diabetic neuropathic cachexia or acute painful neuropathy of diabetes (Ellenberg, 1974; Archer et al., 1983). It is not universally accepted that this entity is pathophysiologically different from DSP (Taylor and Dyck, 1999). Another painful neuropathy experienced by diabetic patients is treatment-induced diabetic neuropathy, also known as insulin neuritis. This entity also is quite controversial in terms of its relationship to more typical diabetic neuropathies, but it is well recognized by clinicians who care for a large number of diabetic patients that a small number of them will develop a severely painful neuropathy at the onset of insulin treatment (Said et al., 1998). Neither of these two unusual neuropathies has any unique neurophysiological feature to specifically support their clinical diagnosis. 32.5.1.1.1. Nerve conduction studies. Changes in the distal sensory responses are the first abnormalities detected on routine nerve conduction studies in DSP. Sural SNAP amplitudes are typically reduced, often

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with a generalized mild to moderate slowing of conduction (Albers et al., 1995). This conduction slowing often is somewhat greater than expected for the degree of axonal loss, but does not fall to a level typically associated with demyelinating neuropathies (Herrmann et al., 2002). Sensory nerve conduction abnormalities may be present in 50% of asymptomatic diabetic patients and in 80% of patients with neuropathic symptoms. Motor nerve conduction abnormalities typically appear later and are less prominent than sensory nerve conduction abnormalities. Again, conduction velocities and distal latencies reflect a degree of slowing greater than expected for axonal loss alone (Kimura and Butzer, 1979; Herrmann et al., 2002). F-wave latencies are also prolonged, with distal segments demonstrating greater slowing than proximal segments (Kimura and Butzer, 1979). Table 32.3 presents data from two large studies comparing motor conduction velocities and F-wave latencies in diabetic patients and controls. Because of the conduction slowing seen in diabetic DSP, it may not be possible to differentiate CIPD from diabetic neuropathy using electrophysiologic criteria alone. One study has demonstrated that widely used formal electrodiagnostic criteria for demyelination may be met in many patients with diabetic neuropathy, and that none of these criteria showed a significant difference between patients with biopsy proven CIDP and diabetic neuropathy (Wilson et al., 2000). 32.5.1.1.2. Needle electromyography. The needle electromyographic examination typically reveals fibrillation potentials and positive waves in intrinsic foot Table 32.3 Comparison of motor conduction velocities in diabetics and controls Study

Reference

Control

Diabetic

Ulnar motor CV

Ref. 1 Ref. 2 Ref. 1 Ref. 2 Ref. 1 Ref. 2 Ref. 1 Ref. 2

60.9 m/s 63.4 m/s 48.6 m/s 49.6 m/s 48.8 ms 49.3 ms 26.3 ms 28.5 ms

55.8 m/s 50.9 m/s 38.6 m/s 39.3 m/s 59.5 ms 60.8 ms 29.8 ms 33.7 ms

Tibial motor CV Tibial F-wave lat. Ulnar F-wave lat.

Key: CV = conduction velocity, Ref. 1 (Fierro, Modica et al., 1987), Ref. 2 (Kimura and Butzer, 1979).

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muscles. If the neuropathy is mild, the needle examination may be entirely normal. More proximal muscles become involved as the neuropathy worsens, but the pattern remains length-related. Chronic re-innervation changes in the motor unit morphology are seen as expected with chronic axonal loss. 32.5.1.1.3. Other electrodiagnostic studies. Abnormalities in blink reflex response testing have been identified in diabetic patients (Mazzotta et al., 1988; Nazliel et al., 2001). Blink reflex response testing is performed by stimulating over the supraorbital nerve while simultaneously recording from bilateral orbicularis oculi muscles. The normal response includes a short latency ipsilateral R1 response followed later by a bilateral R2 response. The response is affected by lesions of the afferent cranial nerve V, the efferent cranial nerve VII, as well as lesions of the brainstem pathway. In diabetics with DSP but no cranial nerve abnormalities, blink response abnormalities were detected in 55% of patients in one study (Nazliel et al., 2001). Blink reflex response testing appears to be a sensitive measure of cranial nerve involvement in diabetics even in the absence of clinically apparent cranial nerve dysfunction. F-wave latency has been studied as a sensitive measure of nerve dysfunction in diabetic DSP. Measurement of the F-wave latency was found to be highly reproducible in diabetic patients (Kohara et al., 2000). This is particularly important in clinical trials where serial measures of nerve dysfunction are followed. The F-wave latency has also been found to often be prolonged in diabetic patients, even when routine nerve conduction studies were normal (Celiker et al., 1996). 32.5.1.1.4. Other studies. Nerve biopsy is typically not clinically indicated in most cases of diabetic neuropathy. It may be needed if there is a question of a coexistent connective tissue disease or vasculitis, or occasionally to help answer the very difficult question of whether a superimposed inflammatory demyelinating neuropathy is present. The nerve biopsy in typical diabetic DSP reveals axonal degeneration, more prominent distally than proximally (Giannini and Dyck, 1995, 1999). Segmental demyelination may be present but is not the most prominent pathology. Regenerating axonal clusters are often present. Blood vessels may be abnormal, as well. Endothelial hyperplasia is seen in nerve arterioles and capillaries just as it is seen in many other tissues of diabetic patients.

JAMES W. TEENER AND JAMES W. ALBERS

Evaluation of the density of nerve fibers in a small area of epidermis taken via small skin punch biopsy is proving to be a reliable method to assess small nerve fiber populations (Kennedy et al., 1996). This technique has the distinct advantage of being easily repeatable and minimally invasive. This makes it ideal to evaluate the progress of neuropathy over time, and for assessing the success of treatments developed for neuropathy. Autonomic involvement often is a feature of diabetic DSP. When the autonomic features predominate, the term diabetic autonomic neuropathy is applied. A myriad of autonomic symptoms and signs, including dry eyes and mouth, altered sweating, pupillary changes, cardiac arrhythmias, orthostatic hypotension, gastroparesis, diarrhea, impotence, and bladder incontinence often exist. Autonomic studies typically performed in the clinical autonomic laboratory include measurement of supine and upright blood pressure, heart rate variation with deep breathing and valsalva maneuver, heart rate change on assuming the upright position and the QSART. More sophisticated laboratories have the ability to measure “beat to beat” blood pressure and its changes with valsalva and position change. These tests confirm the presence of abnormalities when expected clinically and may reveal unsuspected autonomic disturbances in patients without clear autonomic symptoms. Electrodiagnostic studies are available to evaluate genitourinary dysfunction. In addition to urodynamic studies typically performed by urologists, electrodiagnostic studies such as the pudendal nerve conduction study and the bulbocavernosus reflex may provide specific localizing data regarding urogenital dysfunction. The bulbocavernosus reflex is often abnormal in impotent diabetic men. However, studies have revealed that these patients almost always have electrodiagnostic evidence of a diabetic DSP on routine nerve conduction studies, thus bringing into question the utility of these studies in the clinical electrophysiology laboratory (Desai et al., 1988; Bird and Hanno, 1998). Needle examination of the bulbocavernosus muscle and the anal sphincter is also well described. 32.5.1.2. Diabetic radiculopathy/polyradiculopathy/ polyradiculoneuropathy Patients with diabetes are prone to the development of a variety of neuropathic lesions which localize to single or multiple spinal roots. These lesions do not have an apparent structural etiology, and their precise pathogenesis is a matter of controversy (Said, 1994; Krendel and Zacharias, 1997; Said et al., 1997;

NEUROPATHIES ASSOCIATED WITH MEDICAL CONDITIONS

Llewelyn et al., 1998). Some evidence supports the presence of an immune mediated microangiopathy, but the natural history of these disorders is that they typically improve spontaneously over months. This course is quite different from the natural history of true vasculitic neuropathies. Perhaps the most striking of these radiculoneuropathies is the asymmetric painful polyradiculoneuropathy which typically affects one leg. This condition is commonly known as diabetic amyotrophy, proximal diabetic neuropathy, diabetic lumbosacral radculoplexopathy, or Bruns–Garland syndrome (Bruns, 1890; Raff et al., 1968; Asbury, 1977; Bastron and Thomas, 1981; Barohn et al., 1991). This neuropathy typically affects older diabetic patients. It begins with severe thigh, hip and back pain. Leg weakness and atrophy follow days to weeks later, usually involving thigh muscles. Sensory symptoms other than the severe pain are less prominent, although many patients report some degree of paresthesia and numbness. Prominent weight loss often occurs around the time of onset. This neuropathy is often superimposed upon the distal symmetric polyneuropathy. Unusual variants include clinically apparent bilateral involvement and neuropathies with prolonged progression. Typically, the neuropathy stabilizes over months and a slow, albeit typically incomplete, recovery begins. EMG studies reveal changes of a typical diabetic DSP with superimposed acute denervation in muscles of the affected leg, often most severe in proximal musculature. However, the term proximal diabetic neuropathy is somewhat of a misnomer given the evidence of denervation involving paraspinal muscles as well as multiple muscles of the affected leg (Chokroverty, 1982, 1987). Radiculopathies and polyradiculopathies also occur frequently in the thoracic region in diabetic patients (Massey, 1980; Sun and Streib, 1981; Waxman and Sabin, 1981). Pain is a universal complaint, often of abrupt onset but at times evolving over days. It is centered over a thoracic spinal level with radiation in a typical thoracic radicular pattern, although several adjacent levels may be affected. The pain is often severe, boring, stabbing or bandlike and is not relieved by stretching or other position changes. Objective neurological signs may be minimal, but sensory disturbances such as hypesthesia or hyperpathia usually can be demonstrated in the expected thoracic dermatomes. Abdominal muscles may be weak. Nerve conduction studies are of limited utility, except that diabetic thoracic radiculoneuropathy usually occurs in patients with coexistent diabetic DSP.

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Needle examination typically reveals abnormal spontaneous activity in the expected thoracic paraspinal, abdominal wall, and intercostal muscles (Massey, 1980; Sun and Streib, 1981). 32.5.2. Hypothyroidism There is some debate about the clinical importance of the neuropathy associated with hypothyroidism. Certainly, muscle dysfunction associated with hypothyroid myopathy produces more clinically important symptoms, but hypothyroidism is clearly recognized as a cause of a mild polyneuropathy. Many hypothyroid patients report distal paresthesias and sensory loss (Galassi et al., 1984; Nemni et al., 1987; Beghi et al., 1989; Misiunas et al., 1995; Duyff et al., 2000). Compression mononeuropathies are probably a more important clinical problem than polyneuropathy in hypothyroid patients (Purnell et al., 1961; Rao et al., 1980; Khedr et al., 2000). 32.5.2.1. Nerve conduction studies Hypothyroid neuropathy is typically a mild DSP which predominantly involves sensory fibers. Most reports of hypothyroid neuropathy indicate that mild prolongation of sensory distal latencies is the most commonly encountered abnormality on nerve conduction studies. Distal sensory response amplitudes also are slightly reduced. Motor responses are usually normal with some mild amplitude reduction and conduction slowing in rare instances when the neuropathy is of more moderate severity (Dyck and Lambert, 1970; Beghi et al., 1989; Misiunas et al., 1995). 32.5.2.2. Needle electromyography Needle examination is often normal or perhaps indicative of very mild denervation in distal most muscles. Mild myopathic changes are more likely to be seen. 32.5.2.3. Other studies Evoked potential studies may detect mild slowing of central nervous system conduction in hypothyroid patients (Huang et al., 1989; Khedr et al., 2000). Latencies of visual, brainstem and somatosensory evoked potentials are typically slightly prolonged, with demonstrated return to normal in the euthyroid state. 32.5.3. Uremia Prolonged impairment of renal function causes neuropathy. The impairment of renal function typically is

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at least moderately severe, with BUN levels greater than 5–6 mg/dl (Bazzi et al., 1991). When renal function is restored via kidney transplant, or supplemented with dialysis, nerve function improves (Bolton et al., 1971; Malberti et al., 1991). Despite this weighty circumstantial evidence, the mechanism by which uremia results in neuropathy is uncertain. No single toxin has been identified and the pathologic process is presumed to be multifactorial. Clinically, uremic neuropathy typically presents with symmetric distal sensory loss, particularly involving large fiber function (Angus-Leppan and Burke, 1992). Quantitative sensory testing reveals early involvement of large fibers as indicated by impaired vibratory threshold (Klima et al., 1991). Abnormalities of vibratory threshold may precede abnormalities on nerve conduction studies (Hilz et al., 1995). Patients often report tingling paresthesias as well as a constricted, swollen feeling in the feet. The interesting phenomena of reversal of hot/cold perception may occur in uremic neuropathy, whereby a cold stimulus is perceived as hot (Yosipovitch et al., 1995). Restless leg syndrome occurs frequently in uremic patients and may be related to the neuropathy. Weakness typically develops only when the sensory function is severely impaired, although intrinsic foot muscle atrophy may be present. Arms are involved only if the uremia remains untreated and the neuropathy becomes very severe (Nielsen, 1974). 32.5.3.1. Nerve conduction studies Abnormalities of sensory amplitude can be detected prior to patients reporting symptoms in large prospective studies of patients with renal failure (Bazzi et al., 1991). Sensory response amplitudes are reduced or absent in the feet and sometimes in the hands if the neuropathy is severe. Motor involvement is less prominent than sensory involvement. Sensory and motor conduction velocities are often mildly reduced, but not to the range associated with demyelination (Bazzi et al., 1991). 32.5.3.2. Needle electromyography Needle examination reveals changes indicative of distal axonal loss. Although abnormal spontaneous activity may be detected in foot and distal leg muscles, there is some indication that the degree of fibrillation potentials and positive waves is less than expected for the degree of axonal loss. The explanation for this phenomenon is uncertain.

JAMES W. TEENER AND JAMES W. ALBERS

32.5.3.3. Other electrodiagnostic studies F-wave latency has been determined to be a sensitive measure of nerve dysfunction in uremic patients. Prolongation of F-wave latency may be noted in the absence of other abnormalities on nerve conduction studies. The F-wave latency remained stable over a period of 5 years during treatment with hemodialysis (Ogura et al., 2001). In a study of 30 uremic patients, the average ulnar and tibial F-wave latencies were 30.75 and 57.5, respectively. Thirty control subjects had ulnar and tibial latencies of 26.29 and 48.8, respectively (Fierro et al., 1987). 32.5.3.4. Histology Sensory nerve biopsy reveals axonal degeneration involving all fiber sizes, with greatest loss in distal most nerves. There are no histopathologic features specific for uremic neuropathy and, thus, nerve biopsy is only indicated if there is a strong suspicion of an alternative cause for the neuropathy. 32.5.3.5. Other studies Quantitative sensory testing of vibration threshold has been shown to be a particularly sensitive measure of uremic neuropathy. Abnormalities may be detected prior to the development of clinical symptoms or abnormalities on nerve conduction studies (Tegner and Lindholm, 1985; Klima et al., 1991). Autonomic dysfunction may also occur with uremic neuropathy and can be identified via autonomic testing as described above (Vita et al., 1988). 32.5.4. Alcoholism There is no doubt that people who consume alcohol in excess may develop a neuropathy, but there is significant uncertainty regarding the pathophysiology of the neuropathy. Historically, nutritional deficiency most frequently has been blamed for the development of neuropathy (Victor, 1984). The common presence of chronic liver dysfunction among alcoholic patients further complicates the situation. There is growing evidence, however, that alcohol may have a primary toxic effect (Behese and Buchtal, 1977; Koike et al., 2001). It is clear that while many alcoholics have comorbidities, neuropathy does develop in patients who have no apparent nutritional deficiency. The neuropathy associated with alcoholism is a predominantly sensory DSP. The earliest symptoms are sensory loss in the feet with dull ache in the foot

NEUROPATHIES ASSOCIATED WITH MEDICAL CONDITIONS

(Behese and Buchthal, 1977; Hawley et al., 1982). Small fiber-related burning dysesthesias occur in a minority of cases, probably about 20%. As with most neuropathies of this type, the hands become involved as the neuropathy progresses and motor signs and symptoms also become more prominent. The onset is typically indolent, although much more rapid progression has been reported. 32.5.4.1. Nerve conduction studies Distal sensory and motor response amplitudes are reduced, with the SNAP amplitudes being more severely affected. Conduction velocity is preserved or only minimally reduced to a degree consistent with the magnitude of the axonal loss (Behese and Buchthal, 1977; Shields, 1985; Monforte et al., 1995). 32.5.4.2. Needle electromyography Needle examination reveals fibrillation potentials and positive waves in very distal muscles in most cases. More proximal involvement develops as the neuropathy progresses. Chronic reinnervation changes appear over a period of time. 32.5.4.3. Histopathology Sensory nerve biopsy does not reveal any specific pathology in alcoholic neuropathy. The typical changes of axonal degeneration, with a small degree of secondary demyelination, affecting all fiber sizes, is similar to the pathology seen in most toxic or metabolic neuropathies (Behese and Buchthal, 1977).

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32.5.4.4. Other studies Autonomic studies and quantitative sensory testing are often abnormal and may be slightly more sensitive than routine nerve conduction studies in detecting alcoholic neuropathy (Valls-Solé et al., 1991). The clinical importance of these tests in the alcoholic population is uncertain. 32.5.5. Necrotizing vasculitis Necrotizing vasculitis is characterized by inflammation and necrosis of blood vessel walls producing compromise of the vessel and ischemia to dependent organs. Vasculitis can be classified based upon the caliber of vessel involved and by whether the vasculitis is primary or secondary to another systemic disorder such as connective tissue disease, infection, malignancy or even drug reaction. Peripheral nerve is frequently involved by systemic vasculitic disorders, and nerve is the sole target in isolated vasculitis of the peripheral nervous system (Dyck et al., 1972; Moore and Fauci, 1981; Kissel et al., 1985; Dyck et al., 1987). It is critical to identify vasculitis as the cause of a neuropathy because vasculitis frequently responds to immunosuppressive treatment. Table 32.4 summarizes the necrotizing vasculitides most frequently associated with peripheral nervous system involvement. The neuropathy classically ascribed to vasculitis is mononeuritis multiplex. Ischemic injury to peripheral nerves occurs in a relatively random fashion, resulting in a multifocal pattern of neuropathy. With prolonged ischemia, this pattern may merge into a more

Table 32.4 Necrotizing vasculitides commonly associated with neuropathy Vasculitis

1* or 2* to:

Vessel type affected

Laboratory abnormality

Giant cell arteritis Polyarteritis nodosa Churg-Strauss syndrome Wegeners granulomatosis Microscopic polyangiitis Isolated angiitis of PNS Vasculitis 2* to

1* 1* 1* 1* 1* 1* Connective tissue disease Malignancy Infection Cryoglobulinemia Drug induced

Large vessel Medium > Small Small > Medium Small > Medium Small Medium and small Medium and small Medium and small Medium and small Small Small

ESR ESR, RF, CRP ESR, RF, p-ANCA eosinophilia c-ANCA p-ANCA +/− ESR ANA, RF, SSA, SSB, +/− ESR, blood smear for HCL Viral//Fungal/Bact titers, Cx Cryoglobulins

1* = primary, 2* = secondary, ESR = elevated erythrocyte sedimentation rate, RF = rheumatoid factor, CRP = C reactive protein, ANCA = antineutrophil antibody, HCL = hairy cell leukemia, Bact = bacterial, Cx = culture.

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symmetric neuropathy which may be difficult if not impossible to distinguish from DSP. In many patients with vasculitis, a DSP without evidence of multifocality is identified. In this case, a careful history may reveal a stepwise progression of the neuropathy. One study indicates that a vasculitic DSP is identified more often in patients with a longer duration of illness (Hawke et al., 1991). Neuropathy may develop indolently or may present as acute areflexic paralysis resembling Guillain–Barré syndrome. Pain is often a prominent feature of vasculitic neuropathies. Patients with connective tissue disease frequently develop neuropathy. In many cases, the neuropathy is caused by vasculitis. However, other mechanisms of neuropathy likely are important in this population. For example, patients with rheumatoid arthritis develop an axonal neuropathy related to trauma and compression more often than a vasculitic neuropathy (Puechal et al., 1995; Moore, 2000). Vasculitis is identified in a minority of patients with neuropathy related to systemic lupus erythematosus (Olney, 1998). 32.5.5.1. Nerve conduction studies Sensory and motor nerve conduction studies primarily demonstrate evidence of axonal loss with reduction in sensory and motor response amplitudes and conduction velocities appropriate for the degree of axonal loss. Evidence of multifocal rather than symmetric distal involvement should always suggest the possibility of a vasculitic neuropathy. Focal neuropathies which were not clinically apparent may be identified. However, a typical DSP of the axonal type is commonly identified in vasculitis. Another interesting feature of vasculitic neuropathy is the occasional identification of isolated conduction block (Parry and Linn, 1988; Ropert and Metral, 1990; Hawke et al., 1991; Mohamed et al., 1998). Although conduction block is a feature most commonly associated with demyelinating neuropathies, in the case of vasculitic neuropathies, the block likely reflects active or recent ischemia prior to complete conduction failure. Later studies of the same nerve often demonstrate resolution of the conduction block with a more typical “axonal” pattern with reduction in the CMAP amplitude both distally and proximally. The proximal peroneal nerve, the proximal ulnar nerve in the arm, and the posterior tibial nerve are most commonly affected by necrotizing vasculitis. This may be related to the pattern of blood supply to these nerves, particularly to the presence of “water-

JAMES W. TEENER AND JAMES W. ALBERS

shed” regions where vascular supply is minimal (Dyck et al., 1972; Said et al., 1988). 32.5.5.2. Needle electromyography The needle examination may confirm the presence of axonal loss as indicated by evidence of denervation and reinnervation. In addition, the needle examination may confirm the multifocal distribution of the denervation in the case of mononeuritis multiplex. Denervation in the distribution of a single peripheral nerve with relative sparing of muscles of the same myotome but different nerve innervation is strong support for a multifocal process. However, radicular involvement also can develop in vasculitis, as part of a polyradiculoneuropathy. 32.5.5.3. Other electrodiagnostic studies In a large study of mixed cryoglobulinemia, the F-wave latency was the most sensitive measure of nerve dysfunction, being abnormally prolonged in 67% of patients (Ferri et al., 1992). The F-wave latency was also the most sensitive measure of nerve dysfunction in patients with Behcet’s Disease (Budak et al., 2000). Many patients with Behcets’s Disease also have abnormalities on Blink Reflex testing (Sahiner and Aktan, 2000). 32.5.5.4. Histopathology Pathologic confirmation is required for a definitive diagnosis of vasculitis. Typically, a sensory nerve is biopsied. The sural, superficial peroneal or superficial radial nerves are most often chosen for biopsy. Nerve conduction studies may guide the choice of nerve for biopsy. Although vasculitis may be demonstrated in electrophysiologically normal nerves, most clinicians prefer to biopsy nerves having abnormal SNAP amplitudes (Kissel and Mendell, 1992). Muscle biopsy is often performed along with the nerve biopsy to improve the yield of demonstrating definite vasculitis (Said et al., 1988; Collins et al., 2000). A diagnosis of definite vasculitis requires the demonstration of both inflammatory cell infiltration of vessel walls and evidence of vessel wall destruction (Lie, 1995). Evidence of prior vessel damage such as the presence of hemosiderin laden macrophages and intimal thickening are less definitive evidence of vasculitis. Nerve biopsy also reveals decreased nerve fiber density, often with signs of active axonal degeneration. Frequently, there is considerable intra- and interfascicular variability in terms of the degree of axonal degeneration.

NEUROPATHIES ASSOCIATED WITH MEDICAL CONDITIONS

32.5.5.5. Other tests Many connective tissue disorders are associated with neuropathy. In most cases, the neuropathies are caused by vasculitis. Prominent exceptions include the sensory ganglionitis associated with Sjögren’s syndrome and inflammatory demyelinating neuropathies associated with systemic lupus erythematosus. Table 32.5 describes the neuropathies associated with common connective tissue diseases and the serologic tests most useful in confirming the presence of a connective tissue disease. 32.5.6. Sjögren’s syndrome Sjögrens’s syndrome is a systemic autoimmune disorder characterized by lymphocytic infiltration of exocrine glandular tissue resulting in dryness of the eyes, mouth, and other mucous membranes. In addition, there are numerous extraglandular manifestations including involvement of the central and peripheral nervous systems. An estimated 10 to 30% of patients with Sjögren’s syndrome develop peripheral nervous system abnormalities (Bloch et al., 1965). The most common neuropathy seen in patients with Sjögren’s syndrome is a symmetric sensorimotor polyneuropathy (Govoni et al., 1999; Barendregt, 2001). A more unusual pure sensory neuropathy is seen in a small percentage of patients with Sjögren’s syndrome. Occasionally, this ataxic neuropathy may have an acute onset. Electrodiagnostic evidence of a purely sensory neuropathy may lead to the diagnosis of Sjögren’s syndrome (Font et al., 1990; Griffin et al., 1990). In one report of 13 patients with sensory neuropathy and Sjögren’s syndrome, the diagnosis of Sjögren’s syndrome was made after the identification of the neuropathy in 11 of the 13 patients diagnosed (Griffin et al., 1990). The sensory neuropathy may be present even in the absence of the mucous membrane

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dryness, and testing for Sjögren’s syndrome should be carried out whenever a purely sensory neuropathy is identified. Mononeuritis multiplex has also been reported in association with Sjögren’s syndrome (Binder et al., 1988; Inoue et al., 1991). 32.5.6.1. Nerve conduction studies The sensorimotor DSP associated with Sjögren’s syndrome is a typical axonal polyneuropathy with a reduction in sensory greater than motor response amplitudes with little or no slowing of conduction. Because mononeuritis multiplex is also seen in Sjögren’s syndrome and in other autoimmune rheumatologic disorders, the electromyographer must pay close attention to the symmetry of the responses. Asymmetry is suggestive of a multifocal process such as mononeuritis multiplex, and may lead to the identification of necrotizing vasculitis as the cause of the neuropathy. The most striking of the neuropathies associated with Sjögren’s syndrome is the pure sensory neuropathy (Font et al., 1990; Griffin et al., 1990). In this disorder, sensory responses are severely reduced or absent whereas the motor responses are normal or nearly so. The pattern of involvement may be asymmetric or involve the arms more than the legs (Kaplan and Schaumburg, 1991). This pattern is consistent a lesion located at the dorsal root ganglia, a finding which has been confirmed on pathologic study (Griffin et al., 1990). Sensory function mediated via cranial nerves may also be abnormal. In many reported cases, abnormalities of the blink response are identified, suggesting involvement of the Gasserian ganglia (Font et al., 1990; Barendregt et al., 2001). 32.5.6.2. Needle electromyography Needle EMG examination reveals the evidence of denervation in distal greater than proximal muscles in

Table 32.5 Connective tissue disease and neuropathy Disease

Neuropathy types

Serologic abnormalities detected in more than 20% of cases

SLE

DSP, MM, CIDP

dsDNA, ssDNA, Histones, Sm, RNP, SSA, ssDNA, Centromere, Scl-70

Scleroderma MCTD RA Sjögren’s syndrome

DSP, MM? DSP (rare) DSP, MM DSP, MM, DRG, CIDP?

Histones, RNP RF SSA, SSB

DSP = distal symmetric polyneuropathy, MM = mononeuritis multiplex, CIDP = chronic demyelinating polyneuropathy, DRG = dorsal root ganglionitis, SLE = systemic lupus erythematosus, MCTD = mixed connective tissue disease, RA = rheumatoid arthritis.

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patients with the DSP. Denervation is not seen among patients with the purely sensory neuropathy. The needle examination also can support the diagnosis of mononeuritis multiplex by revealing focal areas of denervation in the distribution of individual peripheral nerves, rather than in a strictly length-related, symmetric pattern seen in DSP.

neuropathy displayed diagnostic features consistent with an ischemic pathophysiology. The neuropathies associated with HCV may improve following treatment of the HCV infection with interferon alpha, sometimes in combination with immunosuppression, plasma exchange and other treatments (Khella et al., 1995).

32.5.6.3. Other studies Abnormalities of small fiber sensory function and autonomic function have been reported in Sjögren’s syndrome. Quantitative sensory testing using thermal pain perception thresholds may reveal abnormalities even in the setting of normal nerve sensory and motor nerve conduction studies (Denislic et al., 1995). Abnormalities of cardiovagal and sudomotor function also may be present (Mellgren et al., 1989; Andonopoulos et al., 1990; Kumazawa et al., 1993; Denislic et al., 1995; Mandl et al., 1997; Sorajja et al., 1999). The sweat glands may be a primary site of auto-immune attack in Sjögren’s syndrome, thus affecting neurophysiologic measurements of sweating. This may make the sympathetic skin response and other tests of sudomotor function unreliable measures of autonomic neuropathy in Sjögren’s syndrome (Navarro et al., 1990).

32.5.7.1. Nerve conduction studies The DSP associated with hepatitis C has the electrodiagnostic pattern of a length-related reduction in sensory response amplitude with little or no conduction slowing. Motor function is much less involved, with compound muscle action potential (CMAP) amplitude often being normal. The mononeuritis multiplex associated with hepatitis C is also typical, with evidence of multifocal axonal loss involving both sensory and motor axons. Just as with other vasculitic neuropathies, motor conduction block is occasionally demonstrated. This likely has a mechanism other than focal demyelination, being related to ongoing ischemic injury to axons.

32.5.7. Neuropathies associated with hepatitis Neuropathy is the most common neurological sequelae of hepatitis C virus (HCV) infection, although encephalopathy is seen with some frequency as well (Tembl et al., 1999). There are two principle neuropathy types associated with hepatitis C. Both a predominantly sensory DSP and a mononeuritis multiplex can be seen. In addition, the two neuropathies are not mutually exclusive, and it is common for mononeuropathies to be superimposed upon a DSP. Among most patients with hepatitis C, the presence of neuropathy is associated with cryoglobulinemia. The cryoglobulins, classified as mixed cryoglobulinemia, are associated with vasculitis, and the resulting neuropathy shares the characteristics of other vasculitic neuropathies. In some patients, the vasculitis is severe, involving small-to-medium vessels and is pathologically indistinguishable from polyarteritis nodosa. Among other patients, the vasculitis involves small vessels and is less severe, as more typically seen with cryoglobulinemia of other causes. One small study identified another group of patients with hepatitis C without demonstrable cryoglobulinemia where the

32.5.7.2. Needle electromyography Denervation may be minimal among patients with the DSP related to HCV, as the neuropathy primarily involves sensory fibers. The needle examination can support the diagnosis of mononeuritis multiplex. Here motor axons are involved, and the needle examination may reveal focal areas of denervation in the distribution of affected peripheral nerves, rather than in a strictly length-related, symmetric pattern seen in the polyneuropathy. 32.5.7.3. Histopathology Necrotizing vasculitis is typically detected on nerve biopsy when a relatively severe mononeuritis multiplex is present. As with many vasculitic processes, a combined biopsy of nerve and muscle may provide the best diagnostic yield. In less severe distal polyneuropathies, mild axonal loss is often present. Perivascular inflammation is a common finding, although true vasculitis with vessel wall necrosis may be less frequently present. 32.5.7.4. Other testing There are no detailed reports of autonomic testing or other tests of small fiber function in patients with HCV-related neuropathy. Given that at least a subset of the neuropathies seen in association with HCV involve small fibers, such testing may be expected to be clinically useful. Serologic testing for HCV and

NEUROPATHIES ASSOCIATED WITH MEDICAL CONDITIONS

testing for cryoglobulins should be considered in the evaluation of patients with idiopathic mononeuritis multiplex or primarily sensory DSP.

Table 32.7 Antibodies associated with paraneoplastic neuropathies Neuropathy type

32.5.8. Neuropathies associated with malignancy Peripheral neuropathy is a relatively common occurrence in patients with cancer. Prospective investigation utilizing nerve conduction studies has demonstrated abnormalities in up to 30–40% of patients (Moody, 1965). Malignancy can affect the peripheral nervous system in three ways: (1) Direct invasion or compression of nerves; (2) Remote (paraneoplastic) effects; and (3) Iatrogenic effect of chemotherapy or radiation. Characteristics of the paraneoplastic neuropathies and of the more common neuropathies related to direct effects of malignancy are outlined in Table 32.6. An additional category of malignancy-related neuropathy is neuropathy associated with paraproteinemia. These disorders are covered in Chapter 36 of this volume. Table 32.7 reveals the antibodies clearly linked to neuropathy in association with cancer, and which can be measured routinely in the clinic. Most of these antibodies are seen in association with small cell lung cancer, although the antiCRIMP5/CV2 antibody also is associated with thymoma. Other malignancies that have been associated with neuropathy include carcinoma of the breast, ovaries, stomach, colon, rectum and lymphoprolipherative system (Chad and Recht, 1991; Stubgen, 1995; Hughes et al., 1996; Levin, 1997). Many patients with cancer have a mild axonal DSP without identifiable antibodies. The pathogenic relationship of this polyneuropathy to the cancer is uncer-

659

Subacute sensory

Sensorimotor

Antibody

Associated cancer

Anti-Hu

SCLC

Anti-Amphiphysin ANNA-3 Anti-CRIMP5/CV2 Anti-Hu Anti-Amphiphysin Anti-CRIMP5/CV2

SCLC SCLC SCLC / Thymoma SCLC SCLC SCLC / Thymoma

SCLC = small cell lung cancer.

tain. Although it may be caused by immune-mediated mechanisms, a multifactorial mechanism including medications and cachexia also seems plausible. Because the relationship between this mild DSP and cancer is uncertain, it very likely is not practical or cost effective to screen all patients presenting with an idiopathic neuropathy for cancer. Certainly, anyone with symptoms consistent with one of the well-described paraneoplastic syndromes, such as sensory neuronopathy, should be screened aggressively for cancer. 32.5.8.1. Nerve conduction studies Abnormalities on nerve conduction studies reflect the underlying pathogenesis of neuropathy associated with malignancy. When neuropathies associated with paraproteinemia are excluded, essentially all of the remaining neuropathies associated with malignancy

Table 32.6 Characteristics of neuropathies related to malignancy

Paraneoplastic Sensory neuronopathy Sesorimotor neuropathy Autonomic Motor Infiltrative Mononeuritis Multiplex Polyradiculopathy Cryptogenic

Commonly associated cancer

Neuropathy pattern

Electrodiagnostic features

SCLC

Sensory ganglionopathy

Lymph, SCLC, AL SCLC, AL, Lymph Leuk, AngLL, LG Meningeal metastasis Many

DSP, large fiber involvement Autonomic Motor neuron Multifocal Polyradiculopathy DSP

Reduced SNAPs, non-length related Axonal May be associated with SN Reduced CMAPs, denervation Axonal Axonal Axonal

SCLC = small cell lung cancer, SNAP = sensory nerve action potential, Lymph = lymphoma, AL = lung adenocarcinoma, SN = sensory neuropathy, Leuk = leukemia, AngLL = angiotrophic large cell lymphoma, LG = lymphomatoid granulomatosis, DSP = distal symmetric polyneuropathy.

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are axonal in nature. Sensory neuronopathy is characterized by a striking reduction in the sensory response amplitudes, with sparing of the motor responses. Paraneoplastic vasculitic neuropathy is a mononeuritis multiplex characterized by multifocal sensory and motor involvement, with asymmetric reduction in both sensory and motor response amplitudes. Like most vasculitic neuropathies, this process can become confluent and indistinguishable from an axonal DSP. 32.5.8.2. Needle electromyography Needle electromyography adds little information in the evaluation of paraneoplastic neuropathies, although is does help to confirm the lack of involvement of motor axons in sensory neuronopathy. It also may provide additional evidence of multifocality in the case of mononeuritis multiplex due to paraneoplastic vasculitic neuropathy. 32.5.8.3. Other electrodiagnostic studies Studies of the Blink Reflex in patients with sensory neuropathy have revealed that most patients with a paraneoplastic sensory neuropathy have normal blink responses, while those with idiopathic sensory neuropathy have abnormal blink responses in nearly 50% of cases (Auger, 1999). 32.5.8.4. Other studies Measurement of serum antibody titers of the known paraneoplastic antibodies is useful in the appropriate clinical situations (Table 32.7). Unfortunately, most neuropathies encountered in cancer patients have no known associated antibody. Autonomic dysfunction may be a prominent or even the sole manifestation of paraneoplastic neuropathy, and clinical autonomic testing can help confirm and quantitate the autonomic abnormalities. The best-described autonomic neuropathies occur in association with small cell lung cancer and often the anti-Hu antibody is measurable. Quantitative sensory testing may demonstrate abnormalities in both large and small fiber functions (Lipton et al., 1991). 32.5.9. Sarcoidosis Sarcoidosis is infrequently associated with polyneuropathy, but such a wide variety of neuropathies have been associated with sarcoidosis that the differential diagnosis of many types of unexplained neuropathy must include sarcoidosis. Further, neuropathy may occur as a manifestation of sarcoidosis even in the

JAMES W. TEENER AND JAMES W. ALBERS

absence of systemic evidence of sarcoidosis (Nemni et al., 1981; Said et al., 2002). Serum angiotensin converting enzyme levels are frequently normal in patients with neuropathy found to have sarcoidosis (Said et al., 2002). Patterns of neuropathy associated with sarcoidosis include mononeuritis multiplex, polyradiculopathy, DSP, Guillain–Barré syndrome, as well as pure motor and pure sensory neuropathies (Galassi et al., 1984; Zuniga et al., 1991; Scott et al., 1993; Koffman et al., 1999; Said et al., 2002). Obviously, there is no typical electrodiagnostic pattern suggesting a diagnosis of sarcoidosis. The most direct linkage between neuropathy and sarcoidosis is the identification of non-caseating granulomas within or surrounding nerve. This pathology is only occasionally identified, however. Cranial nerve abnormalities, particularly the facial nerve, are the most common peripheral nervous system abnormalities seen in association with sarcoidosis (Stern et al., 1985). Neurophysiologic studies of cranial nerve function, particularly facial nerve motor studies and the blink reflex study, are abnormal in case where the appropriate cranial nerves are involved. 32.5.10. Neuropathies associated with infectious diseases A variety of infectious diseases are associated with the development of neuropathy. Of particular interest is the link between Campylobacter jejuni and other infectious agents and acute inflammatory neuropathies. This link is discussed elsewhere in this volume. Leprosy, Lyme disease, and diphtheria, all produce rather unique neuropathic syndromes. The neurophysiologic findings seen in association with these infections are presented in Table 32.8 and discussed below. The neuropathies associated with HIV infection are discussed elsewhere in this volume. 32.6. Leprosy Three forms of leprosy, lepromatous, tuberculous and borderline, have been recognized (Ridley and Jopling, 1962). The host immune status determines the particular form of leprosy that develops following infection with Mycobacterium leprae. Tuberculoid leprosy develops when the immune system is intact, producing focal-circumscribed lesions of skin and nerve. The organism prefers cooler regions, and thus superficial nerves are preferentially affected. Granuloma formation is typical and, at

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Table 32.8 Neuropathies associated with selected infectious diseases Infectious agent (disease)

Peripheral nervous system disorder

Primary electrodiagnostic findings

Borrelia burgdorferi (Lyme disease)

DSP

Length-related sensory > motor axonal polyneuropathy Asymmetric sensory and motor axonal loss Reduced CMAP amplitudes in radicular distribution Multifocal conduction slowing and conduction block Focal sensorimotor axonal neuropathy Sensory>motor axonal polyneuropathy Multifocal conduction slowing and conduction block Asymmetric sensory and motor axonal loss Abnormal autonomic studies Reduced CMAP amplitudes in radicular distribution Markedly reduced SNAPs, severe motor conduction slowing, mild motor distal latency prolongation

Mononeuritis multiplex Polyradiculopathy AIDP

HIV/AIDS

Mononeuropathy DSP Demyelinating polyradiculoneuropathy Mononeuritis multiplex

AIDS with CMV

Autonomic neuropathy Progressive polyradiculopathy

Corynebacterium diphtheriae (Diphtheritic neuropathy)

Peripheral neuropathy with frequent cranial neuropathies

Mycobacterium leprae (leprosy) Tuberculoid (TL) Lepromatous (LL)

Borderline

Mononeuropathy multiplex of superficial nerves DSP with superimposed mononeuropathy multiplex Anywhere in the spectrum of L neuropathy seen with TL & L

Focal axonal loss Reduced/absent SNAPs, prominent sensory and motor slowing with minimal distal latency prolongation As above

DSP = distal symmetric polyneuropathy, AIDP = acute inflammatory demyelinating polyneuropathy, CMV = cytomegalovirus, CMAP = compound motor action potential, SNAP = sensory nerve action potential.

times, the nerves are palpably enlarged at affected locations. Lepromatous leprosy develops when the host immune system is impaired. The clinical manifestations are typically more widespread and severe than those in tuberculoid leprosy, including the classic aggressive skin lesions associated with leprosy. Although the affinity for cooler regions is also present, a stocking-glove distribution DSP typically develops in patients with lepromatous leprosy. In patients with borderline leprosy, a partially deficient immune response allows widespread dissemination of the bacterium, but the immune system is sufficiently intact that an inflammatory response is present and likely produces additional tissue damage. The peripheral nervous system manifestations of

borderline leprosy include the spectrum of abnormalities seen in the other forms of leprosy. 32.6.1. Nerve conduction studies Sensory responses typically are reduced in the arms and often absent in the legs. Only mild slowing of conduction is typically seen with sensory conduction studies. However, motor conduction velocities often are substantially slowed, often to 60–70% of the lower limit of normal and occasionally even further. A mononeuritis multiplex type pattern may be seen as well as a more diffuse DSP. Phrenic nerve and facial nerve involvement may be seen, and when clinically indicated, conduction studies of these nerves will confirm the abnormalities.

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32.6.2. Needle electromyography

32.7. Lyme disease

Needle examination typically reveals mild subacute denervation changes in distal muscles, particularly those of the feet and hands. The presence of fibrillation potentials and positive waves as well as more chronic signs of reinnervation such as increased amplitude polyphasic motor units indicates that motor axonal loss is present.

Lyme disease and its numerous systemic manifestations are caused by infection with the tick-borne spirochete Borrelia burgdorferi. The various neuropathic manifestations of Lyme disease are outlined in Table 32.9. The disease process following infection is divided into three stages: early infection, disseminated infection and late-stage infection. The neurologic, and particularly the neuropathic abnormalities, develop in stages 2 and 3. The mechanism by which Lyme disease causes neuropathy in humans is uncertain. In rhesus monkeys, chronic Lyme infection produces mononeuritis multiplex (England et al., 1997). Focal mononeuropathy, multiple mononeuropathies and polyradiculopathies are the typical peripheral nervous system manifestations of stage two Lyme disease (Halperin et al., 1987). Facial mononeuropathy, often bilateral, is a particularly common Lyme-related neuropathy. The EMG findings of these disorders are nonspecific, and there is no particular finding that suggests the presence of Lyme disease. These neuropathies associated with stage two Lyme disease may resolve with good recovery of function. In stage three Lyme disease, a DSP is present in roughly half of patients. EMG studies reveal an axonal DSP in most cases, with more widespread abnormalities than expected clinically. For example, many patients with an apparent mononeuropathy will have evidence of a mild underlying axonal DSP. In the evaluation of Lyme-related mononeuropathies, a more extensive EMG examination than is typically performed is

32.6.3. Other electrodiagnostic studies The latency of the F-wave responses has been demonstrated to be the most sensitive measure of nerve dysfunction in patients with leprosy. Abnormalities may be detected even in the absence of clinically apparent neuropathy (Gupta and Kochar, 1994). 32.6.4. Other studies Lepromatous neuropathy is very rarely seen in the absence of skin lesion. Biopsy of skin lesions may reveal the presence of the acid fast bacilli. Serum antibody testing is also available. Nerve histology differs between the lepromatous and tuberculous forms of leprosy. In tuberculous leprosy, granulomas are present but the bacilli typically cannot be demonstrated in nerve lesions (Barros et al., 1987). Bacilli are present in large numbers in nerve lesions associated with lepromatous leprosy (Job and Desikan, 1968; Job, 1971). True granuloma formation is less typical, although foamy macrophages are abundantly present. Table 32.9

Characteristics of neuropathies associated with selected general medical conditions

Medical condition

Common patterns of neuropathy

Fiber types involved

Conduction slowing may be present

Diabetes mellitus Hypothyroidism Uremia Alcoholism Vasculitis Sjögrens Hepatitis Malignancy related Sarcoidosis Infections

DSP, MF, PM

L, Sm, A

Y

DSP DSP MF,DSP PS, DSP, MF

L L, Sm, A L L, A

Y

MF, DSP, PS, PM MF, DSP DSP, MF,

L, Sm, A L L, Sm, A

Y Y

Key: DSP = Distal Sensory Polyneuropathy, MF = multifocal, including mononeuritis multiplex, PM = purely motor, PS = purely sensory, L = large myelinated fibers, Sm = small nerve fibers, A = autonomic.

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663

recommended to fully evaluate for more widespread subclinical neuropathy (Halperin et al., 1988).

ies are usually performed in the acute to subacute setting before reinnervation has occurred.

32.8. Diphtheritic neuropathy

32.8.3. Histopathology

The neuropathy associated with Corynebacterium diphtheriae is caused by a toxin produced by the bacteria (Kazemi et al., 1973). The neuropathy accompanies diphtheria infection in about 20% of patients. Although mass immunization in developed countries has markedly reduced the appearance of this neuropathy, diphtheria still occurs elsewhere as also in immunocompromized patients. Diphtheritic neuropathy is perhaps best known to neurologists as an obscure disorder seen only in the differential diagnosis of Guillain–Barré syndrome. Diphtheritic neuropathy is preceded by a sore throat, dysphagia, fever and a whitish pharyngeal membrane. Several weeks after onset of the sore throat, cranial nerve abnormalities develop. Most often, a diffuse neuropathy does not develop. When it does, it typically follows the cranial phase, and follows pharyngitis by 3 to 15 weeks. This biphasic appearance of cranial neuropathies followed later by a generalized neuropathy is the cardinal differentiating feature between GBS and diphtheritic neuropathy.

Nerve biopsy is rarely performed. In the few cases reported, segmental demyelination has been present with minimal loss of myelinated fibers (Fisher and Adams, 1956).

32.8.1. Nerve conduction studies

Summary

Nerve conduction studies typically reveal slowing of sensory and motor conduction velocities, prolongation of the distal motor and F-wave latencies and occasionally motor conduction block (Kazemi et al., 1973; Kurdi and Abdul-Kader, 1979; Creange et al., 1995). The degree of conduction slowing typically fulfills strict criteria for demyelinating neuropathy. Often the signs and symptoms are more severe than suggested by the nerve conduction study results, with the nerve conduction abnormalities “catching up” and becoming more apparent with the passage of time. Late in the process, sensory and motor amplitudes are often reduced.

The majority of neuropathies encountered by most clinicians will be associated with an underlying medical condition. Table 32.9 summarizes the medical conditions most frequently associated with neuropathy. The clinician who is faced with an idiopathic neuropathy must consider the possible presence of a large number of medical conditions and perform the appropriate diagnostic studies in an organized manner, guided by the clinical and neurophysiologic data. When caring for patient with a medical condition known to cause neuropathy, the clinician should be alert to early symptoms of neuropathy so that appropriate therapy may be initiated. Neurophysiologic testing may allow neuropathy to be identified at the earliest stages, thus maximizing the chances for a favorable outcome.

32.8.2. Needle electromyography The needle examination often reveals minimal abnormalities in this predominantly demyelinating neuropathy. In prominently weak muscles, motor unit recruitment should be proportionately reduced. Abnormal spontaneous activity is only present if there is some degree of concomitant axonal loss. Changes in motor unit morphology are not reported because stud-

32.8.4. Other studies Autonomic involvement is common, and clinical autonomic testing may reveal evidence of parasympathetic dysfunction. Tachycardia is frequently seen. The diagnosis of diphtheria is confirmed early in the disease by culture of the bacteria from the throat, but later the culture may be negative, particularly if antibiotics have been administered. Serologic measurement of diphtheria antibodies can be performed. These must be evaluated in the context of the patient’s vaccination status, as vaccination against diphtheria will raise antibody titers. Often, the diphtheria titers must be compared with titers against tetanus and poliomyelitis, vaccinations typically given in combination with diphtheria. If titers are present to diphtheria alone, infection with diphtheria is likely.

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CHAPTER 33

Toxic neuropathies James W. Albers* and James W. Teener Department of Neurology, University of Michigan Health System, MI, USA

33.1. Introduction1 Most clinicians at some time in their career have attributed a peripheral neuropathy to an as of yet unidentified “toxic/metabolic” cause. The rationale for the relatively indiscriminate use of such a diagnosis is not entirely without merit, as toxic neuropathies (as in association with alcohol abuse) and metabolic neuropathies (as in association with diabetes mellitus) constitute the most common forms of neuropathies diagnosed in the US today. There may also be the implicit assumption by some clinicians that many neuropathies of unknown cause probably reflect the influence of some neurotoxicant on the peripheral nervous system. Yet, a thorough evaluation of patients who present with a previously unclassified, idiopathic neuropathy frequently identifies a specific cause for the neuropathy. The most common causes identified include genetic, inflammatory, or systemic etiologies, and only occasionally is an unsuspected toxic cause identified (Dyck et al., 1981). Nevertheless, toxic neuropathies are not rare, and their importance exceeds their number in terms of recovery once the cause is identified and further exposure is reduced or eliminated (Sahenk, 1987; Schaumburg and Spencer, 1987). What is special about toxic neuropathies? In general, nothing, as there are no neurological or electrodiagnostic features that reliably distinguish toxic neuropathies from the numerous other types of neuropathy discussed in this volume. As is the case for most neurological disorders, it is not necessary to know the cause of the problem in order to establish the

*Correspondence to: Dr. James W. Albers, MD, PhD. Department of Neurology, 1C325/0032 University Hospital, University of Michigan Health System, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-0032, USA. E-mail address: [email protected] Tel.: +1-734-936-8586; fax: +1-734-936-5185.

general neuroanatomic and neurophysiologic diagnosis of peripheral neuropathy. Classification schemes based on specific neurotoxicants and resultant clinical and laboratory findings have limited utility, other than in the Gestalt approach to establishing a diagnosis. Conversely, assuming, rather than suspecting, the cause of the neuropathy at the onset introduces an assumption into the diagnostic process that may obscure the correct diagnosis. For example, concluding at the beginning of an evaluation that a specific neurotoxicant caused neuropathy just because the patient had the opportunity for exposure may preclude additional evaluations that could identify an alternative explanation for the patient’s neuropathy. The investigation of any patient with a suspected neuropathy begins with establishing the presence of neuropathy. Of course, many peripheral neurotoxicants are also systemic poisons, and the general clinical and laboratory examinations may suggest important clues in identifying a possible toxic cause for a patient’s neuropathy. Unfortunately, most patients found to have a toxic neuropathy have no cardinal features of toxicity. Even those features highly supportive of a toxic cause (e.g., Mees’ lines or a characteristic skin rash) often do not appear until well after the neuropathy is established, limiting their initial diagnostic importance. For these reasons, the emphasis of this chapter is on the use of clinical and electrodiagnostic information to categorize the different forms of neuropathy. As will be seen, some forms of neuropathy are associated with certain neurotoxicants, and these substances should be included in the resultant differential diagnosis. This increased specificity reduces the number of disorders listed in the differential diagnosis, thereby focusing the subsequent investigations. Some consideration will be given to the laboratory investigation of specific toxins, but, in

1

Portions of this chapter rely on materials modified from Albers (1999, 2003).

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general, such investigations are beyond the scope of this chapter. The methodologies used to establish causation will be discussed, as these concepts are fundamental to the investigation of any toxic neuropathy. Finally, some forms of toxic neuropathy are first suspected only when two or more patients with similar types of neuropathy are found to share a common potential exposure. Recognition of such a “cluster” suggests a possible toxic etiology. Regardless of the presentation, however, identification of a toxic neuropathy usually stems from a high level of suspicion and an understanding that numerous substances are capable of producing neuropathy. 33.2. The clinical evaluation of suspected toxic neuropathy The evaluation of a suspected toxic neuropathy requires suspicion that some neurotoxicant explains the patient’s symptoms and signs. When should a toxic etiology be suspected as the cause of a patient’s neuropathy? The simple answer is “always,” because most patients who develop a toxic neuropathy have no distinguishing features. Some guidelines exist, however, to indicate when a toxic etiology should be seriously considered. Foremost is the presence of co-existing systemic signs of toxicity, in addition to the signs of neuropathy. Systemic signs may represent some cardinal feature, relatively specific to a group of toxicants, such as alopecia, Mees’ lines, photosensitivity or laboratory evidence of basophilic stippling. Other features are nonspecific, yet suggest more than the coincidental association of neuropathy and a systemic abnormality such as abdominal pain and psychosis, evidence of a postural tremor, or coexisting hepatic or cardiac failure. The opportunity for exposure, or, in the case of some medications, a known dose of exposure, to an established neurotoxicant clearly raises suspicion for a relationship between exposure and development of neuropathy. Similarly, information that a cluster of individuals with a similar exposure opportunity have developed objective evidence of neuropathy requires investigation. Regardless, the most important guideline is that there is nothing special about the evaluation of a suspected toxic neuropathy. The diagnosis of neuropathy is established independent of knowing the cause of the neuropathy. It is only after the diagnosis of neuropathy is secure that the cause of the neuropathy is established, following the standard differential diagnosis approach.

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In the context of a potential toxic neuropathy, a thorough history is used to identify potential environmental or occupational exposures. Such information, including data about exposure dose, is ultimately important in establishing the cause of an identified neuropathy. However, the exposure history is derived independent of establishing the neuroanatomical diagnosis, and the history format should be identical to that used for any neurological evaluation. In fact, the process of establishing the diagnosis of neuropathy proceeds independently from the process of identifying the cause of neuropathy. Information about the onset and time course (temporal profile) of motor, sensory, and autonomic complaints is reviewed, as is a description of the magnitude, type, and distribution of those complaints. Complaints of sensory loss or weakness should not be taken at face value. All complaints require a description of what the patient is experiencing. Sensory symptoms may reflect altered function (e.g., clumsiness), negative features (e.g., numbness), or positive features (e.g., paresthesias, hyperesthesia, hyperpathia, painful dysesthesias, or distorted sensations). Sometimes, the only complaint reflecting altered sensation involves decreased balance or incoordination. Even the complaint of weakness occasionally is described in confusing ways, such as fingers and toes feeling “stiff” or “numb” as opposed to weak. The history of potential toxic exposures should include a description of frequently used medications, as well as over-the-counter preparations, including vitamins. Social habits, use of alcohol or recreational drugs, or use of chemicals in hobbies should be investigated. The family history should include a description of any neuromuscular problems, pes cavus, or hammertoe deformities. The review of symptoms is important, as positive responses occasionally provide the only indication of an underlying systemic disease. As there is nothing specific about most toxic neuropathies, the resultant clinical signs resemble those produced by neuropathies of other causes. Examination of the peripheral nervous system has been described elsewhere and will not be repeated in detail here. The peripheral nervous system examination is relatively straightforward, but it comprises only one part of the clinical neurological and general physical examinations. Some toxic neuropathies are associated with signs of systemic poisoning. These signs most often involve the skin or nails, in the form of Mees’ line, dermatitis, or abnormal pigmentation (as in a gum lead line). Other features of system toxicity reflect the organ system involved, such as

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hematopoietic, cardiovascular, gastrointestinal, or renal systems. The peripheral nervous system also may be injured in association with the central nervous system, emphasizing the importance of a complete neurological examination. The clinical examination of suspected neuropathy usually emphasizes the most distal portions of the nervous system, as most forms of toxic neuropathy involve the longest and the largest axons in a “dying-back” stocking or stocking-glove distribution (Schaumburg and Spencer, 1987). This distribution reflects involvement of the neuron as the target of many toxins, an involvement that ultimately interferes with the neuron’s ability to maintain its distal axon. Most clinicians find the peripheral nervous system examination less complicated than examination of the central nervous system or behavior. This impression reflects the relative simplicity of peripheral nervous system function in contrast to the complexity of the central nervous system. In the context of suspected neuropathy, the examiner looks for signs of impairment, placing greatest emphasis on the most objective signs. For example, muscle stretch reflexes are sensitive to mild levels of abnormality, yet independent of patient motivation, education, level of concentration, or effort. Subjective signs of peripheral dysfunction include most of the clinical sensory tests, making these tests more difficult to interpret. The sensory examination includes evaluation of large sensory fibers subserving vibration, joint position, and touchpressure (“fine-touch”) sensations, and evaluation of small sensory fibers subserving pin-pain and temperature sensations. Light touch is difficult to quantify but, nevertheless frequently abnormal in large fiber neuropathies. Joint position is a relatively insensitive measure of sensory function relative to vibration sensation. Joint position abnormalities do not appear until a neuropathy becomes moderately severe. In contrast, Romberg testing accentuates the abnormalities of joint position sensation. Maintaining balance with the eyes closed is a functional sensory test when other problems, such as disorders of the vestibular system, are excluded. Normal balance with the eyes closed is inconsistent with other than a mild large fiber sensory neuropathy. Pin-pain sensation is a sensitive indicator of small fiber dysfunction. However, few predominant or exclusive small fiber neuropathies are caused by neurotoxicants. Most neuropathies that involve motor fibers are most severe in the distal lower extremities. Therefore, the feet are examined for atrophy and weakness, look-

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ing for high arches and hammer toe deformities. Experienced clinicians can reliably detect mild motor impairments and distinguish “apparent” weakness, due to pain inhibition or poor effort, from “true” weakness, due to loss of motor axons. Whereas a grip dynamometer is unable to distinguish between poor effort and a neurologic impairment, most clinicians can readily make this distinction (Albers, 2003). Reflex abnormalities are found in most clinically significant neuropathies, typically in the form of absent ankle reflexes. The afferent reflex arc is mediated by large sensory axons, the axons most often involved in all forms of neuropathy, including toxic neuropathies. The reflex examination results are reproducible, and absent ankle reflexes are an important sign of neuropathy. Reflexes that are easily elicited with facilitation should not be considered abnormal. The neurological examination includes substantial redundancy, increasing the overall reliability of combined findings. For example, fine touch, vibration, ankle reflexes, and balance (Romberg) are all mediated by the same large sensory axons. Therefore, a neuropathy producing loss of vibration sensation usually results in a positive Romberg sign and abnormal ankle reflexes. 33.3. The electromyography examination of suspected toxic neuropathy Electromyography (EMG), as used throughout this volume, consists primarily of motor and sensory conduction studies, evaluation of late responses, and the needle EMG examination. Few clinicians would debate the importance of the electrodiagnostic examination in the evaluation of neuropathy. The EMG examination is the foundation of Electrodiagnostic Medicine, and EMG results are used to confirm clinical signs, localize lesions to a degree not clinically possible, and identify pathophysiologic mechanisms (Albers, 1993). With few exceptions, electrodiagnosis is considered the “gold standard” for identifying and defining peripheral nerve abnormalities. Exceptions to this general axiom are primarily related to disorders involving small nerve fibers or sensory receptors, disorders that are usually not attributable to neurotoxic exposure. Nerve conduction studies have a prominent role in the evaluation of suspected neuropathy. The results are important in defining the type, distribution, and degree of peripheral involvement. Importantly, sensory conduction studies are the only noninvasive measures available able to localize sensory loss to the periphery.

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The role of the needle EMG examination in the evaluation of neuropathy is less important than that of nerve conduction studies. The needle EMG examination is used to document the distribution of axonal lesions and identify disorders such as polyradiculopathy that may be clinically indistinguishable from neuropathy. 33.3.1. Background Only a finite number of major pathophysiologic changes are relevant to the EMG classification of neuropathy. These changes include lesions associated with axonal degeneration, axonal stenosis, demyelination, and ionic channel abnormalities (channelopathies) (Aminoff and Albers, 1999). Axonal degeneration produces EMG changes similar to those associated with nerve transection, varying only in degree. Following transection, the distal axon degenerates (Wallerian degeneration). Several of the electrophysiologic changes are not immediately apparent, but they develop as Wallerian degeneration progresses. Landau (1953) showed that nerve stimulation distal to the site of nerve transection continued to evoke muscle contraction (and sensory and motorevoked responses) for several days, in spite of absent voluntary activity. Sensory and motor amplitudes subsequently diminish and ultimately disappear within about one week. The most objective EMG confirmation of “denervation” appears in the form of fibrillation potentials, which appear one to four weeks after the axonal degeneration (Gilliatt and Taylor, 1959). Spontaneous fibrillation potentials reflect muscle fiber hypersensitivity to acetylcholine (ACh). Over time, fibrillation potentials disappear as muscle fibers are reinnervated. When reinnervation is incomplete, as is often the case, the amplitude of persisting fibrillation potentials diminishes in association with muscle fiber atrophy (Albers, 1993). This information is relevant to the evaluation of patients with suspected toxic neuropathy because the most common response to a variety of neurotoxins is a distal “axonopathy” reflecting a metabolic failure of axonal transport of some nutrient essential for maintaining the distal axon (Schaumburg et al., 1983b). The timing of physiological changes after axonal degeneration is important, as many toxic neuropathies present in response to acute exposures. EMG evaluations performed in the first few days after clinical onset of the resultant neuropathy sometimes provide confusing information, which can be reconciled only by repeat evaluation in the context of evolving EMG changes.

JAMES W. ALBERS AND JAMES W. TEENER

Axonal stenosis refers to reduced caliper or atrophy of the distal axon. In some forms of chronic toxic neuropathy, axonal stenosis develops before complete axonal degeneration. Alternately, small caliper axons may reflect regenerating axons. Regardless, conduction along an axon is proportional to axonal diameter, so conduction is reduced along distal axons. Because the axon continues to conduct a nerve impulse, the evoked amplitude remains essentially normal, membrane excitability remains intact, and volitional motor unit recruitment is unaffected (Albers, 1993). Disorders of the myelin sheath (demyelination or dysmyelination) or axonal membrane interfere with nerve conduction (Albers, 1993). Several models of demyelination are relevant to the evaluation of patients with suspected toxic neuropathy, because the metabolic lesions attributable to some peripheral neurotoxins also produce evidence of conduction slowing or conduction block. For many disorders, including several toxic neuropathies, the underlying pathophysiology at a given site along the axon resembles the findings associated with focal nerve compression (Ochoa, 1980). In models of focal compression, structural changes reduces or block local ionic current flow at the site of compression, thereby slowing or blocking propagation of the action potential (Ochoa et al., 1972; Fowler and Ochoa, 1975; Ochoa, 1980). Similar findings are associated with some toxic neuropathies, and decreased conduction velocity is not always diagnostic of primary demyelination. For example, conduction slowing is associated with decreased temperature, but this slowing is unrelated to any abnormality of the myelin sheath. With cooling, the slowing reflects prolonged opening and closing times of ionic channels. Troni et al. (1984) showed that transient hyperglycemia also produces conduction slowing that resolves within hours after glucose levels are normalized. Similarly, prolonged hyperglycemia is associated with decreased nerve myo-inositol and increased polyol pathway activity related to the increased conversion of glucose to sorbitol by aldose reductase (Greene et al., 1990). Reduced myo-inositol levels lead to reduced Na+/K+-ATPase activity and an increase in intracellular Na+. These metabolic changes produce a slight depolarization of the resting membrane potential, decreasing conduction along the axon independent of any structural alteration. A variety of neurotoxins potentially produce similar changes by inactivating or blocking the ionic channels (Sima et al., 1986).

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33.3.2. EMG protocol The most fundamental question addressed by the EMG evaluation involves localization of an abnormality to the peripheral nervous system. Additional questions addressed by the EMG evaluation include: (1) Do abnormalities involve primarily or exclusively sensory axons, motor axons, or a combination of both? (2) Are the abnormalities best explained by a polyneuropathy (diffuse involvement of nerves), a mononeuropathy multiplex (multifocal involvement of individual nerves), or a polyradiculopathy (diffuse involvement of nerve roots)? (3) Is there substantial slowing of nerve conduction to an extent greater than can be explained by loss of large caliber axons? The EMG protocol is designed to answer these questions and thereby characterize the patient’s neuropathy, using anatomical and physiological information to define the patient’s problem. The EMG results do not identify the cause of the patient’s diagnosis. In fact, the EMG results never “diagnose” a toxic neuropathy in isolation, as few EMG findings are specific for any one particular disorder. However, certain results suggest a specific class of disorders, and classification schemes based on combined clinical and EMG results allow the clinician to develop a differential diagnosis that is more focused than the one derived from the clinical evaluation alone. In the evaluation of a suspected neuropathy, the nerve conduction studies are particularly important in the classification scheme described above. The needle EMG examination plays a secondary role, and will usually be abnormal because most peripheral neurotoxins produce some degree of axonal degeneration, independent of an abnormality of the myelin sheath or the axonal membrane. The needle examination also permits evaluation of otherwise inaccessible muscles, such as paraspinal muscles. In this context, the EMG evaluation plays an important role in excluding or identifying disorders that mimic neuropathy, such as a polyradiculopathy, a distinction that cannot always be made clinically. In addition, information derived from the needle examination also addresses questions related to the time and extent of axonal injury more readily than do the nerve conduction study results (Albers, 1993). The use of additional electrodiagnostic tests, such as use of blink reflex studies, nerve excitability, or autonomic testing, should be based on the clinical presence (symptoms or signs) of dysfunction involving the particular areas being tested (e.g., brain stem dysfunction or dysautonomia). The sympa-

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thetic skin response (SSR) is a measure of small nerve fiber function that involves a differential recording from skin between areas of high and low sweat gland density. SSRs can be used to document autonomic impairment involving the sweat glands, but they have limited application in neurotoxic disorders. In general, neither their sensitivity nor specificity is known. Other tests of autonomic nervous function exist (e.g., R-R interval, Q-SART), but none has had extensive application or evaluation in the neurotoxic disorders (Albers, 2002). None of the neurotoxicants described in this chapter exhibits isolated autonomic nervous system toxicity. A few, such as the organophosphate compounds, exhibit transient cholinergic effects in response to acute intoxication, but there is no evidence that autonomic testing facilitates the diagnosis of toxic neuropathy. Indiscriminate use of any electrodiagnostic measures rarely, if ever, results in identification of diagnostically useful information in suspected toxic neuropathies. EMG protocols used to evaluate suspected neuropathy are straightforward. When clinical signs are mild, the evaluation is directed toward the most sensitive or susceptible sites, usually the distal lower extremities. When severe, evaluation of less involved sites is performed because absent responses provide no information about conduction slowing. Bilateral studies of some nerves are used to evaluate symmetry or to identify focal abnormalities at common sites of compression or cumulative trauma. The needle EMG examination supplements the nerve conduction studies, by documenting the presence of a suspected distal to proximal severity gradient, a finding characteristic of most forms of neuropathy. Information derived from motor unit configuration and insertional activity measures (amplitude and distribution) can distinguish acute, subacute, and chronic denervation. 33.3.3. Special considerations In the evaluation of any suspected neuropathy, several features of the EMG study deserve special attention. Amplitude measures reflect the number of activated nerve or muscle fibers, and these measures are particularly sensitive to axonal loss lesions. Therefore, careful electrode placement and use of supramaximal percutaneous stimulation are important in obtaining reliable results. Errors in either produce false-positive information, resulting from low amplitude responses or decreased conduction velocity due to failure to stimulate the largest axons. The distance between the

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stimulation site and the recording electrode also influences sensory and motor amplitudes. When the distance is short, amplitudes are larger than those recorded over longer distances. Similarly, improper surface measurements can result in inaccurate calculation of conduction velocity along the segment being studied. Temperature is perhaps the most important factor known to influence nerve conduction results that can be controlled. Near-nerve temperature has a profound effect on nerve conduction measures of amplitude, conduction velocity, and distal latency. Limb temperature should be monitored, and cool limbs warmed to maintain minimally acceptable temperatures. It is not sufficient to monitor room temperature, as room temperature has little relationship to limb temperature. 33.4. Additional measures There are additional tests used to supplement the clinical examination of sensory function. For example, quantitative sensory testing (QST) is a noninvasive and reproducible quantitative measure of sensation. However, the sensitivity and specificity of QST is known for only a few selected measures, and QST requires good subject cooperation and motivation, as it is sensitive to subtle motivational factors, as well as learning and age-effects. In general, QST has limited specificity, being unable to distinguish central from peripheral sensory disorders. Comparisons of QST with nerve conduction study results obtained from a population of patients with diabetic neuropathy found QST complimentary, but ancillary, to nerve conduction study results, with the sural recording being the best single predictor of mild neuropathy (Redmond et al., 1992). At present, routine clinical application of QST is limited, as is general application of QST in the investigation of toxic neuropathy (Bleecker, 1985, 1986; Beckett et al., 1986; Moody et al., 1986; Maurissen, 1988). Tissue biopsy is occasionally used in neurotoxicology evaluations. For example, among patients with solvent-induced neuropathy associated with n-hexane intoxication, peripheral nerve biopsy shows characteristic focal axonal swellings due to neurofilament aggregates. Biopsy of skin, fascia, muscle, and nerve obtained from patients with eosinophilia-myalgia syndrome associated with l-tryptophan intoxication typically demonstrates perivascular inflammation with lymphocytes and eosinophils. There are few neurotoxic disorders, however, in which tissue biopsy is

JAMES W. ALBERS AND JAMES W. TEENER

indicated, other than to document the presence of problems unrelated to toxic exposure. For example, nerve biopsy can identify the evidence of vasculitis, sarcoidosis, amyloid deposits, and other distinctive pathological changes. Biopsy of most tissues, particularly nerve, is rarely useful in screening in the context of toxic neuropathy. The diagnosis of small fiber neuropathy is made on the basis of the clinical examination, normal or near normal nerve conduction study results, and documented abnormalities using specialized tests of smallfiber function (Lacomis, 2002). Recently, in addition to quantitative sensory testing and conventional nerve biopsy, skin biopsy has been used to evaluate the terminal portions of small nerve fibers, measuring the intraepidermal nerve fiber (IENF) density (Kennedy and Wendelschafer-Crabb, 1996; Holland et al., 1997; Mendell et al., 2001). Skin biopsies obtained from patients with suspected small fiber neuropathy may show a length-related reduction (most severe distally) in the IENF density, even in the presence of normal reflexes and normal sural responses (Holland et al., 1997). A study by the same group evaluated patients with idiopathic “burning feet” for which no cause had been established (Holland et al., 1998). All exhibited neuropathic pain but normal clinical and EMG evaluation. These patients also showed a reduced IENF density. Among patients with sural nerve biopsy, a few had normal results despite the abnormal skin biopsies, suggesting that skin biopsy was more sensitive than sural nerve biopsy for detecting small fiber abnormalities. Although skin biopsy shows potential for evaluating patients with painful small-fiber neuropathies, the sensitivity, specificity, and reproducibility of this technique remains to be determined. This technique appears to have limited application in the evaluation of toxic neuropathy, as few neurotoxicants are known to produce an exclusive small fiber neuropathy. 33.5. Documenting the dose of a substance to which a patient has been exposed A description of the methodologies used to establish the dosage of a specific neurotoxicant to which an individual is exposed is beyond the scope of this chapter. Recent reviews exist that address exposure assessment issues relevant to clinical neurotoxicology (Ford, 1999). Exposure may have little to do with the absorbed dose, and once absorbed, many factors influence development of neurological disease. Many biological monitors are important in estimating the dose

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to which an individual is exposed, including breath, blood, plasma, urine, red blood cells, adipose tissue, hair, nails, and bone. Suffice it to say, numerous factors, including the half-life in different compartments, influence the interpretation of the results vis-à-vis dose. Some techniques that measure substances directly or indirectly in the serum are particularly applicable to ongoing or recent exposures. For example, the effects of organophosphate pesticides on serum butyrylcholinesterase or red blood cell acetylcholinesterase can be measured, as can the metabolites of some organophosphate compounds. For example, 3,5,6 trichloro-2-pyridinol (TCP) is the main metabolite of chlorpyrifos, an organophosphate insecticide, and measurement of TCP in the urine provides a direct indication of recent dose. Occasionally, urinary excretion of the specific substance (e.g., arsenic) can be measured, providing another indication of recent dose to which an individual was exposed. However, laboratory results can be misleading. For example, total arsenic levels in urine contain nontoxic organic arsenic from ingestion of certain seafoods, thereby providing a “false positive” indication of high arsenic exposure. Some substances are stored in specific tissues, including arsenic in hair or nails, lead in bone, and some chlorinated compounds in fat. Measurement of arsenic in hair or nails gives an indication of the magnitude of arsenic dose over a relatively long time (months). Similarly, because absorbed lead is stored in bone, where it has a half-life of more than 25 years, blood lead levels reflect a combination of ongoing exposures from the environment and bone lead stores (Ford, 1999). Based on a patient’s age and residence (e.g., urban or rural), current blood lead levels can be used to determine if greater than anticipated background lead exposures have been experienced by the individual. For many substances, a specific biological measure of the dose to which an individual was exposed is unavailable. The duration and dose of exposure is, however, associated with development of neurotoxicity, and this information is important in establishing the cause of a suspected toxic neuropathy. For example, a toxic neuropathy may result from exposures to some substances that are acute and of relative massive dosage, recurrent and of moderate dosage, or chronic and low dosage. Certain neurotoxicants, such as arsenic, produce neuropathies that differ in their appearance depending on whether the exposure was acute or chronic. Other substances, such as Dapsone, produce neuropathy only after many years of cumula-

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tive exposure. Yet other substances, such as nitrofurantoin, produce different forms of neuropathy as exposure is continued after the first signs of neurotoxicity development (e.g., initially sensory followed by a motor-predominant neuropathy). The reason for these differences is not always clear, but it undoubtedly involves many additional factors including half-life, renal clearance, metabolism, genetic difference, target sensitivity, coexisting illnesses, competition with other neurotoxicants, and the ability and rate of the peripheral nervous system to repair ongoing damage. Fortunately, just as the clinician can establish the diagnosis of neuropathy independent of knowing that the patient was exposed to a particular neurotoxicant, information regarding the exposure profile is relevant only in establishing the cause of a particular neuropathy. It is in this context that the diagnostic scheme used in this chapter that limits the differential diagnosis to a manageable number of conditions for further evaluation has its greatest utility. 33.6. Classification of neuropathies based on EMG results There are many approaches to the classification of neuropathy. Most use clinical or neuropathological information to focus the investigation by reducing the number of disorders that must be considered in the differential diagnosis. The classification that follows relies heavily on EMG results (Donofrio and Albers, 1990), and this scheme is preferred for identifying toxic neuropathies because it incorporates a combination of information involving the modality of abnormality and the suggested pathophysiology. The physician first determines whether the presumed neuropathy is symmetrical and, therefore, consistent with a polyneuropathy, or whether signs are asymmetrical or multifocal, suggesting a mononeuritis multiplex or some atypical form of neuropathy. The information needed to make this determination is derived predominantly from the history and neurological examination results. On occasion, nerve conduction studies show substantial side-to-side amplitude differences, sufficient to suggest asymmetry. The needle EMG results also can sometimes identify subclinical asymmetry, thereby distinguishing, for example, neuropathy from a confluent mononeuritis multiplex. Conversely, asymmetries explainable by some factor unrelated to the neuropathy, such as a preexisting traumatic mononeuropathy, should not detract from a diagnosis of “polyneuropathy.” It is next determined whether

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motor or sensory fibers are involved exclusively. When both fiber types are involved, one involved more than the other (e.g., motor predominant neuropathy), or is the neuropathy best characterized as a combined sensorimotor polyneuropathy? In this classification scheme, the evaluation of motor conduction velocity is important and requires additional explanation. Criteria exist that can be used to identify conduction slowing that likely results from an abnormality of the myelin sheath (Albers and Kelly, 1989). However, conduction slowing, as applied to this classification of neuropathy, is used in a more general sense to include any slowing that cannot be attributed to a typical axonal loss neuropathy. This clarification is important, because several other pathophysiologic conditions produce substantial conduction slowing. These additional conditions include axonal inclusions, axonal stenosis, channelopathies, and selective loss of large axons. Information about conduction slowing comes from several sources, including segmental conduction velocity, F-wave latency, and distal latency. How much slowing is required to be considered abnormal? In this classification scheme, the emphasis is not on fulfilling strict conduction slowing criteria in a simple “yes” or “no” manner. In general, normal or near normal conduction velocities are associated with most axonal neuropathies, whereas abnormal conduction velocities are associated with disorders of the nerve membrane, caliber, or myelin sheath. In general, evidence of reduced motor conduction velocities in the vicinity of 80% of the lower limit of normal or distal latencies and F-wave latencies near or exceeding 125% of the upper limit of normal usually fulfill this requirement (Cornblath et al., 1991). As a general rule, however, conduction velocities less than 70% of the lower limit of normal cannot be attributed to axonal loss alone (Kelly, 1989). Abnormalities of this type should be found in more than one motor nerve. Criteria used to identify acquired demyelination usually rely on information about abnormal temporal dispersion or partial conduction block. Although this information is important, it is not used directly in the classification that follows. This is because several of the exceptions to the general rules about acquired demyelination involve atypical findings that are associated with some forms of toxic neuropathy. At least two explanations exist for the atypical types of conduction slowing associated with some toxic neuropathies. The first explanation involves conduction studies performed very early in the course of a severe, acute

JAMES W. ALBERS AND JAMES W. TEENER

axonal neuropathy. Days before total axonal loss, nerve conduction findings may fulfill the criteria for acquired demyelination, analogous to the findings associated with severe vasculitic neuropathy (Donofrio et al., 1987). The second explanation involves neuropathies with a predilection for the largest motor fibers. These neuropathies also show substantial conduction slowing that resembles hereditary demyelination, differing only in their temporal profile. For these reasons, the classification scheme that follows relies primarily on the presence or absence of conduction slowing, deemphasizing the reliance on abnormal temporal dispersion and partial conduction block. In making the distinction about the presence or absence of substantial conduction slowing, there are three important considerations. The first consideration involves technique, as it is assumed that factors related to limb temperature, use of supramaximal stimulation, and distance measurements have been addressed appropriately. The second consideration involves attention to potential co-existing findings. It is important that conduction slowing from a pre-existing mononeuropathy is not attributed to a generalized neuropathy. The third consideration involves the converse of the second consideration. Namely, generalized conduction slowing that just fails to fulfill criteria of definite slowing should not be ignored. It may be relatively unlikely that the slowing represents a primary axonal neuropathy, particularly if motor response amplitudes are preserved and the findings are widespread. These latter two considerations directly involve overlapping issues involving EMG sensitivity and specificity. As the criteria become more specific, sensitivity is sacrificed, whereas more lenient criteria reduce specificity. Although different types of toxic neuropathy can be classified into broad categories based on EMG findings (e.g., Table 33.1), the categories are not exclusive, and several neuropathies appear in more than one of the categories. This lack of specificity reflects the limited number of responses to nerve injury from any cause, yet the physiological appearances may differ depending on the temporal proximity to injury. Numerous neurotoxicants are capable of producing identical physiologic findings, as are numerous other disorders including inflammatory diseases, hereditary neuropathies, and neuropathies associated with systemic illnesses. At times, any one of a large number of disorders provides an equally plausible explanation for the EMG findings. Further identification of the different forms of neuropathy often

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Table 33.1

Table 33.2

General Classification of neuropathy based on electrodiagnostic findings, modified from Albers (2003)

Toxic neuropathies presenting as a motor or motor greater than sensory neuropathy with conduction slowing, modified from Donofrio et al. (1990), Albers and Berent (1999), and Albers (2003)

1. Motor or motor greater than sensory Conduction slowing No conduction slowing 2. Sensory 3. Mixed sensorimotor Conduction slowing No conduction slowing 4. Mononeuritis multiplex or asymmetric neuropathy

requires recognition of systemic features or identification of a causative risk factor or agent (occupational, social, or pharmacologic). Conversely, symptomatic neuropathy often precedes recognition of a systemic disorder, identification of which may suggest the cause of a patient’s neuropathy. Although the emphasis of this chapter is on toxic neuropathies, the sections that follow include a brief description of the differential diagnosis that best reflects the particular EMG classification. The more general information is included to emphasize the numerous disorders that produce similar forms of neuropathy. More complete discussions exist in the referenced material. Discussion of every known toxic neuropathy is beyond the scope of this chapter. However, the most common or the most characteristic of a particular category are described. 33.6.1. Motor or motor greater than sensory neuropathy, with conduction slowing Conditions associated with a pure motor or a motor predominant neuropathy characterized by conduction slowing are listed in Table 33.2. The list is separated into general subcategories based on the known or suspected pathophysiology or cause, beginning with toxic causes, but followed by other neuropathies with similar patterns, including hereditary, inflammatory/infectious, metabolic, nutritional, or paraneoplastic disorders. At first glance, it might appear that most of the neuropathies would be easily distinguishable by their clinical features. This assumption is incorrect, however, as several of the disorders are virtually indistinguishable from one another. Conversely, the clinical features and temporal profile of a patient with a toxic neuropathy are unlikely to be confused with a slowly progressive hereditary neuropathy. The exception to this generalization is the patient whose neuropathy develops insid-

Amiodarone Arsenic (shortly after exposure) Carbon disulfide Cytosine arabinoside (ara-C) n-Hexane Methyl n-butyl ketone Perhexiline Saxitoxin (sodium channel blocker) Suramin Swine flu vaccine Other neuropathies with similar patterns Hereditary Hereditary motor sensory (demyelinating form CMT [HMSN I]) Hereditary tomaculous (liability to pressure palsy) Inflammatory/infectious Acute inflammatory demyelinating polyneuropathy (AIDP) Chronic inflammatory demyelinating polyneuropathy (CIDP) Diphtheria Dysimmune neuropathies HIV-associated Lyme disease Sjögren’s syndrome Systemic lupus erythematosus Vasculitis (confluent mononeuritis)

iously and is first “discovered” in the setting of a suspected exposure to a known neurotoxicant. For most forms of hereditary neuropathy, a careful family history, examination of close relatives, or genetic testing reduces the confusion. Examination of relatives in suspected disorders like hereditary motor sensory neuropathy type I (HMSN I), the demyelinating form of Charcot–Marie–Tooth disease, is particularly important because asymptomatic individuals with HMSN I may have clinically evident impairments or dramatic EMG abnormalities. Of course, an increasing number of hereditary neuropathies are amenable to genetic testing. Disorders producing these EMG findings are the inflammatory neuropathies, acquired immune diseases that produce demyelinating neuropathy. Included are acute and chronic inflammatory demyelinating polyneuropathy (AIDP and CIDP), as well as other types of dysimmune neuropathies (monoclonal gammopathy, osteosclerotic myeloma, multiple myeloma,

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Waldenström’s macroglobulinemia, gamma heavy chain disease, cryoglobulinemia, lymphoma, systemic lupus erythematosus, Castleman’s disease, occult malignancy, or human immunodeficiency virus infection). Many of these neuropathies are treatable, so their recognition is important. Among these conditions on the list, AIDP and CIDP are the most common, and the two disorders most likely to be confused with several forms of toxic neuropathy listed. Consider, for example, arsenic neuropathy. Neuropathy is a common and feared complication of arsenic intoxication (Poklis and Saady, 1990). Symptoms and signs of neuropathy appear 5 to 10 days after acute exposure and progress over weeks to a flaccid, areflexic quadriparesis with bifacial weakness, often requiring respiratory support. The EMG features of arsenic neuropathy produce substantial diagnostic confusion, based in part on the results obtained at different intervals after an acute exposure. Initial EMG findings are those of a motor greater than sensory neuropathy characterized by reduced amplitudes, borderline-low conduction velocities, absent F-waves, and partial conduction block in several motor nerves suggesting the possibility of acquired demyelination (Donofrio et al., 1987). The magnitude and nonuniform nature of conduction slowing usually suggests the presence of multifocal or segmental demyelination, and the findings are often thought to reflect a diagnosis of AIDP. The descriptions of arsenic neuropathy that identify it as a severe axonal neuropathy, are more characteristic of chronic arsenic intoxication or of findings remote from an acute arsenic poisoning. Follow-up EMG studies of an acute arsenical neuropathy that initially suggest the presence of acquired demyelination, typically show only absent sensory and motor response and severe denervation on the needle examination. There is only a brief time during which the conduction abnormalities are apparent, and all subsequent findings are more consistent with a dying-back axonal neuropathy. Findings suggestive of acquired demyelination probably reflected a generalized axonal failure before complete axonal degeneration. Unfortunately, the time interval during which those findings are present coincides with the period when the clinical diagnosis is unclear. Initial EMG studies may show absent sural responses when median sensory responses are still recordable. This finding is atypical of a “normal sural-absent median” sensory pattern frequently attribute to early AIDP, but it certainly does not exclude the diagnosis (Bromberg and Albers, 1993).

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Arsenic is a general protoplasmic poison, and the systemic features of arsenic poisoning suggest that something other than idiopathic AIDP explains the neuropathy. The initial symptoms of acute arsenic intoxication, nausea and vomiting, are symptoms indistinguishable from a gastrointestinal “flu.” Laboratory abnormalities include evidence of impaired liver function and bone marrow depression producing pancytopenia and basophilic stippling, a nonspecific abnormality of the red blood cell that occurs in response to several toxins. Abnormal liver function frequently accompanies acute AIDP, perhaps reflecting the preceding viral infection. Pancytopenia, however, is atypical of AIDP, although it also may reflect a postviral syndrome. Nevertheless, pancytopenia may provide the first indication of a toxic exposure or result in additional evaluation. An elevated CSF protein often is considered a prominent component of AIDP. In the appropriate clinical setting, it may be used to secure the diagnosis. However, an elevated CSF protein reflects damage to the blood-CSF barrier. The CSF protein is elevated in most patients with severe arsenic neuropathy, particularly when the onset is acute or subacute, as is common. In suspected arsenic neuropathy, additional investigations include a 24-hour urine evaluation for “heavy metals.” Additional clues suggesting a diagnosis of arsenic intoxication as the cause for a patient’s acute neuropathy develop over weeks and include a brownish desquamation of the hands and feet (arsenical dermatitis). About the same time, Mees’ lines appear on the fingernails and toenails. Unfortunately, none of these textbook features of arsenic intoxication typically appears until the diagnosis is no longer in question. Such systemic features are, nonetheless, important findings among patients with recurrent or chronic arsenic exposure. Several hexacarbon solvents and glues are implicated in neuropathy characterized by conduction slowing. Most exposures result from occupational or recreational use. The neuropathy associated with n-hexane is characterized by distal sensory loss, reduced or absent reflexes, weakness, muscle atrophy, and autonomic dysfunction. Among “huffers” who volitionally inhale n-hexane, the most common presentation is a motor greater than sensory neuropathy characterized by reduced evoked amplitudes and conduction velocities into a range suggestive of primary demyelination (Smith and Albers, 1997). Conduction slowing in this neurotoxic neuropathy is thought to reflect secondary myelin damage associated with giant axonal swellings. The axonal swellings reflect accumulation of neurofilaments.

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Inclusion of the swine flu vaccination among the “toxic” causes of neuropathy requires explanation. Epidemiological studies associated an excess number of cases of AIDP among those receiving the A/New Jersey/8/76 (swine flu) vaccination compared to a referent group (Safranek et al., 1991). However, the mechanism was thought to be immune-mediated, in the form of molecular mimicry, not a direct neurotoxic effect. 33.6.2. Motor or motor greater than sensory neuropathy, without conduction slowing Conditions producing a motor or motor greater than sensory neuropathy without conduction slowing are listed in Table 33.3. The list includes several neurotoxicants. However, by far the most prevalent condition listed involves the hereditary disorders, as many “idiopathic” neuropathies are eventually determined to be hereditary or familial. Among adults, the axonal form of Charcot–Marie–Tooth disease (HMSN II) is a common axonal motor greater than sensory neuropathy (Dyck, 1984). This autosomal dominant neuropathy is important because it is not always recognized among family members, and neuropathic symptoms and signs are attributed to “age.” It also is important because the findings are representative of several other conditions in this category. HMSN II begins insidiously after the third decade of life, with symptoms of distal weakness and sensory loss. Signs Table 33.3 Toxic neuropathies presenting as a motor or motor greater than sensory neuropathy without conduction slowing, modified from Albers (2003) and Albers and Berent (1999) Toxic Cimetidine Dapsone Disulfiram (carbon disulfide?) Lead? Nitrofurantoin Organophosphates (organophosphate-induced delayed neurotoxicity; OPIDN) Vincristine and related agents Other neuropathies with similar patterns Hereditary (axonal form of CMT [HMSN II]) Inflammatory/infectious (acute motor axonal neuropathy [AMAN], acute motor sensory axonal neuropathy [AMSAN]) Metabolic (hyperinsulin/hypoglycemia and porphyria) Paraneoplastic (lymphoma)

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include distal muscle atrophy producing an inverted champagne bottle appearance to the legs, pes cavus, hammer toes, hyporeflexia, and mild stocking or stocking-glove distribution sensory loss. The EMG examination shows low amplitude motor responses with normal, or only mildly slowed, conduction velocities. Patients may have normal sensory responses, making it difficult to differentiate the condition from progressive muscular atrophy. The needle EMG examination demonstrates a distal predilection of fibrillation potentials and chronic neurogenic motor unit changes. When the diagnosis is in question, patients with HMSN II and their physicians frequently question whether the neuropathy can be explained by a toxic exposure. Several inflammatory disorders produce a motor greater than sensory axonal neuropathy. This include axonal forms of AIDP, sometimes referred to as acute motor axonal neuropathy (AMAN) (Feasby et al., 1986) and acute motor sensory axonal neuropathy (AMSAN). There also are remote-effect (paraneoplastic) motor neuropathies associated with lymphoma (Schold et al., 1979) or carcinoma (Yamada et al., 1988). An important disorder in the list is “porphyria.” The hepatic porphyrias include acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, a group of metabolic diseases associated with the overproduction of porphyrin precursors and porphyrins. Acute attacks of porphyrias are characterized by the triad of abdominal pain, psychosis, and neuropathy (Bloomer and Bonkovsky, 1989; Sack, 1990; Albers, 2001). The importance of the porphyrias vis-`a-vis toxic neuropathy is related to the large number of substances, particularly medications, capable of inducing a porphyric attack. In this context, patients who share the genetic abnormality associated with the hepatic porphyrias, therefore, represent a particularly susceptible group. Porphyria neuropathy resembles acute AIDP, presenting with weakness, areflexia, dysautonomia, and elevated CSF protein. Mental status changes, an initial proximal predilection, photosensitivity, and biochemical evidence of abnormal porphyrin metabolism are important features of porphyria. Patients with porphyric neuropathy often present with asymmetric weakness, a finding atypical of most forms of neuropathy. For this reason, porphyria also is listed among the conditions producing an asymmetric neuropathy. EMG features of porphyric neuropathy are those of an axonal neuropathy or polyradiculoneuropathy. Motor amplitudes are reduced and conduction is

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normal or minimally reduced, consistent with the loss of large myelinated axons. Abnormal temporal dispersion and abnormal conduction block are not typical features. Motor unit recruitment is decreased consistent with the degree of clinical weakness, and profuse fibrillation potentials appear after the fourth week of weakness, confirming the extent of axonal loss (Albers et al., 1978). Sensory responses may be normal or show diminished amplitude. Rare studies fulfill criteria for primary demyelination, but this may reflect a generalized axonal failure prior to complete axonal degeneration, similar to the findings in acute arsenic neuropathy. Many of the neurotoxicants that produce a motor or motor greater than sensory axonal neuropathy are medications. Vincristine, vinblastine, vinorelbine, and related chemotherapy medications produce an axonal sensorimotor neuropathy. On occasion, however, treatment results in rapidly progressive weakness with little sensory loss resembling a “pure motor” neuropathy or neuronopathy. EMG studies confirm the axonal pathophysiology, with low-amplitude motor responses, mild conduction slowing consistent with loss of large myelinated axons, and profuse fibrillation potentials and neurogenic motor unit changes. The motor “neuropathy” may localize to the motor neuron, not the distal axon, per se, making motor neuronopathy a more accurate descriptor. Dapsone is another medication that produces a motor neuropathy (Gutmann et al., 1976). However, Dapsone neuropathy is an “atypical” neuropathy, which may present with marked asymmetry. Dapsone is metabolized by N-acetyl transferase, the same enzyme the acetylates isoniazid, and susceptible patients may be slow acetylators (Ahrens et al., 1986). Other medications associated with this category of neuropathy include disulfiram and nitrofurantoin (Holmberg et al., 1980; Penn and Griffin, 1982; Davey, 1986). Disulfiram is used to promote alcohol abstinence. Disulfiram blocks the metabolism of alcohol at the acetaldehyde stage, resulting in high levels of acetaldehyde and unpleasant symptoms, forming the rationale for promoting abstinence. Disulfiram produces a dose-related neuropathy characterized by weakness, few or no sensory symptoms or signs, and areflexia (Davey, 1986). Weakness usually develops gradually, but, on occasionally, it may be sufficiently rapid as to mimic AIDP (Palliyath et al., 1990). Nitrofurantoin may produce a motor neuropathy, although it more typically produces a mild neuropathy characterized by paresthesias, pain, and stocking or

JAMES W. ALBERS AND JAMES W. TEENER

stocking-glove sensory loss and distal areflexia. This form of neuropathy is said to occur in about 0.2% of patients receiving nitrofurantoin (Davey, 1986), usually after long-term use for chronic urinary tract infection among elderly females who have impaired renal function and presumably abnormally elevated blood levels (Holmberg et al., 1980; Penn and Griffin, 1982). In contrast, nitrofurantoin-induced motor neuropathy produces a rapid onset of severe weakness. This motor neuropathy is superimposed on the sensory neuropathy but does not produce additional sensory symptoms or signs. Organophosphate esters have application in pesticides and some “nerve gases” (Lotti et al., 1984; Davis et al., 1985; Senanayake and Karalliedde, 1987). These compounds inactivate acetylcholinesterase, and acetylcholine accumulates in muscarinic and nicotinic cholinergic neurons (Moretto and Lotti, 1998). In the setting of an acute intoxication, muscarinic overactivity produces miosis, increased secretions, sweating, gastric hyperactivity, and bradycardia, whereas nicotinic overactivity results in fasciculations and skeletal muscle weakness. Exposure to some organophosphate compounds, in amounts sufficient to produce substantial inhibition of plasma butyrylcholinesterase and red blood cell cholinesterase, may be followed within a few weeks by onset of a rapidly progressive neuropathy. This motor predominant neuropathy develops after recovery from the effects of an acute poisoning, thus the name organophosphate-induced delay neurotoxicity (OPIDN) (Lotti et al., 1984; Senanayake and Karalliedde, 1987). OPIDN is characterized as a distal axonopathy affecting the peripheral nerves and the spinal cord (Moretto and Lotti, 1998). Spinal cord involvement is inferred from late development of the corticospinal tract signs as the neuropathy resolves (Aring, 1942; Abou-Donia and Lapadula, 1990). This combination of neuropathy with pyramidal tract signs has been associated with Jamaica ginger (“jake”) palsy, a syndrome observed commonly during the late 1920s when many Americans purchased adulterated Jamaica ginger to circumvent existing Prohibition laws (Morgan and Penovich, 1978). The adulterant was triorthocresyl phosphate (TOCP), a neurotoxic organophosphate. Like OPIDN, the earliest manifestation of jake palsy was peripheral neuropathy. In time, as the peripheral signs resolved, a pyramidal tract syndrome emerged. Currently, only a few cases of OPIDN are reported world wide per year, typically after a massive suicidal ingestion of an organophosphate insecticide producing life-threatening cholinergic effects

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and requiring intensive medical treatment (Lotti et al., 1986; Moretto and Lotti, 1998). 33.6.3. Sensory neuropathy or neuronopathy, without conduction slowing Neuropathies or neuronopathies characterized by exclusive, severe sensory loss are atypical of most neuropathies. Sensory neuronopathies present with unpleasant paresthesias and numbness in association with signs of choreoathetoid movements (pseudoathetosis), gait ataxia, diminished vibration and joint position sensations, minimally decreased pain sensation, a positive Romberg, and areflexia. The EMG examination shows substantially reduced or absent sensory responses, normal motor responses, and a normal needle evaluation. The differential diagnosis includes a manageable number of disorders (Table 33.4). Among the conditions unrelated to toxic exposures, Sjögren’s syndrome is probably the most common systemic disorder producing a severe sensory neuronopathy. The diagnosis of Sjögren’s syndrome in the presence of a sensory neuronopathy is suggested by accompanying complaints of dry eyes and mouth. The diagnosis is supported by elevated autoantibodies SSA (Ro) and SSB (la) and a salivary gland biopsy showing inflammatory infiltrates (Laloux et al., 1988). A paraneoplastic sensory neuronopathy frequently accompanies a small cell malignancy and anti-neuronal nuclear antibodies (Kiers et al., 1991). Carcinomatous sensory neuronopathy is proba-

Table 33.4 Toxic neuropathies presenting as a sensory neuropathy or neuronopathy, without conduction slowing, modified from Albers (2003) and Albers and Berent (1999) Toxic Cisplatin Ethyl alcohol Metronidazole Nitrofurantoin Pyridoxine Thalidomide Thallium (small fiber) Other neuropathies with similar patterns Hereditary (Friedreich’s ataxia, hereditary sensory) Inflammatory/infectious (Fisher variant of AIDP, human immunodeficiency virus, idiopathic sensory ganglionitis, Lyme disease, Sjogren’s syndrome) Nutritional (gastric resection, isoniazid, vitamin deficiency) Paraneoplastic

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bly the most distinctive remote-effect neuropathy (Donofrio et al., 1989). Chronic Lyme disease has been associated with a sensory neuropathy, as part of acrodermatitis chronica atrophicans (Kindstrand et al., 2000); cranial neuritis remains the most common neurological manifestation of Borrelia infection. Asymmetric or multifocal presentations of dense sensory loss suggest the diagnosis of inflammatory ganglionitis. On occasion, patients who are human immunodeficiency virus (HIV) positive develop a sensory neuronopathy. Vitamin deficiency syndromes, including those associated with thiamine (vitamin B1), pyridoxine (vitamin B6), cobalamin (vitamin B12), and alpha-tocopherol (vitamin E) deficiency show prominent sensory loss. However, only the syndromes associated with pyridoxine and tocopherol show exclusive sensory loss when severe (Nolan and Albers, 2003). Isoniazid anti-tuberculous therapy produces a neuropathy characterized by isolated sensory symptoms and signs during its early stages. With continued treatment, distal weakness may develop. Isoniazid produces neuropathy by depleting pyridoxine, as it combines with pyridoxine, and the combined derivative is excreted, resulting in pyridoxine deficiency (Ross, 1958). The Fisher syndrome is a variant of AIDP, and a presumed immune-mediated disorder that presents with subacute onset sensory loss, gait ataxia, impaired eye movements, and abnormal sensory responses (Fross and Daube, 1987). In addition, numerous forms of hereditary sensory neuropathy exist. The most common neurotoxicants producing a sensory neuropathy or neuronopathy are medications (e.g., cisplatin, isoniazid, metronidazole, nitrofurantoin, and thalidomide) (Lagueny et al., 1986). The best studied of these are cisplatin and related antineoplastic chemotherapy medications. Cisplatin produces a sensory neuronopathy as its main dose-limiting effect. Most patients treated with cisplatin develop symptomatic large fiber sensory loss and diminished reflexes. Sensory response amplitudes are used to monitor the onset of neuropathy during chemotherapy. A close relationship has been demonstrated between the decline in the sensory amplitude and onset of clinical symptoms and loss of reflexes (Molloy et al., 2001). Cisplatin neuronopathy is indistinguishable from the paraneoplastic sensory neuronopathy associated with small cell lung carcinoma. The presence of anti-neuronal nuclear antibodies supports an paraneoplastic cause (Kiers et al., 1991), but does not exclude the possibility of a superimposed toxic neuropathy.

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Pyridoxine (vitamin B6) is an essential vitamin. However, it is also a potent sensory neurotoxicant. Pyridoxine is occasionally taken in “megadoses” to treat a variety of nonspecific syndromes. Schaumburg and associates (1983a) associated dose-related neurotoxicity with excessive (long-term, low level cumulative or short-term, high level) pyridoxine exposure. With large doses, sensory loss may have abrupt onset, be complete and irreversible, and involve all cutaneous and facial and mucous membrane areas (Albin et al., 1987). Like all severe sensory neurotoxicants, sensory responses disappear as sensory loss increases. Alcohol-associated neuropathy is considered among the most common neuropathies. It is, therefore, ironic that a causal relationship between ethyl alcohol exclusive of nutritional deficiency has not been established. Although neuropathy frequently accompanies chronic alcoholism, the cause of the neuropathy is surrounded in controversy (Nolan and Albers, 2003). It is unclear whether alcohol-related neurological manifestations reflect the direct neurotoxicity of alcohol or its metabolites, poor nutrition, genetics, or combinations of these factors (Charness et al., 1989). The pathogenesis of alcohol-related neuropathy remains controversial because most individuals who consume large amounts of alcohol are also nutritionally compromised (Victor et al., 1989). Nevertheless, ethyl alcohol, alone or in combination with vitamin deficiency states, exerts adverse effects at multiple levels of the nervous system (Albers and Bromberg, 1995). The most common form of alcohol-related neuropathy is a slowly progressive sensorimotor axonal neuropathy (Charness et al., 1989). Another classic form of alcohol-nutritional deficiency neuropathy presents with distal burning paresthesias, lancinating leg pain, distal sensory loss, poor balance, and distal areflexia, findings suggestive of a pure sensory neuropathy. EMG evaluation shows only low amplitude sensory responses with slightly prolonged distal latencies in the hands and absent sensory responses in the legs. Motor conduction studies and the needle EMG are unremarkable. On occasion, other neurological manifestations, such as thiamine-responsive Wernicke syndrome (dementia, ophthalmoplegia, and ataxia) may first suggest the possibility of an alcohol-nutritional deficiency syndrome. Systemic evidence of alcohol toxicity includes hepatic cirrhosis. Unfortunately, there is nothing unique to distinguish the sensory neuropathies of excessive alcohol consumption or vitamin deficient states. Support for a nutritional cause of alcohol-related neuropathy includes evidence that neuropathy is not

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induced by excessive alcohol among individuals who receive nutritional supplementation (Victor et al., 1989). Further, a typical Wernicke–Korsakoff encephalopathy and neuropathy occasionally develop after gastroplasty for morbid obesity in the absence of alcohol exposure (Cirignotta et al., 2000). Yet, alcohol is known to impair axonal transport (McLane, 1987), and Behse and Buchthal (1977) reported the occasional development of a typical alcohol neuropathy despite of normal nutrition. A unique neuropathy is associated with thallium intoxication. Thallium, like several other metals and metalloids including arsenic, lead, mercury, and lithium, is a neurotoxicant. Thallium neuropathy, however, is atypical of most other toxic neuropathies in its degree of small nerve fiber involvement. Most reports of acute thallium toxicity emphasize painful dysesthesias in the feet and legs, symptoms reminiscent of arsenic poisoning (Bank, 1980; Wilbourn, 1984; Windebank, 1993; Kubis et al., 1997). Dysautonomia with abdominal colic, nausea, vomiting, diarrhea, and anhidrosis frequently accompany thallium intoxication, often preceding onset of the neuropathy (Kalantri and Kurtz, 1988; Herrero et al., 1995). Findings of markedly diminished pin-pain sensation but preserved reflexes support the impression that thallium produces a small fiber neuropathy. In severe thallium neuropathy, distal weakness develops, so this is not an exclusive sensory neuropathy. In fact, thallium neuropathy may produce quadriparesis and respiratory failure, similar to that seen in AIDP (Andersen, 1984; Cavanagh, 1984). Like many neurotoxicants, thallium induces neuropathy in the setting of systemic poisoning, producing skin rash, Mees’ lines, and, the cardinal clinical feature of thallium neuropathy, alopecia. 33.6.4. Sensory greater than motor (sensorimotor) neuropathy, with conduction slowing Few disorders fulfill the description for this form of neuropathy (Table 33.5). Ironically, the most common neuropathy in the US, diabetic neuropathy, falls in this category. In the context of toxic neuropathy, diabetes is important because a clinically evident or subclinical diabetic neuropathy can present before the diagnosis of diabetes mellitus has been established. Therefore, a patient exposed to a potential neurotoxicant and found to have neuropathy may inadvertently be diagnosed with a toxic neuropathy based on opportunity for exposure. Failure to develop an appropriate differential diagnosis often occurs when the diagnosis appears

TOXIC NEUROPATHIES Table 33.5 Toxic neuropathies presenting as a sensorimotor neuropathy with conduction slowing, modified from Donofrio et al. (1990) Toxic Saxitoxin (red tide) Tetrodotoxin (puffer fish) Other neuropathies with similar patterns Inflammatory/infectious (chronic inflammatory demyelinating [CIDP]) Metabolic (diabetes mellitus, uremic [end stage renal disease])

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out any evidence of abnormal temporal dispersion or partial conduction block (Albers, 1997). Conditions that commonly produce neuropathy, such as diabetes mellitus, are occasionally implicated in the controversy of whether or not an underlying neuropathy of any cause predisposes that individual to a toxic neuropathy. This concept may have its origin in association with the apparent predisposition to compression neuropathy among patients with a known diabetic neuropathy. However, the hypothesis that patients with neuropathy of any cause show increased susceptibility to known neurotoxicants remains unproven. 33.6.5. Sensory greater than motor (sensorimotor) neuropathy, without conduction slowing

obvious. Fortunately, diabetes mellitus is one of only a few sensorimotor neuropathies that produce findings of axonal loss and substantial conduction slowing. Patients who have renal failure independent of diabetes mellitus develop a sensorimotor neuropathy characterized by low amplitude motor and sensory responses, sometimes in association with pronounced conduction slowing (Dyck et al., 1975). This is most apparent among patients with end-stage renal disease, where the degree of conduction slowing is greater than expected if it was due only to loss of large myelinated fibers (Said et al., 1983). Setting aside the discussion of whether or not the conduction slowing in diabetes or uremia represents primary demyelination or a membranopathy, there are few situations or neurotoxicants that produce diagnostic confusion. Arguably, the most common situation to produce diagnostic confusion involves poor technique, because reduced limb temperature produces conduction slowing that resembles the slowing associated with diabetic neuropathy. Of course, conduction slowing due to cool limb temperature also produces increased (not decreased) sensory amplitudes, making the distinction from a toxic-metabolic lesion relatively apparent. Neurotoxicants that block sodium channels reduce conduction velocity, but they are uncommon. Two that do, however, are tetrodotoxin derived from the puffer fish and saxitoxin derived from contaminated shell fish (red tide) (Jacques et al., 1980; Lombet et al., 1988; Long et al., 1990). Blockade of sodium channels decreases the local currents associated with action potential propagation, an effect similar to that seen with reduced temperature that slows conduction velocity. Motor response amplitudes are reduced with-

Sensorimotor neuropathies of the axonal type are the most common neuropathies encountered by the neurologist. Typically, they present with symmetrical sensory signs or with sensory more than motor signs in a stocking or stocking-glove distribution. Signs include diminished touch-pressure, vibration, and pin-pain sensations; distal weakness and muscle atrophy concordant with the degree of weakness; and hypoactive or absent reflexes. Most neuropathies in this category show EMG evidence of low amplitude or absent sensory responses early in the clinical course, followed later by low amplitude motor responses. Criteria for substantial conduction slowing are not fulfilled. The needle examination shows evidence of denervation (fibrillation potentials and positive waves) and reinnervation (chronic motor unit changes). Numerous conditions produce findings of the type described in the preceding paragraph, including many toxic or metabolic neuropathies. The differential diagnosis for an axonal sensorimotor neuropathy includes hereditary, degenerative, metabolic, systemic, nutritional, granulomatous, and toxic disorders. Unfortunately, the numerous disorders are often difficult to distinguish from one another, either clinically or based on EMG results. Further, of all the categories of neuropathy described, this form is likely to include the largest number of idiopathic neuropathies that remain undiagnosed even after extensive evaluation. Some of the neurotoxicants capable of producing an axonal sensorimotor neuropathy are listed in Table 33.6. This table also does not include the other numerous causes that must be included in the differential diagnosis of any sensorimotor neuropathy (see, for example, Donofrio and Albers, 1990). Surprisingly,

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many of the toxic neuropathies in this category are slowly progressive and relatively mild, a generalization that may simply reflect the magnitude of exposure, as many of the items are included among the other categories when exposure is greater. Consider arsenic exposure, for example. Chronic, low-level arsenic exposure in sufficient amounts produces a mild sensorimotor axonal neuropathy. Exposure to higher levels is associated with a severe, acute neuropathy resembling AIDP. For many of the neurotoxicants listed in Table 33.6, the only evidence linking them to a patient’s neuropathy is evidence of an abnormally elevated blood, urine or tissue level. Such a finding, in isolation, is insufficient to establish causation. However, assuming the elevated level reflects ongoing exposure, removal from exposure with a resultant resolution of the neuropathy is strong evidence supporting a causal relationship, as most toxic neuropathies are reversible once ongoing exposure is terminated. Following removal from exposure, there may be progression for a few weeks before stabilization and improvement of the neuropathy (coasting). For a few items listed in the table, there may be additional clues in the form of combined findings suggesting a toxic etiology. Examples include the association of postural tremor and neuropathy produced by lithium or mercury intoxication (Pamphlett and Mackenzie, 1982; Albers et al., 1988), neuropathy with preserved reflexes with abnormal corticospinal tract signs and anemia produced by vitamin B12 deficiency (McCombe and McLeod, 1984), and neuropathy and myopathy produced by colchicine (Kuncl et al., 1987). The role of clinical and EMG follow-up is relevant to the evaluation of slowly progressive sensorimotor neuropathies. On occasion, the cause of a neuropathy is only apparent after a period of continued observation. This is frequently the case in some of the hereditary axonal neuropathies, as additional involved relatives are subsequently identified. The controversy involving ethyl alcohol-related neuropathy was discussed in association with the sensory neuropathies. Regardless of whether or not the alcohol-related neurologic disorders reflect a direct neurotoxic effects of alcohol, its metabolites, nutritional disorders, genetic factors, or combinations of these factors (Behse and Buchthal, 1977; Charness et al., 1989; Victor, 1989), alcohol abuse frequently is associated with an axonal sensorimotor neuropathy characterized by slowly progressive sensory loss, distal weakness, unsteady gait, and areflexia.

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Chronic exposure to some medications, among which phenytoin is a good example, produces a neuropathy. Phenytoin neuropathy is characterized by large fiber sensory abnormalities, imbalance, and hypo- or areflexia. EMG results show low amplitude sensory responses, normal motor responses, and borderline-low motor conduction velocities. The needle examination shows chronic neurogenic changes, with reduced recruitment and large amplitude motor units, but little evidence of abnormal insertional activity, findings indicating very slow denervation so that re-innervation keeps pace with ongoing denervation. The diagnosis of a phenytoin neuropathy often is serendipitous, and abnormalities identified only when an EMG evaluation is performed for a reason unrelated to the question of neuropathy (e.g., radicular pain). 33.6.6. Mononeuritis multiplex, with or without conduction slowing Most neuropathies are characterized by symmetric motor or sensory signs. Generalized neuropathies that defy that axiom are listed in Table 33.7. Hereditary neu-

Table 33.6 Toxic neuropathies presenting as a sensorimotor neuropathy with no conduction slowing, modified from Albers (2003) and Albers and Berent (1999) Acrylamide Amitriptyline Arsenic (chronic) Carbon monoxide Cobalamin (Vitamin B12) deficiency Colchicine (neuromyopathy) Ethambutol Ethyl alcohol Ethylene oxide Gold Hydralazine Isoniazid Lithium Mercury (elemental) Metronidazole Nitrofurantoin Nitrous oxide (myeloneuropathy) Paclitaxel Perhexiline Phenytoin Thallium Vincristine

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ropathy with liability to pressure palsies (HNLPP) may mimic a diffuse sensorimotor neuropathy (Felice et al., 1994). “Inflammatory” disorders of presumed autoimmune etiology constitute the most common cause of asymmetric neuropathies. They include acute motor axonal neuropathy (AMAN), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, and multifocal motor neuropathy (MMN). AMAN represents an axonal form of AIDP, which shows a strong association with anti-ganglioside antibodies against GM1, GD1a, GalNAc-GD1a, or GD1 (Ogawara et al., 2000). MADSAM neuropathy, or Lewis-Sumner syndrome, presents with multifocal motor and sensory loss and nerve conduction evidence of conduction block and other features of demyelination (Saperstein et al., 1999). MMN produces asymmetrical weakness and muscle wasting in association with prominent conduction slowing in motor nerves, but normal sensory responses in the same nerves. Anti-GM1 ganglioside antibodies may be present (Chaudhry et al., 1993). Lyme disease frequently presents as a cranial neuritis involving the facial nerves (Eggenberger, 1993). Finally, this category of “neuropathy” includes disorders caused by structural abnormalities, such as syringomyelia, cervical spondylosis, and

Table 33.7 Toxic neuropathies presenting as a mononeuritis multiplex or asymmetric neuropathy Toxic-metabolic Dapsone Lead Porphyria Trichloroethylene (cranial neuritis) Toxic oil syndrome l-Tryptophan Other neuropathies with similar patterns Hereditary (distal myopathy, hereditary neuropathy with liability to pressure palsies [HNLPP], Kennedy syndrome, progressive muscular atrophy) Idiopathic (atypical motor neuron disease [e.g., Aran–Duchenne], inclusion body myositis) Inflammatory/infectious (acute motor axonal neuropathy [AMAN], diabetic amyotrophy, idiopathic brachial neuritis [Parsonage Turner], Lyme disease, multifocal acquired demyelinating sensory and motor [MADSAM], multifocal motor neuropathy [MMN], poliomyelitis, vasculitis, West Nile virus) Structural (cervical spondylosis, polyradiculopathy, without neuropathy, syringomyelia)

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polyradiculopathy without neuropathy (McGonagle et al., 1990). There are many syndromes producing a mononeuritis multiplex or a markedly asymmetrical motor or motor greater than sensory neuropathy. However, more than 100 years ago, lead was the only neurotoxicant associated with this form of neuropathy. It is curious, therefore, that most descriptions of lead neuropathy were reported at a time when lead also would have been one of the few items appearing in a differential diagnosis of an asymmetric neuropathy. Therefore, a painter, who had an opportunity for exposure to leadbased paints in the early 1990s and who developed an asymmetric motor neuropathy, likely would have been diagnosed with lead neuropathy. The differential diagnosis would not have included the numerous other conditions listed in Table 33.7, as most were not described until the mid- to late-twentieth century. Porphyria was discussed among the forms of motor neuropathy without conduction slowing, and it was noted that asymmetric weakness is a characteristic feature of porphyric neuropathy. The metabolic defects associated the hepatic porphyrias interfere with heme syntheses at sites along the synthesis pathway. All of these sites are close to the site at which lead interferes with heme synthesis. This similar site of action may explain, indirectly, the similarities between the historical descriptions of lead neuropathy and porphyric neuropathy, namely asymmetric, pure motor weakness. It also is conceivable that lead is simply one of the numerous substances capable of inducing porphyric neuropathy among patients with porphyria, not a peripheral neurotoxicant in and of itself. Dapsone neuropathy is included among the motor or motor greater than sensory neuropathies, without conduction slowing. Dapsone (4,4-diamminodiphenyl sulphone) was widely used to treat leprosy without reports of neuropathy. It also is prescribed for a variety of skin conditions, including dermatitis herpetiformis. Initial descriptions of Dapsone-induced neuropathy appeared about 30 years ago in association with chronic, long-term exposures at relatively high dosage (Gutmann et al., 1976; Koller et al., 1977). Most reports include descriptions of asymmetrical weakness in a distribution suggesting a diagnosis of mononeuritis multiplex. However, the paucity of sensory signs is inconsistent with that diagnosis. Trichloroethylene (TCE) exposure is associated with a cranial neuritis with a predilection of trigeminal nerve involvement (Feldman, 1970). This cranial mononeuropathy multiplex is so characteristic of TCE

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over-exposure, that it is thought unwise to incriminate TCE as the cause of a neuropathy unless cranial nerves were involved (Fullerton, 1969). This cranial neuritis is said to follow TCE exposure via inhalation anesthesia (perhaps in combination with soda lime) or occupation exposures (Buxton and Hayward, 1967; Feldman et al., 1970). Eosinophilic myalgia syndrome (EMS) was associated with l-Tryptophan, or perhaps with a novel amino acid contaminant associated with its production (Belongia and et al., 1990; Selwa et al., 1990). EMS consists of eosinophilia, characteristic peau d’ orange skin changes, myalgia, and an atypical mononeuritis multiplex showing patchy sensory loss with sparing of motor fibers in the same nerves. EMS has essentially disappeared after the initial case reports, perhaps because of decreased use of l-tryptophan or because of correction of the defective manufacturing process. Sensory axons may have selectively injured as they transverse the subcutaneous tissues, the primary site of inflammation and perhaps the autoimmune target. As such, sensory involvement may represent a bystander effect, not direct neurotoxicity. A reactive fibrosis of subcutaneous tissue could explain neurologic progression after removal from exposure, another feature atypical of other forms of toxic neuropathy. The 1981 Spanish “toxic-oil syndrome” (TOS) epidemic resembles EMS. Patients diagnosed with TOS showed eosinophilia, myalgia, weakness, and they ultimately developed contractures of the jaw and extremities resembling scleroderma. TOS was linked to consumption of aniline-denatured and refined rapeseed oil that had been illegally marketed as cooking oil (Kaufman, 1991; Verity et al., 1991; Bolster and Silver, 1994; Kaufman and Krupp, 1995). Although many aniline-derived oil components were identified, no causative agent was ever identified for

TOS (Schurz et al., 1996). The similarities between EMS and TOS, including the distribution of prominent sensory involvement, could reflect an underlying vasculitis or fasciitis. 33.6. Establishing the cause of neuropathy The first step in identifying the cause of a neuropathy is to consider the numerous possibilities. In the context of potential toxic neuropathies, pharmaceutical, industrial, recreational, and environmental exposures are all possible considerations. However, the opportunity for exposure does not prove that the exposure caused the neuropathy, even when the exposure is to a known neurotoxicant. Simply identifying the presence of a potential neurotoxicant does not ensure that it produced the neuropathy. Simply put, association does not establish causation. How then does the clinician establish the cause of neuropathy? Fortunately, the methodology use to establish causation is well developed and intuitive to most clinicians, as it resembles the methodology used to establish a clinical diagnosis. Clinicians use the scientific method of hypothesis generation and testing to establish a diagnosis of neuropathy and to formulate a differential diagnosis. However, arriving at the correct neurological diagnosis does not ensure that the cause of the underlying neurological problem has been identified. A separate process is used to establish the cause of neuropathy. The methodology used to establish causation in the context of a suspected toxic neuropathy is sometimes referred to as the Bradford–Hill criteria (1965). These criteria consist of a list of questions that must be considered (Table 33.8). The questions address issues of temporal association, dose, biologic plausibility, and identification and elimination of competing causes to establish a

Table 33.8 Questions useful in establishing a toxic etiology, modified from Hill (1965) 1. 2. 3. 4. 5. 6. 7. 8.

Temporality: appropriate timing of exposure and signs? Plausibility: is the effect biologically plausible? Biological gradient: expected dose-response relationship? Coherence: removal from exposure modifies effect? Existence of animal model? Specificity: cause-effect relationship limited to exposed individuals? Strength of association: high relative risk based on sound epidemiology studies? Consistency: repeated observations among different studies and different investigators? Differential diagnosis: other causes eliminated?

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neurotoxic etiology. The answers to the questions help distinguish association from causation. The fundamental concept involving a temporal association between exposure to a potential neurotoxicant and the subsequent development of neuropathy is important. Yet, temporal association is only one of several important considerations. While it is obvious that the effect (neuropathy) cannot proceed the cause (exposure), general pharmacologic and toxicologic principles of doseresponse are often not considered in establishing causation. A neurotoxicant cannot produce neuropathy without being present in sufficient amount. Unfortunately, the ability to establish a neurotoxic cause frequently is limited by the absence of a definite measure of exposure. The Bradford–Hill criteria also address issues related to epidemiological studies. All scientific studies are not equal. Case reports are useful in generating hypotheses about possible cause-effect issues, but only cohort studies and case-control studies are capable of establishing causation. Conversely, a well-designed but negative cross-sectional study provides no support for a toxic association. To most clinicians, the most difficult question listed among the Bradford–Hill criteria, and the one that requires the greatest clinical experience, is the one related to competing causes. The expression “consistent with” frequently links some clinical symptom, sign, or EMG finding to a particular cause, without acknowledging that the finding likely is consistent with numerous other causes. All causes must be identified before they can be evaluated and possibly eliminated from consideration. The fact that many neuropathies are idiopathic or without known cause complicates this process. The example given earlier involving lead neuropathy highlights the problem of an incomplete differential diagnosis. In the earlier twentieth century, a patient with lead exposure and asymmetrical weakness, a finding consistent with lead neuropathy, could not have been diagnosed with any of the numerous other disorders consistent with asymmetrical weakness because the conditions had not as of then been described. Similarly, development of severe sensory loss and areflexia in the setting of excessive alcohol consumption is consistent with an alcohol-related sensory neuronopathy. If, in fact, this is the only cause of sensory neuropathy known to the clinician, the explanation seems obvious. However, suggesting a toxic etiology just because no other etiology is apparent rarely results in the correct diagnosis, as there is no guarantee that the only cause considered is the correct explanation. In the case of acute sensory loss, an alco-

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hol-related sensory neuronopathy is indistinguishable from the neuronopathy attributable to Sjogren’s syndrome, neoplasm, human immunodeficiency virus, idiopathic sensory ganglionitis, vitamin E deficiency, the Fisher variant of AIDP, and several other neurotoxicants including Vacor, cisplatin, metronidazole, pyridoxine, and thalidomide. Eliminating competing explanations is the most difficult task addressed by the Bradford–Hill criteria. Although it is often difficult to identify a toxic etiology based on some particular findings, there are clues suggesting a possible toxic etiology. These “clues” usually represent some specific cardinal feature of a certain toxin. Recognizing such clues stems from a high level of suspicion, but even casual recognition of some clues raises suspicion for a possible toxic etiology, which then can be explored. A list of clinical or laboratory findings associated with certain neurotoxicants is listed in Table 33.9. These associations, while important, do not establish causation, as few produce features sufficiently characteristic to be considered pathognomonic. In the context of a neuropathy attributable to an occupational or environmental exposure, identifying an “outbreak” or cluster of individuals who share a common exposure should raise clinical suspicion for a common cause. The concept refers to wellestablished, homogeneous forms of neuropathy, not to individuals sharing diverse, nonspecific symptoms such as intermittent paresthesias. The concept also refers to groups of individuals who develop neuropathy within a relatively uniform interval following exposure. In this context, establishing evidence of subclinical neuropathy, based on cross-sectional comparison of unexposed and exposure individuals, should always be viewed cautiously. Such studies, including those using nerve conduction studies or quantitative sensory testing, are incapable of establishing the cause of any identified group differences. When small yet statistically significant group differences are identified within the normal range of any given measure, they usually reflect inadvertent (and unidentified) confounding, not a neurotoxic effect. 33.7. Group evaluations of suspected toxic neuropathy Consider the situation in which a group of individuals has a common exposure to a potential peripheral nervous system neurotoxicant. If there are few or no overt signs of neuropathy among individuals in the group,

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Table 33.9 Selected systemic clues associated with specific peripheral neurotoxicants, modified from Ford (1999) Neurotoxicant

Systemic feature

Acrylamide Arsenic

Irritant dermatitis, palmar erythema, desquamation, hyperhidrosis, axonal swellings Gastrointestinal symptoms, hyper-pigmentation, hyperkeratosis, Mees’ lines, cardiomyopathy, hepatomegaly, renal failure, anemia, basophilic stippling of red blood cells, elevated levels in blood, urine, hair, or nails Dysosmia, glossitis, pigmented skin and nails, atrophic gastritis, achlorhydria, pernicious anemia, megaloblastic anemia, corticospinal tract signs, anemia, low serum B12, elevated serum methylmalonic acid and homocysteine Myopathy (neuromyopathy) After years or decades of use, ?slow acetylators Nutritional factors, Wernicke syndrome (dementia, ophthalmoplegia, and ataxia), midline cerebellar degeneration, abnormal liver function, cirrhosis Irritant dermatitis, axonal swellings Gastrointestinal symptoms, musculoskeletal complaints, weight loss, gum lead line, Mees’ lines, renal failure, anemia, basophilic stippling, bone lead line, elevated levels in blood and bone Postural tremor Anorexia, gingivitis, hypersalivation, papular rash, hyperkeratosis, lens opacities, postural tremor, nephrotic syndrome, respiratory tract irritation, metal fume fever, elevated levels in urine Elderly with impaired renal function Myelopathy Irritant dermatitis, acute cholinergic effects, corticospinal tract residua, ?impaired glucose tolerance, non-cardiogenic pulmonary edema, biological effect on serum and red blood cell cholinesterase activity, urine metabolites of specific organophosphate compounds Gingival hyperplasia, cerebellar ataxia Abdominal pain, encephalopathy (psychosis), neuropathy, photosensitivity, abnormal excretion of porphyrin precursors, genetic predilection Gastrointestinal symptoms, irritant dermatitis, alopecia, non-cardiogenic pulmonary edema Vasodilation with ethanol ingestion, irritant dermatitis, elevated liver function test, cirrhosis Respiratory tract irritation, irritant dermatitis Peau d’ orange skin changes, eosinophilia

Cobalamin (B12) deficiency Colchicine Dapsone Ethyl alcohol n-Hexane Lead Lithium Mercury, elemental Nitrofurantoin Nitrous oxide Organophosphate pesticides Phenytoin Porphyria Thallium Trichloroethylene Toluene l-Tryptophan

how might they be investigated for evidence of a subclinical toxic neuropathy? The question is more than theoretical, and it is a question that is addressed frequently in the context of epidemiological studies. Although the question is straightforward, the answer is complicated by several factors, some of which are beyond the scope of this chapter. The obvious answer to the question is that some measure of peripheral nervous sytem function could be compared to a group of referent individuals with no exposure to the neurotoxicant in question. Yet, only certain types of tests are amenable for quantitative evaluation of the peripheral nervous system function. Nerve conduction studies are the measures most frequently used. They are not particularly uncomfortable, and they are quantitative, reproducible, and independent of subject motivation. In contrast, the needle EMG examination is relatively

uncomfortable and includes subjective determinations and qualitative measures that limit its application to epidemiological investigations. Other neurological measures, such as quantitative sensory testing, while quantitative, are influenced by many factors, including subject motivation, limiting their usefulness in certain types of investigations (e.g., those involving litigation or possible secondary gain). Unfortunately, regardless of the outcome measures used, only certain types of group comparisons among exposed individuals and referent subjects are capable of establishing the cause of any identified differences. This is because most studies, including cross-sectional investigations of exposed and unexposed individuals, cannot be certain that the groups were similar before exposure to the suspected neurotoxicant. Therefore, there is no way of determining that the differences

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reflect exposure to the substance in question or the effect of some unrecognized factor(s). Numerous factors, including age, height, weight, body mass index, hand size, and perhaps even smoking history, educational level or intelligence measures (reflecting socioeconomic factors), and anxiety level potentially influence nerve conduction study results. These influences, referred to as confounding, occur because the factor is associated with the exposure group in some way (e.g., manual labor and large body size and low amplitude sensory responses) but is independent of the cause of the effect under study. In addition, numerous forms of bias (e.g., selection bias, healthy worker effect, low participation rate, misclassification) may introduce systematic errors that influence the results in a positive or negative way, yet defy identification. The results of prospective cohort studies, such as used to evaluate pharmaceutical agents, measure performance before and after exposure, randomly assign subjects to exposure categories, mask subjects and investigators to exposure information, and use objective measures of peripheral nerve function. Cohort studies can establish the cause of identified effects. Such studies are difficult to perform, and certain aspects of these studies, such as randomly assigning subjects to exposure categories, are unrealistic for epidemiological investigations. Prospective cohort studies measure performance at the beginning of a study to establish that the exposure groups are comparable at baseline and then remeasure performance after an interval of additional exposure among the exposed subjects. These studies also can establish whether or not the additional exposure causes a measurable interval deterioration in function. These studies have application in occupational evaluations, but they have limited application to situations involving inadvertent exposure to some suspected neurotoxicant. The investigations most frequently used to evaluate toxic neuropathy involve cross-sectional comparisons of exposed and referent groups. Any results suggesting subclinical group differences within the normal range of the electrophysiological measure must always be interpreted cautiously because of the numerous factors that influence the results, independent of peripheral nervous system pathology. 33.8. Summary There is nothing special about the evaluation of a patient with a suspected “toxic” neuropathy. The initial evaluation of a suspected neuropathy is identical to

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the evaluation of any nervous system problem, regardless of localization. It is neither necessary nor helpful to know the “cause” of the patient’s problem before beginning the investigation. In fact, such information, if incorrect, may hinder an appropriate evaluation if important diagnostic steps are neglected. The clinical and EMG examinations are the most important components of the evaluation of suspected peripheral neuropathy. They are complementary in establishing a diagnosis. Unfortunately, there is no characteristic presentation of a toxic neuropathy, as the most classic form of toxic neuropathy is a sensorimotor, dyingback neuropathy of the axonal type, the form of neuropathy most frequently encountered by the practicing neurologist. However, once a diagnosis of neuropathy has been established, the EMG evaluation can be used to categorize the neuropathy based on sensory or motor involvement and the presence or absence of conduction slowing. The resultant classification serves the important purpose of limiting the number of items that must be considered in the differential diagnosis, thereby directing the subsequent evaluation. In this context, the EMG examination is the most important and useful “test” in recognizing the cause of any given neuropathy. In the context of toxic neuropathy, it is important to understand the methodology used to establish causation. The methodology for establishing a toxic cause of neuropathy is an uncomplicated yet difficult task. It is sometimes approached in the form of questions (Bradford-Hill criteria) that address appropriate timing of exposure and signs, dose-response information, available epidemiological studies, and appropriate animal models of toxicity to demonstrate the feasibility of any potential association. In seeking an explanation for a patient’s neuropathy, systemic or laboratory clues sometimes suggest a possible toxic explanation. For some neurotoxicants, an abnormal body burden is established by direct or indirect laboratory measurement, whereas, for others, characteristic systemic or pathologic clues help ascertain the identity. Most toxic neuropathies improve following removal from exposure. Many of the toxic neuropathies encountered in clinical practice result from exposure to prescribed medications, sometimes after years of use. A familiarity with the numerous neurotoxicants and a high index of suspicion are important clinical attributes for the practicing neurologist. The most important attribute, however, is an ability to formulate an accurate and complete differential diagnosis, before attributing a neuropathy to a toxic etiology.

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CHAPTER 34

Guillain–Barré syndrome David R. Cornblatha,* and Richard A.C. Hughesb b

a Department of Neurology, The Johns Hopkins University School of Medicine, MD, USA Department of Clinical Neurosciences, Guy’s King’s and St Thomas’ School of Medicine, London, UK

34.1. Introduction

34.2. Epidemiology

Guillain–Barré syndrome (GBS) emerged as a distinct clinical entity after Guillain, Barré and Strohl described two soldiers with reversible motor neuropathy associated with an increased cerebrospinal fluid (CSF) protein and normal CSF cell count (Guillain et al., 1916; Hughes, 1990). In 1969, a clinicalpathological series from Boston showed that the underlying pathological basis was usually an acute inflammatory demyelinating polyneuropathy (AIDP) This was confirmed by neurophysiological studies (Asbury et al., 1969; Cornblath, 1990). Major advances in understanding GBS have occurred in the past 15 years. We now recognize that under the umbrella of GBS are several clinical subtypes with distinctive neurophysiological and pathological, and presumably pathophysiological substrates: AIDP, acute motor (AMAN) or motor and sensory (AMSAN) axonal neuropathy, Fisher syndrome (FS), and other rarer variants (Kissel et al., 2001). Epidemiological studies have revealed the importance of viral and bacterial, especially Campylobacter jejuni, infections in triggering the disease (Rees et al., 1995b). Immune responses against gangliosides are induced by these infections and have been implicated in pathogenesis, especially of the axonal forms (Ho et al., 1999). Randomized controlled trials have shown equivalent benefit from plasma exchange (PE) (Raphaël et al., 2004) and intravenous immunoglobulin (IVIg) (Hughes et al., 2004) but not corticosteroids (Hughes and van der Meché FGA, 2004). Intensive care and rehabilitation are critically important aspects of treatment.

The annual incidence of GBS is between 0.4 and 4 per 100000 throughout the world. There is a slight male preponderance, and the disease becomes more common with advancing age. There may be a small peak in the age distribution in young adults (Hughes and Rees, 1997). Apart from rare exceptions (Roman, 1995), GBS is sporadic and lacks seasonality. However, in Northern China, epidemics of the AMAN subtype occur mainly in the summer months and among those from rural districts (McKhann et al., 1991, 1993).

*Correspondence to: David R. Cornblath, MD, FAAN, Meyer 6-181a, The Johns Hopkins Hospital, Baltimore, MD 21287-7681, USA. E-mail address: [email protected] Tel.: +1-410-955-2229; fax: +1-410-502-6737.

34.3. Preceding infections About two-thirds of cases are preceded by symptoms of an upper respiratory or gastrointestinal infection. A wide range of organisms has been implicated (Table 34.1). The commonest identified organisms are Campylobacter jejuni in about 25% and cytomegalovirus in about 15% of cases (Winer et al., 1988; Rees et al., 1995b). There is no tight correlation between the type of preceding organism and the subtype of GBS. For example, although C. jejuni is associated with severe axonal degeneration, in European and North American studies, any of the different forms of GBS may follow this infection (Rees et al., 1995b). A recent Japanese study concluded that all of 22 C. jejuni cases had AMAN not AIDP (Kuwabara et al., 2004). This finding may reflect differing immunosusceptibilities in different races. 34.4. Pathogenesis Most work on pathogenesis centers on the hypothesis of autoimmunity (Hartung et al., 2002; Kuwabara, 2004). This was first proposed because of the close physiological and pathological resemblance between AIDP and experimental autoimmune neuritis induced by either immunizing laboratory animals

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Table 34.1

Campylobacter jejuni carries sialylated glycoconjugates in its wall which resemble gangliosides, so that infection might stimulate the production of crossreactive antibodies (Rees et al., 1995c; Lunn et al., 2000). These observations are of particular interest since a monoclonal antibody to GD1a reacts with rat motor but not sensory axons, supporting the hypothesis that antibodies to GD1a could account for AMAN (Lunn et al., 2000).

Infections and other antecedent events for which there is strong evidence of a causative association with GBS Campylobacter jejuni Haemophilus influenzae (see Mori et al., 2000; Ju et al., 2004) Cytomegalovirus Epstein-Barr virus Mycoplasma pneumoniae Rabies vaccine “Swine flu vaccine” Ganglioside injections (see Illa et al., 1995)

with peripheral nerve myelin or transferring antimyelin protein T cells. Proof that T cell responses to one of these proteins are responsible for AIDP is lacking but investigation continues (Hughes et al., 1999). Another series of investigations suggests that the infecting organisms share homologous epitopes to glycolipid components of the peripheral nerves and, therefore, the immune responses cross-react with the nerves causing disease. In the AMAN form of GBS, the target molecules are postulated to be gangliosides GM1, GM1b, GD1a or GalNAc–GD1a expressed on the motor nerve axolemma. Cross-reactive antibodies would then lead to axonal degeneration, the presumed underlying basis of AMAN and AMSAN. In the AIDP form, immune reactions against target epitopes in Schwann cells or myelin result in demyelination; however, the exact target molecules in AIDP have not yet been identified. Antibodies to peripheral nerve gangliosides are commonly found in some forms of GBS. Anti-GQ1b antibodies are present in almost all patients with FS or with GBS and ophthalmoplegia (Hartung et al., 2002; Kuwabara, 2004). Anti-GM1 antibodies are present in about 25% of patients with GBS, are more common in GBS patients with preceding C. jejuni infection than those without, and are slightly more common in those with AMAN or AMSAN than in AIDP (Yuki et al., 1990; Rees et al., 1995a). Attempts to match antibodies to different GBS subtypes and thus explain the pathogenesis are still ongoing but do not yet allow a clear immunological classification of the most common syndromes (Hughes et al., 1999; Yuki et al., 2000; Hartung et al., 2002). In Chinese patients with AMAN, there was a stronger association with antibodies to GD1a than with GM1 (Ho et al., 1999).

34.5. Genetics Since only about 1 person in a 1000 with C. jejuni infection develops GBS, other factors must be involved. Much work has centered on the C. jejuni serotype. In Japan, when GBS follows C. jejuni, the Penner O:19 serotype is usually responsible although this is a rare cause of uncomplicated enteritis (Yuki et al., 1995; Yuki, 1997). Also likely important are immunogenetic host factors, but these not have been clearly identified. 34.6. Clinical features In typical cases, the first symptoms are numbness, paraesthesia, pain, or weakness, or commonly a combination of all. Numbness and paraesthesia usually affect the distal limbs and spread proximally. Weakness may be initially proximal, distal, or both. Facial nerves are commonly affected; less often the bulbar and ocular motor nerves are also involved. In 25% of patients, respiratory muscles are involved causing respiratory failure and a need for artificial ventilation. Autonomic involvement causes retention of urine, ileus, sinus tachycardia, hypertension, cardiac arrhythmia, and postural hypotension. In severe cases, muscle wasting is evident after about two weeks and may become profound. The disease reaches its nadir in two weeks in most cases and by an arbitrary but agreed definition in four weeks in all. After a variable plateau phase, recovery begins with return of proximal followed by distal functions over weeks or months. Between 4 and 15% of patients die and about 20% are left dead or disabled after a year despite modern treatment (Prevots and Sutter, 1997; Rees et al., 1998; Van Koningsveld et al., 2001). In the survivors, fatigue is a common problem (Bernsen et al., 1999). In a study of 122 GBS subjects 3–6 years after onset, Bernsen and colleagues also found that many patients still suffer from sensory deficit, and a considerable number experience these as moderately to seriously

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disruptive, especially in the legs. Muscle aches and cramps seem to be related to sensory rather than motor dysfunction (Bernsen et al., 2001). In children, pain may be the main presenting symptom and may cloud the assessment of weakness. In children, recovery is more rapid and more likely to be complete (Bradshaw and Jones, 1992). 34.7. Classification Individual patients with GBS may be classified according to whether the myelin sheaths or axons are primarily affected and whether the motor, sensory or autonomic systems are involved (Table 34.2). In North America and Europe, typical patients with GBS usually have AIDP as the underlying subtype, and only about 5% of the patients have axonal subtypes of the disease (Hadden et al., 1998). In northern China, Japan, and Central and South America, axonal forms are more common (McKhann et al., 1991, 1993). In AMSAN, sensory axons are affected as well as motor (Kissel et al., 2001). In AMAN, the neurological deficit is purely motor (McKhann et al., 1991, 1993). Rare cases of acute transient sensory neuropathy may represent AIDP affecting only sensory nerves or roots but need to be distinguished from acute sensory neuronopathy. Autonomic involvement is common in GBS, especially in severe cases with respiratory failure. Some cases of acute dysautonomia without involvement of somatic nerves may be inflammatory and possibly autoimmune. In most cases, the nerve supply of the limb, cranial, and respiratory muscles are diffusely and symmetrically affected; in a minority, the neurological deficit is much more focused. The most frequent example of the latter is the Fisher syndrome consisting of ophthalmoplegia, ataxia and areflexia with variable degrees of bulbar muscle involvement (Kissel et al., 2001). Some Table 34.2 Classification of GBS Acute inflammatory demyelinating polyneuropathy Acute motor and sensory axonal neuropathy Acute motor axonal neuropathy Acute sensory neuronopathy Acute pandysautonomia Fisher syndrome Oropharyngeal and other regional variants Fisher/GBS overlap syndrome

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patients resemble this syndrome at the onset and then develop generalized weakness, FS/GBS overlap syndrome. There is also a rare group that develops bulbar involvement, some of whom also develop upper limb involvement. Most patients with GBS have a monophasic disease. Recurrences occur in less than 3% of patients. Such patients and those whose illness has a protracted onset phase may be difficult to distinguish from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). There is likely to be a spectrum from acute through subacute to chronic inflammatory demyelinating polyneuropathy, reflecting the fact that these illnesses share some pathogenetic mechanisms. 34.8. Diagnostic criteria Diagnostic criteria for GBS were developed in 1978 to classify cases reported during the swine flu epidemic (Asbury et al., 1978). These criteria have stood the test of time and are now considered the gold standard for research and clinical trials (Asbury and Cornblath, 1990). The diagnosis of GBS remains a clinical one supported by laboratory features, especially neurophysiologic examination. The diagnosis requires the presence of an acute motor or sensory and motor polyneuropathy reaching its nadir within four weeks. There must not be another explanation for the illness. CSF examination is routinely done as the finding of an increased CSF protein concentration with a normal CSF cell count is strongly supportive of the diagnosis. However, the CSF is frequently normal during the first week of the disease, so a normal CSF protein does not eliminate the diagnosis. Signs of central nervous system (CNS) involvement indicate most commonly another diagnosis or rarely a CNS accompaniment of otherwise typical GBS. Neurophysiologic studies play a critical role in both diagnosis and classification into GBS subtypes. These studies provide confirmation that the disease is indeed a disorder of peripheral nervous system and not CNS, neuromuscular junction, or muscle (Table 34.3). This requires that the studies provide a sufficient amount of neurophysiologic data for interpretation. In most cases, this will include at least three sensory nerves, preferably sural, median, and ulnar, at least three motor nerves with multisite stimulation and F-waves, preferably peroneal, median and ulnar, and bilateral tibial H-reflexes. In some cases, lesser numbers of nerves or other nerve combinations may be sufficient for diagnosis and classification.

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Table 34.3

found an excellent correlation (Lu et al., 2000). A single study compared several AIDP criteria in a single patient population finding that the criteria are similar but not identical in the identification of the AIDP subtype (Alam et al., 1998). The suggested criteria in Table 34.4 provide a basis for further discussions and research concerning criteria. The main differences in the various criteria are as follows. The identification of demyelination varies among criterion sets (Cornblath, 1990; Meulstee and van der Meche, 1997; Hadden et al., 1998; Ho et al., 1999; Van den Bergh and Pieret, 2004), a parallel problem in defining CIDP. Criteria for an abnormal study may not always be met, as in mild or early patients when neurophysiologic abnormalities may be minor (see below). In other patients, it may not be possible to assign a patient definitely into one or other category. This is a particular problem when motor nerves are inexcitable. In such a circumstance, it is not possible to determine whether the absence of recordable action potentials is due to complete conduction block from demyelination or to axonal degeneration or dysfunction. In this situation, the differentiation may perhaps be made by nerve biopsy but such an investigation is rarely necessary except as a research procedure (Hall et al., 1992; Berciano et al., 1997). Using criteria similar to those in Table 34.4, most patients with GBS in North America and Europe will have the AIDP subtype with smaller numbers of the other subtypes (Hadden et al., 1998). In other regions of the world, the proportion of “axonal” subtypes is greater (McKhann et al., 1991; Kissel et al., 2001).

Differential diagnosis (after Cornblath, 1993) (1) Acute anterior poliomyelitis caused by poliovirus caused by other neurotropic viruses (2) Acute myelopathy space-occupying lesions acute transverse myelitis (3) Peripheral neuropathy Guillain–Barré syndrome post-rabies vaccine neuropathy diphtheritic neuropathy heavy metals biological toxins drug intoxication acute intermittent porphyria vasculitic neuropathy critical illness neuropathy lymphomatous neuropathy (4) Disorders of neuromuscular transmission myasthenia gravis biological or industrial toxins (5) Disorders of muscle hypokalemia hypophosphatemia inflammatory myopathy acute rhabdomyolysis trichinosis periodic paralyses

With this neurophysiologic information, individual patients can be classified into the various subtypes: AIDP or AMSAN or AMAN (Table 34.4). However, unlike the agreed-upon clinical diagnostic criteria, there are no such neurophysiologic criteria for classification. Thus, the criteria have varied in the reported studies (Cornblath, 1990; Meulstee and van der Meché, 1997; Hadden et al., 1998; Ho et al., 1999; Van den Bergh and Pieret, 2004). Most rely primarily on motor conduction studies to identify demyelination with sensory conduction studies providing additional refinement, especially to differentiate AMAN and AMSAM. Two large studies, one a research study in China (Ho et al., 1999) and another a large multinational treatment study (Hadden et al., 1998), used similar criteria successfully (Table 34.4). Using these criteria, a study compared the physiological and pathological correlations in a series of children afflicted with GBS. Comparing the physiological classification from motor and secondarily from sensory conductions to sural nerve pathology, these authors

34.9. Neurophysiology 34.9.1. Findings expected during the evolution of Guillain–Barré Syndrome Three large series initially described the early electrodiagnostic findings in AIDP (Lambert and Mulder, 1963; McLeod, 1981; Albers et al., 1985). In all, over 85% of patients’ early electrodiagnostic studies are abnormal, with the majority showing evidence of demyelination. Up to 13% of studies are normal, but few remain normal if repeated serially (Hadden et al., 1998). The earliest abnormalities are in motor conduction studies with sensory conduction studies abnormal slightly later. As mentioned above, the probability of finding an abnormal and demyelinating study is increased as more nerves are studied and if late

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Table 34.4 Neurophysiological criteria for AIDP, AMSAN, and AMAN (after Ho et al., 1995; Hadden et al., 1998) AIDP At least one of the following in each of at least two nerves, or at least two of the following in one nerve if all others inexcitable and dCMAP ≥ 10% LLN Motor conduction velocity < 90% LLN (85% if dCMAP < 50% LLN) Distal motor latency >110% ULN (120% if dCMAP < 100% LLN) PCMAP/dCMAP ratio < 0.5 and dCMAP ≥ 20% LLN F-response latency > 120% ULN AMSAN1 None of the features of AIDP except one demyelinating feature allowed in one nerve if dCMAP < 10% LLN Sensory action potential amplitudes < LLN AMAN1 None of the features of AIDP except one demyelinating feature allowed in one nerve if dCMAP < 10% LLN Sensory action potential amplitudes > LLN Inexcitable DCMAP absent in all nerves or present in only nerves with dCMAP < 10% LLN Definitions dCMAP: compound muscle action potential amplitude after distal stimulation pCMAP: compound muscle action potential amplitude after proximal stimulation LLN: lower limit of normal ULN: upper limit of normal 1

In the original definitions the difference between AMSAN and AMAN proposed here is implied but not stipulated.

responses, F-waves and H-reflexes, are included (McLeod, 1981; Olney and Aminoff, 1990). Early abnormalities include prolonged distal and F-wave latencies and reduced conduction velocities (< 70 of the mean or < 85% of the lower limit of normal). Over time, more features of axonal degeneration develop, including both reduced evoked amplitudes and abnormal EMG (Hadden et al., 1998). This can complicate the classification of individual patients as the later a study is done, the more likely it is that axon loss will occur and make clear classification into one of the categories less clear. Additional studies of early electrodiagnosis have been completed over the years and for the most part have confirmed the original observations (Ropper et al., 1990; Hadden et al., 1998; Gordon and Wilbourn, 2001). Gordon and Wilbourn looked specifically at the changes in the first week in a group of 31 patients (Gordon and Wilbourn, 2001). They found that the Hreflex was the most frequently abnormal finding, being absent in all but one patient (97%). In order of frequency, other early abnormalities included abnormal F-waves (84%), reduced compound muscle action potential (CMAP) amplitudes (71%), prolonged distal latencies (65%), low-amplitude or absent sensory action potentials (SAP) in the upper limbs (61%),

abnormal temporal dispersion (58%), reduced motor conduction velocities (52%), abnormal upper limb SAP with normal sural SAP (48%), and partial motor conduction block (PMCB) (13%). In 15%, the early study was normal aside from the absent H-reflex. Kuwabara and coworkers confirmed that F-wave abnormalities are one of the earliest findings in GBS (Kuwabara et al., 2000). However, based on serial studies they suggest that this may result from either demyelination, the AIDP form of GBS, or axonal dysfunction, the AMAN form of GBS. Like Hadden and coworkers (Hadden et al., 1988), they found that serial studies were needed to determine the specific pattern present in an individual. A recent Japanese study identified recent C. jejuni infection in 22 (14%) of 159 patients with GBS. Sixteen of these patients were diagnosed at the initial electrophysiological examination as having AMAN, five as AIDP and one could not be classified (Kuwabara et al., 2004). In the five patients diagnosed with an AIDP pattern, the only “demyelinating” abnormalities were mildly prolonged distal motor nerve latencies and serial examinations showed that these remained stable and never became accompanied by dispersion of the compound muscle action potential or other features to suggest demyelination. While these abnormalities might be caused by

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distal demyelination, a more attractive hypothesis is that they are due to distal axonal dysfunction at or near the motor nerve terminals where the blood-nerve barrier is less substantial. This dysfunction might, for instance, be due to antibodies to gangliosides inactivating the voltage-gated sodium channels although more evidence is needed to prove this point. The Japanese authors conclude that C. jejuni causes AMAN but not AIDP. This observation needs to be confirmed in other populations in which AIDP is more frequent and C. jejuni is still the commonest precipitant. There might be important differences in immunosusceptibility between different races. Roth and Magistris found abnormal late responses in almost all of their GBS patients studied early in the disease (average 10 days) (Roth and Magistris, 1999). They termed these indirect discharges and suggested they were caused by proximal re-excitation on motor axons. A confirmatory study is needed concerning this observation. In contrast to these studies which relied mainly on routine nerve conductions and late responses, Brown and Feasby used more sophisticated techniques especially proximal stimulation techniques and found that PMCB is a major electrophysiological abnormality during the first 2 weeks of GBS (Brown and Feasby, 1984). It tends to be distributed in the distal terminals, proximal segments and common compression sites of the peripheral nervous system in the acute phase of GBS (Brown and Snow, 1991; Kuwabara et al., 1999). A blood-nerve barrier deficiency is postulated to be the reason that nerve conduction abnormalities develop at these sites. While PMCB is the sine qua non of peripheral nerve demyelination, PMCB may not always represent structural demyelination as in some reported cases, PMCB reverses too quickly for a structural change to be the underlying mechanism (Susuki et al., 2001). It may be that serum factors have the ability to reversibly block conduction as has been suggested in animals (Hirota et al., 1997; Takigawa et al., 1995).

1997; Hadden et al., 1998). In many studies with systematic EMG, axonal involvement by initial EMG also portends a poorer outcome (Chio et al., 2003).

34.9.2. Nerve conduction studies and outcome The relationship between nerve conduction attributes and clinical outcome has been investigated in many studies. In almost every study low amplitude motor responses are related to a poorer outcome, even though the definition of a low amplitude response may vary among the different studies (Cornblath et al., 1988; McKhann et al., 1988; Meulstee and van der Meche,

34.9.3. Sensory nerve conductions Early observations showed that the sural SAP is frequently normal in GBS while the median SAP is abnormal: the so-called “normal sural-abnormal median pattern” (Murray and Wade, 1980; Albers et al., 1985). This has been recently reconfirmed with the additional information that the ulnar follows a similar but not identical pattern to the median (Bansal et al., 2001; Wee and Abernathy, 2003). 34.9.4. Nerve root stimulation Inaba and coworkers used a novel technique to combine cervical magnetic stimulation (CMS) with F-wave latency to measure root conduction time (RCT) (Inaba et al., 2002). In the AIDP patients, conduction in the proximal motor root segment was considered abnormal in 52% by the RCT and in 47% by the minimal threshold for CMS, whereas both were normal in 85% of ALS patients. Abnormal values returned to normal with time. These findings suggest that the RCT and minimal threshold for CMS might be additional parameters for evaluating motor nerve conduction in AIDP. 34.9.5. Phrenic nerve stimulation Phrenic nerve studies have been used in GBS although their more common use has been in the Intensive Care Unit. Phrenic nerve studies are frequently abnormal in patients with GBS. In one study, phrenic conduction parameters paralleled median conduction parameters but the authors suggested that phrenic conduction could identify subclinical involvement, a finding of prior studies (Cruz-Martinez et al., 2000). Phrenic studies of both nerve conduction and EMG have been shown to predict the need for intubation (Zifco et al., 1996). However, since these studies are not routinely performed, Duranda and coworkers evaluated unintubated patients with GBS to determine whether phrenic studies could predict the need for intubation (Duranda et al., 2003). They found that their patients with the AIDP form of GBS had greater disability scores and lower vital capacities compared to those with equivocal or axonal electrodiagnostic studies. They concluded that AIDP alone was a greater

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predictor of need for ventilation than other electrodiagnostic subtypes. 34.9.6. Motor unit number estimation There are few studies of motor unit number estimation (MUNE) in GBS. Kuwabara and colleagues evaluated MUNE in seven patients with the AMAN form of GBS in order to elucidate the mechanism of recovery (Kuwabara et al., 2001). In their patients with slow recovery, they found that clinical recovery of APB strength began during the fourth week, with an increase in amplitude of distal compound muscle action potentials. MUNE did not change significantly in this early recovery phase and increased slowly with time. They suggested that the main mechanism for early recovery in AMAN may be collateral reinnervation, with nerve regeneration developing later. However, based on clinical and morphological studies, Ho and colleagues speculated that rapid recovery in AMAN occurred by nerve terminal regeneration (Ho et al., 1997). It appears that both mechanisms play a role in recovery in AMAN, depending on the rate of recovery. Similar studies in the AIDP form of GBS would be of interest. 34.9.7. Threshold tracking Kuwabara and co-workers used threshold tracking of median nerve axons at the wrists of patients with AMAN and AIDP to study axonal excitability (Kuwabara et al., 2002). Refractoriness (the increase in threshold current during the relative refractory period) was greatly increased in AMAN patients, but the abruptness of the threshold increases at short interstimulus intervals indicated conduction failure distal to the stimulation (i.e., an increased refractory period of transmission). During the 4-week period from onset, the high refractoriness returned toward normal, and the amplitude of the compound muscle action potential increased, consistent with improvement in the safety margin for impulse transmission in the distal nerve. In contrast, refractoriness was normal in AIDP, even though there was marked prolongation of distal latencies. Supernormality and threshold electrotonus were normal in both groups of patients, suggesting that, at the wrist, the membrane potential was normal and pathology relatively minor. These results support the view that the predominantly distal targets of immune attack are different for AMAN and AIDP.

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34.9.8. Somatosensory evoked potentials In the few studies evaluating somatosensory evoked potentials including patients with FS, somatosensory evoked potentials have been variably reported as abnormal and rarely add further information to the clinical situation (Olney and Aminoff, 1990; Katsuno et al., 2002; Capasso et al., 2003). 34.9.9. Brainstem auditory evoked potentials There are few studies of brainstem auditory evoked potentials in GBS. In a study of FS patients, no brainstem auditory evoked potential abnormalities were found (Katsuno et al., 2002). 34.9.10. Autonomic studies It is well known that dysautonomia may be prominent in GBS (see Section 34.6). In an interesting study of dysautonomia, Asahina and coworkers found that the patterns of autonomic involvement were qualitatively different between AIDP and AMAN (Asahina et al., 2002). Patients with AIDP had cardio-sympathetic hyperactivity, excessive or reduced sudomotor function and preserved skin vasomotor function, while patients with AMAN did not have marked autonomic dysfunction except for the sudomotor hypofunction seen in patients with severe neurological deficits. 34.9.11. Magnetic stimulation Magnetic stimulation has been used in GBS to measure central motor conduction time (CMCT). In most of these studies, abnormalities of CMCT have been mild and the prolongation most likely due to abnormalities at the root level and not in the spinal cord or brain per se (Wohrle et al., 1995; Kalita et al., 2001; Lo and Ratnagopal, 2001). 34.9.12. Skin biopsy to evaluate intra-epidermal nerve fiber density In a study, Pan and coworkers found that END (epidermal nerve density) was a predictor of outcome with those having lower END a worse recovery (Pan et al., 2003). This supports the idea that GBS involves all classes of nerve fibers and that axonal degeneration, measured by any technique, is associated with prolonged recovery.

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34.9.13. Children

present single observations of sensory conductions and conclude that FS is, therefore, an axonopathy as conduction velocities are preserved while evoked amplitudes are reduced (Durand et al., 2001; Katsuno et al., 2002). However, this does not fit with the clinical features of this usually benign syndrome. This dilemma was addressed by Guiloff who studied sensory conduction serially (Guiloff, 1977). He convincingly showed that SAP amplitudes initially fall and then return to normal along with clinical improvement. The time course of these changes is consistent with a sensory demyelinating lesion as the return of sensory amplitudes was too rapid for axonal regeneration. Kimura and coworkers have written on the difficulty of identification of demyelination in sensory conduction studies (Kimura et al., 1986), and this paper confirms those observations.

Much has been written about childhood GBS. In general, the comments concerning GBS in adults apply to children aside from incidence, children being less commonly affected, < 1/100 000/year, and prognosis. Children generally have a better recovery both in terms of speed and completeness (see Ammache et al., 2001 for review). Much has also been written on electrodiagnosis in childhood GBS. In most series, the electrodiagnostic features are clearer as normal studies early in GBS are reported in only 5–14% of children (Bradshaw and Jones, 1992; Delanoe et al., 1998; Ammache et al., 2001) compared to up to 33% of adults (Hadden et al., 1998). As the series are smaller in children, definitive statements about the relationship of electrodiagnostic features to outcome have been less clear. A number of studies have shown that children also have the two major patterns of GBS: AIDP and AMAN. For example, a recent series of 61 children from Argentina found 18 with AMAN and 43 with AIDP (Paradiso et al., 1999). Children with AMAN were younger, evolved more acutely, reached a higher maximum disability score, required assisted ventilation more often, had lower mean level of cerebrospinal fluid protein, improved more slowly, and had a poorer outcome 6 months and 12 months after onset. Electrophysiological findings in those with AIDP revealed a pattern of severe diffuse slowing in children 5 years of age or younger and a multifocal pattern in children 6 years old or older. This difference was not reflected in the clinical picture. In contrast, AMAN showed a uniform pattern with normal sensory conduction, severely reduced compound muscle action potential amplitude, near normal conduction velocity, and early denervation. This paper confirms a number of recent observations in childhood GBS. In an interesting retrospective study of the effect of treatment on the two forms of childhood GBS, Tekgul and coworkers found that after standard intravenous immunoglobulin therapy, children with axonal forms of GBS recover more slowly than those with the demyelinating form, but outcome at 12 months appears to be equally favorable in the two groups (Tekgul et al., 2003). 34.9.14. Fisher syndrome The primary electrophysiological finding in FS is an abnormality of sensory conduction. Most authors

34.10. Treatment 34.10.1. General considerations Theoretical considerations and limited empirical evidence suggest that immunotherapy to correct the underlying immunopathogenic disorder should be started early to reduce the amount of demyelination and axonal degeneration. It follows that assessment and establishment of the diagnosis should be conducted urgently so that treatment can begin before irreversible damage has been done. In many patients, the diagnosis can be easily reached on clinical grounds alone. In others, additional diagnostic tests such as CSF exam and neurophysiological studies are needed and, in fact, these are almost always performed. In some, tests to eliminate other diseases in the differential are required (Table 34.3). Supportive care is the cornerstone of treatment of patients with GBS (Hughes et al., 2005). This includes attention to all the general aspects of care but special attention should be paid to prophylaxis for deep vein thrombosis, cardio-respiratory monitoring, airway protection, tracheostomy, pain, bladder and bowel dysfunction, rehabilitation, and fatigue. The need for close patient monitoring cannot be overemphasized. In-hospital monitoring including the Intensive Care Unit can be life saving. The most immediate concern is the possibility of the rapid development of respiratory failure which occurs in about 25% of patients with GBS. Respiratory failure is more likely in those with rapid progression, bulbar palsy, upper limb involvement, and autonomic

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dysfunction. Frequent measurements of respiratory function may prevent the need for emergency intubation by allowing the decline in respiratory function to indicate the need to perform intubation prophylactically under controlled conditions (Lawn and Wijdicks, 1999; Hughes and McLuckie, 2000). Monitoring for possible cardiac arrhythmia should always be undertaken in patients who require or seem likely to require artificial ventilation (Hughes and McLuckie, 2000). A rehabilitation program should be instituted as soon as possible (Meythaler, 1997). Occupational and Physical therapy should begin during the acute phase, be continued during the plateau phase, and then intensified as improvement begins. Therapy practice varies from unit to unit, and no randomized trials are available to guide the choice of techniques. It is not clear how soon exercise training should begin and how vigorous it should be. Faced with the inadequacy of the evidence (Hughes et al., 2005), the advice, “moderation in all things,” is appropriate. Earlier ambulation can be achieved with lightweight customized anklefoot orthoses and appropriate crutches or canes. 34.10.2. Immunotherapy Complete reviews of treatment are available at the Cochrane library (http://www.cochrane.org/reviews/clibintro.htm), and therefore only summaries are presented here. PE has been convincingly shown to be beneficial in patients with GBS so severe that they are unable to walk (Raphaël et al., 2004). The North American PE trial demonstrated significant benefit from PE given during the first four weeks, but the benefit was greater when treatment was given during the first week (McKhann et al., 1988). The benefit was even less if patients were treated more than two weeks after the onset of neuropathy. It follows from this that patients should be treated as early as possible in the course of their illness. A Cochrane systematic review of IVIg treatment of patients with GBS has been completed (Hughes et al., 2004). Although there are no adequate comparisons with placebo, IVIg hastens recovery from GBS as much as plasma exchange. Randomized trials are needed to decide the effect of IVIg in children, in adults with mild disease, and in adults who start treatment after more than two weeks. One large trial that compared IVIg followed by PE with IVIg alone or PE alone showed no significant advantage to the combined regimen in any of the outcomes measured (Plasma Exchange/Sandoglobulin

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Guillain–Barré Syndrome Trial Group, 1997). A small study comparing immunoabsorption with tryptophan polyvinyl exchange alone and imunoabsorption followed by IVIg showed no significant difference between these regimens after one and 12 months (Haupt et al., 1996). Thus, there is no evidence base to support the use of combination treatments. Paradoxically, despite the inflammatory and probably immune nature of the underlying pathophysiology, it has not been possible to demonstrate a beneficial effect from steroids. A Cochrane systematic review of any form of corticosteroid or adrenocorticotrophic hormone treatment of patients with GBS has been completed (Hughes and van der Meché, 2004). There was no difference in outcome by any measure between the steroid and no steroid/placebo patients. The conclusion that steroids are not beneficial in GBS has not been altered by the recent results of a large multicenter trial comparing IVIg alone and IVIg with intravenous methylprednisolone (Hughes, 2004; van Koningsveld et al., 2004). Despite the successes of current treatment with IVIg or PE, at least two difficult issues remain. First, the current treatments are not fully satisfactory. About 20% of treated patients die or are left disabled. Better treatments are urgently needed. Second, clinicians are unsure what to do when a GBS patient fails to improve two or three weeks after their initial treatment, a frequent problem. A trial is needed to determine whether a further course of IVIg or the use of PE at this stage is beneficial (Farcas et al., 1998). There is no consensus about the management of this problem. References Alam, TA, Chaudhry, V and Cornblath D (1998) Electrophysiological studies in the Guillain–Barré syndrome: distinguishing subtypes by published criteria. Muscle Nerve, 21: 1275–1279. Albers, JW, Donofrio, PD and McGonagle, P (1985) Sequential electrodiagnostic abnormalities in acute inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve, 8: 528–539. Ammache, Z, Afifi, AK, Brown, CK and Kimura, J (2001) Childhood Guillain–Barré syndrome: clinical and electrophysiologic features predictive of outcome. J. Child Neurol., 16: 477–483. Asahina, M, Kuwabara, S, Suzuki, A and Hattori, T (2002) Autonomic function in demyelinating and axonal subtypes of Guillain–Barré syndrome. Acta Neurol. Scand., 105: 44–50.

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Campylobacter jejuni infection. J. Neuroimmunol., 62: 53–57. Rees, JH, Thompson, RD, Smeeton, NC and Hughes, RAC (1998) An epidemiological study of Guillain–Barré syndrome in South East England. J. Neurol. Neurosurg. Psychiatry, 64: 74–77. Roman, GC (1995) Tropical neuropathies. In: H-P Hartung (Ed.), Peripheral Neuropathies: Part 1. Baillière Tindall, London, pp. 469–487. Ropper, AH, Wijdicks, EFM and Shahani, BT (1990) Electrodiagnostic abnormalities in 113 consecutive patients with Guillain–Barré syndrome. Arch. Neurol., 47: 881–887. Roth, G and Magistris, MR (1999) Indirect discharges as an early nerve conduction abnormality in the Guillain–Barré syndrome. Euro. J. Neurol., 42: 83–89. Susuki, K, Johkura, K, Yuki, N, Hasegawa, O and Kuroiwa, Y (2001) Rapid resolution of nerve conduction blocks after plasmapheresis in Guillain–Barré syndrome associated with antiGM1b IgG antibody. J. Neurol., 248: 148–150. Takigawa, T, Yasuda, H, Kikkawa, R, Shigeta, Y, Saida, T and Kitasato, H (1995) Antibodies against GM1 ganglioside affect K+ and Na+ currents in isolated rat myelinated nerve fibers. Ann. Neurol., 37: 436–442. Tekgul, H, Serdaroglu, G and Tutuncuoglu, S (2003) Outcome of axonal and demyelinating forms of Guillain–Barré syndrome in children. Pediatr. Neurol., 28: 295–299. Van den Bergh, PYK and Pieret, F (2004) Electrodiagnostic criteria for acute and chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve, 29: 565–574. Van Koningsveld, R, van Doorn, PA, Schmitz, PIM and van der Meché, FGA (2001) Changes in referral pattern and its effect on outcome in patients with Guillain–Barré syndrome. Neurology, 56: 564–566. van Koningsveld, R, Schmitz, PIM, van der Meché, FGA, Visser, LH, Meulstee, J, van Doorn, PA,

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 35

Chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy Praful Kelkara,* and Suraj Ashok Muleyb a Department of Neurology, University of Iowa, IA, USA Department of Neurology, VAMC, University of Minnesota, MN, USA

b

35.1. Introduction It is important to recognize and correctly diagnose immune-mediated neuropathies, as they are potentially treatable, often with remarkable success. Neuropathies secondary to vasculitis or inflammatory vasculopathy have been considered in Chapter 32. Immune-mediated demyelinating neuropathies resulting from autoimmune attack primarily on the myelin sheaths of peripheral nerves are discussed in this chapter. Although myelin is the primary site of the immune insult, these neuropathies are invariably associated with some degree of secondary axonal degeneration and, therefore, their clinical and electrophysiological findings include both demyelinating and axonal features making the diagnosis challenging in many cases. These neuropathies typically cause relapsing or progressive weakness and often numbness, and generally respond to immune suppressive therapies. The spectrum of chronic, acquired, immunemediated, demyelinating neuropathies includes: (1) Predominantly motor, largely symmetric, neuropathy with proximal and distal weakness— chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); (2) Multifocal motor neuropathy (MMN) with conduction block; (3) Distal acquired demyelinating sensory and motor neuropathy (DADS); and (4) Multifocal sensory and motor neuropathy, also called multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) or Lewis Sumner syndrome. * Correspondence to: Praful Kelkar, M.B.B.S., M.D. Department of Neurology, 2RCP, University of Iowa Hospitals, 200 Hawkins Drive, Iowa City, IA 52242, USA. E-mail address: [email protected] Tel.: +1-319-384-5617; fax: +1-319-356-4505.

There is an ongoing debate as to whether these different neuropathies constitute distinct syndromes or they are part of a spectrum of the same disease (Lewis, 1999; Parry, 1999). These neuropathies share several common clinical features and may have similar pathogenesis. They are immunemediated and often respond to some form of immune therapy. Also, many patients have, or develop over time, overlapping clinical and electrophysiological features, suggesting that they form a continuum of a spectrum. However, some of these, in particular MMN and DADS, have distinct clinical features and treatment responses, suggesting rather distinct pathogenetic mechanisms. Until we understand the precise molecular and immunological mechanisms involved in the evolution of these different clinical syndromes, we cannot clearly determine whether they are distinct diseases or part of a continuum. It is, in general, useful to consider these syndromes separately since clinical and electrophysiological findings, prognosis, and response to treatment may be quite different. It is important to understand the “typical” and “distinctive” features of these disorders that help to differentiate between them. However, many patients have atypical or “overlap” features and do not fit neatly into one category. Also, some patients do not have all the features required to make a definitive diagnosis of a particular entity, but may respond to immune therapies similar to the more “typical patients.” They, therefore, should not be excluded from the diagnosis of an acquired dysimmune neuropathy and can be considered “forme fruste” presentations of the disease (Kelkar, 2004). When should CIDP or one of its variants be considered? Given the clinical heterogeneity of these disorders it is sometimes difficult to make the diagnosis unless a high degree of suspicion is maintained during clinical evaluation. Table 35.1 lists the clinical features that should arouse strong suspicion for an acquired,

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Table 35.1 Clinical features that suggest the diagnosis of an acquired, immune-mediated, demyelinating neuropathy Clinical features

Possible diagnosis

Fluctuating or relapsingremitting course Presence of diffuse hyporeflexia Predominantly motor neuropathy with proximal and distal weakness Sensory ataxia Multifocal weakness with normal sensations with little or no atrophy Multifocal sensory-motor neuropathy with little or no atrophy

CIDP CIDP CIDP

35.2. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) CIDP is an acquired, immune-mediated, predominantly motor, largely symmetric, demyelinating polyradiculoneuropathy, which typically presents with progressive or stepwise evolution, or with a relapsing–remitting course, and commonly responds to corticosteroid and other immune therapies. 35.2.1. Historical background

DADS MMN

Lewis–Sumner

immune-mediated, demyelinating neuropathy, and a careful search should then be undertaken to make a more definitive diagnosis. Table 35.2 summarizes the clinical, electrophysiological, and laboratory features of these neuropathies.

Recurrent neuritis was first described by Eichhorst in 1876 (Eichorst, 1876). The first report of a chronic corticosteroid-responsive polyneuropathy was published in 1955 by James Austin (Austin, 1955). Since then, recurrent neuritis has been described under various names, including recurrent polyneuritis, progressive hypertrophic neuritis, and chronic progressive Guillain–Barré syndrome. In 1975, Dyck described 53 patients with distinctive clinical and histopathological features (Dyck et al., 1975) and called it Chronic Inflammatory Polyradiculoneuropathy (CIP), and pointed out slowing of nerve conduction velocities. In 1977, Torvik and Lundar (Torvik and Lundar, 1977) proposed the term “chronic demyelinating neuropathy” to emphasize the demyelinating features. The currently

Table 35.2 Comparison of chronic, acquired, immune-mediated, demyelinating polyneuropathies (Saperstein et al., 2001) CIDP

DADS neuropathy

MADSAM Neuropathy MMN

Symmetric; proximal + distal

Symmetric; distal only; mild or no weakness

Asymmetric; distal > proximal; upper limbs > lower limbs

Sensory deficits

Symmetric

Symmetric

Reflexes

Reduced or absent symmetrically

Reduced or absent symmetrically

Usually symmetric

Usually symmetric Prolonged distal latencies Uncommon

Clinical features Weakness

Electrophysiology Abnormal CMAPs Demyelinating features Conduction Block

Frequent

Asymmetric; distal > proximal; upper limbs > lower limbs Multifocal (distribution Absent of individual nerves) Reduced or absent Reduced or absent (multifocal or (multifocal or diffuse) diffuse)

Asymmetric (multifocal)

Asymmetric (multifocal)

Frequent

Frequent

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY

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Table 35.2 Continued

Abnormal SNAPs Laboratory Findings CSF protein M-protein

CIDP

DADS neuropathy

MADSAM Neuropathy MMN

Usually symmetric

Usually symmetric

Asymmetric (multifocal)

SNAPs are normal

Usually elevated Occasionally present; usually IgG or IgA

Usually elevated Rarely present

Usually normal Rarely present

Rarely present

Frequently present (50%) Occasional; minimal findings

Anti-GMI antibodies

Rarely present

Usually elevated IgM-present in the majority; 50–70% are MAG-positive Not present

Sensory nerve biopsy: demyelination/ remyelination Treatment response Prednisone Plasma exchange

Frequent

Frequent

Frequent; sometimes asymmetric

Yes Yes

Poor* Poor*

IVIg Cyclophosphamide

Yes Yes

Poor* Poor*

Yes Possible (more study needed) Yes Possible (more study needed)

No No Yes Yes

*

When associated with an IgM-MGUS (treatment responses in DADS neuropathy patients without a MGUS are more similar to those with CIDP). SNAPs, sensory nerve action potentials.

used term “chronic inflammatory demyelinating polyradiculoneuropathy” was finally proposed by Dyck (Dyck et al., 1982) to incorporate both the demyelinating and the inflammatory features of the neuropathy.

●

●

35.2.2. Clinical features of CIDP ●

The typical features of CIDP are summarized below (modified from Dyck (Dyck et al., 1993) ●

●

●

●

CIDP is a largely symmetric polyradiculoneuropathy or polyneuropathy, affecting both motor and sensory fibers, tending to affect distal and proximal muscles. Infrequently cranial nerves, phrenic nerves, or the central nervous system may also be affected. The characteristic symptoms are weakness, numbness and paresthesias. The course is progressive, stepwise progressive, or relapsing. In untreated patients, the maximal neurologic deficit is reached eight weeks or more from onset. CSF protein is generally elevated to 1.5 to 4 times normal values and lymphocytes are usually less than 5/ml2.

Electrodiagnostic studies show evidence of focal demyelination along with some degree of axonal injury. A therapeutic trial of plasma exchange, IVIG, or steroids usually results in unequivocal improvement in the neurologic disability. Pathological hallmark is inflammatory demyelination in nerve roots and peripheral nerves, which may be seen in sural nerve biopsies in some patients, but is usually inferred from clinical and electrophysiologic evaluations.

Atypical features include predominantly distal involvement, pure sensory form with ataxia, marked asymmetry, associated CNS demyelination, and prominent cranial nerve involvement (Lewis and Sumner, 1982; Rotta et al., 2000). The diagnosis is straightforward in patients with the classical features consisting of symmetric proximal and distal weakness, areflexia, and elevated spinal fluid protein. However, in practice it is often difficult to make a correct diagnosis because of clinical heterogeneity of the disease, patchy multifocal involvement of the nerves, and predilection for proximal nerve segments, which are technically difficult to assess

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directly. Extensive careful electrophysiological studies are often necessary prior to diagnosis. Moreover, limitations of the electrophysiological and pathological techniques in distinguishing between primary demyelinating and axonal processes can add to the diagnostic difficulties. Because of these difficulties the disease tends to be under-diagnosed and patients are often left untreated despite worsening of their condition (Latov, 2002). 35.2.3. Electrophysiological diagnosis of CIDP The hallmark of CIDP is the presence of segmental demyelination with subsequent remyelination in the peripheral nerves. In contrast to hereditary demyelinating polyneuropathies demyelination/remyelination in acquired disorders is a multifocal-segmental process. Inherited disorders such as Charcot–Marie–Tooth

Right median

CV motor

5 mV/D

Rec : APB Dist

Dist

100 mA

230 100 mA

Elbow 160

100 mA

Axilla

cv motor

5 mV/D

5 ms/D

85 mA 190

Bel Elb Dist

100 mA

115

Ab Elb Dist

Amp

Area

Dur

7.0

9.2

38.3

8.6

33.8 m/s

−43 %

−27 %

41 %

13.8

5.2

27.9

12.1

20.5 m/s

−50 %

−28 %

23 %

21.6

2.6

20.2

14.9

dLAT/CV

Amp

Area

Dur

80

Wrist Dist

dLAT/CV

Right ulnar

Rec : ADM Dist

5 ms/D

80

Wrist

Dist

(CMT) are characterized by uniform slowing of nerve conduction velocities when different segments of the same nerve or equivalent segments of different nerves are compared and lack conduction block or temporal dispersion (Lewis and Sumner, 1982; Miller et al., 1985). Whereas CIDP is characterized by multifocal, non-uniform slowing of nerves and often has segmental waveform changes, consisting of conduction block or temporal dispersion (Fig. 35.1). Electrophysiological studies are critical in the evaluation of CIDP. One shortcoming of electrodiagnostic studies is that while disproportionate slowing of nerve conduction velocities or segmental waveform changes can confirm the presence of primary demyelination, their absence does not rule it out. Using the criteria as discussed below presence of acquired primary demyelination can be demonstrated with fair degree of certainty. However, sensitivity for these criteria is only

100 mA

135

Axilla

100 mA

5.8

6.9

33.6

9.2

36.5 m/s

−44 %

−34 %

24 %

11.0

3.9

22.1

11.4

27.4 m/s

−19 %

−7 %

15 %

15.2

3.1

20.6

13.1

29.3 m/s

−38 %

−44 %

−5 %

19.8

2.0

11.4

12.4

Fig. 35.1 Median and ulnar motor nerve conduction studies in a patient with CIDP showing prolonged distal latencies, multifocal non-uniform slowing, and segmental waveform changes (conduction block or temporal dispersion).

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY

about 60–70%, therefore, these criteria cannot be used to “rule out” the diagnosis of CIDP. Less stringent clinical and electrophysiological criteria may be more sensitive in the appropriate clinical setting (Hughes, 2001 Saperstein et al., 2001; Magda et al., 2003). 35.2.3.1. Motor nerve conduction studies in CIDP The electrophysiological correlates of acquired demyelination/remyelination include marked conduction slowing, conduction block, and temporal dispersion. However, since axon loss almost always occurs in CIDP that can cause conduction abnormalities due to dropout of the large myelinated fibers, it is sometimes difficult to ascertain if there is primary demyelination. Buchthal and Behse (1977) found that CMT II patients

713

with axon loss had conduction velocities greater than 60%. Cornblath et al. (1992) reported that in ALS nerve conduction velocities rarely fell below 80% of the lower limit of normal and distal latencies and F-wave latencies rarely exceed 1.25 times the upper limit of normal, providing limits to the changes in motor conduction that can result from axon degeneration. Based on these studies Kelly (1983) and Albers and Kelly (1989) proposed the first electrophysiological criteria for CIDP requiring slowing of conduction velocities to less than 60% of the normal mean or less than 75% of the lower limit of normal. Since then several authors have proposed diagnostic criteria (Table 35.3). The AAN ad hoc committee criteria (1991) were developed for research purpose

Table 35.3 Proposed diagnostic criteria for CIDP (A) Albers and Kelly (Albers and Kelly, Jr., 1989): three out of four must be met (1) (2) (3) (4)

Reduced MNCV in two or more nerves: 130% of ULN Partial conduction block or abnormal temporal dispersion in 1 or more nerves: >30% drop in amplitude Prolonged F-wave latency in one or more nerves: >130% of ULN

(B) Modified Albers and Kelly (Bromberg, 1991) Similar except MNCV: reduced MCNV in one or more nerves: 80% of LLN (b) >150% of ULN if amplitude is 15% change in duration between proximal and distal sites and >20% drop in negative peak area or peak- to peak-amplitude between proximal and distal sites; additional studies such as stimulation across short segments or recording of individual motor units required for confirmation Significantly reduced conduction velocity (a) 80% of LLN (b) 80% of LLN (b) >150% of ULN if amplitude is 120% of ULN if amplitude is >80% of LLN (b) >150% of ULN if amplitude is 9 ms in multiple nerves, which was arbitrarily defined in a retrospective study using receiver-operating characteristic curves, may be an adjunctive finding in suspected CIDP (Thaisetthawatkul et al., 2002). However,

larger prospective studies are required to validate this claim. In generalized neuropathies such as CIDP composite indices of multiple nerve conduction parameters may be more sensitive or reproducible than single findings. In one retrospective study of patients diagnosed with CIDP addition of ulnar, peroneal, and tibial motor nerve conduction velocities, with or without inclusion of sural sensory NCV and distal motor latencies, was found to be 92.6% sensitive (Dyck et al., 2003). Interestingly, in this study median nerve Fwaves were found to be more sensitive than the composite indices. It is not known how sensitive and specific these calculations are in making diagnosis prospectively in patients suspected of CIDP. The sets of diagnostic criteria discussed above require abnormalities in nerve conduction parameters that are suggestive of primary demyelination in 2 or more nerves. However, abnormalities even in a single nerve may be sufficient to support the diagnosis of possible CIDP in the appropriate clinical setting (Rotta et al., 2000; Magda et al., 2003). Several motor nerves should be carefully evaluated in patients suspected to have CIDP. Typically bilateral median, ulnar, peroneal, and tibial nerves are included

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY

in the electrodiagnostic studies. In each nerve the following parameters should be studied––distal motor latency, CMAP waveform and amplitude, conduction velocity and waveform assessment across multiple segments, and F-waves. Findings that suggest the presence of primary acquired demyelination and thus help make a diagnosis of CIDP are summarized in Table 35.4. Conduction block and temporal dispersion are helpful when present. However, in one large study only 11.7% of patients with CIDP showed temporal dispersion and 13.3% had conduction block (Barohn et al., 1989). 35.2.3.2. F-wave studies in CIDP F-wave analysis is important for making a diagnosis of CIDP, since the nerve roots bear the brunt of the disease and F-waves are particularly susceptible to demyelination given the long pathway involved. The most common finding in CIDP is absent or abnormally prolonged F-waves. Abnormal chronodispersion or F-wave impersistence can be occasionally seen in some nerves even with normal conventional motor nerve conduction studies and minimum F-wave latencies (Fraser and Olney, 1992; Kiers et al., 1994). In one study of median, ulnar, and tibial F-waves in 43 patients with CIDP, at least one of these F-wave parameters was abnormal in 95% of the nerves (Kiers et al., 1994). F-waves were most frequently absent (49%) or delayed (38%). Abnormal chronodispersion was seen in 8 nerves and impersistence in 5 nerves, with normal minimum F-wave latency. Median, ulnar, and tibial F-wave studies are most suited for patients with suspected CIDP, whereas peroneal F-waves that can be difficult to elicit even in normal subjects, are less useful. In each nerve, at least

715

Stimulation M

F

Fig. 35.2 M and F responses obtained by stimulation of a nerve at a mid-point, e.g., stimulation of the median nerve at the elbow, which facilitates calculation of the F-wave ratio as described in the text.

10 F-wave recordings should be performed in each nerve with stimulation at supramaximal intensity. F-wave ratio: proximal to distal latency ratio is calculated with stimulation of the median or ulnar nerves at the elbow, and peroneal or tibial nerve at the popliteal fossa. These stimulation sites are roughly at the mid point between the spinal cord and the distal recording sites. It is assumed that various limbs of different length have the same proportion for the proximal and distal segments. F-ratio is shown in Fig. 35.2 (Kimura, 1978). F-ratio =

=

Proximal latency Distal latency F−M−1 2

×

1 M

=

F−M−1 2M

where F, F-wave latency; M, motor latency, 1 ms is subtracted to offset for anterior horn cell activation delay. Abnormal F-ratio is reported in Guillain–Barré syndrome indicating more slowing in the proximal segments (Kimura, 1978). Although similar findings can

Table 35.4 Electrophysiological findings that suggest the presence of primary demyelination in suspected CIDP Marked slowing of nerve conduction velocity across non compressive segments (median nerve across the wrist, ulnar nerve across the elbow, peroneal nerve across the fibular head) Marked prolongation of F-waves or absence of F-waves Conduction block or temporal dispersion across non compressive segments Marked prolongation of distal motor latency Recording technique The following nerves should be tested on both sides (unless the criteria are fulfilled by studying a smaller number of nerves or points) Median (wrist, elbow, axilla, Erb’s point) Ulnar (wrist, elbow, axilla, Erb’s point) Peroneal (ankle, below fibular head, above fibular head) Tibial (ankle, popliteal fossa) Ten consecutive F-waves should be recorded from each nerve, and the minimal latency measured

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35.2.3.4. Needle electromyography in CIDP Extensive documentation of needle EMG findings in CIDP is not readily available, since the diagnosis is made by nerve conduction studies. Axon loss is common in CIDP and the degree of axon loss increases with duration of the illness. Hence, fibrillation potentials and motor unit abnormalities are seen especially in the distal muscles (Albers and Kelly, 1989; Barohn et al., 1989).

be expected in CIDP, it has not been systematically studied. 35.2.3.3. Sensory nerve conduction studies in CIDP With surface recording characteristic finding in the vast majority of patients with CIDP is the absence or reduction of sensory nerve action potentials (SNAP) in both upper and lower extremities. (McCombe et al., 1987; Barohn et al., 1989), rather than slowing of conduction velocities. With near nerve recording and averaging of multiple responses it may be possible to demonstrate small and temporally dispersed SNAPs with prolonged latencies or occasionally conduction block (Fig. 35.3). Slowing in sensory nerves, when present, is often less pronounced than the motor nerves and abnormalities in sensory nerve conductions can be explained by loss of axons in most cases (Krarup and Trojaborg, 1996).

35.2.3.5. Other techniques in CIDP 35.2.3.5.1. Nerve root stimulation in CIDP. Demyelination in CIDP can be limited to the nerve roots. Routinely, this is assessed indirectly by studying F waves. However, F-waves can be normal if sufficient numbers of large myelinated fibers are unaffected. Nerve roots stimulation may offer additional information about conduction along the most proximal segments

Right median nerve (motor)

A

wrist−APB

4.1 ms

elbow−APB

−70%

36 m/s

−82%

38 m/s

− 2.5 μV +

axilla−APB

B

Right median nerve (sensory)

44 m/s

− 0.5 μV

Dig III−wrist

+ 49 m/s

Dig III−elbow

Dig III−axilla

Fig. 35.3 Motor and sensory nerve action potentials from a patient CIDP with motor and sensory conduction block. (A) CMAP from abductor pollicis brevis muscle. (B) Sensory nerve action potentials recorded at writs, elbow, and axilla. Note, absent response at the axilla. (C) SNAP recorded from sural nerve Reproduced from Krarup and Trojaborg, 1996, with permission from Oxford University Press.

C

Left sural nerve 50 m/s

− 0.5μV +

4 S

8

12

16

20

24

28

32

36 ms

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY

of the nerves. Nerve roots can stimulated either by insertion of a needle in the paraspinal area at the level of the lamina (Berger et al., 1987) or by using magnetic stimulation (Cros et al., 1990; Ertekin et al., 1994). The site of nerve activation is probably at the intervertebral foramina where the nerve roots exit and not at the most proximal level. Nonetheless, these techniques can give information about proximal segments that are not assessed directly by the routine nerve conduction studies. In one study of 31 patients with definite, probable or possible CIDP, 20 had proximal conduction block with root stimulation, whereas only seven patients met the published criteria for the diagnosis (Menkes et al., 1998). We find that one can rarely be sure of supramaximal stimulation with nerve root stimulation and an abnormal study at best can only suggest a possible conduction block. Furthermore, a muscle may be innervated by more than one root (e.g., C8 and T1 roots) innervating abductor pollicis brevis, whereby stimulation of one root may suggest spurious conduction block. Magnetic stimulation probably stimulates lesser number of fibers but can be used for initial screening for proximal conduction block. Root conduction time may be a useful additional parameter for evaluating proximal motor conduction (Inaba et al., 2002). This is calculated by subtracting motor latency obtained with cervical magnetic stimulation from total peripheral conduction time (F-latency−M-latency−1). 35.2.3.5.2. Surface EMG in CIDP. Surface EMG can be used to detect partial motor conduction block in patients with CIDP (Chaudhry et al., 2003). Ratio of the amplitude of the compound muscle action potential with distal stimulation to that evoked volitionally is significantly reduced in patients with conduction block proximal to the site of distal stimulation. This technique may be useful in detecting very proximal conduction block, which is difficult to diagnose with routine nerve conduction studies, if an upper motor lesion is ruled out. However, the volitional response is effort dependent, making this technique less reliable. 35.2.3.5.3. Motor unit number estimation (MUNE). MUNE is useful in assessing the degree of motor unit loss in chronic axonopathies (Bromberg et al., 2003; Lawson et al., 2003; Lewis et al., 2003) and, accordingly, can help quantitate the degree of axon loss in CIDP. Theoretically, MUNE may be able to detect a focal conduction block, with reduction in the number

717

of motor units recorded with stimulation proximal to the site of the lesion when compared with more distal stimulation. However, in one study of ulnar nerve entrapment at the elbow with focal conduction block, MUNE failed to detect motor unit drop out (Jillapalli et al., 2003). In this study the proximal CMAP amplitude declined in parallel with a decline in average single surface-recorded motor unit potential (SMUP) amplitude. Therefore, the MUNE, calculated by dividing the maximal CMAP by SMUP amplitude estimate, was relatively unchanged. Preferential involvement of large thickly myelinated nerve fibers in focal compressive neuropathies may be the explanation for reduced proximal SMUP amplitude in this study. 35.2.3.5.4. Single-fiber EMG (SFEMG). SFEMG has been used to quantify the extent of axon loss in patients with CIDP. Increased fiber density and abnormal jitter are related to the secondary axon loss and reinnervation (Oh, 1989; Gantayat et al., 1992) which, not surprisingly, correlate with the extent of fibrillation potentials in these muscles. Padua et al. (2001) reported an intriguing technique for investigating possible conduction block. They used SFEMG needle to record from the muscle with stimulation distal and proximal to sites of suspected conduction block, and found blocking of motor unit potentials in 16 of the 17 patients with clinical suspicion of conduction block. They found no abnormalities in 20 healthy subjects; however, they did not have disease controls with axonal or inherited demyelinating neuropathies. This is an interesting technique that needs to be validated with further studies, since technically inadequate stimulation at proximal sites will lead to spurious conduction block, as with surface recording. Furthermore, intramuscular needle recording electrodes are more susceptible to movement induced by muscle contraction. 35.2.3.5.5. Reflex testing. In the majority of patients with CIDP tendon reflexes are either hypoactive or absent. In patients with a clinical picture of CIDP and normal or increased tendon reflexes on physical examination, electronically recorded tendon-reflex response (T-reflex) may help to ascertain abnormality of the myotatic reflex. Mean T-reflex latency is prolonged in the majority of patients with CIDP and even in those with brisk or normal reflexes on clinical testing (Kuruoglu and Oh, 1994; van Dijk et al., 1999).

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35.2.3.5.6. Axonal excitability testing, microneurography, and threshold tracking (also see activity dependent conduction block in MMN). Activity dependent excitability changes are seen in sensory and motor nerves in patients with CIDP. Sensory nerve action potentials recorded with intraneural microelectrodes show marked reduction in amplitude and increase in latency when stimulated with impulse trains > 20 Hz (Kuwabara et al., 1999). These abnormalities may be a result of conduction slowing or block caused by activity-dependent hyperpolarization secondary to demyelination (Bostock and Grafe, 1985; Cappelen-Smith et al., 2000). In one study, compound motor action potential elicited by supramaximal stimulation of motor nerves after maximal voluntary contraction for 60 seconds, was significantly reduced in patients with symptomatic CIDP, but not in CIDP patients who are asymptomatic (Kuwabara et al., 1999). Indices of axonal excitability can be measured by using the technique of threshold tracking as described by Bostock (Bostock et al., 1998; Kiernan et al., 2000). These indices are dependent on Na+ and K+ channels, membrane potentials, and properties of axonal membrane and myelin. Demyelination exposes the paranodal and internodal axonal membrane, altering the density of Na+ and K+ channels, which can alter passive and active membrane potentials. Median nerves evaluated at the wrist in CIDP have shown increased threshold to hyperpolarizing currents (Cappelen-Smith et al., 2000; Sung et al., 2004). Threshold electrotonus (mean threshold changes produced by subthreshold current) after hyperpolarizing current was increased in some patients with CIDP, whereas response to depolarizing current was unaltered. These change in threshold electrotonus were more common in patients with “diffuse” demyelination on routine nerve conduction studies (Sung et al., 2004). 35.2.4. Other findings in CIDP 35.2.4.1. Cranial nerve involvement in CIDP Cranial nerves are infrequently involved in CIDP. Optic neuritis, ophthalmoplegia, facial weakness, phrenic nerve palsy, and bulbar involvement have been reported (Kawakami et al., 1998; Lee et al., 1999; Rotta et al., 2000; Holtkamp et al., 2001; Costello et al., 2002; Kimber et al., 2003; Macia et al., 2003; Stojkovic et al., 2003; Zhuang et al., 2003). In one study of 28 nerves in 14 patients with CIDP direct facial responses and blink reflex commonly

P. KELKAR AND S.A. MULEY

abnormal (Kimura, 1982). Direct facial responses were absent in four and delayed in 11. Blink reflex showed absent R1 in seven and delayed in 13, and R2 responses were also frequently delayed. It is not stated if these patients had clinical involvement of facial nerve or not, but presumably at least some of them had subclinical conduction abnormalities. Cruccu et al. (1998) reported findings suggesting subclinical involvement of trigeminal nerve in CIDP with abnormal motor responses in facial or masseter muscles. They found marked prolongation of the masseter early inhibitory reflex (also called first silent period, SP1) after mental nerve stimulation and prolonged R1 and R2 on blink reflex testing. Such findings may supplement documentation of demyelination in the appropriate clinical context. 35.2.4.2. Central changes in CIDP Central nervous system involvement is known to occur in CIDP, including clinical signs of myelopathy such as brisk reflexes, MRI signal changes, and abnormalities on visual or brainstem auditory evoked responses (Mendell et al., 1987; Pakalnis et al., 1988; Provinciali et al., 1989; Ohtake et al., 1990; Stojkovic et al., 2000). Occasionally, clinical course and MRI findings may resemble multiple sclerosis in association with CIDP (Kinoshita et al., 1994; Pereon et al., 1994; Fee and Fleming, 2003; Rodriguez-Casero et al., 2003). Abnormalities in blink reflex suggesting central delay have been reported in patients with CIDP with central findings (Komori et al., 1990). 35.2.4.3. Pure sensory CIDP? It is uncertain if a pure sensory ataxic form of CIDP exists, wherein there are only sensory signs and symptoms, there is demyelination and slowing in sensory nerves, and no abnormalities in motor nerves. Most patients with “sensory” CIDP have slowing of conduction velocities in motor nerves (sometimes symmetrical and distally predominant (Rotta et al., 2000; Saperstein et al., 2001), as seen typically in DADS neuropathy –– see Chapter 36), or they eventually develop weakness (Oh et al., 1992; Berger et al., 1995). 35.2.4.4. Pure motor CIDP Most patients with CIDP have sensory findings on clinical examination and SNAPs are reduced or absent. However, pure motor form of CIDP has been described, presenting as a relapsing–remitting illness, particularly in pediatric or young patients. These patients had motor findings consistent with CIDP with

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY

normal sensory examinations, tendon reflexes, SNAPs, and sural nerve biopsies, and they showed response to steroids. (Trojaborg, 1998; Sabatelli et al., 2001; Busby and Donaghy, 2003). 35.2.5. CIDP in diabetes mellitus Diabetes mellitus (DM) is known to cause conduction abnormalities in nerves along with axon loss, hence making a diagnosis of CIDP in patients who have DM can be difficult (Wilson et al., 1998). Incidence of diabetes in CIDP and vice versa may be higher when compared with general population (Miyasaki et al., 1999; Sharma et al., 2002). Diabetic nerves may be more susceptible to immune attack, and immunemediated vasculopathy has been shown to cause multifocal diabetic neuropathies including diabetic amyotrophy (Said et al., 1994; Llewelyn et al., 1998; Kelkar et al., 2000)and diabetic mononeuritis multiplex (Said et al., 2003; Kelkar and Parry, 2003). There are no specific guidelines for making a diagnosis of CIDP in DM, and the use of electrophysiological criteria for idiopathic CIDP can be applied to patients with DM. (Sharma et al., 2002; Haq et al., 2003). These patients also respond to immune modulating therapies; however, the response may not be as prompt or as good as patients without diabetes. 35.3. Multifocal motor neuropathy (MMN) 35.3.1. Background MMN is an intriguing disorder in which motor fibers are preferentially affected by an immune-mediated process leading to conduction block, whereas sensory fibers are largely unaffected. Parry and Clarke (1985, 1988) described five patients with progressive weakness and atrophy and normal sensations and reflexes, mimicking motor neuron disease. These patients had persistent conduction blocks in motor nerves with normal sensory conductions. MMN causes slowly progressive weakness, most often affecting upper extremity nerves. Muscle cramps, fasciculations or myokymia are common. Lack of atrophy in significantly weak muscles is frequent due to the demyelinating nature of the underlying pathology. In contrast to ALS, there are no upper motor neuron signs and the weakness is multifocal rather than segmental. It is sometimes associated (50 –70%) with high titers of anti-GM1 antibodies (Parry, 1996; Katz et al., 1997; Pestronk, 1998).

719

35.3.2. Motor nerve conduction studies in MMN The hallmark of this disorder is the presence of persistent conduction blocks in nerve segments, which are not prone to entrapment, often associated with conduction slowing or temporal dispersion. Interestingly normal sensory nerve conductions can be documented through the segments in which the motor fibers have a conduction block (Fig. 35.4). CMAP amplitude is often reduced in the affected muscles due to presence of co-existing secondary axon loss, which is common especially in chronic cases (Katz et al., 1997). 35.3.2.1. Electrophysiological criteria of MMN American Association of Electrodiagnostic medicine has recently published diagnostic criteria for diagnosis of MMN (Olney et al., 2003). See Table 35.5. Although these are heavily weighted towards finding CB (definite or probable), it is important to recognize that it may not be possible to demonstrate conduction blocks even after careful studies, as the site of pathology may be very proximal in the brachial plexus or at the level of the nerve roots (Pakiam and Parry, 1998). In one series of 16 patients with clinically defined MMN, only five had CB in 1 or more nerves, while 15 patients had other features of demyelination, namely temporal dispersion and conduction slowing (Katz et al., 1997). Therefore, stringent adherence to criteria that require demonstration of conduction block in multiple nerves would lead to underdiagnosis of this treatable condition. Patients with MMN without demonstratable CB (Pakiam and Parry, 1998) and patients with possible CB (Nobile-Orazio et al., 2002) have clinical picture and response to treatment similar to MMN with conduction block. There is a report of 3 IVIG responsive patients with mono-focal motor neuropathy and conduction block in whom weakness and partial conduction block was restricted to one nerve (Felice and Goldstein, 2002), suggesting that they had a partial form of MMN. In our experience, patients with MMN most often have multifocal weakness in the distribution of individual nerves, rather than segmental or diffuse weakness. It may only be possible to demonstrate conduction block or convincing focal demyelination in one nerve, while other nerves may show reduced CMAP amplitude without conduction abnormalities. Therefore, excluding patients who do not have conduction blocks in 2 or more nerves from treatment cannot be recommended.

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2 ms Palm

50 μV

LAT 1 ms

AMP mV

1.5 48.44 5 ms

LAT 1 ms

1 mV

AMP mV

3.1 49.61 4.2 39.58

5.7 1.297 6.5 1.305

4.9 37.76 Wrist

6.6 1.206

5.7 36.59

9.7 0.401

6.6 37.50

Fig. 35.4 A patient with multifocal motor neuropathy showing evidence of conduction block in the median motor fibers (A) in the forearm segment between 10 and 15 cms proximal to wrist, along with reduction of conduction velocity. The sensory fibers (B) conduct normally through the same segment.

10.9 0.555 5 cm

5 cm

5 cm

Elbow

A

B

It is important to study the affected nerves and include Erb’s point stimulation to look for proximal conduction block, although it can be technically challenging. Also nerves that are not routinely studied such as the musculocutaneous nerve with recording from biceps

brachii should be studied if clinically involved (Fig. 35.5). Conduction block and other changes of demyelination are most often detected in nerves-muscles with significant weakness, but more diffuse, subclinical changes can also be seen (Van Asseldonk et al., 2003).

Table 35.5

35.3.3. Sensory nerve conduction studies in MMN

Consensus criteria for diagnosis of MMN (Olney et al., 2003) Definite Weakness in multifocal distribution with normal sensations Definite CB in 2 nerves, excluding common sites of compression Normal sensory conduction across the same segment Normal sensory conductions in 3 nerves. Absence of UMN signs. Probable 2a. Probable conduction block in 2 or more nerves 2b. Definite CB in 1 nerve and probable in 1.

Sensory nerve studies are typically normal in patients with MMN (Parry, 1996), both through the site of the conduction block and distal to it (Fig. 35.4). Pathologically mild axon loss (Parry and Clarke, 1988) or mild changes of demyelination/ remyelination can be seen even in sensory nerves with normal electrophysiological studies (Corse et al., 1996). 35.3.4. Needle EMG in MMN Fibrillation potentials and motor unit changes are seen especially in chronic cases, since some degree of axon loss in common (Katz et al., 1997).

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY

5 mV 5 ms

Fig. 35.5 A patient with MMN and possible conduction block in the right musculocutaneous nerve with reduction in the amplitude and area with Erb’s point stimulation and reduced conduction velocity on the right side.

Musculocutaneous nerve Recording site: Bicceps

Side Stim

Lat ms

Amp Dur mV Ms

Lt Lt

Axilla 2.1 Erb's 4.9

Rt Rt

Axilla 2.85 6.2 Erb's 7.25 1.7

721

Area

CV M/s

14.78 13.05 117.1 9.18 13.0 75.88 78.6

Fasciculations or myokymia may also been seen in the weak muscles (Roth et al., 1986) (Fig. 35.6). This may be due to focal potassium channel dysfunction at the site of demyelination induced by disruption of blood-nerve barrier and lack of Schwann cellmediated extracellular potassium regulation. Potassium channel dysfunction can lead to the membrane depolarization, thereby accounting for the conduction block (depolarization block), fasciculations, and myokymia (Kaji et al., 1995). 35.3.5. Other techniques 35.3.5.1. Nerve root stimulation Similar to CIDP, nerve root stimulation offers another technique for documenting a very proximal conduction block in MMN (Menkes et al., 1998). However, it is difficult to completely assure supra-maximal stimulation. Finding normal response on the contralateral side with relative ease can be helpful in suggesting a possible conduction block. 35.3.5.2. Activity dependent conduction block in MMN Rate-dependent conduction block was initially described in the central nervous system (McDonald and Sears, 1970), which can explain some clinical features in multiple sclerosis such as fatigue. Bostoc and Grafe (1985) first demonstrated this type of conduction failure in peripheral nerves. This is caused by activation of the electrogenic sodium-potassium pump, which leads to membrane hyperpolarization

16.9 16

66.83 15.6 50

after passage of high frequency impulses. Demyelinated axons undergo greater hyperpolarization due to increased load of sodium ions. This illustrates that abnormal axonal excitability, as well as structural damage to the myelin, causes conduction block. Many patients with MMN complain of fatigue in affected muscles. In one study, the authors found that conduction block in these patients worsened transiently following maximum voluntary contraction, a phenomenon referred to as activity dependent conduction block, presumably due to hyperpolarization of the axons (Kaji et al., 2000). 35.3.5.3. Surface EMG in MMN Similar to CIDP (Chaudhry et al., 2003) surface EMG can theoretically be used to detect partial motor conduction block in patients with MMN, although this has not been evaluated. 35.3.5.4. Single-fiber EMG (SFEMG) in MMN In MMN, increased jitter and fiber density are found even in clinically unaffected muscles, which improve with intravenous immunoglobulin treatments (Lagueny et al., 1998). 35.4. Lewis-sumner syndrome 35.4.1. Background Lewis et al. (1982) described five patients with multifocal motor and sensory symptoms, with conduction

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Fig. 35.6 Myokymia from extensor digitorum muscle in a patient with MMN with conduction block.

block in motor nerves and abnormal sensory studies. Since then, several additional cases have been reported (Oh et al., 1997; Saperstein et al., 1999; Van den Berg-Vos et al., 2000). It is also referred to as MADSAM neuropathy (Multifocal acquired demyelinating sensory and motor). Although MADSAM neuropathy is similar to MMN there are some differences; spinal fluid protein is elevated more often in MADSAM neuropathy, demyelination on sural nerve biopsy is more prominent in MADSAM neuropathy, anti-GM1 antibodies are not present in MADSAM neuropathy, and unlike with MMN some patients with MADSAM neuropathy may be responsive to steroids (Saperstein et al., 1999).

35.4.2. Motor nerve conduction studies in Lewis–Sumner syndrome The hallmark of this disorder is presence of persistent conduction blocks in non-compressive segments, often associated with conduction slowing or temporal dispersion, similar to MMN with conduction block. 35.4.3. Sensory nerve conduction studies in Lewis–Sumner syndrome In contrast to MMN, sensory nerve conductions are abnormal in Lewis–Sumner syndrome. Sural SNAPs are almost always absent in these patients and other

Fig. 35.7 Median nerve conduction studies in a Patient with Lewis–Sumner syndrome. A1 = stimulation at the wrist. A2 = stimulation at the elbow. (Left) Motor conduction, time base 5 ms/division, sensitivity 2 mV/division. There is severe reduction of the compound muscle action potential on elbow versus wrist stimulation, indicating partial motor conduction block. (Right) Sensory conduction, time base 2 ms/division, sensitivity 10 μV/division. The sensory nerve action potential is normal on wrist stimulation but absent on elbow stimulation, indicating conduction block or severe temporal dispersion in sensory nerve fibers. Motor conduction and sensory conduction in the right median nerve were normal. (Reproduced from Van den Berg-Vos et al., 2000, with permission from Lippincott Williams and Wilkins).

CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY

SNAPs (median, ulnar, radial) are often diminished in amplitude (Saperstein et al., 1999). Occasionally conduction block or segmental temporal dispersion can be seen in sensory nerves (Van den Berg-Vos et al., 2000). (See Fig. 35.7). References Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) (1991) Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Report, Neurology, 41: 617–618. Albers, JW and Kelly, JJ, Jr (1989) Acquired inflammatory demyelinating polyneuropathies: clinical and electrodiagnostic features. Muscle Nerve, 12: 435–451. Austin, JH (1955) Recurrent polyradiculoneuropathy; observations of a case treated with corticotropin and cortisone. Trans. Am. Neurol. Assoc., 105–110. Barohn, RJ, Kissel, JT, Warmolts, JR and Mendell, JR (1989) Chronic inflammatory demyelinating polyradiculoneuropathy Clinical characteristics, course, and recommendations for diagnostic criteria. Arch. Neurol., 46: 878–884. Berger, AR, Busis, NA, Logigian, EL, Wierzbicka, M and Shahani, BT (1987) Cervical root stimulation in the diagnosis of radiculopathy. Neurology, 37: 329–332. Berger, AR, Herskovitz, S and Scelsa, S (1995) The restoration of IVIg efficacy by plasma exchange in CIDP. Neurology, 45: 1628–1629. Bostock, H, Cikurel, K and Burke, D (1998) Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve, 21: 137–158. Bostock, H and Grafe, P (1985) Activity-dependent excitability changes in normal and demyelinated rat spinal root axons. J. Physiol., 365: 239–257. Bromberg, MB (1991) Comparison of electrodiagnostic criteria for primary demyelination in chronic polyneuropathy. Muscle Nerve, 14: 968–976. Bromberg, MB, Swoboda, KJ and Lawson, VH (2003) Counting motor units in chronic motor neuropathies. Exp. Neurol., 184 (Suppl. 1): S53–S57. Buchthal, F and Behse, F (1977) Peroneal muscular atrophy (PMA) and related disorders I Clinical manifestations as related to biopsy findings, nerve conduction and electromyography. Brain, 100(1): 41–66.

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 36

Peripheral neuropathies associated with plasma cell dyscrasias Chelsea Grow* and John J. Kelly Department of Neurology, George Washington University, USA

36.1. Introduction Plasma cell dyscrasias with related neuropathies are a heterogeneous yet important group of neuropathies. The detection of such a neuropathy may lead to the detection of an occult lymphoproliferative disorder. Though diverse in presentation, there are certain clinical and electrodiagnostic features that may guide the clinician. The pathogenetic relationship of the M-protein, although well established in some syndromes, is more often ill defined. Familiarity with the characteristic and electrophysiologic features of each will enable the clinician to recognize these disorders. Plasma cell dyscrasias (PCD), synonymous with monoclonal gammopathy (MG), are a heterogeneous group of disorders (Table 36.1). The frequency of MG in the general population is estimated at 2% in those aged 50–70 and about 3% in those older than 70 years (Hallen, 1963; Kyle and Dyck, 1993). Most of these patients have monoclonal gammopathy of undetermined significance (MGUS), which used to be called benign monoclonal gammopathy. As Kyle and colleagues pointed out when they coined the term MGUS, however, the risk of progression of MGUS to a malignant gammopathy is about 1% per year, reaching an ultimate frequency of 25–30% (Kyle et al. 2002). Approximately 10% of patients with idiopathic peripheral neuropathy will have an associated monoclonal gammopathy (Kelly et al., 1981; Kyle and Dyck, 1993; Kissel and Mendell, 1996), about six times the frequency of monoclonal proteins (Mproteins) in the general population (Kissel and Mendel, 1996). In half of those with idiopathic peripheral neuropathy and an M-protein, a plasma cell * Correspondence to: Chelsea Grow, DO, George Washington University, 2150 Pennsylvania Avenue, Washington, DC 20037, USA. E-mail address: [email protected] Tel.: +1-202-741-2719; fax: +1-202-741-2722.

dyscrasia other than MGUS can be detected (Kissel and Mendell, 1996). However, the pathogenetic association of the M-protein to the neuropathy is often unclear. In some cases, the M-protein has antibody activity against components of the nerve. Although PCD-associated neuropathies are heterogeneous, in some there are typical clinical and electrophysiologic patterns that help to identify particular syndromes, which can occasionally suggest an undiagnosed plasma cell dyscrasia. This chapter will outline the electrophysiologic and pathological findings encountered with the PCD-associated neuropathies. 36.2. Clinical syndromes 36.2.1. MGUS-associated neuropathies Monoclonal gammopathy of undetermined significance may be associated with neuropathy in approximately 5% of all neuropathy patients and 10% of idiopathic neuropathy patients (Kelly et al., 1981). MGUS is caused by a proliferation of a nonmalignant clone of plasma cells that secretes a monoclonal protein. M-proteins are composed of one heavy chain (IgM, IgA, or IgG) and a single light chain (kappa or lambda). The M-protein is usually detected on serum protein electropheresis but, occasionally, serum protein immunoelectropheresis (IEP) or immunofixation electropheresis (IFE) is required to detect small amounts of monoclonal protein. IEP and IFE are always needed to characterize the single heavy and light chain types and thus confirm their monoclonal nature (Keren et al., 1988). MGUS is generally defined as a monoclonal gammopathy with an M-protein level of less than 3 g/dl and minimal amounts of monoclonal light chains in the urine. In addition, medical complications such as lytic bone lesions, anemia, hypercalcemia, or renal insufficiency should be absent and a bone marrow aspirate should contain less than 10% nonmalignant plasma cells (Kyle, 1978). Eventhough IgG is the most frequently encountered

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Table 36.1*** Major features of peripheral neuropathies associated with PCD Electrodiagnostics

Clinical

Disorder

Demyelination

MNCV

Axonal

Weakness

Sensory

Pathology

IgM–MGUS

+++

Very slow

+

+

+++

IgG, IgA-MGUS

++

+

++

++

++

MM*

+

Nml to mild slow

++

+

+

OSM

+++

Very slow

+

+++

+

Primary amyloid **

−

+++

+/++

+++

Waldenstrom’s macroglobulinemia

+++

Nml to mild slow Very slow

Myelin splitting/widened lamellae Segmental demyelin/axon-al degeneration Axonal degener, minimal secondary demyelin. Segmental demyelination Axonal degen

+

++

+++

Seg. demyelin, axonal degen, may have widened lamellae if MAG +

Cryoglobulinemia

+

Nml to mild slow

+++

++

++

Vasculitis of vasa nervosum

PCD, plasma cell dyscrasia; MNCV, -motor nerve conduction studies. * = root involvement or superimposed polyradiculopathy. ** = autonomic dysfunction.

M-protein in MGUS in general, the frequency of monoclonal IgM is overrepresented in patients with neuropathy and MGUS (60% IgM, 30% IgG, 10% IgA) (Ropper and Gorson, 1998). For pathological and clinical purposes, the MGUSrelated neuropathies can be divided into two categories: IgM- and non-IgM (IgG and IgA)-associated neuropathy. 36.2.1.1. IgM-associated neuropathy The best characterized of MGUS neuropathies are patients with IgM paraproteins with activity against specific antigenic components of the peripheral nerve. These neuropathies usually present as an insidious distal, symmetric, sensory dominant polyneuropathy. Sensory symptoms, especially paresthesias, predominate with neuropathic pain being less common. Patients usually demonstrate a slowly progressive loss

of large fiber sensory modalities with impaired touch and vibration sense, proprioception, and areflexia. A postural tremor of the upper extremeties and gait ataxia are common (Yeung et al., 1991; Kyle and Dyck, 1993; Smith, 1994; Kissel and Mendell, 1996). Cranial nerves and autonomic functions are spared. Males predominate with the median onset age in the sixth decade. Variants, including a motor dominant presentation, are rare (Gordon et al., 1997). In these patients, IgM often displays antigenic activity against components of the myelin sheath, including glycoproteins and glycolipids (Hartung et al., 1996). In about half of the IgM neuropathy patients, the IgM proteins react against myelin-associated protein (MAG). MAG, a 100-kDa glycoprotein that makes up about 1% of peripheral nerve myelin, is concentrated in periaxonal and paranodal loops of myelin and appears to act as an adhesion molecule, which

PERIPHERAL NEUROPATHIES ASSOCIATED WITH PLASMA CELL DYSCRASIAS

helps to hold together the myelin layers (Quarles, 1980). Anti-MAG antibodies cross-react with the main P0 protein of myelin, PMP-22, and several complex glycosphingolipids such as SGPG (Ilyas et al., 1984; Chou et al., 1986; Ariga, 1987; Bollensen et al., 1988). A pathogenic role for the anti-MAG antibody in neuropathy is better established than with IgG and IgA antibodies. In humans, anti-MAG antibodies are associated with characteristic widening of the myelin lamellae, presumbly due to a complement-dependent attack of the anti-MAG antibodies, which interferes with the neural adhesion properties of MAG. Passive transfer of serum into cat nerve induces focal demyelination not characteristic of the human disease. However, in chickens, anti-MAG serum causes neuropathy with similar widening of the myelin lamellae (King and Thomas, 1984; Hays et al., 1987; Tatum, 1993). Patients with anti-MAG antibodies generally have a slowly progressive sensory ataxia with loss of largefiber sensory modalities and Romberg’s sign (Hafler et al., 1981; Latov, 1995; Kissel and Mendell, 1996; Pestronk et al., 1991; Van Den Berg et al., 1996). Distal limb weakness develops later in the course. The patients are on an average older than idiopathic CIDP patients, with a mean age of 62 years, and are male predominant (Katz et al., 2000). Though disease progression is slow in most cases, incapacitation can occur, with 16% disability at 5 years, 24% at 10 years and 50% at 15 years (Nobile-Orazio et al., 2000). In one study of unselected patients with distal demyelinating ataxic sensory neuropathy, two-thirds of patients had an IgM-kappa M-protein and 67% of those had anti-MAG antibodies (Katz et al., 2000). Therefore, this disorder is a prominent cause of primarily sensory ataxia late in life due to demyelinating neuropathy. IgM-MAG and non-MAG reactive neuropathies are often difficult to separate clinically since they have similar clinical and electrophysiologic attributes (Gosselin et al., 1991; Suarez and Kelly, 1993), except that the MAG-reactive group are older age and male predominant (Nobile-Orazio et al., 2000). Prolonged therapy with monthly plasma exchange and/or continuous oral or pulsed intravenous cyclophosphamide can be effective in these patients (Blume et al., 1995). Interferon alpha was beneficial in one trial (Mariette et al., 1997). Rituximab, a monoclonal antibody directed against the CD20 receptor on the B-cell surface membrane, may be a promising treatment for anti-MAG and anti-GM1 antibody mediated neuropa-

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thy, and possibly other IgM-related neuropathies. In one small study, all five patients treated with Rituximab had improved function and increased quantitative strength measurements within 3–6 months after treatment. In addition, titers of serum autoantibodies were reduced and side-effects were tolerable (Levine and Pestronk, 1999). Other reports have linked IgM monoclonal gammopathy with antiganglioside antibody reactivity. In a study, Eurelings et al. (2001) found that 15% of their patients with monoclonal gammopathy and polyneuropathy had elevated antiganglioside titers. The antiganglioside reactivity was significantly associated with a demyelinating polyneuropathy and an IgM monoclonal gammopathy. The presence of high titers of anti-GD1b and anti-GQ1b antibodies were associated with a predominantly sensory ataxic neuropathy. Other studies have linked anti-SGPG antibodies with axonal neuropathy or motor neuron disease (Rowland et al., 1995; Baumann et al., 1998), whereas anti-sulfatide antibodies have been associated with a predominantly sensory neuropathy (Pestronk et al., 1991; Nemni et al., 1993; Van den Berg et al., 1993). Despite these associations, individual subtypes of antibodies have not been shown to change the management or affect the prognosis of neuropathy associated with IgM monoclonal gammopathy (Eurelings et al., 2001). 36.2.1.1.1. IgM electrodiagnostics 36.2.1.1.1.1. Nerve conduction studies. Patients with IgM-MGUS related neuropathy have been compared to IgG or IgA MGUS related neuropathy in several studies (Gosselin et al., 1991; Suarez and Kelly, 1993; Simovic et al., 1998). Clinically, these two syndromes may be similar although IgM-associated neuropathies have more ataxia and more sensory loss with less weakness than non-IgM (Gosselin et al., 1991; Suarez and Kelly, 1993). On nerve conduction studies, the IgM-associated patients demonstrate a predominantly demyelinating pattern mixed with some axonal features (Suarez and Kelly, 1993). Evoked CMAPs can usually be obtained from median and ulnar motor nerves but less commonly from peroneal or tibial nerves. SNAPs are frequently low in amplitude or unobtainable in upper and lower extremeties. Motor conduction velocities are slowed, with mean velocities of 39.7 m/s in the ulnar, 36.6 m/s in the median, and 26.3 m/s in the peroneal nerves. The slowing generally is significantly worse than in patients with IgG gammopathy (Gosselin et al., 1991; Suarez and Kelly,

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1993). Distal latencies are also significantly prolonged in the IgM group compared to non-IgM patients. When the IgM and IgG neuropathies were directly compared, the mean distal motor latencies were 9.3 vs. 5.5 ms in the median nerve, respectively, and 6.6 vs. 3.3 ms in the ulnar nerve, respectively. The mean peroneal conduction velocity was 22 m/s in the IgM group versus 36 m/s in the IgG group (Simovic et al., 1998). The ulnar sensory potential was absent more often in the IgM-MGUS group (Simovic et al., 1998). Thus, these studies suggest a greater degree of electrodiagnostic features associated with demyelination in the IgM group compared to the IgG- or IgA-MGUS group. Though neuropathy with IgM-MGUS and antiMAG antibody may meet the electrodiagnostic criteria for CIDP, IgM-MAG neuropathy can often be distinguished electrophysiologically based on factors described above. Recognition of this pattern is important since discovery of an IgM gammopathy suggests a poor response to conventional treatments for CIDP and the need for stronger immunosuppressant treatment (Nobile-Orazio et al., 2000). In addition, these patients need to be watched, like all MGUS patients, for the development of malignant gammopathies such as Waldenstrom’s Macroglobulinemia (Kelly et al., 1981; Kyle and Dyck, 1993; Dimopoulos et al., 2000). Various measures of distal latency have been shown to separate anti-MAG neuropathy from CIDP or CIDPMGUS with IgG and IgA M-proteins. Kaku et al. (1994) and others (Kelly, 1990; Katz et al., 2000) reported a consistent feature of disproportionate increase in distal latencies in MAG-CIDP. A derivative of the DL, the terminal latency index (TLI), has been shown to be a sensitive markers of MAG-CIDP (Trojaborg et al., 1995; Kaku et al., 1994; Cocito et al., 2001), as it captures disproportionate distal demyelination. Median nerve TLIs of < 0.26 and ulnar nerve TLIs of < 0.33 were identified as threshold values in antiMAG neuropathy, with a sensitivity of 90.9% and specificity of 94.4% for median nerve, and 54.5 and 94.4%, respectively, for the ulnar nerve (Cocito et al., 2001). Trojaborg et al. (1995) demonstrated the utility of the residual latency as a parameter for distinguishing anti-MAG neuropathy from idiopathic CIDP. Residual latency, (measured distal motor latency– (d-80)/(conduction velocity), where d = actual conduction distance), was considerably longer in patients with the highest titers of anti-MAG antibody. He also showed that these patients had slower motor nerve conduction velocities and shorter TLIs, indicating a pronounced conduction slowing in the most distal segments, as com-

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pared to idiopathic CIDP patients. F-wave latencies did not contribute to differentiation between the groups, however, presumably because the distal slower was diluted by the longer proximal conduction times and increased variability of proximal conduction. Based on these studies, the presence of an insidious polyneuropathy syndrome of predominantly large fiber involvement with sensory ataxia and demyelinating features on nerve conduction studies, especially with disproportionate prolongation of distal motor latencies, should raise the probability of anti-MAG related neuropathy. While anti-MAG neuropathy rarely presents with anything other than a demyelinating pattern on nerve conduction studies, anti-SGPG antibodies alone were found in 91% of the demyelinating polyneuropathies and 50% of axonopathies in one study (Chassande, 1998). Therefore, the anti-SGPG antibodies alone are less specific for a slowly progressive, predominantly sensory, demyelinating polyneuropathy than antiMAG antibody and may present with pure motor axonopathy (Rowland et al., 1995). 36.2.1.1.1.2. Needle EMG. In the IgM neuropathies, there is usually chronic denervation changes particularly involving the distal intrinsic foot muscles (Nobile-Orazio, 1992). 36.2.1.1.1.3. Pathology: IgM anti-myelin associated glycoprotine. A characteristic widening of the interperiod lines of the myelin lamellae, so-called ‘myelin splitting,’ is seen by electron microscopy (King and Thomas, 1984). Immunoflourescent studies of sural nerve biopsies from patients with neuropathy and anti-MAG IgM monoclonal gammopathy shows the IgM deposits on the affected myelin sheaths where MAG is distributed and reveals complement fixation (Mendell et al., 1985; Ritz et al., 1999). No consistent binding of monoclonal protein to myelin sheaths is seen consistently in nerve biopsies from patients with IgG or IgA MGUS. 36.2.1.2. Non-IgM neuropathy: IgG and IgA-related neuropathy The pathogenetic relationship between IgG and IgA gammopathy and neuropathy is less defined (Latov, 1987; Vallat et al., 1996) than that for IgM. The prevalence of neuropathy is much lower in patients with IgG than with IgM MGUS (Nobile-Orazio et al., 1992), explaining the lower representation of IgG in large series of patients with MGUS neuropathy (Gosselin et al., 1991; Yeung et al., 1991; Suarez and

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Kelly, 1993). IgG-MGUS is a heterogeneous disorder both clinically and electrophysiologically. It may present as a slowly progressive, distal sensorimotor neuropathy or as a sensory ataxia with frequent falls, similar clinically to the IgM anti-MAG neuropathy (Yeung et al., 1991; Simovic et al., 1998; Gorson et al., 2002). It may also present itself as a moderate to severe, motor-predominant, chronic progressive or relapsing demyelinating polyneuropathy indistinguishable from CIDP (Ad Hoc Subc of AAN, 1991; Di Troia et al., 1999). It may also simulate the sensory variant of CIDP (Katz et al., 2000; Gorson et al., 2002). In one study, the more closely these neuropathies resembled CIDP, the greater the chance that these patients improved with IVIG (Gorson et al., 2002). Since IgG is the most frequent monoclonal gammopathy in population studies, the association between IgG and CIDP may be due to chance or the monoclonal gammopathy may be an epiphenomenon. A pathophysiologic connection has not yet been established. IgA MGUS has the least frequent association with neuropathy. These patients typically have a chronic progressive distal sensorimotor neuropathy, though rarely they may present with a pure motor neuropathy (Bosch et al., 1982; Yeung et al., 1991). These patients can also present with a CIDP-like picture similar to IgG-MGUS (Cocito et al., 2001). There is a report of a patient with IgA lambda MGUS and a demyelinating neuropathy who had a clinical, electrophysiological and ultrastructural changes on nerve biopsy very similar to those of MAG-polyneuropathy (Vallat et al., 2000). 36.2.1.2.1. IgG and IgA MGUS electrophysiologic studies. Nerve conduction studies patterns are more heterogeneous in IgG MGUS with two main varieties described (Yeung et al., 1991; Bleasel et al., 1993; Suarez and Kelly, 1993; Di Troia et al., 1999). A demyelinating neuropathy indistinguishable from CIDP may be present. Marked slowing of the motor nerve conduction velocities, often with conduction block and dispersion of the compound muscle action potentials, may be found (Bleasel et al., 1993). In one study, 59% of the patients had a CIDP-type pattern with motor conduction velocities below 30 m/s in the peroneal nerve or below 35 m/s in the median nerve or both in the majority (Di Troia et al., 1999). Another study noted the mean upper limb motor nerve conduction velocity to be 22.6 m/s (Yeung et al., 1991). Gorson et al. (2002) reported 9/20 patients with IgG MGUS had at least one demyelinating feature, and 7/20 patients fulfilled criteria for possible or probable

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CIDP (lacking cerebrospinal fluid or biopsy for definite CIDP (Report from Ad Hoc Subcommittee of the AAN, 1991). Distal latencies are prolonged, but not as disproportionately as in anti-MAG neuropathy. Sensory nerve conduction studies are universally abnormal (Bleasel et al., 1993). Sural sensory nerve action potentials are usually absent. Needle EMG shows reduced interference patterns in the muscles sampled and scattered high amplitude, polyphasic motor unit potentials, likely from secondary axonal damage in a primary demyelinating neuropathy (Bleasel et al., 1993). The other electrophysiological pattern is one of a primary axonal neuropathy, although a mixed pattern may be found in others. Motor amplitudes are slightly reduced in the legs with mild slowing of the conduction velocities. Distal muscles, especially the foot muscles, may show signs of active and chronic denervation with reinnervation. Sural potentials are usually absent or very low (Gorson et al., 2002). In this group of patients, with predominantly sensory impairment, sensory and motor nerve conduction velocities were never below 35 m/s in the peroneal, median, or sural nerves (Di Troia et al., 1999). The IgA-related neuropathies as a whole are uncommon and when present, may reveal slowing of the motor conduction velocities indicating an underlying demyelinating process, though in a few cases reports of axonopathy have been seen (Yeung et al., 1991). 36.2.1.2.2. Pathology: IgG related neuropathy. Sural nerve biopsy often shows mild to moderate loss of myelinated fibers of all diameters, endoneurial edema and onion bulb formation, 35–85% segmental degeneration and 0–20% axonal degeneration, and occasional IgG binding to myelin sheaths and blood vessels by direct and indirect immunoflourescence (Bleasel et al., 1993). This process is easily distinguished from the IgM anti-MAG neuropathy with widely spaced myelin lamellae, which is not present in IgG neuropathy (Yeung et al., 1991). 36.2.1.3. CIDP-MGUS Between 49 and 62% of polyneuropathies associated with IgM monoclonal gammopathy are demyelinating with variable degrees of concominant axonal damage (Nobile-Orazio et al., 1992, 1994), and 53% of patients with IgG-MGUS are diagnosed with chronic inflammatory demyelinating polyneuropathy (Di Troia et al., 1999). Some regard MGUS with antiMAG antibodies as a subset of CIDP but this disorder

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has a different presentation, pathology, and response to treatment so most would not regard it as a form of CIDP. MGUS with IgM M-protein lacking MAG reactivity also shows little homology to classical CIDP and differs in response to treatment. However, IgG- or IgA-MGUS patients may have a mostly demyelinating polyneuropathy very similar to CIDP in all respects including response to treatment and have been referred to as are CIDP-MGUS. This term does not imply a causal relationship, however, and the association may occur by chance alone. According to a study by Gorson and Ropper (1997), the main distinguishing factors with CIDP-MGUS and CIDP were less weakness at the time of evaluation, more imbalance, greater leg ataxia and more vibratory loss in the CIDP-MGUS group. There was also more often absent ulnar and median sensory potentials in the CIDPMGUS group. However, these are minor points and do not necessarily imply a different pathophysiology. 36.2.1.3.1. Axonal forms of MGUS. Though MGUS neuropathy is usually either demyelinating or mixed, studies have reported cases of primary axonal disease in 22–44% of MGUS cases (Notermans et al., 1994, 1996; Gorson and Ropper, 1997). Non-MAG IgM neuropathy or IgM antibody with chondroitin sulfate C and endoneurium reactivity may present with predominant axonal features as well (Sherman et al., 1983; Freddo et al., 1985; Nobile-Orazio et al., 1994). Diminished compound muscle action potentials, absent sural sensory nerve potentials, diminished ulnar sensory nerve action potentials and normalor slightly decreased nerve conduction velocities with normal distal latencies are the findings in these cases (Gorson and Ropper, 1997). 36.3. Primary amyloid neuropathy Primary or nonfamilial amyloidosis is the “internist’s neuropathy” since it is a fascinating multisystem disorder of the peripheral nervous system, kidneys, heart, and gastrointestinal tract. It is primarily a disease afflicting older men with a median age at diagnosis of 65 years. Fifteen percent of patients present with neuropathy with prominent neuropathic pain such as burning and dysethesias with loss of pain and temperature in the distal limbs (Kelly et al., 1979; Duston et al., 1989). In addition to small fiber sensory dysfunction, patients often have profound dysautonomia that may be severe and present early in the disease course with orthostasis, malabsorption, episodic diar-

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rhea, impotence, bladder and sweating disturbances, and hypoactive pupils. Loss of large fiber-mediated sensation and weakness are usually less prominent and come later. Ninety percent of patients have a monoclonal serum protein, usually IgG lambda (Kyle and Bayrd, 1975). In a few cases, only light chains (BenceJones proteins) are detected in the urine. 36.3.1. Primary amyloidosis-electrodiagnostics 36.3.1.1. Nerve conduction studies Conventional nerve conduction studies demonstrate a symmetric sensorimotor axonal neuropathy. Temperature control is crucial since the autonomic involvement can result in cool feet. Motor conduction velocities are usually just below normal range. In only 6 of 67 nerves studied, the motor conduction velocity was below 60% of the mean normal value (approximately 80% of the lower limit of normal) (Kelly et al., 1979). Compound muscle action potentials are typically mildly decreased in amplitude. Distal latencies are often prolonged in proportion to the degree of slowing of conduction velocities except in the case of carpel tunnel syndrome due to amyloid deposition at the flexor retinaculum, which is common in amyloid neuropathy. Sensory nerve compound action potentials are unobtainable in most cases, and if present, amplitudes are diminished with either no or minimal prolongation of distal sensory latencies, except in the presence of carpal tunnel syndrome (Kelly et al., 1979). In approximately 25% of the cases, median motor and sensory distal latencies are disproportionately prolonged and patients will have symptoms of carpel tunnel syndrome. Thus, the presence of a painful distal axonal neuropathy with bilateral carpel tunnel syndrome, with or without autonomic involvement, should suggest underlying amyloidosis, amongst other possibilities. 36.3.2. Needle EMG Fibrillation potentials are present predominantly in distal leg muscles in most cases. Motor unit potentials are consistent with chronic denervation and reinnervation changes in a length-dependent fashion (Kelly et al., 1979). 36.3.3. Autonomic testing As mentioned, small fiber and autonomic failure is pronounced in this disorder. Autonomic testing is often

PERIPHERAL NEUROPATHIES ASSOCIATED WITH PLASMA CELL DYSCRASIAS

helpful. Skin vasoconstrictor reflexes are impaired, indicating a lesion of sympathetic adrenergic fibers (Fealey, 1997). Postganglionic anhidrosis is the rule, although preganglionic lesions can occur (Fealey, 1997). Sudosympathetic nerves are involved, thus thermoregulatory sweat test (TST) are often abnormal. Heart period responses to deep breathing and to Valsalva maneuver are much reduced (Fealey, 1997). Orthostatic hypotension is often present and tilt table testing can help establish the neurogenic cause of syncope by demonstrating blunted heart rate. 36.3.4. Primary amyloidosis-pathology If a sensory neuropathy or evidence of organ involvement is present, biopsy of the sural nerve or the involved viscera has a high diagnostic yield. The sural nerve is positive in 90% of the cases with neuropathy. Abdominal fat pad, skin, or rectal biopsy also have high rates of positivity, generally in the range of 80–90%. Biopsy of two sites is generally recommended, such as nerve and fat pad. Amyloid is typically seen in the epior perineurium in a thickened blood vessel wall. Teased nerve fiber studies show axonal degeneration with secondary demyelination (Kelly et al., 1979). Diagnosis is confirmed by congo red birefringence under polarized light and immunohistochemical studies that can identify the specific types of amyloid.

36.4. Multiple myeloma Peripheral neuropathy associated with multiple myeloma is relatively uncommon, reported to occur in only 3–5% of myeloma patients (Silverstein and Doniger, 1963; Currie et al., 1970). However, a prospective study reported an incidence of 13% by clinical examination and 40% by performing routine NCVs on all patients (Walsh, 1971). The majority of patients have IgG kappa monoclonal proteins in serum or kappa light chains in urine. The clinical manifestations of this neuropathy are heterogeneous, but four overall patterns have been reported (Kelly et al., 1981a). (1) The most common form is a slowly progressive, mild distal sensorimotor polyneuropathy. There is mild involvement of all sensory modalities and mild distal symmetric weakness of legs more than arms, with lack of pain or autonomic features, separating it from amyloid neuropathy. Ankle jerks may be lost but reflexes tend to be preserved.

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This pattern tends to occur late in the disease and sometimes may be a manifestation of chemotherapy toxicity. (2) A rare pure sensory variant that resembles the sensory neuronopathy syndrome can be seen in lung cancer. These patients may present with relatively pure sensory loss with pain and sensory ataxia. (3) A pure motor variant, with a monophasic course of severe bilateral proximal and distal weakness with fasciculations resembling either GBS or CIDP. (4) A painful dysethetic distal polyneuropathy with loss of pain and temperature associated with amyloidosis that can occur in up to 30–40% of patients. Aside from the myeloma, these patients otherwise resemble those with primary systemic amyloidosis (Kelly et al., 1979). 36.4.1. Multiple myeloma-electrodiagnostics 36.4.1.1. Nerve conduction studies Though symptomatic peripheral neuropathy is uncommon in multiple myeloma, there is a 40% prevalence of neuropathy based on abnormal nerve conduction studies (Walsh, 1971). (1) The most common is the distal sensorimotor form, which usually has the features of an axonal neuropathy on nerve conduction studies. Motor conduction velocities reveal mild slowing with slightly low amplitudes of the CMAPs. SNAPs are low or absent. (2) The sensory variant is notable for unobtainable SNAPs in upper and lower extremities with preservation of motor nerve conduction velocities and compound muscle action potentials. In addition, needle EMG is usually normal or has minor changes. (3) The motor variant may have moderate slowing of motor conduction velocities with features suggestive of a demyelinating process with secondary axonal changes. (4) The co-existence with amyloidosis can produce the typical pattern of amyloid neuropathy discussed above. There are low amplitude compound muscle action potentials, slight slowing of conduction velocities and mild prolongation of distal latencies, except in cases of median nerve involvement at the wrist where there is disproportionate prolongation of distal latencies in these cases. Sensory nerve

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compound action potentials are frequently unobtainable. In addition, autonomic symptoms and abnormal autonomic testing are common. In addition to the neuropathies mentioned above, malignant infiltration of nerve roots may cause a superimposed polyradiculopathy, or spinal cord compression from vertebral fracture. 36.4.2. Needle EMG Needle EMG in most cases, except for the pure sensory variant, reveals fibrillation potentials and motor unit potential changes that are most prominent distally. 36.4.3. Pathology-multiple myeloma As evidenced on electromyographic studies, there is axonal attenuation as well as secondary segmental demyelination in multiple myeloma neuropathies (Victor et al., 1958; Ohi et al., 1985). However, most studies have not carefully sepaˆrated the various syndromes based on clinical and elctrophysiological findings. 36.5. Osteosclerotic myeloma and the poems syndrome Although osteosclerotic myeloma (OSM) accounts for only 3–5% of myelomas, upto 85% of patients present with polyneuropathy (Kelly et al., 1983; Soubrier et al., 1994). OSM is associated with neoplastic plasma cell proliferation occurring as single or multiple plasmacytomas. These manifest as sclerotic bone lesions, and may be associated with the POEMS or Crow–Fukase syndrome. The associated neuropathy is demyelinating in type and has a relatively homogeneous presentation, unlike the typical lytic myeloma neuropathies discussed above. Distinct electrodiagnostic features also differentiate it from multiple myeloma or CIDP (Kelly et al., 1981a). Although there is a report of it occuring concurrently with CIDP (Katz et al., 2000), distinctive differences in nerve conduction studies between the two entities have been reported (Sung et al., 2002). This is of importance since prognosis differs in POEMS and typical lytic myeloma. Nakanishi et al. (1984) reported that 34 out of 58 Japanese patients with POEMS syndrome died after a mean survival of 33 months, usually secondary to heart failure, intractable pleural effusions or ascites. However, tumoricidal irradiation of a plasmacytoma

can result in improvement in the neuropathy and even some endocrine manifestations with prolonged survival (Kelly et al., 1981a). These patients typically present with a relentlessly progressive, predominant motor polyneuropathy that can be incapacitating. They have diminished reflexes in the arms and areflexia in the legs. Weakness is moderate to severe with proximal and distal involvement. Sensory loss is usually limited to large fiber modalities, and is overshadowed by the weakness. Cranial nerves are spared. Cerebrospinal fluid usually reveals elevated protein with a mean value of 166 in one large series (Kelly et al., 1981a, 1983). 36.5.1. Nerve conduction studies The overall pattern on nerve conduction studies is demyelinating. Motor nerve conduction velocities are moderately to markedly slowed, with median values of 24.5 m/s for the ulnar, 25 m/s for the median nerve, and 14 m/s for the peroneal (Kelly et al., 1981a). Sensory nerve conduction velocities, if obtainable, are slowed as well. There are low compound muscle action potentials, prolonged distal latencies and dispersion of the compound muscle action potentials with proximal stimulation, characteristics of a demyelinating process. Sensory nerve compound action potentials are low or unobtainable in most cases. Differentiating factors from CIDP have been reported (Sung et al., 2002). In POEMS, slowing of the conduction velocities are more prominent in the intermediate portion of the nerve with sparing of distal nerve segments, whereas CIDP typically is multifocal with involvement of both intermediate and distal nerve segments. Significantly greater terminal latency index (TLI) seen in POEMS also supports this pattern of demyelination. Secondly, conduction block, the hallmark of acquired demyelination, occurs in just 6% of POEMS. Lastly, as opposed to CIDP, markedly attenuated or absent compound muscle action potentials in the tibial nerves are noted in POEMS, secondary to axonal loss, even when the median and ulnar compound muscle action potentials are normal (Sung et al., 2002). 36.5.2. Evoked potentials Median somatosensory evoked potentials have shown reduced N9 amplitude with a moderately prolonged latency. In addition, the interpeak latency between N9 and N13 may be prolonged, suggesting conduction delay in the dorsal root (Shibasaki et al., 1982).

PERIPHERAL NEUROPATHIES ASSOCIATED WITH PLASMA CELL DYSCRASIAS

36.5.3. Pathology Segmental demyelination is the most common feature, with demyelinating changes more prominent in the proximal nerve trunk and spinal roots than in the distal nerve segments (Sobue et al., 1992).

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The subset of patients with monoclonal IgM nonreactive with known peripheral nerve antigens tend to have a prominent axonal rather than demyelinating pattern (Ropper and Gorson, 1998). The subset of patients with co-existing cryoglobulinemia or amyloidosis will have patterns on electrodiagnostic testing consistent with the findings mentioned above.

36.6. Waldenstrom’s macroglobulinemia Approximately 5–10% of patients with WM have peripheral neuropathy (Seligmann et al., 1976; Dimopoulos et al., 2000). WM neuropathy is heterogeneous although the monoclonal IgM M-protein, usually with a kappa light chain, often has antibody activity against myelin antigens (Latov et al., 1980). A progressive sensory-ataxic neuropathy, with predominant paresthesias and marked proprioceptive loss, with late moderate weakness and diffuse areflexia, has been reported, which predates WM by a mean of four years. These patients have anti-MAG activity in their IgM fraction and likely are the same syndrome that occurs in IgM-MGUS. WM patients who lack MAG reactivity, however, have a more heterogeneous pticutre, which may include a distal sensorimotor polyneuropathy or a mainly sensory neuropathy (Dellagi et al., 1983). According to Dimopoulos et al. (2000), the WM associated neuropathies can best be classified into five categories: (a) IgM anti-Mag antibody demyelinating polyneuropathy antibody; (b) Monoclonal IgM with ganglioside reactivity and demyelinating polyneuropathy (non-MAG); (c) Monoclonal IgM polyneuropathy with nonreactivity to known antigens; (d) Cryoglobulinemic neuropathy; and (e) Amyloid polyneuropathy

36.6.1. Electrodiagnostics Since nearly 50% of the sera from these patients react with MAG, the electrodiagnostic pattern is similar to that with the IgM anti-MAG antibody listed above (Dalakas and Engel, 1981; Dimopoulos et al., 2000). Accordingly, the features are those of demyelination, with slowing of conduction velocities and prolonging of distal motor and sensory latencies. Conduction block is not common. The needle EMG often shows denervation potentials caused by concominant axonal degeneration (Dimopoulos et al., 2000).

36.6.2. Pathology The type of pathology depends on the underlying etiology of the neuropathy. In the cases of anti-MAG reactivity, the characteristic findings of the widened lamellae of the myelin sheath area can be seen. 36.7. Cryoglobulinemic neuropathy Cryoglobulins are proteins (usually IgG or IgM) that precipitate when cooled and redissolve with warming. Type I consists of a monoclonal IgG or IgM immunoglobulin and may be associated with a lymphoproliferative disorder. Types II and III are mixed, with type II having both a polyclonal IgG component and a monoclonal Rheumatoid Factor (RF) IgM component and type III containing a polyclonal RF component (Brouet et al., 1974). Cryoglobulinemia may be associated with lymphoproliferative disorders, connective tissue diseases such as SLE or Rheumatoid arthritis, or chronic infections such as Hepatitis C or bacterial endocarditis. Often there is no underlying cause for the cryoglobulins, and these patients are labeled as having essential mixed cryoglobulinemia (EMC). In a study by Garcia-Bragado et al. (1988), there was a prevalence of peripheral neuropathy in 43.7% of patients with EMC. Patients may develop systemic signs of fatigue, purpura, glomerulonephritis, and arthralgias. The neuropathy is characteristically painful at the onset, and may be accompanied by paresthesias and the Raynaud’s phenomenon in the colder temperatures. The onset may be acute in some cases with a mononeuritis multiplex pattern, and may even become confluent with time. More commonly, there is a progressive, symmetric, distal sensorimotor pattern that may be superimposed on mononeuropathies. 36.7.1. Electrodiagnostic testing Cryoglobulinemic neuropathy most often has an axonal pattern on electrodiagnostic testing. There is usually a moderate to severe decrease in CMAP

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amplitude in the tibial and peroneal nerves with less reduction in the median and ulnar nerves (GarciaBragado et al., 1988). Sural sensory nerve action potentials are often unobtainable. Nerve conduction velocities, distal latencies and F-waves are usually normal. In cases of mononeuritis, there are amplitude reductions in the affected motor or sensory nerve with relatively preserved nerve conduction velocities. 36.7.2. Needle EMG Fibrillation potentials and positive sharp waves are often present reflecting denervation due to axonal damage. There is moderate loss of motor units with decreased recruitment predominantly in the distal muscles of the lower extremities (Garcia-Bragado et al., 1988). 36.7.3. Pathology Sural nerve biopsy may show perivascular inflammatory cuffing with myelinated fiber loss, axonal degeneration and necrotizing arteritis of the epineurial vessels. Occlusion of the vasa nervorum by cryoglobulins may result in nerve infarcts (Garcia-Bragado, 1988). 36.8. Conclusion Information of the immunological aspects of the monoclonal gammopathies is vastly expanding and shedding light on the pathogenetic relationship of the monoclonal proteins and paraproteinemic neuropathies. Though they are diverse in presentation, these neuropathies are classifiable according to key clinical and electrodiagnostic features detectable by the clinician. Appropriate management is usually aimed at suppressing the monoclonal protein if there is proven anti-nerve antibody activity. Careful study of these patients will lead to a better understanding of these neuropathies and may help in the search for more beneficial treatments in the management of these immune-mediated polyneuropathy. References Ariga, T, Kohriyama, T, Freddo, L, Latov, N, Saito, M, Kon, K, Ando, S, Suzuki, M, Hemling, ME, Rinehart, KL Jr, Kusunoki, S and Yu, RK (1987) Characterization of sulfated glucuronic acid containing glycolipids reacting with IgM M-proteins in patients with neuropathy. J. Biol. Chem., 262: 848–853.

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Baumann, N, Harpin, ML, Marie, Y, Lemerle, K, Chassande, B, Bouche, P, Meininger, V, Yu, RK and Leger, JM (1998) Antiglycolipid antibodies in motor neuropathies. Ann. NY Acad. Sci., 845: 322–329. Bleasel, AF, Hawke, SH, Pollard, JD and McLeod, JG (1993) IgG monoclonal paraproteinemia and peripheral neuropathy. J. Neurol. Neurosurg. Psychiatry, 56: 52–57. Blume, G, Pestronk, A and Goodnough, LT (1995) Anti-MAG antibody-associated polyneuropathies: improvement following immunotherapy with monthly plasma exchange and IV cyclophosphamide. Neurology, 45: 1577–1580. Bollensen, E, Steck, AJ and Schachner, M (1988) Reactivity with the peripheral myelin glycoprotein P0 in serum from patients with monoclonal IgM gammopathy and polyneuropathy. Neurology, 38: 1266–1270. Bosch, EP, Ansbacher, LE, Goeken, JA and Cancilla, PA (1982) Peripheral neuropathy associated with monoclonal gammopathy. Studies of intraneural injections of monoclonal immunoglobulin sera. J. Neuropathol. Exp. Neurol., 41: 446–459. Brouet, JC, Clauvel, JP, Danon, F, Klein, M and Seligmann, M (1974) Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am. J. Med., 57: 775–788. Chassande, B, Leger, JM, Younes-Chennoufi, AB, Bengoufa, D, Maisonobe, T, Bouche, P and Baumann, N (1998) Peripheral neuropathy associated with IgM monoclonal gammopathy: correlations between M-protein antibody activity and clinical/electrophysiological features in 40 cases. Muscle Nerve, 21: 55–62. Chou, DK, Ilyas, AA, Evans, JE, Costello, C, Quarles, RH and Jungalwala, FB (1986) Structure of sulfated glucuronyl glycolipids in the nervous system reacting with HNK-1 antibody and some IgM paraproteins in neuropathy. J. Biol. Chem., 261: 11717–11725. Cocito, D, Durelli, Isoardo, G (2003) Different clinical, electrophysiological and immunological features of CIDP associated with paraproteinemia. Acta Neur0l. Scand., 108: 274–280. Cocito, D, Isoardo, G, Ciaramitaro, P, Migliaretti, G, Pipieri, A, Barbero, P, Cucci, A and Durelli, L (2001) Terminal latency index in polyneuropathy with IgM paraproteinemia and anti-MAG antibody. Muscle Nerve, 24: 1278–1282. Currie, S, Henson, RA, Morgan, HG and Poole, AJ (1970) The incidence of the non-metastatic neuro-

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Levine, T and Pestronk, A (1999) IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using Rituximab. Neurology, 52: 1701–1704. Mariette, X, Chastang, C, Clavelou, P, Louboutin, JP, Leger, JM and Brouet, JC (1997) A randomised clinical trial comparing interferon-alpha and intravenous immunoglobulin in polyneuropathy associated with monoclonal IgM. The IgM-associated Polyneuropathy Study Group. J. Neurol. Neurosurg. Psychiatry, 63: 28–34. Mendell, JR, Sahenk, Z, Whitaker, JN, Trapp, BD, Yates, AJ, Griggs, RC and Quarles, RH (1985) Polyneuropathy and IgM monoclonal gammopathy: studies on the pathogenetic role of antimyelin-associated glycoprotein antibody. Ann. Neurol., 17: 243–254. Nakanishi, T, Sobue, I, Toyokura, Y, Nishitani, H, Kuroiwa, Y, Satoyoshi, E, Tsubaki, T, Igata, A and Ozaki Y (1984) The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology, 34: 712–720. Nemni, R, Fazio, R, Quattrini, A, Lorenzetti, I, Mamoli, D and Canal, N (1993) Antibodies to sulfatide and to chondroitin sulfate C in patients with chronic sensory neuropathy. J. Neuroimmunol., 43: 79–85. Nobile-Orazio, E, Barbieri, S, Baldini, L, Marmiroli, P, Carpo, M, Premoselli, S, Manfredini, E and Scarlato, G (1992) Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies. Acta Neurol. Scand., 85: 383–390. Nobile-Orazio, E, Manfredini, E, Carpo, M, Meucci, N, Monaco, S, Ferrari, S, Bonetti, B, Cavaletti, G, Gemignani, F, Durelli, L, Barbieri, S, Allaria, S, Sgarzi, M and Scarlato, G (1994) Frequency and clinical correlates of anti-neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy. Ann. Neurol., 36: 416–424. Nobile-Orazio, E, Meucci, N, Baldini, L, Di Troia, A and Scarlato, G (2000) Long-term prognosis of neuropathy associated with anti-MAG IgM M-proteins and its relationship to immune therapies. Brain, 123: 710–717. Notermans, NC, Wokke, JH, Lokhorst, HM, Franssen, H, van der Graaf, Y and Jennekens FG (1994) Polyneuropathy associated with monoclonal gammopathy of undetermined significance. A prospective study of the prognostic value of clinical and laboratory abnormalities. Brain, 117: 1385–1393. Notermans, NC, Wokke, JH, van der Berg, LH, van der Graaf, Y, Franssen, H, Teunissen, LL and

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Lokhorst, HM (1996) Chronic idiopathic axonal polyneuropathy. Comparison of patients with and without monoclonal gammopathy. Brain, 119: 421–427. Ohi, T, Kyle, RA and Dyck, PJ (1985) Axonal attenuation and secondary segmental demyelination in myeloma neuropathies. Ann. Neurol., 17: 255–261. Pestronk, A, Li, F, Griffin, J, Feldman, EL, Cornblath, D, Trotter, J, Zhu, S, Yee, WC, Phillips, D, Peeples, DM and Winslow, B (1991) Polyneuropathy syndromes associated with serum antibodies to sulfatide and myelin-associated glycoprotein. Neurology, 41: 357–362. Quarles, RH (1980) Glycoproteins from central and peripheral myelin. In: GA Hashim (Ed.), Myelin: Chemistry and Biology, Liss, New York, pp. 55–77. Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force (1991) Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology, 41: 617–618. Ritz, M, Erne, B, Ferracin, F, Vital, A, Vital, C and Steck, AJ (1999) Anti-MAG IgM penetration into myelinated fibers correlates with the extent of myelin widening. Muscle Nerve, 22: 1030–1037. Ropper, AH and Gorson, KC (1998) Neuropathies associated with paraproteinemia. N. Eng. J. Med., 338: 1601–1607. Rowland, LP, Sherman, WL, Hays, AP, Lange, DJ, Latov, N, Trojaborg, W and Younger, DS (1995) Autopsy-proven amyotrophic lateral sclerosis, Waldenstrom’s macroglobulinemia, and antibodies to sulfated glucuronic acid paragloboside. Neurology, 45: 827–829. Seligmann, M, Preud’homme, JL and Brouet, JC (1976) Surface cell markers in human lymphoid malignancies. Recent Results Cancer Res., 56: 91–97. Sherman, WH, Latov, N, Hays, AP, Takatsu, M, Nemni, R, Galassi, G and Osserman, EF (1983) Monoclonal IgM kappa antibody precipitating with chondroitin sulfate C from patients with axonal polyneuropathy and epidermolysis. Neurology, 33: 192–201. Shibasaki, H, Ohnishi, A and Kuroiwa, Y (1982) Use of SEPs to localize degeneration in a rare polyneuropathy: studies on polyneuropathy associated with pigmentation, hypertrichosis, edema, and plasma cell dyscrasia. Ann. Neurol., 12: 355–360. Silverstein A and Doniger DE (1963) Neurologic complications of myelomatosis. Arch. Neurol., 147: 534–544.

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Yeung, KB, Thomas, PK, King, RH, Waddy, H, Will, RG, Hughes, RA, Gregson, NA and Leibowitz, S (1991) The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinemia. Comparative clinical, immunological and nerve biopsy findings. J. Neurol., 238: 383–391.

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CHAPTER 37

Charcot–Marie–Tooth disease and related disorders Barbara E. Shapiroa,*, Mark C. Hannibal and Phillip F. Chanceb a

Neuromuscular Research, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, OH, USA b Neurogenetics Laboratory, Division of Genetics and Developmental Medicine, University of Washington School of Medicine, WA, USA

37.1. Overview Charcot–Marie–Tooth (CMT) neuropathy (also called Hereditary Motor and Sensory Neuropathy; HMSN) is a heterogeneous group of inherited diseases of peripheral nerves (Dyck et al., 1993a). Collectively, CMT is a common disorder affecting both children and adults and, in some cases, may lead to significant disability. An estimated 1 in 2500 persons has a form of CMT, establishing it as a major diagnostic category within neurogenetic diseases (Skre, 1974). Modes of inheritance seen in CMT include autosomal dominant, autosomal recessive and X-linked forms. The various chromosomal locations, causal genes and genetic mechanisms underlying forms of CMT and related disorders are given in Table 37.1. The onset of symptoms in CMT is most often during the first or second decade of life, although it may be delayed until adulthood. For some forms of CMT, presymptomatic individuals who have inherited the disorder may be detected by electrodiagnostic (EDX) studies as early as infancy (see below). Although both motor and sensory nerves are affected in all forms of CMT, motor function is generally significantly more impaired. The principal clinical features of CMT include distal muscle weakness and atrophy, impaired sensation and absent or hypoactive deep tendon reflexes. Variation in clinical phenotype (both intrafamilial and interfamilial) is wide and may range from patients with severe distal weakness and atrophy with marked hand and foot deformity, to individuals whose only clinical finding is pes cavus with minimal or no * Correspondence to: Barbara E. Shapiro, M.D., Ph.D., Associate Professor of Neurology, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 441065098, USA. E-mail address: [email protected] Tel.: (216)844-7768; fax: (216)844-7624.

distal muscle weakness. Most often, patients are afflicted with signs and symptoms related to muscle loss and weakness, typically involving the lower legs and feet, then later progressing to affect the hands and distal forearms. A history of steppage gait with tripping and falling is typically elicited. Patients may also present with complaints related to foot deformity (pes cavus or high-arched feet; hammer toes), that results from loss of intrinsic muscles of the feet. In some instances, CMT patients may report sensory-related problems, such as limb pain, numbness or paresthesias. In contrast to muscle weakness-related problems, such complaints are usually less common, despite unequivocally impaired sensation on examination. In some patients, a postural tremor affecting the upper limbs is present. 37.2. Classification systems for CMT A current classification system for CMT disease divides this group of disorders into those having apparent Schwann cell dysfunction leading to loss of peripheral nervous system myelin (known as demyelinating CMT, CMT type 1 or “CMT1”) and those forms with putative axonal degeneration (known as axonal CMT, CMT type 2 or “CMT2”) (Dyck et al., 1993a). Individuals with CMT1 have reduced motor and sensory nerve conduction velocities (NCVs) on EDX testing (typically less than 38–40 m/s in the upper limbs) and the pathological finding of hypertrophic demyelinating neuropathy (“onion bulbs”). In contrast, patients with CMT2 may be expected to have normal or near normal NCVs, with axonal neuropathy and relative preservation of the myelin sheath. Another phenotype, manifesting in infancy with marked slowing of NCVs (typically less than 10 m/s) is referred to as Dejerine-Sottas disease (DSD) or CMT3. CMT4 is used to designate rare autosomal recessive forms that may be demyelinating or axonal and CMTX refers to an X-linked form.

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Table 37.1 Genetic spectrum of inherited neuropathies

Charcot–Marie–Tooth Type 1 (HMSNI) CMT1A CMT1B CMT1C CMT1D Charcot–Marie–Tooth Type 2 (HMSNII) CMT2A CMT2B CMT2C CMT2D CMT2E CMT2B1 Dejerine-Sottas (CMT 3, HMSNIII) DSD

Charcot–Marie–Tooth (Other) CMTX CMT4A CMT4B CMT1 AR D (HMSNLom) Congenital Hypomyelination CH Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) HNPP

Locus

Gene

Mode

17p11.2–p12 1q22–q23 16p12–p13 10q21–q22

PMP22 P0 SIMPLE EGR2

AD AD AD AD

1p35–p36 1p35–36 3q13–q22 12q23–q24 7p14 8p21 11q21

KIF1B MFN2 RAB7 Unknown GARS NEF-L LMNA

AD AD AD AD AD AD AR

17p11.2–p12 1q22–23 10q21–q22

PMP22 P0 EGR2

AD AD AD

Xq13.1 8q13–q21 5q23–q33 11q13 8q24

Cx32 GDAP1 Unknown MTMR2 NDRG1

X-linked AR AR AR AR

1q22–q23 10q21–q22

P0 EGR2

AD AR

17p11.2–p12

PMP22

AD

Genetic spectrum of inherited neuropathies. Abbreviations: PMP22 (peripheral myelin protein 22), P0 (myelin protein zero); SIMPLE (small integral membrane protein of late endosome); Cx32 (connexin32), EGR2 or Krox-20 (early growth response 2 gene); GDAP1 (ganglioside-induced differentiation-associated protein-1); MTMR2 (myotubularin-related protein-2); SBF2 (set binding factor 2); NDRG1 (N-myc-downstream regulated gene 1); KIFIB (kinesin); RAB7 (small GTP-ase late endosomal protein gene 7); GARS (glycyl tRNA synethase); NEF-L (neurofilament, light chain); LMNA (lamin A/C); MFN 2 (mitofusin-2).

Another frequently used system of classification within CMT designates this group of disorders as hereditary motor and sensory neuropathies (HMSN). Under this system HMSNI refers to CMT1 and HMSNII refers to CMT2. Other less frequently diagnosed forms of HMSN include HMSNIII (also called Dejerine-Sottas disease or CMT3, see below) and HMSNIV (also known as Refsum disease, see Chapter 38) (Dyck et al., 1993a). Other rare forms include HMSN Type V, that refers to patients with spastic paraplegia and peripheral neuropathy. The pathology in these cases is quite heterogeneous. Sural nerve biopsies have shown onion bulb formation, loss of myelinated fibers or no specific pathology. Yet another form,

HMSNVI, refers to patients with peripheral neuropathy and optic atrophy, and HMSN VII refers to patients with peripheral neuropathy and retinitis pigmentosa. 37.3. Electrodiagnostic testing in CMT Electrodiagnostic studies play a pivotal role in the diagnosis of inherited neuropathies. It is important to obtain EDX testing on all probands, persons at risk, and parents, if possible. Once a peripheral polyneuropathy is established by EDX testing, it can often be further categorized as primary demyelinating vs. axonal loss (see Chapter 10). Axonal loss polyneuropathies are characterized by low to absent compound motor action

CHARCOT–MARIE–TOOTH DISEASE AND RELATED DISORDERS

potentials (CMAPs) with normal or slightly slowed nerve conduction velocities (NCVs), and sensory nerve action potentials (SNAPs) that are either reduced in amplitude or absent. In contrast, demyelinating polyneuropathies are characterized by marked slowing of conduction velocities and prolonged distal latencies. Furthermore, inherited demyelinating neuropathies, particularly CMT1, have uniform and symmetric conduction velocity slowing comparing different nerves from side to side and different segments of nerves such as proximal vs. distal. In contrast, acquired demyelinating neuropathies typically have non-uniform, asymmetric conduction velocity slowing. Another cardinal feature of acquired demyelinating neuropathies is the presence of conduction block along motor nerves at non-entrapment sites (Lewis and Sumner, 1982; Lewis et al., 2000). Conduction block is virtually diagnostic of an acquired and potentially treatable demyelinating disorder and excludes an inherited disorder. Temporal dispersion with proximal stimulation of motor nerves is also seen in acquired demyelinating peripheral neuropathies, though in rare cases may also be seen in severe inherited demyelinating peripheral neuropathies where the CMAP amplitudes are low (Jones et al., 1996; Lewis et al., 2000). The specific EDX findings seen in each of the major forms of CMT are discussed with each disorder below. 37.4. Major forms of demyelinating CMT (CMT1) 37.4.1. Genes for CMT1 Autosomal dominant is the most frequently encountered mode of inheritance in CMT1. Furthermore, the majority of CMT1 pedigrees are linked to chromosome 17p11.2–12 and are designated as CMT1A (Vance et al., 1989). Genetic linkage studies have also indicated that some CMT1 pedigrees demonstrate linkage to the long arm of chromosome 1 (Bird et al., 1983), and are designated as CMT1B. Pedigrees with autosomal dominant CMT1 that maps to chromosome 16p13 are designated as CMT1C (Street et al., 2002). CMT1D pedigrees are linked to chromosome 10q21–q22 (Warner et al., 1998). 37.4.2. CMT1A 37.4.2.1. Etiology and pathogenesis The locus for CMT1A maps to chromosome 17p11.2–p12 (Vance et al., 1989) and is associated with a tandem DNA duplication (Lupski et al., 1991;

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Raeymaekers et al., 1991). The size of the duplication is approximately 1.5 megabases (Mb) and it has been detected in many ethnic groups (Raeymaekers et al., 1992). The duplication in most pedigrees is inherited as a stable Mendelian trait; however in some instances, it may arise as a de novo event. Nine of ten patients with sporadic CMT1 had evidence of de novo genesis of the 17p11.2–12 duplication (Hoogendijk et al., 1992). Therefore, the de novo duplication in CMT1A may actually account for some cases of CMT1, which were thought to occur on the basis of an autosomal recessive mode of inheritance. When seen as a de novo event the duplication results more commonly from an error in spermatogenesis, however approximately 10% of de novo cases may have resulted from an error in oogenesis (Blair et al., 1996). The duplication is also associated with the generation of a novel 500-kb SacII junctional fragment, detected by markers mapping within the duplicated region (Lupski et al., 1991). The majority of patients with both inherited and de novo CMT1A associated with the duplication have a novel fragment of approximately the same size. Features consistent with CMT1A were detected in patients with either partial or complete trisomy 17p, providing direct support for a hypothesis that the duplication in CMT1A has phenotypic consequences through a gene dosage mechanism (Chance et al., 1992; Lupski et al., 1992). The trembler mutation (Tr) in mouse is a dominant disorder, which results in a hypomyelinating neuropathy and is a murine model for CMT1A (Falconer, 1951). A gene for the Tr locus was identified when a point mutation was found in the peripheral myelin protein-22 (PMP22) gene (Suter et al., 1992), which is expressed in Schwann cells. These observations in Tr mouse suggested that the human PMP22 gene might map to chromosome 17p11.2–12 in the region of the CMT1A gene, and might actually be the critical gene for CMT1A. PMP22 was found to map to the CMT1A gene region (Matsunami et al., 1992). The PMP22 gene encodes a 160-amino acid membrane-associated protein with a predicted molecular weight of 18 kilodalton (kDa) that is increased to 22 kDa by glycosylation. The PMP22 protein is localized to the compact portions of peripheral nerve myelin, contains four putative transmembrane domains, and is highly conserved in evolution (Fig. 37.2) (Patel et al., 1992; Snipes et al., 1992, 1995). It is postulated that the neuropathy phenotype in patients with the 17p11.2–12 duplication results from having three copies of PMP22 leading to a speculated 50% increase

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in expression at this locus (Chance et al., 1992). Studies of sural nerve biopsy specimens taken from CMT1A patients suggested that PMP22 message and protein levels are increased in comparison to that of normal persons (Yoshikawa et al., 1994; Gabriel et al., 1997; Schenone et al., 1997). Missense mutations within the PMP22 gene have been found in rare patients lacking the commonly associated DNA duplication (Valentijn et al, 1992; Roa et al., 1993; Navon et al., 1996). Interestingly, the point mutation in one family is identical to that found in the Tr-J mouse, a variant of Tr. Given the marked degree of clinical variation seen in patients with the duplication it is difficult to draw generalizations regarding the clinical phenotype resulting from various point mutations as opposed to that caused by the duplication (Gabreels-Festen et al., 1995). The expression level of PMP22 is crucial for proper myelination of peripheral nerves, as seen by the effects of trisomic overexpression (CMT1A) and monosomic underexpression (hereditary neuropathy with liability to pressure palsies (HNPP; see below). It is therefore possible that mutations mapping outside the PMP22 coding region that influence transcription levels of the PMP22 gene or the stability of the PMP22 mRNA may also lead to a demyelinating phenotype.

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37.4.2.2. Clinical presentation Patients typically present in early childhood, with a classic foot deformity (pes cavus and hammer toes though pes planus can also be seen) (Fig. 37.1B), or in some cases a delay in motor milestones. Weakness, if present, affects the lower leg anterior compartment muscles early in the disease. Over time, weakness and wasting of the anterior compartment muscles may lead to footdrop and a steppage gait (Fig. 37.1A). Some patients describe muscle cramps. Deep tendon reflexes are absent at the ankles and usually depressed or absent at the knees. In more advanced cases, there is wasting and weakness of the intrinsic hand muscles (Fig. 37.1C) and deep tendon reflexes are depressed or absent in the upper extremities. Mild sensory loss affecting large fiber modalities is noted in the lower extremities, despite the absence of sensory complaints. Kyphoscoliosis can be seen. The peripheral nerves are often enlarged and palpable, especially the brachial plexus in the upper arm, and the greater auricular nerve in the neck (Fig. 37.1D). Cranial nerve and long tract signs are notably absent. 37.4.2.3. Laboratory findings In patients with CMT1, cerebrospinal fluid (CSF) may show a moderate elevation of protein in over half of all cases, without pleocytosis. Pathology of peripheral

Fig. 37.1 Physical findings in Charcot–Marie–Tooth disease. (A)Wasting of the anterior compartment muscles of the legs. (B) Pes cavus. Note the high-arched, foreshortened foot. (C) Wasting of the intrinsic hand muscles. (D) Enlargement of the great auricular nerve. Reproduced from Rosenberg (Ed.), (1998) Hereditary neuropathies and CMT syndrome (Atlas of Clinical Neurology, 2.14 with permission from Current Medicine, Philadelphia).

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Fig. 37.2 Localization of myelin components in mammalian sheaths in the central nervous system and peripheral nervous system. Mutations in myelin protein zero (P0) (Charcot–Marie–Tooth type 1B [CMT-1B], Dejerine-Sottas disease [DSD], congenital hypomyelination), peripheral myelin protein-22 (PMP-22) (CMT-1A), DSD, hereditary neuropathy with liability to pressure palsies), and connexin32 (Cx32) (CMT-X). Intracellular and extracellular refer to the cytoplasm of the myelinating Schwann cell. (MBP = myelin basic protein; PLP = proteolipid protein; MAG = myelin-associated glycoprotein.) (Reproduced from Lewis et al. (2000) Electrophysiological features of inherited demyelinating neuropathies: a reappraisal in the era of molecular diagnosis. Muscle Nerve, 23: 1472–1487 reprinted with permission of John Wiley and Sons, Ltd).

nerve shows segmental demyelination with concentric proliferation of Schwann cells and onion bulb formation. Unmyelinated fibers are not affected. Peripheral nerve biopsy is no longer a standard part of the evaluation of CMT1 given the characteristic EDX findings and the availability of clinical DNA testing. Imaging of the lumbar spine either with CT myelography or MRI scanning may show enlargement of the cauda equina and ganglia, and may be more common in patients homozygous for the PMP22 duplication (Pareyson et al., 2003). 37.4.2.4. Electrodiagnostic findings Nerve conduction studies in CMT1A show marked uniform slowing of conduction velocity in all nerves, usually below 70% of the lower limit of normal. The EDX findings in CMT1 subtypes (A through D) are essentially indistinguishable from each other (Bird et al., 1997). In most patients with CMT1A, median and ulnar conduction velocities range between 15 and 30 m/s with occasional patients reaching a NCV of 40 m/s (Kaku et al., 1993a, 1993b). Maximal slowing evolves during the first three to five years with little change after

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that (Garcia et al., 1998). Slowing has been documented in patients as young as six months of age, and is generally evident by the age of two, making nerve conduction studies extremely helpful in early diagnosis (Thomas, 1999). Hence, in any patient two years of age or older who is suspected of CMT1 with normal nerve conduction velocities, the diagnosis is essentially excluded. Distal latency may increase during the first 10 years. Because conduction velocity slowing is seen uniformly along all segments of nerve in CMT1A, EDX studies that measure proximal segments of nerve as well as proximal nerves also reveal marked slowing. Accordingly, minimal F-response latencies, all components of the blink reflex, facial nerve latencies, and phrenic nerve latencies are markedly prolonged in CMT1A (Ito et al., 1998; Glocker et al., 1999; Lewis et al., 2000; Sagliocco et al., 2003). In one study of facial nerve function, marked conduction velocity slowing was noted in patients with CMT1 and DSD without any clinical evidence of facial palsy. Slowing was noted in both the extracranial and intracranial segments of the facial nerve, using standard surface recording and stimulating electrodes and transcranial magnetic stimulation, respectively (Glocker et al., 1999). In a study of phrenic nerve function in patients with CMT1A between the ages of 10–58 with no respiratory complaints or respiratory compromise, the average distal latency was markedly prolonged at 18.6 ms (compared with 6.05 ms for the control group), in the setting of normal CMAP amplitudes (Sagliocco et al., 2003). Brainstem auditory evoked potentials have also shown a high incidence of peripheral acoustic nerve involvement in patients with CMT1 (Scaioli et al., 1991). As in most demyelinating polyneuropathies, there is some secondary axonal loss. Accordingly, CMAP amplitudes are absent or low in the lower extremities and borderline or low in the upper extremities. While there is often little correlation between the degree of conduction velocity slowing and clinical disability, CMAP amplitude reduction is more closely related to disability, since it is a marker of axonal loss (Krajewski et al., 2000). In addition, there is no relationship between conduction velocity slowing and sex, age, severity of disease, and length of symptomatic disease (Kaku et al., 1993a, 1993b; Krajewski et al., 2000). Axonal loss has also been demonstrated in distal muscles in patients with CMT1A using motor unit number estimation (MUNE) as an endpoint measure, employing the spike-triggered averaging technique (Lawson et al., 2003; Lewis et al., 2003), and

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may be a more sensitive measure of axonal loss than CMAP amplitude. Despite earlier suggestions to the contrary, conduction block is not a feature of CMT1 in general, and CMT1A in particular (Kaku et al., 1993a, 1993b). Failure to achieve supramaximal stimulation at proximal sites, due to exceptionally high threshold, may account for some of the drop in proximal amplitudes reported (Lewis et al., 2000). Excessive temporal dispersion (>20% increase in duration) with proximal stimulation is also extremely rare in CMT1, more commonly seen in DSD (see below). Sensory potentials are often absent due to the more profound effect of phase cancellation on SNAPs than CMAPs. When recorded, they are often low in amplitude with slowing in latencies, similar to the motor latencies (Krajewski et al., 2000). Using quantitative sensory measures, vibration and thermal thresholds are most affected in patients with CMT1 (Ericson et al., 1999). Needle electromyography (EMG) typically shows evidence of distal reinnervation (long, large, polyphasic motor unit action potentials [MUAPs]) with little active denervation (fibrillation potentials, positive sharp waves). Magnetic stimulation studies have shown normal central motor conduction times in patients with CMT1 (Claus et al., 1990), and somatosensory evoked potentials have shown normal central sensory conduction times in CMT1 (Scaioli et al., 1991; Aramideh et al., 1992). Autonomic tests of heart rate and blood pressure control were normal in one study of patients with CMT1, though impaired sweating function was found in the extremities, suggesting dysfunction of sympathetic fibers in the peripheral nerves (Ingall et al., 1991). 37.4.3. CMT1B The clinical presentation in CMT1B is identical to that seen in CMT1A (Lewis et al., 2000). Mutations in the human myelin protein zero gene (P0) that was mapped to chromosome 1q22–q23 are the molecular basis of CMT1B (Hayasaka et al., 1991, 1993a). P0 is the major structural component of peripheral nervous system myelin (approximately 50% of protein mass) and represents approximately 7% of Schwann cell message (Lemke, 1993). P0 is a member of the immunoglobulin gene super-family of cell adhesive molecules and localizes to the compact portion of peripheral nerve myelin (Fig. 37.2). P0 protein is composed of 248 amino acids constituting an intracellular

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and a glycosylated extracellular domain with a single transmembrane segment. Analysis of P0 as a candidate gene for CMT1B revealed point mutations in affected individuals from pedigrees with this disorder (Hayasaka et al., 1993), including different point mutations (Asp90Glu and Lys96Glu) in the two pedigrees originally linked to chromosome 1. The point mutations in these families fully cosegregated with the CMT1B phenotype suggesting that abnormalities in the P0 gene are responsible for CMT1B. Numerous additional mutations in P0 associated with CMT1B pedigrees have been described (Nelis et al., 1994; Gabreels-Feston et al., 1996; Warner et al., 1996), firmly establishing mutations in this crucial component of peripheral nerve myelin as the molecular basis of CMT1B. 37.4.3.1. Electrodiagnostic findings The EDX findings in CMT1B are virtually indistinguishable from CMT1A (see above) (Bird et al., 1997). 37.4.4. CMT1C Genetic mapping studies in two families with autosomal dominant CMT1 that was unlinked to chromosome 1 or 17 detected a locus for this disorder on chromosome 16p13.1–p12.3, designated as CMT type 1C (CMT1C) (Chance et al., 1990; Street et al., 2002). Affected individuals in these families manifest characteristic CMT1 symptoms including high-arched feet, distal muscle weakness and atrophy, depressed deep tendon reflexes, sensory impairment, slow nerve conduction velocities and nerve demyelination. Mutations in the lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF/SIMPLE) gene are the molecular basis of CMT1C (Street et al., 2003). In the three families described the phenotype cannot be distinguished from that seen in other forms of CMT1 (Street et al., 2003). The precise biological function of LITAF/SIMPLE is unknown. LITAF/SIMPLE mRNA is detected in sciatic nerve but in contrast to other genes causing CMT1, its expression level is not altered after nerve injury. Originally described as a transcription factor involved in TNF alpha gene regulation (Myokai et al., 1999), further analysis indicates that LITAF/SIMPLE encodes a small integral membrane protein of lysosomes/late endosomes (Moriwaki et al., 2001). It has been proposed that altered lysosomal function and protein degradation may have an impact on myelin development and maintenance based on the upregulation of this pathway in the Tr-J mouse

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(Notterpek et al., 1997). If this idea proves correct, mutated LITAF/SIMPLE may exert its effect through a similar mechanism (Street et al., 2003). 37.4.4.1. Electrodiagnostic findings The EDX findings in CMT1C are virtually indistinguishable from CMT1A (see above) (Bird et al., 1997). 37.4.5. CMT1D Autosomal dominant mutations in the zinc-finger transcription factor EGR2/Krox20 have been found in patients with severe forms of demyelinating CMT1 and DSD (Warner et al., 1998; Bellone et al., 1999). Congenital Hypomyelination (CH) Warner et al., 1998) is another severe demyelinating neuropathy of infantile-onset that shows absence of peripheral nervous system (PNS) myelin from birth. EGR2/Krox20 is a zinc-finger transcription factor with a crucial role in the regulation of PNS myelination and Krox20deficient mice show a total lack of myelin (amyelination) (Topilko et al., 1994). Overexpression of EGR2/ Krox20 in Schwann cells lead to increased expression of MPZ, PMP22, GJB1/Cx32, periaxin (PRX) and other myelin-related genes. EGR2/Krox20 mutations leading to CMT1 or DSD may act through a toxic gain-of-function mechanism as heterozygous murine EGR2/Krox20-deficient animals are normal. 37.4.5.1. Electrodiagnostic Findings The EDX findings in CMT1D are virtually indistinguishable from CMT1A (see above) (Bird et al., 1997). 37.5. Dejerine–Sottas disease 37.5.1. Clinical features Dejerine–Sottas disease (DSD; also called HMSNIII or CMT3) is a severe, infantile and childhood onset, hypertrophic demyelinating polyneuropathy (Dyck et al., 1993a). Patients with DSD present in infancy or early childhood. Infants may present with hypotonia, although the more common presentation is a delay in reaching motor milestones, foot deformities (pes cavus; club foot), and primarily distal weakness with ataxia. Weakness progresses during childhood to involve the thighs, trunk, and upper extremities. Many patients do not achieve ambulation. Weakness in the hands may result in a characteristic claw hand deformity. Areflexia is common. Sensory loss involving large fiber

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modalities may be so marked as to result in pseudoathetosis. Peripheral nerves are enlarged, especially at the brachial plexus and greater auricular nerve. Kyphoscoliosis may be seen. Other associated features may include sensorineural hearing loss, short stature, facial weakness, pupillary abnormalities and nystagmus. The clinical features of DSD overlap with those of severe CMT1. For this reason, it may be strongly debated whether the continued clinical separation of CMT1 and DSD is warranted. 37.5.2. Genetic features Molecular genetic studies indicate that DSD may be associated with point mutations in the P0 or the PMP22 genes (Hayasaka et al., 1993b; Roa et al., 1993) although pedigrees have been described that lack mutations in either the P0, the PMP22 or the connexin32 (Cx32) gene (see below) (Rautenstrauss et al., 1994). Analysis in two pedigrees with DSD identified mutations in PMP22 (Met69Lys and Ser72Leu), both located within the second transmembrane segment (Hayasaka et al., 1993b). On the other hand, mutations in clinically typical patients with DSD have also been detected in the P0 gene (Roa et al., 1993). In an analysis of two unrelated patients with DSD, apparent de novo mutations were identified in the extracellular domain (Ser63Cys) and within the transmembrane portion (Gly163Arg) in the P0 gene. A third patient with DSD had a de novo insertional mutation in exon 6 (Rautenstrauss et al., 1994). Interestingly, in patients with the DSD phenotype studied to date, all mutations have been present in the heterozygous state, suggesting that DSD is caused by dominantly acting genetic defects. Many patients with DSD appear to represent sporadic (isolated) cases and are usually thought to result from an autosomal recessive gene. Point mutation in the P0 gene is also a mutational mechanism for congenital hypomyelinating neuropathy (CHN), an even more severe form of DSD (Warner et al., 1996). 37.5.3. Laboratory findings In patients with DSD, marked elevation in CSF protein is present in the majority of patients. The cauda equina and ganglia may also be enlarged on imaging of the lumbar spine. Peripheral nerve biopsy reveals hypomyelination, demyelination, and large onion bulb hypertrophy. Peripheral nerve biopsy is not usually part of the evaluation of DSD, given the characteristic EDX findings and the availability of clinical DNA testing.

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37.5.4. Electrodiagnostic findings In DSD, nerve conduction studies are rather homogeneous among patients, and show uniformly markedly slow conduction velocities along all nerves, as low as 2–6 m/s. In nearly all the cases, motor conduction velocities in the upper extremities are below 10 m/s, although median motor conduction velocities as high as 21 m/s are described in some patients (Roa et al., 1993). Distal motor latencies are commonly six to seven times normal. Ulnar distal latencies as long as 25 to 50 ms have been reported. Thus, if longer sweep speeds are not used, the motor responses may be incorrectly recorded as absent. Marked conduction velocity slowing is also seen in the extracranial and intracranial segments of the facial nerve (Glocker et al., 1999). The CMAP amplitudes in the upper extremities are low, usually below 20% the lower limit of normal for age, and are usually absent in the lower extremities. SNAPs are typically absent. In one study of 11 patients with DSD, the ulnar CMAP duration increased 40.6 ± 20.8%, the area decreased 31.9 ± 18.3%, and the amplitude decreased 31.8 ± 10.22%. In some patients, the CMAP area dropped more than 50% between proximal and distal sites (Miller et al., 1985; Miller, 1985). Most feel that this drop represents pseudoconduction block, and that the more accepted criteria for conduction block are not valid for nerves with conduction velocities below 10 m/s and very low CMAP amplitudes. Because of the low CMAP amplitudes, F-responses are generally not obtainable. In addition, nerves are generally difficult to stimulate and supramaximal stimulation may be difficult to achieve. With the profound slowing, marked temporal dispersion, usually a sign of an acquired demyelinating neuropathy, has been noted. This, along with the pseudo-conduction blocks, makes the differentiation from acquired demyelinating neuropathies at times difficult. EMG testing usually shows varying amounts of active denervation (positive sharp waves and fibrillation potentials) with reduced recruitment of somewhat large, prolonged, polyphasic motor unit action potentials. However, EMG may be essentially normal in children, reflecting the pure hypomyelination/demyelination nature of DSD in some children, with sparing of the motor axons (Jones et al., 1996).

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37.6. Hereditary neuropathy with liability to pressure palsies 37.6.1. Overview Hereditary neuropathy with liability to recurrent pressure-sensitive palsies (HNPP; also called tomaculous neuropathy) is an autosomal dominant disorder that produces painless episodic, recurrent, focal demyelinating nerve palsies (Windebank, 1993). HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome and other entrapment neuropathies may be frequent manifestations of HNPP. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or “sausage-like” formations. Mild overlap of clinical features with Charcot–Marie–Tooth disease type 1 (CMT1) may lead HNPP patients to be misdiagnosed as having CMT1. HNPP is most often caused by a 1.5 megabase pair (Mb) deletion on chromosome 17p11.2–p12 (Chance et al., 1993). 37.6.2. Clinical features in HNPP HNPP was first described by De Jong in 1947, and results in entrapment or compressive neuropathies in some cases preceded by minor compression or trauma of the affected peripheral nerve. The most vulnerable sites are the wrist, elbow, knee and shoulder, affecting the median, ulnar and peroneal nerves and brachial plexus respectively (De Jong, 1947; Windebank, 1993). A history of limb trauma or prolonged positioning of the limb may be obtained in some cases. The onset of HNPP is usually in childhood or adolescence, with a high degree of penetrance; however, clinically asymptomatic obligate gene carriers are sometimes noted. When palsies occur they may be debilitating, lasting for days to weeks, and may require use of a lower limb brace or ankle-foot orthosis in cases of prolonged peroneal palsies. Hypoactive deep tendon reflexes and mild pes cavus may be observed in clinically asymptomatic patients. The spectrum of clinical presentation in HNPP is quite broad and variable and may range from clinically asymptomatic or subclinical to, more typically, recurrent palsies and in some advanced cases progressive residual deficits mimicking indolent forms of CMT1 (Windebank, 1993). Guidelines for the diagnosis of

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HNPP have been reported previously (Dubourg et al., 2000). The typical presentation is that of recurrent peripheral mononeuropathies that develop during adolescence, causing attacks of numbness, muscular weakness, and atrophy after minor compression or trauma. Sometimes there is no identifiable precipitating factor (Mouton et al., 1999). Peroneal palsies at the fibular neck and ulnar neuropathies at the elbow are common. Some patients experience acute and transient purely sensory symptoms such as paresthesias in the lateral femoral cutaneous nerve distribution. Facial nerve involvement is noted rarely, although in some cases recurrent facial palsy may be the initial clinical manifestation in isolation (Poloni et al., 1998). Some patients experience recurrent painless brachial plexopathies, which tends to occur more commonly in women than men (Mouton et al., 1999). These can be distinguished from patients with hereditary neuralgic amyotrophy who experience recurrent painful brachial plexopathies. Other patients have a progressive mononeuropathy or a polyneuropathy that clinically resembles CMT1, with pes cavus, distal weakness and sensory loss, and absent ankle jerks. Some patients are asymptomatic, although neurologic examination reveals subtle signs of pes cavus or absent ankle reflexes (Amato et al., 1996; Mouton et al., 1999). While most patients present in adolescence or early adulthood, rarely patients experience initial symptoms in childhood or after the age of 50. Men present at an earlier age than women. Phenotypic heterogeneity may be noted within families. The clinical features are similar in those patients with and without the 1.5-Mb deletion (Amato et al., 1996). In an analysis of 39 HNPP patients from 16 unrelated pedigrees, two thirds of patients had the typical presentation of acute mononeuropathy and the remaining subjects were thought to have features consistent with a more long-standing polyneuropathy. Furthermore, it was noted that over 40% of affected persons were unaware of their illness and 25% of patients were essentially symptom free at the time of observation (Pareyson et al., 1996). In a study of the clinical and neurophysiological findings in 99 patients with HNPP (Mouton et al., 1999), the majority of patients (70%) presented with a typical history of a single, focal episode of neuropathy; however there were patients with short term or chronic sensory syndromes, as well as asymptomatic gene carriers. Rarely patients with HNPP may present with a more fulminant course in which palsies affecting more than one

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limb are seen (Crum et al., 2000). Other rare associations with HNPP include a report of central nervous system demyelination (Amato et al., 1996). Very few studies have addressed the epidemiology of HNPP; one such study from Western Finland reported a prevalence of 16 cases per 100 000 (Meretoja et al., 1997). 37.6.3. Genetic features in HNPP The genetic locus for HNPP maps to chromosome 17p11.1–12, where it is most commonly associated with a 1.5 Mb (megabase pair) DNA deletion (Chance et al., 1993), exactly the region that had been shown to be duplicated in CMT1A. In a study of 156 patients with HNPP, 84% were found to have the associated DNA deletion (Nelis et al., 1996). HNPP deletions and CMT1A duplications of different sizes have been observed, although they are very rare. The 1.5 Mb region as well as the deletions and duplications of “aberrant” size harbor the peripheral myelin protein-22 (PMP22) gene. The PMP22 gene encodes a 160-amino acid membrane-associated protein with a predicted molecular weight of 18 kDa that is increased to 22 kDa by glycosylation (Manfioletti et al., 1990). PMP22 protein is localized to the compact portion of peripheral nerve myelin, contains four putative transmembrane domains, and is highly conserved in evolution (Patel et al., 1992). In addition to the common DNA deletion, nine point mutations have been reported in HNPP, including a 2-basepair (bp) deletion, one single bp deletion, a single bp insertion, three point mutations, and two splice site mutations (Nicholson et al., 1994). 37.6.4. Histopathological features in HNPP In 1972, Behse and colleagues documented the pathological features of HNPP (Behse et al., 1972). Histological assessment of sural nerve biopsies reveals segmental de- and remyelination. The presence of tomacula or “sausage” shaped structures is an important pathological signature of HNPP. Tomacula consist of massive redundancy or overfolding of variable thickness layers in the myelin sheath (Madrid and Bradley, 1975). It should be noted that tomacula are not likely to be a pathognomonic feature of HNPP. They may also be seen in Charcot–Marie–Tooth neuropathy type 4B (with myelin outfolding), IgM paraproteinemic neuropathy, chronic inflammatory

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demyelinating polyneuropathy and Dejerine–Sottas disease (Sander et al., 2000). While tomacula are generally considered an important diagnostic feature of HNPP, rare patients showing axonal regeneration and lacking tomacula have been observed (Sessa et al., 1997). 37.6.5. Origin of the HNPP deletion/CMT1A duplication The mechanism underlying the generation of the CMT1A DNA duplication and HNPP deletion has been the subject of numerous investigations. Since the vast majority of the duplications and deletions in unrelated patients and in de novo duplication/deletion patients are the exact same size, it is hypothesized that a precise, recurring mechanism may account for the generation of the duplicated CMT1A chromosome and the deleted HNPP chromosome (Chance et al., 1994). It was proposed that the deleted chromosome in HNPP and the duplicated chromosome in CMT1A are the reciprocal products of unequal crossing over, a likely mechanism for generating the DNA duplication and the deletion. A low-copy number repeat sequence (CMT1A-REP element) was identified flanking the 1.5Mb segment on chromosome 17p11.2–p12 (Pentao et al., 1992). The CMT1A-REP sequence that is an intrinsic structural property of a normal chromosome 17, appears to mediate misalignment of homologous chromosomal segments during meiosis, with subsequent crossing over to produce the CMT1A duplication or HNPP deletion. Analysis of de novo rearrangements leading to either the CMT1A duplication or the HNPP deletion suggests that this result of unequal crossing over between homologous chromosomes occurs during spermatogenesis. However, analysis of de novo HNPP deletions suggests that they may be also generated by unequal sister chromatid exchange during oogenesis (Lopes et al., 1997). The origin of the CMT1A-REP repeat has been investigated through an analysis of homologous sequences in nonhuman primates. The CMT1A-REP repeat arose during primate evolution. Southern blot analysis indicated that the chimpanzee has two copies of a CMT1A-REP-like sequence, whereas the gorilla, orangutan, and gibbon have a single copy. These observations suggest that the CMT1A-REP sequence appeared as a repeat before the divergence of chimpanzee and human, but after gorilla and human around six to seven million years ago (Kiyosawa and Chance, 1996; Keller et al., 1999).

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37.6.6. Laboratory findings In patients with HNPP, peripheral nerve biopsy reveals focal thickenings of the myelin sheaths, tomacula, as described earlier. However, peripheral nerve biopsy is not usually part of the evaluation of HNPP given the characteristic EDX findings and availability of clinical DNA testing. 37.6.7. Electrodiagnostic findings In HNPP, EDX studies show a demyelinating polyneuropathy characterized by prolonged distal motor latencies out of proportion to forearm or leg conduction velocities or F-wave latencies. These findings may be seen in clinically affected patients, as well as in asymptomatic gene carriers. The prolonged distal latencies imply a predominantly distal myelinopathy, although in one study of 12 patients with HNPP, only the median and peroneal distal motor latencies were prolonged, while distal ulnar and tibial latencies were minimally prolonged or normal, as were distal latencies to more proximal muscles (Li et al., 2002). Superimposed entrapment neuropathies are noted at typical sites, such as the ulnar nerve at the elbow and the peroneal nerve at the fibular head (Amato et al., 1996; Pareyson et al., 1996; Mouton et al., 1999; Anderson et al., 2000; Li et al., 2002; Hong et al., 2003). While focal motor conduction velocity slowing is common at entrapment sites, conduction block across entrapment sites is relatively uncommon, occurring in 2–22% of nerves in most series (Magistris and Roth, 1985; Uncini et al., 1995; Hong et al., 2003). Variation in the incidence of conduction block in various studies may be due to different criteria used to determine conduction block, and the time course between the onset of clinical symptoms and when the nerve is studied. It should be emphasized that the lack of conduction block does not preclude the diagnosis of HNPP. The SNAPs are reduced in amplitude and slowed or may be absent (Anderson et al., 2000; Hong et al., 2003). When the SNAPs are present, the distally accentuated slowing is also noted. In one study, mean sensory NCV was 85.6% ± 10.6% of the lower limit of normal, and significantly slower than sensory conduction velocities in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) (Anderson et al., 2000). The EDX features of HNPP are similar in those patients with and without the 1.5-Mb deletion,

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although one study showed that patients without the deletion have longer distal peroneal motor latencies, while those with the deletion have slower ulnar motor conduction velocities (Amato et al., 1996). Asymptomatic patients with HNPP show similar EDX findings to symptomatic patients (Gouider et al., 1995; Mouton et al., 1999). In one study, reduced SNAPs and focal motor slowing at the elbow were less frequently seen in asymptomatic patients (who tended to be younger than symptomatic patients), but when asymptomatic patients older than 15 years were studied, the EDX findings were similar to the symptomatic patients (Mouton et al., 1999). The prominent distal slowing, focal slowing, and occasional conduction blocks across entrapment sites result in an asymmetrical nerve conduction pattern which may be confused with an acquired demyelinating polyneuropathy such as CIDP. However, nerve conduction velocity slowing and conduction blocks across non-entrapment sites, as seen in CIDP, are not seen in HNPP. This pattern is also strikingly different from the uniform slowing of nerve conduction velocities seen in patients with CMT1. 37.7. Major forms of axonal CMT (CMT2) 37.7.1. Overview CMT2 is less common than CMT1, accounting for approximately 30% of all hereditary motor and sensory neuropathies (Harding and Thomas, 1980). Many loci are identified that cause CMT2 in different families, with both autosomal dominant (designated CMT2) and autosomal recessive inheritance (AR-CMT2 or CMT4C). The X-chromosome linked hereditary motor and sensory neuropathies may also show NCVs in the normal range, further confusing the clinical and genetic evaluation. While PMP22 gene duplication in CMT1A, MPZ(P0) mutations in CMT1B or GJB1(Cx32) mutations in CMTX are fairly common, it is unclear at the present time whether mutations in any single gene will be a common cause of autosomal dominant CMT2. It is possible that GDAP1 mutations (see below) may emerge as a relatively frequent cause of autosomal recessive CMT2 (CMT4C). In general, CMT2 has a later age of onset, produces less involvement of the intrinsic muscles of the hands, and lacks palpably enlarged nerves. Extensive demyelination with “onion bulb” formation is not present in CMT2. Axonal pathological changes consist of a loss of large myelinated axons and signs of regeneration with abundant small thinly-myelinated axons (Dyck et al., 1993a).

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A subset of patients who were initially thought to have CMT2 because of only mild slowing of NCVs, has been found to have CMT1 or CMTX with MPZ(P0) or GJB1(Cx32) mutations, respectively (Marrosu et al., 1998). When 49 patients with a clinical and histopathological diagnosis of CMT2 were examined for mutations in the P0 gene, three heterozygous single nucleotide changes were detected: Asp61Gly, Tyr119Cys, and Thr124Met. (Senderek et al., 2000). Interestingly, Cx32 mutations (see below) have been inferred to be the underlying genetic defect in a subset of patients with CMTX, initially thought to have CMT2 (Timmerman et al., 1996). 37.7.2. Laboratory findings Extensive demyelination with “onion bulb” formation is not present in CMT2. Axonal pathological changes consist of a loss of large myelinated axons and signs of regeneration with abundant small thinly-myelinated axons (Thomas et al., 1996). Clinical DNA testing is not widely available for most forms of CMT2, but a few reference laboratories will sequence the NEFL gene that causes CMT2E. Also, sequencing of the GDAP1 gene is available for recessive forms of CMT that span the range of phenotypes: severe demyelinating CMT4A, severe axonal CMT4C4 with vocal cord paresis and severe axonal or intermediate CMT4C5 without accessory features. 37.7.3. Electrodiagnostic findings Motor nerve conduction studies in most forms of CMT2 reflect that this is a primary axonal peripheral neuropathy. NCVs are generally normal or only slightly slowed in affected persons. CMAP amplitudes are usually low in amplitude or absent in the lower extremities, and normal or low in amplitude in the upper extremities. SNAPs are absent or low in the lower extremities. EMG testing usually shows mild active denervation (positive waves and fibrillation potentials), along with signs of chronic reinnervation including reduced recruitment of large, prolonged, polyphasic motor unit action potentials. Axonal loss has also been demonstrated in a distal to proximal gradient in patients with CMT2 employing motor unit number estimation (MUNE) as an endpoint measure, using the spike-triggered averaging technique (Lewis et al., 2003). These findings are consistent with a length-dependent axonal degeneration, and may be a more sensitive measure of axonal loss than CMAP amplitude.

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Using quantitative sensory measures, vibration and thermal thresholds were most affected in patients with CMT2 (Dyck et al., 1993b; Ericson et al., 1999). Magnetic stimulation studies indicate normal central motor conduction times in patients with CMT2 (Claus et al., 1990). Autonomic tests of heart rate and blood pressure control were normal in one small study of patients with CMT2, though impaired sweating function was found in the extremities, suggesting dysfunction of sympathetic fibers in the peripheral nerves (Ingall et al., 1991). 37.7.4. CMT2A Genetic linkage studies in three CMT2 families established a locus for CMT2A on chromosome 1p35–p36 (Ben et al., 1993b). A subsequent analysis of 11 CMT2 families found only one was linked to 1p35–p36 (Timmerman et al., 1996). A mutation in KIF1B, an axonal motor protein was found in one Japanese pedigree (Saito et al., 1997; Zhao et al., 2001). An Italian family has also been linked to this 1p35–p36 locus (Muglia et al., 2001). The reported age of onset varied widely in this family, from 1 year to 50 years, with a trend of earlier onset in the youngest generation. EDX testing in this family revealed a primary axonal peripheral neuropathy: median motor conduction velocity ranged from 40 to 64 m/s, median sensory amplitudes were low in about half the patients, and peroneal motor and sural sensory responses were absent in the lower extremities. On EMG, mild denervation with reduced recruitment of motor unit action potentials was noted in the distal muscles of all patients studied. More recently mutations in the Mitofusin gene 2 (MFN2) were identified in seven families, demonstrating that MFN2 mutations are possibly more common in CMT2A (Züchner et al., 2004). MFN2 is a mitochondrial GTPase that is ubiquitously expressed (Santel and Fuller, 2001). MFN2 is located in the outer mitochondrial membrane and regulates the mitochondrial membrane and regulates the mitochontrial network architecture by fusion of mitochondria. Homozygous MFN2 knockout mice are not viable and die in midgestation due to placental defect while heterozygote mice are reported to be phenotypically normal (Chen et al, 2003). 37.7.5. CMT2B Limb ulceration is a prominent feature of CMT2B. The gene for CMT2B maps to chromosome 3q13–q22 (Kwon et al., 1995) and results from mutations in the RAB7 gene (Verhoeven et al., 2003). RAB7 is a member

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of the Rab family of ras-related GTPases that are involved in intracellular membrane trafficking. The onset of CMT2B is in the second or third decade of life. The degree of neuropathy ranges from mild to severe, with distal muscle weakness and wasting often preceding the onset of sensory loss, foot ulceration, infections and amputations of the toes. It has been argued that CMT2B could be classified as a hereditary sensory and autonomic neuropathy, but motor features are a common feature to the families with RAB7 missense mutations. 37.7.6. CMT2C Further genetic heterogeneity within CMT2 is evidenced by the identification of kindreds with the features of axonal neuropathy, weakness of the diaphragm, and vocal cord paralysis. Such pedigrees carry the designation of CMT2C, which has been mapped to chromosome 12q23–q24 (Klein et al., 2003). The onset of CMT2C is typically slow and insidious, with respiratory symptoms and alterations in voice. The muscles of the hand become weak and atrophic, but leg weakness may often be asymptomatic. EDX testing reveals an axonal sensorimotor peripheral neuropathy. NCVs are generally normal or mildly slowed in affected persons. CMAP amplitudes are low in amplitude or absent in the lower extremities, and normal or low in amplitude in the upper extremities. SNAPs are absent or low in the lower extremities. EMG testing shows mild active denervation (positive sharp waves and fibrillation potentials) with chronic reinnervation including reduced recruitment of large, prolonged, polyphasic motor unit action potentials (Dyck et al., 1993b). Phrenic nerve stimulation reveals low or absent CMAP amplitudes in the majority of patients (Dyck et al., 1993b). Laryngeal EMG examination of one patient with CMT2C revealed fibrillation potentials and reduced recruitment of large, polyphasic motor unit action potentials in some, but not all, laryngeal muscles (Dray et al., 1999). 37.7.7. CMT2D Presenting with predominantly upper limb involvement, CMT2D maps to chromosome 7p14 (Ionasescu et al., 1996), and results from mutations in the glycyl tRNA synthetase gene (GARS) (Antonellis et al., 2003). Onset of CMT2D in one North American family was in the second or third decade of life, with sensory deficits reaching the same prevalence as motor impairment. The degree of progression in CMT2D

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seems to be mild. Four mutations in GARS have been reported, and some families show evidence of distal hereditary motor neuropathy 5/distal spinal muscular atrophy V (HMN V/dSMA-V), proving these are allelic disorders (Antonellis et al., 2003). 37.7.8. CMT2E In a large Russian pedigree having an autosomal dominant axonopathy, a CMT2 gene was mapped to chromosome 8p21 (designated CMT2E) and a mutation was found in the neurofilament-light (NEFL) gene (Mersiyanova et al., 2000). A nonconservative missense mutation (A998C; Gln333Pro) in the neurofilament light chain gene (NEFL) cosegregates with CMT2E (Mersiyanova et al., 2000). The NEFL gene encodes a protein, which is one of three major NF protein constituents. The NEFL Gln333Pro mutation site is located within the coil 2B domain of the NEFL protein, the last and largest of four coil domains that form the rod region. Supporting evidence of the single-point mutation found within the Russian pedigree comes from murine studies. A Leu394Pro mutation in the same coil domain in the mouse orthologue resulted in a severe peripheral neuropathy. Interestingly, NEFL null mice do not have a CMT-like phenotype, suggesting a dominant gain-of-function mechanism for these NEFL mutations. A second Slovenian family has been identified with a slowly progressive CMT with onset in the first decade of life (Georgiou et al., 2002). Distal leg involvement precedes distal arm involvement, and all patients were ambulatory 20–30 years after disease onset. A Pro22Ser missense mutation was found to segregate with CMT2 disease. NEFL mutations have also been associated with CMT1 type F (CMT1F) (De Jonghe et al., 2001; Jordanova et al., 2003) with some patients in these pedigrees having near normal NCVs, suggesting that phenotypic overlap between CMT1 and CMT2 may occur with an identical mutation in a family. 37.7.9. CMT2F A single Russian family has been reported with typical CMT2 with onset in the second and third decade of life, initial lower limb involvement and slowly progressive disability. Mild to moderate sensory deficits, including pain and temperature, occur in the feet and hands. Lifespan was not decreased. Linkage analysis identified a locus on chromosome 7q11–q21 (Ismailov et al., 2001). On EDX testing, the findings were consistent

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with an axonal sensorimotor peripheral neuropathy (Ismailov et al., 2001).

37.8. Other rare forms of CMT (CMT4) 37.8.1. General comments Rare autosomal recessive families with motor and sensory neuropathy have been reported, particularly in Tunisian families with parental consanguinity. Both demyelinating and axonal types have been described, and given the designation CMT4 or CMT AR. One form of autosomal recessive demyelinating neuropathy has been mapped to chromosome 8q13–q21 (CMT4A) (Ben Othmane et al., 1993a). Another form, CMT4B, has been mapped to 11q22 and is associated with mutations in the myotubularin-related protein-2 gene (MTMR2) (Bolino et al., 2000). Typically, these autosomal recessive forms of CMT are more severe than their autosomal dominant counterparts. Recently, the gene responsible for hereditary motor and sensory neuropathy-Lom (HMSNL) was identified (Kalaydjieva et al., 2000). HMSNL occurs in groups of Romani (Gypsy) that are descended from a small founder population—the Vlax, or Danubian Roma. Mutation analysis of genes in this region identified the N-myc downstream-regulated gene 1 (NDRG1) as the gene responsible for HMSNL, by the presence of a premature termination codon at position 148. 37.8.2. CMT4C1 A consanguineous Moroccan family defined a new locus for an autosomal recessive, axonal neuropathy on chromosome 1q21.2–1q21.3 (Bouhouche et al., 1999). Affected members of the family had severe onset in the second decade of life with rapid evolution extending to involvement of the proximal muscles in six of nine individuals. Three of these severely affected individuals developed kyphoscoliosis. In four consanguineous Algerian families, a founder mutation was identified in the LMNA gene encoding Lamin A/C nuclear envelope protein. In addition to classical features of CMT, five of eight individuals have weakness and amyotrophy of proximal muscles of the pelvic girdle. Four patients developed moderate dorsal scoliosis less than 4 years after symptom onset (Tazir et al., 2004). Lamin A/C mutations may lead to a variety of disorders, including dominant or recessive Emery-Dreifuss muscular dystrophy, dominant limb-girdle muscular

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dystrophy type 1B, dominant dilated cardiomyopathy with atrioventricular conduction defect, and dominant Dunnigan type familial partial lipodystrophy. EDX findings are consistent with an axonal sensorimotor peripheral neuropathy (Bouhouche et al., 1999). 37.8.3. CMT4A and CMT4C4 CMT4C4 is a recessive axonal neuropathy with severe childhood onset and vocal cord paresis. It is due to mutations in the GDAP1 gene, encoding gangliosideinduced differentiation-associated protein-1 (Cuesta et al., 2002). It is clear now that a spectrum of allelic neuropathies is associated with mutations in GDAP1 and linked to chromosome 8q21.1. CMT4A, a recessive demyelinating CMT, was the first phenotype found with GDAP1 mutations in four Tunisian families (Baxter et al., 2002). The first CMT4C4 families reported were of Spanish ancestry, and affected individuals were often nonambulatory at the end of the first decade of life, and developed hoarseness and signs of vocal cord paresis in the second decade of life (Cuesta et al., 2002; Sevilla et al., 2003). One family had a C487T transition in exon 4 that generated a nonsense mutation designated Q163X; all affected individuals were homozygous for this mutation. A proband from a second family was heterozygous for the Q163X mutation and a C581G transversion in exon5 that generated another nonsense mutation, S194X. The proband from the third family was also heterozygous for the Q163X mutation and an insertion 863insA in exon 6 that leads to a frameshift and truncation of the coding region designated T288fsX290. Segregation of these mutations in the family confirmed Mendelian inheritance. A consanguineous Moroccan family was found to have homozygous S194X mutations present in affected sisters (Nelis et al., 2002). The chromosome region surrounding GDAP1 showed a common haplotype to the Spanish family with CMT4C and heterozygous S194X/Q163X mutations. The axonal phenotype did not include vocal cord paresis. However, the two children in the Moroccan family had yet to reach the second decade of life at which hoarseness and signs of vocal cord paresis developed in the Spanish family. A third report of a Moroccan family confirms the axonal nature of CMT4C4 and the vocal cord paresis (Azzedine et al., 2003). The two affected siblings shared the previously reported S194X nonsense allele and a novel G929C transversion in exon 6 causing a R310Q missense allele. This latter mutation is in the glutathione

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S-transferase domain of GDAP1. One affected member of the family was nonambulatory by 20 years of age and developed paralysis of one hemidiaphragm as an adult in his thirties. EDX findings in patients with GDAP1 mutations reveal great variability in nerve conduction velocities, reflecting the wide range of neuropathologic abnormalities, sometimes within the same family (Nelis et al., 2002). Some patients (CMT4C4) have normal or only slightly slowed nerve conduction velocities with reduced or absent CMAP amplitudes being an early sign, and low or absent SNAPs, consistent with an axonal sensorimotor peripheral neuropathy. EMG examination shows active denervation (fibrillation potentials, positive sharp waves) and chronic reinnervation. Others (CMT4A) have markedly slowed conduction nerve conduction velocities with reduced or absent CMAPs and SNAPs, consistent with a primarily demyelinating sensorimotor peripheral neuropathy (Nelis et al., 2002). EMG examination shows chronic reinnervation in distal muscles. 37.9. DI-CMT: dominant intermediate forms CMT 37.9.1. DI-CMTA DI-CMTA is an autosomal dominant CMT with intermediate features between a pure demyelinating and axonal phenotype. Often, nerve pathology is mixed: on EDX testing, measures of motor nerve conduction velocities span the cutoff of 38 m/s in the upper extremities, and axonal degeneration will be seen with onion bulb formation. A previously reported Italian family (Rossi et al., 1985) defined the locus for DI-CMTA when linkage analysis mapped it to 10q24.1–q25.1 (Verhoeven et al., 2001). Onset begins in the first and second decades of life with slow progression. There appears to be more rapid progression in the fifth decade with severe distal weakness in the lower leg and hands, however no cases have been wheelchair bound. Peripheral nerve biopsies showed prevalent demyelinating features, including onion bulbs and myelin splits with uncompacted and irregularly enlarged lamellae. These were typically located at the Schmidt-Lantermann incisures and in the paranodal region. Axonal features were also described with regeneration clusters, large fiber loss, Bungner’s bands and unmyelinated fiber involvement (Malandrini et al., 2001). On EDX testing, the median motor NCVs fell into the range of 25–45 m/s.

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37.9.2. DI-CMTB DI-CMTB is another autosomal dominant CMT with intermediate features described in a large, four-generation Australian family (Kennerson et al., 2001). Little clinical data are available to document the natural history in this family. Linkage of the locus for DI-CMTB to chromosome 19p12–p13.2 was demonstrated. Sural nerve biopsy showed axonal degeneration, loss of large-diameter fibers, rare segmental demyelination and remyelination with onion bulb formation (Kennerson et al., 2001). On EDX testing, median motor NCVs ranged from 24 to 54 m/s. 37.10. HMSN-P (HMSNO) Hereditary Motor and Sensory Neuropathy, proximal type, HMSN-P is an autosomal dominant disorder with a founder on the Japanese island of Okinawa (Takashima et al., 1997). Eight families were described with proximal muscle weakness occurring after 30 years of age, absent deep tendon reflexes and sensory disturbances. Linkage analysis in these families identified a locus at chromosome 3p14.1–q13. Muscle cramps in the extremities or abdominal muscles were the most common initial symptom. Fasciculations were noted early in the course of this disorder, primarily in the truncal and extremity muscles. Mild peripheral dysesthesia was the most common sensory symptom. Weakness was progressive with relative sparing of neck flexor and extensor muscles. Most were nonambulatory 5 to 20 years after disease onset. Some have required artificial ventilation. With advanced disease, muscle strength is preserved only in the cranial nerve area-these patients are difficult to clinically distinguish from those with amyotrophic lateral sclerosis. Sural nerve biopsy showed a marked decrease of large myelinated fibers and a moderate decrease of small myelinated fibers. There were no onion bulbs. One autopsy study showed loss of neurons in the dorsal root ganglia, severe loss of anterior horn cells and loss of myelinated fibers in the dorsal funiculus and peripheral nerves. Associated findings included creatine kinase elevation (average 301 ± 243 IU/L, normal 26–200 IU/L), type II hyperlipidemia, and diabetes mellitus. Seven of sixteen had non-insulin-dependent diabetes mellitus and four had impaired glucose tolerance (Takashima et al., 1997). EDX testing showed peripheral nerve axonal degeneration. Sensory nerve action potentials were absent or reduced. Posterior tibial nerve conduction velocities

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were slowed, but median motor NCVs were normal except in one patient in whom no action potentials were detected. 37.11. X-linked CMT (CMTX) 37.11.1. Overview CMTX is a common neuropathy with features of a demyelinating neuropathy, absence of male-to-male transmission, and an earlier age of onset and faster rate of progression in males. CMTX accounts for approximately 10% of all patients thought to have a type of demyelinating CMT (i.e., CMT1). CMTX should be suspected when the commonly associated chromosome 17 duplication is not present and there is no history of father-to-son transmission of the neuropathy. 37.11.2. Genetic features of CMTX The gene for CMTX maps to chromosome Xq13–q21 and results from point mutations in the gap junction beta-1 gene (GJB1), also known as the connexin-32 (Cx32) gene (Bergoffen et al., 1993). GJB1/Cx32 encodes a major component of gap junctions and is expressed in peripheral nerves. Cx32 protein is structurally similar to PMP22, the protein involved in CMT1A. Both proteins contain four putative transmembrane domains in similar orientation. Over 200 different mutations in the GJB1/Cx32 gene have been described in patients with CMTX, and the distribution pattern of these mutations suggests that all parts of the connexin32 protein are functionally important (Bone et al., 1997). GJB1/Cx32 has a pattern of expression in peripheral nerve similar to that of other structural myelin genes, that is, the expression of GJB1/Cx32 is immediately down regulated following crushed or transected nerve experiments. However, immunohistochemical studies show a different localization for the Cx32 protein. Unlike PMP22 and MPZ(P0) that are present in compact myelin, Cx32 is located at uncompacted folds of Schwann cell cytoplasm around the nodes of Ranvier and at Schmidt-Lanterman incisures (Bergoffen et al., 1993). This localization suggests a role for gap junctions composed of Cx32 in providing a pathway for the transfer of ions and nutrients around and across the myelin sheath. Mutations in the Cx32 protein have been suggested to alter its cellular localization and its trafficking and interfere with cell-to-cell communication (Deschenes et al., 1997; Yoshimura et al., 1998).

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37.11.3. Laboratory findings It remains to be determined whether CMTX is a primarily axonal loss or demyelinating disorder. Some have reported pathologic findings consistent with axonal loss (Hahn et al., 1990; Birouk et al., 1998), while others have reported findings consistent with a primary demyelinating neuropathy (Mostacciuolo et al., 1991; Nicholson et al., 1993; Bahr et al., 1999). DNA testing is clinically available for GJB1/Cx32 mutations causing CMTX. Associated central nervous system (CNS) findings have been reported in some patients, including transient and reversible neurologic deficits (weakness, numbness, abnormalities of cranial nerves, dysarthria, aphasia) associated with reversible, confluent white matter lesions seen on MRI of the brain (Panas et al., 1998; Hanemann et al., 2003; Taylor et al., 2003). 37.11.4. Electrodiagnostic findings The EDX findings in CMTX are complicated, with significant gender differences. Motor NCVs in males are, in general, more reduced than in females, and often fall in the intermediate range, usually between 30 and 40 m/s in the upper extremities. Females may have normal NCVs or mild or intermediate slowing (Birouk et al., 1998). CMAP amplitudes are often low in median, ulnar and peroneal nerves with intermediate slowing. SNAPs are abnormal in most patients, especially in the lower extremities. EMG examination shows rare active denervation (fibrillation potentials, positive sharp waves) with chronic reinnervation (reduced recruitment of large motor unit action potentials) in distal muscles. Some studies have shown subclinical EDX abnormalities along CNS pathways in patients with CMTX (Nicholson et al., 1996; Bahr et al., 1999). In a study of one large family with CMTX and a novel Asn205Ser mutation in the Cx32 gene, abnormalities were found along motor and sensory CNS pathways on visual and brainstem auditory evoked potentials, and along central motor pathways with transcortical magnetic stimulation testing (Bahr et al., 1999). Interestingly, no white matter lesions were noted on brain MRI of the index patient, who was the only patient tested. 37.12. Differential diagnosis in CMT and related disorders The differential diagnosis of CMT1 and 2 includes other genetic metabolic and multisystem disorders

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that present in childhood, adolescence, or early adulthood and result in neurologic syndromes associated with peripheral neuropathy and foot deformities. The spinocerebellar ataxias including Friedreich’s Ataxia and the leukodystrophies (see Chapter 38) should be considered in the differential diagnosis. However, these disorders can usually be distinguished from CMT through careful neurologic examination looking for long tract, cranial nerve, or cerebellar signs that are not seen in CMT. Other inherited peripheral neuropathies must also be considered. Patients with Refsum disease have a demyelinating peripheral neuropathy that may resemble CMT1 clinically and electrophysiologically (see Chapter 38). CSF protein is commonly elevated in Refsum disease, and may be markedly elevated (100–700 mg/dl). Peripheral nerve pathology demonstrates demyelination with onion bulb formation, as in CMT1. However, other features are present including retinitis pigmentosa, lens opacities, ichthyosis, sensorineural hearing loss and ataxia that are not seen in CMT1. Phytanic acid is elevated in the serum. HNPP and CMT may be confused with one another. However, patients with HNPP will usually give a history of recurrent pressure palsies occurring either spontaneously or with minimal trauma, such as recurrent foot drop from leg crossing, that differentiates them from CMT. Furthermore, EDX testing differentiates HNPP from CMT1 and CMT2. In CMT1, there is marked uniform slowing of NCV in all nerves, both proximally and distally. In CMT2, NCVs are normal or slightly reduced. In contrast, in HNPP the distal latencies are prolonged out of proportion to the mildly reduced or normal NCVs. Hereditary sensory and autonomic neuropathy must also be considered in the differential diagnosis of CMT, although autonomic and sensory manifestations should distinguish this from CMT1. However, a rare phenotype of CMT2 (CMT2B), as mentioned above, presents with primarily sensory rather than motor symptoms. Patients with distal spinal muscular atrophy (SMA) or inherited forms of distal myopathy have distal leg weakness that may be accompanied by foot drop and pes cavus, mimicking CMT. However, these disorders can usually be easily distinguished from CMT by the lack of sensory impairment on neurologic examination, and normal sensory nerve action potentials (SNAPs) on EDX testing. Joint contractures that may be seen in the distal form of SMA, are not seen in CMT. Juvenile onset amyotrophic lateral sclerosis must also be considered, although the presence of long

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track signs and lack of sensory impairment on neurologic examination will usually distinguish this disorder from CMT. Acquired forms of immune-mediated demyelinating neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) that may present in childhood or early adolescence must also be differentiated from CMT1 and HNPP. CSF protein may be elevated in each of these disorders. However, EDX testing should differentiate an acquired from an inherited demyelinating neuropathy such as CMT1 or HNPP. In acquired demyelinating neuropathy, the EDX findings are asymmetric from limb to limb, with conduction velocity slowing and prolonged latencies noted in some nerves but not others. Conduction block may be noted at non-entrapment sites, which are not seen in inherited demyelinating neuropathies. Hereditary neuralgic amyotrophy (HNA) may also be confused with HNPP. HNA is an autosomal dominant disorder that presents with recurrent episodes of brachial plexopathy. Unlike HNPP, however, the brachial plexopathy associated with HNA is painful, and there is no evidence of a generalized peripheral polyneuropathy, or multiple or recurrent compressive mononeuropathies. A subset of families with HNA display mildly dysmorphic features including hypotelorism, a long nasal bridge, and upslanting palpebral fissures. The gene for HNA maps to chromosome 17q25 (Pellegrino et al., 1996; Stogbauer et al., 1997). Multifocal motor neuropathy with conduction block (MMN) should also be differentiated from HNPP. MMN is an autoimmune-mediated predominantly motor disorder, often more prominent in the distal upper extremities, with motor conduction blocks at non-entrapment sites on EDX testing. A lack of sensory impairment on neurologic examination, normal sensory nerve action potentials on EDX testing, and the chronic progressive rather than recurrent nature of the disorder should help distinguish it from HNPP. Peripheral neuropathy secondary to a variety of systemic illnesses that may present in childhood such as renal failure, and neuropathy secondary to chronic toxin exposure such as lead should also be considered. These can usually be sorted out through an evaluation for systemic illness or toxin exposure. The differential diagnosis of patients with Dejerine–Sottas Disease includes a host of genetic disorders that may present as a floppy infant, including CHN, severe phenotypes of CMT1, leukodystrophies, spinal muscular atrophy (Werdnig-Hoffman

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disease), and other disorders present with hypotonia and weakness in infancy. 37.13. Clinical evaluation and diagnosis Careful neurologic evaluation including family history usually suggests the diagnosis of some form of CMT. Prior to performing genetic testing on individuals and family members, an accurate diagnosis of neuropathy, consistent with a form of CMT (CMT1, CMT2, CMTX, etc.), should be established. As noted above, other causes of peripheral polyneuropathies (e.g. heavy metal poisoning, immune neuropathies) should be considered and, if necessary, excluded. Environmental exposures may involve multiple family members, thereby possibly mimicking a hereditary illness. Since CMT is usually a chronic, slowly progressive disease, one should be suspicious of cases that seemingly have a rapid course of deterioration. While sensory loss is common, sensory complaints such as tingling, burning or pain are uncommon and suggest an acquired neuropathy. The neurological findings show tremendous variability between families and among patients within the same family with CMT, and possibly even more variability in gene carriers for HNPP. In mild cases of CMT, the only physical findings may include mild pes cavus and depressed deep tendon reflexes. Examination of multiple family members for subtle signs of polyneuropathy may help to establish the diagnosis. 37.14. General approach to the patient The pedigree is of paramount import and may assist in making the diagnosis. The genetic counseling given will depend not only upon the accuracy of diagnosis, but also the type of CMT and the mode of inheritance. For example, the occurrence of male-to-male transmission excludes the possibility of CMTX. The sporadic male can be especially difficult to evaluate, as the pattern of inheritance could be autosomal dominant, X-linked, or even autosomal recessive. Sporadic cases may also represent de novo duplications (CMT1A), or de novo deletions (HNPP). False paternity is another explanation for apparent sporadic CMT or HNPP. For this reason, if possible both parents should be examined clinically and by EDX methods in order to determine if there is any evidence for neuropathy. If a proband has evidence for CMT1, determination of NCV is a useful screening tool for parents and other at risk family members.

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Studies have determined that the CMT1 gene is penetrant in early life and correct disease status can probably be determined with NCV screening by the age of five years (Nicholson, 1991). However, if a proband’s NCVs are normal or only mildly slowed, the diagnosis may be CMT2. In this case, the EDX screening exam will need to focus on determination of sensory and motor amplitudes, to look for axonal loss (low or absent CMAP and SNAP amplitudes with normal or mildly slowed NCVs), and other EDX signs of denervation such as large, re-innervated MUAPs. Note, however, that patients with CMTX may be misdiagnosed with CMT2 based on NCV values. The overwhelming proportion of CMT1 and CMT2 pedigrees have autosomal-dominant inheritance. In pedigrees that lack male-to-male inheritance or cases in which males are apparently more severely affected than females and have an earlier onset, CMTX should be suspected. CMTX should also be suspected in males with transient CNS events and reversible white matter lesions on MRI scan of the brain. Determination of autosomal dominant versus X-linked CMT is important as genetic counseling for these two modes of inheritance is different. For autosomal dominant CMT the likelihood of an affected parent (of either sex) having an affected child is 50% for each pregnancy regardless of the sex of the child. For CMTX, all daughters of an affected father will inherit the gene, and none of the sons will carry the gene or be affected. For a woman with CMTX there is a 50% likelihood of her having affected children regardless of their sex. However, heterozygous females are generally less clinically affected than hemizygous males. In CMT1 that is autosomal dominant, first-degree relatives should be examined as early as possible. It has been estimated that 70–80% of patients with a clinical diagnosis of CMT1 carry the 17p11.2–12 duplication (Wise et al., 1993; Ionasescu, 1995). The DNA duplication is highly specific for CMT1A and may provide a useful marker for screening suspected patients and at risk family members. DNA testing for CMT1A is available and has become an accepted part of the evaluation of patients with suspected hereditary neuropathies. The 1.5-Mb deletion of 17p11.2–12 is highly specific for HNPP. On the whole, the duplication appears to account for the vast majority of CMT1A patients as does the deletion account for the majority of HNPP patients. However, rare patients with either CMT1A or HNPP have DNA sequence alterations in the PMP22 gene (see above). In reality, however, there have been very few point mutations

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detected in the PMP22 gene in patients who lack the duplication. Given a consistent clinical picture, intermediate NCVs, and lack of male-to-male transmission, a search for mutations in the cx32 gene is justified. Sequencing of the P0 gene for mutations associated with CMT1B or of the PMP22 gene for mutations associated with CMT1A or DSD is available. DNA testing for CMT1B has recently become more widely available, and should be carried out in patients in whom the more commonly encountered chromosome 17p11.2–12 duplication or less common point mutations associated with CMT1A are not found. Strictly speaking, there is very limited laboratory testing available for any form of CMT2, although specific genetic abnormalities have been identified for several forms within this group of disorders. The decision as to whether or not CMT2 patients should be routinely screened for mutations in either the P0 or the Cx32 genes is a difficult one. It should be kept in mind that some apparently mild acting mutations in either of these genes (typically associated with demyelinating neuropathies) may lead to minimal demyelination and a clinical picture suggestive of an axonal neuropathy (i.e. CMT2). 37.15. Treatment and management 37.15.1. CMT Patients with CMT frequently benefit from physical therapy where indicated, including heel cord strengthening and stretching exercises. Application of anklefoot orthoses (AFOs) are useful to alleviate foot drop. Some patients may actually benefit from surgical corrective procedures to the foot or toes. These latter cases should be surgical candidates only when pain or difficulty walking resulting from severe foot deformity cannot be managed by more conservative, non-surgical means. An unusual finding of enhanced neurotoxic effects of vincristine has been reported, and patients with CMT should be aware that their neuropathy may worsen with vincristine, a common chemotherapeutic agent (Hogan-Dann et al., 1984; Graf et al., 1996). 37.15.2. Treatment in HNPP There is no specific treatment for HNPP. The current therapy consists of conservative management and symptom easing measures. The first and perhaps most important element of the treatment is early detection

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and diagnosis of the disease. The knowledge that HNPP is often triggered by compression or trauma of the peripheral nerves gives the patient the possibility to avoid those movements or joint positions that most often evoke an HNPP episode. Another element of the treatment is conservative management to avoid evoking HNPP episodes. Two basic rules apply: (1) excessive force or repetitive movements should be reduced to a minimum; (2) extreme, awkward or static joint positions should be avoided. Since the wrist, elbow, knee and shoulder are the most vulnerable sites, special management rules can be considered. At the wrist (carpal tunnel), episodes are mostly caused by forceful gripping, repetitive movements or extreme wrist bending. Tools and gloves can be used to improve grip, and wrist splints can prevent extreme wrist bend during the night. At the elbow, episodes are mostly triggered by repetitive or sustained bending and by habitual leaning on the elbows. Management consists of elbow pads to reduce pressure, a headset for use during long telephone conversations, and eventually an elbow splint during the night. The most frequent trigger at the knee is habitual crossing of the legs. A lower leg brace can stabilize ankles in case this causes recurrent stretch injury at the knee. The complexity of the brachial plexus means that many factors can evoke an HNPP episode at the shoulder. Avoiding overhead work or sleeping with the arms overhead, and maintaining a good posture can reduce the risk. Surgical decompression of nerves in HNPP is controversial and must be decided on an individual basis. There is some evidence that surgical repair of carpal tunnel syndrome in HNPP is of little benefit and transposition of the ulnar nerve at the elbow may produce poor results because the nerves are especially sensitive to manipulation and minor trauma. Patients must also be warned against prolonged immobilization or unintended stretch or compression of peripheral nerves, for example during surgery. As in other neurogenetic disorders, genetic counseling is a useful adjunct to the neurologic evaluation and treatment measures. 37.16. Prognosis in CMT The prognosis for many individuals with CMT is relatively favorable and it is very important to communicate this message to patients and to give them hope. Although occasional patients with CMT1 are confined to a wheelchair, most can anticipate remaining ambulatory with the use of simple bracing and having only a mild to moderate degree of impair-

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ment in functional strength. Patients with CMT2 generally also remain ambulatory throughout their lifetime. Patients with DSD are often wheelchair bound in childhood or by adolescence. Patients with CMT and HNPP have a normal life expectancy, with the important exception of patients with CMT2C, with diaphragmatic and vocal cord involvement, who may have a shortened lifespan from complications related to respiratory and bulbar insufficiency. Other very rare forms of CMT may also be associated with a severe phenotype, including Hereditary Motor and Sensory Neuropathy, proximal type (HMSN-P), in which most patients were nonambulatory 5 to 20 years after disease onset and some required artificial ventilation, CMT4C1 in which some affected members had severe onset in the second decade of life with rapid evolution extending to involvement of the proximal muscles, some of whom developed kyphoscoliosis, and CMT4C4 in which affected individuals were often nonambulatory at the end of the first decade of life, and developed hoarseness and signs of vocal cord paresis in the second decade of life. The prognosis in HNPP is relatively benign, although rare patients develop a progressive peripheral neuropathy. Acknowledgements Supported by the Muscular Dystrophy Association, the Charcot–Marie–Tooth Association and the National Institutes of Health (NINDS). References Amato, AA, Gronseth, GS, Callerame, KJ, KaganHallet, KS, Bryan, WW and Barohn, RJ (1996) Tomaculous neuropathy: A clinical and electrophysiological study in patients with and without 1.5-Mb deletions in chromosome 17p11.2. Muscle Nerve, 19: 16–22. Anderson, PB, Yuen, E, Parko, K and So, YT (2000) Electrodiagnostic features of hereditary neuropathy with liability to pressure palsies. Neurology, 54: 40–44. Antonellis, A, Ellsworth, RE, Sambuughin, N, Puls, I, Abel, A, Lee-Lin, S-Q, Jordanova, A, Kremensky, I, Christodoulou, K, Middleton, LT, Sivakumar, K, Ionasescu, V, Funalot, B, Vance, JM, Goldfarb, LG, Fischbeck, KH and Green, ED (2003) Glycyl tRNA synthetase mutations in Charcot–Marie–Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet., 72: 1293–1299.

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Aramideh, M, Hoogendijk, JE, Aalfs, CM and Posthumus, M et al. (1992) Somatosensory evoked potentials, sensory nerve potentials and sensory nerve conduction in hereditary motor and sensory neuropathy type I. J. Neurol., 239: 277–283. Azzedine, H, Ruberg, M, Ente, D, Gilardeau, C, Perie, S, Wechsler, B, Brice, A, LeGuern, E and Dubourg, O (2003) Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. Neuromuscul. Disord., 13: 341–346. Bahr, M, Andres, F, Timmerman, V, Nelis, ME, Van Broeckhoven, C and Dichgans, J (1999) Central visual, acoustic, and motor pathway involvement in a Charcot–Marie–Tooth family an Asn205Ser mutation in the connexin 32 gene. J. Neurol. Neurosurg. Psychiat., 66(2): 202–206. Baxter, RV, Ben Othmane, K, Rochelle, JM, Stajich, JE, Hulette, C, Dew-Knight, S, Hentati, F, Ben Hamida, M, Bel, S, Stenger, JE, Gilbert, JR, Pericak-Vance, MA and Vance, JM (2002) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot–Marie–Tooth disease type 4A/8q21. Nat. Genet., 30: 21–22. Behse, F, Buchthal, F, Carlsen, F and Knappeis, GG (1972) Hereditary neuropathy with liability to pressure palsies: electrophysiological and histopathological aspects. Brain, 95: 777–794. Bellone, E, Di Maria, E, Soriani, S, Varese, A, Doria, LL and Ajmar, F et al. (1999) A novel mutation (D305V) in the early growth response 2 gene is associated with severe Charcot–Marie–Tooth type 1 disease. Hum. Mutat., 14: 353–354. Ben Othmane, K, Hentati, F, Lennon, F, Ben Hamida, C, Blel, S, Roses, AD, Pericak-Vance, MA, Ben Hamida, M and Vance, JM (1993a) Linkage of a locus (CMT4A) for autosomal recessive Charcot–Marie–Tooth disease to chromosome 8q. Hum. Mol. Genet., 2: 1625–1628. Ben Othmane, K, Middleton, LT, Loprest, LJ, Wilkinson, KM, Lennon, F, Rozear, MP, Stajich, JM, Gaskell, PC, Roses, AD and Pericak-Vance, MA et al. (1993b) Localization of a gene (CMT2A) for autosomal dominant Charcot–Marie–Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics, 17: 370–375. Bergoffen, J, Scherer, SS, Wang, S, Scott, MO, Bone, LJ, Paul, DL, Chen, K, Lensch, MW, Chance, PF and Fischbeck, KH (1993) Connexin mutations in X-linked Charcot–Marie–Tooth disease. Science, 262: 2039–2042.

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 38

Other inherited neuropathies Kevin B. Boylana,* and Vinay Chaudhryb a Department of Neurology, Mayo Clinic, FL, USA Department of Neurology, Johns Hopkins University School of Medicine, MD, USA

b

38.1. Hereditary sensory and autonomic neuropathy The hereditary sensory and autonomic neuropathies (HSAN) are rare inherited disorders categorized on clinical grounds into five types, HSAN1–5 (Dyck, 1993). Clinical manifestations of HSAN primarily involve sensory and autonomic dysfunction. Sensory features tend to predominate, accounting for earlier designation of these conditions as hereditary sensory neuropathies (HSN). The present classification was applied as autonomic involvement became recognized as a common feature (Dyck, 1993). Diagnosis is based on clinical findings and nerve biopsy, although the causative genes for several forms (discussed below) are known and genetic diagnosis for these is feasible. Treatment for all forms of HSAN1–5 is supportive. Recent data on the clinical and genetic features of HSAN1 suggest that the classification of HSAN as types 1–5 warrants revision, but the traditional nosology will be used here because it has been generally applied in the literature (Vance, 2000; AuerGrumbach et al., 2003). Among or in addition to HSAN1–5 are possible subtypes classified on clinical grounds, often reported in a single kindred lacking a specific genetic diagnosis (Thrush, 1973; Cavanagh et al., 1979; Dyck et al., 1983a, c; Donaghy et al., 1987; Dyck, 1993; Larner et al., 1994; Marbini et al., 1994; Alvarez et al., 1996; Stogbauer et al., 1999; Polo et al., 2000; Mendell, 2001b). Whether these disorders should be placed in established HSAN categories or warrant separate designation is unresolved. Classification of *Correspondence to: Kevin B. Boylan, MD, Department of Neurology, 4500 San Pablo, Road, Jacksonville, Florida 32224, USA. E-mail address: [email protected] Tel.: +1-904-953-7104; fax: +1-904-953-7233.

inherited neuropathies of this type on clinical grounds is problematic, as evidenced by the discovery that genetic heterogeneity exists for HSAN1 (Dyck and Schaid, 2000; Vance, 2000; AuerGrumbach et al., 2003). Neurophysiological testing is an important means of characterizing the various forms of HSAN as types 1–5, but specificity of neurophysiological features for a given HSAN type is subject to revision as the genetic basis of these disorders is further determined (Dyck and Schaid, 2000). In general, neurophysiological data on HSAN are limited. In many published reports few details regarding neurophysiological testing are given. In addition, some investigations occurred prior to availability of quantitative sensory testing, and in some cases, severity of sensory loss or young age of the patient precluded meaningful testing. Published neurophysiological data in most reports are from patients for whom a diagnosis of HSAN was made on clinical grounds, rather than by genetic testing. Neurophysiological testing in HSAN does not allow specific diagnosis, but is the key in examining the nature and extent of sensory and autonomic involvement. Peripheral motor abnormalities occur in these disorders and should be sought with nerve conduction studies and needle EMG, because while motor features may be obvious in some forms, in others, symptoms and physical findings may be minimal. Brief descriptions of HSAN1–5 follow, with emphasis on neurophysiological features. Clinical neurophysiological findings are outlined in Table 38.1. 38.1.1. Hereditary sensory and autonomic neuropathy1 (HSAN1) Hereditary sensory and autonomic neuropathy (HSAN1) is probably the most common form of HSAN, typically showing autosomal dominant inheritance (Dyck, 1993; Auer-Grumbach et al., 2003).

Sensory amplitudes NL/↓/ absent↓ Motor amplitudes ↓/absent; DML SL↑; CV NL to SL↓

Limited data; similar to 3q13 form

AD/3q13/(RAB7)

AD/Unknown linkage; clinically similar to 3q13 form AR/Unknown linkage

AR/9q31/IKAP

AR/3q13/NTRK1

AR & AD/unknown linkage

HSAN2

HSAN3

HSAN4

HSAN5

NL

Sensory amplitudes SL↓; CV NL/ ↓ Motor amplitudes NL/SL↓; DML NL; CV NL/SL↓ Sensory amplitudes SL↓; CV NL/ SL↓ Motor amplitudes NL/SL↓; DML NL; CV NL/SL↓

Sensory responses absent Motor amplitudes NL/↓, esp. peroneal; CV NL/SL↓

Sensory amplitudes NL/↓; CV NL Motor amplitudes NL; CV SL

AD/9q22/(SPTLC1)

HSAN1

Nerve conductions

Inheritance linkage Gene

Type

Hereditary sensory and autonomic neuropathies

Table 38.1

NL

NL

NL

NL or distal limb fibrillation potentials; MUP c/w chronic denervation

Limited data; similar to 3q13 form

NL or distal limb fibrillation potentials; MUP c/w chronic denervation

NL or distal limb fibrillation potentials; MUP c/w chronic denervation

Needle EMG

NL

Absent

NL

NL (?)

Sympathetic skin response

NL Heat; NL Cold; NL Vibration

↓Heat; ↓Cold; ↓Vibration (Vibration less impaired than heat and cold thresholds)

↓Heat; ↓Cold; ↓Vibration

↓Heat; ↓Cold; ↓Vibration

↓Heat; ↓Cold; ↓Vibration

Quantitative sensory testing

772 K.B. BOYLAN AND V. CHAUDHRY

OTHER INHERITED NEUROPATHIES

Onset is in the second decade or later. The characteristic phenotype is a progressive dying-back axonopathy affecting pain and temperature sensation, accompanied by dermal ulceration of the feet, usually the plantar surfaces. Burning, lancinating foot pain may or may not be present. Impaired sensation in the hands to temperature and pain can eventually develop. Distal limb weakness may be present. Clinical subtypes of HSAN1, some potentially with autosomal recessive or possible X-linked inheritance, are considered by some investigators to be forms of HSAN1 (Dyck, 1993). An autosomal-dominant peripheral neuropathy with prominent motor involvement in addition to severe distal sensory loss and foot ulceration, linked to chromosome 3q13, has produced disagreement as to whether the condition represents a form of HSAN1 or axonal Charcot– Marie–Tooth disease (CMT 2, HMSN 2) (Kocen and Thomas, 1970; Vance et al., 1996; Elliott et al., 1997; Vance, 2000). The 3q13 form is included in this discussion because it may, in some patients, closely resemble the more generally accepted phenotype of HSAN1, and is in the differential diagnosis of these patients (AuerGrumbach et al., 2003). Peripheral nerve biopsy reveals loss of all fiber diameters, but predominantly small myelinated and unmyelinated fibers (Aδ- and C- fibers), with fiber loss more pronounced distally (Dyck, 1993). Postmortem data showing degeneration of dorsal root ganglia neurons suggests a sensory ganglioneuropathy presenting clinically as a dying-back axonopathy (Denny-Brown, 1951; Dyck, 1993). The typical phenotype of autosomal dominant HSAN1 has mainly sensory features, but in some patients there is accompanying distal weakness (Dyck, 1993). Predominantly sensory and sensory/motor presentations may occur in the same kindred in families linked to chromosome 9q22, with mutations in the gene encoding serine palmitoyl transferase long chain base -1 (SPLTC 1) (Auer-Grumbach et al., 2003). This enzyme catalyzes a rate-limiting step in sphingolipid synthesis. A gain of function effect is hypothesized leading to increased synthesis of ceramide and resulting apoptotic cell death. A more consistently sensory/motor phenotype is linked the small GTP-ase late endosomal protein (RAB7) on chromosome 3q13–q22 (Verhoeven et al., 2003). This protein belongs to the Rab family of Rasrelated GTP-ases that function in intracellular membrane trafficking. Clinically similar families not linked to either locus are reported (Auer-Grumbach et al., 2000; Bellone et al., 2002).

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38.1.1.1. Neurophysiological evaluation The neuropathy of HSAN1 is progressive, and abnormalities on clinical neurophysiological testing are expected to worsen over time (Dyck, 1993; Shivji and Ashby, 1999). In some kindreds, neurophysiological testing (i.e., nerve conduction studies or quantitative sensory testing) may reveal evidence of sensory neuropathy in affected subjects lacking overt sensory symptoms (Dyck, 1993). Neurophysiological findings are outlined in Table 38.1. 38.1.1.2. Nerve conduction studies Electrophysiological features of HSANI are summarized in Table 38.1. Typically, nerve conduction studies show reduced amplitude or absent sensory nerve action potentials with preserved conduction velocity and distal latency (Whitaker et al., 1974; Elliott et al., 1997; Shivji and Ashby, 1999; AuerGrumbach et al., 2000; Pareyson, 2003). In vitro near nerve recordings show reduced Aδ- and C- fiber potentials (Dyck, 1993). Motor conduction velocities typically are normal, although mild to moderate conduction velocity slowing and CMAP dispersion may be found (Whitaker et al., 1974; Dyck, 1993; AuerGrumbach et al. 2000; Dubourg et al., 2000; Bellone et al., 2002). Reduced compound muscle action potential amplitudes, especially in intrinsic foot muscles are reported for families with significant motor involvement (Dyck, 1993; Elliott et al., 1997; AuerGrumbach et al., 2000, 2003; Dubourg et al., 2000; Bellone et al., 2002). Clinical phenotype and nerve conduction findings may be similar in peripheral neuropathy linked to 9q22 and 3q13, even though the 9q22 condition in the literature tends to be referred to as a form of HSAN1 and the 3q13 disorder is generally considered a type of CMT2 (Elliott et al., 1997; Auer-Grumbach et al., 2000; Dubourg et al., 2000; Auer-Grumbach et al., 2003). Affected subjects in a family with 3q22 linkage and a RAB7 mutation had preserved H-reflexes even in patients in whom the sural response was absent (Elliott et al., 1997). H-reflex data from patients with peripheral neuropathy linked to 9q22 would be of interest as the distinction may be useful diagnostically. 38.1.1.3. Electromyography Needle EMG examination may demonstrate fibrillation potentials in distal lower extremity muscles, with motor unit potential changes consistent with chronic motor denervation and reinnervation even in patients without detectable weakness (Dyck, 1993). These

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abnormalities may be pronounced in families with significant motor involvement (Whitaker et al., 1974; Elliott et al., 1997; Auer-Grumbach et al., 2000; Dubourg et al., 2000; Bellone et al., 2002; AuerGrumbach et al., 2003). Fibrillations have been reported in some families, but in others no abnormalities of spontaneous activity were found (Whitaker et al., 1974; Elliott et al., 1997; Auer-Grumbach et al., 2000). 38.1.1.4. Quantitative sensory testing Sensory thresholds are increased for touch pressure, vibration, pain and temperature, especially the latter (Ohta et al., 1973; Dyck, 1993; Shivji and Ashby, 1999). 38.1.1.5. Autonomic testing Sudomotor dysfunction is prominent in the lower limbs and is identifiable by quantitative sudomotor axon reflex testing (QSART) (Low et al., 2003). Sympathetic skin response (SSR) was reported in one series to be normal in six patients with HSAN 1, but the authors provided no clinical details as to how the diagnosis of HSAN 1 was established (Shivji and Ashby, 1999). 38.1.2. Hereditary sensory and autonomic neuropathy (HSAN2) Hereditary sensory and autonomic neuropathy (HSAN2) is an autosomal recessive disorder affecting all sensory modalities, recognized at birth or in early childhood (Dyck, 1993; Pareyson, 2003). Painless ulceration of the fingers and plantar surfaces, unnoticed fractures, and Charcot joints are not uncommon, with eventual development of distal mutilating acropathy. Light touch, vibratory, and joint position sensation are more affected early in the course than pain or temperature sensation. Tendon reflexes are usually absent. Autonomic features include loss of sweating in the distal limbs and bladder dysfunction, without postural hypotension. Strength is normal despite neurophysiological evidence of motor axonal loss. Sural nerve biopsy shows decreased fascicular size, with essentially absent myelinated fibers and reduced numbers of unmyelinated fibers. The gene locus (or loci) is unknown. 38.1.2.1. Neurophysiological evaluation Neurophysiological findings in HSAN2 are shown in Table 38.1.

K.B. BOYLAN AND V. CHAUDHRY

38.1.2.2. Nerve conduction studies Sensory nerve action potentials are absent (Schoene et al., 1970; Ohta et al., 1973; Miller et al., 1976; Nukada et al., 1982; Janzer et al., 1986; Dyck, 1993; Corsi et al., 2002; Low et al., 2003). CMAP amplitude and motor conduction velocity are normal or reduced, particularly for the peroneal nerve (Schoene et al., 1970; Ohta et al., 1973; Miller et al., 1976; Nukada et al., 1982; Janzer et al., 1986; Larner et al., 1994; Corsi et al., 2002). Although generally a static disorder clinically, serial nerve conduction studies may demonstrate progression (Dyck, 1993; Larner et al., 1994). Near nerve recordings from the sural nerve demonstrate absent evoked responses corresponding to Aα- and Aδ-fibers, and low amplitude C-fiber potential (Ohta et al., 1973). 38.1.2.3. Electromyography Needle EMG may be normal or reveal long duration, polyphasic MUP with reduced recruitment (Miller et al., 1976; Nukada et al., 1982; Larner et al., 1994; Corsi et al., 2002). Fibrillation potentials may be found in distal limb muscles, mainly the lower limb (Dyck, 1993). 38.1.2.4. Quantitative sensory testing Sensory thresholds are increased to temperature and vibratory stimuli, especially the latter (Dyck, 1993). 38.1.2.5. Autonomic testing Sudomotor abnormalities are held to occur in a generalized distribution, without orthostatic hypotension (Low et al., 2003). In one series, a patent with HSAN2 was reported to have had a normal “sweat test,” but no details were provided as to its methodology (Nukada et al., 1982). 38.1.2.6. Other testing Median and tibial somatosensory evoked potential scalp latencies were delayed in a patient reported by Nukada et al. (1982). The authors attributed this to “peripheral delay.” Results of cutaneous silent period and mixed nerve silent period studies were reported in a patient with the HSAN2 phenotype (Corsi et al., 2002). The cutaneous and mixed nerve silent periods were detectable in the upper limb despite absence of standard upper and lower limb peripheral sensory potentials. It is noteworthy that the cutaneous silent period was identified only with simultaneous stimulation of two digital nerves rather than with stimulation of a single

OTHER INHERITED NEUROPATHIES

nerve, as in normals. The cutaneous and mixed nerve silent periods each showed delayed latency and shortened duration in the patient examined. 38.1.3. Hereditary sensory and autonomic neuropathy (HSAN3) Hereditary sensory and autonomic neuropathy 3 (HSAN3), also known as Riley-Day syndrome or familial dysautonomia, is a severe congenital disorder with autosomal recessive inheritance (Mahloudji et al., 1970; Pearson, 1979; Dyck, 1993; Hilz et al., 1999; Low et al., 2003). Incidence is increased among Ashkenazi Jews. Peripheral autonomic, sensory, and motor neurons are affected, resulting in esophageal and gastroesophageal dysmotility, unexplained fluctuations in body temperature and blood pressure, blotchy skin, and alacrima. Recurrent vomiting and pulmonary infections are typical. Excessive sweating may occur. Developmental delay and seizures are not unusual. Autonomic features predominate; in conjunction with absence of fungiform papillae of the tongue these features distinguish HSAN3 from other forms of HSAN. Sural nerve shows marked reduction in unmyelinated fibers and lesser reduction of myelinated fibers. Cervical and thoracic sympathetic ganglia, and trigeminal sensory ganglia show reduced numbers of neurons. The disorder is linked to the IKB kinase complex-associated protein (IKAP) gene on chromosome 9q31. 38.1.3.1. Neurophysiological evaluation Neurophysiological findings in HSAN3 are summarized in Table 38.1. 38.1.3.2. Nerve conduction studies Sensory and motor nerve conduction velocities are normal or decreased (Mahloudji et al., 1970; Aguayo et al., 1971; Axelrod et al., 1981; Hilz et al., 1999; Low et al., 2003). Hilz et al. (1999) reported on 17 patients with HSAN3 aged 10–41 years. Peroneal and median motor conduction velocities and sural conduction velocity were decreased in most patients; peroneal motor latency was prolonged in on half of the subjects. The authors did not mention motor or sensory amplitudes. In other reports, sensory amplitudes were normal to moderately decreased, but motor amplitudes were normal (Aguayo et al., 1971; Axelrod et al., 1981). In two series, the observation was made that the ulnar antidromic sensory potential in some patients showed an unusual bifid wave form,

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suggestive of two populations of nerve fibers, one with slower conduction velocity (Brown and Johns, 1967). 38.1.3.3. Electromyography Needle EMG is normal (Aguayo et al., 1971). 38.1.3.4. Quantitative sensory testing Sensory thresholds to cold, heat and vibratory stimuli are increased (Hilz et al., 1999). Vibration sensitivity is less impaired than temperature thresholds. 38.1.3.5. Autonomic testing Sympathetic skin response (SSR) is normal (Hilz et al., 1999). This test may help distinguish HSAN3 fron other forms of HSAN, especially HSAN4, in which SSR is absent. 38.1.3.6. Other testing Axelrod et al. (1981) reported prolongation of median, tibial, and peroneal somatosensory evoked potential peak latencies, but did not discuss interpeak latencies. They noted that the lower limb SEP responses were difficult to obtain, and that the responses were absent in five of their nine patients. 38.1.4. Hereditary sensory and autonomic neuropathy (HSAN4) Hereditary sensory and autonomic neuropathy (HSAN4) (congenital insensitivity to pain with anhydrosis) is an autosomal recessive disorder marked by insensitivity to pain, self-mutilation, anhydrosis, and mild mental retardation (Dyck, 1993; Rosemberg et al., 1994; Hilz et al., 1999). The principal defect involves first-order neurons mediating pain and temperature sensation. Pain and temperature sensation are severely reduced, with less impairment of vibratory sensation. Strength and tendon reflexes are preserved. Significant self-injury, such as biting off the tip of the tongue or bone fractures, may occur without evidence of pain. Intradermal injection of histamine causes a wheal but no axon flare (Nolano et al., 2000). Sural nerve biopsy demonstrates an essential absence of unmyelinated and small myelinated fibers and less prominent reduction of large fibers (Dyck, 1993). Severe reduction of cutaneous innervation is reported in skin biopsies (Nolano et al., 2000; Verze et al., 2000). In some families HSAN4 is linked to chromosome 3q, with mutations in the gene for tyrosine kinase A-nerve growth factor (trkA/NGF) (Indo et al., 1996; Indo, 2001).

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38.1.4.1. Neurophysiological evaluation Neurophysiological findings in HSAN4 are outlined in Table 38.1. 38.1.4.2. Nerve conduction studies Motor and sensory nerve conduction studies are normal in several reported cases, although sensory nerve action potential amplitudes may be reduced with mild slowing of conduction velocities (Rosemberg et al., 1994; Berkovitch et al., 1998; Haworth et al., 1998; Hilz et al., 1999; Nolano et al., 2000; Shatzky et al., 2000). A similar pattern of abnormalities may be seen for motor nerve conduction studies. The abnormalities generally are less severe than in HSAN2 or HSAN3 (Hilz et al., 1999). 38.1.4.3. Electromyography Needle EMG typically is normal in HSAN4 (Berkovitch et al., 1998; Hilz et al., 1999). 38.1.4.4. Quantitative sensory testing Thresholds to cold and warm perception are uniformly increased (Hilz et al., 1999; Nolano et al., 2000). Threshold to vibratory stimulation may be increased or normal (Hilz et al., 1999). 38.1.4.5. Autonomic testing Sympathetic skin response is absent, a useful means of in distinguishing HSAN4 from HSAN3, in which SSR is normal (Hilz et al., 1999; Nolano et al., 2000; Shatzky et al., 2000). In a single case report, cardiovascular reflexes, including R–R interval, Valsalva ratio, tilt test, and blood pressure response to hand grip, were normal (Nolano et al., 2000). Pilocarpine iontophoresis produced no sweating, but the site(s) of stimulation was not specified. 38.1.4.6. Other testing In a single patient, microneurography was reported to show absence of cutaneous sympathetic nociceptor C-fiber activity with preserved Aβ sensory activity (Nolano et al., 2000). 38.1.5. Hereditary sensory and autonomic neuropathy (HSAN5) Hereditary sensory and autonomic neuropathy (HSAN5) is distinguished by nociceptive sensory loss characterized as “indifference” to pain rather than “insensitivity” to pain (Dyck, 1993). Subjects have

K.B. BOYLAN AND V. CHAUDHRY

normal sensation to other modalities. Clinically significant anhydrosis and mental retardation are not seen in HSAN5 (Toscano et al., 2002). Intradermal injection of histamine provokes a normal axon flare (Low et al., 1978; Landrieu et al., 1990; Toscano et al., 2002). However, diagnosis of HSAN5 may not be straightforward and there is disagreement in the literature as to classification of patients said to have this condition, especially in separating HSAN4 from HSAN5 (Dyck, 1993; Toscano et al., 2002). Some authors question whether the primary defect may be central rather than peripheral, as sural nerve biopsy may be normal (Landrieu et al., 1990). Yet, some patients meeting the clinical description of HSAN5 have been shown to have a reduction in the numbers of small myelinated fibers and less significant reductions of unmyelinated fibers in peripheral nerve (Low et al., 1978; Dyck et al., 1983b). In addition, reports of families with HSAN5 include potential autosomal dominant and possible autosomal recessive inheritance (Low et al., 1978; Dyck et al., 1983b; Landrieu et al., 1990). Designation of HSAN5 as a clinical entity seems valid, particularly in view of the patient reported on by Tosacano et al. (2002) in whom linkage to TRKA was essentially eliminated. Resolution of basic questions regarding classification of patients with this form of HSAN will require identification of the causative gene(s) (Dyck, 1993; Toscano et al., 2002). 38.1.5.1. Nerve conduction studies Sensory and motor nerve conduction studies are normal (Dyck et al., 1983b). 38.1.5.2. Electromyography Needle EMG examination is normal (Dyck et al., 1983b). 38.1.5.3. Quantitative sensory testing Temperature and vibratory thresholds are normal (Amato and Dumitru, 2002). 38.1.5.4. Autonomic testing Sympathetic skin response (SSR) was normal in the patient of Toscano et al. (2002). Low reported abnormal Valsalva ratio in a 6-year-old girl subsequently categorized by Dyck as HSAN5 (Low et al., 1978; Dyck, 1993). 38.1.5.5. Other testing Tibial somatosensory evoked potential studies in a single case report showed delayed latency of the scalp

OTHER INHERITED NEUROPATHIES

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potentials; no response could be recorded over the spine (Dyck et al., 1983b).

Table 38.2.

38.2. Familial amyloid polyneuropathy

(FAP) Amyloidogenic Protein

Peripheral neuropathy associated with amyloid deposition in peripheral nerve may occur in familial or nonfamilial forms of amyloidosis (Hund et al., 2001; Mendell, 2001a). Familial amyloid polyneuropathy is discussed here, while nonfamilial amyloid polyneuropathy has been discussed in Chapter 36. The term amyloid refers to deposits of proteinaceous material that demonstrates apple-green birefringence under polarized light microscopy when stained with the histochemical dye Congo Red (Mendell, 2001a). Amyloid in familial amyloid polyneuropathy is derived from accumulation of one of three genetically abnormal plasma proteins, transthyretin, apoliporotein A-1, or gelsolin. Classification of these conditions, previously based on clinical features or ethnic origin of affected families, now is based on the molecular pathogenesis (Coelho, 1996; Mendell, 2001a). Original designations, Types 1–4, and the current nomenclature are shown in Table 38.2. All are autosomal dominant. Diagnosis is made by demonstration of amyloid in affected tissues. Rectum, skin, kidney, and sural nerve have optimal yield as biopsy sites, although the result may be negative owing to nonuniform distribution of amyloid in target tissues. Antibody staining of amyloid in biopsy preparations is possible for transthyretin, apolipoprotein A-1, and gelsolin in order to establish a diagnosis of familial amyloidosis. Genetic diagnosis by DNA mutation analysis is possible but of limited practical utility in clinical practice because more than one causative mutation has been identified for each of the three forms of familial amyloidosis (Zalin et al., 1991; Kiuru, 1998; Hund et al., 2001; Mendell, 2001a). The three types of familial amyloidosis are briefly reviewed below, followed by discussion of neurophysiology of these disorders.

Classification of familial amyloid polyneuropathies

Original designation

Transthyretin

FAP 1 FAP 2

Apoliprotein A-1 Gelsolin

FAP 3 FAP 4

Portuguese Indiana/ Swiss Iowa Finnish

Modified from Mendell, 2001a.

dysautonomia, vitreous opacities, cardiomyopathy, and nephropathy. Onset is from the third to sixth decade. The neuropathy involves prominent sensory and autonomic dysfunction. Patients typically present with painful paresthesia of the feet. Sensory loss involves pain and temperature more than vibration and joint position. Distal limb weakness with foot drop and intrinsic hand muscle weakness may develop. Cranial nerves are generally spared aside from ocular abnormalities such as impaired pupillary reaction. Autonomic features include postural hypotension, gastrointestinal dysmotility, and urinary retention. Central nervous system manifestations attributed to leptomeningeal or brain parenchymal amyloid deposits may occur rarely (Montagna et al., 1996). Early death may result from cardiac involvement if significant cardiomyopathy develops. In some families, however, carpal tunnel syndrome is an early feature, followed by a mild generalized sensory motor peripheral neuropathy and minimal autonomic dysfunction. This variation reflects in part genetic heterogeneity related to the underlying mutation, of which at least 60 in the transthyretin gene are reported, as well as other genetic and nongenetic modifying factors (Reilly et al., 1995; Mendell, 2001a). Liver transplantation is a treatment of established benefit (Coelho, 1996; Ikeda et al., 1997; Pomfret et al., 1998).

38.2.1. Transthyretin amyloidosis Transthyretin is synthesized primarily in liver and appears to serve as a transport protein for thyroid hormone and vitamin A (Hund et al., 2001; Mendell, 2001a). Transthyretin amyloidosis encompasses Type 1 (Portuguese) and Type 2 (Indiana/Swiss) familial amyloidosis. Manifestations include a variable degree of painful sensory motor peripheral neuropathy,

38.2.2. Apolipoprotein A-1 amyloidosis Apoliprotein A-1 is synthesized mainly in liver, and functions in reverse transport of cholesterol from tissues to the liver for excretion. This form of amyloidosis, originally designated Type 3 familial amyloidosis, is characterized by sensory motor peripheral neuropathy, usually without significant autonomic involvement

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(Van Allen et al., 1969; Mendell, 2001a). Onset ranges from the third to eighth decade. Painful numbness of the lower limbs develops initially, leading gradually to panmodal sensory loss in the distal limbs. Sensory ataxia and loss of reflexes may occur. Muscle weakness and atrophy may or may not be prominent features in some patients, but hearing loss often is. Cardiac involvement is mild; peptic ulcer disease and renal disease are often seen. The latter may result in early death from renal failure. Amyloid deposits are found in peripheral and autonomic nerve, dorsal root ganglia and spinal roots. Other locations include the renal vasculature, testicles (causing impotence), and hypothalamus and pituitary. Treatment is supportive, directed particularly at managing renal manifestations. 38.2.3. Gelsolin amyloidosis Gelsolin is an actin binding protein synthesized primarily in muscle (Kiuru, 1998; Mendell, 2001a). The disorder is marked by corneal lattice dystrophy, cranial neuropathies, peripheral neuropathy, and skin changes. Onset age is variable but usually in the fourth or fifth decade. Corneal lattice dystrophy is attributed to amyloid deposits in trigeminal sensory nerves in the cornea, and can be identified using a slit lamp. Facial neuropathy is more obvious clinically, but hearing loss and motor impairment from involvement of cranial nerves 8, 10, and 12 also occur. Furrowing of the tongue and macroglossia may be noticed. Peripheral neuropathy is mild, with reduced vibratory and touch sensation and milder loss of pain and temperature. Tendon reflexes and motor function in the limbs are normal, or mildly impaired in advanced cases. Deposition of amyloid in skin may alter facial appearance owing to reduced skin turgor. Visceral organ involvement tends otherwise to be insignificant, and lifespan is normal unless oropharyngeal weakness leads to aspiration. Treatment is supportive. 38.2.4. Neurophysiological evaluation Neurophysiological abnormalities in familial amyloid polyneuropathies stem from characteristic target tissue sites of amyloid deposition. The relative extent of peripheral nerve, autonomic, and cranial nerve abnormalities varies among transthyretin, apoliprotein A-1, and gelsolin amyloidosis. Each disorder has characteristic patterns of nerve involvement, the extent influenced by the specific mutation and duration of disease. Neurophysiological changes in familial

K.B. BOYLAN AND V. CHAUDHRY

amyloidosis are not by themselves diagnostic, but may contribute significantly in defining the clinical manifestations of the disorder. Neurophysiological testing has also proven useful in assessing the response to treatment in the case of liver transplantation for transthyretin amyloidosis. The following review applies to the transthyretin and gelsolin amyloidoses, as detailed neurophysiological data on apolipoprotein A1 amyloidosis are not available. Disease-specific features are noted. 38.2.5. Nerve conduction studies The nerve conduction findings in general are those of a symmetrical, predominantly axonal peripheral neuropathy (Blom et al., 1981; Kiuru, 1998). However, patients with gelsonin amyloidosis demonstrate motor nerve conduction velocity slowing and prolongation of distal latencies that suggest demyelination in addition to axonal loss (Boysen et al., 1979; Sunada et al., 1993; Kiuru and Seppalainen, 1994). In transthyretin amyloidosis sensory nerve action potentials tend to be diminished in amplitude or absent, with normal to moderately abnormal distal latency and conduction velocity (typically within 70% of the lower limit of normal) (Luis, 1978; Blom et al., 1981; Sobue et al., 1990; Montagna et al., 1996). Motor nerve conduction studies may be normal, and are generally less abnormal than the sensory findings in a given patient, although lower limb motor responses (i.e., recorded from the extensor digitorum brevis) may be absent (Luis, 1978; Blom et al., 1981; Sobue et al., 1990; Montagna et al., 1996). The abnormalities in transthyretin and gelsolin amyloidosis are generally proportional to disease duration and age of the patient, and develop in a length-dependent pattern (Luis, 1978; Boysen et al., 1979; Kiuru and Seppalainen, 1994; Montagna et al., 1996). In transthyretin amyloidosis nerve conduction studies, particularly sensory amplitudes, may help in detecting the disease presymptomatically (Luis, 1978). In some forms of transthyretin amyloidosis, and in gelsolin amyloidosis, median neuropathy at the wrist (carpal tunnel syndrome) may be the principal finding on nerve conduction studies in the limbs (Boysen et al., 1979; Blanco-Jerez et al., 1998). Facial nerve motor amplitude may be significantly reduced in gelsolin amyloidosis (Kiuru and Seppalainen, 1994). Montagna and colleagues reported “some improve ment” in motor nerve conduction features in two patients with transthyretin amyloidosis 18 months after liver

OTHER INHERITED NEUROPATHIES

transplantation, but provided no details (Montagna et al., 1996). 38.2.6. Electromyography Needle EMG in transthyretin and gelsolin amyloidosis reveals evidence of chronic motor denervation and re-innervation with fibrillation potentials in limb muscles in a length-dependent pattern in patients with significant motor involvement (Boysen et al., 1979; Blom et al., 1981; Kiuru and Seppalainen, 1994). In transthyretin amyloidosis Blom et al. (1981) found increased fiber density in upper and lower limb muscles, with greater abnormality in the lower extremity. In one series, spontaneous repetitive bursts of voluntary motor unit potential activity was noted in facial muscles of three patients with transthyretin amyloidosis (Montagna et al., 1996). In gelsolin amyloidosis muscles innervated by the facial nerve are most consistently and severely abnormal, particularly the frontalis (Kiuru and Seppalainen, 1994). Similar but less prominent abnormality is reported for the tongue. Myokymia in the frontalis muscle has been reported (Kiuru and Seppalainen, 1994). 38.2.7. Quantitative sensory testing Thresholds to temperature stimuli (heat and cold) tend to be more abnormal than vibratory threshold in transthyretin amyloidosis (Amato and Dumitru, 2002). No published data are available for apoliprotein A-1 amyloidosis or gelsolin amyloidosis. 38.2.8. Autonomic testing Autonomic abnormalities in familial amyloidosis are reported mainly for transthyretin amyloidosis. Abnormal quantitative sudomotor axon reflex (QSART) in a length-dependent pattern is common in transthyretin amyloidosis (Mendell, 2001a). Heart rate variation to deep breathing is reduced. Valsalva maneuver and tilttable test also may be abnormal. Clinically significant autonomic findings are generally do not occur in gelsolin amyoloidosis, although tilt table test and heart rate variation to deep breathing may be abnormal (Kiuru et al., 1994; Kiuru, 1998). 38.2.9 Other testing Blink response in gelsolin amyloidosis may reveal absent or unstable R1 response and prolonged R1

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latency (Darras et al., 1986a; Kiuru and Seppalainen, 1994). Sympathetic skin response in transthyretin amyloidosis shows amplitude reduction in proportion to disease severity, with significantly reduced amplitude or absent response in patients with clinical evidence of neuropathy in the upper and lower limbs (Montagna et al., 1996; Shivji and Ashby, 1999). In two of the patients examined 18 months after liver transplantation, recovery of previously absent sympathetic skin response was observed (Montagna et al., 1996). Median somatosensory evoked potentials in gelsolin amyoloidosis may exhibit delayed N13 latency (Kiuru and Seppalainen, 1994). 38.3. Fabry disease Fabry disease is an X-linked recessive disorder caused by mutations of the lysosomal hydrolase α-galactosidase A (Burns et al., 2003). Deficiency of this enzyme leads to accumulation of ceramide trihexoside in neural, renal, vascular, and other tissues. A characteristic cutaneous manifestation in hemizygous males, angiokeratoma corpora, is found in the perineal and periumbilical regions (O’Brien et al., 1975). Renal insufficiency and premature vascular disease with stroke, hypertension, and myocardial infarction may occur (Mitsias and Levine, 1996). Death usually results from renal, cardiac, or cerebrovascular complications (Burns et al., 2003). Hemizygous males develop length-dependent, painful peripheral neuropathy in the first to third decades, and experience recurrent episodes of debilitating distal limb pain. Female heterozygotes typically demonstrate mild or no symptoms (Bird and Lagunoff, 1978). Additional neurological features include diminished sweating and other signs of autonomic dysfunction (Cable et al., 1982; Low and McLeod, 1993). Pathological studies of peripheral nerve demonstrate involvement predominantly of unmyelinated and small myelinated sensory fibers (C- and Aδ- fibers) in peripheral nerve, as well as autonomic and sensory ganglia (Onishi and Dyck, 1974; Sima and Robertson, 1978; Pellissier et al., 1981). Large sensory and motor fibers are relatively spared, especially early in the disease (Sheth and Swick, 1980; Morgan et al., 1990). Autonomic dysfunction is detectable neurophysiologically, but generally is not clinically significant in Fabry disease (Cable et al., 1982; Low and McLeod, 1993). Diagnosis is by

780

demonstration of decreased α-galactosidase A in leukocytes or plasma (Burns et al., 2003). Treatment with intravenous α-galactosidase A has shown promising results for improvement of renal function and vascular complications but success with neuropathic pain is mixed (Burns et al., 2003). No data on the effects of treatment on neurophysiological test results are available as yet. 38.3.1. Neurophysiological evaluation Neurophysiological evaluation in Fabry disease is useful in characterizing the nature of peripheral neuropathic involvement. Findings with the techniques discussed do not allow specific diagnosis, but may help suggest the presence of a primarily small fiber neuropathic disorder and lead to definitive testing. 38.3.2. Nerve conduction studies Several reports involving small numbers of patients indicate normal nerve conduction in Fabry disease (Onishi and Dyck, 1974; Sima and Robertson, 1978; Pellissier et al., 1981; Ro et al., 1999), although some investigators found slowing of motor conduction velocity and prolongation of motor distal latency in male hemizyogotes and carrier females (Sheth and Swick, 1980). However, these latter data have been questioned for failure to control for renal disease (Luciano et al., 2002). A recent study in which patients with significant renal involvement were excluded showed no abnormalities on standard nerve conduction studies other than an increased incidence of median nerve entrapment at the wrist (Luciano et al., 2002). Median abnormalities included slowing of median sensory conduction velocity and prolongation of median motor distal latency. One study comparing near nerve sensory recordings with results from standard surface recordings from the sural nerve found no significant difference in sensitivity between the two techniques in detecting abnormalities of sensory evoked responses or conduction velocity (Luciano et al., 2002). 38.3.3. Electromyography Several reports indicate normal results on needle EMG examination in Fabry patients (Onishi and Dyck, 1974; Pellissier et al., 1981). Luciano et al. (2002) performed limited EMG examination of 20 patients and found signs of motor denervation in three,

K.B. BOYLAN AND V. CHAUDHRY

but could not establish that the abnormalities were related to Fabry disease. 38.3.4. Quantitative sensory testing In 22 patients reported on by Luciano et al. (2002) increased thermal detection thresholds were found in 82% of patients. Abnormality was more often found in the feet and hands, and cold hypoesthesia was noted more frequently than warm hypoesthesia. Vibration detection threshold was normal in all but two patients who showed increased thresholds in the hand. Similar data were reported by the same group in an earlier study (Syed et al., 2000). 38.3.5. Autonomic testing Autonomic dysfunction is common in Fabry hemizygotes and is reported in female carriers, but is less important clinically than peripheral sensory effects of the disease (Cable et al., 1982; Low and McLeod, 1993). Decreased sweating is often noted. Gastrointestinal manifestations include nausea, cramps and diarrhea. Postural hypotension also may occur. In a study conducted by Cable et al. (1982) sudomotor function measured as eccrine sweat gland activity in 10 patients was found to be abnormal in all of them. Cardiovascular responses were normal, including tilt. However, Mutoh et al. (1988) reported on a manifesting female carrier with clinically significant orthostatic hypotension with sympathetic and parasympathetic failure. 38.3.6. Other testing Ro and colleagues reported on current perception thresholds testing at 5 Hz, 250 Hz and 2 kHz in patients with Fabry disease (Ro et al., 1999). Testing at lower frequencies, 5 Hz and 250 Hz, was more sensitive in detecting sensory neuropathy than 2 kHz. However, no correlation was found between current perception thresholds and clinical symptoms scores, renal function and disease duration, leaving in question the clinical utility of this technique in Fabry disease. Cutaneous silent period (CSP) recorded with tibial nerve/sural stimulation in 12 patients showed a range of abnormalities that tended to correlate with the extent of sensory loss on quantitative sensory testing (Syed et al., 2000). CSP recorded in the hand with median nerve stimulation showed no difference

OTHER INHERITED NEUROPATHIES

between Fabry patients and controls. The test was judged “relatively insensitive” in patients with mild to moderate sensory loss, however. Limited data on the sympathetic skin response (SSR) in Fabry disease are available. In 20 Fabry patients in a single study, the SSR was abnormal in only one, suggesting that this technique has limited sensitivity in Fabry disease (Luciano et al., 2002). 38.4. Globoid cell leukodystrophy Globoid cell leukodystrophy, also known as Krabbe disease, is an autosomal recessive disorder of central nervous system and peripheral nervous system myelin, caused by mutations in the β galactosidase gene on chromosome 14q24.3–q23.1 (Suzuki et al., 1995). Neurological manifestations stem from progressive degeneration of central and peripheral nervous system myelin. Myelin degeneration in the CNS is accompanied by galactocerebroside-laden macrophages, or globoid cells. Globoid cells are not found in peripheral nerve, but inclusion material is present in perivascular macrophages and Schwann cells (Thomas et al., 1984; Loonen et al., 1985). Diagnosis can be made by assay of β galactosidase in leukocytes or cultured skin fibroblasts. Three forms of globoid cell leukodystrophy can be distinguished on the basis of the age of onset: (1) early infantile; (2) late infantile/juvenile; and (3) adolescent/adult (Loonen et al., 1985; Suzuki et al., 1995). The early infantile form is most frequent, presenting in the first 6 months of life with irritability and feeding difficulty. Progressive mental deterioration, weakness, and spasticity ensue, leading to blindness, deafness, quadriplegia, and death in most cases by the age of two years. Peripheral neuropathy is detectable as early as the first weeks of life, but may go unrecognized in association with other disease complications (Hogan et al., 1969). However, in some patients, peripheral neuropathy may be a presenting feature (Marks et al., 1997; Korn-Lubetzki et al., 2002). Spinal fluid protein tends to be elevated, especially in early onset disease (Dunn et al., 1969; Loonen et al., 1985). MRI of the brain typically shows symmetrical periventricular and cerebellar white matter changes and cerebral atrophy (Suzuki et al., 1995). Late infantile/juvenile and adolescent/adult forms of globoid cell leukodystrophy are less common than the early infantile form (Arvidsson et al., 1995; Suzuki et al., 1995). Presentation and clinical manifestations are variable, including spasticity, dementia, ataxia,

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cortical blindness and optic atrophy (Duncan et al., 1970; Morgan et al., 1990; Phelps et al., 1991; Arvidsson et al., 1995; Zafeiriou et al., 1996). Peripheral neuropathy in these forms is usually milder than that seen in the early infantile form, but may be a presenting sign (Loonen et al., 1985; Marks et al., 1997; Henderson et al., 2003). No efficacy was demonstrated in initial reports of treatment of globoid cell leukodystrophy with bone marrow transplantation (Burns et al., 2003). However, recent data on bone marrow transplantation using hematopoietic stem cells in patients with late onset or presymptomatic globoid cell leukodystrophy are encouraging. Although outcome data are limited, clinical, radiographic, and neurophysiological findings suggest that stabilization or improvement of motor and cognitive abnormalities can be achieved. 38.4.1. Neurophysiological evaluation Central nervous system signs may overshadow evidence of peripheral neuropathy in globoid cell leukodystrophy (Hogan et al., 1969). Neurophysiological testing may facilitate diagnostic evaluation by identifying signs of a demyelinating peripheral neuropathy in conjunction with central demyelination, and lead to confirmatory laboratory testing (Henderson et al., 2003). 38.4.2. Nerve conduction studies Nerve conduction velocities may be normal or decreased regardless of the age of onset, but abnormality is more likely with infantile onset disease (Loonen et al., 1985). When abnormal, nerve conduction studies typically show symmetrical slowing of motor and sensory conduction velocities in the range of 70–80% of the lower limit of normal or less (Dunn et al., 1969; Hogan et al., 1969; Duncan et al., 1970; Thomas et al., 1984; Zafeiriou et al., 1996; Marks et al., 1997; Zafeiriou et al., 1997; Henderson et al., 2003). In the affected infants and children, conduction velocities may be in the range of 10 m/s (Dunn et al., 1969; Zafeiriou et al., 1996). Conduction velocity slowing is typically worse in the lower that upper limbs (Dunn et al., 1969). Conduction block is not seen (Miller et al., 1985). Distal motor latencies can be moderately prolonged and motor amplitudes mildly to moderately decreased, but may be normal despite significant conduction velocity slowing (Dunn et al., 1969; Darras et al., 1986a; Zafeiriou et al., 1996, 1997;

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Marks et al., 1997; Henderson et al., 2003). Sensory nerve action potential amplitudes typically are significantly reduced or are absent (Dunn et al., 1969, 1976, Thomas et al., 1984; Henderson et al., 2003). Sensory latencies are prolonged (Dunn et al., 1969, 1976; Henderson et al., 2003). The abnormalities may gradually worsen with disease progression or remain relatively static (Dunn et al., 1969; Thomas et al., 1984; Arvidsson et al., 1995; Zafeiriou et al., 1996, 1997). Patients may present with primarily motor features, mimicking motor neuron disease in spite of the existing evidence on nerve conduction studies of sensory involvement (Henderson et al., 2003). Of three children status post bone marrow transplant for treatment of globoid cell leukodystrophy, serial nerve conduction studies demonstrated improved motor nerve conduction velocities in one child (Krivit et al., 1998). 38.4.3. Electromyography Needle EMG examination may reveal an increased proportion of polyphasic voluntary motor unit potentials (Hogan et al., 1969; Duncan et al., 1970; Dunn et al., 1976). However, EMG may in some patients be normal despite marked reduction in motor conduction velocity (Thomas et al., 1984; Darras et al., 1986b). Fibrillation potentials and positive sharp waves develop in line with motor axonal degeneration as the disease progresses (Marks et al., 1997). 38.4.4. Other testing Brain stem auditory evoked potentials may show prolongation of wave I–V interpeak latencies (Marks et al., 1997; Zafeiriou et al., 1997). Absence of waves III–V also has been reported (Darras et al., 1986b). Abnormality of visual-evoked potential latency ranges from mild delay to absence of the response (Thomas et al., 1984; Darras et al., 1986b; Zafeiriou et al., 1996, 1997). Somatosensory evoked potential studies typically show prolonged cortical latencies (Zafeiriou et al., 1996, 1997). EEG may demonstrate abnormalities such as bihemispheric or generalized slowing; findings may be asymmetric (Hogan et al., 1969; Duncan et al., 1970; Loonen et al., 1985; Arvidsson et al., 1995; Suzuki et al., 1995; Zafeiriou et al., 1997). It is not clear from published reports whether evoked potential or EEG abnormalities may antedate development of white matter changes on cranial MRI.

K.B. BOYLAN AND V. CHAUDHRY

38.5. Metachromatic leukodystrophy Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder of myelin in which galactosyl sulfatide accumulates in the central nervous system and in peripheral nerve (Kolodny and Fluharty, 1995). Pathological findings include metachromatic granules in Schwann cells and endoneurial and perivascular macrophages. Onset ranges from infancy through the seventh decade. Dementia, motor regression/gait ataxia, and spasticity are typical presenting signs. Visual loss, quadriparesis, and peripheral neuropathy also are seen in children. Infantile, juvenile, and adult forms are distinguished by disease severity as well as the age of onset. The infantile form is usually fatal in childhood. The phenotype is less severe in the juvenile and adult forms, which tend to be dominated by mental regression and behavioral abnormalities. Spinal fluid protein may be elevated, particularly in infantile and early juvenile onset MLD. CT and MRI images of the brain typically demonstrate diffuse, progressive white matter signal changes. Peripheral neuropathy may be a dominant feature in children, and rarely, in adults (Yudell et al., 1967; Aziz and Pearce, 1968; De Silva and Pearce, 1973; Martinez et al., 1975; Fressinaud et al., 1992; Comabella et al., 2001). The metachromatic leukodystrophy phenotype may be caused by mutations at one of three genetic loci: (1) arylsulfatase A on chromosome 22; (2) prosaposin on chromosome 10; and (3) multiple sulfatase deficiency (Kolodny and Fluharty, 1995). Most reported cases are caused by mutations in the arylsulfatase A gene (Burns et al., 2003). Diagnosis can be made through assay of arylsulfatase in peripheral leukocytes or cultured skin fibroblasts (Kolodny and Fluharty, 1995). Urine sulfatide determination may be a useful confirmatory test. Sural biopsy also may be diagnostic, but is less commonly performed, given the availability of biochemical testing. Bone marrow transplantation is effective in controlling some features of the disorder, including peripheral neuropathy, if performed before the pathological effects are well established (Imaizumi et al., 1994; Burns et al., 2003). However, there is relatively less impact on the central nervous system demyelination and brain atrophy (Imaizumi et al., 1994). 38.5.1. Neurophysiological evaluation Clinical neurophysiological testing can play an important role in the evaluation of patients with

OTHER INHERITED NEUROPATHIES

metachromatic leukodystrophy. Case reports suggest that neurophysiological abnormalities may be detectable before symptoms develop (Pilz and Hopf, 1972; Clark et al., 1979). Identification of a demyelinating peripheral neuropathy in conjunction with other features characteristic of the disorder may lead to definitive diagnostic testing. This disorder is an example of the diagnostic value of neurophysiological testing in patients in whom central nervous system findings might otherwise overshadow clinically important peripheral nervous system pathology. 38.5.2. Nerve conduction studies Sensory nerve action potentials usually show decreased amplitude and may be absent (Yudell et al., 1967; Martinez et al., 1975; Thomas et al., 1977; Bosch and Hart, 1978; Clark et al., 1979; Hahn et al., 1982; Wulff and Trojaborg, 1985; Fressinaud et al., 1992; Cameron and Jones, 1996; Comabella et al., 2001). Sensory distal latencies are prolonged with conduction velocity slowing (Yudell et al., 1967; Thomas et al., 1977; Wulff and Trojaborg, 1985; Fressinaud et al., 1992). Motor amplitudes are typically mildly to moderately decreased with conduction velocity slowing in the range of 20–40 m/s in the upper limbs and 10–20 m/s in the lower limbs, with comparable prolongation of distal motor latencies (Fullerton, 1964 Yudell et al., 1967; Aziz and Pearce, 1968; De Silva and Pearce, 1973; Martinez et al., 1975; Thomas et al., 1977; Clark et al., 1979; Shapiro et al., 1979; Hahn et al., 1982; Wulff and Trojaborg, 1985; Fressinaud et al., 1992; Cameron and Jones, 1996; Comabella et al., 2001). Less prominent motor conduction velocity slowing in late adult-onset disease has been reported (Bosch and Hart, 1978). F-wave latencies are prolonged proportionately to the degree of motor conduction velocity slowing (Fressinaud et al., 1992; Comabella et al., 2001). Stimulation thresholds may be significantly increased (Fullerton, 1964). Temporal dispersion and conduction block are reported in some children and adult patients (Clark et al., 1979; Miller et al., 1985; Wulff and Trojaborg, 1985; Fressinaud et al., 1992; Cameron and Jones, 1996; Comabella et al., 2001). 38.5.3. Electromyography Needle EMG may demonstrate fibrillation potentials and positive sharp waves in conjunction with long duration, high amplitude and polyphasic voluntary motor unit potentials (Aziz and Pearce, 1968; De Silva

783

and Pearce, 1973; Martinez et al., 1975; Hahn et al., 1982; Cameron and Jones, 1996). However, in some patients, EMG is normal (Yudell et al., 1967; Wulff and Trojaborg, 1985; Cameron and Jones, 1996). 38.5.4. Other testing Brain stem auditory evoked potentials in infantile, juvenile, and adult patients may show increased interpeak latencies and loss of waveforms. In the infantile form this can occur before nerve conduction abnormality is detectable (Denny-Brown, 1951). Abnormalities are found most consistently in infantile onset MLD; results may be normal in juvenile and adult onset cases (Wulff and Trojaborg, 1985). Visual and somatosensory evoked potentials can demonstrate central condition slowing and poorly formed peaks in infantile, juvenile, and adult onset disease (Wulff and Trojaborg, 1985). The abnormalities may be asymmetrical. In a single report motor evoked potential studies of the upper and lower limbs showed prolonged central and peripheral conduction times, but no technical details were given (Fressinaud et al., 1992). EEG may be normal or show generalized or focal abnormalities (Yudell et al., 1967; De Silva and Pearce, 1973; Martinez et al., 1975; Thomas et al., 1977; Hahn et al., 1982; Wulff and Trojaborg, 1985; Fressinaud et al., 1992). 38.6. Refsum disease Refsum disease is an uncommon autosomal recessive condition caused by impaired α-oxidation of phytanic acid (Wills et al., 2001). Mutation of phytanol coenzyme A hydroxylase leads to increased levels of phytanic acid in blood and other tissues, including peripheral nerve and brain (Skjeldal et al., 1987; Wills et al., 2001). Clinical signs include retinitis pigmentosa (considered pathognomic), peripheral neuropathy, pes cavus, anosmia, cerebellar ataxia, sensorineural deafness, and other cranial nerve involvement (Miller, 1985; Skjeldal et al., 1987; Thomas, 1988). Spinal fluid protein is elevated. Cutaneous ichthyosis is common. Onset ranges from the first to the fifth decade. The course is typically progressive, although acute and relapsing presentations are reported (Harari et al., 1991; Kuntzer et al., 1993; Lou et al., 1997). The peripheral neuropathy of Refsum disease tends to have demyelinating features, including hypertrophic changes with onion bulb formation on nerve

784

biopsy, but well-documented cases more in keeping with axonal pathology are described (Dotti et al., 1985; Miller, 1985; Thomas, 1988; Gelot et al., 1995; Lou et al., 1997). The basis for this variation is not known (Salisachs et al., 1982). Nerve pathology is ascribed to a length-dependent axonal dying-back process with segmental demyelination (Thomas, 1971; Dotti et al., 1985). Autonomic features occur, including impaired sweating in the distal limbs, generally in parallel with ichthyosis (Wills et al., 2001). Skeletal features include characteristic shortening of the lateral toes, particularly the fourth toe (Wills et al., 2001). Diagnosis is based on demonstration of defective phytanol coenzyme A hydroxylase function (Skjeldal et al., 1987; Wills et al., 2001). Phytanic acid levels in peripheral blood are elevated in most patients, but the levels are variable. Increased phytanic acid levels are found in other peroxisomal disorders, and normal levels may be found in some Refsum patients with otherwise typical clinical features and documented enzyme dysfunction (Skjeldal et al., 1987). Treatment with dietary restriction of phytanic may lead to clinical improvement, including improvement of peripheral neuropathy (Dickson et al., 1989; Burns et al., 2003). Significant response to treatment may be seen with plasma exchange in acute exacerbations (Dickson et al., 1989; Harari et al., 1991; Lou et al., 1997; Burns et al., 2003). 38.6.1. Neurophysiological evaluation Refsum disease is notable among inherited demyelinating neuropathies because nerve conduction findings, while usually in keeping with demyelination, may in some patients be more suggestive of axonal pathology (Gelot et al., 1995; Lou et al., 1997). In addition, fluctuation of disease activity over time may coincide with acute exacerbations resembling Guillain–Barré syndrome or a relapsing course similar to chronic inflammatory demyelinating polyneuropathy (Dickson et al., 1989, Harari et al., 1991; Leppert et al., 1991; Lou et al., 1997).

K.B. BOYLAN AND V. CHAUDHRY

Miller, 1985; Thomas, 1988; Gelot et al., 1995). Abnormalities of conduction velocity and reduced amplitude are more pronounced in the lower limbs than the upper limbs, compatible with a lengthdependent process (Lou et al., 1997). Reductions in conduction velocity may be nonuniform, considered atypical for inherited peripheral neuropathy (Lewis and Sumner, 1982; Kuntzer et al., 1993). In some reported cases, motor amplitudes alone were reduced, without associated changes in conduction velocity (Gelot et al., 1995). Preserved sensory nerve conduction velocities and sensory amplitudes with abnormal motor nerve conduction results have been described (Lou et al., 1997). In the few case reports in which data are provided, CMAP dispersion and conduction block were not found (Kuntzer et al., 1993; Gelot et al., 1995; Lou et al., 1997). CMAP amplitudes may decline gradually over time despite appropriate treatment (Kuntzer et al., 1993). In some patients, however, stabilization or improvement of nerve conduction velocities and motor and sensory evoked amplitudes may occur, in parallel with improvement of physical findings such as weakness (Dickson et al., 1989; Lou et al., 1997). 38.6.3. Electromyography Needle EMG tends to show signs of chronic denervation (Dotti et al., 1985; Kuntzer et al., 1993; Gelot et al., 1995). Fibrillation potentials may occur. Kuntzer and colleagues performed quantitative longitudinal investigation of the same patient over a 21-year period using macro EMG and single fiber EMG (Kuntzer et al., 1993). Their patient experienced two subacute exacerbations of sensory loss in the first 11 years of follow-up and remained stable thereafter. These data in conjunction with turns-amplitude analysis lead the authors to postulate recurrent segmental demyelination as the basis for the patient’s clinical course. Fiber density in the biceps brachii and tibialis anterior was increased; serial single fiber EMG data were not reported. 38.6.4. Autonomic testing

38.6.2. Nerve conduction studies Sensory amplitudes usually are reduced with prolongation of distal latencies (Leppert et al., 1991; Kuntzer et al., 1993; Gelot et al., 1995). Motor conduction velocity may be decreased in the range of 10 m/s or less, but in some patients it is normal (Fryer et al., 1971;

Limited data are available on autonomic testing in Refsum disease. Sympathetic skin response (SSR) may be present despite evidence of peripheral neuropathy on nerve conduction studies (Kuntzer et al., 1993). Absent SSR also is reported (Kuntzer et al., 1993). Although cardiac conduction defects and sudden death are

OTHER INHERITED NEUROPATHIES

recognized complications of Refsum disease, few data are reported on cardiac autonomic testing. In a single case report R–R interval was normal (Kuntzer et al., 1993). 38.6.5. Other testing Visual, auditory, and somatosensory evoked potential latencies may be prolonged (Harari et al., 1991; Leppert et al., 1991). 38.7. Adrenomyeloneuropathy Adrenomyeloneuropathy is one of several allelic phenotypes of adrenoleukodystrophy, an X-linked inherited peroxisomal disorder (Moser, 1997; Burns et al., 2003). Very long chain fatty acid (VLCFA) levels in central and peripheral nervous system myelin, adrenal cortex, and testes are increased. The mutation involves a gene encoding a peroxisomal transmembrane adneosine triphosphate-binding cassette transporter on chromosome Xp28, resulting in defective peroxisomal β-oxidation of saturated unbranched very long chain fatty acids. The most severe phenotype in this group is adrenoleukodystrophy, a progressive disorder with psychomotor retardation, hearing, speech, and gait abnormality, as well as seizures and adrenal insufficiency (Addison disease). Adrenomyeloneuropathy primarily affects the spinal cord and peripheral nerve, with variable but usually mild cerebral involvement. Manifestations of the mutation are minimal in some patients, and any of the phenotypic variants may occur in a given family. Gradual progression is the rule in all forms. Adrenoleukodystrophy usually presents between ages four and six years, but in 15% of patients it may be delayed until adolescence or adulthood (Moser, 1997). Adrenomyeloneuropathy usually presents in the third or fourth decade, most commonly as a progressive spastic paraparesis with impotence and incontinence, and peripheral neuropathy. Tendon reflexes may be diminished or normal. Patients tend to become nonambulatory over a 5-to-15-year-period provided cerebral involvement is minimal. Significant cerebral involvement correlates generally with a more rapid decline, progressing to a vegetative state within 5 years. Although the disorder is X-linked, females may show signs of adrenomyeloneuropathy, but the age of onset is in the third to fifth decades. Adrenal insufficiency, seen in 70% of males, is rare in women. Adrenal insufficiency is treated with replacement

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therapy. No effective treatment is available for central and peripheral nervous systems manifestations of the disorder. Levels of VLCFA (C24–26) are increased in plasma, providing a means of diagnosis (Moser, 1997). Sural nerve shows reduced myelinated fibers with scattered onion bulb formations (Thomas, 1993). Unmyelinated fibers are less affected. Electron microscopy shows lamellated nuclear inclusions in the Schwann cells. Postmortem shows spinal cord atrophy and long tract demyelination (Schaumburg et al., 1977). In adrenoleukodystrophy, there is cerebral demyelination with perivascular inflammation, often involving mainly the occipitoparietal region (Moser, 1997). 38.7.1. Neurophysiological evaluation Neurophysiological evaluation in this disorder can help in narrowing the differential diagnosis in a patient presenting with spastic paraparesis, by revealing peripheral motor and sensory abnormalities (Chaudhry et al., 1996). 38.7.2. Nerve Conduction studies Sensory and motor nerve conduction findings reflect mixed axonal and demyelinative pathology (Chaudhry et al., 1996; van Geel et al., 1996). Results can be normal in mildly affected patients (Chaudhry et al., 1996). Sensory and motor nerve conduction studies may show variably decreased amplitude, prolongation of distal latencies, and conduction velocity slowing (Vercruyssen et al., 1982; van Geel et al., 1996). H-reflex latency is prolonged (Chaudhry et al., 1996). Motor abnormalities are more common than sensory abnormalities; the peroneal nerve having the highest frequency in one large series (Vercruyssen et al., 1982; Chaudhry et al., 1996). The distal peroneal motor response may be absent in some patients (van Geel et al., 1996). Prolongation of distal motor latency is not necessarily proportional to the degree of motor conduction velocity slowing in a given nerve (Chaudhry et al., 1996). Motor conduction block is not seen (van Geel et al., 1996). Reduction in motor conduction velocities is in the range of 70–80% of the lower limit of normal. In a series of 23 patients with median disease duration of 10 years ( distal), and areflexia. Sensory loss is generally mild and may be more prominent proximally in a “bathing trunk” distribution. Porphyric neuropathy should be considered as a differential diagnosis of the more common rapidly progressive ascending paralysis, Guillain–Barré syndrome. Spinal fluid may show albuminocytological dissociation as seen with Guillain–Barré syndrome. Acute attacks are invariably associated with increased urinary excretion of aminolevulinic acid or porphobilinogen or both (Table 38.3 and Fig. 38.1). Measuring 24-hour urinary excretion of porphobilinogen and aminolevulinic acid and 24-hour fecal excretion of protoporphyrin and coproporphyrin during a symptomatic period are the most helpful methods of determining whether a particular set of symptoms and signs is due to acute porphyria (See Table 38.3). Plumboporhyria, characterized by severe deficiency of hepatic 5-aminolevulinic acid, is the least common of the porphyria and results in an increase of aminolevulinic acid, and not porphobilinogen. Since porphyrins are light sensitive, specimens must be stored in the dark and tested as soon as possible. Treatment is largely supportive during the acute crisis and includes fluid management, ventilatory support, management of heart rate and blood pressure (autonomic dysfunction), and avoiding medications that are known to precipitate an acute attack. Oral and intravenous administrations of glucose and haem arginate that result in feedback inhibition of heme synthesis, are the mainstays of treatment. Recovery from an acute attack may take several months. Toxicity from excess ALA is thought to be one pathogenic mechanism, although the mechanism is still poorly understood (Bonkovsky, 1993). Heme deficiency, leading to deficiency of heme proteins including cytochromes, and free radical damage, are other speculative mechanisms for the neuropathy (Monteiro et al., 1991; Lindberg et al., 1999). 38.8.1. Neurophysiological evaluation The primary aim of neurophysiological evaluation is to confirm the presence of a diffuse, predominantly

OTHER INHERITED NEUROPATHIES

787

Glycine + Succinyl CoA

↓ δ-Aminolevulinic acid (ALA)

↓

ALA dehydratase; Plumboporphyria

Porphobilinogen

↓

Porphobilinogen deaminase; Acute intermittent porphyria

Excreted in urine

Hydroxymethylbilane

↓ Uroporphyringen III

↓ Coproporphryinogen III

↓

Coproporphryinogen oxidase; Hereditary coproporphyria

Excreted in feces

Protoporphryinogen IX

↓

Protoporphryinogen oxidase; Variegate porphyria

Protoporphryin IX

↓ Heme

Fig. 38.1 Heme biosynthesis pathway and sites of defects for the porphyrias resulting in neurological dysfunction

motor, axonal process, and exclude a demyelinating neuropathy. Unlike most other neuropathies, the electrophysiological findings follow a proximal to distal gradient. Even though the electrophyisology shows a primarily axonal process, the pathology has been variously reported as demyelinating (Denny-Brown, 1945; Gibson and Goldberg, 1956) axonal (Cavanagh and Ridley, 1967; Sweeney et al., 1970; Defanti et al.,

1985) or mixed axonal and demyelinating (Anzil and Dozic, 1978). The reported demyelinating changes are subtle and likely to be a secondary phenomenon to the wallerian degeneration. This is supported by pathological studies in porphobilinogen deficient mice in which porphyric neuropathy is associated with a marked decrease in large-caliber (>8 μm) axons and ultrastructural changes consistent with primary

Table 38.3 Features of porphyric neuropathy

Disease

Enzyme & inheritance

Plumboporphyria Acute intermittent porphyria

ALA dehydrase autosomal recessive δ-Porphobilinogen deaminase autosomal dominant

Hereditary coproporphyria

Coproporphrinogen oxidase autosomal dominant

Variegate porphyria

Protoporphrynogen oxidase autosomal dominant

Accumulation Products

Skin rash

Urinary ALA

No

Urinary ALA and PBG

No

Urinary ALA, PBG, Copro III, fecal Copro III Urinary ALA, PGB, Copro III, fecal Copro and Protoporpiynogen

Yes

Yes

Symptoms (all forms) Abdominal pain, psychiatric . disturbance and acute axonal neuropathy Motor > sensory; upper limbs > lower Facial weakness and dysphagia, and respiratory failure may occur Autonomic features, esp. sympathetic hyperactivity are common

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motor axon degeneration, secondary Schwann cell reactions, and axonal regeneration (Lindberg et al., 1996). 38.8.2. Nerve conduction studies Like the clinical manifestations, sensory nerve abnormalities are mild compared to the abnormalities in the motor nerves. Normal sensory nerve physiology was reported in four of the six patients studied by Albers et al. (1978) and three outof five patients reported by Flugel and Drushky (1977). In the patients with reported sensory abnormalities, the SNAP amplitudes are reduced with relatively preserved latency or velocity. In contrast motor nerve conduction studies are invariably abnormal. Albers et al. (1978) reported eight patients with porphyria, all of whom showed reduced amplitudes of the CMAP with relatively preserved distal latency, conduction velocity, and F-wave latencies. Flugel and Druschke (1977) also reported similar findings in 20 patients, 16 symptomatic (one during an acute attack, nine with past attacks of neuropathy, and six with past attacks without neuropathy), and four asymptomatic (relatives of patients with porphyria with biochemical findings but no symptoms). The authors found that motor conduction velocities were lower in patients with neuropathy than in symptomatic patients without neuropathy (patients had abdominal or psychiatric attacks) and still lower than in patients who were completely asymptomatic. Overall, however, the authors concluded that the electrodiagnostic findings represented a “primary or predominantly axonal” type of lesion. Serial nerve conduction studies, performed by Albers et al. (1978) in two patients within 5 weeks of paresis, showed progressive reduction in CMAP amplitudes, again with normal conduction velocities. Two other cases, studied early (3 months) by the same authors, were shown to have an increase in amplitude at the latter end point suggesting axonal regeneration. Zimmerman and his colleagues. showed that sensory nerve action potential amplitudes also reduced by more than 50% when followed sequentially, with preservation of the velocities (Zimmerman and Lovelace, 1968; Zimmerman, 1984). Additional case reports have documented predominantly axonal neuropathy, however, some features suggestive of demyelination have also been described (temporal dispersion, prolonged F-waves, and prolonged distal latencies) (Barohn et al., 1994).

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38.8.3. Electromyography Prominent fibrillation potentials and positive sharp waves have been noted to occur in proximal and distal muscles in 4 of the 10 patients who were still weak at the time of the study (Zimmerman and Lovelace, 1968; Ridley, 1969; Flugel and Druschky, 1977; Albers et al., 1978). Albers et al. (1978) described a proximal to distal gradient in the appearance of abnormal spontaneous activity. Early on, 1–2 weeks after onset of symptoms, fibrillation potentials were only seen in the paraspinal muscles; next (2 weeks to a month) later, fibrillation potentials reduce in paraspinal muscles and occur more in the proximal muscles; and months later, fibrillation potentials were most prominent in the distal muscles, compared to the proximal or paraspinal muscles. The authors interpret this to reflect that the lesion localizes to the root or anterior horn cell, with Wallerian degeneration first taking place in short axons followed by the larger axons (Albers et al., 1978). Even though early clinical findings and physiological findings suggest more proximal involvement, studies performed months or years later show evidence of denervation-reinnervation in distal muscles more than proximal muscles, as is typical for dying-back axonal neuropathies. The authors speculate that the early changes in proximal muscles represent a terminal axonopathy (Zimmerman, 1984). Even though large duration, high amplitude units of neurogenic change are commonly seen, some patients with proximal muscle weakness have been reported to have “myopathic” motor units (Zimmerman, 1984). This is likely to be secondary to involvement of terminal axons resulting in non-motor unit pattern of muscle fiber loss. 38.8.4. Sympathetic skin response Sympathetic skin response, measured from the hands and feet, were normal in one patient, indicating the relative sparing of the postganglionic sympathetic unmyelinated C-fibers (Zimmerman, 1984). 38.8.5. Autonomic testing Laiwah noted that autonomic functions including Valsalva maneuver, heart rate variation with deep breathing, heart rate response to standing, and blood pressure response to hand-grip were abnormal in eight patients during the acute attack (Laiwah et al., 1985). Only the orthostatic blood pressure recording was comparable to normal controls. All abnormalities

OTHER INHERITED NEUROPATHIES

improved on subsequent retesting during remission. The same authors also reported that Valsalva maneuver and heart rate variation with deep breathing were also reduced for latent porphyrias and for patients in remission. Like diabetic autonomic neuropathy, tests of parasympathetic dysfunction become abnormal earlier and more frequently than tests of sympathetic function. There was no correlation between presence and severity of abdominal pain and autonomic dysfunction. R–R variation with deep breathing was reduced in one patient in the clinicopathological exercise reported, again confirming the presence of autonomic dysfunction (Zimmerman, 1984). 38.8.6. Other testing EEG studies were reported in 34 patients with porphyria. Diffuse abnormalities were seen with generalized slowing (2–5/s) in 60% of the cases (Stein and Tschudy, 1970). Two patients, studied by the same authors during remission, had normal EEG. Three patients had focal abnormalities and two showed subclinical epileptiform activity. Reichenmiller reported remarkable involvement of the visual system in three patients, one with an amaurosis fugax and clinical and seizure equivalents on EEG (Reichenmiller, 1970). 38.9. Lipoproteins and neuropathy Because lipids are hydrophobic, they are packaged into spherical structures called lipoprotein particles. Lipoproteins are composed of lipids (cholesterol, triglycerides, and phospholipids) and proteins (apolipoproteins). The five major subtypes of lipoproteins, [chlylomicrons, very low-density lipoproteins, intermediate-density lipoproteins (IDL), low-density lipoproteins (VLDL) and high-density lipoproteins (HDL)], vary in their lipid and apolipoprotein content (Genest, 2003). The function of lipoproteins is to transport lipids from the gut and liver to the sites of utilization (fat and muscle), and transport cholesterol molecules to peripheral tissues for membrane synthesis and hormone (steroids) and bile acid synthesis. Peripheral neuropathy is associated with three disorders of lipoproteins: Tangier disease, abetalipoproteinemia and familial hypolipoproteinemia. 38.9.1. Tangier disease Tangier disease (TD) is a rare syndrome caused by severe deficiency of high-density lipoproteins (HDL) in

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plasma. Since HDL normally functions to transport cholesterol from peripheral cells to the liver by reverse cholesterol transport, a deficiency of HDL results in accumulation of cholesterol esters in various tissues including macrophages, tonsils (orange color), lymphadenopathy, hepatosplenomegaly, premature coronary artery disease and peripheral neuropathy. A cellular ATP-binding cassette transporter (ABC) called ABCA1 mediates the first step of reverse cholesterol transport: the transfer of cellular cholesterol and phospholipids to apolipoproteins. Mutations in the geneencoding ATP-binding cassett 1 (ABCA1) have been identified in Tangier disease. Homozygotes typically have very low or absent HDL and apolipoprotein A-I, the major apoprotein found in HDL (Oram, 2000). Peripheral neuropathy is the most disabling feature of Tangier disease and affects about 50% of patients with Tangier disease. Three patterns are recognized: transient or relapsing often asymmetrical neuropathies (including isolated cranial nerve deficits); slowly progressive symmetrical neuropathy most marked in distal upper limbs (syringomyelia-like) and a slowly progressive symmetrical sensory motor neuropathy most marked in the lower limbs (Kocen et al., 1967; Thomas et al., 1973). Multiple mononeuropathies, including oculomotor nerve, long thoracic nerve, or any of the limb nerves, may be involved. The syringomyelic presentation includes wasting of hand muscles, loss of pin and temperature sensibility, and facial diplegia. The length-dependent sensory motor neuropathy pattern is the least common variant. Deposits of cholesterol esters in tonsils, liver, spleen, rectal mucosa, and cornea lead to the other nonneurological manifestations of the Tangier disease. Laboratory findings include severe deficiency or absence of HDL, decreased plasma cholesterol, and increased triglyceride levels. This is in contrast to the hypocholesterolemia of abetalipoproteinemia and familial hypobetalipoproteinemia patients in whom the triglyceride levels are decreased (Table 38.2). Normal serum cholesterol levels, however, do not exclude Tangier disease and measurement of HDL should be done if the diagnosis is suspected (Pollock et al., 1983). Sural nerve biopsy shows loss of myelinated fibers, regenerative clusters and lipid accumulation in nonmembrane bound vacuoles in Schwann cells, endoneurial fibroblasts, macrophages, and perineurial cells. Pollock et al assessed nerve morphometry in four patients with Tangier disease (Pollock et al., 1983). Three patients with a relapsing and remitting multiple

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mononeuropathy had prominent peripheral nerve demyelination and remyelination with affected internodes clustered along particular nerve fibers. This may explain the remissions and exacerbations seen in Tangier disease. In patients with syringomyelia like presentation however, axonal degeneration rather than demyelination is the prominent finding (Engel et al., 1967; Thomas et al., 1973; Pollock et al., 1983; Gibbels et al., 1985; Marbini et al., 1985; Pietrini et al., 1985). There is no treatment available and even a low cholesterol diet or other diet alterations do not alter the disease. In future, gene therapy may be possible since the gene defect has been precisely identified. 38.9.1.1. Neurophysiological evaluation There is limited information available for neurophysiological findings given that it is an extremely rare syndrome with barely 60 cases being reported worldwide. As suggested by the clinical features, physiological abnormalities may be limited to individual nerves, show a length dependent neuropathy, or show selective bilateral upper extremity nerve involvement. Most reported cases suggest demyelinating physiology, although axonal loss has been reported in individual case reports. 38.9.1.2. Nerve conduction studies Sensory potentials are absent in the named nerves affected in mononeuropathies. SNAP are also absent in the upper limb nerves in patients with syringomyelic presentation. This distinguishes it from syringomyelia, in which the sensory potentials are normal despite loss of pin and temperature sensibility, since the lesion is proximal to the dorsal root ganglia. Pollock’s report of four cases, noted prolonged distal latency of sensory nerves in two, absent sensory response in one, and normal sensory conduction in a fourth patient (Pollock et al., 1983). Motor nerve conduction studies showed demyelinating findings with reduced conduction velocity across the elbow segment in one patient, increased distal latency of the common peroneal nerve in one, normal study in one, and absent motor response in the fourth patient (Pollock et al., 1983). Similar demyelinating physiology in motor and sensory fibers, was reported in individual case reports of three patients, all of whom showed increased distal latency, reduced conduction velocity in the median, ulnar, peroneal and tibial nerves (Gibbels et al., 1985; Marbini et al., 1985; Pietrini et al., 1985). However, in the two cases reported by Engel, normal conduction

K.B. BOYLAN AND V. CHAUDHRY

times and distal latencies were reported (Engel et al., 1967). Pollock compared the pseudosyringomyelic neuropathy with multiple mononeuropathy and reported findings predominantly of axonal loss in the former and demyelination in the latter (Pollock et al., 1983). 38.9.1.3. Electromyography Needle EMG shows denervation changes in the affected nerve innervated muscles. The findings of denervation are more prominent in the pseudosyringomyelic form than the multiple mononeuropathy form (Engel et al., 1967; Pollock et al., 1983). 38.9.1.4. Evoked potentials In one case of syringomyelia-like syndrome evoked potential studies were done (Gibbels et al., 1985). Strobe-flash-evoked visual potentials showed a pathological P2 latency of 109 ms bilaterally (normal value 100 ± 2.5 ms). Segmental SSEP of C6 and C8 were pathological with both amplitude and latency abnormalities. 38.9.1.5. Quantitative sensory tests Marked abnormalities of touch–pressure sensation, thermal discrimination, and pricking pain thresholds were reported in the hand but not the foot of patients with syringomyelia-like presentation (Dyck et al., 1978). 38.9.2. Abetalipoproteinemia and familial hypobetalipoproteinemia Abetalipoproteinemia is characterized by complete absence of chlylomicrons, VLDL, and LDL. Homozygous hypobetalipoproteinemia has similar features. Like Tangier disease, deficiency of beta lipoproteins results in hypocholesterolemia. However, unlike Tangier disease in which the triglyceride levels are normal or elevated, triglycerides are reduced in abetalipoproteinemia and hypobetalipoproteinemia (Table 38.2). Fat malabsorption (steatorrhea), acanthocytosis of erythrocytes, atypical retinitis pigmentosa, spinocerebellar degeneration, ceroid myopathy, and peripheral neuropathy are all manifestations of abetalipoproteinemia (Wichman et al., 1985; Thomas, 1988). Abetalipoproteinemia has autosomal recessive inheritance, while familial hypobetalipoproteinemia has autosomal dominant inheritance but requires homozygosity for neurological manifestations. Mutation of the microsomal triglyceride transfer protein gene localized on

OTHER INHERITED NEUROPATHIES

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chromosome 4 is responsible for abetalipoproteinemia, and mutation of the apo B gene on chromosome 2 is responsible for familial hypobetalipoproteinemia. The earliest neurological finding is the loss of muscle stretch reflexes due to sensory neuronopathy. Areflexia has been documented at 3–5 years of age. Gait disturbance, which has central and peripheral basis, large fiber sensory loss (absent vibration and proprioception with markedly positive Romberg’s sign), intentional tremor, and dysarthria can all be present. Stocking glove pattern of sensory loss can be seen. Some of the features, including pes cavus, kyphoscoliosis, ataxia, and peripheral neuropathy, are similar to Friedreich’s Ataxia. Clinical Neurological manifestations of abetalipoproteinemia and familial hypobetalipoproteinemia are indistinguishable (Miller et al., 1980). Defects in absorption and transport of fat-soluble vitamins, particularly vitamin E is responsible for the neurological manifestations. Therefore, high-dose vitamin E therapy is helpful in slowing down the neurological manifestations of the disease.

involvement clinically (Wichman et al., 1985). An increased incidence of polyphasic potentials (17– 38% as compared to 12% as the author’s upper limit of normal) was reported. One patient showed prolonged mean duration of the motor unit potentials compatible with regeneration by local sprouting. The findings are distally prominent. Miller described similar findings although one of their three patients showed myotonic discharges (Miller et al., 1980).

38.9.2.1. Neurophysiological evaluation The neurophysiological findings represent the presence of sensory > motor axonal loss with length-dependent features. The neurophysiological findings only confirm the presence and severity of the neuropathy.

Friedreich’s Ataxia is an autosomal recessive neurodegenerative disease characterized by progressive gait and limb ataxia, dysarthria, lower limb areflexia, decreased vibration sense, muscle weakness of the legs, and positive extensor plantar response. Hypertrophic cardiomyopathy and increased incidence of diabetes mellitus are nonneurological manifestations of Friedreich’s Ataxia (Klockgether et al., 1996; Cooper and Bradley, 2002; Durr, 2002; Panas et al., 2002; Alper and Narayanan, 2003; Wilson, 2003). The causative mutation has been identified to be a triplet repeat expansion of the first intron of the frataxin gene located on chromosome 9q13 (Durr, 2002). The expansion causes a severe reduction in the expression of frataxin, a mitochondrial protein. The phenotype of Friedreich’s Ataxia is due to deficiency of frataxin that causes a decrease in activity of the iron–sulfur enzymes, progressive mitochondrial iron accumulation, and oxidant damage to the mitochondria. Even though cerebellar dysfunction and pyramidal tract signs are present early in the disease, sensory neuronopathy with marked loss of vibration loss and areflexia are constant features of this disease. In fact, the presence of sensory neuropathy helps distinguish Friedreich’s Ataxia from the autosomal dominant spinocerebellar ataxias. In the latter, even if sensory neuropathy is noted, it tends to be asymptomatic.

38.9.2.2. Nerve conduction studies The most prominent abnormality reported is the reduction in sensory nerve action potential amplitudes. Compared to the controls, the reduction in amplitudes was 77–99% in the three sisters with abetalipoproteinemia (Wichman et al., 1985). The reduction in SNAP amplitude was most marked in the distal portions of the nerves and in the older patients. The conduction velocity reduction in sensory axons appeared to be explained by a marked loss of large fibers and/or regenerative components. In contrast, CMAP amplitudes and velocities are relatively preserved. Mille et al. (1980) also reported normal distal latencies and conduction velocities in three patients. The CMAP amplitude was reduced and the SNAP was reduced or undetectable in two patients and near the lower limit of normal in one. 38.9.2.3. Needle electromyography In the 3 cases reported by Wichman, fibrillation potentials were noted to be present in 1– 8 sites of 10 tested even though these patients had minimal motor

38.9.2.4. Autonomic testing Beat-to-beat variation in heart rate with deep breathing was normal in three cases studied and none of the three cases had clinical autonomic dysfunction (Wichman et al., 1985). 38.9.2.5. Evoked potentials Somatosensory evoked potentials demonstrated dorsal column dysfunction in two patients reported by Tack et al. (1988). 38.10. Friedreich’s Ataxia

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38.10.1. Neurophysiological studies Sensory axonal loss with preservation of motor fibers is the consistent finding. Since this is considered to be a ganglionopathy, the findings may not be length dependent. 38.10.2. Nerve conduction studies Selected absence of the SNAP in Friedreich’s Ataxia has been reported by several authors (McLeod, 1912; Bouchard et al., 1979; Caruso et al., 1987). Zouari et al. (1998) reported findings of nerve conduction in 28 patients. This group also contained patients with vitamin E deficiency. In the group without vitamin E deficiency, the authors reported severe reduction or absence of sensory amplitudes in upper and lower limbs. Mean CMAP amplitudes and conduction velocities were reported normal. Longitudinal study of 15 patients over 3–7 years of follow up did not show significant change in the physiology (Santoro et al., 1999). In one study, an inverse correlation between the size of GAA1 expansion and the SNAP amplitudes (at the wrist and medial malleolus) was noted in 56 patients. No effect of disease duration was found (Santoro et al., 1999). Although most reports suggest that the neuropathy is mainly sensory and axonal, a report of Friedreich’s Ataxia presenting as uniformly demyelinating sensory and motor neuropathy, physiology of HMSNI, is also available (Panas et al., 2002). These authors report four patients from three families, however, had autosomal recessive inheritance along with trunk and gait ataxia. The molecular analysis showed that the affected individuals were homozygous for the mutation in the X25 gene, characteristic of Friedreich’s Ataxia. 38.10.3. Quantitative sensory testing A generalized reduction of prickling pain sensation (mean 21% compared to controls 78%) was reported in 14 patients examined with QST, with all but two patients failing to even perceive a painful sensation in the foot. Tactile thresholds were significantly increased as well. Cold, warm, and heat pain thresholds were also reportedly increased in the foot region (Nolano et al., 2001). 38.10.4. Evoked potentials 38.10.4.1. Somatosensory evoked potentials SEPs were either not recordable or showed delayed latency of the N20 or P40 responses and reduction of

K.B. BOYLAN AND V. CHAUDHRY

amplitudes in one study (Zouari et al., 1998). In another study, the response originating in the brachial plexus (Erb’s point potential) was absent or reduced in amplitude with no prolongation of peak latency, and the response generated in the cauda equina (N18) was absent in the nine cases reported (Beltinger et al., 1987). Central conduction times (N13a/N20, N13b/N20) were delayed. There was moderate to marked attenuation of the primary cortical response to median nerve stimulation. In one patient, N20 disappeared during the course of the disease. Similarly, the tibial nerve stimulated cortical response was either absent or markedly delayed. 38.10.4.2. Pattern-reversal visual evoked potentials (VEP) Of the 22 patients with Friedreich’s Ataxia, reported by Carroll et al. (1980), 14 (64%) had an abnormal VEP study which was always binocular and comprised absent response, or increased P100 latencies. The P100 amplitude was also generally reduced in that group. The waveform, temporal dispersion, and interocular differences were normal in almost all patients with identifiable responses, including those with prolonged VEP latencies. Electroretinograms recorded from three selected patients were either normal or minimally abnormal. The only VEP parameter that correlated with either the duration of the generalized disease or the visual acuity was the P100 amplitude. A good correlation was found between the VEP and the clinical neuro-ophthalmic findings. These authors concluded that there was a high incidence of asymptomatic visual pathway involvement in Friedreich’s Ataxia and that changes in Friedreich’s Ataxia differ from those found in typical demyelinating optic neuropathy in that progressive nerve fiber locc secondary to axonal degeneration is the likely mechanism (Carroll et al., 1980). 38.10.4.3. Brain stem auditory evoked potentials (BAEPs) BAEPs showed absence of wave III and/or V components in five patients and showed prolonged I–IV interpeak latencies in two patients in one study (Coppola et al., 1999). 38.10.4.4. Central conduction time Central sensory conduction time and central motor conduction time were reported to be abnormal in all eight patients with FA and retained reflexes phenotype (Coppola et al., 1999). A study of central motor

OTHER INHERITED NEUROPATHIES

conduction by magnetic stimulation of the cortex performed in 13 patients with classical Friedreich’s Ataxia phenotype, showed abnormality in all patients (CruzMartinez and Palau, 1997). Follow up over several years showed significant decrement of the amplitude of motor evoked potentials, suggesting progressive pyramidal involvement as the cause of clinical worsening in FA. 38.11. Spinocerebellar ataxia The autosomal dominant spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders with cerebellar ataxia as a common feature. Other systems such as basal ganglia, anterior horn cells, and dorsal root ganglia may be affected, giving rise to varied clinical expression (Pulst and Perlman, 2000). Genetic loci are identified for 23 forms of SCA (SCA 1–8, 10–14, 16, 17 and dentatorubral pallidoluyisian atrophy) (van de Warrendurg, 2005). In 10 forms of SCA in which the genetic basis is known, the mutation involves expansion of a CAG or CTG, or an ATTCT repeat (Chung et al., 2003). Molecular pathogenesis of these disorders may involve a toxic gain of function related to expansion of the repeat. Reviews of this rapidly developing field have been published (van de Warrenburg, 2005; Schols, 2004). Peripheral motor and sensory findings in SCA may be overshadowed by ataxia and associated signs such as oculomotor abnormalities, optic atrophy or retinopathy, extrapyramidal signs such as parkinsonism or choreoathetosis, and dementia (Geschwind et al., 1997a; Riess et al., 1997). In some patients, peripheral sensory and motor abnormalities may be identified only on neurophysiological testing. Overlap of clinical and pathological features and intrafamilial variability among SCA types make classification by clinical findings alone unreliable, so the presence or absence of peripheral motor or sensory abnormalities is of limited value diagnostically. Designation of SCA types is based on genetic testing (van de Warrenburg, 2005; Pulst and Perlman, 2000). Peripheral neuropathy or anterior horn cell involvement is reported in SCA 1–4, 6 and 8 (Schols et al., 1998; Pulst and Perlman, 2000). Sensory neuropathy is seen in SCA1, although lower motor neuron disease may be more significant clinically, leading to death from respiratory insufficiency. Sensory neuropathy or neuronopathy associated with loss of dorsal root ganglion neurons is frequent in SCA 4 (Flanigan et al., 1996; Nachmanoff et al., 1997). Sural nerve in SCA 2

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and 4 shows decreased large myelinated fibers (Filla et al., 1995; Nachmanoff et al., 1997). The frequency of peripheral neuropathy in published series is essentially 100% for patients with SCA1 and 4, but is less is frequent for SCA2, 3 and 6 (Geschwind et al., 1997a, 1997b, Schols et al., 1998; Pulst and Perlman, 2000). Assessment of these data are limited in that a significant number of reports do not include detailed neurophysiological evaluation. Sensory loss usually involves impairment of touch, vibration and proprioception more than pain and temperature sensation (Filla et al., 1995; Flanigan et al., 1996; Subramony et al., 1996; Geschwind et al., 1997a, 1997b; Zhuchenko et al., 1997; Schols et al., 1998; Koob et al., 1999). Weakness attributable to peripheral motor axonal loss or lower motor neuron involvement may be present as diffuse amyotrophy or involve distal muscles primarily (Filla et al., 1995; Flanigan et al., 1996; Schols et al., 1998). Abnormalities are said to be mainly sensory in SCA4 although distal lower limb weakness is reported (Flanigan et al., 1996; Nachmanoff et al., 1997). Sensory and motor deficits occur in SCA1, 2, 3 and 6 (Filla et al., 1995; Flanigan et al., 1996). Detailed information in this regard in SCA8 was not provided (Koob et al., 1999). 38.11.1. Neurophysiological evaluation Published reports suggest that nerve conduction studies, electromyography and evoked potential studies may play a useful role in the clinical assessment in SCA, but in general, detailed reports on neurophysiological findings in these disorders are lacking. Evaluation of obvious deficits as well as investigation of possible subclinical abnormalities can aid in the diagnosis of a multi-system neurodegenerative disorder and help establish an indication for genetic testing. Discussion here is limited to reports in which the diagnosis of SCA was confirmed by DNA testing. 38.11.2. Nerve conduction studies Motor nerve conduction findings in a family with SCA 1 showed mild or borderline conduction velocity slowing in two of the five patients examined, but critical assessment is precluded by the limited information provided (Nino et al., 1980). A family with SCA2 showed decreased sensory amplitudes with mildly reduced motor and sensory conduction velocities and normal motor amplitudes, but no details were otherwise given (Filla et al., 1995).

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Nerve conduction data for SCA4 were reported for 13 patients in a single kindred, but only sensory nerve amplitudes were discussed (Flanigan et al., 1996). Twelve patients had absent sural response; radial sensory response was absent in one. Of unclear significance is the family member with absent radial sensory response but normal sural response. Nachmanoff reported on one patient with SCA4 who demonstrated absent median and “tibial” nerve sensory responses at the age of 66 years (Nachmanoff et al., 1997). In 10 German patients from 9 families with SCA6, evidence of peripheral neuropathy was found in six subjects (Schols et al., 1998). Signs of a predominantly axonal sensory and motor peripheral neuropathy were found in four. A fifth patient had similar findings but sural conduction velocity was reduced to approximately 80% of the lower limit of normal with normal amplitude and decreased sural amplitude alone was seen in the final patient. The overall findings were relatively mild and assessment of the data is limited owing to lack of information regarding possible superimposed conditions that could have played a role in the findings. 38.11.3. Electromyography Needle EMG data on SCA are quite limited, despite evidence of motor neuropathy, or amyotrophy clinically in some forms, including SCA1, 2, 4, and 6 (Ranum et al., 1994; Dubourg et al., 1995; Filla et al., 1995; Genis et al., 1995; Kameya et al., 1995; Flanigan et al., 1996; Nachmanoff et al., 1997; Schols et al., 1998; Pulst and Perlman, 2000; Chung et al., 2003). In SCA1, Goldfarb et al. (1996) noted EMG evidence of “spinal motor neuron hyperexcitability and possible neuron damage” but provided no specifics. In SCA6, Schols et al. found “chronic neurogenic changes” in 5 of the 10 patients examined; 4 had abnormalities on motor nerve conduction studies, and 1 had only reduced sural amplitude. On a general note, ataxia may limit assessment of voluntary MUAP owing to erratic voluntary muscle contraction. 38.11.4. Other testing Magnetic stimulation of central motor pathways showed slowing of central motor conduction in SCA6, but was normal in SCA2 (Filla et al., 1995; Flanigan et al., 1996; Nachmanoff et al., 1997; Schols et al., 1998). Somatosensory evoked potentials demonstrated increased central conduction time in

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SCA1,3, and 22. Normal results for motor and somatosensory evoked potential studies were reported for SCA2, but brain stem auditory evoked potentials were abnormal (Filla et al., 1995). Abnormal BSAP also were reported in SCA4, 6, and 22 (Nachmanoff et al., 1997; Schols et al., 1998; Chung et al., 2003). 38.12. Giant axonal neuropathy Giant axonal neuropathy is a rare progressive disorder of childhood with central and peripheral nervous system involvement (Tandan et al., 1987; Ouvrier, 1989; Flanigan et al., 1998). Age at presentation varies but is nearly always by 7 years, usually with gait ataxia. Most patients become nonambulatory owing to progressive sensory motor peripheral neuropathy. Central nervous system signs include tremor, nystagmus, dysarthria, cerebellar ataxia, extensor plantar responses, and seizures. Ptosis and external ophthalmoplegia may occur. Mental retardation or mental decline after initial normal development is sometimes present. Tightly curled hair is characteristic, found in nearly all the patients. Skeletal abnormalities include short stature, pes planus or cavus and high arched palate. Progressive decline may lead to death by the third decade. Sural nerve biopsy is diagnostic, demonstrating giant axonal swellings that on electron microscopy contain abnormal accumulation of neurofilaments. Similar widespread lesions are found in the central nervous system, including the optic nerves and tracts (Berg et al., 1972; Koch et al., 1977; Tandan et al., 1987). Giant axonal neuropathy is caused by mutations in the gigaxonin gene on chromosome 16q24. The gene product is a cytoskeletal protein that may function in actin–cytoskeletal interactions (Flanigan et al., 1998). 38.12.1. Neurophysiological evaluation Data on the clinical neurophysiological findings in giant axonal neuropathy are limited to individual case reports. Evaluation of larger numbers of patients by a single examiner or group is essentially prevented by rarity of the disorder. Neurophysiological evaluation is useful in characterizing the neuromuscular findings in this disorder, as the findings are those of a primarily axonal peripheral neuropathy (Ouvrier, 1989; Kumar et al., 1990). Associated abnormalities on evoked potential testing reflect central axonal pathology.

OTHER INHERITED NEUROPATHIES

38.12.2. Nerve conduction studies Sensory nerve action potential amplitudes are decreased or absent, with mild abnormality of distal latencies and conduction velocities (Mizuno et al., 1979; Tandan et al., 1987; Kumar et al., 1990; Mohri et al., 1998). Motor amplitudes are normal or reduced, but may be absent, especially when recorded from intrinsic foot muscles (Tandan et al., 1987; Kumar et al., 1990). Motor conduction velocities and distal motor latencies range from normal to moderately abnormal, with more pronounced abnormality in the lower limbs (Mizuno et al., 1979; Tandan et al., 1987; Kumar et al., 1990; Mohri et al., 1998). It is noteworthy that nerve conduction studies may be normal early in the course even if signs such as gait ataxia are present (Koch et al., 1977; Tandan et al., 1987; Kumar et al., 1990). While reliability of these data might be questioned, indirect support comes from a report in which sural biopsy was normal in a clinically affected patient at the age of 2 years but abnormal at age 7 years (Gambarelli et al., 1977). The data suggest that neurophysiological testing is an unreliable means of presymptomatic diagnosis. 38.12.3. Electromyography Needle EMG examination reveals high amplitude and complex motor unit potentials with positive wave and fibrillation potentials, in a distribution in keeping with a length-dependent axonal peripheral neuropathy (Koch et al., 1977; Mizuno et al., 1979; Tandan et al., 1987; Kumar et al., 1990). 38.12.4. Other testing Visual, brainstem auditory, and somatosensory evoked potentials may be abnormal, a reflection of central nervous system involvement (Mizuno et al., 1979; Majnemer et al., 1986; Kumar et al., 1990; Mohri et al., 1998). EEG is abnormal in some patients; abnormalities may include generalized spike activity, sharp and slow waves, and focal slowing in some patients (Koch et al., 1977; Mizuno et al., 1979; Ouvrier, 1989), although EEG may be normal (Mohri et al., 1998). 38.13. Mitochondrial encephalomyopathies Mitochondrial encephalomyopathies are a diverse group of uncommon conditions caused by functional

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abnormality of mitochondria (DiMauro and Davidzon, 2005; Simon and Johns, 1999). Clinical manifestations are characteristically expressed in organ systems with high oxidative metabolic requirements, including the nervous system and skeletal muscle. Myopathy in these conditions is typically associated with characteristic histological changes under light and/or electron microscopy of skeletal muscle biopsy (DiMauro et al., 1985). Mitochondrial disorders can be caused by mutations in mitochondrial or nuclear DNA (DiMauro and Moraes, 1993; Nardin and Johns, 2001). Mitochondrial DNA derives almost entirely from the oocyte, resulting in the inheritance of mitochondrial DNA mutations from the maternal line. Nuclear DNA mutations showing mendelian inheritance of mitochondrial disease, as well as sporadic occurrence are also reported (Nardin and Johns, 2001; Pulkes et al., 2003). Establishing the diagnosis of a mitochondrial disorder may be complex and typically involves a variety of investigations, including laboratory tests, neurophysiological studies, imaging studies, muscle biopsy, and DNA testing (DiMauro and Moraes, 1993; Nardin and Johns, 2001). Neuromuscular manifestations of mitochondrial disease may present as part of a complex multi-system disorder or primarily as a neuromuscular disorder (Nardin and Johns, 2001). Onset age ranges from infancy to late adulthood. Specific constellations of organ system involvement are reported in mitochondrial diseases, but significant clinical overlap is reported among the various presentations (Petty et al., 1986; Nardin and Johns, 2001). Similarly, mitochondrial DNA or nuclear DNA mutations may be associated with multiple clinical presentations (Nardin and Johns, 2001; Sciacco et al., 2001). Frequency of clinically evident peripheral neuropathy in mitochondrial encephalomyopathies is in the range of 20–25% (Nardin and Johns, 2001). Peripheral neuropathy may be clinically significant or subclinical, and can be overshadowed by myopathy or other organ system involvement. Several mitochondrial syndromes have been described in which peripheral neuropathy may be an important feature (Table 38.4) (McDonald et al., 2002). These include a broad range of clinical presentations, and review of these is beyond the scope of this section. The peripheral neuropathy in these disorders can be axonal or demyelinating, but the former is more common in published series (Nardin and Johns, 2001). Evidence of peripheral neuropathy may be confined to abnormalities on nerve conductions studies (Yiannikas

796 Table 38.4 Mitochondrial disorders in which peripheral neuropathy occurs (modified from McDonald, et al., 2002) Present in essentially all cases NARP MNGIE SANDO Mixed sensory–motor peripheral neuropathy Chronic demyelinating peripheral neuropathy Present in some patients Cuban optic neuropathy Leigh syndrome MELAS MERRF Mitochondrial DNA depletion syndromes Multiple symmetric lipomatosis Mitochondrial trifunctional β-oxidation defect MELAS: mitochondrial encephalopathy, lactic acidosis and stroke-like episodes; MERRF: myoclonus epilepsy with ragged red fibers; MNGIE: myo-, neuro-, gastrointestinal encephalopathy; NARP: neuropathy, ataxia, retinitis pigmentosa; SANDO: sensory ataxic neuropathy, dysarthria and ophthalmoplegia

et al., 1986). Patients with clinically evident peripheral neuropathy may demonstrate mitochondrial abnormalities on sural nerve biopsy, suggesting that mitochondrial dysfunction is the cause of the peripheral neuropathy (Schroder, 1993; Nardin and Johns, 2001). A variety of therapies for mitochondrial encephalomyopathies have been studied, but none are of proven benefit (Burns et al., 2003). 38.13.1. Neurophysiological evaluation Variability in the clinical expression of mitochondrial disorders extends to the findings on neurophysiological evaluation of these patients. Rather than support the diagnosis of a specific mitochondrial disorder, nerve conduction studies and EMG are useful in primarily identifying or confirming signs of nerve and/or muscle involvement when such a disorder is suspected, leading to definitive testing, such as DNA mutation analysis of peripheral blood or tissue biopsy. 38.13.2. Nerve conduction studies Motor and/or sensory evoked amplitudes may be normal or decreased to absent, although reduced

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sensory amplitudes are reported more often (Petty et al., 1986; Yiannikas et al., 1986; Holt et al., 1990; Coker, 1993; Hara et al., 1994; Uncini et al., 1994; Rusanen et al., 1995; Chalmers et al., 1996; van Domburg et al., 1996; Chu et al., 1997; Gulati et al., 2001; Karppa et al., 2003). Motor and sensory conduction velocities are usually normal or mildly decreased (Petty et al., 1986; Yiannikas et al., 1986; Coker, 1993; Uncini et al., 1994; Barak et al., 1995; van Domburg et al., 1996; Chu et al., 1997; Karppa et al., 2003). Abnormalities may be more pronounced in the lower extremities (Rusanen et al., 1995; van Domburg et al., 1996; Chu et al., 1997). In some published reports, the findings are characterized as showing signs of a mixed axonal and demyelinating process (Nishino et al., 2000; Soykan et al., 2002; Karppa et al., 2003). Temporal dispersion in neuropathy with demyelinating features has been reported (Uncini et al., 1994; Fang, 1996). Relatively more pronounced conduction velocity slowing compatible with demyelination is reported in some forms of mitochondrial encephalomyopathy, but is less common than findings suggestive of axonal pathology (Uncini et al., 1994; Fang, 1996). Motor and sensory distal latencies may be prolonged. 38.13.3. Needle electromyography EMG may show abnormalities compatible with a myopathy (Yiannikas et al., 1986; Uncini et al., 1994; Sciacco et al., 2001). Findings characteristic of motor denervation have been reported in some patients, and mixed myopathic and neurogenic features may be seen (Petty et al., 1986; Barak et al., 1995; Chalmers et al., 1996; van Domburg et al., 1996; Chu et al., 1997; Naumann et al., 1997; Nagashima et al., 2001). Abnormal spontaneous activity such as fibrillation potentials is reported but appears to be relatively infrequent (Carvalho et al., 1993; Chu et al., 1997; Nardin and Johns, 2001). Some investigators have noted decreased recruitment with normal appearing voluntary motor unit potentials (Hara et al., 1994; Klimek et al., 1997). 38.13.4. Other testing EEG may be contributory and should be routine if seizures are suspected (Smith and Harding, 1993; Scaioli et al., 1998). Visual, auditory, somatosensory, and motor-evoked potentials may aid in the assessment of central conduction, depending upon the clinical pres-

OTHER INHERITED NEUROPATHIES

entation (Lupo et al., 1992; Sartucci et al., 1993; Nakamura et al., 1995; Rigaudiere et al., 1995; Korres et al., 1999; Finsterer, 2001). 38.14. Other inherited neuropathies Other rare inherited disorders in which peripheral neuropathy is a central feature or part of a multi-systemic condition are briefly discussed in this section. 38.14.1. Infantile neuroaxonal dystrophy Infantile neuroaxonal dystrophy is a neurodegenerative disorder of unknown cause that presents usually by the age of 2 years with progressive psychomotor regression, visual loss, hypotonia, and weakness (Aicardi and Castelein, 1979; Nardocci et al., 1999). Early in the course, nerve conduction studies and needle EMG may be normal. Motor and sensory nerve conduction studies show progressive loss of SNAP and CMAP amplitudes in a length-dependent pattern (Nardocci et al., 1999). Conduction velocities may be normal or mildly decreased (Aicardi and Castelein, 1979; Nardocci et al., 1999). Needle EMG may reveal signs of active and chronic motor denervation (Aicardi and Castelein, 1979; Ramaekers et al., 1987; Nardocci et al., 1999). Abnormalities on needle EMG tend to develop earlier than abnormalities on nerve conduction studies (Nardocci et al., 1999). 38.14.2. Cockayne syndrome Cockayne syndrome is a rare progeric disorder caused by defective DNA repair, presenting in early childhood (Woods, 1998). The inheritance is autosomal recessive. Nerve conduction studies show uniform conduction velocity slowing compatible with demyelination (Miller et al., 1985). Needle EMG may reveal evidence of chronic motor denervation but usually is unremarkable (Moosa and Dubowitz, 1970; Lewis et al., 1982; Grunnet et al., 1983; Vos et al., 1983). 38.14.3. Ataxia telangiectasia Ataxia telangiectasia is an autosomal recessive disorder of DNA repair caused by a mutation in the ataxia telangiectasia mutated gene on chromosome 11q22.3 (Woods, 1998). Patients develop motor delay, cerebellar ataxia, oculocutaneous telangiectasia, increased frequency of sinopulmonary infections, and oculomotor dyspraxia, usually by the age of 5 years, although later onset may

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occur. Axonal sensory motor neuropathy also develops (Malandrini et al., 1990). Neurophysiological abnormalities tend to develop in parallel with signs of cerebellar ataxia (Kwast and Ignatowicz, 1990). Sensory nerve action potentials show reduced amplitude or are absent, with normal or only mild slowing of sensory nerve conduction velocities and prolongation of distal sensory latencies (Dunn, 1973; Martinez et al., 1977; Kwast and Ignatowicz, 1990). In one relatively large series, reduced sensory amplitudes were found by the age of 7 years (Kwast and Ignatowicz, 1990). Motor nerve conduction velocities may be normal or mildly decreased with reduced motor amplitudes and prolongation of terminal latencies (Dunn, 1973; Martinez et al., 1977; Kwast and Ignatowicz, 1990). Motor conduction velocities typically are within 70% of the lower limit of normal. However, Lelli et al. (1995) reported more significant motor conduction velocity slowing in two of their eight patients. Needle EMG examination may reveal fibrillation potentials and signs of chronic motor denervation in distal limb muscles (Goodman et al., 1969; Dunn, 1973). Nerve conduction and needle EMG abnormalities tend to be more pronounced in the lower limbs than in the upper limbs (Kwast and Ignatowicz, 1990; Woods and Taylor, 1992).

38.14.4. Marinesco–Sjögren syndrome Marinesco–Sjögren syndrome is an autosomal recessive disorder linked to chromosome 5q31, presenting usually in infancy with reduced mentation, cataracts, cerebellar ataxia, hypergonadotrophic hypogonadism, skeletal deformity, and myopathy (LagierTourenne et al., 2003). A number of published reports indicate that polyneuropathy is also a feature of Marinesco–Sjogren syndrome, but recent DNA linkage data raise doubt as to whether polyneuropathy does in fact occur in Marinesco–Sjögren syndrome linked to 5q31 (Lagier-Tourenne et al., 2003). Nevertheless, it remains clear that central features of Marinesco–Sjögren syndrome may occur in conjunction with peripheral neuropathy in some patients (Muller-Felber et al., 1998). Genetic heterogeneity in Marinesco–Sjögren syndrome with peripheral neuropathy is apparent in that a “subtype” of the disorder with demyelinating peripheral neuropathy and episodes of rhabdomyolysis was linked to chromosome 18qter, while linkage to 5q31 or 18qter was excluded in two other families with peripheral neuropathy and features of Marinesco–Sjögren syndrome

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(Muller-Felber et al., 1998; Merlini et al., 2002; Lagier-Tourenne et al., 2003). Neurophysiological findings in published cases of Marinesco–Sjögren syndrome tend to reflect either myopathy or peripheral neuropathy. The former include evidence of myopathy on needle EMG and normal nerve conduction studies aside from reduced motor amplitudes attributed to myopathy (Alter and Kennedy, 1968; Torbergsen et al., 1991; Sasaki et al., 1996; Farah et al., 1997). Findings in peripheral neuropathy range from nerve conduction velocity slowing to ≤70% of the lower limit of normal with decreased motor and sensory amplitudes and prolongation of distal latencies, to mildly reduced conduction velocities and motor and sensory amplitudes (Hakamada et al., 1981; Alexianu et al., 1983; Bromberg et al., 1990; Zimmer et al., 1992; MullerFelber et al., 1998). Needle EMG may demonstrate fibrillations and signs of chronic motor denervation (Alexianu et al., 1983; Bromberg et al., 1990; MullerFelber et al., 1998). 38.14.5. Sialidosis type 1 Sialidosis type 1, or cherry-red spot-myoclonus syndrome is a disorder of glycoprotein degradation marked by nonpigmentary retinal degeneration with a cherry-red spot in the macula, disabling myoclonus, generalized seizures and peripheral neuropathy (Thomas and Beaudet, 1995). Onset is usually in the second decade. Detailed neurophysiological data are limited to a single case report, in which motor and sensory conduction velocities were mildly to moderately reduced and sural response absent (Steinman et al., 1980). Needle EMG was normal. 38.14.6. Hereditary tyrosinemia type 1 Hereditary tyrosinemia type 1, or hepatorenal tyrosinemia, is an autosomal recessive disease caused by deficiency of fumarylacetoacetate hydrolase (Mitchell et al., 1995). Onset is in infancy or early childhood. Presentation is variable, involving mainly hepatic and renal manifestations, including acute liver failure, cirrhosis, renal Fanconi syndrome and glomerulosclerosis. Neurologic crises with acute painful peripheral neuropathy are an important feature in some patients (Mitchell et al., 1990; Gibbs et al., 1993; Burns et al., 2003). These episodes are similar to those of intermittent porphyria or inflammatory demyelinating polyradiculoneuropathy, and may be a

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presenting sign (Gibbs et al., 1993). Neurologic crises may progress to weakness, potentially involving respiratory muscles and requiring mechanical ventilation (Mitchell et al., 1990). Nerve conduction studies during these events show decreased motor and sensory amplitudes with preserved or reduced conduction velocities (Mitchell et al., 1990; Gibbs et al., 1993). Needle EMG may reveal fibrillations. Recovery may occur despite a prolonged attack (Mitchell et al., 1990). Dietary and pharmacological treatments are effective and may control episodic crises (Burns et al., 2003). 38.14.7. Hyperoxaluria type 1 Primary hyperoxaluria occurs in two forms, each caused by a different enzyme deficiency (Burns et al., 2003). Systemic complications arise only from the Type 1 form, hepatic alanine-glyoxylate aminotransferase deficiency. Manifestations include childhood onset of nephrolithiasis and obstructive uropathy, myopathy, arthritis, and peripheral neuropathy. Eventual renal failure is a major clinical feature (Moorhead et al., 1975; Bilbao et al., 1976; Hall et al., 1976; Farreli et al., 1997). Painful paresthesias and distal weakness may occur, although the neuropathy in some patients is subclinical (Burns et al., 2003). Nerve conduction studies demonstrate findings compatible with a mixed axonal and demyelinative polyneuropathy, with reduced amplitude or absent motor and sensory responses, prolongation of distal latencies, and conduction velocity slowing to as much as 70% or less of the lower limit of normal (Moorhead et al., 1975; Bilbao et al., 1976; Hall et al., 1976; Farreli et al., 1997). Needle EMG examination may reveal fibrillation potentials and signs of chronic partial motor denervation in distal limb muscles (Moorhead et al., 1975; Bilbao et al., 1976; Hall et al., 1976; Farreli et al., 1997). Renal failure in reported patients raises the possibility that the peripheral neuropathy is contributed to significantly by uremia, but some authors have noted that worsening of peripheral neuropathy after initiation of hemodialysis and marked spontaneous activity on needle EMG in hyperoxaluria Type 1 contrast with findings in uremic neuropathy (Moorhead et al., 1975; Bilbao et al., 1976; Hall et al., 1976; Farreli et al., 1997). Combined liver–renal transplantation may be indicated in severely affected patients, and may allow improvement in neuropathic features (Galloway et al., 1998; Burns et al., 2003).

OTHER INHERITED NEUROPATHIES

38.14.8. Cerebrotendinous xanthomatosis Cerebrotendinous xanthomatosis, or 27-hydroxylase deficiency, is an autosomal recessive lipid storage disorder in which cholesterol and cholestanol accumulation occurs in all tissues, including the nervous system (Salen et al., 1983; Bjorkhem and Boberg, 1995). Tendon xanthomas develop in nearly all the patients. Additional features include cataracts, progressive dementia, ataxia, spasticity and peripheral neuropathy. Presentation typically is in late childhood or adolescence, with death occurring in the fourth to sixth decades. Motor and sensory nerve conduction velocities are mildly to moderately reduced in a length-dependent pattern with prolongation of distal latencies (Kuritzky et al., 1979; Argov et al., 1986). Sensory nerve action potentials may be absent or show decreased amplitude (Kuritzky et al., 1979; Argov et al., 1986). On needle EMG significant motor denervative changes are apparently not found, although details in published reports are limited (Argov et al., 1986). Treatment with chenodeoxycholic asset may result in significant clinical improvement, including improvement of nerve conduction velocities (Burns et al., 2003). References Aguayo, AJ, Nair, CP and Bray, GM (1971) Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy. Arch. Neurol., 24: 106–116. Aicardi, J and Castelein, P (1979) Infantile neuroaxonal dystrophy. Brain, 102: 727–748. Albers, JW, Robertson, WC, Jr. and Daube, JR (1978) Electrodiagnostic findings in acute porphyric neuropathy. Muscle Nerve, 1: 292–296. Alexianu, M, Christodorescu, D, Vasilescu, C, Dan, A, Petrovici, A, Magureanu, S and Savu, C (1983) Sensorimotor neuropathy in a patient with MarinescoSjogren syndrome. Eur. Neurol., 22: 222–226. Alper, G and Narayanan, V (2003) Friedreich’s ataxia. Pediatr. Neurol., 28: 335–341. Alter, M and Kennedy, W (1968) The MarinescoSjogren syndrome. Hereditary cerebello-lental degeneration with mental retardation. Minn. Med., 51: 901–906. Alvarez, E, Ferrer, T, Perez-Conde, C, LopezTerradas, JM, Perez-Jimenez, A and Ramos, MJ (1996) Evaluation of congenital dysautonomia other than Riley-Day syndrome. Neuropediatrics, 27: 26–31.

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Amato, AA and Dumitru, D (2002) Hereditary neuropathies. In: D Dumitru, MJ Zwarts, AA Amato (Eds.), Electrodiagnostic medicin., Hanley & Belfus, Inc., Philadelphia, PA, pp. 899–936. Anzil, AP and Dozic, S (1978) Peripheral nerve changes in porphyric neuropathy: findings in a sural nerve biopsy. Acta. Neuropathol. (Berl.), 42: 121–126. Argov, Z, Soffer, D, Eisenberg, S and Zimmerman, Y (1986) Chronic demyelinating peripheral neuropathy in cerebrotendinous xanthomatosis. Ann. Neurol., 20: 89–91. Arvidsson, J, Hagberg, B, Mansson, JE and Svennerholm, L (1995) Late onset globoid cell leukodystrophy (Krabbe’s disease)—Swedish case with 15 years of follow-up. Acta. Pediatr., 84: 218–221. Auer-Grumbach, M, Wagner, K, Timmerman, V, De Jonghe, P and Hartung, HP (2000) Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci. Neurology, 54: 45–52. Auer-Grumbach, M, De Jonghe, P, Verhoeven, K, Timmerman, V, Wagner, K, Hartung, HP and Nicholson, GA (2003) Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review. Arch. Neurol., 60: 329–334. Axelrod, FB, Iyer, K, Fish, I, Pearson, J, Sein, ME and Spielholz, N (1981) Progressive sensory loss in familial dysautonomia. Pediatrics, 67: 517–522. Aziz, H and Pearce, J (1968) Peripheral neuropathy in metachromatich leucodystrophy. Br. Med. J., 4: 300. Barak, Y, Arnon, S, Wolach, B, Raz, Y, Ashkenasi, A, Glick, B and Shapira, Y (1995) MELAS syndrome: peripheral neuropathy and cytochrome C-oxidase deficiency: a case report and review of the literature. Isr. J. Med. Sci., 31: 224–229. Barohn, RJ, Sanchez, JA and Anderson, KE (1994) Acute peripheral neuropathy due to hereditary coproporphyria. Muscle Nerve, 17: 793–799. Becker, DM and Kramer, S (1977) The neurological manifestations of porphyria: a review, Medicine (Baltimore), 56: 411–423. Bellone, E, Rodolico, C, Toscano, A, Di Maria, E, Cassandrini, D, Pizzuti, A, Pigullo, S, Mazzeo, A, Macaione, V, Girlanda, P, Vita, G, Ajmar, F and Mandich, P (2002) A family with autosomal dominant mutilating neuropathy not linked to either Charcot–Marie–Tooth disease type 2B (CMT2B) or

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Chung, MY, Lu, YC, Cheng, NC and Soong, BW (2003) A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23. Brain, 126: 1293–1299. Clark, JR, Miller, RG and Vidgoff, JM (1979) Juvenileonset metachromatic leukodystrophy: biochemical and electrophysiologic studies. Neurology, 29: 346–343. Coelho, T (1996) Familial amyloid polyneuropathy: new developments in genetics and treatment. Curr. Opin. Neurol., 9: 355–359. Coker, SB (1993) Leigh disease presenting as Guillain–Barré syndrome. Pediatr. Neurol., 9: 61–63. Comabella, M, Waye, JS, Raguer, N, Eng, B, Dominguez, C, Navarro, C, Borras, C, Krivit, W and Montalban, X (2001) Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G—>A mutation and a newly identified missense mutation (Thr408Ile) in a Spanish family. Ann. Neurol., 50: 108–112. Cooper, JM and Bradley, JL (2002) Friedreich’s ataxia. Int. Rev. Neurobiol., 53: 147–173. Coppola, G, De Michele, G, Cavalcanti, F, Pianese, L, Perretti, A, Santoro, L, Vita, G, Toscano, A, Amboni, M, Grimaldi, G, Salvatore, E, Caruso, G and Filla, A (1999) Why do some Friedreich’s ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study. J. Neurol., 246: 353–357. Corsi, FM, Fausti, S, Serrao, M, Casali, C, Parisi, L and Piazza, G (2002) Electromyographic mixed nerve and cutaneous silent period in evaluating the A-delta fibers in a patient with hereditary sensory-autonomic neuropathy. Funct. Neurol., 17: 31–34. Cruz-Martinez, A and Palau, F (1997) Central motor conduction time by magnetic stimulation of the cortex and peripheral nerve conduction follow-up studies in Friedreich’s ataxia. Electroencephalogr. Clin. Neurophysiol., 105: 458–461. Darras, BT, Adelman, LS, Mora, JS, Bodziner, RA and Munsat, TL (1986a) Familial amyloidosis with cranial neuropathy and corneal lattice dystrophy. Neurology, 36: 432–435. Darras, BT, Kwan, ES, Gilmore, HE, Ehrenberg, BL and Rabe, EF (1986b) Globoid cell leukodystrophy: cranial computed tomography and evoked potentials. J. Child Neurol., 1: 126–130. De Silva, KL and Pearce, J (1973) Neuropathy of metachromatic leucodystrophy. J. Neurol. Neurosurg. Psychiatry, 36: 30–33.

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CHAPTER 39

Diseases of cranial nerves and brainstem G. Cruccu* and A. Truini Department of Neurological Sciences, La Sapienza University, Italy

39.1. Introduction In the cranial nerve territory, motor function is assessed with transcranial magnetic stimulation and electrical stimulation of the extra-cranial nerve branches, sensory function with trigeminal-reflex techniques. These methods are described in Chapters 10 and 25. Although this chapter concentrates on the diagnostic applications of neurophysiological methods in disease rather than on the methods themselves, it includes a short technical section on the trigeminal evoked potentials after electrical or laser stimuli. Neurophysiological findings in patients with trigeminal lesions, craniofacial pains, and facial, accessory, and hypoglossal neuropathies have been discussed in detail. This chapter also deals with the cranial nerve involvement in systemic or extra-segmentary diseases such as polyneuropathy, motor neuron disease, and myasthenia. Clinical neurophysiology of the optic, vestibulocochlear, glossopharyngeal and vagal nerves is not discussed here. 39.2. Anatomical-functional organization of the trigeminal system 39.2.1. Peripheral pathways The trigeminal nerve, the largest cranial nerve, takes its name from its three major sensory branches: the ophthalmic (V1), maxillary (V2), and mandibular nerves (V3). All three convey information about touch, temperature, pain, and proprioception from the

* Correspondence to: Professor Giorgio Cruccu, Dipartimento Scienze Neurologiche, Viale Università 30, 00185 Roma, Italy. E-mail address: [email protected] Tel.: +39-06-49914718; fax: +39-06-49914758.

mouth, face, and scalp, to the brainstem (Fig. 39.1). The trigeminal nerve originates in the posterior cranial fossa, emerging from the pons, with a small motor root (portio minor, 7500 myelinated fibers) and a large sensory root (portio major, 170 000 myelinated fibers) (Pennisi et al., 1991). The fibers of the sensory root arise from the pseudounipolar cells of the semilunar ganglion (Gasserian ganglion), which is located in a dura mater cavity (Meckel’s cave) in the middle cranial fossa (Fig. 39.1). The ophthalmic nerve (25 000 fibers), the smallest of the three trigeminal divisions, is a purely sensory nerve. It runs along the lateral wall of the cavernous sinus, below the oculomotor and trochlear nerves. Just before entering the orbit through the superior orbital fissure, it divides into three branches, the lachrymal, frontal, and nasociliary nerves. These branches supply the cornea, nasal cavity, and skin of the upper eyelid, dorsum of the nose, forehead, and scalp as far as back as the border between the anterior two-third and the posterior third of the scalp (an area innervated by the great occipital nerve). The maxillary nerve (50 000 fibers), again a purely sensory nerve, lies in an intermediate position and its pathway runs between the ophthalmic and mandibular nerves. It exits the skull through the foramen rotundum, enters the orbit and then the infraorbital canal on the floor of the orbit, and finally reaches the facial skin through the infraorbital foramen. The main terminal branches of the maxillary nerve convey sensory information from the lower eyelid, zygoma, nose, medial cheek, and upper lip. While running in the maxillary bone, the nerve also gives off a series of tiny branches to innervate the nasal and oral cavity, including the upper teeth. The mandibular nerve (78 000 fibers), the largest of the trigeminal divisions, is a mixed nerve, made up of a large sensory root and a small motor root, which merge immediately after their skull-exit through the foramen ovale. In the infratemporal fossa, below the

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G. CRUCCU AND A. TRUINI

A

B

V1

V2

V3

C SOF MC

v1

1

GG

v2

3

2

FR

IV

FO 4

v3

MN

Fig. 39.1 Anatomy of the trigeminal system. (A) Cutaneous territories of the first (V1), second (V2), and third (V3) trigeminal divisions. (B) Peripheral distribution of the trigeminal nerves. (C) Brain stem trigeminal nuclei and trigeminal divisions arising from the gasserian ganglion. MC = Meckel’s cave; Mn = motor nerve; SOF = superior orbital fissure; FR = foramen rotondum; FO = foramen ovale; GG = gasserian ganglion; 1 = mesencephalic nucleus; 2 = main sensory nucleus; 3 = motor nucleus; 4 = spinal trigeminal nucleus (Modified from: Hutchins et al., 1989 with permission).

skull base, the nerve divides into several motor and sensory branches. Motor nerves innervate the jawclosers (masseter, temporalis, medial and lateral pterygoid muscles) and jaw-openers (mylohyoid and anterior belly of the digastric muscles), as well as the tensor veli palatini and the tensor tympani muscles. The main sensory nerves (buccal, lingual, inferior alveolar, mylohyoid, mental and auriculotemporal nerves) innervate the mandibular portion of the oral cavity including the anterior two-thirds of the tongue, teeth and periodontium, the skin anterior to the ear, tympanic membrane, temporomandibular joint, the skin overlying the mandible, and lower lip. Among features peculiar to the trigeminal system is the unique innervation of the corneal mucosa and

dental pulp: probably because they serve a protective sensory function alone, they are innervated solely by Aδ and C nociceptors. The mechanical sensations projected to the teeth are mediated by periodontal mechanoreceptors. Corneal sensations are mostly unpleasant if not frankly painful. The corneal nerve endings are indeed densely supplied with nociceptive transmitters such as substance P (SP) and calcitonin gene-related peptide (CGRP). The proximal axons of the Gasserian ganglion cells form the sensory root, which enters the mid ventrolateral pons together with the motor root. The transition from Schwann cell myelination to oligodendroglial myelination begins a few millimeters away from the root entry zone. The intra-axial fibers

DISEASES OF CRANIAL NERVES AND BRAINSTEM

of the primary neurons head toward the various nuclei that constitute the trigeminal brainstem complex extending from midbrain to the C2 segment of the spinal cord. 39.2.2. Trigeminal nuclei The trigeminal motor nucleus is located in the dorsolateral pontine tegmentum, ventromedial to the trigeminal main sensory nucleus. Trigeminal motoneurons receive a strong inhibitory input from mechanoreceptors and free nerve endings. The powerful inhibition exerted by cutaneous and intraoral Aβ mechanoreceptors and Aδ nociceptors probably compensates for the unusual organization of the jaw-closing motoneurons because— unlike spinal motoneurons—they undergo neither reciprocal inhibition nor Renshaw inhibition: the jaw-openers are devoid of muscle spindles and all trigeminal motoneurons lack recurrent axons. This organization, in particular the inhibition arising from perioral and intraoral receptors, contributes to speech control, exerts a defensive action during mastication, and has been thought to play a role in masticatory myofascial pains. The mesencephalic nucleus of the trigeminal sensory complex extends in the dorsomedial tegmentum from the level of the trigeminal motor nucleus in the pons to rostral midbrain. This sensory nucleus, rather than the ganglion, contains the cell bodies of primary sensory neurons; these convey information from proprioceptors of the oculomotor and masticatory systems. The Ia axons of mesencephalic neurons that innervate the muscle spindles of jaw-closing muscles, at a short distance from their cell bodies, give off short collaterals that connect monosynaptically with jaw-closing motoneurons in the pons, and mediate the jaw jerk (or mandibular stretch reflex). Compared to the other trigeminal sensory nuclei, the main sensory nucleus is a small gray mass lying in the dorsolateral pontine tegmentum, close to the motor nucleus. It receives the most important input from the Aβ myelinated afferents that convey tactile information from capsulated mechanoreceptors in all trigeminal territories (Darian Smith, 1966). The spinal trigeminal complex consists of the trigeminal descending tract (intra-axial primary afferents) and spinal nucleus (second-order neurons). The primary afferents descend caudally, always keeping lateral to the nucleus, down to the C2 spinal segment. The tract contains Aβ large-myelinated, Aδ smallmyelinated, and unmyelinated (C) afferents conveying tactile, thermal, and nociceptive inputs from all trigeminal territories, as well as primary afferents of other cranial nerves (VII, IX, X) conveying sensory

815

input from the ear, pharynx, and larynx. All these afferents connect with the second-order neurons in the spinal nucleus, which extends from mid pons to C2 and is rostrocaudally divided into three sub-nuclei: oralis, interpolaris, and caudalis (Johnson et al., 1991). Nucleus oralis, the most rostral, merges in the pons with the main sensory nucleus. Nucleus interpolaris, located in between the other two nuclei, extends from the rostral pole of the hypoglossal nucleus to the obex. The rostral subnuclei of the spinal trigeminal nucleus along with the main sensory nucleus help to relay and modulate the orofacial touch sense; they mostly contain low-threshold mechanoreceptive neurons (LTM) that provide the higher brain levels with detailed information on tactile sensations (Darian Smith, 1966). In contrast, nucleus caudalis is universally considered as the main brainstem nucleus serving orofacial nociception. 39.3. Neurophysiological problems in the trigeminal territory 39.3.1. Nerve conduction studies and reflex responses Because the motor nerves run deep in the orofacial structures and reach their target muscles only from their inner surface, standard conduction studies are impossible. As an alternative, transcranial magnetic stimulation (TMS) yields motor evoked potentials (MEPs) in the contracting masseter. Masseter MEPs have a 6 ms latency. Unfortunately, the intracranial trigeminal motor root is harder to stimulate than that of the facial nerve; it requires transcranial electrical stimulation, which excites the motor root at its foramen-ovale exit, yielding 2 ms responses in the masseter (Cruccu et al., 1989). Alternatively, the masseteric nerve can be stimulated directly by inserting a fine needle below the zygomatic arch into the infraorbital fossa (Fig. 39.2): very-low-intensity stimuli evoke an M-wave in the masseter (1.6 ms latency) and subjects perceive only the muscle twitch; during voluntary contraction, the same stimuli also evoke an H-reflex (5–6 ms latency) in the masseter and temporalis muscle (Macaluso and De Laat, 1995; Cruccu et al., 2001a). Conduction of the mylohyoid (M-wave latency 2.3 ms) and deep temporal nerves (M wave latency 2.1 ms) can be investigated with an intra-oral pediatric stimulator (Dillingham et al., 1996). With the exception of the supraorbital nerve, the sensory nerves run into bone canals and when they emerge on the facial surface divide into tiny terminals that intermingle with facial nerve terminals. It is almost

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G. CRUCCU AND A. TRUINI

H

T Stim M M SP

Fig. 39.2 Heteronymous temporalis H-reflex and masseter M-wave after electrical stimulation of the masseteric nerve. Left: schematic representation of the human infratemporal fossa in coronal section, showing the temporalis muscle and deep temporal nerves (T), the masseter muscle and masseteric nerve (M), and the site of stimulation with a monopolar needle electrode (Stim). Right: H-reflex (H), M-wave (M), and silent period (SP) in a representative subject during maximum voluntary contraction; raw signals (superimposition of 8 trials). Upper traces: bipolar surface EMG recording from the right temporalis muscle. Calibration 20 ms/0.5 mV. Lower traces: bipolar surface recording from the right masseter muscle. Calibration 20 ms/2 mV (From: Cruccu et al., 2001a with permission from Blackwell Publishing).

impossible to deliver electrical stimuli to the facial skin without exciting facial nerve terminals and thus eliciting motor responses that mask the sensory nerve action potentials. Over the past years, efforts have continued to find a reliable method of recording trigeminal-evoked scalp potentials. Several studies have investigated trigeminal evoked potentials elicited by surface electrical stimulation of the lips or gums. Although many investigators have discussed the clinical applicability of these responses, their neural origin has never been proved. One reason is that electrical stimulation of the facial skin unavoidably evokes direct motor responses in facial muscles and several trigeminal reflexes that contaminate or hide the genuine neural signals. A definitive demonstration of this drawback came from a study in curarized subjects, showing that the scalp potentials elicited by surface stimulations consist of myogenic artifacts alone (Leandri et al., 1987). Hence, because of its own anatomical-functional organization, the neurophysiological assessment of the trigeminal system has so far mostly relied on reflex responses (see Chapter 24). 39.3.2. Electrically-elicited and laser-elicited EPs The only certainly genuine and reliable electricallyelicited trigeminal evoked potentials are the very early waves of the scalp potentials described by Leandri and associates (1987). Using two fine needles inserted into the infra-orbital foramen (thus avoiding direct stimulation of motor nerve fibers) they recorded from the scalp the far-fields generated by trigeminal primary

afferents in the first 1–4 ms (before any reflex could appear). These neural signals, consisting of three main components (W1, W2, and W3), are recorded by a scalp electrode at the vertex with a non-cephalic reference. According to intraoperative recordings W1 originates from the proximal part of the maxillary nerve, W2 from the retrogasserian root, and W3 from the intrapontine portion of trigeminal afferents directed toward the brainstem nuclei (Fig. 39.3). This method, undeniably invasive and technically difficult, is excellent for guiding percutaneous interventions for the treatment of trigeminal neuralgia: the position of the intracranial operating needle can be located, and the severity of the lesion monitored, without awaking the patient from anesthesia (Leandri et al., 1996). The best tool for assessing nociceptive pathway function is laser stimulation (Treede et al., 2003). Laser-generated radiant heat pulses selectively excite free nerve endings in the superficial skin layers, activate Aδ and C mechanothermal nociceptors, and evoke scalp potentials (LEPs) generated by the cingulate gyrus and operculoinsular cortices (Treede et al., 2003) (Fig. 39.4). By varying the area of the irradiated spot and the stimulus intensity, it is possible to excite preferentially Aδ (evoking pinprick sensations) or C receptors (evoking warmth or burning sensations) (Cruccu et al., 2003). Because of the short conduction distance and the high receptor density, the trigeminal territory is particularly advantageous for LEP recording. Trigeminal-LEPs are higher-amplitude and far more easily recorded than LEPs after limb stimulation. Trigeminal-LEPs have

DISEASES OF CRANIAL NERVES AND BRAINSTEM

817

Cz (−)

W2

W3

S W1

2 μV

Cv7 (+) 0

1

2

3

4

5

6

7

8 ms

Fig. 39.3 Trigeminal somatosensory evoked potentials. Left: placement of the stimulating and recording electrodes. Electrical stimulation of the infraorbital nerve by two fine-needles inserted into the infraorbital foramen (S). The active electrode is placed at the vertex (Cz), the reference electrode is placed over the spinous process of the seventh cervical vertebra (Cv7). Right: Early waves of the trigeminal somatosensory evoked potentials. Two averaged signal (500 trials each) are superimposed (From Aramideh et al., 2002 with permission from Elsevier).

A

B

Cz (-)

V1 V1

(+) A2

V2

N150

5 μV 0

200

400

600

A1 (+)

V3

C V3

V2

P220

9 μV

- 9 μV

ms

Fig. 39.4 Trigeminal laser evoked potentials. (A) trigeminal laser evoked potentials (LEPs) in a representative normal subject. Two series of 10 trials collected and averaged after stimulation of the cutaneous territories of the first (V1), second (V2), and third (V3) trigeminal divisions. (B) schematic representation of the stimulating and recording technique. The laser pulses are delivered to the skin bordering the upper and lower lips (V2 and V3) and the skin above the eyebrove (V1). The active electrode is placed on the vertex (Cz), the reference to linked earlobes (A1-A2). (C) scalp topography of the grand average LEPs in five subjects (120 trials) after stimulation of the lower lip. Widespread maximum-amplitude negativity in the central regions at 150 ms. Widespread maximum-amplitude positivity in the central regions at 220 ms.

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G. CRUCCU AND A. TRUINI

been recently studied in Wallenberg syndrome (Cruccu et al., 1999), classical and symptomatic trigeminal neuralgia (Cruccu et al., 2001b), trigeminal sensory neuropathy (Cruccu et al., 2003), postherpetic neuralgia (Truini et al., 2003), temporomandibular disorders (Romaniello et al., 2003), and headache (Valeriani et al., 2003). In general, the LEP latency is only abnormal in conditions that engender structural damage, such as herpes zoster, compression by tumors, or multiple sclerosis. In temporo-mandibular disorders, tension-type headache, or migraine, the LEP latency—though other types of abnormalities may be found—is always normal. 39.4. Trigeminal neuropathy 39.4.1. Involvement of trigeminal nerve branches and roots Trigeminal nerve branches are exposed to many different types of lesion, due to trauma, surgical damage, tumors, inflammatory, or infectious diseases (Cruccu and Deuschl, 2000). In some instances, the only clinical manifestations are paresthesias or pain, and electrodiagnostic examination is the only way to assess, localize, and quantify the functional deficit. Electrodiagnostic techniques mainly rely on trigeminal reflexes, elicited through activation of afferents from the three trigeminal branches (Tables 39.1 and 39.2). Trigeminal LEPs and MEPs after transcranial stimulation (Cruccu et al., 1989, 1990a) are also useful in some instances. The short-latency responses of trigeminal reflexes (R1 blink reflex, SP1 masseter inhibitory reflex, and jaw jerk) are far more sensitive to extra-axial trigemi-

nal nerve lesions than the long-latency responses (R2 blink reflex and SP2 masseter inhibitory reflex). One reason is that they are supplied by fewer reflex afferents. In addition, they exhibit less variability and have a smaller normal range than polysynaptic responses (Cruccu and Deuschl, 2000) (Table 39.1). In unilateral trigeminal nerve lesions, when the affected side is stimulated, either the afferent impulses to the brain stem are slowed, or, in severe damage, totally obstructed, resulting in an afferent delay or a block of the reflex responses, respectively. The delay of the reflex responses can either be due to demyelination (slowing of conduction) or axonal loss (reduced spatial summation at central synapses); severe damage, regardless of the cause, often produces a complete afferent block and absent reflex responses. Stimulation of the unaffected side produces normal ipsilateral (direct) and contralateral (consensual) reflex responses. To localize the site of lesion, it is essential to study trigeminal reflexes evoked from all the three divisions. Abnormalities in all divisions of the trigeminal nerve indicate a trigeminal root lesion in the middle or posterior cranial fossa. Cerebellopontine angle tumors, after the earlier involvement of vestibulo-choclear and facial nerves, typically produce mechanical damage to the proximal portion of the trigeminal root, thus causing delay or absence of the early responses in all trigeminal divisions. An abnormality in one division alone suggests a more peripherally located lesion. The blink reflex can be abnormal in lesions of the supraorbital nerve branch or, more proximal, the ophthalmic division of the trigeminal nerve. Herpes zoster, a disease that frequently manifests with supraorbital skin eruption and

Table 39.1 Latency of brainstem reflexes in 100 normal subjects aged from 15 to 80 years Latency (ms) Median Mean SD Range 20-year-old subjectsa 70-year-old subjectsa a

R1 blink reflex

R2 blink reflex

Corneal reflex

Jaw Jerk

Masseter SP1

Masseter SP2

10.9 10.9 0.7 9.3–12.4 10.4

34 33.9 3 28–41 32

40 40.2 4.4 34–50 39

6.8 6.8 0.8 5–10 6.5

12 11.8 0.8 10–13.6 11.1

45 45.1 5.2 38–60 42

11.2

35

43

7.0

12.3

48

Standard curve calculations for age-latency function.

DISEASES OF CRANIAL NERVES AND BRAINSTEM

819

Table 39.2 Typical abnormalities of brainstem reflexes and their diagnostic indications

Lesion/Disease (1) Facial neuropathy (2) Focal trigeminal neuropathy (distal) (3) Focal trigeminal neuropathy (retrogasserian and root entry zone) (4) Sensory polyneuropathy (5) Sensory-motor polyneuropathy (6) Ganglionopathy (7) Dorsal midbrain lesion (8) Dorsal pontine lesion (9) (10) (11) (12)

Midline medullary lesion Lateral medullary lesion Suprasegmental (pyramidal) Suprasegmental (extrapyramidal)

Abnormal responses to ipsilateral stimulation

Abnormal responses to contralateral stimulation

R1 and d-R2 either R1 or SP1 or JJ (R2 or SP2)

c-R2 Normal

R1 and SP1 and JJ (R2 and SP2)

Normal

R1 and SP1 and JJ (R2 and SP2) All abnormal R1 and SP1 (R2 and SP2) JJ All can be abnormal according to the site of the lesion c-R2 and c-SP2 d- and c-R2 d- and c-SP2 Normal Enhanced excitability of R2 and SP2

R1 and SP1 and JJ (R2 and SP2) All abnormal R1 and SP1 (R2 and SP2) Normal Normal c-R2 and c-SP2 Normal d- and c-R2 (d- and c-SP2) Enhanced excitability of R2 and SP2

R1: early blink reflex. d- and c-R2: direct and crossed late blink reflex. SP1 and SP2: early and late masseter inhibitory reflex. JJ: jaw jerk. Responses in parentheses are less frequently affected.

sensory disturbances, affects the first division of the trigeminal nerve, thus producing an abnormal blink reflex and no masseter inhibitory reflex and jaw jerk abnormalities (Fig. 39.5). LEPs after supraorbital stimulation have been studied in postherpetic neuralgia, demonstrating a severe impairment of small myelinated afferents (Cruccu et al., 1990b; Truini et al., 2003). In lesions of the infra-orbital nerve or, more proximally, the maxillary root, the masseter inhibitory reflex may be abnormal after infraorbital nerve stimulation. Damage to the mental nerve or the trigeminal mandibular root may cause masseter inhibitory reflex abnormalities. Features of denervation or reinnervation, or both, in masseter-EMG indicate a lesion of the masseteric nerve or, more proximally, the trigeminal motor root. An EMG abnormality may occur with or without an abnormal jaw-jerk, i.e., a delay or absence on the involved side; the reverse is also true (Ongerboer de Visser and Goor, 1974; Goor and Ongerboer de Visser, 1976). An isolated abnormality of the jaw-jerk poses two problems. First, both sensory and motor fibers can be damaged. Transcranial stimulation of the trigeminal motor root or masseter EMG may disclose the motor dysfunction. Second, because the jaw-jerk afferents are extremely sensitive

to compression, the jaw-jerk may often be the only affected response. Because the jaw jerk is also strongly influenced by dental occlusion, it is also necessary to test whether the reflex abnormality disappears in different positions of the mandible or during clenching (Kimura et al., 1994; Cruccu et al., 1997). If not, the extra-cranial and intracranial pathways must be carefully examined with magnetic resonance imaging. Bone tumors may affect trigeminal nerve branches on their way out of the cranial cavity or maxillary bones. Bone tumors involving the Gasserian ganglion can affect all three trigeminal branches. Others, such as in the so-called numb-chin syndrome, damage only the mental nerve, either at the base of the skull or at the mandible (Bruyn and Boogerd, 1991). Iatrogenic damages after dental or maxillofacial surgery are frequent causes of maxillary and mandibular nerve involvement. 39.4.2. Selective involvement of the Gasserian ganglion In patients with neuronopathy due to Sjogren’s syndrome, and other connective tissue diseases, the Gasserian ganglia can be selectively involved (Lecky et al., 1987). In Sjogren’s syndrome, Gasserian ganglia

820 Fig. 39.5 Trigeminal reflexes and trigeminal evoked potentials in postherpetic neuralgia. Corneal reflex (CR), blink reflex (BR), masseter inhibitory reflex (MIR) after infraorbital (V2) and mental (V3) stimulation, jaw jerk (JJ), and trigeminal somatosensory evoked potentials (TSEP) after infraorbital nerve stimulation in a patient with postherpetic neuralgia involving the first and the second trigeminal divisions. On the affected side the R1 component of the blink reflex is absent, the R2 component of the blink reflex and SP1 component of the masseter inhibitory reflex after infraorbital stimulation are delayed. W1 of the trigeminal evoked potential is reduced in amplitude and the later waves are absent (Modified from Cruccu et al., 1990b with permission from the BMJ Publishing Group).

G. CRUCCU AND A. TRUINI

Normal side

Affected side

CR

BR

MIR V2

MIR V3

JJ

TSEP

W2W3 W1 W1

involvement may be accompanied by a more widespread sensory neuronopathy (Griffin et al., 1990). In these cases, circulating antibodies are probably responsible for the involvement of dorsal root and Gasserian ganglia (Graus et al., 1988), both incompletely protected by the blood-brain barrier. Gasserian ganglia neurons can also be involved by neuronopathy related to paraneoplastic syndromes. Neurophysiological studies can be used to localize the dysfunction in the Gasserian ganglia neurons, differentiating it from the involvement of the trigeminal branches. A lesion involving the third trigeminal branch is usually demonstrated by finding neurophysiological deficits in reflexes relayed by afferents from that specific branch. If the lesion lies in the Gasserian ganglia neurons, but not in the nerve fibers, neurophysiological testing will still show abnormalities in reflexes elicited by the cutaneous afferents carried by the mandibular branch, but the jaw jerk will remain completely normal (Valls-Sole et al., 1990), because the cell bodies of the afferents subserving the reflex are located, rather than in the ganglion, in the mesencephalic nucleus. Sparing of the jaw jerk with impair-

ment of the cutaneous trigeminal reflexes has also been found in degenerative neuronopathies, such as Kennedy’s disease (Antonini et al., 2000) (Fig. 39.6). 39.4.3. Hemimasticatory spasm Hemimasticatory spasm is a very rare condition, often associated with hemifacial atrophy (Kaufman, 1980), and is characterized by painful involuntary contractions of the masseter and temporalis muscles on one side. Kaufman (1980) stressed the close similarity with hemifacial spasm, and proposed that the spontaneous activity was generated in the trigeminal nerve fibers. The involuntary movements are paroxysmal and may appear as brief twitches (resembling those of hemifacial spasm) or prolonged spasms (lasting a few seconds to several minutes, and resembling cramps), or both. The spasms are intensely painful, violent, and sometimes of sudden onset: during a spasm patients may bite their tongue, dislocate their temporomandibular joint, or even break their teeth. The involuntary movement may be evoked by yawning, speaking, closing the mouth, chewing, or other voluntary movements of the mouth

DISEASES OF CRANIAL NERVES AND BRAINSTEM

Control R1

R2

SP1

SP2

Patient

A

B

821 Fig. 39.6 Trigeminal reflexes in Kennedy’s disease. (A) Early (R1) and late (R2) responses of the blink reflex. (B) Early (SP1) and late (SP2) masseter inhibitory reflex. (C) Jaw jerk (JJ) in a normal subject (control) and in a patient with Kennedy’s disease (patient). Calibration 10 ms / 0.2 mV in A and B, 5 ms / 1 mV in (C). In the patient, the blink reflex and the SP1 of the masseter inhibitory reflex were delayed, and the jaw jerk was normal (Modified from Antonini et al., 2000).

JJ

C

and jaw, as well as by electrical shocks, delivered to the muscle belly of the facial skin. Needle electromyography of masticatory muscles shows no denervation potentials. The spontaneous activity resembles that of the hemifacial spasm (short bursts of 100–200 Hz discharges in one or few synchronized motor unit potentials), and that of muscle cramps (tonic 50–70 Hz discharges of a compound potential comprising many synchronized motor unit potentials (Cruccu et al., 1994) (Fig. 39.7). The jaw-jerk is absent on the affected side. Study of the masseter inhibitory reflex during the spasm shows an efferent block, i.e., SP1 and SP2 are completely absent in the affected muscle, regardless of the side of stimulation. The silent periods are absent probably because the motor potentials are ectopically generated along the nerve, and cannot be suppressed by the reflex inhibitory input on the motoneurons. Hemimasticatory spasm is probably secondary to a purely motor trigeminal neuropathy (Thompson et al., 1986), as indicated by the finding of a focal slowing of conduction in motor nerve fibers (Cruccu et al., 1994). 39.5. Brainstem lesions The trigeminal sensory nuclei and reflex circuits extend from the mesencephalon to the spinal cord. Hence, they are rarely spared in focal brainstem lesions. The hallmarks of trigeminal lesions are pain and loss of facial sensation. The distribution of the sensory deficit may sometimes help determining the site of the lesion because topographic distribution of the nerve branches differs from the sensory representation of the cutaneous afferents in the spinal trigeminal nucleus. A sensory deficit following the anatomical distribution of a nerve branch is probably caused by damage

to that nerve branch, whereas a sensory deficit distributed in layers around the mouth may suggest involvement of the trigeminal nucleus of the descending spinal tract, whose afferents from around the mouth are located more rostrally, and from posterior facial areas more caudally. Neurophysiological assessment brings another piece of information. As a general rule, peripheral lesions affect both blink reflex components to a similar extent or—more often—affect more R1 than R2. Peripheral lesions rarely cause delay or absence of R2 with sparing of R1. In contrast, intra-axial lesions often affect R1 or R2 separately. Very discrete lesions limited to the upper pons may cause a delay or absence of R1 alone (Kimura, 1975). In a group of 260 patients with multiple sclerosis, Kimura (1975) found a delayed or absent R1 blink reflex in 40% of the patients in the absence of clinical signs of brain stem damage. Because the varied patterns of trigeminal reflex abnormalities reflect damage at various trigeminal system levels, they help in diagnosing the precise site of the demyelinating lesion. Pontine lesions, regardless of their origin, may produce various trigeminal reflex abnormalities, according to the precise site of lesion. In general, ventral lesions involving the trigeminal afferents before they divide toward their respective circuits may induce abnormalities of all responses (Fig. 39.8). Dorsal lesions, including tumors that involve the floor of the fourth ventricle and the trigeminal nuclei, may yield selective abnormalities. Ischemic infarctions in the rostral two-thirds of the brain stem are usually ventral and paramedian and rarely impair the trigeminal pathways.

822

A

B

C

Fig. 39.7 EMG findings in hemimasticatory spasm. (A) High-frequency discharges of a single motor unit potential. Calibration: 10 ms/1 mV. (B) Brief bursts of multiple motor unit potentials (corresponding to the clinically evident twitches). Calibration: 100 ms/1 mV. (C) Large compound potential of multiple synchronized motor units discharging tonically at 60 Hz (corresponding to the clinically evident prolonged spasm). Calibration: 50 ms/10 mV (From Cruccu et al., 1994 with permission from the BMJ Publishing Group).

Wallenberg’s syndrome is commonly associated with an abnormality of R2 blink reflex, whereas R1 is spared (Ongerboer de Visser and Kuypers, 1978; Aramideh et al., 1997; Cruccu and Deuschl, 2000). This pattern of abnormality is caused by block of afferent impulses traveling through the descending trigeminal spinal tract. Stimulation of the intact side elicits bilaterally normal responses. Some patients may have a mixed afferent–efferent abnormality (Table 39.2), seen as an afferent delay or block after stimulation of the affected side. Stimulation of the normal side elicits normal direct responses, but consensual responses are delayed or absent because of a delay or complete obstruction of impulses through crossed interneurons. When an infarction extends medially beyond the spinal trigeminal tract and its nucleus the symptoms often last a long time and most

G. CRUCCU AND A. TRUINI

patients never recover completely (Valls-Sole et al., 1996; Aramideh et al., 1997; Vila et al., 1997). Conversely, an afferent delay or block of R2 response after stimulation of the affected side coincides in most patients with a more rapid and complete recovery of symptoms. Valls-Sole and associates (1996) found different types of abnormalities in brainstem reflexes studied in patients with Wallenberg’s syndrome corroborated by MRI, confirming that this syndrome manifests with neurophysiological heterogeneity. Most patients with contralateral facial sensory deficit had normal blink reflexes bilaterally, suggesting the impairment of the ascending trigemino-thalamic tract. In these patients, the lesion was located relatively ventromedially in the brain stem. In patients with Wallenberg’s syndrome the abnormalities of the R2 component of the blink reflex are constantly associated with those of trigeminal-LEPs (Cruccu et al., 1999, 2003). Patients whose magnetic resonance imaging showed infarcts in the upper or middle portion of the medulla had masseter inhibitory reflex involvement, suggesting that the afferent fibers mediating the masseter inhibitory reflex actually descend as far as the upper half of the medulla. The finding of an abnormal jaw-jerk with normal masseter EMG features may reveal a midbrain lesion involving structures adjacent to the aqueduct (Ongerboer de Visser and Goor, 1976; Ongerboer de Visser, 1982; Ongerboer de Visser et al., 1990). Combined features of denervation or reinnervation in the masseter EMG point to impairment of the trigeminal motor nucleus in the dorsolateral region of the mid-pons. In general, examination of the trigeminal reflexes is useful for excluding structural lesions and in predicting magnetic resonance imaging results in patients with symptoms related to trigeminal nerve dysfunction. 39.6. Craniofacial pains 39.6.1. Neuropathic pains A diagnostic protocol for patients with trigeminal pain should rely primarily on the trigeminal reflexes: the finding of any abnormality implies an underlying structural lesion. In all patients with pain secondary to a documented disease, such as symptomatic trigeminal neuralgia, postherpetic neuralgia, benign tumors of the cerebellopontine angle and multiple sclerosis, even in those patients who have no clinical signs or complaints other than pain, trigeminal reflex testing will invariably disclose trigeminal dysfunction

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Normal side

Affected side

CR BR

MIR V2

MIR V3

JJ

TSEP

W3 W2

W1

823 Fig. 39.8 Trigeminal reflexes and trigeminal evoked potentials in multiple sclerosis. Corneal reflex (CR), blink reflex (BR), masseter inhibitory reflex (MIR) after infraorbital (V2) and mental (V3) stimulation, jaw jerk (JJ), and trigeminal somatosensory evoked potentials (TSEP) after infraorbital nerve stimulation in a patient with trigeminal neuralgia due to a demyelinating plaque in the trigeminal root entry zone. On the affected side all the responses are delayed. The W1 and W2 waves of the trigeminal evoked potentials are normal, the later waves are absent (Modified from Cruccu et al., 1990b with permission from the BMJ Publishing Group).

W2

W1

(Cruccu et al., 1990b). Reflex responses are more extensively and markedly affected in patients with constant pain than in those with paroxysmal pain. This distinction agrees with the classical notion that a dysfunction of few fibers provokes paroxysmal pain, whereas severe damage does not. Indeed, neuralgic pain is relieved by surgical deafferentation whereas constant pain is often worsened. In symptomatic trigeminal pains, the trigeminal reflexes yield a very high sensitivity, probably because they allow examination of all three divisions. The most sensitive reflexes are the R1 blink reflex and the SP1 masseter inhibitory reflex (Cruccu et al., 1990b). Trigeminal neuralgia (TN) may have no apparent cause (idiopathic, essential, or classical TN) or be secondary to multiple sclerosis or benign tumors in the posterior fossa compressing the trigeminal root (symptomatic TN). Many investigators nevertheless refute the term idiopathic TN because they support the view that, when no lesion affecting the trigeminal system can be demonstrated, TN is constantly related to

vascular compression of the trigeminal nerve root by tortuous or aberrant vessels. Although, like others, we have occasionally seen patients with mild reflex abnormalities (Kimura et al., 1970; Ongerboer de Visser and Goor, 1974; Cruccu et al., 1990b), in most patients with classical trigeminal neuralgia, all the reflexes are normal. The finding of any abnormality should nonetheless promote further investigation to search for a cause that may require surgical attention; this holds particularly true in young patients. The most commonly reported causes of “symptomatic” neuralgia are benign tumors of the cerebellopontine angle impinging on the proximal portion of the trigeminal root, and multiple sclerosis with a plaque in the root entry zone. In these cases, trigeminal reflexes constantly show abnormalities of R1, SP1 and jaw jerk (Fig. 39.8). Patients with symptomatic TN and about 50% of those with classical TN have abnormal LEPs (Cruccu et al., 2001b) (Fig. 39.9). Hence, LEPs may indicate trigeminal dysfunction also in patients with normal trigeminal reflexes and no evidence of a

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function in patients with burning mouth syndrome. Although they demonstrated abnormalities of both nociceptive and non-nociceptive trigeminal pathway function, thus indicating a possible neuropathic etiology of BMS (Forssell et al., 2002), we have never found trigeminal reflex abnormalities and LEPs in patients with burning mouth syndrome. Atypical facial pain is a diagnosis of exclusion to describe a facial chronic pain that does not have the characteristics of cranial neuralgias and is not associated with identified lesions affecting the trigeminal system or the facial tissues. This diagnosis is not accepted by the IASP and no agreement has been reached on diagnostic criteria. Again, similarly to BMS, electrophysiological and functional neuroimaging studies have reported trigeminal pathway abnormalities. According to these findings, atypical facial pain should be considered as a neuropathic pain. Yet all the patients with atypical facial pain we have examined invariably had normal findings on clinical examination and electrophysiological testing. Painful temporomandibular disorders (TMD) are a condition characterized by spontaneous pain and tenderness in the masticatory muscle and temporomandibular joint and other symptoms related to the masticatory apparatus. The cause of the disease is still controversial. Most investigators agree on a multifactor origin, with muscle hyperactivity and changes in the

structural lesion of the trigeminal system. LEPs, possibly because they are mediated by a small number of afferents, are diagnostically more sensitive than trigeminal reflex testing. Naturally, the finding of normal LEPs by no means excludes the diagnosis of idiopathic TN. This diagnosis relies solely on the clinical description of paroxysmal pain. Post-herpetic neuralgia (PHN) is a neuropathic pain, typically occurring in the elderly, and persisting more than 3 months after skin eruption of herpes zoster (Dworkin and Portenoy, 1996). Most often PHN involves thoracic dermatomes (about 50% of patients), but the ophthalmic division of the trigeminal nerve is another very common distribution (22–25% of patients) (Loeser, 1986; Watson et al., 1988). In ophthalmic PHN the sensory disturbances consist of hypoesthesia, involving all sensory modalities, and pain. Trigeminal reflexes and LEPs constantly showed damage to both large-size and small-size trigeminal afferents (Truini et al., 2003). 39.6.2. Pains of uncertain etiology Burning mouth syndrome (BMS) is characterized by sore mouth, burning pain in the tongue or other oral mucous membranes. Several studies used quantitative sensory testing, electrophysiological methods, and functional neuroimaging to assess trigeminal sensory

Normal Side

Painful side

V1

V2

V3

0

200

400

600

800

ms

0

200

400

600

800

ms

Fig. 39.9 Laser evoked potentials in trigeminal neuralgia. Laser evoked potentials (LEPs) in a patient with idiopathic trigeminal neuralgia in the perioral region. Two series of 10 artifact-free trials collected and averaged after stimulation of the supraorbital (V1), upper lip (V2), and lower lip skin (V3) on the normal and painful sides. Note the high reproducibility of the signals after a relatively low number of trials and delay (V2) or absence (V3) of the LEPs after stimulation of the painful territory (From Cruccu et al., 2001b with permission from Lippincott Williams and Wilkins).

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peripheral input from periodontal mechanoreceptors and muscle spindles as the key mechanisms (De Laat et al., 1985; De Laat, 1987; Cruccu et al., 1997). Reports over the years have described an array of neurophysiological abnormalities in patients with TMD. Studies eliciting masseter inhibitory reflex with toothtap (De Laat, 1987), tooth-electrical (Sharav et al., 1982) and cutaneous electrical stimulation (Turker et al., 1990), have reported conflicting results in TMD, possibly because recordings of silent periods depend notably on the quality of the input, as well as on dental occlusion, and bite force. Because the double shock technique ensures equal input and output for the two responses, the recovery cycle provides a measure of the excitability of the interneurons alone (Kimura et al., 1994). In our experience, the masseter inhibitory reflex usually recovers normally in patients with TMD. Hence, the lack of facilitation in these patients’ responses excludes central hyperactivity as the primary cause of their masticatory dysfunction and pain (Cruccu et al., 1997). Equally contradictory results emerge from jaw-jerk studies in TMD. In clinical practice, the finding of a jaw-jerk asymmetry in a given patient by no means dictates a diagnosis of TMD. Jaw-jerk amplitudes and side asymmetries vary widely in normal subjects (Cruccu and Ongerboer de Visser, 1999). Yet some patients with TMD may even show a unilaterally absent jaw jerk. A useful diagnostic point to remember is that in a patient with no other trigeminal abnormality, a unilaterally absent jaw jerk can be caused a functional impairment. It does not necessarily imply damage to the nerve fibers or brainstem, and should warrant stomatognathic investigations before an MRI study. 39.6.3. Headache Several studies have dealt with trigeminal reflex testing in patients with headache and reported an array of neurophysiological abnormalities. The findings are conflicting. Whereas some investigators reported a shortened SP2 component of the masseter inhibitory reflex in tension-type headache, though not in migraine (Schoenen et al., 1987), others did not (Bendtsen et al., 1996). Numerous studies have also described various blink reflex abnormalities in patients with headache. Again, the results of these studies are controversial; some studies reported an increased latency of R1 in patients with tension-type headache, others found a shorter latency of R1 in patients with chronic paroxysmal hemicrania and hemicrania continua and cervicogenic headache (Sand and Zwart, 1994). Bank

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and associates (1992) reported a delay of R2 blink reflex in patients with migraine. In cluster headache, the blink reflex has been found suppressed on the painful side (Raudino, 1990). The excitability of the trigeminal nociceptive pathway probably undergoes major changes in headache. A recent study showed normal trigeminal-LEPs in patients with migraine and those with tension-type headache, thus demonstrating sparing of nociceptive trigeminal pathways, but when changes in LEP amplitudes were measured across consecutive repetitions, patients with migraine had a reduced habituation of LEPs. This LEP abnormality may reflect abnormal excitability of the cortical areas involved in pain processing (Valeriani et al., 2003). 39.7. Facial nerve 39.7.1. Anatomy The facial nerve is a mixed motor and sensory nerve. The motor component supplies the mimetic muscles and the platysma, stapedius, stylohyoideus and posterior belly of the digastric muscles. The motor nucleus lies deep in the lower part of the pons, dorsal to the superior olivary nucleus and ventro-medial to the spinal tract of the trigeminal nerve. From this origin, the fibers bend to enclose the nucleus of the abducent nerve. They then exit from the pons and run in the cerebellopontine angle. The other component of the facial nerve, the intermediate nerve (pars intermedii of Wrisberg), lies adjacent to the motor component. It contains three sensory components: the fibers of taste for the anterior two-thirds of the tongue, a few somatic sensory fibers from the middle ear region, and general visceral afferents. The sensory fibers arise from the genicular ganglion, located at the geniculum of the facial nerve in the facial canal. The intermediate nerve also contains preganglionic parasympathetic motor fibers. These fibers terminate in the peripheral ganglia. From these ganglia, postganglionic fibers branch to the submaxillary, sublingual, lachrymatory, nasal, and soft palate glands. The sensory peripheral branches and the parasympathetic preganglionic fibers continue into the chorda tympani and the greater superficial petrosal nerves. As the intermediate nerve enters the lower border of the pons, the taste pathways end in the upper part of the fasciculus solitarius; the somatic sensory pathway ends in the trigeminal spinal nucleus. The parasympathetic preganglionic fibers originate from the superior

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salivatory nucleus consisting of cells scattered in the reticular formation, dorsomedial to the facial nucleus. The facial nerve and the intermediate nerve emerge at the lower border of the pons in the recess between the olive and the inferior peduncle: the motor part of the facial nerve lies more medial than the sensory part. From this origin, these two roots pass lateralward and forward with the acoustic nerve to the internal acoustic meatus. In the meatus the motor root lies in a groove on the upper and anterior surface of the acoustic nerve, the sensory root lying between them. In the facial canal in the petrous bone, the facial nerve is first directed lateralward between the cochlea and vestibule; it then bends backward, and arches downward behind the tympanic cavity to run vertically to the stylomastoid foramen. The point where it changes its direction is the geniculum, where the genicular ganglion is located. Here, the greater petroseal nerve emerges from the main root. The nerve to the stapedius muscle gives off after the geniculum, where the facial nerve is directed vertically behind the tympanic cavity. After the emergence of the nerve to the stapedius muscle, the chorda tympani also branches off as it passes downward behind the tympanic cavity, about 6 mm from the stylomastoid foramen. On emerging from the stylomastoid foramen, the facial nerve branches off giving rise to fibers that end in the digastric and stylohyoid muscles. It then runs forward in the parotid gland, and divides behind the ramus of the mandible into the temporofacial and cervicofacial roots. The temporofacial root divides into the temporal and the zygomatic branches; the cervicofacial root gives rise to the buccal, mandibular, and cervical branches. The temporofacial root supplies the frontalis, orbicularis oculi, nasalis, and corrugator muscles. The cervicofacial root supplies the buccinator, orbicularis oris, quadratus labii superioris, and platysma muscles. 39.7.2. Facial neuropathy Facial nerve palsy may be related to several causes, including nerve compression due to tumors of the posterior fossa (Kimura and Lyon, 1973), trauma (Li et al., 2004), toxins and infectious disease (Gavin et al., 1997; Couch, 2004). A common infectious agent that causes facial neuropathy, is the varicella zoster virus (Ramsay Hunt syndrome) (Sweeney and Gilden, 2001). Guillain–Barrè syndrome (Rosler et al., 1995), Miller–Fisher syndrome (Keane, 1994; Mori et al., 2001), and Lyme disease (Smouha et al., 1997;

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Halperin, 2003) often cause a subacute bilateral facial palsy. Patients with sarcoidosis may suffer from recurrent facial palsy (Lower et al., 1997). A frequent and subclinical involvement of the facial nerve has also been reported in patients with hereditary motor-sensory neuropathy (HSMN) type I and III (Glocker et al., 1999a). In most patients, because no cause is found, facial nerve palsy is termed as idiopathic, or Bell’s palsy. Bell’s palsy is a relatively benign condition with an incidence rate of approximately 25 per 100 000 (Katusic et al., 1986). It may occur at any age, although it is more frequent in adults than in children. Bell’s palsy arises from an acute inflammatory process that damages the nerve in its intra-osseal portion. Recent studies detected herpes simplex type 1 (HSV-1) DNA in the endoneurial fluid of facial nerves in patients with Bell’s palsy. A series of separate investigations showed that HSV-1 persists in a latent state in geniculate ganglion (Murakami et al., 1996; Schulz et al., 1998); patients with Bell’s palsy have increased antibody titers against herpes simplex virus (Tomita and Hayakawa, 1972). These findings raise the possibility that idiopathic facial palsy is caused by a reactivation of HSV-1. Facial palsy may be accompanied by hyperacusia, loss of tearing and dysgeusia. The presence of the whole range of symptoms indicates the site of lesion proximal to the emergence of the greater superficial petrosal nerve. Hyperacusia develops with lesions involving the branch to the stapedius muscle; dysgeusia when the lesion involves the corda tympani. Lesions at the stylomastoid foramen, or even more distal cause only facial weakness. A lesion of the facial nerve within the parotid gland spares the branches supplying the posterior auricular muscle. Electrophysiological studies of the facial nerve commonly include standard nerve conduction studies, by stimulating the nerve at its emergence at the stylomastoid foramen, and EMG. They should ideally be also supported by the blink reflex and, whenever possible, magnetic stimulation of the intracranial portion of the nerve (Fig. 39.10). These two techniques can help to localize the exact site of lesion, and provide information on the severity and prognosis of facial palsy. The blink reflex is a trigemino-facial reflex, which examines the whole course of the facial nerve. (Chapter 24) Magnetic stimulation of the facial nerve can be performed by positioning the coil parietoccipitally; the magnetic stimuli excite the facial nerve at its entrance in the petrous bone, thus evaluating the whole peripheral path of the facial nerve.

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Control

Patient

S3 S2 S1

S2

S1 S3 5 ms

0.5mV

Fig. 39.10 Facial nerve motor conduction study in Guillain–Barré syndrome. Left: schematic representation of the stimulating and recording technique. The active electrode is placed on the nasalis muscle, the reference on the tip of the nose. Electrical stimuli excite the facial nerve at its exit from the skull at the stylomastoid foramen (S1), magnetic transcranial stimuli excite the intracranial facial root at the level of the petrous bone (S2), and contralateral transcranial magnetic stimuli excite the facial motor cortex (S3). Right: motor responses recorded in the nasalis muscle after stimulation of the facial nerve (S1), the intracranial root (S2), and the contralateral motor cortex in a normal subject (control) and in a patient with Guillain–Barré syndrome (patient). In the patient with Guillain–Barré syndrome, besides the delayed motor responses, note the marked reduction in amplitude after root stimulation and the absence of responses after cortical stimulation, probably due to conduction block in the proximal portion of the nerve (Modified from Glocker et al., 1999 with permission from John Wiley & Sons Inc.).

Bell’s palsy. In the first 4–5 days of Bell’s palsy, the direct motor response (M-wave), obtained after electrical stimuli of the facial nerve at its emergence at the stylomastoid foramen, is normal. The axonal degeneration, starts in the intraosseal portion, and reaches the point of stylomastoid stimulation in about five days (Valls-Sole and Montero, 2003). In this second stage of disease, the reduction of the M-wave after electrical stimulation at the stylomastoid foramen will be correlated to the amount of the axonal loss. Timing for the examination should take into account that the amplitude of the M-wave may keep decreasing until the tenth-twelfth day (Valls-Sole and Montero, 2003). The amplitude of the nasalis M-wave, in patients with Bell’s palsy studied by Rosler and associates within 3 months from the onset of the facial palsy (1995), was 1.2 mV, with a range between 0 and 3.8 mV (the normal range reported in this study being 0.8–4 mV). The amplitude ratio between the M-wave on the affected and the normal side also provides valuable information on the prognosis. When the M-wave on the affected side is more than 50% than that of the normal side the patient may expect a good prognosis. In the early stage of facial palsy, EMG recordings give poor clinical information, showing either a limited recruitment or no voluntary activity at all. After 14–20 days, the EMG recordings will show

spontaneous activity, such as fibrillation potentials and positive sharp waves, due to the distal degeneration of the motor axons. In patients with severe axonal loss, after axonal regeneration and sprouting, EMG recordings will identify regeneration, showing polyphasic motor unit potentials (Valls-Sole and Montero, 2003). The motor response obtained by magnetic stimulation of the intracranial portion can show abnormalities from the onset of the facial palsy. This finding demonstrates that the lesion is sited in the intraosseal portion of the nerve (Rosler et al., 1995). The abnormalities may consist of a reduced amplitude motor response, far more reduced in amplitude than that obtained after electrical stimulation of the nerve at the stylomastoid foramen, or even no motor response at all (Rosler et al., 1995). In patients with Bell’s palsy studied by Rosler and associates (1995), the amplitude of the motor response in nasalis muscle was 0.2 mV, and 72% out of patients had no responses after magnetic stimulation (normal limit for amplitude was 0.8–3.8 mV). In contrast, electrical stimuli at the stylomastoid foramen yielded an M-wave of 1.2 mV in amplitude, and only in 4% of the patients did the electrical stimuli fail to evoke motor responses. Because reduced amplitude motor response may result not only from axonal loss but also from a focal

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hypoexcitability, it does not necessarily entail a bad prognosis; conversely, the finding of an almost normal motor response signifies a good prognosis (Glocker et al., 1994; Rosler et al., 1995). The blink reflex examines the whole course of the facial nerve and provides valuable information right from the onset of the palsy (Kimura, 1989; Cruccu and Deuschl, 2000). Virtually all patients show abnormalities of the R1 and R2 components in the ipsilateral orbicularis oculi muscle, regardless of the side of stimulation. Most patients have a complete absence of responses; some just have a delay and an amplitude reduction. The latter findings, or the reappearance of previously absent responses, indicate a conduction defect without substantial axonal loss, so that the patient will completely, or almost completely, recover. In patients without distal degeneration, the latency of R1 is usually delayed slightly (2 ms in the series reported by Kimura (1975). In contrast, in patients with substantial degeneration, R1 is usually absent for months or years. Recovery is nearly always unsatisfactory because of facial synkinesis due to aberrant regeneration; an aberrant R1 response appears in lower facial muscles, such as the orbicularis oris or the mentalis (Cruccu and Deuschl, 2000). Facial neuropathies of different etiologies. Rosler and associates (1995) studied patients with facial palsies with different etiologies. Lyme-related facial palsy had electrophysiological abnormalities similar to those of Bell’s palsy. In patients with Lyme disease latency and amplitude of the M-wave recorded from nasalis muscle after stylomastoid stimulation was within the normal limits. Only magnetic stimulation of the proximal portion of the nerve could show abnormalities; also in Lyme-related facial palsy the damage involves its intra-osseal portion. Patients suffering from Bell’s palsy and Lyme disease usually had a typical dissociation between the amplitude of the M-wave after distal electrical stimulation (which was almost unaffected) and the motor response after proximal magnetic stimulation (which had an amplitude reduction) (Glocker et al., 1994; Rosler et al., 1995). Ramsay-Hunt syndrome usually provokes a severe facial palsy, with predominant axonotmesis and poor recovery. In this disorder, the electrophysiological abnormalities, unlike those in Bell’s and Lyme-related facial palsies, are related to viral invasion of the neuronal soma with cell death. In the series by Rosler (1995), patients with Ramsay Hunt syndrome had an M-wave latency of 4.3 ms (within the normal limits), but an amplitude of 0.6 mV, and in almost 25% of patients no response could be recorded after stylomas-

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toid stimulation. In patients with Ramsay-Hunt syndrome, the amplitude reduction of the electrically elicited M-wave was in the same range as the motor response after proximal magnetic stimulation. Consequently, the clinical grade of palsy and the prognosis correlates significantly with the amplitude reduction of the distally elicited M-wave. HIV-related facial palsy can show various patterns of electrophysiological abnormalities, depending on the type of the nerve impairment in an HIV patient. HIV-related facial palsy frequently resembles Bell’s palsy, with a site of lesion in the intraosseal portion, and predominantly consisting of neuroapraxia (Kohler et al., 1995). However, HIV-related facial palsies with severe axonotmesis have also been reported (Rosler et al., 1995). Guillain–Barré syndrome often provokes a bilateral facial palsy. The main abnormalities consist of latency prolongation, both to distal electrical and proximal magnetic stimulation. A significant amplitude reduction may also be present, being related to conduction block, as happens in limb nerves (Fig. 39.10). A subclinical involvement of the facial nerve is common in HMSN I and III (Kimura, 1970; Glocker et al., 1999a). The main abnormality consists of a significant slowing of the conduction velocity. The latency of the nasalis M-wave after stylomastoid stimulation was 9.8 ms in patients studied by Glocker and associates (1999a) (normal limits reported by Rosler and colleagues, 1995: 2.4–5.1 ms). The slowing of conduction velocity affects the whole facial nerve, but it is predominantly distributed in the distal segment, as it is for limb nerves; axonal loss may be present, however, manifesting with amplitude reduction of the M-wave (0.8 mV). Sarcoidosis may provoke facial nerve palsy associated with fever, uveitis, and parotid gland swelling (Heerfordt’s syndrome) (Glocker et al., 1999b). In Heerfordt’s syndrome, the motor responses to stylomastoid electrical stimulation and intracranial magnetic stimulation are normal in the early stage of palsy. After a few days, whereas distal stylomastoid electrical stimulation elicits normal M-waves, magnetic intracranial stimulation shows abnormal motor responses. These findings suggest that the primary lesion is located proximal to the facial canal (probably in the cerebellopontine angle) and the inflammation then spreads distally into the facial canal. Furthermore, the absence of an abnormality of the M-wave elicited by electrical stylomastoid stimulation during the whole course of the disease demonstrates that this condition is related to a purely demyelinating process (Glocker et al., 1999b).

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Tumors of the cerebellopontine angle can damage the facial nerve by compression. Although the facial nerve impairment is often subclinical, electrophysiological testing can detect abnormalities also in patients without facial weakness (Normand and Daube, 1994). In these patients, the blink reflex is more sensitive than nerve conduction studies and EMG recordings (Normand and Daube, 1994), probably because it can assess the whole path of the facial nerve, in particular the proximal portion located in the cerebellopontine angle. Furthermore, in patients with compression of the facial nerve at the cerebellopontine angle, nerve conduction studies and EMG recordings can only demonstrate axonal loss, whereas the blink reflex can also show slowing of conduction. 39.7.3. Postparalytic facial syndrome Bell’s palsy usually resolves in a few weeks, leaving no trace of any nerve damage. A substantial percentage of axons undergo Wallerian degeneration in 20% of patients (Valls-Sole, 2002). After axonal damage, facial nerve axons grow and again make contact with the muscle fibers, beginning at approximately 3 months after the lesion. This process usually leads to a progressive recovery of muscle activity in the previously paralyzed side. Yet axonal regeneration does not usually provide normal function. Instead, synkinesis, myokimic discharges, and even muscle spasms can develop as a result of aberrant axonal regeneration (Valls-Sole et al., 1992; Valls-Sole 2002; Valls-Sole and Montero 2003). The degree of dysfunction related to such postparalytic facial syndrome (PFS) depends, among other factors, on the degree of initial axonal damage. Synkinetic movements may be so severe as to lead to massive muscular contractions of the whole hemiface, reported by some patients as spasms, resembling those occurring in primary hemifacial spasm. Automatic or emotional facial movements can trigger very uncomfortable mass contractions, leading to what the patients describe as a “spasm.” Although the spasms reported by patients with PFS may mimic those observed in primary hemifacial spasm (HFS), a careful clinical and neurophysiological examination will usually separate the two entities. In HFS, the involuntary twitches of the muscles of one hemiface are not necessarily triggered by voluntary or automatic muscle contraction. This finding is a crucial differential sign that differentiates the twitches in HFS from the mass contractions of PFS, which are always started by intended muscular contraction. Several

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electrodiagnostic findings may also be helpful to distinguish PFS from HFS. For instance in patients with PFS, the R1 blink reflex may be abnormal and the amplitude of the M-wave smaller on the affected side than on the normal side. On needle EMG recordings, whereas in patients with HFS spontaneous activity is frequent and almost continuous, in those with PFS it is scarce and limited to synkenesia following voluntary contraction of the facial muscles. As in patients with HFS, abnormal responses, such as the R1-like response, are also seen in patients with PFS. Even so the two processes differ conspicuously regarding the characteristics of the abnormal orbicularis oris response to supraorbital nerve stimulation. In lateral spread, in patients with HFS, the stimulus may or may not elicit the ephaptic response, whereas in patients with abnormal regeneration, the abnormal orbicularis oris response is practically always present. 39.7.4. Hemifacial Spasm Hemifacial spasm (HFS) is characterized by involuntary, clonic movements, which progress to sustained tonic contractions of the facial muscles on one side. HFS is idiopathic in most instances (“primary” HFS), but a comprehensive medical history and a series of tests are needed to rule out intra-axial or extra-axial brain stem pathology. Several types of posterior fossa tumors have also been reported in association with hemifacial spasm (Inoue et al., 1995; Digre and Corbett, 1988; Glocker et al., 1998). Although there is no general agreement, the most commonly reported cause of “primary” HFS is a compression by a vascular malformation or an artery, often a cerebellar artery, impinging on the facial nerve at its exit from the pons (Digre and Corbett, 1988; Moller, 1999). Consistent with the “neurovascular conflict” hypothesis, patients improve after surgical intervention at the posterior fossa (Nielsen and Jannetta, 1984). Yet some evidence also suggests that facial motoneurons are hyperexcitable in HFS (Valls-Sole and Tolosa, 1989; Valls-Sole and Montero, 2003). For example, a larger R2 response is elicited on the affected side than on the contralateral side and an increased recovery of the blink reflex response to the test stimulus in the paired stimulation technique (Valls-Sole and Tolosa, 1989). Probably, extrinsic irritation of the facial nerve at the posterior fossa generates an antidromic bombardment of inputs to facial motoneurons that cause excitability changes and spontaneous or reflex firing of motoneurons after a “kindling” effect (Martinelli et al., 1992).

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Standard needle EMG recordings show neither denervation potentials nor abnormalities of motor unit potentials, but paroxysmal activity consisting of motor unit discharges at very high frequencies (upto 300 Hz). The firing pattern may comprise a short burst (10–100 ms) of a single or a few motor units or a prolonged spasm of several synchronized motor units lasting even few seconds. Hyperventilation can trigger paroxysmal activity. In patients with HFS, the M-wave is normal, but it may be followed by high frequency after-discharges, best examined with needle electrodes. According to the classic study by Nielsen (1984a, 1984b) afterdischarges may consist of two different types of responses, after-activity, and late-activity. Afteractivity immediately follows the direct motor response and usually lasts 10–20 ms. Late-activity appears after a period of electrical silence. It consists of short trains of potentials lasting 50–100 ms (Nielsen, 1984a, 1984b). The interspike frequency of after-discharges is very high, as it is for the spontaneous activity (Fig. 39.11). The spontaneous or evoked high-frequency discharges are related to ectopic excitation occurring at a point along the nerve where the membrane resting potential is unstable, possibly because of demyelination. Selective stimulation of the mandibular branch of the facial nerve can evoke late responses (between 7 and 10 ms) in the orbicularis oculi muscle; and selective stimulation of the zygomatic branch can evoke a late motor response in the lower facial muscles. This cross talking between upper and lower facial muscles is also termed as “lateral spread” (Fig. 39.11). Lateral spread is frequently shown by recording the abnormal response of the orbicularis oris to supraorbital nerve stimuli. This response is most probably generated through ephaptic activation of neighboring demyelinated or poorly myelinated fibers of the facial nerve innervating the perioral muscles by those that naturally carry the reflex volley to the orbicularis oculi (Nielsen, 1984b). Blink reflex studies are very useful in the evaluation of HFS. In recordings from the orbicularis oculi muscle, R1 and R2 are sometimes slightly delayed on the ipsilateral side, although not all investigators agree with this finding (Eekhof et al., 2000). Stimulation of the supra-orbital nerve also evokes anomalous responses that resemble the R1 blink reflex in the ipsilateral perioral muscles. An R2-like response occasionally appears in lower facial muscles of normal subjects, but R1 never does (Cruccu and Deuschl, 2000). In HFS, the latency of the R1-like response in

G. CRUCCU AND A. TRUINI

R1 R2 Ooc

Me

Fig. 39.11 EMG findings in hemifacial spasm. Supraorbital nerve stimulation, needle recording from orbicularis oculi (Ooc) and mentalis (Me) muscles. The supraorbital nerve stimulation evokes an R1-like response in mentalis muscles at a latency similar to that of the orbicularis oculi R1 response. The R2 component is followed by a burst of activity synchronously in Ooc and Me muscles. Calibration 20 ms/0.2 mV for Ooc muscle and 20 ms/0.5 mV for Me muscle (Modified from Nielsen, 1984).

lower facial muscles is similar to the latency of the orbicularis oculi R1 response (Fig. 39.11). HFS due to posterior fossa tumors is rare (symptomatic HFS). Patients with symptomatic HFS may have abnormal responses due to the lateral spread phenomenon, caused by ephaptic transmission between neighboring demyelinated or poorly myelinated fibers damaged by tumors. The latency of the ephaptic response should depend on the site of cross transmission. The latency of the abnormal response is expectedly shorter if HFS originates distally than if it originates proximally. But Glocker et al. (1998) demonstrated that the site of cross transmission cannot be determined reliably by measuring the latency of the abnormal response, probably because of the size and diameter of the axons participating in ephaptic transmission differ, as does the extent of the focal demyelination at the lesion site. Because the electrophysiological examination does not warrant a clearcut differentiation between primary and symptomatic HFS, a neuroimaging study is essential in all patients with HFS. 39.8. Accessory nerve 39.8.1. Anatomy The accessory nerve is a motor nerve that consists of two parts: a cranial and a spinal. The fibers of the cra-

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nial part arise from the cells of the nucleus ambiguus and emerge as a few rootlets from the medulla, below the roots of the vagus. It runs lateralward to the jugular foramen, and then passes through it. The spinal accessory motor nucleus lies in the dorsolateral portion of the ventral horn, in a direct line with the nucleus ambiguus of the medulla. The spinal accessory nucleus extends from the lower medulla to the first five or six cervical segments. As the spinal accessory axons emerge from the cervical spine the fibers unite to form a single trunk, which ascends and enters the skull through the foramen magnum. It then extends to and passes through the jugular foramen. In the jugular foramen, it receives a few filaments from the cranial part of the nerve, or else joins it for a short distance and then separates from it again. As the accessory nerve exits from the jugular foramen, the cranial part joins the vagus nerve, directed to pharyngeal and laryngeal muscles. Hence, the cranial component of the accessory nerve should be considered as an aberrant group of fibers belonging to the vagus nerve. The spinal accessory nerve descends between the carotid artery and the jugular vein and runs obliquely downwards, behind the upper part of the sternomastoid muscle. It gives rise to several terminal branches (that join with branches from the second and probably the third cervical nerves) to this muscle. Then the accessory nerve courses obliquely downwards and laterally, to end in the deep surface of the trapezius muscle, where it forms a plexus with the third and fourth cervical nerves. The importance of the cervical motor supply to the trapezius muscle is still being debated. Autopsy and intraoperative findings suggest that it is minimal and inconsistent in many subjects, accordingly surgical accessory nerve section usually provokes severe and irreversible trapezius palsy (Soo et al., 1990; Nori et al., 1997). 39.8.2. Accessory neuropathy Motoneurons of the accessory nerve may be involved in motor neuron disease, poliomyelitis, syringomielia, and spinal cord tumors. Accessory nerve palsy is frequently related to surgical trauma during lymphonode biopsy, less common causes are penetrating or blunt trauma, damage due to radiotherapy (Berry et al., 1991), carotid endoarterectomy (Sweeney and Wilbourn, 1992), and coronary artery bypass (Marini et al., 1991). Furthermore, accessory nerve palsy may also be caused by tumors and metastasis involving the skull base. When these condi-

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tions involve the jugular foramen, also the ninth and tenth cranial nerves are involved (Vernet syndrome). Lesions involving the posterior retroparotid (Villaret syndrome) or the laterocondylar space (Sicard Collet syndrome) affect all the lower four cranial nerves, accessory nerve included (Prashant and Franks, 2003). In accessory nerve palsy, the angle of scapula is shifted laterally and downward. The main clinically relevant deficit is weakness of shoulder elevation. The paralysis of sternomastoid muscle causes weakness when the face is rotated toward the opposite shoulder. An isolated accessory neuropathy manifesting with pain in the shoulder and weakness of trapezius muscles can sometimes develop for unknown reasons (idiopathic accessory neuropathy). This syndrome has been regarded as similar to the neuralgic amyotrophy involving brachial plexus (Eisen and Bertrand, 1972; Chalk and Isaacs, 1990). The site of the lesion is probably at the point where the nerve exits from the posterior margin of the sternomastoid, distal to the motor branch for the sternomastoid muscle. In idiopathic accessory neuropathy, the motor conduction time, investigated by recording the M-wave from trapezius muscle after accessory nerve stimulation, as it exits from behind the sternomastoid muscle, is usually normal. However, Eisen and Bertrand (1972) reported a side-to-side asymmetry in M-wave amplitude, thus indicating an axonal loss. Needle electromyography of sternomastoid and trapezius muscles usually shows a variable amount of positive sharp waves and fibrillations. Recovery is the rule. The electrophysiological study of the accessory nerve usually relies on M-wave recordings from trapezius muscle after accessory nerve stimulation at the midpoint of the posterior border of the sternomastoid muscle. With this method, the upper limit of the normal trapezius M-wave is considered to be 3.2 ms (Eisen and Bertrand, 1972). An alternative method consists of stimulating the accessory nerve, more proximally, at the base of the skull with a needle electrode inserted below the mastoid or by magnetic stimulation delivered at the same point (Priori et al., 1991). With this method, the electrically-elicited M-wave recorded from the sternomastoid muscle has a latency of 2 ms and amplitude of 6 mV; the M-wave from trapezius muscle has latency of 3.5 ms and amplitude of 7.7 mV. Magnetic stimulation, and electrical stimulation yield almost similar latencies and amplitudes: 2.3 ms and 5.5 mV for the sternomastoid muscle and 3.7 ms and 7.3 mV for the trapezius muscle. The proximal stimulation assesses the whole path of the nerve

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and thus may disclose a proximal conduction block and identify the exact site of lesion. Proximal stimulation, whether electric or magnetic, is the most reliable method of studying accessory nerve palsies, particularly when a skull-base lesion is suspected. Electrical stimulations are more accurate for conduction studies, magnetic stimulations are less painful. 39.9. Hypoglossal nerve 39.9.1. Anatomy With the exception of the palatoglossus muscle (innervated by pharyngeal branches of the vagus nerve), the hypoglossal nerve innervates all the intrinsic and extrinsic muscles of the tongue. The hypoglossal nerve fibers arise from the cells of the hypoglossal nucleus, which is an upward prolongation of the ventral horn. The upper part of the hypoglossal motor nucleus corresponds with the lower portion of the medial eminence of the rhomboid fossa; in this location, the nucleus causes a focal bulging of the floor of the fourth ventricle (hypoglossal trigone). The lower part of the nucleus extends downward in the medulla. The motor axons emerge in the antero-lateral sulcus between the pyramid and the olive. The rootlets of this nerve merge into two bundles that pass through the hypoglossal canal in the occipital bone, and then unite. The nerve descends almost vertically and deeply; it is located postero-medially to the internal carotid artery and internal jugular vein. It then passes forward between the vein and artery, and lower in the neck becoming superficial below the posterior belly of the digastric muscle and the occipital artery. After crossing the external carotid and lingual arteries below the tendon of the digastric, the nerve reaches the hyoglossus muscle. It then runs forward passing beneath the tendon of the digastric, the stylohyoideus, and the mylohyoideus muscles. It continues forward in the fibers of the genioglossus muscle as far as the tip of the tongue. At the under surface of the tongue, numerous branches pass upward into the substance of the organ to supply its intrinsic muscles. Although the ansa hypoglossi looks like a hypoglossal-nerve branch, it is constituted by cervical fibers arising from the second and third cervical nerves. Branches for the geniohyoideus, sternohyoideus and sternothyreoideus muscles originate from the convexity of the ansa hypoglossi; the motor axons for these muscles do not have their cell body in the hypoglossal nucleus.

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39.9.2. Hypoglossal neuropathy Motoneurons of the hypoglossal nerve may be involved in motor neuron disease and poliomyelitis. Skull base lesions, most frequently tumors, can affect the hypoglossal nerve and all the lower four cranial nerves (Sicard Collet and Villaret syndromes). Skull base lesions may also cause isolated hypoglossal nerve palsy (Keane, 1996; Combarros et al., 1998), and the nerve can be damaged by injury or surgical therapy to the neck. Hypoglossal nerve palsy may also result from compression by an aneurysm, or kinking of the vertebral artery (Rollnik et al., 1996), carotid dissection (Hagemann et al., 2003), as a complication of endoarterectomy (Wilson et al., 1994), and Chiari malformation (Keane, 1996). In these cases, the hypoglossal nerve palsy is frequently irreversible: only few patients achieve complete recovery (Keane, 1996). Hypoglossal nerve palsy is a rare complication of acute infectious mononucleosis in childhood (Zafeiriou and Pavlou, 2004). Rarely does the Guillain–Barré syndrome affect the hypoglossal nerve unilaterally (Sakakibara et al., 2002). One case report describes idiopathic unilateral hypoglossal nerve palsy with an excellent outcome (Giuffrida et al., 2000). A viral etiology is supposed. Hypoglossal nerve palsy manifests with dysarthria, difficulty in swallowing, ipsilateral tongue atrophy and deviation to the weak side when the tongue is protruded. The motor conduction study of the hypoglossal nerve commonly entails stimulation of the nerve in the submandibular region, just medial to the angle of the jaw. But because this method can be unreliable when the lesion is located at a more proximal site (e.g., in skull base tumors) the hypoglossal nerve root should be tested with magnetic or electrical stimulation. To excite the hypoglossal root, high-intensity (painful) electrical stimuli are necessary. A preferable alternative, whenever possible, is to deliver magnetic stimuli with the coil in the usual parieto-occipital position, optimal to excite the intracranial nerve roots (Fig. 39.12). With distal electrical stimulation, transcranial magnetic stimulation of the proximal portion of the nerve, and also transcranial magnetic stimulation of the contralateral motor cortex, the whole hypoglossal pathway can be investigated and the exact site of lesion identified (Fig. 39.12). This combined method is particularly useful in patients with amyotrophic lateral sclerosis, who may have a tongue weakness secondary to dysfunction of the lower or the upper motoneuron.

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Urban and associates (1998) indicate, as the normal limit for the M-wave latency after electrical stimulation medial to the jaw, 3.8 ms. The normal limit for more proximal stimulation with magnetic stimuli is of course longer: within 5 ms, with a lower amplitude limit of 1 mV (Urban et al., 1998). 39.10. Involvement of cranial nerves in polyneuropathy, motor neuron disease, and myasthenia 39.10.1. Polyneuropathy Polyneuropathies often induce bilateral abnormalities of the trigeminal reflexes (Auger, 1996; Cruccu et al., 1998; Urban et al., 1999). Studying the pathophysiology of Sjogren’s neuronopathy, Valls-Sole and associates (1990) recorded the whole series of trigeminal responses, and found that in patients with Sjogren’s syndrome the blink reflex and masseter inhibitory reflex were severely affected, whereas the jaw jerk was spared. In contrast, patients with distal polyneuropathies of various origins (selected explicitly because of trigeminal involvement) also had an abnor-

3.7 ms

S3

S1 S2

4.8 ms

S2

S1

9.1 ms

S3

Fig. 39.12 Hypoglossal nerve motor conduction study. Left: schematic representation of the stimulating technique. Electrical stimuli excite the hypoglossal nerve immediately below the angle of the mandible (S1); parietoccipital magnetic stimuli excite the hypoglossal root (S2), and contralateral magnetic stimulation excites the primary motor cortex (S3). Right: recording from tongue muscles with surface electrodes. Motor responses to stimulation of the distal portion of the hypoglossal nerve (S1), the intracranial nerve (S2), and the contralateral motor cortex (S3). Calibration: 2 ms/1 mV for S1 and S2, and 5 ms/1 mV for S3 (Modified from Urban et al., 1998 with permission from Oxford University Press).

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mal jaw jerk. Because the Ia afferents from muscle spindles of jaw-closing muscles have their cell body in the mesencephalon rather than in the ganglion, the selective sparing of the jaw jerk indicates a ganglionopathy. Paraneoplastic syndromes may induce a widespread sensory neuronopathy, known as the Denny–Brown syndrome. This condition causes degeneration of the posterior columns of the spinal cord, secondary to degeneration of the dorsal root ganglia, associated with antineuronal nuclear antibodies (Graus et al., 1986). Involvement of the Gasserian ganglia neurons may also lead to trigeminal neuronopathy manifesting with neurophysiological features resembling those in connective tissue disorders, such as Sjogren’s syndrome. Patients with chronic demyelinating inflammatory polyneuropathy (CIDP) or severe diabetic polyneuropathy often have subclinical trigeminal dysfunction (Cruccu et al., 1998). This is best disclosed by demonstrating an abnormal delay in the latency of the masseter SP1 after electrical stimulation of the mental-nerve (Fig. 39.13). The cramped anatomical route of the reflex afferents in the mandibular canal and below the internal pterygoid muscle and fascia might contribute to the nerve damage. Several studies demonstrated a subclinical involvement of facial, accessory, and hypoglossal nerves in patients with hereditary motor-sensory neuropathy (HMSN) (Glocker et al., 1999a; Kumagai-Eto et al., 2004). Cranial nerves may be also involved in Burkitt’s lymphoma, acquired immunodeficiency syndrome, hemolytic-uremic syndrome, Gaucher’s disease, temporal arteritis, sarcoidosis, rheumatoid arthritis, Wegener’s granulomatosis, leukemia, in hyper- or hypothyroidism and in meningitis due to different infectious agents (Aramideh et al., 2002). 39.10.2. Motor neuron disease Motor neuron disease often manifests with a lower cranial nerve involvement. The brainstem motor nuclei most commonly affected by amyotrophic lateral sclerosis, progressive muscular atrophy, and the juvenile and adult types of progressive bulbar palsy are those of the vagal, glossopharyngeal and hypoglossal nerves. Motor nuclei of other cranial nerves are less frequently affected. Of the muscles supplied by the former nerves, those of the tongue are most easily accessible to needle EMG examination. The finding of fibrillation potentials and positive sharp waves or both, with or without fasciculation poten-

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28 26 24

CIDP DN

Latency (ms)

22 20 18 16 14 12 10 R1

SP1

Fig. 39.13 Trigeminal reflex abnormalities in polyneuropathy. Scatterplot of the latency of the delayed R1 blink reflex and masseter SP1 in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) or diabetic neuropathy (DN). Horizontal lines indicate mean normal latency (thick line) and upper normal limit (thin line). The three black dots out of range on top of the R1 column represent absent responses (From Cruccu et al., 1998 with permission from John Wiley & Sons Inc.).

tials, demonstrates bulbar involvement. The patient must be asked to relax the tongue as much as possible during recording because spontaneous activity may be confused with the numerous motor unit potentials that are usually present. A proper diagnosis occasionally depends on demonstrating the involvement of the corticobulbar tract. In such cases magnetic transcranial stimulation of the corticobulbar tract, might be of great value. Several studies (Urban et al., 2001; Desiato et al., 2002) demonstrated an early and in most cases subclinical corticobulbar tract involvement of the central motor pathways to the orofacial muscles and tongue in amyotrophic lateral sclerosis. Urban and associates reported that tongue MEPs demonstrated an upper motor neuron dysfunction in 53% of patients, a frequency higher than that yielded by limb MEPs. 39.10.3. Neuromuscular transmission defects The most frequently performed electrodiagnostic technique in the diagnosis of myasthenia gravis repet-

itive nerve stimulation (RNS) of peripheral nerves at 2–5 Hz. With this technique, a decrement of 10% or more in the amplitude or area of the compound muscle action potential (CMAP) elicited from two or more nerves is generally regarded as a postsynaptic defect of neuromuscular transmission, thus leading to the diagnosis of myasthenia gravis. Neck and proximal limb muscles are more frequently involved in myasthenia gravis than distal muscles; hence, repetitive stimulation of the accessory nerve has proven more reliable than repetitive stimulation of the ulnar or median nerve at the wrist. Another technique routinely used in bulbar and ocular myasthenia gravis is facial RNS (recording from the nasalis, orbicularis oculi muscles) The reliability of facial RNS may, however, be reduced by technical factors that produce artifactual false positive or false-negative decrements. For example, subthreshold nerve stimulation may result in a false-positive decrement, whereas overstimulation may produce volume conduction of the stimulus to a branch of the trigeminal nerve causing a false-negative decrement. Furthermore, the site of stimulation for facial RNS and the high stimulus intensity often required for supramaximal stimulation can make testing intolerable for the patient. Recent studies (Pavesi et al., 2001; Rubin et al., 2004) have now demonstrated that myasthenia gravis can be reliably diagnosed with repetitive stimulation of the masseteric nerve. Its sensitivity can be higher than that of accessory RNS, and testing is well tolerated by the patient and technically easier than facial RNS. The masseteric nerve is stimulated by a monopolar needle electrode inserted 1.5 cm through the skin below the zygomatic arc and anterior to the temporomandibular joint into the infratemporal fossa. The anode is a surface electrode placed over the ipsilateral earlobe. The masseter M-wave is recorded by placing the active electrode over the muscle belly and the reference electrode about 2 cm below the angle of the jaw (Macaluso and De Laat, 1995; Cruccu et al., 2001a). Stimulation is delivered in trains of 9 stimuli at a frequency of 3 Hz. Stimulus intensity is 150% of that needed to obtain a maximal M-response. The decrement in both amplitude and area of the M-response is calculated between the first and the fifth stimulus. Another technique reported to be reliable in the diagnosis of myasthenia gravis is hypoglossal RNS (Lo et al., 2002). This technique seems to be more sensitive rather than the others, mainly in patients with myasthenia gravis whose predominant manifestation is dysphagia. Single fiber electromyography (SFEMG) is

DISEASES OF CRANIAL NERVES AND BRAINSTEM

far more sensitive than RNS in detecting abnormalities in myasthenia gravis (Sanders et al., 1979; Stalberg, 1980). SFEMG can detect a subclinical impairment of neuromuscular transmission (an increased jitter) that does not cause neuromuscular block. In contrast, RNS yields diagnostic findings only in muscles with severe neuromuscular blocks: in muscles having only an increased jitter it may show no significant decrement (Gilchrist et al., 1994). In patients with mild generalized myasthenia gravis or in those in remission, single fiber EMG measurement of motor end plate jitter (Trontelj et al., 1988) is probably more sensitive in the orbicularis oculi muscle than in the frontalis muscle. On the other hand, the jitter in the frontalis muscle has a markedly higher diagnostic yield than jitter in limb muscles. This difference is even more pronounced in the ocular form of myasthenia gravis (Sanders et al., 1979). Normal jitter in a weak muscle excludes abnormal neuromuscular transmission as the cause of weakness. Single fiber EMG is abnormal in conditions that mimic ocular myasthenia gravis, such as progressive external ophthalmoplegia (Krendel et al., 1987). References Antonini, G, Gragnani, F, Romaniello, A, Pennisi, EM, Morino, S, Ceschin, V, Santoro, L and Cruccu, G (2000) Sensory involvement in spinal-bulbar muscular atrophy (Kennedy’s disease). Muscle Nerve, 23: 252–258. Aramideh, M, Ongerboer de Visser, BW, Koelman, JH, Majoie, CB and Holstege, G (1997) Late blink reflex response abnormality due to lesion of the lateral tegmental field. Brain, 120: 1685–1692. Aramideh, M, Valls-Sole, J, Cruccu, G and Ongerboer de Visser, BW (2002) Assessment of disorders of the cranial nerves. In: W Brown, C Bolton, MJ Aminoff (Eds.), Neuromuscular Function and Disease, Saunders, Philadelphia, pp. 757–780. Auger, RG (1996) Latency of onset of the masseter inhibitory reflex in peripheral neuropathies. Muscle Nerve, 19: 910–911. Bank, J, Bense, E and Kiraly, C (1992) The blink reflex in migraine. Cephalalgia, 12: 289–292. Bendtsen, L, Jensen, R, Brennum, J, ArendtNielsen, L and Olesen, J (1996) Exteroceptive suppression of temporal muscle activity is normal in chronic tension-type headache and not related to actual headache state. Cephalalgia, 16: 251–256.

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Berry, H, MacDonald, EA and Mrazek, AC (1991) Accessory nerve palsy: a review of 23 cases. Can. J. Neurol. Sci., 18(3): 337–41. Bruyn, RP and Boogerd, W (1991) The numb chin. Clin. Neurol. Neurosurg., 93: 187–193. Chalk, C and Isaacs, H. (1990) Recurrent spontaneous accessory neuropathy J. Neurol. Neurosurg. Psychiatry, 53: 621. Combarros, O, Alvarez de Arcaya, A and Berciano, J (1998) Isolated unilateral hypoglossal nerve palsy: nine cases. J. Neurol., 245: 98–100. Couch, RB (2004) Nasal vaccination, Escherichia coli enterotoxin, and Bell’s palsy. N. Engl. J. Med., 26: 860–861. Cruccu, G and Deuschl, G (2000) The clinical use of brainstem reflexes and hand-muscle reflexes. Clin. Neurophysiol, 111: 371–387. Cruccu, G and Ongerboer de Visser, BW (1999) The jaw reflexes. Recommendations for the practice of clinical neurophysiology. Clin. Neurophysiol., (Suppl. 52), 241–245. Cruccu, G, Berardelli, A, Inghilleri, M and Manfredi, M (1989) Functional organization of the trigeminal motor system in man. A neurophysiological study. Brain, 112: 1333–1350. Cruccu, G, Inghilleri, M, Berardelli, A, Pauletti, G and Manfredi, M (1990a) Cortico-facial and corticotrigeminal projections. A comparison by magnetic brain stimulation in man. Electroencephalogr. Clin. Neurophysiol., (Suppl. 41), 140–144. Cruccu, G, Leandri, M, Feliciani, M and Manfredi, M (1990b) Idiopathic and symptomatic trigeminal pain. J. Neurol. Neurosurg. Psychiatry, 53: 1034–1042. Cruccu, G, Inghilleri, M, Berardelli, A, Pauletti, G, Casali, C, Coratti, P, Frisardi, G, Thompson, PD and Manfredi, M (1994) Pathophysiology of hemimasticatory spasm. J. Neurol. Neurosurg. Psychiatry, 57: 43–50. Cruccu, G, Frisardi, G, Pauletti, G, Romaniello, A and Manfredi, M (1997) Excitability of the central masticatory pathways in patients with painful temporomandibular disorders. Pain, 73: 447–454. Cruccu, G, Agostino, R, Inghilleri, M, Innocenti, P, Romaniello, A and Manfredi, M (1998) Mandibular nerve involvement in diabetic polyneuropathy and chronic inflammatory demyelinating polyneuropathy. Muscle Nerve, 21: 1673–1679. Cruccu, G, Romaniello, A, Amantini, A, Lombardi, M, Innocenti, P and Manfredi, M (1999) Assessment of trigeminal small-fiber function: brain and reflex responses evoked by CO2-laser stimulation. Muscle Nerve, 22: 508–516.

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 40

Diseases of the nerves in the shoulder girdle and upper limb Scott Riggins* and John D. England Neuroscience Department, Deaconess Billings Clinic, Billings, MT, USA

40.1. Introduction Neuropathies involving the upper limbs are common, with each mononeuropathy being discussed in detail. The most common neuropathies are presented first, followed by a discussion of the less common proximal neuropathies. Additionally, many of the generalized diseases that may affect the nerves in the shoulder girdle and upper limb have been described. We focus primarily on mononeuropathies but it is important to remember that many generalized or multifocal neuropathies may appear superficially to be mononeuropathies. However, with a careful history, physical examination, and electrodiagnostic study, the appropriate diagnosis can be elucidated and appropriate treatment instituted. This chapter also emphasizes the importance of nerve conduction studies and electromyography and their crucial role in determining diagnosis, prognosis and directing treatment. Radiographic studies, especially MRI, are often helpful in confirming the diagnosis of a neuropathy and documenting associated abnormalities such as soft tissue masses, tumors and bony lesions. The anatomy of the nerves that arise from the brachial plexus are illustrated in Fig. 40.1. 40.2. Median nerve 40.2.1. Anatomy The median nerve is derived from nerve roots C5 through T1, upper, middle and lower trunks, and medial and lateral cords of the brachial plexus. The median *

Correspondence to: Scott Riggins, MD, Deaconess Billings Clinic, Neuroscience Department, 2825 Eighth Avenue North, Billings, Montana 59107, USA. E-mail address: [email protected] Tel.: +1-406-238-2500; fax: +1-406-238-280540.

nerve travels in the medial upper arm next to the brachial artery. At the elbow, the median nerve is located just medial to the brachial artery and biceps tendon and travels between the two heads of pronator teres innervating both the flexor carpi radialis and pronator teres muscles. The nerve then splits into the anterior interosseous nerve, which innervates flexor digitorum profundus (2,3), pronator quadratus, and flexor pollicis longus muscles. The median nerve subsequently dives below the “tendinous arch” between the two heads of flexor digitorum superficialis. The palmar cutaneous sensory branch arises proximal to the carpal tunnel and supplies sensation to the thenar eminence. At the level of the wrist, the nerve traverses the “carpal tunnel.” The nerve then gives branches to five muscles: abductor pollicis brevis, opponens pollicis, flexor pollicis brevis (superficial head), and first and second lumbricals. The nerve continues as the digital sensory branch supplying sensation to digits one, two, three, and the lateral aspect of digit four (Fig. 40.2). 40.2.2. Sites of injury The most common site of injury affecting the median nerve is at the wrist (carpal tunnel). The usual cause is nonspecific tenosynovitis. Other causes of carpal tunnel syndrome include the following: Conditions: Other: Rheumatoid Arthritis Old fractures Acromegaly Direct trauma/compression Amyloidosis Repetitive injury Pregnancy Ganglion Hypothyroidism Idiopathic Gout Hereditary neuropathy with liability to pressure Palsies (HNPP) Renal failure Diabetes mellitus

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Dorsal scapular (C5) Scprascapular C5−6

C5

Upper trunk

Lateral pectoral C5−7

Musculocutaneous Lateral cord

C6 Axillary

Thoracodorsal

#

*

Radial

C7 Middle trunk

C8

Posterior cord

Long thoracic C5−7

Median

Medial cord Ulnar Lower trunk T1

Medial pectoral C7−8

Fig. 40.1 Brachial plexus.

Other sites of median nerve injury are located more proximally and include the elbow, forearm, upper arm, and axilla. Causes include the following: (1) Pronator syndrome. As described above the median nerve travels between the two heads of the pronator teres and may be compressible at this site. However, in the absence of clear trauma, this remains a very controversial syn-drome. (2) Ligament of struthers/spurs (3) Sublimis bridge (4) Ganglion (5) Direct trauma 40.2.2.1. Clinical: carpal tunnel syndrome The classical history is one of intermittent numbness and tingling usually involving the first three digits that is exacerbated by specific hand positions or tasks (i.e., holding a telephone, driving, etc.). There is usually a history of nocturnal awakening with paresthesia. There often is a history of pain in the wrist and hand that can be referred to the elbow and even as proximal as the shoulder. Patients often complain of decreased fine facility, which is often due to sensory symptoms rather than true weakness.

On examination, patients may have decreased sensation to pinprick and/or light touch in the first three digits and sometimes may have decreased sensation in the lateral aspect of the fourth digit. More severe cases may have weakness and atrophy of median-innervated thenar musculature while more proximal medianinnervated muscles and ulnar-innervated hand muscles remain normal. Tinel’s sign at the wrist may be positive in up to 60% of cases, but it is a nonspecific sign. Phalen’s sign (flexing wrists at 90˚ for one minute) is somewhat more specific. 40.2.2.2. Clinical: proximal median neuropathy With a lesion in the forearm or elbow, the patient often complains of pain in the forearm as well as decreased sensation in the first three digits as well as over the thenar eminence (the palmar cutaneous sensory branch arises proximal to the carpal tunnel). The patient may also complain of weakness involving more proximal muscles. On examination, the patient may have decreased sensation to pinprick and light touch over the first three digits as well as over the thenar eminence. Motor examination may show decreased strength of more proximal median innervated muscles such as pronator

DISEASES OF THE NERVES IN THE SHOULDER GIRDLE AND UPPER LIMB

Median

nerve

Ligament of struthers

Two heads of pronator

PT FCR PL

FDS

FDP 2,3 FPL AIN PQ Palmar sensory

Carpal tunnel

APB OP FPB(S) L1,2

Digital sensory

PT = pronator teres; FCR = flexor carpi radialis FDS = flexor digitorum sublimis; FDP 2,3 = flexor digitorum profundus (2,3) FPL = flexor pollicis longus; anterior interosseous nerve; PQ = pronator quadratus APB = abductor pollicis brevis; OP = opponens pollicis FPB(S) = flexor pollicis brevis, superficial head L 1,2 = lumbricles 1 and 2

Fig. 40.2 Median nerve.

teres and flexor carpi radialis as well as muscles innervated by the anterior interosseous nerve. 40.2.3. Diagnostic studies Localization of a median neuropathy is best accomplished with a combination of clinical and electrodiagnostic findings. A summary of these pertinent clinical and electrophysiologic findings is contained in Table 40.1. The mean sensitivities and specificities for different nerve conduction techniques for the diagnosis of carpal tunnel syndrome are reviewed in Table 40.2. The recommendation below are derived from this data.

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Nerve conduction studies are the most sensitive and specific test available for the diagnosis of carpal tunnel syndrome with a sensitivity up to approximately 85% and a specificity in the high 1990s (AAEM, 1999a; Jablecki et al., 2002). The following nerve conduction studies are recommended: (1) Median digital sensory nerve action potential (either antidromic or orthodromic across the wrist) at 13 or 14 cm. If this is abnormal, then an ulnar sensory study should be done to exclude a more diffuse neuropathy. (2) If the median digital sensory potential is normal, then at least one of the following median sensory studies should be performed. (A) Ring finger technique or thumb technique: Ring finger technique compares the median sensory distal or peak latency compared to the corresponding ulnar sensory distal or peak latency recording from the fourth digit at the same distance of 13 or 14 cm (Jackson and Clifford, 1989). Thumb technique compares the median sensory distal or peak latency compared to the corresponding radial sensory distal or peak latency recording from digit one at the same distance (Carrol, 1987; Jackson and Clifford, 1989). (B) Palmar technique compares the median mixed nerve latency with the ulnar mixed nerve latency (recording over the nerves at the wrist and stimulating in the palm at a distance of 8 cm)(Kimura, 1979). (C) Comparison of median sensory nerve conduction across the carpal tunnel to conduction in the forearm or in the palm. (3) Median motor nerve conduction study. 40.2.4. Further studies (1) Lumbrical muscle technique. This can be particularly helpful if the median sensory action potential and median motor response from the thenar eminence are absent. The diagnosis of carpal tunnel syndrome can be confirmed by demonstrating an increased median motor distal latency to the second lumbrical muscle. The ulnar motor distal latency to the adjacent interosseous muscle can be used for comparative purposes. (2) Needle EMG testing of other C8–T1 innervated muscles should be performed to rule out C8 radiculopathy or lower trunk/medial cord brachial plexopathy.

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Table 40.1 Clinical and electromyographic localization of median neuropathies Median neuropathy prox

Lower trunk brachial PI

Digits 1–3 ± 4 and thenar eminence APB + proximal median muscles

Digits 6 ± 4 and medial Digits 2–4 aspect of forearm Lower trunk C7 innervated innervated muscles muscles

↓

↓

Normal–digits 5 ↓

Normal

Median neurop wrist Clinical Numbness Weakness

Digits 1–3 ± 4 APB/OP

C7 Radiculopathy

NCS Sensory digits 1–3 amplitude Latency Motor (Thenar eminence) amplitude Latency

↑ ↓ or normal

Normal ↓

Normal ↓

Normal Normal

↑

Normal

Normal

Normal

EMG APB FDI EIP FPL PT Triceps PSP

+ − − − − − −

+ − − + ± − −

− + + + − − −

− − ± − + + ±

APB = abductor pollicis brevis; OP = opponens pollicis; FDI = first dorsal interossei; EIP = extensor indicis propius; FPL = flexor pollicis longus; PT = pronator teres; PSP = paraspinal muscles; NCS = nerve conduction studies; EMG = electromyography. (From data in Preston and Shapiro, 1998; Levin, 1999, 2002)

The severity of the neuropathy is often determined by nerve conduction studies and electromyography. There is some variability in the reporting of severity among electromyographers but most agree that denervation of the median innervated thenar muscles is consistent with a severe median neuropathy, whereas the lack of denervation but the prolongation of the median motor distal latency indicates moderate disease. Mild disease is suggested by the prolongation of the median sensory distal latency with normal median motor nerve conduction studies.

(Feuerstein et al., 1999; Gerritsen et al., 2002a). Pyridoxine remains a controversial treatment for carpal tunnel syndrome and high levels of pyridoxine (>200 milligrams per day) can cause a polyneuropathy (England and Asbury, 2004). There is evidence for the short-term use of steroid injections and wrist splints but their long-term efficacy is often poor (Gerritsen et al., 2002a; Graham et al., 2004; Armstrong et al., 2004 ). If symptoms continue or worsen with conservative treatment, surgical intervention is often required. 40.3. Ulnar nerve

40.2.5. Treatment The severity of carpal tunnel syndrome helps to determine the treatment. In mild to moderate carpal tunnel syndrome with no muscle wasting, conservative management is the treatment of choice. Multiple conservative modalities are available including pyridoxine, nonsteroidal anti-inflammatory medications, occupational therapy, steroid injections, and wrist splinting

Ulnar neuropathy is the second most common mononeuropathy. 40.3.1. Anatomy The ulnar nerve is derived from the C8 and T1 nerve roots, lower trunk, and medial cord of the brachial plexus. The ulnar nerve travels in the upper arm riding

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Table 40.2 Sensitivity and specificity for nerve conduction studies in the diagnosis of carpal tunnel syndrome (CTS)

Ring finger tech (antidromic) Thumb technique (antidromic) Palmar technique (mixed nerve) Lumbrical tech

Median sensory (wrist/palm) antidromic Median motor (wrist/palm) orthodromic Median sensory (antodromic) Median motor (orthodromic)

Recording electrode

Stimulation point

Sensitivity

Specificity

Ring electrodes around the fourth digit Ring electrodes around the first digit Median nerve at the wrist and Ulnar nerve at the wrist Palm over second lumbrical/interossei

Wrist (median and ulnar nerves)

.85

.98

Wrist (median and radial nerves)

.65

.99

Palm (median and ulnar at 8 cm)

.71

.97

Wrist (median and ulnar nerves equidistant) Wrist (median) and Palm (median)–at half the distance Wrist (median) and Palm (median)

.56

.98

.74

.97

.69

.98

Wrist (median)

.65

.98

Wrist (median)

.63

.98

Ring electrodes around the second digit Thenar eminence

Ring electrodes around the second digit Thenar eminence

From data in Jablecki et al., 2002.

close to the distal humerus. It then passes through the ulnar groove between the medial epicondyle and the olecranon. The nerve is quite superficial at this point and travels underneath the aponeurosis between the two heads of the flexor carpi ulnaris where it dives deep through the flexor carpi ulnaris. This aponeurosis (humeroulnar arcade) forms the roof of the cubital tunnel. The cubital tunnel can begin as far as 3 cm distal to the medial epicondyle. This anatomical fact can be important when testing the ulnar nerve by nerve conduction studies. After traversing the cubital tunnel, the nerve gives off branches to the flexor carpi ulnaris and flexor digitorum profundus to digits four and five. Approximately 5–8 cm proximal to the wrist, the dorsal ulnar cutaneous sensory nerve originates from the ulnar nerve and supplies sensation to the dorsal surface of the hand. The ulnar nerve continues through Guyon’s canal and then divides into motor branches to the ulnar-innervated hand muscles and the digital sensory branch (Fig. 40.3).

40.3.2. Sites of injury The most common site of injury is at or near the elbow where lesions occur primarily at two sites: the ulnar groove and the cubital tunnel. Multiple possible etiologies exist for ulnar neuropathy at the elbow. The most common being: (1) Trauma (fractures/soft tissue injury) “tardy palsy” can be seen years after elbow fracture (usually supracondylar or medial epicondyle fractures). (2) Direct pressure At the ulnar groove the nerve is superficial and is susceptible to direct compression. With flexion of the arm, the flexor carpi ulnaris (FCU) aponeurosis tightens over the nerve and the nerve also tenses in the ulnar groove. Therefore, the nerve can be damaged at both sites, especially at the ulnar groove where the nerve is easily compressed by leaning on the elbow with flexion of the arm.

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S. RIGGINS AND J.D. ENGLAND

Ulnar

nerve

Ulnar groove

Cubital tunnel FCU FDP 4,5 To hypothenar muscles

Dorsal ulnar cutaneous Interossei Guyon’s canal To FPB (deep) and AP

Interossei

Lubricals (3,4)

Palmaris brevis Abductor DM Flexor DM Opponens DM

To FPB (deep) and AP

Lumbricals (3,4) Common palmar digital sensory

Common palmar digital sensory

FCU = flexor carpiulnaris; FDP 4,5 = flexor digitorum profundus; FPB = flexor pollicis brevis; AP = adductor pollicis

Fig. 40.3 Ulnar nerve.

(3) Bony Deformities Arthritis (osteo/rheumatoid) Old Fractures (4) Prolapse of the ulnar nerve. (5) Soft tissue masses. Ulnar nerve injury at the wrist and hand is a distant second in regards to probable sites of injury. At the wrist, the injury most commonly occurs at Guyon’s canal. However, the nerve can be injured at other sites distal to Guyon’s canal (See Fig. 40.3). Etiologies include repeated hand trauma (in which an object is repeatedly pressed against the palm, i.e., jackhammer operator/bicyclist, etc.), ganglionic cysts, and direct acute trauma.

40.3.3. Clinical 40.3.3.1. Ulnar neuropathy at the elbow An intimate understanding of ulnar nerve anatomy is essential to understanding the clinical findings associated with an ulnar neuropathy at the elbow. The only sensory branches distal to the elbow include the palmar sensory branch, dorsal ulnar cutaneous branch and the terminal sensory branch. Therefore, patients often complain of decreased sensation in the fifth and usually fourth digits extending to the medial aspect of the palm. The sensory disturbance should not extend proximal to the wrist since there are no ulnar sensory fibers that supply sensation to the forearm. The finding

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of decreased sensation in the forearm suggests a more proximal lesion at the brachial plexus or root level. Pain, especially over the medial aspect of the forearm, and sensitivity over the ulnar groove are frequent complaints. Hand weakness varies, depending upon severity and site of the ulnar neuropathy. The sensory examination is variable. In some patients, the sensory examination is normal. In others, decreased sensation to pinprick and light touch occurs in the fifth and usually the fourth digits. The medial palm and medial aspect of the dorsal surface of the hand may also be affected (dorsal ulnar cutaneous branch and palmar cutaneous branches). Motor examination may show weakness and atrophy of ulnar-innervated hand muscles. Other nonulnar, C8 and T1 innervated muscles should not be affected. Flexor carpi ulnaris and flexor digitorum profundus may be weak. These muscles are affected to a much lesser degree than the ulnar-innervated hand muscles. The reason for this is that the fascicles to the proximal muscles are not as frequently injured as those that are destined for the hand intrinsic muscles (Stewart, 2000).

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The ulnar nerve should be palpated along its length for any bony abnormalities or masses that may be compressing the ulnar nerve. 40.3.3.2. Ulnar neuropathy at the wrist Symptoms vary depending upon the location of the lesion. One of the distinguishing factors between an ulnar neuropathy at the wrist and at the elbow is the sparing of dorsal ulnar cutaneous and palmar cutaneous sensory branches that occurs with an ulnar neuropathy at the wrist. 40.3.4. Diagnostic studies Unfortunately, many patients have ulnar neuropathies that are difficult to localize. Differential diagnosis for ulnar neuropathy includes lower trunk/medial cord brachial plexopathies and C8/T1 radiculopathies. Clinical and electrodiagnostic features that are helpful in making these distinctions are contained in Table 40.3. Electrodiagnostic studies are essential to determine the site of ulnar neuropathy as well as to determine if a lesion is primarily demyelinating (neurapraxia) or

Table 40.3 Clinical and electromyographic localization of ulnar neuropathies UNW

UNE

Brachial plex

C8 Radic

Clinical Numbness

Digit 5 ± 4

Digit 5 ± 4

Digit 5 ± 4

Weakness

ADM/FDI

ADM/FDI ± FCU/FDP(4,5)

Digit 5 ± 4 and medial aspect of forearm Median/radial/ulnar LT MC innervated muscles

↑ or Normal

Normal

Normal

Normal

↓ Normal Normal ↓

↓ ↓ or Normal Normal ↓

↓ ↓ ↓ ↓

Normal Normal Normal ↓ or Normal

+ − − − −

+ − + − −

+ + + + −

+ ± + + ±

NCS Sensory digit 5 latency Amplitude DUC amplitude Med antebrachial Motor (ADM) EMG FDI/ADM APB FCU/FDP(4,5) EIP PSP

C8 innervated muscles

FDI = first dorsal interosseous; ADM = abductor digiti minimi; FCU = flexor digitorium profundus (4,5); DUC = dorsal ulnar cutaneous; APB = abductor pollicis brevis; EIP = extensor indicis proprius; PSP = paraspinal muscles; NCS = nerve conduction studies; EMG = electromyography; UNW = ulnar neuropathy at the wrist; UNE = ulnar neuropathy at the elbow. From data in Preston and Shapiro, 1998; Levin, 1999, 2002.

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primarily axonal (axonotmesis/neurotmesis). Whether a lesion is primarily demyelinating or primarily axonal is important in determining prognosis and treatment. Furthermore, careful electrodiagnostic studies can diagnose generalized neuropathies that affect the ulnar nerve. The suggested NCS and EMG protocol for ulnar neuropathy at the elbow and wrist are summarized below (AAEM et al., 1999b, c). There have been multiple studies published testing the ulnar nerve with different elbow positions. With the elbow in full extension, the distance measured over the skin from below elbow to above elbow stimulation sites underestimates the true length of the nerve. This causes a falsely low conduction velocity across the segment. The best correlation between skin measurement and length of the nerve are with the elbow flexed between 70 and 90˚. Any elbow position can be used as long as elbow position and references are reported (AAEM et al., 1999c). Nerve conduction studies: (1) Ulnar sensory from digit 5 stimulating at wrist, at approximately 3 cm distal to medial epicondyle and above elbow (at approximately 10 cm). (2) If the ulnar sensory from digit 5 is abnormal consider dorsal ulnar cutaneous sensory testing. (3) Ulnar motor (recording from ADM) with stimulation points similar to #1. If the ulnar sensory or motor nerve conduction studies are abnormal testing should be performed on other nerves to rule out a more diffuse process. If the above testing is not conclusive then consider the following: (4) Ulnar motor (recording from FDI) with stimulation points similar to #1. (5) Ulnar “inching” around the elbow (Azrieli et al., 2003). (6) Ulnar “inching” across the wrist if ulnar neuropathy at wrist suspected (Cowdery et al., 2002). This involves short increment stimulation from below to above Guyon’s canal. See Table 40.4 for sensitivities and specificities for different techniques. (7) Needle EMG testing which should definitely include FDI as this muscle is often more affected then ADM.

S. RIGGINS AND J.D. ENGLAND

The most definitive localization of a lesion is accomplished by showing evidence of conduction block or focal slowing across a specific short segment of the nerve (i.e., elbow). Therefore, it is important to test both the ulnar sensory potential and ulnar motor potential at stimulation points below and above the elbow looking for conduction block or slowing across the segment. The “inching” technique, where stimulation is started distal to a suspected lesion and the stimulator is moved in short increments across the lesion looking for slowing or conduction block is important for specific localization. This can be done both at the wrist as well as the elbow (Miller, 1979; Cowdery et al., 2002, respectively). Performing a dorsal ulnar cutaneous (DUC) sensory nerve conduction study can be useful in assessing the site of an ulnar neuropathy. An unelicitable or low dorsal ulnar cutaneous sensory action potential suggests a lesion proximal to the wrist since the DUC nerve arises from the ulnar nerve proximal to Guyon’s canal. However, a normal dorsal ulnar cutaneous nerve conduction study does not exclude an ulnar neuropathy at the elbow for two reasons: (1) lesions may not be severe enough to affect sensory axons in this nerve; and (2) fascicular sparing of nerve fibers destined for the dorsal ulnar cutaneous nerve may occur. Needle EMG testing should include the ulnarinnervated muscles, (first dorsal interosseous, abductor digiti minimi, and flexor digitorum profundus 4,5 (FDP) and/or flexor carpi ulnaris (FCU)). This helps differentiate an ulnar neuropathy at the wrist and elbow since branches to FDP (4,5) and FCU arise in the upper forearm. If FDP (4,5) and FCU are affected, the site of the ulnar neuropathy is at least as proximal as the elbow. However, the inability to demonstrate denervation of these muscles does not exclude an ulnar neuropathy at the elbow. Other nonulnar-innervated C8 and T1 innervated muscles should also be checked to exclude a medial cord/lower trunk lesion or C8/T1 radiculopathy. 40.3.5. Pitfalls (1) A Martin–Gruber anastamosis (median to ulnar crossover in the forearm) can be mistaken for partial conduction block of the ulnar nerve. (2) Elbow position can be a source of error as mentioned above.

There are three main questions to be answered by nerve conduction studies/EMG:

40.3.6. Further testing

(1) Which nerve/nerves are involved? (2) Where does the lesion localize? (3) Is it a demyelinating or axonal lesion?

If bony abnormalities, masses, or soft tissue injuries at the elbow or wrist are suspected, plain radiographs, CT scans, or MRI scans may be indicated.

DISEASES OF THE NERVES IN THE SHOULDER GIRDLE AND UPPER LIMB

849

Table 40.4 Sensitivity and specificity of nerve conduction studies in the diagnosis of ulnar neuropathy at the wrist Recording electrode

Stimulation point

Abnormal values

Sensitivity

Specificity

CB (>20% amp decrease or CV 75% decrease in the proximal CMAP with the needle stimulation. (b) CB > 30% decrease in the proximal CMAP amplitude. (c) SNCV, slowing in NCV > 6 m/s; CB> 20% decrease in the proximal CMAP amplitude. (d) > 50% decrease in the proximal CMAP amplitude. Test was performed by recording from the anterior tibialis muscle. * The near-nerve sensory nerve conduction. ** Axonal loss in 64% of cases. *** Pure axonal loss ( 50% amplitude decrease) NR, no response Reproduced from Oh, SJ (1998) Clinical Electromyography. Nerve Conduction Studies, IIIrd edn. with permission by Lippincott, Williams and Wilkins, Philadelphia.

This test is severely limited by the frequent difficulty of obtaining the CMAP in the extensor digitorum brevis in these patients. In Katirji and Wilbourn’s series (1988), the EDB recording was not available in 39% of cases. An alternative method under this circumstance is recording of the CMAP in the anterior tibialis or peroneus longus muscle (Singh et al., 1974; Redford, 1974; Katirji and Wilbourn, 1988). Slowing across the fibular head in this method was noted in 62% of patients, a substantial increase from 36% in the EDB recording (Singh et al., 1974). Katirji stated that the peroneal motor nerve conduction with recording

from the anterior tibialis muscle is the single most important electrophysiologic study; it localized all 52 lesions, causing conduction block at the fibular head (Katirji and Wilbourn, 1988). The disadvantage of this latter technique, however, is that the NCV across the fibular head cannot be compared with the distal NCV, but by comparing the amplitude difference below and above the fibular head, the conduction block can be recognized in addition to the slow NCV. Using this technique, Redford (1964) reported slow NCV in nine and conduction block in all of 10 patients studied with peroneal palsy. One unusual finding in this neuropathy

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

A 42.7

2 mV 5 msec

B 20.3

2 mV 5 msec

C 500 mV 5 msec

Fig. 41.1 Motor nerve conduction in peroneal compression neuropathy at the fibular head. (A) Compound muscle action (CMAP) with stimulation at the ankle. (B) CMAP with stimulation below the fibular head. Motor NCV in the ankle-below fibular head segment is 42.7 m/s. (C) CMAP with stimulation above the fibular head. The motor NCV across the fibular head is 20.3 m/s. Conduction block is also obvious (Reproduced from Oh, SJ (1998) Clinical Electromyography. Nerve Conduction Studies, IIIrd ed. with permission by Lippincott, Williams & Wilkins, Philadelphia).

is the high frequency of axonal loss (low CMAP without any evidence of focal demyelination): 55–64% of cases (Katirji and Wilbourn, 1988; Sourkes and Stewart, 1991). The most sensitive electrophysiological test is the sensory conduction study with the near-nerve needle technique, which should include the segments distal and proximal to the fibular head (Table 41.2) (Singh et al., 1974; Smith and Trojaborg, 1986). The diagnostic sensitivity averages 84%. Comparison of the slow sensory NCV across the fibular head with the distal NCV is the best method. The amplitude was a poor indicator of the site of the lesion (only 15%). Although the CNAPs in the popliteal fossa were dispersed to more than six components in 80% of patients with crossed leg palsy, compared with 10% in normal nerves, this phenomenon was also unsatisfactory in localizing the lesion because it was also observed in peroneal paresis due to causes other than acute compression. Though Wilbourn (1986) recommended side-to-side comparison of the sensory CNAP amplitude of the superficial peroneal nerve with surface electrodes for the calculation of axon loss, data on abnormal superficial peroneal nerve conduction in this neuropathy are limited. Levin recorded the sensory CNAP at the ankle over the intermediate dorsal cutaneous nerve and at the knee 2 cm proximal to the

863

fibular head simultaneously with stimulation of the superficial peroneal nerve 14 cm proximal to the ankle (Levin et al., 1986). In 6% of the normal cases, no response was observed. In 11 cases of peroneal mononeuropathy (four acute and seven chronic), the sensory CNAP was absent at the knee in eight cases (four acute and four chronic). In seven of these eight abnormal cases, the sensory CNAP at the ankle was normal, confirming conduction block across the fibular head. In all 11 cases, the motor nerve conduction was abnormal. De Carvalho et al. (2000) also reported normal sensory CNAP in the superficial peroneal nerve at the ankle in five patients with severe common peroneal neuropathy, confirming the selective sparing of distal sensory fibers in this neuropathy. Mixed nerve conduction was studied in four patients by Gilliatt et al. (1961). In every case, diminution in the mixed CNAP with slowing of the NCV was found on the affected side compared with the unaffected leg. By using an “inching” technique at an interval of 2 cm for motor conduction, Brown and Yates (1982) were able to localize the major abnormalities at or adjacent to the fibular head. A later study localized the lesion proximal to the fibular head (Brown and Watson, 1991). Axon loss (measured by comparing the CMAP area to that of the normal side) was greatest in EDB fibers, whereas the percentage of conduction block was greatest in the anterior-lateral muscles. Using the short-segment stimulation technique, Kanakamedala and Hong (1989) found that a majority of the lesions were located just proximal to the fibular head. Brown et al. (1976) also performed the intraoperative motor nerve conduction in two patients with this disorder and found the most abnormal conduction to be proximal or distal to the entry of the common peroneal nerve into the peroneus longus muscle. These abnormalities were characterized by conduction block and delayed latency. In patients with common peroneal nerve palsy due to multiple causes, including 14 cases of spontaneous or compression palsy, it was found that those in whom motor NCV in the fibular head-ankle segment was greater than 30 m/s made good recovery, but that patients with a motor NCV of less than 30 m/s (or where the motor NCV could not be recorded) had a worse prognosis (Berry and Richardson, 1976). The needle EMG found active denervation in some muscles innervated by the peroneal nerve in all cases (Sourkes and Stewart, 1991; Katirji, 1999). However, Sourkes et al. (1991) found that muscles innervated by the deep peroneal nerve were more frequently and

864

severely denervated than those innervated by the superficial peroneal nerve. One study compared the electrophysiological findings in six patients with complete recovery and eight patients with incomplete recovery (Smith and Trojaborg, 1986). The authors concluded that normal sensory conduction distal to the fibular head is compatible with a good prognosis, whereas slowing along this segment, reduced or absent sensory CNAPs, slowing along the distal motor fibers to the EDB, or absent motor conduction suggest a poorer prognosis. Cruz-Martinez found significant improvement in the motor NCV and in the conduction block index (CMAP above the knee/ankle%) in repeated tests three weeks to seven months after onset of palsy in 20 patients, when the recovery was either complete or near-complete (Cruz-Martinez et al., 2000). This included three HNPP cases. The lateral half of the extensor digitorum brevis muscle may be innervated by a branch of the superficial peroneal nerve (accessory deep peroneal nerve). Gutmann (1970) described two patients with complete deep peroneal nerve palsy caused by a fibular chondroma and a ganglion cyst who showed relatively normal motor conduction of the accessory deep peroneal nerve. This finding led him initially to conclude that the deep peroneal neuropathy was only partial in one case. An awareness of the anatomical variation in the innervation of the extensor digitorum brevis muscle is important for correct clinical and electrophysiological evaluations of deep peroneal nerve lesions but is of limited practical value in the diagnosis of crossed leg palsy since most lesions are found proximal to or at the neck of the fibula and thus above the origin of the accessory branch of the nerve.

SHIN J. OH

as well as by a ganglion or mass (Gutmann, 1970; Oh, 1998). Electrophysiological tests can identify deep peroneal neuropathy by abnormal motor nerve conduction in the peroneal nerve conduction below the fibular head and denervation process in the needle EMG confined to the deep innervated muscles, the anterior tibialis, extensor hallucis, and extensor digitorum brevis muscles. Superficial peroneal nerve conduction is normal and needle EMG in the peroneal muscles is normal (Fig. 41.2). Among 116 cases of common peroneal mononeuropathy, Katirji (1999) found eight cases of this neuropathy and all of them showed axonal loss. Focal demyelination was also reported in a case with a neurolemma in this nerve (Oh, 1998). 41.2.3. Superficial peroneal neuropathy The superficial peroneal nerve branches off from the common peroneal nerve at the fibular head. It supplies Deep peroneal N.

A

23.2 FH

PF 0.5 mV

41.2.2. Deep peroneal neuropathy The deep peroneal nerve is the main branch of the common peroneal nerve and innervates the anterior tibialis, extensor hallucis, extensor digitorum longus, and peroneus tertius muscles. At the ankle it passes under the extensor retinaculum and divides into two terminal branches: the lateral branch to the extensor digitorum brevis muscle and the medial branch to the small sensory territory in the web space between the first and second toes. Deep peroneal neuropathy is characterized by footdrop with sparing of the peroneus muscles and is a rare entity. This nerve can be compressed in anterior tibial compartment syndrome (Rorabeck et al., 1972),

5 ms Superficial peroneal N.

10 μV 2 ms

Fig. 41.2 Nerve conduction in deep peroneal neuropathy. Conduction block and slow motor NCV (23.2 m/s) in the ankle (A)—below fibular head (FH) segment in the peroneal motor nerve conduction. *Response through the posterior tibial nerve at popliteal fossa. Normal sensory CNAP in the superficial peroneal nerve (Reproduced from Oh (1998), Principles of clinical electromyography: Case studies with permission by Williams & Wilkins, Baltimore).

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

motor innervation to the peroneus longus and brevis muscles. After exiting from the fascia near the distal third of the leg, a pure sensory branch divides into two sensory branches, the medial (MDC) and intermediate dorsal cutaneous (IDC) nerves. These run downward to provide cutaneous sensation to the anterolateral aspect of the lower leg and the entire surface of the dorsum of the foot except for two small areas: one in the first web of the toes innervated by the deep peroneal nerve and the other on the lateral surface of the foot innervated by the sural nerve. The medial dorsal cutaneous (MDC) nerve innervates sensation to the medial two-third of the dorsum of the foot and intermediate dorsal cutaneous (IDC) nerve, to the lateral aspect of the dorsum of the foot between the MDC nerve territory and the sural nerve territory. Superficial peroneal neuropathy can occur in rare peroneal compartment syndrome, which is similar to anterior compartment syndrome in that muscle swelling and necrosis are confined to the peroneal muscles (Davies, 1979). Isolated superficial peroneal neuropathy due to compression is rare. Most compression in the superficial peroneal neuropathy is at the fascial exit, producing superficial peroneal sensory neuropathy. The author observed one such case after prolonged driving in a small Volkswagen automobile. The needle EMG shows denervation process confined to the peroneus longus and brevis muscles. Superficial peroneal motor nerve conduction with the recording electrodes in the peroneus muscles may show an abnormal response. Electrical stimulation on the exposed superficial peroneal nerve during surgery did not produce twitching in one case (Davies, 1979). 41.2.4. Superficial peroneal sensory neuropathy Superficial peroneal sensory neuropathy occurs when the superficial peroneal nerve is compressed at the fascial opening after having given off its motor branches. This usually occurs spontaneously. Affected patients have pain, numbness, and sensory impairment over the territory of the SP nerve, including the anterolateral area above the ankle. Often they have localized tenderness and Tinel’s sign, or a palpable “bulge” at the fascial opening. There are some cases demonstrating sensory impairment on the dorsum of the feet alone. In these cases, usually the MDC and IDC nerve territories are involved together. Surgical decompression at the fascial opening is the most effective treatment in this condition. Laurencin et al. (1995) reported one case of Schwannoma of the superficial peroneal nerve at the

865

fascial opening presenting as pain and dysesthesia on the fourth toe and fourth webspace. The best electrodiagnostic method for superficial sensory neuropathy is the nerve conduction technique described by Izzo et al. (1981). Recording surface electrodes are placed at the medial and intermediate dorsal cutaneous nerves at the ankle and the stimulating surface electrodes, proximal to the recording electrodes at the superficial peroneal sensory nerve in the lateral lower aspect of the shin. This technique is easy to perform and tests the nerve conduction of the MDC and IDC nerves separately. Unfortunately, in 10% of the 60–89-year-old group, the SNAP is not obtainable in this nerve (Falco et al., 1994). This is in contrast to the absence of sural SNAP in 2% of cases in the sural nerve. Thus, it is best to compare with the other normal side. An orthodromic method for superficial sensory neuropathy with surface electrodes is also available (Oh, 2003). Sridihara and Izzo (1985) reported two cases of sensory neuropathy of the SP nerve terminal (distal) branches. Two patients had numbness and tingling of the dorsum of the foot, which was aggravated by activity, decreased sensation over the MDC and IDC territory, a soft tissue bulge over the anterolateral aspect of the leg 10 cm above the lateral malleolus, and positive Tinel’s sign and tenderness over the bulge. Electrodiagnostic studies revealed an unrecorded sensory CNAP in one case and prolonged distal latency of the terminal sensory branches of the SP nerve in the other. Surgical decompression of the nerve at the bulge by fasciectomy relieved symptoms. In almost all cases of isolated superficial sensory neuropathy, the sensory nerve conduction of this nerve can identify the lesion. We also use this nerve conduction in identifying the pathway of the superficial peroneal nerve for the nerve biopsy (Oh, 2001). 41.2.5. Medial and intermediate dorsal cutaneous neuropathy Individual medial dorsal and intermediate dorsal cutaneous neuropathies can occur with a lesion at the ankle or the dorsum of the foot. Trauma, surgical injury, and external compression, such as is caused by tight shoes, are known causes of neuropathy. Classically, an individual branch, the MDC, IDC, or the first proper digital nerve, is involved in isolation. Thus, pain, dysesthesia, and sensory impairment are confined to the small area innervated by the individual nerve branch. Clinical diagnosis depends solely on the

866

SHIN J. OH

distribution of the sensory impairment. Often Tinel’s sign is present at the site of the lesion. An epidermoid cyst, a ganglion, and an “injection” have also been reported as causes. Surgical neurolysis has been helpful in relieving pain in cases where a mass or fibrosis was the cause of these individual neuropathies. Oh et al. (2001) described antidromic and orthodromic sensory nerve conduction techniques for the MCD and ICD nerves. In the orthodromic method, the recording electrodes are placed in the MDC and IDC nerves at the ankle, and the stimulating electrodes are distal to the recording electrodes along two branches of the MDC and two branches of the IDC. Authors were able to confirm the diagnosis by these techniques in seven patients: two with proper digital neuropathy, two with MDC neuropathy, and three with IDC neuropathy.

Lt prox intermed SP n

Among seven cases, a definite cause for the distal SP neuropathy was found in only four: a ganglion in one, a burn scar in one, tight shoes in one, and trauma in one. In three cases, no cause was found although the most likely cause was external pressure (Fig. 41.3). Though the abnormality in six of these cases was obvious in the NCS, side-to-side comparison of amplitude had to be studied in one case, indicating the need for this comparison in some patients. Proximal superficial peroneal nerve conduction on the lower shin are normal. Preston and Logigian reported a case of needle- or injection-induced MDC neuropathy after placement of a needle in the dorsum of the foot for venography. Proximal SP nerve conduction showed an absent medial but a normal intermediate dorsal cutaneous branch potential (Preston and Logigian, 1988).

36.8

Lt intermed cut IV n

Rt intermed cut IV n

25.6

10 μV 2 ms

Fig. 41.3 Left intermediate dorsal cutaneous neuropathy. No consistent CNAP was noted in this nerve. Normal response was noted in the proximal intermediate dorsal cutaneous nerve and right intermediate dorsal cutaneous nerve. The Arabic numbers above the CNAP represent the NCVs.

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

41.2.6. Anterior tarsal tunnel syndrome Anterior tarsal tunnel syndrome is a rare entrapment neuropathy of the terminal branches of the deep peroneal nerve beneath the inferior extensor retinaculum of the ankle. Only a handful of cases of anterior TTS have been reported. Akyuz et al. (2000) found 14 cases of anterior TTS among 320 patients with pain and/or numbness of their feet, and “Namaz” (or the kneeling/prone posture for prayer) was the cause for his patients. Trauma, tight shoes, osteophytes, pressure from the extensor hallucis brevis muscle, pes cavus, and Namaz are listed as known causes. Patients typically complain of pain on the dorsum of the foot, especially at night, which is relieved by a change in foot position (Kraus et al., 1977). This resembles the nocturnal paresthesia of CTS. Clinically there may be sensory deficits in the web between the first and second toes and paresis and atrophy of the extensor digitorum brevis muscle. If one branch of the nerve is involved, sensory deficit or EDB paresis may be the only finding. Prolonged terminal latency and acute or chronic denervation in the EDB muscle are the classical findings in ATTS (Boreges et al., 1981; Andersen et al., 1992). All of nine tested cases had prolonged terminal latency (Marinacci, 1968; Boreges et al., 1981). In one case, a focal conduction block was documented by the inching stimulation technique (Andersen et al., 1992). The site of stimulation should be proximal to the lesion at the ankle (Dawson et al., 1990). EMG may show chronic or acute denervation in the EDB muscles. Akyuz et al. (2000) found prolonged terminal latency, low CMAP amplitude, and normal NCV in the peroneal nerve in 14 cases of ATTS. Since this is a common finding in many neuropathies or even in normal individuals, it has to be interpreted with caution in the clinical context. If the sensory branch of the deep peroneal nerve is involved, then its nerve conduction should be abnormal as described above. However, such a finding has not been described in any case of ATTS. 41.2.7. Deep peroneal sensory neuropathy The sensory branch of the deep peroneal nerve is the terminal branch innervating the sensory fibers of the first dorsal web space. Sensory impairment in this small area is observed in this neuropathy. Compression of this nerve may be due to local trauma or tight shoes. Antidromic and orthodromic nerve conduction techniques for this sensory nerve have been described (Lee

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et al., 1990; Ponsford, 1994; Oh, 2003). In the antidromic method, there is a serious technical difficulty in distinguishing between the SNAPs from the superficial and deep peroneal nerves. The orthodromic method with recording electrodes on the nerve at ankle and stimulating electrodes over the first web space is the only reliable method (Ponsford, 1994). A significant reduction of SNAP amplitude is observed in normal subjects over 40 years of age and, hence, an absent SNAP in older subjects may not be of clinical significance. This disorder, caused by tight shoes in two women, was identified by a low SNAP amplitude and prolonged latency (4.6 m/s) by the antidromic method in one case (Posas and Rivner, 1992) and by slow NCV by the orthodromic method in the other (Ponsford, 1994). 41.2.8. Lateral cutaneous neuropathy of the calf (lateral sural cutaneous nerve) The lateral cutaneous sensory nerve of the calf (lateral sural cutaneous nerve) is the only nerve that branches out from the common peroneal nerve before it reaches the fibular head. Lateral cutaneous neuropathy of the calf is extremely rare. LCNC neuropathy was reported in two cases in diabetics, suggesting that minimal pressure on this nerve by the deep fascia is clinically significant enough to induce compression neuropathy in diabetic patients known to be susceptible to nerve compression (Finelli and DiVenedetto, 1978; Gaggini et al., 1985). One case of entrapment of this nerve was reported (Hackman and Zwimpfer, 1998). Sensory nerve conduction test of this nerve (orthodromic as well as antidromic) with stimulation at the common peroneal nerve proximal to the fibular head and recording at the LCSN distal to the stimulating site was reported (Campagnolo et al., 2000). No case so far has been confirmed by this technique. 41.3. Femoral neuropathy The femoral nerve is formed within the psoas muscle from the posterior divisions of the L2, L3, and L4 spinal nerves and emerges beneath the inguinal ligament lateral to the femoral artery and vein. In the thigh, it divides into motor branches to the quadriceps muscles and a sensory branch to the anterior thigh (medial femoral cutaneous nerve). The saphenous nerve is the terminal branch of the femoral nerve, which descends through the subsartorial (Hunter’s) canal and emerges from it just above the knee, innervating the medial aspect of the lower leg and the arch of the foot.

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The most common cause of femoral neuropathy, however, is often said to be diabetes (Calverley and Mulder, 1960). Though the femoral nerve is predominantly involved in diabetic amyotrophy, there is a more widespread denervation process involving the roots and lumbosacral plexus in this disorder. Femoral neuropathy is clinically characterized by the presence of one or more of three findings: (a) weakness of the quadriceps; (b) reduced or absent knee jerk reflex; and (c) sensory impairment over the anteromedial aspect of the thigh and the medial aspect of the lower leg. Weakness of the iliopsoas muscle indicates that either the upper lumbar plexus or the L2 or L3 roots are involved. Weakness of the hip adductors also indicates that the patient has either a lumbar plexopathy or an L2, L3, L4 radiculopathy. Femoral motor nerve conduction techniques with the recording electrodes in the vastus medialis or rectus femoris muscles and with the stimulating electrode at the inguinal ligament lateral to the femoral artery are available (Stohr et al., 1978; Oh, 2003). This technique can best be used with side-to-side comparison of the latency and amplitude. Denervation process confined to the quadriceps muscles indicates femoral neuropathy. Depending on the degree of involvement of a particular branch, one may find some discrepancies in the EMG abnormalities among the quadriceps muscles. EMG abnormalities in the iliopsoas muscle indicate either involvement of the origin of the femoral nerve or lumbar plexopathy (Busis, 1999). The femoral and saphenous nerve conduction studies distinguish femoral neuropathy from lumbar radiculopathy. Even in patients with diabetic amyotrophy, a prolonged terminal latency in the femoral nerve was noted in 64–67% of cases (Chokroverty et al., 1977; Subramony and Wilborn, 1977). This is in addition to widespread evidence of polyradiculopathy and peripheral neuropathy (Oh, unpublished data). In a few patients with traumatic injury of the femoral nerve at the inguinal area, prolonged latency of the femoral nerve, low CMAP amplitude and absence of the saphenous CNAP were consistent findings (Fig. 41.4) (Young and Norris, 1976; Cranberg, 1979; Rottenberg and DeLisa, 1981; Reinstein et al., 1984). Kuntzer et al. (1997) studied the clinical and prognostic features of 31 patients who had femoral neuropathy and found that the percentage of axon loss derived by comparison of the vastus medialis CMAP amplitude on the affected and unaffected sides after stimulation of the femoral nerve is the only significant variable. The best prognosis was seen in patients who had an estimated

SHIN J. OH

axon loss of no more than 50%, with all patients fulfilling this criterion showing improvement within one year. Fewer than half the patients who had axon loss greater than 50% showed improvement. Patients who had greater degrees of axon loss took longer to improve. This rule is applicable regardless of the cause of femoral mononeuropathy. These authors recommend repeated estimate of axonal loss as an objective monitoring measurement in the follow-up of femoral neuropathy. 41.3.1. Saphenous neuropathy The saphenous nerve is the terminal sensory branch of the femoral nerve, which supplies the cutaneous branches to the medial aspect of the knee and the lower leg. Saphenous neuropathy is clinically characterized by sensory impairment on the medial aspect of the knee and lower leg. The most common cause of saphenous neuropathy is a complication of the removal of the adjacent saphenous vein during coronary bypass surgery, occurring in 12 of 421 patients in one prospective study (Lederman et al., 1982). A rare entrapment of the saphenous nerve at the exit from Hunter’s canal was reported (Morgan et al., 2002). Two orthodromic sensory nerve conduction techniques with needle recording electrodes at the inguinal ligament with stimulation at the knee and ankle and two antidromic sensory nerve conduction with surface electrodes are available (Oh, 2003). Among these techniques, Wainapel’s method with the surface recording electrodes just anterior to the medial malleolus and the surface recording electrodes proximal to the recording site deep to the medial border of the tibia is the most easily performed and reproducible test in my view (Wainapel et al., 1978). Side-to-side comparison is important. The saphenous nerve conduction was abnormal in a few patients with this disorder, revealing either a slow NCV or absent CNAPs (Oh, unpublished data). Helmer reported a case of saphenous nerve entrapment by pes anserine bursitis at the proximal tibia. This neuropathy was confirmed by absent sensory CNAP of saphenous nerve conduction and, eight months after initial therapy, the left saphenous potential approaching the opposite side values was obtained in this case (Helmer et al., 1991). Saphenous nerve somatosensory-evoked potential studies have been described. Synek and Cowan (1983) reported abnormal saphenous SEP in four cases of intra-abdominal femoral neuropathy (Synek, 1985). Trainer et al. (1992) found absence of the saphenous

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

cortical SEP in one case and prolonged latency compared with the normal side in three cases of saphenous neuropathy. Among these four cases, saphenous nerve conduction confirmed this neuropathy in one case, but in the other three cases, saphenous nerve conduction showed no response in the normal side, which made this test unreliable. On this basis, Trainer claimed that the saphenous SEP is preferred for diagnosis and performed at the infrapatellar and descending branches of the right and left saphenous nerve with recording from the Cz–Fz electrode. 41.3.2. Medial (anterior) femoral cutaneous sensory neuropathy Anterior (medial) femoral cutaneous neuropathy producing sensory loss over its territory with sparing of the femoral and saphenous nerves following femoral artery reconstructive surgery was reported (Belsch, 1991). A medial femoral cutaneous sensory nerve conduction technique with the stimulating electrodes at the femoral nerve at the inguinal ligament and with the recording electrodes on the femoral-popliteal line distal to the stimulating electrode is now available (Lee et al., 1995). We found this technique easy to perform and helpful in confirming femoral neuropathy and medial femoral cutaneous sensory neuropathy by either the absence of sensory CNAP or low CNAP amplitude in this nerve, as well as in ruling out lumbar radiculopathy (Fig. 41.4) (Oh, unpublished). Again, the side-to-side comparison is essential for adequate interpretation of this technique. 41.4. Sciatic neuropathy The sciatic nerve is the major nerve originating from the L4–S3 spinal nerves and the lumbosacral trunk. There are four nerves, which originate from the lumbosacral plexus: the superior gluteal nerve (L4, L5, S1), the inferior gluteal nerve (L5, S1, S2), the posterior femoral cutaneous nerve (S1, S2, S3), and pudendal nerve (S2, S3, S4). The sciatic nerve leaves the pelvis through the greater sciatic foramen (the sciatic notch) below the piriformis muscle. The inferior gluteal nerve and the posterior femoral cutaneous nerve also pass through the sciatic notch below the piriformis muscle. The only nerve that passes above the piriformis is the superior gluteal nerve. Thus, the sciatic nerve may be entrapped by the piriformis muscle as it leaves the pelvis through the greater sciatic notch and crosses its sharp edge (Kopec and Thompson,

869

1963). Other nerves (the inferior gluteal and posterior femoral cutaneous nerves) are usually also involved. The sciatic nerve consists of two distinct nerve trunks, the medial trunk (the posterior tibial nerve) and the lateral trunk (the common peroneal nerve). The medial trunk arises from the posterior divisions and the lateral trunk from the anterior divisions of the L4–S2 spinal nerves. The sciatic nerve innervates the hamstring muscles. The short head of the biceps femoris is the only muscle that is innervated by the lateral trunk, all other hamstring muscles being innervated by the medial trunk. No sensory branch arises from the sciatic nerve itself. Proximal sciatic neuropathy should be differentiated clinically from common peroneal nerve palsy because the peroneal branch is always more involved in sciatic neuropathy (Van Langenhove et al., 1989; Katriji and Wilbourn, 1994). The greater vulnerability of the lateral trunk is most likely due to a combination of factors: (a) it is more firmly fixed and angulated at the sciatic notch; and (b) it contains larger and fewer fascicles and less connective tissue than the medial trunk, and so has less tensile strength (Sunderland, 1953). The most common cause of proximal sciatic neuropathy is trauma because of the proximity of the sciatic nerve to the hip joint (Yuen et al., 1995). In fact, total hip arthroplasty is the most common cause of sciatic neuropathy (Yuen et al., 1995). Sciatic neuropathy is the most common neurological complication from intramuscular gluteal injections, accounting for 96% of the cases (Obach et al., 1983). Crisci et al. (1989) reported a case of trochanteric sciatic neuropathy caused by the combination of an underlying prominent lesser trochanter and sitting on hard benches. The needle EMG study localized the lesion to the proximal sciatic nerve. The nerve conduction study showed no response in the peroneal and posterior tibial nerves and absent CNAP in the sural and superficial peroneal nerves. Wilbourn and Mitsumoto (1988) reported four cases of proximal sciatic neuropathy caused by prolonged sitting. All patients had footdrop. The needle EMG showed denervation process in the sciatic-innervated muscles, typically including the hamstrings. Nerve conduction studies showed absent CNAPs in the sural and superficial peroneal nerves and low CMAP amplitude in the peroneal and posterior tibial nerves. Piriformis syndrome is a pure pain syndrome characterized by hip pain radiating down the back of the thigh and dyspareunia in a female patient (Pace, 1976). Classic piriformis syndrome should not be

870

SHIN J. OH Left

Right

A. Femoral motor nerve conduction

5 mV 5 ms

0.5 mV 5 ms

B. Saphenous sensory conduction

5 μV

5 μV 1 ms

1 ms

C. Medial femoral cutaneous sensory conduetion

10 μV 1 ms

10 μV 1 ms

Fig. 41.4 Nerve conduction abnormality in femoral neuropathy. (A) Low CMAP in the right femoral nerve. (B) Absent sensory CNAP in the right saphenous nerve. (C) Absent CNAP in the right medial femoral cutaneous nerve (Reproduced from Oh SJ (1998) Principles of clinical electromyography: Case studies with permission by Williams & Wilkins, Baltimore).

associated with any neurological abnormality (Pace, 1976). Sciatic neuropathy is less common in the thigh and is most frequently caused by missile wounds (Yuen and So, 1999). The peroneal, posterior tibial, sural, or all three nerves may be involved. Three sciatic motor nerve conduction tests are available (Oh, 2003). Stimulation of the proximal sciatic nerve is made with a needle electrode inserted deep into the gluteal fold. The distal sciatic nerve is

stimulated at the popliteal fossa using a surface electrode. Recording of the CMAP is made from the gastrocnemius, ADQ, AH, or EDB muscles. Inaba et al. (1996) used high-voltage low-intensity electrical (HVLI) stimulation for stimulation of the proximal sciatic nerve. Their technique has the advantage of the capability of noninvasive stimulation at the proximal sciatic nerve but it requires an HVLI stimulator. We have not found any study of the proximal sciatic nerve conduction in proximal sciatic

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

neuropathy, even in the series with the largest number of cases of sciatic neuropathy (Yuen et al., 1995). We had one case of sciatic neuropathy in a thin alcoholic patient in whom the sciatic motor nerve conduction was slow. Nerve conduction in peroneal, posterior tibial, sural, and superficial peroneal sensory nerves is usually tested in the work-up of sciatic neuropathy. Thus, it is not used for the localization of focal neuropathy but for differentiation between pre- and postganglionic lesions and determination of axon loss (Yuen et al., 1995). NCV and latency were normal for motor and sensory nerve conduction in all cases. Abnormalities in the sensory CNAP amplitude were found in 71% of tested cases for the sural nerve and in 83% of cases for the superficial peroneal nerve, indicating postganglionic lesion. Abnormalities in the CMAP amplitude were found in 80–89% of tested cases for the peroneal nerve and in 52% of tested cases for the posterior tibial nerve. F-wave abnormality was found in 85% of tested cases for the peroneal nerve and in 57% for the posterior tibial nerve. The peroneal division was more severely affected than the posterior tibial division in 64% of cases, supporting the well-known clinical observation. Exceptions were gunshot wounds and femur fractures, which may affect the posterior tibial division more severely (Yuen et al., 1995). Most patients (93%) had electrodiagnostic signs of axonal loss. The most surprising finding in Yuen’s study was normal sural sensory CNAP amplitude in 29% of tested cases and normal CNAP amplitude of both the superficial peroneal and sural nerves in 9%. This led the author to conclude that normal sural and superficial peroneal nerve conductions do not necessarily rule out sciatic neuropathy. One of our patients with sciatic neuropathy at the high popliteal fossa had mild slowing in the sural, superficial peroneal, and medial plantar nerves (Oh, 1988) (Fig. 41.5). The needle EMG is vital in localizing the lesion in sciatic neuropathy. For sciatic plexopathy, the needle EMG test in the gluteal muscles is critical because the superior and inferior gluteal nerves are the only nerves which branch from the sciatic nerve in the pelvic floor. Denervation process in these muscles localizes the lesion to the sciatic plexus within the pelvic floor. Proximal sciatic neuropathy is identified by detecting the denervation process in the hamstring muscles. The most challenging clinical situation for electromyographers is sciatic neuropathy in patients who have involvement of only the peroneal division and complete clinical and electrodiagnostic sparing of the

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32.6 Lt

46.0 Rt

10 μV 1 ms

Fig. 41.5 Superficial peroneal nerve conduction in a case of low sciatic neuropathy at the popliteal fossa. Slow (32.6 m/s) sensory NCV in the left superficial peroneal nerve compared with normal NCV (46.0 m/s) in the right (Reproduced from Oh, SJ. Principles of clinical electromyography: Case studies with permission by Williams & Wilkins, Baltimore).

tibial division (Katriji and Wilbourn, 1994; Yuen et al., 1995). The needle EMG in the short head of the biceps femoris is critical in these patients because this is the only muscle which is innervated by the lateral trunk (Fig. 41.6). Denervation process in this muscle localizes the lesion proximal to the midthigh, where the branch to the short head of the biceps femoris exists the peroneal division of the sciatic nerve, and differentiates sciatic neuropathy from common peroneal neuropathy at fibular head. Synek (1987) stated that the SEP study is essential in detecting a sciatic nerve lesion because the sensory nerve conduction in the proximal segment of the sciatic nerve is not possible with the conventional technique. Synek reported abnormal SEP (latency delay and amplitude reduction compared with the normal side) in the posterior tibial or peroneal SEP in five of seven patients with proximal sciatic neuropathy, including a case of pyriformis syndrome (Synek, 1985, 1987). The H-reflex from the gastrocnemius and T-reflex of ankle should be abnormal in sciatic neuropathy. However, they are commonly used for the diagnosis of S1 radiculopathy.

872

SHIN J. OH Fig. 41.6 EMG needle insertion in the short head of biceps femoris. Patient is in a lateral decubitus position. EMG needle is inserted anterior to tendon of the long head of biceps femoris and 3–4 finger breath proximal to the fibular head. (Reproduced from Katirji, MB and Wilbourn, AJ (1994), High sciatic lesions mimicking peroneal neuropathy at the fibular head. J. Neurol. Sci., 121: 173 with permission by Elsevier).

41.5. Poster tibial (tibial) neuropathy The posterior tibial nerve is a continuation of the medial trunk of the sciatic nerve. It passes through the popliteal fossa and then deep between the two heads of the gastrocnemius muscle. In the calf, it innervates the gastrocnemius, soleus, posterior tibialis, flexor digitorum longus and hallucis longus muscles. At the ankle, it passes through the tarsal tunnel. Within the tarsal tunnel, it is divided into three branches: the medial and lateral plantar nerves and the calcaneal branch. Medial plantar nerve innervates the abductor and flexor hallucis, and flexor digitorum brevis muscles and supply the sensation to the medial 2/3 of plantar surface of the foot. Lateral plantar nerve innervates the abductor and flexor digitii quinti muscles and supply the sensation to the lateral 1/3 of plantar surface of the foot. Calcaneal (medial calcaneal) nerve is the pure sensory nerve subserving the sensation on the heel. 41.5.1. Tarsal tunnel syndrome TTS, the most common form of entrapment neuropathy of the tibial nerve, is a compression neuropathy of the posterior tibial nerve and its branches within the

fibro-osseous tunnel that lies beneath the flexor retinaculum on the medial side of the ankle. Although it is analogous to carpal tunnel syndrome (CTS), clinical recognition of TTS lags far behind that of CTS. TTS is rarer compared with CTS. In our laboratory, we make the diagnosis of one case of TTS versus roughly 100 cases of CTS (unpublished data). Modellit and Cioni (1998) studied the issue of association between CTS and TTS. They performed the near-nerve needle sensory nerve conduction of the plantar nerves and posterior tibial motor nerve conduction in 65 patients with CTS. None of them complained of any symptoms of TTS. Plantar NCV was slow in 10 (15%) patients, in five of whom distal latency was prolonged, indicating subclinical TTS in 10 patients. Ulnar, peroneal, and sural nerve conduction were normal. The whole group of CTS patients showed a significant reduction in mean NCV and a substantial increase in mean distal latency of the posterior tibial nerves in comparison with controls. In two (13%) of 15 patients with TTS, CTS studies showed slow sensory NCV in the finger–wrist and prolonged distal latency, indicating the presence of subclinical CTS in these patients. None of them had any complaint of CTS. All the TTS groups showed a significant reduction in mean sensory NCV of the median

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

nerve and distal latency in comparison with controls. Thus, these studies found a close association between CTS and TTS. As in CTS, the most common cause of TTS is idiopathic, as noted in 36–43 % of cases (Radin, 1983; Oh, 1987). Among the known causes, the most common is trauma, accounting for one-third of cases (Oh, 1987). This high frequency of trauma in TTS is in good contrast to the low trauma frequency, 20%, as the cause of CTS (Stevenson, 1966) and is presumably related to the greater susceptibility of the foot to injury. Typical symptoms include burning pain and paresthesia on the toes and along the sole of the foot. Classically, the symptoms are increased by activity, are diminished by rest, and often become worse at night. The most helpful diagnostic criteria are a positive Tinel’s sign at the ankle and objective sensory loss in the territory of any of the terminal branches of the posterior tibial nerve. Local tenderness at the tarsal tunnel is another common finding. Weakness of toe flexion and atrophy of the abductor hallucis muscle are rare. Three orthodromic sensory nerve conduction techniques for the medial and lateral plantar nerves with surface recording electrodes are available (Oh et al., 1985; Ponsford, 1988; Oh, 2003). Recording electrodes are placed in the posterior tibial nerve at the ankle and stimulation electrodes are positioned either on the toes with ring electrodes or on the nerves at the metatarsal area. Mixed nerve conduction of the medial and lateral plantar nerves is possible with the surface electrode at the ankle and stimulation 14 cm distal to the recording site on the nerves (Saeed and Gatens, 1982). Interdigital sensory nerve conduction of the plantar nerves can also be studied with the near-nerve needle recording at the ankle and the stimulation of interdigital nerves with special interdigital stimulating electrodes (Oh et al., 1985; Oh, 2003). The nerve conduction study is the test of choice for confirming the diagnosis of TTS in 90–100% of cases (Oh et al., 1979, 1985; Galardi et al., 1994; Modellit et al., 1998) (Table 41.3) (Figs. 41.7.and 41.8). Until 1979, prolonged terminal latency in the medial and lateral plantar nerves was used as an objective diagnostic criterion for TTS. However, the diagnostic sensitivity of the terminal latency is low, prolongation having been observed in 17 to 55.4% of cases (Oh et al., 1979, 1985). The overall diagnostic sensitivity of the terminal latency in the literature is 43%. Theoretically, the sensitivity of motor-conduction studies could be increased by stimulating the nerve

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above and below the tarsal tunnel to distinguish between nerve lesions in and distal to the tunnel (Felsenthal et al., 1992), but this technique remains to be proven. In contrast, sensory nerve conduction studies with a surface electrode and signal averaging are far superior in confirming the diagnosis of TTS, being abnormal in 90.5–100 % of cases (Oh et al., 1979; Galardi et al., 1994; Modellit et al., 1998). Sensory nerve conduction was abnormal in all nerves in which the terminal latency was prolonged. Both plantar nerves should be tested because in some cases only one nerve is affected. Abnormality in sensory nerve conduction is expressed either by absent CNAP or slow NCV. Modellit and Cioni (1998) found absent CNAP or slow NCV in 77% of cases but were able to increase the diagnostic sensitivity to 91% by comparing the NCV from the unaffected side or distal sural nerve conduction: > 8 m/s difference was considered abnormal. Since the CNAP of plantar nerves is not obtainable in some older normal individuals, Oh et al. (1985) have used the near-nerve needle technique for the sensory nerve conduction of the plantar nerve for diagnosis of TTS. This technique improved the diagnostic sensitivity from 90.5 to 96% in Oh’s series and, further, was able to elucidate the basic pathological process of TTS as a focal segmental demyelination on the basis of frequent observation of markedly slow NCV and dispersion phenomenon (Oh, 2002). Saeed and Gatens (1982) described a technique for recording mixed nerve conduction in the medial and lateral plantar nerves. This technique has the advantage of not relying on the aid of a signal averager. We had some difficulty in consistently obtaining the CNAP from the lateral plantar nerve with this technique. A similar technical difficulty was observed by Dumitru et al. (1991) and Ponsford (1988). Saeed and Gatens (1982) reported absent CNAP in the medial and lateral plantar nerves in one case of TTS. Delisa and Saeed (1983) reported one case of TTS in which CNAP was absent in the lateral plantar nerve. Galardi et al. (1984) reported 86% accuracy of abnormality with mixed nerve conduction in 14 cases of TTS compared with 100% accuracy with the sensory nerve conduction. They claimed that the specificity of mixed nerve conduction is higher than that of sensory nerve conduction for the diagnosis of TTS, based on their observation that the sensory CNAP was absent in two unaffected limbs, and they did not have any technical difficulty in obtaining mixed nerve conduction. This technical difficulty of obtaining the sensory CNAP is easily overcome by the near-nerve needle

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Table 41.3 Nerve conduction findings in tarsal tunnel syndrome Galardi (1994)* (N = 14)

Oh (1985)** (N = 25)

Modellit** (1998) (N = 65)

Parameters

Oh (1979)* (N = 21)

Terminal latency Medial plantar nerve Prolonged latency Low-amplitude CMAP Lateral plantar nerve Prolonged latency Low-amplitude CMAP Sensory nerve conduction Medial plantar nerve Absent CNAP Slow NCV Low-amplitude CNAP Dispersion phenomenon Lateral plantar nerve Absent Slow NCV Low-amplitude CNAP Dispersion phenomenon Mixed nerve conduction Medial plantar nerve Absent CNAP Slow NCV Low-amplitude CNAP Asymmetric low-amplitude CNAP Lateral plantar nerve Absent CNAP Slow NCV Low-amplitude CNAP Asymmetric low-amplitude CNAP

11 (54.4%)

3 (21.4%)

4 (17%)

36 (55.4%)

10 (47.6%) 7

3 (21.4%) 0

1 1

36 (55.4%) 9

3 0

(N = 44) 23 (52%) 12

7 7 19 (90.5%)

14 (100%)

(N = 21) 11 (52.3%) 5 6

8 (57.1%) 4 2

24 (96%)

59 (91%)(1)

2 16 10

23 (35%) 25 (38.5%)(2)

14 (N = 18) 10 (55.5%) 2 3

13 (92.8%) 0 0

6 4 5

(N = 44) 22 (50%) 7 (16%)(3)

5 12 (85.7%)

1 2 4 3

6 1 1 3

* These cases were studied with surface recording electrodes (10). **These cases were studied with near-nerve needle recording electrodes. (1) Absent CNAP or slow NCV was observed in 50 (77%) feet. Relative slowing was observed in 9 feet (see below). (2) 8 m/s between affected and unaffected MP nerve and/or between MP and distal sural nerves of the affected side was found in 9 feet. (3) 8 m/s between affected and unaffected LP nerve was found in 4 feet. (4) In Modellit’s series, the needle EMG chronic neurogenic pattern (loss of MUP during full effort) in 17 (45%) of 38 feet, in 8 (21%) of which there was also fibrillations and PSW in abductor hallucis and/or digiti minimi muscles. (Reproduced from Oh, SJ (1998) Clinical Electromyography. Nerve Conduction Studies, IIIrd edn. By permission of Lippincott, Williams And Wilkins, Philadelphia.

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

875

26.1

23.3

I

III-IV

30.7

27.8

24.6 24.7 I-II

IV-V 30.2 31.1 23.8 25.0 V

II-III

1 μV

28.9

2 ms

32.6

Fig. 41.7 Sensory nerve conduction abnormalities in tarsal tunnel syndrome. The sensory compound nerve action potentials (CNAPs) are obtained with the near-nerve technique. Slow maximum and negative-peak NCVs in medial plantar nerve and normal maximum and negative-peak NCVs in lateral plantar nerve (Reproduced from Oh, SJ (1985) The near-nerve sensory nerve conduction in tarsal tunnel syndrome. J Neurol Neurosurg Psychiatry, 48: 1001, with permission by the BMJ Publishing Group).

I

IV-V 23

21

1 μV 2 msec

12 I-II 22

0.5 μV 2 msec 9.8

II-III 22

V

Fig. 41.8 Sensory nerve conduction abnormalities in tarsal tunnel syndrome. The sensory compound nerve action potentials (CNAPs) are obtained with the near-nerve technique. Slow maximum NCV and dispersion phenomenon in I, I–II, and II–III interdigital nerves. The Roman numeral indicates the stimulating digit; the Arabic number under each CNAP denotes the maximum sensory nerve conduction (NCV) (m/s). No CNAP is obtained with V digit stimulation. (Reproduced from Oh, SJ (1998) Clinical Electromyography, Nerve Conduction Studies, IIIrd ed. with permission by Lippincott, Williams & Wilkins, Philadelphia).

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sensory nerve conduction technique. David and Doyle (1996) described the near-nerve needle sensory nerve conduction technique for the tarsal tunnel segment with the hope that this technique would differentiate TTS from distal sensory neuropathy. The usefulness of this technique in TTS remains to be proven. We found it extremely difficult to perform. The needle EMG study shows denervation process in the involved intrinsic muscles of the feet: abductor hallucis, abductor and flexor digitii quinti muscles (Oh, 2002). In fact, in the series by Modellit et al. (1998), the needle EMG showed a chronic neurogenic pattern (loss of MUP during full effort) in 17 (45%) of 38 feet, in eight (21%) of which there were also fibrillations and PSW in the abductor hallucis and/or digiti minimi muscles. The value of the EMG is limited further by the

frequent observation of denervation potentials in normal persons. In some cases where the differential diagnosis from lumbosacral radiculopathy or distal peripheral neuropathy is not clinically easy, appropriate electrophysiological tests are needed to rule out these possibilities. Electrophysiological improvement was documented in three patients with TTS who had clinical improvement after surgical decompression (Fig. 41.9) (Oh et al., 1991). The near-nerve sensory nerve conduction of the plantar nerve 14 months–3.5 years after surgery showed improvement in motor and sensory nerve conduction. However, minor abnormalities still existed in the sensory nerve conduction in all three cases. Modellit et al. (1998) also reported nerve conduction improvement in three cases and no improvement in one case after surgical decompression. With

Before

After

27.6 I

28.6

28.0 I-II

31.0

29.5

IV-V

0.5 μV 2 ms

1 μV 2 ms

Fig. 41.9 Sensory nerve conduction in a patient with tarsal tunnel syndrome before and after the decompression operation. In the I-II interdigital nerve, the CNAP was absent before but was recorded after the operation. Number above the potentials represent the maximal NCV (m/s). Notice difference between in the amplitude calibration before and after the operation (Reproduced from Oh, SJ et al. (1991) Electrophysiological improvement following decompression surgery in tarsal tunnel syndrome. Muscle Nerve, 14: 409, with permission by John Wiley & Sons, Inc.).

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

local steroid injections, nerve conduction improvement was documented in two cases. Ward and Porter (1998) reported the neurophysiological and clinical outcomes of surgical decompression in 22 patients with TTS. In only 42% of cases, was there a satisfactory outcome, and a larger reduction in the distal latency corresponded well to an improvement in symptoms. They did not perform sensory nerve conduction in their patients. Some of the patients studied by Modellit et al. (1998) showed a slow tibial motor NCV, and the mean MCV was significantly lower than that of controls. Dumitru and Marquis (1991) reported an attenuation of amplitude in the medial plantar SEP compared with normal side in two cases of tarsal tunnel syndrome. 41.5.2. Medial plantar neuropathy The medial plantar nerve innervates the four mediallylocated muscles and the medial two-thirds of the plantar aspect of the foot. The medial plantar nerve is often compared to the median nerve of the wrist. The medial plantar nerve can be compressed in isolation along its pathway distal to the tarsal tunnel,

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thereby producing medial plantar neuropathy (MPN). MPN has been reported with malignant schwannoma, leprosy, tenosynovial cysts, entrapment at the abductor tunnel, and reversible “jogger’s foot” (Rask, 1978). The common site of compression in MPN is at the abductor tunnel (the fibromuscular tunnel behind the navicular tuberosity). Clinically, these patients have burning pain/tingling numbness over the medial two-thirds of the sole of the foot and Tinel’s sign and tenderness over the medial plantar nerve at the entrance of the abductor tunnel. It is not easy to differentiate MPN from TTS with predominant involvement of the medial plantar nerve. In the series by Oh and Lee (1987), 14 of 43 TTS patients had medial plantar neuropathy on clinical grounds. In three cases, the nerve conduction test identified additional lateral plantar nerve abnormalities indicative of TTS, but in 11 cases, the differentiation between MPN and TTS was a clinical challenge: Tinel’s sign localized at the tarsal tunnel in TTS and at the abductor tunnel in MPN. The sensory nerve conduction study of the plantar nerves can confirm the diagnosis of MPN, being selectively abnormal in the medial plantar nerve and normal in the lateral plantar nerve (Fig. 41.10) (Oh and 28.7

27.4 9.5

III-IV

I

32.0

1 μV

31.0

32.2

27.4 6.6

I-II

IV-V 36.7

31.7

2 μV

1 μV

1 μV

28.6 28.3 V

II-III 32.3

33.5

2 μV

1 μV

2 msec

Fig. 41.10 The compound nerve action potential (CNAPs) of the interdigital nerves in medial plantar neuropathy. Sensory nerve conduction in a patient with medial plantar neuropathy. Slow NCV and dispersion phenomenon in the I and I-II interdigital nerves. The Roman numerals indicate the stimulated digits. The Arabic numbers under and above each CNAP denote the maximum and the negative-peak NCV (m/s). The Arabic number between two arrows indicates the duration of CNAP in ms (Reproduced from Oh and Lee (1987) Medial plantar neuropathy. Neurology, 1410, with permission by Lippincott, Williams & Wilkins).

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SHIN J. OH

Lee, 1987). We used the near-nerve needle sensory nerve conduction technique of the interdigital nerve (Oh et al., 1985). Absent sensory CNAPs or slow NCV with low CNAP amplitude were observed in the medial plantar nerve in four cases. Budak et al. (2001) found the significantly slower sensory NCV of medial plantar nerve in 56 feet of 28 pes planus subjects indicating asymptomatic medial plantar neuropathy in this condition. The needle EMG in the abductor hallucis brevis and flexor digitorum brevis (I–III) muscles may show denervation in this disorder.

producing lateral plantar neuropathy. Sensory loss is confined to the lateral one-third of the sole of the foot. Weakness of the abductor digiti quinti may be possible but is clinically difficult to document. Lateral plantar neuropathy as a clinical expression of TTS was observed in two of 25 cases of TTS in the series by Oh et al. (1985). Belding (1993) reported a case of lateral plantar neuropathy due to neurilemoma in the tarsal tunnel. Oh and colleagues reported eight patients with this neuropathy, confirmed by abnormal sensory NCS confined to the lateral plantar nerve: absent CNAP in four cases and low CNAP amplitude in four cases (Oh et al., 1999) (Fig. 41.11). We used the near-nerve needle sensory nerve conduction technique of the interdigital nerve (Oh et al., 1985). Terminal latency to the abductor digiti quinti (ADQ) muscle was normal in five of six tested cases. Most likely this neuropathy was due to a lesion distal to the branching of the inferior calcaneal nerve. Needle EMG may show signs of denervation in the ADQ muscle if the lesion is proximal enough to

41.5.3. Lateral plantar neuropathy The lateral plantar nerve is often compared to the ulnar nerve in that it supplies motor branches to the remaining muscles of the lateral plantar aspect of the foot and cutaneous innervation to the lateral one-third of the plantar aspect of the foot. The lateral plantar nerve can be compressed in isolation along its pathway distal to the tarsal tunnel,

30.7

37.4 III−IV

I

35.0 42.8

31.6

IV−V

I−II

23.6

27.8 36.5 0.5 μV 1 ms

Fig. 41.11 Sensory nerve conduction in lateral plantar neuropathy. Slow maximum and negative-peak NCV in the IV–V and V interdigital nerves. The Roman numerals indicate the stimulated digits. The Arabic numbers under and above each CNAP denote the maximum and the negative-peak NCV (m/s) (Reproduced from Oh et al. (1999) Lateral plantar neuropathy. Muscle Nerve, 22:1236, with permission by John Wiley & Sons, Inc.).

24.6

30.0 V II−III

26.5 40.0

0.5 μV 2 ms

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

involve the inferior calcaneal branch. However, if the lesion is distal to this division, then needle EMG abnormalities are confined to the flexor digiti quinti brevis muscle, sparing the ADQ muscle. 41.5.4. Inferior calcaneal neuropathy The inferior calcaneal nerve is the first branch of the lateral plantar nerve innervating the abductor digiti quinti muscle (Del Toro et al., 1998). In orthopedic and podiatric literatures, entrapment of this nerve has been implicated as a common and treatable cause of anterior heel pain syndrome (Bexter and Pfeffer, 1992). This nerve is believed to be entrapped between the deep fascia of the abductor hallucis muscle and the medial head of the quadratus plantae muscle. Patients are usually athletes with no neurological abnormality. Section of the deep fascia is said to be effective in relieving pain. Baxter and Pfeffer (1992), who advocate entrapment neuropathy of this nerve, were not able to find any abnormality in the needle EMG and NCS in nine tested patients. Park and Del Toro (1996) reported a low CMAP amplitude from the ADQ muscle in the motor nerve conduction and fibrillation in the ADQ muscle in a case of isolated inferior calcaneal neuropathy. The patient seffered from heel pain that began during a competitive volleyball game and complained of mild anteromedial heel pain at the time of evaluation. He had mild tenderness on the anteromedial heel anterior to the calcaneus and inability to actively abduct his left 5th toe. Öztuna et al. (2002) studied the motor latency and sensory nerve conduction of the medial and lateral plantar nerve in 25 cases with heel pain and did not find any case with a prolonged motor latency in the lateral plantar nerve. Instead, they found sensory nerve conduction abnormality in the lateral plantar nerve in 88% of cases with additional abnormality in the medial plantar nerve in 36% of cases. Thus, this study did not confirm the inferior calcaneal nerve as the entrapped nerve in this condition. 41.5.5. Medial calcaneal (calcaneal) neuropathy Isolated medial calcaneal neuropathy is rare. Brooks (1952) has described a patient with calcaneal neuropathy due to a ganglion in the tarsal tunnel, which produced numbness in the heel and hypesthesia localized to the undersurface of the heel. Oh et al. (1985) observed one case of calcaneal neuropathy in 25 patients with tarsal tunnel syndrome. There has been some controversy with regard to calcaneal neuropathy as a cause for heel pain (Henricson and Vestom, 1984), with many

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maintaining that this is caused by entrapment of the calcaneal nerve. However, the proof is still lacking (Park and Del Toro, 1995). Park and Del Toro (1995) described a method of antidromic sensory nerve conduction of the medial calcaneal nerve (MCN) with the recording surface electrodes in the medial calcaneal nerve between the medial malleolus and heel and the stimulating surface electrodes proximal to the recording electrodes in the posterior tibial nerve. Seror (1995) raised a legitimate question about the technical reliability of their method because of possible volume-conduction response from the tibial nerve. Seo et al. (2002) reported an orthodromic near-nerve needle sensory-nerve conduction method with the near-nerve needle as the recording electrode located proximally in the posterior tibial nerve and with surface stimulating electrodes distally between the medial malleolus and heel. This technique is capable of recording the sensory nerve action potentials of MCN in isolation and reported four cases of medial calcaneal neuropathy, three of which were confirmed by their technique (Seo et al., 2002). Two patients had TTS involving the MCN and two had Wartenberg migratory sensory neuropathy. Electrophysiologically, medial calcaneal neuropathy was confirmed by slow NCV, low CNAP amplitude and/or absent CNAP in three cases (Fig. 41.12). In one case, the NCS showed findings suggestive of medial calcaneal neuropathy: the CNAP amplitude of the involved MCN was 49% of the normal side, too minimal for a definitive diagnosis of medial calcaneal neuropathy. This indicates that Seo and Oh’s orthodromic near-nerve needle sensory nerve conduction method is the only reliable method (Seo et al., 2002). 41.5.6. Interdigital neuropathy (Morton’s neuroma) Morton’s neuroma refers to III–IV interdigital neuropathy and is not uncommon. Typically, the patient complains of pain on the plantar aspect precisely localized between the III–IV metatarsal heads, often with radiation to the toes. Walking or standing precipitates the pain, and rest gives relief. Nearly all the patients have tenderness on the interdigital nerve between the metatarsal heads. Sensory impairments are often detectable in the affected clefts and toes. Repeated trauma on the interdigital nerve is the most common accepted cause of this disorder. Pathologists have consistently found a proliferation of fibrous connective tissue within the plantar digital nerve and its supporting stroma in Morton’s neuroma. Thus

880

SHIN J. OH Medial calcaneal nerve

Distal posterior tibial nerve

34.4

26.4 Case 1

5 μV

10 μV

1 ms

1 ms

35.7 31.3 Case 2

0.5 μV 2 ms

5 μV 2 ms

Fig. 41.12 Medial calcaneal neuropathy. Sensory nerve conduction in medial calcaneal neuropathy. Abnormal sensory nerve conduction in cases 1 and 2 in contrast to relatively normal distal posterior tibial nerve conduction: slow sensory NCV in case 1 and low CNAP in case 2. Motor artifact (*) is present in the responses recorded in the distal posterior tibial mixed nerve conduction study. Numbers above the CNAPs represent the negative-peak sensory NCVs (From Seo, JH and Oh, SJ (2002) Nearnerve needle sensory conduction study of the medial calcaneal nerve: New method and report of four cases of medial calcaneal neuropathy. Muscle Nerve, 26:657, with permission by John Wiley & Sons, Inc.).

Morton’s “neuroma” is really a misnomer and should be more accurately described as a fibroma. Guiloff et al. (1984) tried the electrophysiological evaluation of the interdigital nerves in vain with surface electrodes. They stimulated the involved digital nerve with ring electrodes and recorded the sensory CNAP at the ankle and compared with the response from the other foot. Only in six (38%) cases did they find an absent response in the involved nerves compared with normal response in the unaffected side. In others, the response was either normal (three cases), absent bilaterally (five cases), and absent in the unaffected side (two cases).

Oh et al. (1985) devised a method for recording CNAPs from various interdigital nerves of the foot with a near-nerve needle as the recording electrode at the ankle and a specially designed interdigital stimulator as the stimulating electrode. They reported electrophysiological abnormalities in five cases of interdigital neuropathy. These were characterized by a selective decrease in the amplitude of the CNAP in the involved interdigital nerve (“abnormal dip phenomenon”), a relatively normal NCV, and normal duration of CNAP (Fig. 41.13). “Dip phenomenon” (a selective decrease in the amplitude of the CNAP in one interdigital nerve between neighboring interdigital nerves with

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

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the affected nerve was abnormally slow in six cases. The amplitude of CNAP was not affected. This finding is in contrast to that of Oh et al. (1985), who reported that the amplitude was selectively decreased in the affected nerve (dip phenomenon) in Morton’s neuroma. This discrepancy was apparently due to the difference in techniques.

II-III

41.5.7. Medial plantar digital proper nerve syndrome (Joplin’s neuroma)

III-IV

IV-V

1 μV 2 ms 3.0

Fig. 41.13 Interdigital neuropathy. Sensory nerve conduction in Morton’s neuroma. The shape of the III–IV interdigital CNAP is abnormal, and a dip phenomenon is obvious (Reproduced from Oh, SJ et al. (1984) Electrophysiological diagnosis of the interdigital neuropathy of the foot. Muscle Nerve, 7:224, with permission by John Wiley & Sons, Inc.).

normal amplitude) was present in 18% of normal controls. However, the amplitude of CNAPs in the interdigital nerve with “dip” was always greater than 50% of the CNAP amplitude in the preceding interdigital nerve. In patients with interdigital neuropathy, the amplitude oft the CNAP in the involved nerve was less than 50% of that in the preceding interdigital nerve. This is called “abnormal dip phenomenon”. Diagnosis of interdigital neuropathy was confirmed electrophysiologically by the abnormal dip phenomenon in four cases and by the abnormal shape and prolonged duration of the CNAP in one case. Using the same nearnerve needle technique, de Almeida et al. (2002) confirmed this finding in 18 cases of interdigital neuropathy. Abnormal dip phenomenon is the most common finding seen in 67% of cases. Other findings were the relative dip phenomenon (less than 50% decrease in amplitude) in 22% of cases, slow NCV in 17%, and dispersion phenomenon in 22%. On the other hand, Falck et al. (1984) used a different technique to measure the sensory nerve conduction in the interdigital plantar nerves of the foot with the nearnerve needle as the recording electrode at the ankle as well as the stimulating electrode on the mesial branch of the interdigital nerve. In the diagnosis of Morton’s neuroma, these authors suggested comparing the NCVs of the four interdigital nerves with each other, rather than comparing individual interdigital nerves with the normal mean. In patients with Morton’s neuroma, the NCV of

Joplin described a pain syndrome due to traumatic perineurial fibrosis of the proper digital nerve, which is sometimes called “Joplin’s neuroma” (Joplin, 1971; Meritt and Subotnick, 1982). This syndrome is usually characterized by pain in the medial aspect of the foot involving the great toe and an enlarged (cord-like) nerve immediately proximal to the interphalangeal joint, which is painful to palpation. Hypesthesia or hyperesthesia to pin prick over the medial aspect of the great toe was found in some cases (Ginnestras, 1973). Tinel’s sign is present on the medial aspect of the metatarsophalangeal joint in some cases. The diagnosis of this neuropathy can be confirmed by the sensory NCS of the MPPD nerve, using a near-nerve needle as a recording electrode at the tibial nerve at the ankle and as a stimulating surface electrode selectively at the MPPD nerve in the great toe (Fig. 41.14) (Cichy et al., 1995). A low CNAP and normal NCV were found in one case (Cichy et al., 1995), and in three other cases, CNAP was absent (Marques and Barreira, 1996). In one patient with normal neurological findings despite numbness and chronic burning pain on the medial aspect of the great toe, this test was normal (Marques and Barreira, 1996). 41.5.8. Proximal posterior tibial neuropathy Since the posterior tibial nerve is deeply located in the popliteal fossa and calf, this nerve is rarely compressed externally. Most of these lesions are “mass lesions” or due to compression of the nerve by an anatomical variation. The presence of a Baker’s cyst high in the calf, a nerve sheath tumor, synovial cyst, tendinous arch of the soleus muscles, or localized hypertrophic mononeuropathy may be responsible for isolated tibial neuropathy (Oh and Meyer, 1999). The hallmark of proximal tibial neuropathy is weakness of the plantar flexors and invertors, which distinguishes this neuropathy from TTS, in which weakness does not occur. Proximal tibial neuropathy can be distinguished from S1 radiculopathy

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SHIN J. OH

Needle

Surface

R

0.2 μV 2 ms

L

1 μV 2 ms

Fig. 41.14 Sensory compound nerve action potentials (CNAPs) in the right (R) and left (L) medial plantar proper digital nerves in Joplin’s neuroma after surface and needle stimulation. CNAP amplitudes on the right are significantly reduced (note different sensitivity for the upper and lower tracings). CNAP latencies on the right are longer than those on the left, but they are still within normal limits (Reproduced from Cichy, SW et al. (1995) Electrophysiological studies in Joplin’s neuroma. Muscle Nerve, 18:672, with permission by John Wiley & Sons, Inc.).

because of weakness of the tibial muscle (plantar invertor). Three patients in whom the first symptoms of TTS emerged after an acute event proximal to but not affecting the ankle have been reported (Augustijn and Vanneste, 1992). Nerve conduction of the tibial nerve should be able to confirm tibial neuropathy. In mild cases, the mixed nerve conduction may be the only way to document abnormality. Sural and plantar nerve sensory nerve conduction may be abnormal. Denervation process was detected in the flexor hallucis and digitorum longus, abductor hallucis, and abductor digiti minimi muscles. Denervation process is also detected in the gastrocnemius, soleus, and posterior tibialis muscles if the lesion is proximal to the popliteal fossa. In S1 radiculopathy, denervation process was absent in the flexor halucis and digitorum longus and posterior tibial muscles, which are innervated by L5 root. The H-reflex and T (electronic tendon reflex)-reflex should also be abnormal in this neuropathy. 41.6. Lateral femoral cutaneous neuropathy (meralgia paresthetica) The lateral femoral cutaneous nerve originates from the L2 and L3 spinal nerves. Meralgia paresthetica is a

clinically benign entrapment neuropathy of the lateral femoral cutaneous nerve of the thigh. The site of entrapment is the point at which the nerve pierces the inguinal ligament or the fascia lata upon entering the thigh at or near the level of the anterior superior iliac spine. Diagnosis is usually based on the presence of dysesthesia over the usual territory of the lateral femoral cutaneous nerve. A conduction study of the lateral femoral cutaneous nerve can be used as an objective diagnostic aid in this disorder. Unfortunately, the sensory nerve conduction of this nerve is technically difficult to do. This is partly due to the fact that meralgia paresthetica is commonly seen in obese individuals and it is not easy to localize the nerve in such patients. For this reason, many different techniques have been advocated. There are at least seven techniques for the sensory nerve conduction of this nerve (Oh, 2003). This test can be done orthodromically and antidromically (Oh, 2003). Laguency et al. (1991) observed that the antidromic sensory CNAP was more easily obtained than the orthodromic I personally recommend the antidromic technique with stimulation 6-10cm distal to the anterior superior iliac spine and recording distally in the nerve. Thus, it is always important to compare the test result in the affected side with that in the unaffected side. In 87% of cases, this nerve conduction was abnormal: CNAP was either absent or low in amplitude. The most prominent abnormality is an absence of sensory CNAP, as observed in 49% of reported cases (Stevens and Rosselle, 1970; Butler et al., 1974; Sarala et al., 1979; Lysens et al., 1981; Lagueny, 1992; Spevak and Prevac, 1995) (Table 41.4). The sensory NCV was slow in 18% of cases (Fig. 41.15). The somatosensory evoked potential test has also been used to detect this disorder but has a limited value. Synek found a prolonged latency of the first negative cortical potential in the lateral femoral cutaneous cortical SEP in five of six patients with meralgia paresthesica (Synek, 1985; Synek and Synek, 1986). Lagueny et al. (1991) reported normal absolute latency in 17 of 19 cases, a prolonged latency of the first positive cortical potential in two, an abnormal side-to-side latency difference in four, and an abnormal side-to-side amplitude difference (> 50%) in six patients. Thus 11 (58%) of 19 cases showed a normal SEP by any standard. According to Lagueny, no electrophysiological parameter has shown any predictive value in the outcome of this disorder (Languency et al., 1991). Seror (1999) found an abnormal SEP in only eight of 30 patients, indicating an inferior diagnostic sensitivity.

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Table 41.4 Nerve conduction abnormalities in meralgia paresthetica Number with sensory nerve conduction Number of Patients

Investigators Stevens, Roselle (1970) Butler, Johnson, Kaye (1974) Sarala, Nishihira, Oh (1979) Lysens, Vandendriessche, VanMol (1981) Laguency, Deliac et al. (1991) Spevac, Prevac (1995) Seror (1999)

4 1 9 5 19 14 30

Normal

Low amplitude

2

1

Slow NCV

Absent CNAP 1 1 6 5 9 5 13

3 6 1 0

4 4 17

2 8

NCV, nerve conduction velocity. CNAP, compound nerve action potential. (Reproduced from Oh, SJ (1998) Clinical Electromyography. Nerve Conduction Studies, IIIrd edn. By permission of Lippincott, Williams and Wilkins, Philadelphia).

41.7. Obturator neuropathy The obturator nerve is formed within the psoas muscle from the ventral divisions of the L2, L3, and L4 spinal nerves and descends through the psoas muscle. It passes through the obturator foramen, where it divides into anterior and posterior branches which innervate the hip adductors magnus, longus, and brevis, and the obturator externus muscles. Sensory fibers supply a

small area of skin on the medial aspect of the middle and lower thirds of the thigh. Patients with obturator neuropathy have hip adductor weakness and sensory loss in a small area on the medial thigh, though sensory loss is usually minimal. A motor nerve conduction technique for this nerve has been reported with a concentric needle inserted into the belly of the gracilis muscle as the recording electrode and surface stimulating electrodes at the level of the

66.7

Rt Rt 10 μV Lt 34.8

2 ms Lt

56 5 μV 2 ms

A

B

Fig. 41.15 Nerve conduction abnormality in meralgia paresthetica (A) Right (Rt), Normal sensory compound nerve action potential (CNAP). Sensory nerve conduction velocity (NCV) is 66.7 m/s. Left (Lt), Sensory CNAP. Sensory NCV is 34.8 m/s (Reproduced from Sarala, PK et al. (1979) Meralgia paresthetica: electrophysiologic study. Arch. Phys. Med. Rehabil., 60 : 30, with permission by Elsevier). (B) Sensory nerve conduction with near-nerve stimulation and recording. Rt, no CNAP is obtained. Lt, normal sensory NCV at 56.0 m/s. (Reproduced from Oh (1998) Principles of clinical electromyography: Case studies by permission of Williams & Wilkins, Baltimore).

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pubic tubercle and the lumbar root. So far, no case of obturator neuropathy has been reported by this technique (Uldag et al., 2000; Oh, 2003). The electrophysiological diagnosis of this neuropathy is best confirmed by the presence of acute and chronic denervation process confined to the hip adductors on the needle EMG: the adductor longus, adductor brevis, and gracilis muscles. The most extensive study of obturator neuropathy was reported in 22 patients (acute in 18; chronic in four) from the Mayo Clinic EMG laboratory based on unequivocal neurogenic findings (fibrillation potentials or high-amplitude, long duration complex MUPs limited to muscles innervated by the obturator nerve (hip adductors) (Sorenson et al., 2002). Pellegrino et al. (1988) reported active denervation process in the adductor longus muscles in a patient who developed bilateral obturator neuropathy, most likely compressing the nerve at the bony obturator foramen, during prolonged dorsal lithotomy positioning. Bradshaw et al. (1997) reported 32 cases of a previously undescribed condition in athletes, “obturator neuropathy,” a fascial entrapment of the obturator nerve where it enters the thigh. This condition represents a type of groin pain in athletes that is treatable by surgical means. There is a characteristic clinical pattern of exercise-induced medial thigh pain commencing in the region of adductor muscle origin and radiating distally along the medial thigh. Needle electromyography demonstrates denervation of the adductor muscles. Surgical neurolysis treatment provides the definitive cure of this problem, with athletes returning to competition within several weeks of treatment. The surgical findings are entrapment of the obturator nerve by a thick fascia overlying the short adductor muscle. Synek (1987) reported an abnormal SEP in a patient with obturator neuropathy. 41.8. Sural neuropathy The sural nerve is formed from two anastomotic branches, one from the tibial nerve and other from the common peroneal nerves. Sural neuropathy is characterized by sensory loss in the posterolateral aspects of the lower third of the calf and the lateral aspect of the dorsum of the foot. The most common cause of sural neuropathy among 40 cases in the literature was trauma in 2/3 of cases (Rafaeian et al., 2001). This does not include sural neuropathy, which occurs invariably after the sural nerve biopsy and graft. Seror (2002) reported 20 cases, the largest sample of sural neuropathy. Iatrogenic causes accounted for 12 (60%) of these 20 cases.

SHIN J. OH

Antidromic sural sensory nerve conduction technique with recording electrodes behind the lateral malleolus and stimulating electrodes proximal to the active recording electrode just lateral to the midline of the width of the calf muscle is well-known. Orthodromic sensory nerve conduction technique is also available. Several antidromic and orthodromic sensory nerve conduction techniques in the distal sural nerve on the lateral aspect of the dorsum of the foot were also reported (Oh, 2003). Distal sural nerve conduction is critical in identifying the distal sural neuropathy (Seror, 2002). Seror (2002) defined sensory CNAP abnormality as abnormal when the involved side/healthy side ratio amplitude is ≤ 45%. Using this criterion, all of the 20 cases of sural neuropathy were identified by the sural nerve conduction. In 16 of these 20 cases, the classical orthodromic sensory nerve conduction was abnormal: absent CNAP in eight and low amplitude in six. In five cases, the distal sural nerve conduction identified the distal nerve lesion in five cases. In one case, proximal conduction block was identified by a more proximal testing. Gradual electrophysiological improvement from absent CNAP was documented in two cases by Schuchumann and colleagues and one case by Refaeian (Rafaeian et al., 2001). 41.9. Pudendal neuropathy The pudendal nerve is the main nerve innervating the sensory and motor functions in the perineal area. Pudendal nerve injury is extremely rare because the nerve is deeply located and well protected. This nerve is rarely damaged following orthopedic surgery, especially femur fractures, and pelvic fracture (Amarenco et al., 2001). Pudendal neuropathy in cyclists has been well known. Bulbocavernous reflex testing, pudendal somatosensory evoked potential, pudendal motor latency study with St. Mark’s pudendal electrodes, and sensory nerve conduction of the dorsal nerve of the penis are available for study of nerve lesion in the pelvic area (Oh, 2003) (Fig. 41.16). Amrenco et al. (2001) reported six patients with pudendal neuropathy following orthopedic surgery including retraction on a fracture table. These patients had hypesthesia in the region of the penis, scrotum, and perineum, with impotence in three cases and hypo-orgasm in three. Needle EMG in the bulbocavernous muscles showed denervation in two cases. Bulbocavernous reflex was normal. Pudendal somatosensory evoked potentials showed delayed latency in four cases. Sensory nerve conduction of the dorsal nerve of the penis and pudendal nerve motor latency were abnormal in all cases. This study clearly

DISEASES OF THE NERVES IN THE PELVIC GIRDLE AND LOWER LIMBS

A Rt

Lt

50 μV

40

885

Fig. 41.16 Sacral plexus neuropathy. (A) Bulbocavernous reflex: absent response on the right (Rt) and normal response (40 ms in latency) on the left. (B) Fibrillations and positive sharp waves in the right bulbocavernous muscle. (Reproduced from Oh (1998) Principle of Clinical Electromyography: Case Studies by permission of Williams & Wilkins, Baltimore).

20 ms

B

0.1 mV 10 ms

provided a better diagnostic yield in the sensory nerve conduction of the dorsal nerve of the penis and pudendal nerve motor latency test in detection of pudendal neuropathy. A case of pudendal nerve entrapment in Alcock’s canal was diagnosed clinically by unilateral ochialgia and proctalgia and by a prolonged left pudendal nerve distal motor latency (Ramsden et al., 2003). One case of entrapment neuropathy of the pudendal nerve was diagnosed by the prolonged latency of the bulbocavernous reflex (Pisani et al., 1997). Penile neuropathy characterized by erectile dysfunction and hypoesthesia or paresthesia of the penis can be diagnosed by abnormal sensory nerve conduction of the dorsal nerve of the penis (Amarenco et al., 1997). The most common etiology of this neuropathy is diabetes (Lin and Bradley, 1985; Kaneco and Bradley, 1986). On the basis of a prolonged pudendal terminal latency and anal reflex latency and SFEMG evidence of denervation of the anal sphincter, Swash et al. (1985) suggested that idiopathic fecal incontinence is caused by a stretch injury of the pudendal nerve as a result of the

descent of the pelvic floor during childbirth or repeated straining during defecation. Subsequent studies showed that pudendal neuropathy (documented by prolonged pudendal terminal motor latency) is generally associated with poor surgical outcome of fecal incontinence (Olsen and Rao, 2001). 41.10. Superior gluteal neuropathy The superior gluteal nerve is the only nerve that passes through the sciatic notch above the piriformis muscle. Thus, it may be damaged while other nerves of the sciatic notch are spared. This nerve innervates the gluteus medius and minimus and tensor fascia latae muscles. One case of entrapment of this nerve between the suprapiriformis foramen was reported (Rask, 1980). Two cases of injection-induced superior gluteal neuropathy were also reported in which the needle EMG showed denervation process in the gluteus medius and minimus muscles (Obach et al., 1983). Another case of injectioninduced superior gluteal neuropathy was reported by the

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denervation process on the needle EMG in the gluteus medius and tensor fascia lata muscles (Willick et al., 1998). Three cases of iatrogenic superior gluteal mononeuropathy were also detected by the denervation process in the needle EMG in three cases: one after partial nephrectomy and two following revision of a total hip arthroplasty (Donofrio et al., 1998). This rare neuropathy has become another complication of hip arthroplasty. Twenty-three percent of 81 patients provided EMG evidence of this neuropathy after hip replacement using the Hardinge (posterior) approach in a prospective study (Ramesh et al., 1996). Pre- and post-operative EMG studies showed subclinical damage to the superior and inferior gluteal nerves in 77 and 88%, respectively, regardless of whether a posterior or lateral approach was used in hip replacement (Abitol et al., 1990). These high figures could well be due to local trauma. 41.11. Inferior gluteal neuropathy The inferior gluteal nerve is one of four nerves which pass through the sciatic notch below the piriformis muscle. The others are the sciatic, posterior femoral, and pudendal nerves. Thus, the inferior gluteal nerve is almost never damaged without associated lesions of the other three nerves. This nerve innervates the gluteus maximus muscle alone. A syndrome of buttock pain, cutaneous anesthesia in the distribution of the posterior femoral cutaneous nerve, and EMG evidence of marked denervation of the gluteus maximus has been described in five patients with recurrence of colorectal carcinoma (Laban et al., 1982). The authors suggested that malignant tissue compressed the inferior gluteal and posterior cutaneous nerves of the thigh as they passed below the piriformis muscle. Two cases of infrapiriformis foramen syndrome resulting from infragluteal injection with involvement of the inferior gluteal, posterior femoral cutaneous, pudendal, and sciatic nerves (Obach et al., 1983) have been reported. The most prominent needle EMG findings in these two cases were denervation in the gluteus maximus muscles with less involvement of the sciatic-innervated muscles. 41.12. Posterior femoral cutaneous neuropathy Posterior femoral cutaneous neuropathy produces paresthesia over the lower buttock and/or the posterior aspect of the thigh and is caused by injections, pressure from prolonged bicycle riding, and tumors in the presacral region that presumably compress the nerve in its intrapelvic course (Stewart, 2000).

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Dumitri and Nelson (1990) described an antidromic sensory nerve conduction method for the posterior femoral cutaneous nerve with recording electrodes distally and stimulating electrodes proximally in the midline of the posterior thigh. Iyer and Shields (1989) confirmed a case of injection-induced posterior femoral cutaneous neuropathy in which the sensory CNAP was absent in the involved posterior femoral cutaneous nerve but obtained in the normal side. Injection-induced posterior femoral cutaneous neuropathy was confirmed in another case by absent CNAP in the affected side in the presence of 9 μV response in the normal side (Tong and Haig, 2000). Dumitru and Marquis (1988) reported an attenuation of amplitude in the posterior femoral cutaneous cortical SEP compared with the opposite side in a case of posterior femoral cutaneous neuropathy. Another case of this neuropathy was also confirmed by the cortical SEP demonstrating “response difference” (Mobbs et al., 2002) In principle, sensory nerve conduction of this nerve will help localize the lesion to the sciatic plexus. No such case has been reported as yet. 41.13. Iliohypogastric, ilioinguinal, and genitofemoral neuropathies These nerves arise from the upper lumbar plexus and innervate the inguinal region, the upper anterior and medial thigh, and a small part of the genital area. Neuropathy involving these nerves is usually due to surgical incision and postoperative adhesions in the lower abdomen and inguinal area (Stewart, 2000). Diagnosis of these disorders is based purely on the demonstration of sensory abnormalities confined to the sensory territory of each nerve and relief of pain by the injection of a local anesthetics at the trigger point. Electrophysiological tests confirming these disorders are extremely limited. A nerve conduction test for the ilioinguinal nerve has been described with a monopolar needle near the midline above the pubic symphysis as the recording electrode and with a monopolar needle medial to the anterior superior iliac spine for simulation (Ellis et al., 1992; Oh, 2003). We were able to make a diagnosis of ilioinguinal neuropathy in one case by a more than 50% decrease of the CMAP amplitude in the ilioinguinal nerve conduction test (Fig. 41.17) (Oh, 1998). Fibrillations and positive sharp waves were also documented in the internal oblique and transverse muscles innervated by this nerve. T12/L1 radiculopathy should be ruled out by the needle EMG in paraspinal muscles.

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Acknowledgement This chapter is modified from part of Chapter 22 in Oh, SJ (2003). Clinical Electromyography. Nerve Conduction Studies, IIIrd edn. with permission from Lippincott, Williams & Wilkins, Philadelphia.

Lt

References Rt

0.5 mV 5 ms

Fig. 41.17 Ilioinguinal motor nerve conduction in right ilioinguinal neuropathy following herniorrhaphy. Low CMAP in the right (Rt) ilio-inguinal nerve conduction compared with the left (Lt) one. (Reproduced from Oh (1998) Principle of Clinical Electromyography: Case Studies by permission of Williams & Wilkins, Baltimore).

Knockaert et al. (1996) evaluated the value of needle EMG in ilioinguinal-iliohypogastric entrapment syndrome. Diagnosis of this entrapment syndrome is based on a typical clinical triad: (1) muscular type iliac fossa pain, radiating to the back, the inner upper part of the thigh, and the proximal part of the scrotum or the labia majora; (2) altered sensory perception in the innervated cutaneous area; and (3) a circumscribed trigger point medial to and below the anterosuperior iliac spine and relief of pain by injection of local anesthetics (Knockaert et al., 1989). In 15 (60%) of 25 cases in the definite group, the needle EMG in the abdominal muscles in the lower iliac fossa was abnormal. Abnormalities are usually limited to increased polyphasic MUPs (more than 50% of MUPs) in these muscles. Unless fibrillations or PSW are detected, increased polyphasic MUPs alone should not be interpreted to be definitely abnormal. Rabie and Dory (2003) evaluated a 22-year-old male with an iliohypogastric neuropathy (sensory loss over the right upper lateral gluteal region innervated by hypogastric branch) following a traumatic right retroperitoneal hemorrhage with SSEP. With electrical stimulation of the nerve over the iliac crest and recording electrodes at Cz and Fpz. Right iliohypogastric somatosensory evoked potential (SSEP) peak onset latency was 45 msec with an amplitude of 0.22 μV, while the left iliohypogastric SSEP latency was 34.5 msec with an amplitude of 0.5 μV.

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Swash, M, Snooks, SJ and Henry, MM (1985) A unifying concept of pelvic floor disorders and incontinence. J. Roy. Soc. Med., 78: 906–911. Synek, VM (1985) Assessing sensory involvement in lower limb nerve lesions using somatosensory evoked potential techniques. Muscle Nerve, 8: 511–515. Synek, VM (1987) Role of seomatosensory evoked potentials in the diagnosis of peripheral nerve lesions; recent advances. J. Clin. Neurophysiol., 4: 55–73. Syneck, VM (1987) The pyriformis syndrome: review and case presentation. Clin. Exp. Neurol., 23: 31–37. Synek, VM and Cowan, JC (1983) Saphenous nerve voked potntials and the assessment of intraabdominal lesions of the femoral nerve. Muscle Nerve, 6: 453–456. Synek, VM and Synek, BJL (1986) Intractable meralgia paresthetica after repeated abdominal surgery. EMG Clin. Neurophysiol., 26: 103–106. Tong, HC and Haig, A (2000) Posterior femoral cutaneous nerve mononeuropathy: a case report. Arch. Phys. Med. Rehabil., 81: 1117–1118. Trainer, S, Durey, A, Chevallier, B and Liot, F (1992) Value of somatosensory evoked potentials in saphenous entrapment neuropathy. J. Neurol. Neurosurg. Pschiatry, 55: 461–465. Uludag, B, Ertekin, C, Turman, AB, Demir, D and Kiylioglu, N (2000) Proximal and distal motor nerve conduction in obturator and femoral nerves. Arch. Phys. Med. Rehabil., 81: 1166–1170.

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved

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CHAPTER 42

Other mononeuropathies Richard J. Lederman* Department of Neurology, Cleveland Clinic Foundation, OH, USA

42.1. Introduction The subjects discussed in this chapter represent a diverse group of disorders, with multiple etiologies and varied clinical expression. At the same time, there is the potential for significant overlap and redundancy among the different sections, as well as the distinct possibility of repetition of material dealt with in previous chapters of this volume. The topics dealt with here include sports-related injury, mononeuropathy in musicians, perioperative mononeuropathy, localized hypertrophic mononeuropathy, idiopathic progressive mononeuropathy, postherpetic neuralgia and segmental zoster paresis, and complex regional pain syndrome/reflex sympathetic dystrophy. I will attempt to review the spectrum of mononeuropathies that are relevant for each of these categories, but where duplication is obvious, I will discuss only those aspects of the clinical manifestations and diagnostic studies that are specific to that particular entity. 42.2. Sports injury The large majority of injuries to athletes are musculoskeletal in type, but reviews of sports-related neurological disorders suggest that there is hardly a named peripheral nerve that is immune to injury and virtually no sports activity that has avoided implication as a precipitating cause (Pecina et al., 1993; Wechsler and Busis, 1994; Dawson et al., 1999a). The mononeuropathies selected for discussion here are the most common and for which electrodiagnostic (EDX) studies have some relevance. In most cases, only a very brief clinical description is required and, generally, * Correspondence to: Richard J. Lederman, MD, PhD, Department of Neurology, S-91, 9500 Euclid Avenue, Cleveland, OH 44195, USA. E-mail address: [email protected] Tel.: +1-216-444-5545; fax: +1-216-445-1563.

review of EDX studies can be limited to those specific to sports-related injury. Tables 42.1 and 42.2 list those mononeuropathies that will be discussed, along with the most common athletic activities in which they have been described. 42.2.1. Long thoracic neuropathy A lesion of the long thoracic nerve produces shoulder pain, weakness of flexion and abduction of the arm, and a winged scapula. The clinical syndrome was thoroughly reviewed by Johnson and Kendall (1955) and attributed to a variety of etiologies. Stanish and Lamb (1978) reported acute serratus anterior weakness occurring in an inexperienced weight lifter. Gregg et al. (1979) described 10 similar cases in athletes, ranging in age from 11 to 47 years, and associated with a variety of athletic activities. Schultz and Leonard (1992) added 4 examples in a weight lifter, baseball player, golfer, and tennis player. In each case, traction of the long thoracic nerve was hypothesized, although with this disorder, as well as many other upper limb (and particularly proximal) mononeuropathies, one must always recognize the possibility that the inciting event was irrelevant and that the lesion represents a restricted form of neuralgic amyotrophy. If nerve conduction studies (NCS’s) are utilized, there is often a reduction in compound muscle action potential (CMAP) amplitude with or without prolongation of distal latency (DL) compared to the normal side (Schultz and Leonard, 1992). In 1 of their 4 cases, CMAP amplitude was 1.6 mV compared to 6.5 mV on the normal side; DL was slightly shorter on the affected side. Needle electromyography (EMG) reveals spontaneous discharges and reduced activation of motor unit action potentials (MUAPs) acutely. With incomplete lesions, reinnervation potentials will be seen (Schultz and Leonard, 1992); recovery is reported to be excellent in almost all such cases (Gregg et al., 1979; Schultz and Leonard, 1992).

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Table 42.1

Table 42.2

Mononeuropathies in sports: upper extremity

Mononeuropathies in sports: lower extremity

Nerve affected

Athletic activity

Nerve affected

Athletic activity

Long thoracic Brachial plexus

Weight lifting, tennis, backpacking Football, wrestling, mountain climbing Volleyball, baseball, weight lifting, fencing Baseball, football, hockey, volleyball Weight lifting, rowing Weight lifting, racquet sports Baseball, racquet sports, weight lifting Bicycling Racquet sports, baseball, weight lifting, gymnastics Racquet sports, baseball, bicycling, golf, sport climbing Bowling

Obturator Peroneal Sural Posterior tibial (tarsal tunnel) Posterior tibial, lateral plantar

Soccer, football Running, soccer, hockey Baseball Running, climbing, dance Running, dance

Suprascapular Axillary Musculocutaneous Radial Ulnar, elbow Ulnar, wrist/hand Median, proximal Median, wrist (CTS) Digital

Gregg et al. (1979) emphasized the usefulness of EDX testing to predict time to recovery, although no details of their EMG studies were given. 42.2.2. “Burners” or “stingers” This clinical syndrome is characterized by a burning or stinging pain lasting seconds, followed by numbness and/or weakness, generally in a C5–6 or upper trunk brachial plexus distribution, usually lasting minutes. This is associated with sudden forceful extension or contralateral neck flexion, most commonly seen in football players and wrestlers. A survey of 201 college football players (Sallis et al., 1992) indicated that 65% had experienced such an event during their college careers. Many players have multiple such episodes that can result in long-lasting or even permanent weakness. Controversy persists as to whether the lesion is at the level of the cervical roots or brachial plexus. EDX studies have provided evidence favoring both sites and have not resolved the debate. Clancy et al. (1977) described 13 high school and college athletes (11 football players, 2 wrestlers) with “upper trunk brachial plexus injuries,” 10 of whom underwent EDX studies. NCS with Erb’s point stimulation was normal. Active denervation was seen in deltoid, spinati, and biceps muscles, but was notably absent in serratus

anterior and rhomboids. Robertson et al. (1979) studied 10 football players with upper limb weakness and found fibrillation potentials in at least 1 muscle supplied via the upper trunk of the brachial plexus; no spontaneous discharges were seen in cervical paraspinals, rhomboids, or serratus anterior. Ulnar nerve conduction studies, including stimulation in the supraclavicular fossa, were normal. Di Benedetto and Markey (1984), utilizing C5 root as well as Erb’s point stimulation and needle EMG, found proximal slowing in multiple nerves in 16 of the 18 athletes with a history of more than 1 stinger episode. Decreased MUAP recruitment and increased polyphasia were seen in up to 2/3; fibrillations were said to be “sparse.” Upper trunk brachial plexopathy was suspected; this was further supported by a later study, including evidence of reduction in the frequency of episodes by the use of a specially-designed orthosis (Markey et al., 1993). Krivickas and Wilbourn (2000) reported EDX studies in 40 athletes with the “burner” syndrome. The absence of fibrillation potentials in the cervical paraspinal muscles of all patients was taken as evidence supportive of a brachial plexus localization, but lack of abnormality of sensory NCS, including radial and median sensory nerve action potentials (SNAPs), recording from the thumb, was considered evidence to the contrary. However, they favored a brachial plexus localization for most. Poindexter and Johnson (1984) studied 12 football players with a stinger syndrome and reported “abnormal findings” on needle EMG in 7, 1 in “anterior primary division” only and 6 in “posterior primary division” only. They attributed these changes to C6 radiculopathy. Other non-electrophysiologic data may also support a cervical root localization. Rockett (1982) reported exploring such cases surgically (no number is given) and finding scarring of the C5 and, to a lesser degree, C6 roots at their emergence from the transverse processes. Meyer et al. (1994) studied 40 football players with

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stingers and suggested that 85% had experienced neckextension injuries with root compression (determined by history and clinical exam) and 15% had experienced stretch of the brachial plexus. Brachial plexus injury may also occur in other athletic activities, including mountain climbing, that involve carrying a heavy backpack (Hirasawa and Sakakida, 1983). In these cases, compression is assumed to be the predominant mechanism, onset is less acute, and recovery with conservative management is the rule (Hirasawa and Sakakida, 1983). 42.2.3. Suprascapular neuropathy Suprascapular nerve injury produces shoulder pain, generally with weakness of abduction and external rotation of the shoulder. A history of trauma is often obtained. Since the first case descriptions by Clein (1975), a number of large series have been reported (Callahan et al., 1991; Vastamäki and Göransson, 1993; Antoniadis et al., 1996), describing the usual site of entrapment at the suprascapular notch, as well as the surgical approach and outcome. Among the 9 cases of suprascapular nerve palsy reported by Berry et al. (1995), 2 incurred injury while lifting weights and 1 while wrestling. Aiello et al. (1982) reported a fencing instructor with suprascapular entrapment at the spinoglenoid notch, producing selective denervation of the infraspinatus muscle. Ferretti et al. (1987), after finding isolated infraspinatus weakness in 3 members of the Italian volleyball team, surveyed 96 high-level European volleyball players and found 12 with isolated infraspinatus atrophy and/or weakness on the dominant side. Similar findings were reported by both Montagna and Colonna (1993) and Holzgraefe et al. (1994), the latter group identifying a suprascapular nerve lesion in 22 of 66 international-level volleyball players, always in the “smashing” arm. EDX studies have at least partially confirmed the suspected localization of the lesion to the spinoglenoid notch. The patient reported by Aiello et al. (1981) had prolonged CMAP latency to the infraspinatus with Erb’s point stimulation (12.0 ms, N = 2.6–4.2 ms), as well as a low amplitude response, with normal latency (2.8 ms, N = 2.0–3.2 ms) and amplitude recording supraspinatus. There were signs of denervation in the infraspinatus on needle EMG; the supraspinatus was normal. Similar findings were seen in 3 patients studied by Ferretti et al. (1987) and in the 6 players reported by Montagna and Colonna (1993). Holzgraefe

895

et al. (1994) were able to study 30 German volleyball players with needle EMG and, unlike the previous reports, found signs of at least partial denervation in the ipsilateral supraspinatus as well as infraspinatus muscles in 12 of the 30 (40%), despite lack of clinical weakness of the former. This obviously raises doubts about the site of suprascapular nerve entrapment in these athletes. 42.2.4. Axillary neuropathy Axillary nerve lesions, most commonly traumatic in origin, produce shoulder pain along with weakness of abduction, flexion, and extension, and sometimes localized sensory loss on the lateral upper arm. Most cases reported in athletes have occurred during contact sports (Berry and Bril, 1982; Perlmutter et al., 1997). An unusual and controversial axillary neuropathy is attributed to compression within the quadrilateral space, defined by the subscapularis and teres minor muscles superiorly, the teres major inferiorly, the humerus laterally, and the long head of the triceps medially (Cahill and Palmer, 1983). These patients usually present with insidious onset of pain and weakness; typically, they lack any evidence of motor or sensory impairment on examination. The diagnosis is usually confirmed by demonstrating compression of the posterior humeral circumflex artery on angiographic study. Surgical decompression is recommended for those not responding to conservative treatment. EDX studies reported in 2 female volleyball players (Paladini et al., 1996) revealed reduced CMAP amplitude and prolonged distal latency recording from the deltoid, stimulating in the axilla; conduction velocity from Erb’s point to the axilla was normal (unfortunately, in these 2 cases, no contralateral study was reported). Needle EMG showed fibrillation potentials in the deltoid, with reduced inerference pattern. One patient had a subsequent study a year later, with disappearance of denervation potentials and improvement in the NCS. Redler et al. (1986) and Cormier et al. (1988) each reported a baseball pitcher with the same syndrome. EDX studies described by Redler et al. (1986) were normal, although an arteriogram showed the expected compression. Neither player elected to have surgery; 1 changed his pitching motion, with “promising” early results. In the 1 sports-related axillary neuropathy reported by Berry and Bril (1982), EMG abnormalities were said to be “mild,” no details were given. Magnetic resonance imaging (MRI) may provide useful information. In 3 cases of quadrilateral space

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syndrome reported by Linker et al. (1993), selective atrophy of the teres minor was identified. 42.2.5. Musculocutaneous neuropathy This relatively rare mononeuropathy was first reported associated with heavy exercise by Braddom and Wolfe (1978). The clinical syndrome is characterized generally by painless weakness of elbow flexion with atrophy of the biceps brachii; sensory loss on the radial aspect of the forearm is less commonly seen. Three of the patients reported have been weight lifters (Braddom and Wolfe, 1978; Siao et al., 1991) and two have been rowers (Mastaglia, 1986; Pecina and Bojanic, 1993). Etiology has been considered to be compression of the nerve as it passes through the coracobrachialis muscle. Prognosis has generally been good for full recovery. NCS has usually been reported to show a reduced biceps CMAP and increased distal latency with Erb’s point stimulation; the lateral antebrachial cutaneous SNAP may be reduced in amplitude as well. Needle EMG shows denervation in the biceps and brachialis, with sparing of the coracobrachialis. The few followup studies in these and similar cases have shown partial to nearly complete resolution, consistent with the clinical recovery (Braddom and Wolfe, 1978; Mastaglia, 1986; Pecina and Bojanic, 1993; Sander et al., 1997). 42.2.6. Radial neuropathy The radial nerve is potentially susceptible to compression at several points along its course. Lotem et al. (1971) described 3 men with proximal radial palsies following muscular effort; 1 developed this after performing elbow extension exercises against weights. Elbow extension was normal on exam, with weakness of extensors of the wrist and fingers and sensory loss in the first web space of the hand. Recovery was complete in 2 within 2 to 4 weeks. Compression by the fibrous arch of the triceps at the spiral groove was postulated. Sinson et al. (1994) reported 2 softball pitchers with proximal radial neuropathies, one at the spiral groove, the other at the level of the brachial plexus; both were attributed to the “windmill” pitching motion. A second type of radial neuropathy occurring in the radial tunnel has been suggested as a cause for intractable elbow and forearm pain, “resistant tennis elbow” (Roles and Maudsley, 1972; Lister et al., 1979). Weakness of radial-innervated muscles has been notably absent in these cases. Dickerman et al.

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(2002) described a power lifter with radial tunnel syndrome, resolving with change in his exercise regimen. Most cases are not sports-related. Of Roles and Maudsley’s (1972) 36 cases, only 3 were attributed to racquet sports. Although surgery has generally been promoted for patients not responding to more conservative measures (Roles and Maudsley, 1972; Lister et al., 1979), Sotereanos et al. (1999) have urged “great caution” before undertaking surgical release. In the proximal syndrome, EDX studies generally reveal absent CMAPs from the extensor digitorum communis with stimulation above the spiral groove; radial sensory responses have been normal. Needle EMG shows decreased MUAP recruitment and fibrillations in all radial-innervated muscles distal to the triceps, including the anconeus in 1 case (Lotem et al., 1971; Mitsunaga and Nakano, 1988; Streib, 1992; Sinson et al., 1994). The patient of Sinson et al. (1994) with involvement of the brachial plexus showed denervation in the triceps as well. Follow-up EMG studies have shown improvement in all reported cases. Elleker (1991) reviewed the clinical and EDX features of radial tunnel syndrome. In 12 cases, 4 showed either mild slowing of motor conduction velocity or reduced CMAP amplitude recording across the radial tunnel, along with mild MUAP changes in 2 cases. Rosén and Werner (1980) found no abnormalities in the resting state, but demonstrated prolongation of DL across the radial tunnel with moderate active supination and a significant increase in MUAP amplitude, duration, and polyphasia in 28 patients with resistant tennis elbow. Using the same supination technique, however, Verhaar and Spaans (1991) found an increase in DL in only 1 of 16 such patients and identified increased polyphasia in the extensor digitorum brevis in a single patient. Van Rossum et al. (1978) found no abnormality on NCS or needle EMG in 10 consecutive patients diagnosed with chronic tennis elbow. Overall, the results of EDX testing in this entity must be considered uncertain. 42.2.7. Ulnar neuropathy The clinical syndrome associated with ulnar neuropathy at the elbow is well known and needs no elaboration here (Kincaid, 2003). Glousman’s (1990) review provides a comprehensive summary of the subject in the athlete. Barnes and Tullos (1978) reviewed their experience with 100 “symptomatic” baseball players, 50 of whom had elbow problems, including ulnar neuropathies. Only 1 of them required ulnar

OTHER MONONEUROPATHIES

nerve transposition. Andrews and Timmerman (1995) reviewed the outcome of elbow surgery in 72 professional baseball players, although only 11 (15%) were treated for ulnar neuropathy; the majority had osteophytes, loose bodies, or ligamentous injury. Of the 72, 64 (89%) were pitchers. Del Pizzo et al. (1977) reported surgical results for ulnar neuropathy at the elbow in 19 baseball players, including 17 pitchers. A similar problem can be seen in adolescent pitchers, as well (Godshall and Hansen, 1971); ulnar neuropathy at the elbow is occasionally seen in weight lifters amd those engaged in racquet sports (Sicuranza and McCue, 1992; Wechsler and Busis, 1994). EDX studies of ulnar neuropathy in athletes are relatively uncommon. Krivickas and Wilbourn (2000) included 19 cases among the 216 peripheral nerve injuries reported, but no details are given, except that the weight lifters were likely to show slowing of conduction at the elbow. Glousman (1990) considered NCS and EMG to be helpful, when positive, and noted a correlation with severity of clinical disease, but correctly pointed out that a negative study does not rule out ulnar neuropathy. In the series of Andrews and Timmerman (1995), only 19 of 72 patients had a preoperative NCS/EMG and only 4 out of 19 had a “mild abnormality” in nerve conduction velocity (included, presumably, among the 11 diagnosed with ulnar neuropathy); needle EMG was normal in all 19 cases. Del Pizzo et al. (1977) only utilized EDX studies in 5 of the 19 athletes with ulnar neuropathy and 3 out of 5 had normal nerve conduction. Distal ulnar neuropathy is most commonly seen in bicycle riders, often termed “handlebar palsy” or “cyclist’s palsy.” The nerve is compressed in the region of the ulnar tunnel (Guyon’s canal). The exact site determines whether this affects sensory fibers alone (rarely), sensory and motor fibers to the intrinsic hand muscles, or just motor function, either including all the intrinsics or sparing the hypothenar muscles (Shea and McClain, 1969; Aulicino, 1990). Eckman et al. (1975) were the first to describe this in bicyclists. NCS in their patient revealed normal distal ulnar sensory latencies, 3.0 and 3.2 ms bilaterally, (the dorsal ulnar sensory branch should be normal in all such cases) and prolonged motor DL to both the first dorsal interosseous (6.9 ms, 4.7 ms on the normal side) and the abductor digiti quinti (5.9 ms, 4.4 ms on the normal side). Noth et al. (1980) reported 4 cyclists, 2 of whom underwent EDX testing. In these cases, there was involvement of the superficial sensory branch clinically and electrically as well as the deep

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motor branch, including the hypothenar. CMAP amplitude, recording from hypothenar, was reduced (case #1: 0.5 mV versus 8.5 mV; case #2: 10 m/s) or conduction block. Twelve of the 40 patients (30%) had median nerve conduction velocities outside the normal range and 5 patients had abnormal EMG in median-innervated muscles. Intra-operative mixed median NCSs above and below the pronator teres were also performed, preand postoperatively in 10. None showed “clear-cut”

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EDX evidence of median neuropathy at the pronator muscle. Overall, only 2 patients were considered to have definite electrophysiologic evidence of pronator teres syndrome (Hartz et al., 1981). CTS can occur in athletes, including bicyclists, baseball pitchers, racquet users, golfers, and sport climbers (Aulicino, 1990; Wechsler and Busis, 1994; Peters, 2001). In Krivickas and Wilbourn’s (2000) series, 39 of the 43 median neuropathies demonstrated on EDX testing were at or distal to the wrist; 25 of these were considered asymptomatic. They reported 5 weight lifters, a baseball player, and a wrestler among those with symptoms of CTS. EDX findings with CTS in athletes are not different from those in the general population and need not be described here. Hsu et al. (2002) described a mid-palmar median neuropathy in a golfer; EDX studies showed a sensory and motor conduction block 2–3 cm distal to the wrist crease.

Leach et al. (1989) studied 5 of their 8 patients with NCS. All were normal at rest but all 5 developed decreased common peroneal (motor) conduction velocity across the fibular head after running. In the series reported by Fabre et al. (1998), all 60 patients had a “marked decrease” in SNAP amplitude, a decrease in motor nerve conduction velocity, or both (no specific numbers given).

42.2.9. Digital neuropathy

42.2.13. Posterior tibial branch neuropathies

Seventeen cases of impingement of the ulnar palmar branch of the digital nerve to the thumb of bowlers were described by Dobyns et al. (1972) and a similar lesion was reported in a baseball player by Belsky and Millender (1980). None of the patients in the series by Dobyns et al. (1972) underwent EDX studies.

The most common posterior tibial nerve disorders described in athletes are entrapment of the first branch of the lateral plantar nerve, producing chronic heel pain, and the tarsal tunnel syndrome, causing pain and paresthesias in the sole and toes (Schon and Baxter, 1990; McCrory et al., 2002). Fredericson et al. (2001) reported a competitive gymnast with heel pain and lateral plantar entrapment. Baxter (Schon and Baxter, 1990) estimates having treated about 20 athletes with tarsal tunnel syndrome. McCrory et al. (2002) recommend EDX studies in cases of suspected tarsal tunnel syndrome, although these techniques are often considered insensitive and technically challenging. Park and Del Toro (1996) described a competitive volleyball player with heel pain; NCS yielded a low amplitude CMAP in the abductor digiti quinti pedis and needle EMG revealed denervation in that muscle only. Of 33 patients with heel pain referred to Schon et al. (1993) for EDX studies, 6 were runners. Among 27 patients out of 33, whose EDX studies were analyzed, 23 of the 38 heels studied showed at least 1 abnormal finding, most commonly prolonged motor latencies and decreased CMAP amplitudes.

42.2.10. Obturator neuropathy This has been reported to be a cause of groin pain in the athlete, primarily in “Australian Rules football and soccer players” (Bradshaw et al., 1997; Brukner et al., 1999). These authors report having treated “over 150” such patients. Needle EMG was said to show denervation in the adductor longus and brevis when utilized in patients having symptoms longer than 3 months. 42.2.11. Peroneal neuropathy Compression of the common peroneal nerve, or one of its branches, does not appear to be common among athletes, although Leach et al. (1989) reported 8 such cases, including 7 runners and 1 soccer player. An active jogger with common peroneal neuropathy was described by Møller and Kadin (1987). Of 60 patients with peroneal mononeuropathy treated surgically by Fabre et al. (1998), one was a soccer player, another, a triathlete. MacDonald et al. (2002) reported 5 hockey players suffering blunt trauma to the peroneal nerve while playing.

42.2.12. Sural neuropathy Bryan et al. (1999) reported a baseball coach who developed a sural neuropathy while pitching, due to a hematoma in the gastrocnemius muscle. A sural NCS showed diminished SNAP amplitude (2 μV versus 22 μV on the asymptomatic side) and a slightly increased DL (5.2 ms versus 4.2 ms). Surgical exploration and release was successfully carried out 8 weeks after the injury.

42.3. Mononeuropathies in musicians The incidence and prevalence of mononeuropathies, or peripheral nerve disorders in general, among musicians

OTHER MONONEUROPATHIES

899

is not known. It can be stated, however, that these disorders are commonly reported in reviews from clinics where performing artists are seen in large numbers, ranging from 4% of musicians attending a general medical clinic in the UK (Winspur, 1998) to 48% of those seen in the practice of a neurologist specializing in peripheral nerve disease (Charness, 1992). Blau and Henson (1977), in their pioneering report, considered mononeuropathies rare among instrumental musicians. Since then, a number of reviews have suggested otherwise (Lederman, 1986, 1989, 1993, 2003; Dawson, 1995; Winspur, 1998; Dawson et al., 1999b; Spinner and Amadio, 2000). Table 42.3 lists, in descending order of frequency, the mononeuropathies that we have seen in our instrumental musician population. The following discussion, however, will be limited to the most commonly encountered, or in a few cases, to those for which some EDX data in the instrumentalist are available. Many of these focal neuropathies and the diagnostic procedures used to study them are extensively reviewed elsewhere in this volume or, in some cases, in this chapter; only the diagnostic studies pertaining to the instrumentalist will be reviewed.

arm or hand. Paresthesias, numbness, and weakness in the arm and hand vary with the specific root involved. It might be surmized that instrumentalists, particularly violinists and violists who grip the instrument between the chin and the shoulder, would be particularly susceptible to this disorder, but our data do not support this. Charness (1992), however, suggested that playing posture may well be a factor in his 4 cases. Blau and Henson (1977) reported 3 musicians suspected to have cervical radiculopathy. Our series includes 32 instrumentalists; the C6 root was involved in 13, C7 in 11, C8 in 6, C5 in 1 and 1 was considered indeterminate. EDX testing was carried out in 18 of our 32 cases of cervical radiculopathy, using standard NCS and needle EMG. Of these, 15 were confirmatory of the diagnosis, with needle EMG evidence of active and/or chronic denervation in C6 distribution (5 cases), C7 (5 cases), and C8 (6 cases, 1 with contralateral C7); 2 were negative, and 1 considered equivocal. MRI of the cervical spine was the standard imaging procedure in most cases. Occasionally, myelography followed by computed tomographic (CT) scan was utilized, because of a contraindication to MRI, claustrophobia, or need to supplement the information obtained from the MRI.

42.3.1. Cervical radiculopathy The clinical syndrome of cervical radiculopathy is well known, with pain generally spreading from the neck to the interscapular region and to the ipsilateral Table 42.3 Mononeuropathies in instrumental musicians (author’s series) Nerve/syndrome Brachial plexus (thoracic outlet syndrome) Ulnar, elbow Median (carpal tunnel syndrome) Cervical radiculopathy Digital Median, other Ulnar, other Long thoracic Trigeminal sensory (“trumpeter’s lip”) Radial Facial (Bell’s palsy) Suprascapular Spinal accessory

Number of patients 75 66 64 32 15 12 7 7 7 5 3 2 2

42.3.2. Thoracic outlet syndrome (TOS) The controversies regarding this disorder are widely recognized and it is not feasible to debate them here. TOS among musicians is discussed by a number of authors (Lederman, 1987; Newmark, 1996; Dawson et al., 1999b; Spinner and Amadio, 2000). Lascelles et al. (1977) included a flutist among their patients with what they called the “pain and paresthesias” form of TOS. Charness (1992) described 40 such patients, Hochberg (Hochberg and Lederman, 1995) 70, and Winspur (1998) 9. Our series includes 75 musicians with TOS; none of our patients, or any of those noted above, had the “true neurogenic” form of the disorder. These patients have pain and paresthesias in 1 (or occasionally both) upper limb, which are usually positionsensitive and can be provoked by specific maneuvers, such as hyperabduction or downward traction on the arm. The neurological exam is almost always normal. The application of EDX and other techniques for investigating TOS is dealt with elsewhere in this volume (see Chapter 31) and I will focus only on studies reported in instrumental musicians. Roughly one-third of our patients have undergone EDX testing, primarily in an effort to exclude some other disorder including

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cervical radiculopathy and ulnar or median neuropathy. No abnormality other than incidental and generally mild median neuropathy at or distal to the wrist has been identified. Suffice it to say that we have not found the technique of ulnar NCS “across” the thoracic outlet (Urschel and Razzuk, 1972) useful (Wilbourn and Lederman, 1984). Charness (1992) considered EDX testing unreliable for diagnosing TOS in his musicianpatients. Winspur (1998) characterized EDX testing in TOS as “of no value” in confirming the diagnosis. Newmark et al. (1985) looked at somatosensory evoked potentials (SEPs) in 5 instrumental musicians with “clear clinical evidence of TOS” and found a “slight” attenuation in N13 amplitude with normal latency in 1 patient. Our experience has been similarly unrewarding (Lederman, 1987). X-ray of the cervical spine has been of limited usefulness in our series. The finding of an occasional cervical rib does not usually influence the diagnostic impression. The flutist reported by Lascelles et al. (1977), in fact, had bilateral cervical ribs, although symptoms were unilateral. The patient did undergo surgical resection on the symptomatic side, reportedly with relief of symptoms. Cervical spine x-ray may also reveal the typical changes of the droopy shoulder configuration (see Lederman, 1987), but this is not necessary for diagnosis.

RICHARD J. LEDERMAN

Lederman (1996) reported 5 instrumentalists with shoulder pain and unilateral scapular winging, due to long thoracic nerve dysfunction. Two additional musicians have been seen since that report. None of these cases could clearly be linked directly to playing the instrument; most may well represent localized forms of neuralgic amyotrophy. EDX studies were carried out in 3 patients; fibrillations were seen in the serratus anterior in all 3. No MUAPs could be activated in 1; neurogenic MUAPs were seen in the other 2. One patient had a follow-up EMG 10 years after the first, with normal results, although slight scapular winging persisted.

half), with or without weakness. The most striking clinical feature among the musicians is the virtually exclusive involvement of the left arm in bowed string players (22/25 left only, 3 bilateral). Given the position of playing the instrument, this strongly suggests that sustained flexion of the elbow, combined with forearm supination (especially with violin and viola, which accounts for almost all of the cases) and repetitive finger flexion, is the primary predisposing cause. Charness (1992) identified 72 instances of ulnar neuropathy among the 192 nerve entrapment syndromes encountered in 117 musicians. He also found a preponderance of left-sided involvement in string players, with right or bilateral symptoms in pianists (the majority of keyboard players in our series had left ulnar neuropathy). In Hochberg’s clinic (Hochberg and Lederman, 1995), 40 instances of ulnar neuropathy were found among the 1000 musicians evaluated. Among the two-thirds of our patients diagnosed with ulnar neuropathy who have undergone EDX testing, around half have evidence of slowing of ulnar motor conduction velocity at the elbow and a smaller number have axonal loss, as demonstrated by decrease in the ulnar SNAP or CMAP. Only a few have shown denervation on needle EMG. Charness et al. (1996) studied 27 musicians with a clinical diagnosis of ulnar neuropathy. Of 17 studied with surface recording, 5 (29%) showed focal slowing across the elbow (defined as >13 m/s less than adjacent segments) whereas 15/19 (79%) showed slowing (>16 m/s for motor and >20 m/s for sensory) with near-nerve recording. One additional patient had a focal conduction block at the elbow on surface recording. Quantitative EMG was further helpful in confirming the clinical diagnosis. MacLean (1993) has discussed the EDX approach to ulnar neuropathy in the musician. In the same journal, Amadio (1993) and Nolan and Eaton (1993) affirmed the usefulness, but relatively low sensitivity (less than 50%) of standard EDX studies in confirming the clinical diagnosis of ulnar neuropathy at the elbow. Both also stated that x-rays of the elbow may be helpful in some cases.

42.3.4. Ulnar neuropathy (elbow)

42.3.5. Ulnar neuropathy (wrist)

This is now the second most common mononeuropathy in our series, after TOS. There are 66 instrumentalists with ulnar neuropathy at the elbow. The clinical presentation is familiar to most of us and consists of medial elbow pain with sensory symptoms generally confined to the little and ring finger (most often just the ulnar

This is far less common than entrapment at the elbow. We have 2 such cases in our series, 1 seen only postoperatively. Wainapel and Cole (1988) reported 2 flutists with ulnar entrapment at Guyon’s canal; 1 had pure motor involvement, sparing the hypothenar muscles, whereas the other appeared to have a pure sensory

42.3.3. Long thoracic neuropathy

OTHER MONONEUROPATHIES

syndrome. EDX testing in the first case showed normal sensory and motor NCS except for prolonged DL to the first dorsal interosseous (5.2 ms); neurogenic MUPs were found in that muscle on needle EMG. In the second case, only a mild prolongation of DL of the SNAP, recording ring finger, was found (2.9 ms versus 2.3 ms on the normal hand). 42.3.6. Median neuropathy (CTS) CTS, the most common upper extremity entrapment neuropathy in the general population, has also been the most common in several reports from performing arts medicine clinics. Amadio and Russotti (1990) found 5 cases among 40 musicians evaluated (13%), Winspur (1998) identified 4 patients with CTS among 323 musicians (1%), and Dawson (1999) reviewed 98 cases of CTS from among 1354 instrumentalists seen in his practice (7%). Charness (1992) identified 24 instrumentalists with CTS out of the 117 with upper extremity nerve entrapment syndromes (21%). CTS was found in 62 patients in our series, out of 1420 instrumentalists seen (4%), and representing 20% of the focal neuropathies in this group. Unlike ulnar neuropathy, CTS appeared to be more common in keyboard players than in other groups; in addition, in both keyboard and string instrumentalists, it was more common in the right than left hands, although often bilateral. MacLean (1993) reviewed the EDX approach to CTS in the instrumentalist, including the minimum requirement of median motor and sensory NCS, along with ulnar motor and ulnar and/or radial sensory studies. In his view, this will suffice if the clinical picture is consistent with CTS and median conduction is slowed at the wrist. The routine in our laboratory, in musicians as well as others, is to perform at least a screening needle EMG for concomitant abnormalities and, if the routine median sensory and motor studies are normal or equivocal, to perform median palmar (mixed motor and sensory) NCS as well. In our series, 53 of the 62 patients diagnosed with CTS underwent EDX studies; an abnormality was identified in 50/53, bilateral in 35 of the 50. The value of other diagnostic procedures for CTS, such as ultrasound, CT scan, and MRI of the wrist, has not been investigated in the musician population, to my knowledge. 42.3.7. Median neuropathy (proximal) Occasional musicians will present with median neuropathies other than CTS. These include the pronator

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and the anterior interosseous syndromes. Kopell and Thompson (1958) described a pianist with pronator syndrome in their early paper on this subject. One of the 7 patients reported by Morris and Peters (1976) was a “fiddler;” he suffered from weakness of the flexor pollicis longus as well as thenar muscles, sensory loss in median distribution, and tenderness over the pronator teres. Charness (1992) described a cellist, who also allegedly had TOS and an ulnar neuropathy at the elbow. A harpist in our series developed an apparent proximal median neuropathy after repetitively tuning multiple harps prior to a concert; at the time of my evaluation 5 months later, she had focal pronator tenderness but a normal neurological exam. EDX studies can be expected to show focal median motor slowing or conduction block in the proximal forearm, with normal distal motor and sensory latencies. This is apparent in 5 of the 7 cases reported by Morris and Peters (1976). The fiddler appears to have had a normal NCS; needle EMG in this patient was not described. Our patient had a normal EDX study. Anterior interosseous neuropathy represents another proximal median nerve lesion. I have seen 4 such cases in musicians, including 3 violinists and 1 young piano student. (I am not aware of any others in the literature.) Two of these were of acute onset and a third (in the young pianist) came on subacutely while recovering from a shoulder injury. The fourth patient had a remote history and slight residua when seen. Three of the four were suspected of having localized forms of neuralgic amyotrophy; one of these subsequently underwent a negative exploration elsewhere. EDX studies in the 3 cases of recent onset all showed denervation in flexor pollicis longus, flexor digitorum profundus 2, 3, and pronator quadratus on needle EMG, with normal standard median sensory and motor NCS. 42.3.8. Radial neuropathy Posterior interosseous neuropathy (PIN) has been described in a pianist, 1 of 5 cases included in the classic paper by Woltman and Learmonth (1934). Charness (1992) reported 7 such cases in musicians. I have seen only 1 patient with PIN; he had previously undergone surgical decompression of the radial tunnel, with suggestive evidence preoperatively of weakness. Maffulli and Maffulli (1991) reported “transient” PIN occurring in the left arm during and after playing the violin, with pain in wrist and finger extensors. No muscle weakness was identified at rest. Their analysis attributed this to

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prolonged pronation of the forearm. A letter to the editor pointing out that the left forearm of violinists is supinated during playing (Lederman, 1991), led to their stating that it was the right arm that was affected; unfortunately, this error has been frequently perpetuated in the literature. EDX studies of PIN in musicians have been reported by Charness (1992). Four of his patients had an abnormal EMG, including 1 who had a focal conduction block identified at the time of surgery. Posterior cutaneous neuropathy in a drummer was reported by Makin and Brown (1985). I have seen a similar lesion in a double bass player. Makin and Brown’s (1985) patient had no evidence of denervation in radial-innervated muscles. Our patient did not undergo EDX study. 42.3.9. Digital neuropathy Cynamon (1981) first described sensory loss on the distal radial surface of the left index finger of a flutist after prolonged playing, attributed to pressure against the instrument. Charness (1992) reported a similar case, along with 5 other digital neuropathies in string and wind players. I have seen 15 instrumentalists with digital neuropathies, including 3 with “flutist’s neuropathy.” Only 9 of the 15 were related to playing the instrument (Lederman, 2003). Patrone et al. (1989) described a violinist with digital nerve compression attributed to joint hypermobility, with recurrent subluxation at the fifth metacarpal-phalangeal joint. I am unaware of any EDX studies in these patients, although it would certainly be possible to record antidromically distal to the site of compression in some cases (Casey and Le Quesne, 1972). 42.3.10. Lower extremity neuropathies Schwartz and Hodson (1980) and Howard (1982) each reported a treble viola da gamba player with saphenous neuropathy, attributed to pressure from the instrument that is held between the lower legs. Mladinich and De Witt (1974) described a guitar player who developed a peroneal palsy after several hours of playing with her legs crossed. This was confirmed by EDX study. 42.3.11. Cranial neuropathy Trigeminal branch compression producing sensory loss of a segment of the lip of a trumpeter was reported

RICHARD J. LEDERMAN

by Martin and Lederman (1987). We have seen 7 such patients, including 4 brass and 3 woodwind instrumentalists. Frucht (2000) described a French horn player with a similar disorder. EDX testing would not likely be fruitful. Facial palsy (Bell’s) may occasionally occur in an instrumentalist and would obviously have a major impact on the ability to play a woodwind or brass instrument. I have seen this in 2 French horn players and a clarinetist. Fortunately, all have had sufficient recovery to be able to resume playing. 42.4. Perioperative mononeuropathies Peripheral nerve complications of surgical procedures were clearly recognized before the end of the nineteenth century. Slocum et al. (1948) reviewed the history of these disorders and emphasized their relationship to malpositioning on the operating table. Subsequent reviews have confirmed and extended these observations (Nicholson and Eversole, 1957; Britt and Gordon, 1964; Dawson et al., 1999c). Information regarding the frequency of these complications has been sought, primarily by retrospective analysis. Dhunér (1950) reviewed the records of “approximately” 30 000 operations at the Karolinska Institute over a 6-year period and found 31 peripheral nerve complications (0.1%). Parks (1973) retrospectively surveyed general surgical procedures over a 13-year period in Denver and found 72 such complications after 50 000 operations (0.14%). It is highly likely that these numbers are gross underestimates. Although virtually any peripheral nerve can potentially be injured during a surgical procedure, we will review the more commonly encountered postoperative mononeuropathies, along with the diagnostic studies that have been utilized to investigate them. These are listed in Tables 42.4 and 42.5. 42.4.1. Facial neuropathy Injury to the facial nerve may occur intracranially (e.g., during removal of an acoustic neuroma), within the temporal bone (most commonly during mastoidectomy), or extracranially (particularly with parotidectomy). Oliver (1980), Green et al. (1994), and Wilbourn (1998) have reviewed the subject in considerable detail from different perspectives. Sampath et al. (1997) retrospectively reviewed 611 operations for acoustic neuroma. The facial nerve was anatomically preserved in 97.5%; normal or near-normal facial nerve function was seen in the immediate postoperative period in 62.1%, in 85.3%

OTHER MONONEUROPATHIES

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Table 42.4

Table 42.5

Perioperative neuropathies: upper extremity

Perioperative mononeuropathies: lower extremity

Nerve affected

Surgical procedure(s)

Nerve affected

Surgical procedure(s)

Facial

Acoustic neuroma; mastoidectomy; parotidectomy Neck dissection, lymph node biopsy, cardiac surgery, carotid endarterectomy Thoracic surgery Abdominal, thoracic surgery

Ilioinguinal, genitofemoral, iliohypogastric Femoral

Herniorrhaphy; pelvic surgery

Spinal Accessory

Long thoracic Brachial plexus, upper trunk Brachial plexus, lower trunk Brachial plexus, variable Phrenic Ulnar Median

Lateral femoral cutaneous Obturator

Median sternotomy Liver transplantation, TOS surgery Cardiac surgery Multiple procedures (arm positioning) Carpal tunnel release, open versus endoscopic

at 6 months, and in 89.7% at 1 year. The usefulness of EDX study in these patients was briefly reviewed by Wilbourn (1998). Harner et al. (1987) reviewed their experience with continuous intraoperative monitoring during acoustic neuroma removal and showed a twofold improvement in facial nerve preservation among those with large tumors who were monitored compared to those who were not. Taha et al. (1995) utilized facial nerve stimulation at the brainstem and distally at the internal auditory meatus, recording with subdermal electrodes in the orbicularis oris and orbicularis oculi muscles following tumor excision. They calculated the proximal-to-distal ratios of CMAP amplitude and found a correlation with final outcome. In those with ratios of 2:3 or higher, good final facial nerve function was achieved; those who had ratios of < 1:3 had either fair or poor ultimate facial nerve function. 42.4.2. Spinal accessory neuropathy Although early radical neck dissections for malignancy commonly included sacrifice of the spinal accessory nerve (SAN), more recent evidence has suggested that sparing the nerve does not decrease the cure rate (Carenfelt and Eliasson, 1980). However, these authors found that, despite attempts to preserve the SAN, 23/35 patients had some degree of paresis of the trapezius. Zibordi et al. (1988) compared trapezius

Sciatic Peroneal Saphenous

Hysterectomy; other abdomino-pelvic (lithotomy; renal transplantation) Multiple procedures; cardiac; spine Hip arthroplasty; abdomino-pelvic surgery Hip replacement Lithotomy position; knee surgery Groin/vascular surgery; cardiac

and sternomastoid muscle strength in 37 patients undergoing SAN-sparing neck dissection to healthy controls and to 10 patients in whom the radical neck dissection included SAN transection. Among the latter, 100% had either 1/5 or 2/5 strength in the trapezius; in the group with SAN-sparing, 89% had normal strength and 9% had 4/5 power. Perhaps a more distressing situation is the occurrence of SAN lesions after surgery limited to the posterior triangle of the neck, most commonly lymph node biopsy (Vastamäki and Solonen, 1984; Berry et al., 1991; Williams et al., 1996). SAN has also been seen, much less commonly, following cardiac surgery (Lederman and Wilbourn, 1991; Marini et al., 1991) and carotid endarterectomy (Sarala, 1982; Sweeney and Wilbourn, 1992; Yagnik and Chong, 1996). EDX evaluation of 10 postoperative SAN lesions was reported by Petrera and Trojaborg (1984a), using needle electrode stimulation and recording from the trapezius. They emphasized the increased DL on the affected side and the presence of signs of denervation on needle EMG in 8 of the 10. Latencies were normal in 2, although motor responses were “slightly reduced in amplitude.” Serial studies demonstrated improvement in latencies and signs of reinnervation in 6, leading to conservative management. In 2 cases, EDX studies at 3 months showed complete lesions and nerve grafting or repair was carried out. Donner and Kline (1993) also used both clinical and EDX techniques to evaluate 58 postsurgical SAN palsies, including lymph node biopsy complication in 42, tumor excision in 14, carotid endarterectomy in 1, and

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face lift in 1. They used needle EMG evidence of reinnervation as a guide to determining surgical versus nonoperative management. Friedenberg et al. (2002) reviewed 23 patients with postsurgical SAN lesions, who had undergone percutaneous SAN stimulation and surface recording over the trapezius and had been treated conservatively. Half the patients had a poor outcome, based on pain and/or weakness; changes in CMAP amplitude correlated better with functional outcome than findings on needle EMG. 42.4.3. Long thoracic neuropathy The long thoracic nerve is less commonly injured during surgical procedures than is the spinal accessory, although Emmel et al. (1996) found that 80% of children undergoing surgery for coarctation of the aorta had shoulder girdle abnormalities. Of 21 who underwent needle EMG of the serratus anterior, 20 had abnormalities. Kauppila and Vastamäki (1996) reported 32 cases of iatrogenic serratus anterior palsy following a variety of surgical procedures. All were confirmed by EDX studies, but no details were provided. Petrera and Trojaborg (1984b) described 5 postoperative long thoracic neuropathies studied by needle electrode stimulation at the supraclavicular fossa and recording by needle at the fifth or sixth ribs laterally. Two had markedly prolonged distal motor latencies (22, 24 ms; N = 3.6–6.4 ms, depending on distance) and 4/5 had low amplitude motor responses; in 1 case, the nerve was inexcitable. Low-amplitude MUAPs were seen in 4/5. There does not appear to be sufficient evidence in the literature to recommend using EDX data to predict outcome after surgical trauma; the consensus, however, is that overall recovery after trauma to the long thoracic nerve is poor. 42.4.4. Brachial plexopathies Prior to the median sternotomy era, postoperative brachial plexus injuries were primarily seen following abdominal or pelvic operations and predominantly involved the upper trunk fibers (Clausen, 1942; Ewing, 1950; Britt and Gordon, 1964). The most frequent, but by no means the only, explanation for these injuries has been traction on the plexus, often associated with the Trendelenberg position on the operating table. EDX studies of these lesions have been uncommon; when reported, they usually have suggested conduction block as the predominant

RICHARD J. LEDERMAN

mechanism (Wilbourn and Shields, 1993; Murray and Wilbourn, 2000). The median sternotomy approach to open heart surgery has been associated with brachial plexopathy primarily affecting the lower trunk fibers, generally attributed, again, to stretch or traction (Sharma et al., 2000). Vander Salm et al. (1980) studied the effect of arm position during surgery as a possible contributing factor and found no correlation, although they identified a possible mechanism by demonstrating a high frequency of posterior first rib fractures, presumably related to sternal retraction. However, a later study found no correlation between the presence of a rib fracture and the occurrence of brachial plexus symptoms (Vander Salm et al., 1982). A Cleveland Clinic prospective study of neurological complications of open heart surgery identified a brachial plexopathy in about 5% (Lederman et al., 1982; Hanson et al., 1983). They suggested, based on an apparent correlation between the side of the brachial plexopathy and the site of internal jugular vein cannulation in 3 out of 4 cases, that needle trauma or hematoma formation might contribute. However, two subsequent prospective studies, including a total of 1335 patients, failed to show such a correlation (Tomlinson et al., 1987; Vahl et al., 1991) and most authors now attribute the bulk of these to the effects of the required sternal retraction. In a prospective study of neurological complications of coronary bypass surgery, 37/312 patients (11.9%) developed peripheral nerve lesions, including brachial plexopathies in 21 (Shaw et al., 1985). EDX studies in the median sternotomy-associated brachial plexopathies reported by Hanson et al. (1983) were confirmatory of localization to the C8/T1 fibers in 11/13 and to the upper trunk in 2/13. One additional patient with a clinically mild lower trunk brachial plexopathy had a normal EDX study. Levin et al. (1998) studied an additional 14 patients with median sternotomy-related brachial plexopathy and found that the ulnar sensory and motor responses were the most frequently affected. They suggested that the C8/ulnar motor and sensory fibers might be preferentially affected at the cervical root level rather than more distally in the lower trunk of the brachial plexus. Hickey et al. (1993) studied the usefulness of median and ulnar SEPs in 30 patients undergoing cardiac surgery as a potential predictor of postoperative brachial plexus lesions. Interestingly, they saw transient changes in SEPs in 4/30 during central venous cannulation and significant changes in 21/30 (70%) during chest wall retraction. Sixteen of these reverted

OTHER MONONEUROPATHIES

toward normal during the surgery; the other 5 showed persistent changes throughout the surgery and all 5 had postoperative neurological deficits. They suggested that intraoperative SEPs could be used to predict brachial plexus injury with heart surgery. However, a subsequent study by Seal et al. (1997) involving 20 open heart surgery patients, also showed SEP changes in 75% during sternal retraction, but there were no postoperative brachial plexopathies in that series and, hence, no evidence that the SEP changes could be used to predict injury. Given the small number of patients studied and the frequency of brachial plexopathy of about 5% of median sternotomy patients (Hanson et al., 1983; Tomlinson et al., 1987), the conclusions reached by Seal et al. (1997) may be questioned. Brachial plexopathy has been reported in a number of cases following liver transplantation. Menegaux et al. (1994) reviewed 427 orthotopic liver transplantation procedures and identified brachial plexus injuries in nine cases. Katirji (1989) studied 7 such cases among 120 adults undergoing liver transplantation (5.8%). The EDX data suggested axonal lesions and recovery was slow and often incomplete. One additional surgical procedure that has been associated with injury to the brachial plexus is first rib resection for TOS (Cherington et al., 1986; Wilbourn, 1988). These patients typically had the “symptomatic” or “disputed” form of TOS preoperatively. They subsequently suffered injury to the brachial plexus, documented clinically and by EDX, either limited to the lower trunk/medial cord fibers or more diffuse, often accompanied by changes suggestive of reflex sympathetic dystrophy in addition (Wilbourn, 1988). 42.4.5. Phrenic nerve injury The incidence of phrenic nerve injury in the course of cardiac surgery has been variously estimated at anywhere from 2% to 73%, depending on the method used to demonstrate it and the frequency of its clinical importance has also been debated (Cohen et al., 1997; Tripp and Bolton, 1998). The generally accepted mechanism has been cold-induced injury from the cardioplegic solutions utilized during the procedure. Using transcutaneous phrenic nerve stimulation, Markand et al. (1985) found reduced amplitude diaphragmatic CMAPs in 5/44 patients, 3 on the left and 2 on the right (1 absent, 75–90% decreased in 2, 50–60% decreased in 2). Dimopoulou et al. (1998) studied 63 patients after cardiac surgery and noted absence of the diaphragmatic CMAP in 12, 11 on

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the left only and 1 bilaterally, and increased latency of the diaphragmatic CMAP in 1 (left, 7.3 msec preoperatively and 10.5 ms after surgery). Of the risk factors, only the use of ice slush appeared to be significant. Mazzoni et al. (1996) reported 12 patients monitored intraoperatively using transcutaneous phrenic nerve stimulation; all 12 received intracoronary cold perfusion. Six of these were also given topical ice-cold solutions. In the latter group, 3 patients showed abnormal phrenic nerve conduction; none in the intracoronary cooling only group showed an abnormality. DeVita et al. (1993) reported a series of 92 consecutive patients undergoing open heart surgery. Of these, 78 (85%) had an abnormal postoperative chest x-ray; 42 of the 78 (54%) had abnormal ultrasonography of diaphragmatic motion. Phrenic NCS were carried out in these 42 patients and 24 (57%) had phrenic neuropathy based on prolonged CMAP latency (no specific numbers given), representing 26% of the entire operative group. Those with abnormal phrenic NCS took longer to recover postoperatively than patients with abnormal diaphragmatic motion but normal NCS; the latter group recovered more slowly than those with normal postoperative diaphragmatic function. Overall, however, most patients in all groups recovered fully. 42.4.6. Ulnar neuropathy Injury to the ulnar nerve perioperatively has been considered common and attributed to arm position (Prielipp et al., 2002). Kroll et al. (1990) reviewed a total of 1541 closed claims from insurance company files related to anesthetic injuries, over 90% occurring between 1985 and 1995. Of these, 227 (15%) involved nerve injuries and 77 of those (34%) represented perioperative ulnar neuropathies. Warner et al. (1994b) carried out a retrospective survey of over 1 million noncardiac surgical procedures at Mayo Clinic and found an incidence of persistent ulnar neuropathies in 1 per 2729 patients (0.04%). In a subsequent prospective study, ulnar neuropathy developed postoperatively in 7 of 1502 (0.5%) patients undergoing noncardiac surgical procedures; 6/7 were men, all at least 50 years of age, and symptoms did not begin until 2 or more days after surgery (Warner et al., 1999). They suggested a number of possible predisposing factors. Patients undergoing renal transplantation may be particularly susceptible (Zylicz et al., 1984). Miller and Camp (1979) performed EDX studies in 8 patients, again all men, who had evidence of ulnar

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neuropathy a minimum of 6 months and an average of 2 years following a surgical procedure. NCS, including inching when feasible, and needle EMG suggested axonal loss as the predominant mechanism and localization to the cubital tunnel when this could be determined. Alvine and Schurrer (1987) carried out a prospective study of 6538 surgical patients and identified 17 (0.26%) who developed a postoperative ulnar neuropathy. They performed NCS bilaterally and found abnormal slowing across the elbow on the unaffected as well as the affected side, although the degree of slowing did not meet currently accepted criteria in all cases (Campbell et al., 1999). Their data was interpreted as suggesting that such patients may have a predisposition, perhaps a subclinical ulnar neuropathy preoperatively. Few studies have looked at EDX findings before and after surgical treatment of ulnar neuropathy. Friedman and Cochran (1987) performed ulnar motor nerve conduction velocity studies and needle EMG before and after anterior transposition in 23 patients with moderate (30%) or severe (70%) ulnar neuropathies. There was a reasonable correlation between the severity of clinical and EDX findings preoperatively. Postoperatively, 70% improved clinically and there was a highly significant correlation with improved conduction velocity (p < 0.0005). However, among the 30% with a poor outcome, the conduction velocity also improved, although not to the same degree of significance (p < 0.05). They cautioned against using preoperative EDX findings as predictors of surgical outcome (Friedman and Cochran, 1987). In a study of 27 medial epicondylectomies in patients with clinically mild ulnar neuropathy (no evidence of weakness or atrophy), Robinson et al. (1992) reported ulnar motor conduction velocity across the elbow averaging 48% of normal preoperatively (26.4 ± 8.7 ms) and 85% of normal after surgery (46.7 ± 9.7 ms). They favor using abnormal EDX studies as a preoperative criterion for patients with mild ulnar neuropathies. Kline and Nulsen (1972) reviewed their experience with operative management of 18 ulnar nerve lesions, utilizing intraoperative NCS to identify those in which axonal continuity would suggest a favorable outcome without requiring nerve repair. 42.4.7. Median neuropathy (CTS) Rosenbaum and Ochoa (2002) reviewed the complications of carpal tunnel surgery, both open and endoscopic, including injury to the median nerve proper as

RICHARD J. LEDERMAN

well as its palmar cutaneous, recurrent thenar motor, and digital branches. Palmer and Toivonen (1999) reported the results of questionnaires sent to members of the American Society for Surgery of the Hand regarding such complications. Endoscopic release was associated with 265 nerve lacerations, whereas 230 nerve injuries were reported following open release, including not only median but ulnar nerve injuries as well. The total number of procedures on which these numbers were based was not recorded. Jimenez et al. (1998) reviewed six currently utilized endoscopic techniques and found no significant differences in success rates or complication among them or when compared to open procedures. However, there appears to be some differences in the specific injuries; laceration of the palmar cutaneous and thenar motor branches is reported with considerably higher frequency in open procedures, whereas digital branch and “unspecified” median nerve lacerations, and particularly ulnar nerve lacerations appear to be more common in endoscopic procedures (Jimenez et al., 1998; Palmer and Toivonen, 1999; Braun et al., 2002; Rosenbaum and Ochoa, 2002). EDX studies generally improve following carpal tunnel release, regardless of the technique (see Rosenbaum and Ochoa, 2002 for review), although often, NCSs do not return to normal, despite full clinical recovery (Melvin et al., 1968; Seror, 1992). Braun and Jackson (1994) reported that EDX studies did not provide significant prognostic information regarding functional recovery or return to work after surgery; it should be noted, however, that 26 of their 151 patients did not undergo EDX testing preoperatively and another 50 had normal studies before surgery. Braun et al. (2002) emphasized that performance of EDX studies in patients suffering complications are compromised by preoperative abnormalities; if thenar motor weakness develops following surgery, it is important to perform needle EMG in the first 2 weeks, to differentiate pre-from postoperative denervation changes. 42.4.8. Ilioinguinal, genitofemoral, and iliohypogastric neuropathies Sensory loss or pain due to injury to 1 of these 3 nerves has been estimated to occur in up to 24% of hernia repairs (Al-dabbagh, 2002). It is less common following other pelvic operations. Cardosi et al. (2002) reviewed records of 1210 women suffering nerve injury after major pelvic surgery and found 23 cases (1.9%), including 5 ilioinguinal/iliohypogastric

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and 4 genitofemoral neuropathies. Both medical and surgical management has been advocated (Starling et al., 1987; Lee and Dellon, 2000; Cardosi et al., 2002). No reliable EDX techniques are available for these nerves; SEPs may possibly be of some help if clinical assessment is not definitive (Dumitru et al., 2002). Knockaert et al. (1996) performed needle EMG of the abdominal muscles in 41 patients suspected of having ilioinguinal or iliohypogastric injury and found abnormalities in 21 (51%). 42.4.9. Femoral neuropathy Most iatrogenic femoral nerve injuries occur in the course of abdomino-pelvic surgery, with some estimates of incidence in abdominal hysterectomy over 10% (Chan and Manetta, 2002). The lithotomy position for pelvic procedures may be an independent risk factor (Al Hakim and Katirji, 1993; Warner et al., 1994a); thin body habitus increases the risk in both situations (Warner et al., 1994a; Chan and Manetta, 2002). Surgery on the hip joint is another well-recognized cause (Weber et al., 1976; Hudson et al., 1979; Schmalzried et al., 1991; Kim and Kline, 1995). A recent prospective study of femoral neuropathy after renal transplantation showed an incidence of 2.2% (Sharma et al., 2002). Most cases are due to stretch or compression and resolve spontaneously (Chan and Manetta, 2002), but some may require surgical exploration and grafting (Kim and Kline, 1995). Needle EMG of the quadriceps is the most useful EDX procedure (Weber et al., 1976) although recording the femoral CMAP may also be helpful (Al Hakim and Katirji, 1993). Synek and Cowan (1983) utilized saphenous SEPs to assess femoral nerve function, particularly for intra-abdominal lesions. Both Hudson et al (1979) and Kim and Kline (1995) used femoral NCSs intraoperatively to decide between neurolysis and grafting for treatment of severe femoral neuropathies; 47 of the 78 lesions in the latter series were iatrogenic. 42.4.10. Lateral femoral cutaneous neuropathy (meralgia paresthetica) In the classic paper by Ecker and Woltman (1938), 10 cases of this rather common mononeuropathy were identified, following a variety of surgical procedures. Shaw et al. (1985) described 5 such cases among 37 peripheral nerve disorders following coronary bypass graft surgery in 312 patients. Mirovsky and

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Neuwirth (2000) reported 21 lateral femoral cutaneous nerve injuries in a series of 105 elective spine procedures, 6 of them bilateral. These were attributed to pressure from a surgical frame, retroperitoneal hematoma or traction, and trauma at the time of graft harvesting from the iliac crest. The latter cause was also seen in the series reported by Nahabedian and Dellon (1995). The usual EDX approach consists of side-to-side comparison of SNAP amplitude (Lagueny et al., 1991), although SEPs have also been suggested, particularly if some question of a more proximal lesion has been raised (Synek, 1985; Wiezer et al., 1996). In my experience, EDX studies are only infrequently helpful or necessary, partly because of the technical difficulty in recording, even from the asymptomatic side, and partly because the area of sensory loss is usually so characteristic as to leave little doubt as to diagnosis. 42.4.11. Obturator neuropathy This is a relatively uncommon lesion, generally related to hip arthroplasty, or to abdominal or pelvic surgery. Groin or thigh pain is the most common symptom, sometimes accompanied by thigh weakness or paresthesias. Weber et al. (1976) prospectively studied 28 patients undergoing 30 total hip arthroplasties with EMG 1 day before and 18–21 days after surgery. Of these, 21 showed EMG evidence of nerve injury, including 8 with obturator neuropathy alone and 5 with obturator plus sciatic nerve involvement. None of the patients had any symptoms and only 2 of the 21 had mild weakness found on exam. Two patients with obturator neuropathies were reported by Bischoff and Schönle (1991) following intraabdominal surgery, with active denervation seen on needle EMG of the adductor muscles. Of 22 cases reported by Sorenson et al. (2002), 14 were related to a surgical procedure; all 22 were confirmed by EMG evidence of fibrillation potentials or neurogenic MUAPs in obturator-innervated muscles. Bilateral obturator neuropathies were reported by Pellegrino and Johnson (1988) following prolonged urologic surgery, again with EMG confirmation. 42.4.12. Sciatic mononeuropathy Schmalzried et al. (1991) reviewed retrospectively a series of 3126 consecutive total hip replacements and identified 53 postoperative neuropathies (1.7%), including 42 involving the sciatic nerve only and

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6 with combined sciatic and femoral nerve injury. Of the 48 with sciatic nerve involvement, only the peroneal division was affected in 26, peroneal and tibial portions in 19, and tibial alone in 3. Edwards et al. (1987) attributed the majority of sciatic/peroneal neuropathies after total hip arthroplasty to the associated leg lengthening. Eggli et al. (1999) reviewed 508 consecutive total hip replacements for developmental dysplasia and found no correlation between lengthening and nerve injury. They concluded that the degree of technical difficulty during the surgical procedure was a more relevant factor. Of the 73 patients with sciatic mononeuropathies reviewed by Yuen et al. (1994), 16 (22%) were related to hip arthroplasty; in the majority, regardless of etiology, the peroneal division was preferentially affected. A number of factors appear to contribute to this phenomenon (Goldberg and Goldstein, 1998). Of 17 peripheral nerve lesions seen in the 14 patients undergoing hip arthroplasty studied by Weber et al. (1976), 10 involved the sciatic nerve. Sciatic neuropathies may also occur following other types of surgery, including gynecologic procedures (Burkhart and Daly, 1966) and cardiac surgery (McManis, 1994). Detailed EDX studies in a patient with post-hip arthroplasty sciatic neuropathy have been reported by Goldberg and Goldstein (1998). In keeping with the expected distribution, the peroneal CMAPs and superficial peroneal SNAP were absent, with reduced amplitude sural SNAP (4.2 μV compared to 12.7 μV on the uninvolved side) and a suggestively decreased tibial CMAP (9.2 mV compared to 14.1 mV on the opposite side). Needle EMG showed abundant fibrillations, more prominent in peroneal—than in tibial— innervated muscles. Similar findings were reported in the 100 patients with sciatic neuropathy studied by Yuen et al. (1995). The peroneal division was more severely affected in 64% whereas the tibial division was preferentially affected in only 8 patients; 7 of these were associated with trauma to the thigh or hip region (gunshot wounds or fractures). 42.4.13. Peroneal neuropathies The superficial position of the common peroneal nerve as it wraps around the neck of the fibula makes it susceptible to external pressure during surgical procedures, particularly in lithotomy position (Britt and Gordon, 1964). Warner et al. (1994a) retrospectively reviewed 198 461 surgical procedures performed in the lithotomy position at the Mayo Clinic from 1957

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to 1991 and identified 55 lower extremity neuropathies (1/3608), of which 43 involved the common peroneal nerve. In a retrospective review of 612 cases of iatrogenic nerve injuries that were later explored surgically, the common peroneal was the most frequently affected in the lower limb (Khan and Birch, 2001). Aprile et al. (2000) reviewed 36 cases of peroneal mononeuropathy studied in their EMG laboratory and identified 11/36 (31%) as perioperative injuries, 5 after hip replacement and 3 after tibial osteotomy. There were 8 peroneal neuropathies in the prospective Cleveland Clinic study of 421 patients (1.9%) undergoing coronary bypass graft surgery (Lederman et al., 1982). In a retrospective analysis of 20 718 cardiothoracic surgical procedures, 39 cases (0.19%) of common peroneal neuropathy were identified (Vazquez-Jimenez et al., 2002). In the large series of common peroneal neuropathies studied by Katirji and Wilbourn (1988), 29/116 were perioperative, including 16 related to heart surgery. The most common setting today for postoperative peroneal palsy is knee surgery. Rose et al. (1982) identified 23 peroneal-nerve palsies following 2626 consecutive knee arthroplasties (0.87%). Small (1990) compared the results of a retrospective survey of 3034 meniscal repairs, in which 6 peroneal nerve injuries were identified (0.2%), to a prospective series of 3874 arthroscopic meniscal repairs performed by a select group of experienced surgeons. No peroneal neuropathies were identified and only 1 nerve injury (saphenous) occurred. It has been pointed out that the deep peroneal nerve may be preferentially injured during arthroscopic knee surgery (Esselman et al., 1993; Wilbourn, 1998), although this selectivity may not be unique to perioperative cases (Sourkes and Stewart, 1991). EDX studies of perioperative peroneal palsies generally follow standard protocols for all common peroneal neuropathies (Katirji and Wilbourn, 1988). These authors pointed out that, although the majority of these lesions can be localized to the fibular head, only a minority represent pure conduction block. Indeed, among the 29 perioperative neuropathies in their series, 25 showed evidence of axon loss, an important point when predicting rate and degree of recovery. Wilbourn (1998) has emphasized the importance in these cases of recording peroneal CMAPs from the tibialis anterior in addition to the extensor digitorum brevis and of performing superficial peroneal sensory NCS as well as a “rather extensive” needle EMG. Kim et al. (2002) reviewed the importance of serial EMG studies in

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monitoring the progress of these lesions postoperatively over the subsequent 3–6 months to decide if and when to intervene surgically. 42.4.14. Saphenous neuropathy Inadvertent injury to the saphenous nerve may occur in infra-inguinal vascular reconstructions, including femoropopliteal bypass grafts and deep femoral angioplasty. Adar et al. (1979) identified 15 cases of severe saphenous neuralgia among 55 patients undergoing 1 of these procedures and an additional 10 had mild symptoms. Three other patients had delayed onset of similar symptoms; thus 28/55 (51%) presumably experienced trauma to the saphenous nerve during the procedure. Roder et al. (1984) reviewed 216 groin dissections for various arterial procedures in 158 patients, 17 of whom developed saphenous neuralgia (11%), more commonly women than men. Among 109 patients undergoing femoropopliteal artery bypass, Urayama et al. (1993) identified postoperative saphenous neuralgia in 22 (17%). Saphenous neuropathy also occurs following coronary bypass surgery and can be directly correlated with saphenous vein harvesting. In the Cleveland Clinic series (Lederman et al., 1982), 13 saphenous neuropathies were found among the 421 patients studied prospectively, always on the leg selected for vein dissection. Nair et al. (1988) found sensory loss in 45 of 50 consecutive patients examined 48 hours after saphenous vein harvesting for coronary bypass. At 6–8 weeks, only 13 patients had residual sensory loss; the method of wound closure significantly influenced the recovery of function. Mountney and Wilkinson (1999) studied 39 limbs in 32 consecutive patients undergoing bypass graft surgery; 35/39 limbs (90%) had some saphenous territory sensory loss in 3 days. At an average of 20 months, postoperatively, 72% still had some loss of feeling, most commonly anterior to the incision on the lower leg. Injury to the saphenous nerve also occurs with knee arthroscopy. In the retrospective series reviewed by Small (1990), saphenous nerve injury was identified in 30 of 3034 arthroscopic meniscal repairs. In the entire series of 375 069 knee arthroscopies, 229 nerve injuries were recorded (0.06%), including 97 involving the saphenous nerve (43% of the total). It should be noted, however, that the exact type of 108/229 nerve injuries was unspecified. As indicated above, in a subsequent prospective study limited to experienced surgeons, only 1 saphenous neuropathy was reported in

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8791 arthroscopic knee procedures (Small, 1990). Kim et al. (2002) reviewed the relative risks for the various branches of the saphenous nerve during arthroscopic surgery at the knee. Mochida and Kikuchi (1995) found injury to the infrapatellar branch in 18 of 81 knees in 68 patients. Based on subsequent cadaver studies, they made specific recommendation on the insertion of the arthroscope to minimize the risks of saphenous injury. Although techniques for saphenous NCS (Wainapel et al., 1978; Kimura et al., 1983) and SEP (Synek and Cowan, 1983) are available, no systematic study of postoperative complications has been carried out, to the best of my knowledge. Generally, a clinical assessment is all that is required. 42.5. Localized hypertrophic mononeuropathy This is a rare disorder of peripheral nerve, the etiology of which remains uncertain. It presents with progressive, painless sensorimotor loss in a peripheral nerve distribution, most commonly appendicular, occasionally cranial (Chang et al., 1993; Kania et al., 2001). There is fusiform enlargement of the nerve, with whorls of concentrically laminated cells reminiscent of “onionbulb” formation. It remains uncertain whether this represents a perineurial cell neoplasm (Bilbao et al., 1984; Suarez et al., 1994; Emory et al., 1995), or hyperplasia of either Schwann or perineurial cells, in response to a traumatic or inflammatory stimulus (Hawkes et al., 1974; Peckham et al., 1982; Phillips et al., 1991; Yassini et al., 1993). Mitsumoto et al. (1980) initially characterized the lesion as a perineurioma but subsequently (Mitsumoto et al., 1992) considered it to represent reactive hyperplasia. Differentiation of perineurial from Schwann cells has largely depended on their immunoreactivity, but both patterns have been reported. EDX testing in these patients has invariably demonstrated signs of progressive axonal loss. NCS reveal decreased amplitude or absent SNAPs and CMAPs with no evidence of conduction slowing or block in the affected nerve, when that can be determined, or in clinically unaffected nerves. Needle EMG demonstrates active and chronic denervation in muscles supplied by the hypertrophic nerve (Mitsumoto et al., 1980; Phillips et al., 1991; Mitsumoto et al., 1992). Intraoperative EDX studies may be used to aid with decisions regarding management (Phillips et al., 1991; Yassini et al., 1993; Gruen et al, 1998). Absence of or markedly reduced action potentials across or distal to the lesion led Gruen et al (1998) to resect and repair with a nerve graft.

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In addition to EDX testing, peripheral nerve imaging may be helpful both in localization and in characterizing the lesion as hypertrophic (Simmons et al., 1999; Takao et al., 1999; Heilbrun et al., 2001). MRI with contrast and utilization of fat suppression images appears to be most effective in visualizing the lesions (Simmons et al., 1999; Takao et al., 1999). 42.6. Idiopathic progressive mononeuropathy This is a controversial entity, which may simply reflect our inability to demonstrate an anatomical cause for the clinical syndrome. Engstrom et al. (1993) described 6 young patients (age 9–27 years at onset) with progressive, painless sensory loss or motor weakness in the distribution of a single peripheral lower extremity nerve. All 6 underwent extensive evaluation, including surgical exploration in 5, with no tumor, hypertrophy, or site of compression identified. A similar case of sciatic mononeuropathy, with onset at the age of 3 years, had been reported by Jones et al. (1988). Of 73 patients with sciatic mononeuropathy reported by Yuen et al. (1994), 9 were considered to be idiopathic and 5 were characterized as chronic and progressive (including 2 previously reported by Engstrom et al., 1993). Weig et al. (2000) reported 4 cases of “unexplained” mononeuropathy, but only 1 of these, affecting the femoral nerve in a 14-year-old girl, failed to have any demonstrable focal lesion of the peripheral nerve. Limited follow-up information available from the series of Engstrom et al. (1993) suggests either continued slow progression or stabilization. I have seen 2 adults with progressive mononeuropathy over several years, affecting the ulnar and radial nerves, respectively, with no lesion demonstrable on extensive imaging studies. Neither one, however, wished to proceed to exploration. EDX testing in the reported cases referred to above revealed decreased or absent SNAPs and CMAPs, with denervation potentials in appropriate muscles on needle EMG (Jones et al., 1988; Engstrom et al., 1993; Yuen et al., 1994; Weig et al., 2000). MRI studies are of value in looking for sites of compression or other focal pathology. In the absence of such focal lesions, the only finding may be abnormal signal in the denervated muscles. 42.7. Postherpetic neuralgia and segmental zoster paresis Neurological complications of acute zoster (shingles) that represents the reactivation of varicella-zoster

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virus, include postherpetic neuralgia and segmental zoster paresis (Gilden et al., 2000). 42.7.1. Postherpetic neuralgia This is generally defined as a pain syndrome in dermatomal distribution persisting at least 1 month after the onset of the herpetic eruption (Kost and Straus, 1996) or, alternatively, 1–3 months after the disappearance of the rash (Nurmikko, 1995). Its frequency after acute reactivation of varicella-zoster clearly increases with age, from less than 10% in younger patients to over 70% in those over 70 years of age (Kost and Straus, 1996). In addition to the pain that can be excruciating, there is often segmental sensory loss, allodynia, and hypersensitivity to touch. Symptoms generally last for months; the risk of persistence for more than 1 year is said to be 2–3% (Nurmikko, 1995). There are relatively few EDX studies of patients with postherpetic neuralgia. Mondelli et al. (2002) prospectively studied 158 patients with acute shingles, from 3 weeks to 2 months after onset of the rash, utilizing standard NCS and needle EMG. Patients with involvement of dermatomes not easily studied (e.g., thoracic, C2–4, L1–2, and S2–4) were excluded. There was clinical evidence of postherpetic neuralgia in 31% of the cases. The authors found absent or reduced amplitude SNAPs in 60% of all patients, and abnormality of CMAPs in 18%, with no apparent correlation between presence or severity of EDX changes and the presence or absence of postherpetic neuralgia. Of those with rash localized to the head, 31% had abnormal blink reflexes. This confirmed an earlier study of a smaller number of patients by the same group (Mondelli et al., 1996), which demonstrated SNAP and CMAP abnormalities with approximately equal frequency in those both with and without postherpetic neuralgia. In a study to investigate the role of small myelinated fibers in postherpetic neuralgia, Truini et al. (2003) studied laser-evoked potentials in 40 patients and 12 healthy controls. They found that the threshold for perception of the stimulus was higher among patients with postherpetic neuralgia and that the amplitude of the laser-evoked potential was significantly lower in the affected dermatome than on the opposite side. There was, however, no correlation between the level or duration of pain and the degree of abnormality of the evoked potentials.

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42.7.2. Segmental zoster paresis Although acute zoster is primarily a disorder characterized by pain, rash, and cutaneous sensory changes, a small percentage of patients develop muscular weakness as well. Several clinical reviews are available (Grant and Row, 1961; Thomas and Howard, 1972; Gardner-Thorpe et al., 1976; Merchut and Gruener, 1996). The incidence of this syndrome following acute zoster is probably about 5% (Thomas and Howard, 1972), although the frequency of subclinical motor involvement may be much higher (Greenberg et al., 1992). Weiss et al. (1975) reviewed 117 hospitalized patients with herpes zoster and identified 6 with limb paresis. Onset of weakness is usually within 2–3 weeks of the rash, although generally earlier in patients with facial involvement. Recovery of motor function is usually slow but generally complete or nearly so in about 75% (Grant and Rowe, 1961; Thomas and Howard, 1972; Weiss et al., 1975; Gardner-Thorpe et al., 1976; Merchut and Gruener, 1996). EDX studies in segmental zoster paresis have consistently revealed changes of axon degeneration in myotomal distribution. Grant and Rowe (1961) reported EMG results in 3 of their 5 cases, showing fibrillations in 1 and reduced or absent MUAPs on attempted voluntary activation in all 3. Follow-up studies 1–9 years later were reported to be normal in 2 of the 3, although one of these still had a “drop-foot gait,” rendering that interpretation somewhat doubtful. The recovery phase was specifically studied by Sachs (1996) in one patient who was serially examined with NCS and needle EMG from 2 months after onset of leg weakness until 20 months later. He showed a gradual increase in CMAP amplitude over the first year, although reaching only 27% of the normal contralateral response amplitude, and MUAP changes reflecting proximal to distal reinnervation over the 20 months. Thomas and Howard (1972) reported EMG results in 18 of their 61 cases, with fibrillation potentials “universally present” in affected muscles, including the paraspinals, along with reduced numbers of MUAPs firing at a rapid rate. Sensory and motor nerve conduction was said to be normal in “all but 3 cases.” Gardner-Thorpe et al. (1976) described electrophysiological studies in 11 patients and found spontaneous discharges in 9 and excess polyphasic MUAPs in 7. Some reduction in motor and sensory nerve conduction velocity was found in 5 patients, but the results were considered inconclusive for a demyelinating component. Most of the changes

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reported have been interpreted as being in radicular distribution, although Merchut and Gruener (1996) have reviewed the evidence suggesting that more peripheral axonal lesions may also occur. Cioni et al. (1994) studied 52 patients with acute thoracic herpes zoster, at least 1 month after the onset of the eruption. EMG of paraspinal muscles showed fibrillations and/or positive sharp waves in 18/52 (35%), almost always in at least 2 contiguous myotomes and often beyond the levels clinically involved. Active denervation potentials had disappeared by the time of the 6month follow-up examination. Neuroimaging generally adds little to the information obtained by clinical and EDX evaluation. Hanakawa et al. (1997) reported gadolinium enhancement of multiple thoracolumbar roots on MRI in a patient with segmental zoster paresis involving the proximal right lower extremity clinically and electrically. The patient also had bifacial weakness and had enhancement of the facial nerves bilaterally, as well. Similar MRI findings have been reported previously by Osumi and Tien (1990). 42.8. Complex regional pain syndrome I (CRPS-I)/reflex sympathetic dystrophy (RSD) There are few, if any, topics in medicine, let alone neuroscience, that generate as much controversy as reflex sympathetic dystrophy (RSD), now preferably called complex regional pain syndrome, type I (CRPS-I). It is neither appropriate, nor possible to discuss these controversies in this setting, although one cannot avoid referring to these issues in reviewing the clinical criteria and diagnostic studies. 42.8.1. Clinical features of CRPS-I Regardless of whether one uses the term RSD or CRPS, or one of a number of alternatives (Veldman et al., 1993), there is general agreement that this represents a chronic pain syndrome, usually but not invariably involving 1 limb, which develops following a trauma of variable severity, often relatively mild. The clinical symptoms and signs are usually characterized as sensory, autonomic, motor, and trophic (Baron, 2003; Wasner et al., 2003). The predominant sensory symptom is pain, which is generally out of proportion to the severity of the inciting event. Hyperalgesia, allodynia, and sensory deficits, the latter often beyond a single peripheral nerve distribution, are also noted. Among presumed autonomic features

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are side-to-side temperature differences, trophic changes, abnormalities of vascular perfusion, sudomotor dysfunction, either excessive or deficient, and edema. The latter 3 findings, particularly, have suggested the possibility that inflammation plays a role in the early phases (Bennett, 2001; Birklein et al., 2001). Motor abnormalities may include weakness, which is often difficult to quantitate because of the influence of pain; tremor, which likely represents enhanced physiologic tremor (Deuschl et al., 1991); impaired coordination; and, in about 10% of cases, dystonia. Among trophic changes described are osteoporosis, joint stiffness, and even ankylosis. CRPS-I generally evolves in stages, although the terminology and descriptive features again differ. A commonly utilized paradigm would include an acute phase, commonly lasting 3-6 months, a subacute or dystrophic stage, lasting another 6 months, and a chronic or atrophic stage (Knobler, 1997). Staging may have important diagnostic and therapeutic implications, since many of the tests to be described below yield differing results depending on the stage, and therapy is generally assumed to be most effective in the early stage. In 1995, the recommendations of a working group, convened to attempt a clarification of the taxonomy and clinical features of this disorder, were published (Stanton-Hicks et al., 1995). The terms “complex regional pain syndrome,” types I (RSD) and II (causalgia) were introduced, the latter differing from the former only in that a specific nerve injury can be defined. These criteria were later subjected to analysis and revision in an attempt to improve internal validity (Harden et al., 1999). These attempts can only be considered partially successful, failing to breach the wide gap in acceptance of the concepts involved (Baron et al., 1999; Ochoa, 1999), as well as falling short of improving acceptance of the criteria for research purposes (van de Beek et al., 2002; Reinders et al., 2002). 42.8.2. Diagnostic tests for CRPS-I Although there are many diagnostic tests which have been advocated as helpful in establishing a diagnosis of CRPS-I, most authorities would seem to agree that there are no studies which are specific or reliable (Wasner et al., 1998; Baron et al., 1999; Rho et al., 2002; Wasner et al., 2003). In view of the great diversity of the studies utilized, and the limited applicability of most of these to other disorders discussed in this volume, this review will be restricted to a few examples of

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each technique as applied to the diagnosis of CRPS-I. A significant problem with all of these studies is that there is no “gold standard” for making the diagnosis clinically, as well as by laboratory procedures; hence the determination of an effective diagnostic test is based on a potentially flawed and insecure clinically defined population. 42.8.2.1. Bone and vascular scintigraphy The three-phase bone scan can be helpful in identifying patients with CRPS-I and separating them from those with other conditions associated with trophic bony changes, although few would appear to agree with Driessens et al. (1999) who state that “To establish the diagnosis of RSD, the performance of bone scintigraphy is an absolute necessity. . . . In view of the importance of early diagnosis and treatment, it should be considered severe negligence not to perform bone scintigraphy with the slightest suspicion of RSD.” The most prominent changes are seen in the third phase, in which there is a diffuse increase in uptake around the distal joints. These changes are generally limited to the first year or so of symptoms, after which the bone scan typically reverts to normal. Paice (1995) reported a study of 63 patients with unexplained arm pain, 26% of whom satisfied criteria for definite or probable RSD. In this group, the sensitivity of bone scintigraphy with technetium-99 was 50% and the specificity 92%. Schiepers et al. (1998) studied 50 patients with upper limb pain, utilizing the three-phase bone scan, supplemented with vascular scintigraphy with labelled human serum albumin to assess the integrity of the vasculature. Thirty patients were determined by consensus clinical criteria to have RSD. There were 25 bone scans considered positive, 20 negative, and 5 equivocal, for a sensitivity in the total group of 73% and specificity of 86%. Vascular scintigraphy was viewed as helpful in staging. Driessens et al. (1999) also utilized vascular scintigraphy for staging, typically finding hypervascularization in the earliest stage and diminished blood flow and volume in the second stage (although their definitions of the stages differ from those mentioned above, referring to an initial warm or hypertrophic phase and a second cool or atrophic stage). Zyluk (1999) reported three-phase bone scintigrams in 70 patients with RSD and 30 with hand injuries without RSD. Abnormalities along the metacarpal bones and in the metacarpophalangeal joints in phase 3 achieved sensitivity and specificity of about 80%. Oyen et al. (1993) used scintigraphy with indium111-labelled immunoglobulin G to investigate vascular

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permeability in early RSD and found increased extravasation in the first 5 months of symptoms, not flow-dependent, suggesting that inflammation may be an important mechanism in the early stage of RSD. 42.8.2.2. X-ray and magnetic resonance imaging (MRI) That x-ray changes occur in CRPS-I/RSD has been known for more than a century (Sintzoff et al., 1997; Driessens et al., 1999), consisting of diffuse and patchy demineralization of bone, mainly distal and peri-articular in distribution. However, these changes are not pathognomonic and can be seen in disuse and what Driessens et al. (1999) have called “pseudodystrophy.” MRI may help differentiate these entities. Turner-Stokes (2002) described MRI findings of periarticular marrow edema, soft tissue swelling, and joint effusions. Sintzoff et al. (1997) report decreased signal intensity in bone marrow on T1-weighted images and increased signal on T2-weighted scans as well as fat suppression images in RSD. There may be diffuse enhancement with gadolinium. These changes are said to allow differentiation from other bone lesions. 42.8.2.3. Laser doppler flowmetry Alterations in blood flow to the affected limb have been presumed to be related to autonomic dysregulation. Bej and Schwartzman (1991) studied 8 patients in dystrophic or atrophic stages of RSD, using laser Doppler flowmetry at rest as well as with provocative maneuvers, including Valsalva and the cold pressor test. They found significantly greater increased blood flow in the affected limb, compared to the unaffected limb, in the patients after these two maneuvers (but not with hyperventilation, static grip, or exercise). Flow decreased or remained stable in normal control limbs. Birklein et al. (1998) studied 20 affected limbs (19 arms, 1 leg) in early RSD, using laser Doppler flowmetry and a variety of provocative maneuvers, including mental arithmetic. They found impaired vasoconstriction in the symptomatic limb only with mental arithmetic and not with the peripheral stimuli, such as the cold pressor test and sudden deep breath or inspiratory gasp. Wasner et al. (1999) studied a 52-year-old woman within 2 weeks of onset of CRPS-I and reported complete functional loss of cutaneous sympathetic vasoconstrictor activity in the affected limb. Using forced breathing, they induced phasic changes in blood flow in the asymptomatic limb but virtually no changes in blood flow in the affected limb, as measured by laser Doppler flowmetry. This

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was interpreted as suggestive of inhibition of sympathetic neuronal activity. 42.8.2.4. Thermography Differences in skin temperature between the affected and asymptomatic limb are among the most common findings in patients with CRPS-I. Both increased and decreased temperature have been identified, depending on the duration of the disorder. Chelimsky et al. (1995) reviewed the records of 387 patients with chronic limb pain referred to the Mayo Clinic Autonomic Laboratory, assigning a probability score for the diagnosis of RSD. They measured resting skin temperature on multiple sites of the limbs bilaterally, using infrared thermography. Mild asymmetry was defined as a 0.5–1.0 ° C difference at 3–4 sites and moderate asymmetry by at least a 0.5 ° C difference in > 4 sites or a 1 °C difference at > 2 sites. An increase in resting skin temperature was seen in patients both with and without RSD, although only the minority in each group, generally in those with a shorter duration of symptoms. An increased limb temperature tended to predict a good response to sympathetic block. Bruehl et al. (1996) found resting skin temperature asymmetry to be helpful in discriminating RSD from non-RSD chronic limb pain, basing the diagnosis of RSD on clinical criteria and response to sympathetic block. They suggested using a difference of 0.6 ° C or more if specificity and sensitivity are equally important but a cutoff of 0.8 °C or even 1.0 ° C if specificity is more critical. Gulevich et al. (1997) studied 205 limb pairs in 185 patients, along with 24 controls, utilizing infrared telethermography to measure resting and stressed (cold water immersion of an asymptomatic limb) skin temperature differences. Of the 205 limb pairs, 73 were diagnosed clinically as CRPS-I, 70 as non-CRPS-I, and 62 as “possible” CRPS-I. Excluding the possible CRPS-I group, they found a sensitivity of 93% and specificity of 89%, using the criterion of abnormal warming of the symptomatic limb of at least 0.5 ° C after cold stress. Wasner et al. (2002) measured limb skin temperature thermographically in 25 patients with CRPS-I, 15 patients with other chronic limb pain syndromes, and 20 healthy controls under baseline conditions and after whole body cooling and warming using a thermal suit. Considering a resting side-to-side temperature difference of < 2.0 ° C normal, they determined a sensitivity of only 32% for diagnosing CRPS-I and a specificity of 100%. However, with a mean maximal temperature asymmetry during cooling and warming of 4.5 ± 0.6 ° C in the CRPS-I group compared to 1.0 ± 0.2 ° C

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in the patients with other chronic pain syndromes and 1.3 ± 0.1 ° C in healthy controls, the sensitivity rose to 76% and specificity fell to 93% for controlled thermoregulation.

abnormal vibration responses and H-reflex recovery curves, but could not be distinguished from those with other forms of dystonia or from those controls mimicking dystonia.

42.8.2.5. Sudomotor function testing Techniques for testing both resting sweat output (RSO) and provoked sweating (quantitative sudomotor axon reflex test, QSART) have been utilized to aid in the evaluation of patients with CRPS-I. Chelimsky et al. (1995) defined mild asymmetry of RSO as a side-to-side difference of >25% and moderate asymmetry as > 50%. Normal values for the QSART were given as 0.70 to 5.42 μL for males and 0.16 to 3.03 μL for females. They found an increased RSO on the affected side predictive of RSD with 94% specificity. A decreased QSART response on either or both sides was less specific, but the single best autonomic test correlate of the diagnosis of RSD. The combination of the two factors had a specificity of 98%. Birklein et al. (1997) studied 27 patients with RSD and found no significant differences in baseline sweating between affected and unaffected sides. There was, however, a significantly greater response to induced sweating by QSART (P < 0.004) on the affected side, but no correlation with skin temperature. Sandroni et al. (1998) studied 102 consecutive patients with posttraumatic chronic limb pain prospectively, combining clinical and autonomic test criteria. RSO was abnormal in only 29%, most often reduced; QSART was abnormal in 62%, 38% showing a reduced response and 24% an increase in response. They advocated a combined clinical and laboratory approach to the diagnosis of CRPS-I, focusing on QSART asymmetry (regardless of the direction) and RSO as well as the severity and distribution of pain and the presence of allodynia.

42.8.2.7. Systemic sympathetic blockade Local sympathetic blockade has been the traditional procedure on which the diagnosis of RSD/CRPS-I has rested for most of the twentieth century. An alternative, proposed because of technical as well as theoretical criticisms of this procedure, was suggested by Raja et al. (1991), the infusion of phentolamine, an α-adrenergic antagonist. However, sufficient concerns have been raised about the reliability of this test by Verdugo and Ochoa (1994), among others, that most now consider this to be of limited, if any, usefulness (Max and Gilron, 1999).

42.8.2.6. Electrodiagnostic testing There is little or no evidence that standard EDX testing is particularly useful in the evaluation of CRPS-I. Koelman et al. (1999) studied soleus H-reflex testing as a means of evaluating patients with dystonia associated with CRPS. They tested 5 patients with causalgia-dystonia and compared the results with 13 patients having dystonia from other causes and 48 healthy controls. They also studied the H-reflex in 5 controls who were asked to mimic dystonic foot posture. Parameters included the H/M ratio, the response to a vibratory stimulus, and recovery curves. The causalgia-dystonia patients had normal H/M ratios but

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Peripheral Nerve Diseases Handbook of Clinical Neurophysiology, Vol. 7 J. Kimura (Ed.) © 2006 Elsevier B.V. All rights reserved.

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CHAPTER 43

Developments in the assessment of peripheral nerve function David Burkea,* and Matthew C. Kiernanb a

Institute of Clinical Neurosciences, University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia b Prince of Wales Medical Research Institute, University of New South Wales and Department of Neurology, Prince of Wales Hospital, Australia

43.1. Introduction The term “electrodiagnostic testing” underestimates the value of clinical neurophysiological procedures, by focusing on only one of the roles of neurophysiology in clinical medicine. Indeed, an exclusive focus on diagnosis is not in the long-term best interests of clinical neurophysiology as a clinical specialty because ultimately anatomical visualization of lesions due to developments in imaging may render functional testing of little clinical value: precisely this has happened with visual-evoked potentials in multiple sclerosis. It is worth pointing out that the principles underlying routine nerve conduction studies have not changed in almost 50 years, an era that has seen dramatic changes in medicine. There have been advances in nerve conduction studies, particularly with the advent of averaging, but otherwise progress has come from using a different technique to stimulate at a different site and record potentials from hitherto untested regions. Our tests still rely on the ability to record an artificially synchronized volley set up by an unnatural stimulus. Continued reliance on an unchanged test principle virtually guarantees that this approach will soon outlive its usefulness. The procedures that are covered in this volume document function, and much of their diagnostic value rests on how accurately a test of function can localize a lesion and define its pathology. A functional test has the potential to provide unique data that differ from and complement tests that define the anatomical extent of a lesion or lesions. Accordingly, the future of clinical neurophysiology will involve: * Correspondence to: Professor David Burke, Office of Research and Development, Medical Foundation BuildingK25, University of Sydney, NSW 2006, Australia. E-mail address: [email protected] Tel.: +61-2-9036-3091; fax: +61-2-9036-3092.

(i) A continuing role in diagnosis. (ii) Measurements of function that allow neural status to be monitored in patients unable to cooperate because they are: (a) too young, (b) paralyzed in the Intensive Care Unit, (c) unconscious due to disease, or (d) unconscious during an operative procedure on or near nervous tissue. (iii) Development of tests that quantify deficits accurately so that cross-sectional and longitudinal studies can be undertaken to assess natural history and/or the response to treatment. While molecular advances may result in a new generation of effective therapies targeted to specific cellular processes, only tests of functional status will establish whether controlling the pathophysiological mechanisms targeted by these therapies results in a clinical benefit. Clinical testing is a relatively blunt and subjective method of quantifying function, but the test–retest variability of routine nerve conduction studies and EMG is such that they are little better than clinical examination in providing quantitative data suitable for detecting small changes in follow-up studies. In addition, some of the features documented in these tests (e.g., conduction slowing) are the consequence rather than the cause of the functional deficit and are not primarily responsible for symptoms. (iv) A unique role that neurophysiological procedures can play is the provision of insight into disease mechanisms and how a disorder produces the symptoms and signs that contribute to a patient’s disability. With these biases, we will focus on five areas, emphasizing techniques that are not in widespread usage, regardless of whether they are “new” or established. These areas are: (1) Microneurography; (2) The adequacy of current tests of conduction block; (3) Quantitative sensory

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testing; (4) Tests of muscle strength, the degree of effort and central fatigue; and (5) Tests of spinal reflex function during voluntary effort. Other important issues that could have been covered in this chapter are addressed elsewhere in this volume—measurements of axonal excitability in patients with diffuse disorders of peripheral nerve in Chapter 17 by Lin, Kiernan, Burke and Bostock, measurements of the number of motor units in a muscle group in Chapter 12 by Mark Bromberg, and tests of autonomic function in Chapter 22 by Francis O. Walker.

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depends on the recording of normal neural traffic in cooperative human subjects, and this has allowed, for example, correlation of cutaneous sensation with the discharge properties of different receptors and the stimuli applied to them. Microneurography is the only technique that provides insight into the neural correlates of natural behavior and, while it has little place in the diagnostic armamentarium (see later), it has provided unique data about normal function and its disturbances, and its value and limitations therefore warrant coverage in this chapter. Figure 43.1 is reproduced from volume 1 of this series (Burke et al., 2003).

43.2. Microneurography The technique of microneurography, introduced by Vallbo and Hagbarth (1968) and Hagbarth and Vallbo (1968), provides a unique method to investigate how peripheral nerve axons discharge under natural conditions. It has been used to shed light on cutaneous sensation, motor control mechanisms, pain and sympathetic function (Vallbo et al., 1979). Microneurography

43.2.1. Technique In microneurography, a sterilized microelectrode is inserted manually through the skin into an underlying nerve trunk, and the electrode tip then guided into the desired nerve fascicle. The electrodes are usually monopolar tungsten electrodes with a shaft diameter of ~200 μm, tapered to a tip of 1–5 μm and insulated to the

Fig. 43.1 Unitary recording from a human muscle spindle afferent. For the recording on the right, the tungsten microelectrode was inserted percutaneously into a motor fascicle of the ulnar nerve at the wrist. The target muscle was identified by the responses to intraneural electrical stimulation and the responses to passive and active movements of the digits. The recording was made from the afferent of a spontaneously active (presumed secondary) spindle ending in the fourth dorsal interosseous. The spindle ending increased its discharge during extension (right panel) and passive abduction (not shown) at the fourth metacarpophalangeal joint, the responses to stretch and shortening being essentially static. A sketch of the technique is on the left. The microelectrode was introduced manually. When in situ, it was supported without rigid fixation at one end by its connecting lead and at the other by the skin and subcutaneous tissue. Its position was adjusted within the nerve until the tip penetrated the desired nerve fascicle. Minor adjustments were then made to bring the desired neural activity into focus. Note that the microelectrode had a shaft diameter of ~200 μm and that the largest axons have a diameter of ~20 μm. From Burke et al. (2003), with permission from Elsevier.

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tip. To obtain good single unit recordings from large myelinated axons, the electrode impedance measured at 1 kHz is usually of the order of 100–300 kΩ. Most authorities use electrical stimulation through the microelectrode as a method to guide insertion; auditory feedback of the response to percussion of tendon or skin confirms when the needle tip is within a nerve fascicle. Manipulating the position of the recording tip within the fascicle is relatively easy for experienced experimenters, and it is possible to focus on different types of activity—multiunit activity, single-unit activity and the activity of unmyelinated axons, afferent or efferent. Axons with background activity are preferentially detected because their discharge can be heard, and the recording can then be focused on this activity. Singleunit recordings are those in which the activity of a single unit stands out from background activity and noise, with a sufficiently large spike that it can be heard and seen reliably, and are usually from the largest axons because the amplitude of the action potential is a function of the square of axon diameter. With all recordings, it is necessary to identify the axon(s) being studied. With afferent axons, this involves characterizing the properties of the receptor in skin or muscle from which the axon arises. However, muscle afferent recordings may be used to infer fusimotor function, and there are then specific issues that need to be considered. 43.2.2. Bias in microneurographic recordings For reasons given above, most studies are dominated by recordings from axons that are large and have a background discharge. There are few recordings from small myelinated axons. On the other hand, because a number of unmyelinated axons lie in the cytoplasm of a Schwann cell, it can be relatively easy to isolate afferent C-fibers and sympathetic efferents. Recording from the latter is helped by the characteristic spontaneous discharge of sympathetic efferents (Vallbo et al., 1979), a discharge that produces an audible guide when searching the fascicle. 43.2.3. Safety Microneurography is a traumatic procedure, involving skin puncture and nerve impalement, and these carry risks of infection, direct damage to axons and perineural or intraneural bleeding. In the 35 years that the technique has been used, strict attention to an aseptic technique, minimization of painful probing

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and restricting the frequency of and interval between experiments on the same nerve have resulted in only a few anecdotal reports of long-lasting deficits. It is likely that these deficits resulted from a small intraneural hematoma. On the other hand, the technique can cause discomfort or even pain, particularly when the needle tip is among nociceptive afferents or when inadvertently strong electrical stimuli are delivered. Some edema is inevitable, and a muscle ache or radiating paresthesias can often be triggered by stretching or percussing the experimental site. Such symptoms resolve spontaneously, usually over a few days. 43.2.4. Compound sensory action potentials The microelectrode only records the activity of some of the axons in a fascicle, and any one recording site may therefore not provide a representative sample of axons in the fascicle. This limits the diagnostic value of the technique. By averaging the multiunit response to an electrical stimulus, activity in small myelinated and unmyelinated axons can be demonstrated in the compound sensory action potential. Such recordings have been used to study cutaneous sensation or the development of nerve block (Torebjörk and Hallin, 1973; Mackenzie et al., 1975). 43.2.5. Specific issues when using muscle spindle afferent discharge to study fusimotor function In routine nerve conduction studies, it is possible to stimulate cutaneous afferents selectively but, with stimulation of mixed nerve trunks, the muscle afferent contribution is quantitatively small compared with that of cutaneous afferents. Given that the conduction velocities of the fastest muscle and cutaneous afferents are similar if not identical (Macefield et al., 1991), it is difficult to distinguish components that are solely due to muscle afferents. Of all available techniques, microneurography is the least indirect for studying fusimotor function in human subjects. However, it is rarely possible to control all disturbances to the spindle. In human subjects, spindle endings may respond to mechanical stimuli that are not immediately obvious, such as respiration and the arterial pulse (Hagbarth et al., 1975; McKeon and Burke, 1981) or the mechanical twitch produced by single motor units (McKeon and Burke, 1983). To make valid conclusions about fusimotor function from recordings from spindle afferents, perturbations to the

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highly sensitive spindle ending must be controlled. In addition, the classification of afferents must be beyond dispute: indeed, it has been suggested that some of the findings on α/γ coactivation from human studies can be attributed to incorrect identification of Ib afferents as Ia (Prochazka and Hulliger, 1983), though this provocative suggestion has not been accepted by most proponents of microneurography. As mentioned above, muscle spindle endings are extremely sensitive to minute perturbations, and small disturbance to the spindle’s environment within the muscle may not be apparent to inspection. EMG electrodes and force and length transducers must be used to provide reasonable certainty that the receptor-bearing muscle is truly relaxed. No single EMG setup can guarantee recording from every motor unit in a muscle, no length transducer can detect motor-unit activity that does not produce movement, and no force transducer will keep a limb absolutely isometric. Hence, it may be impossible to generate data with the same degree of precision as it is in animal experiments, but this disadvantage is offset by the ability to study volitional processes in cooperative human subjects, capable of generating or changing motor drives on request.

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current alters when there are changes in temperature. That these processes can be responsible for a change in a patient’s clinical state is well documented in multiple sclerosis. The change in clinical state is not due to a change in pathology: all that is required is that conduction at rest be sufficiently impaired that a significant number of axons generate an action current that may just or may just not reach threshold. Conduction block is easy to identify when it is complete, such that stimulation below the site of the lesion produces a clear compound muscle action potential (CMAP) but stimulation above it produces no discernible potential. Problems arise when the potential from the proximal site is present but smaller than expected, and the question that must then be answered is whether this represents partial conduction block. It is a thesis of this section that partial conduction block is common, particularly in demyelinating diseases, and that fluctuations in the ability of impaired axons to conduct impulses across the site of pathology may be responsible for some of the typical symptomatology in these diseases. The following focuses on maneuvers that can produce or accentuate partial conduction block. 43.3.1. Conduction of impulse trains

43.2.6. Place in electrodiagnosis While it might be interesting to document conduction in normal or pathologically slow axons, such data rarely affect the decision-making process. Microneurography, whether it involves recordings from cutaneous afferents, muscle afferents or sympathetic afferents, contributes little to diagnosis. The technique is, however, capable of providing information that cannot be obtained in any other way about peripheral nerve function. 43.3. Conduction block When assessed electrophysiologically in demyelinating diseases or at sites of compression, conduction block is often assumed to be an absolute phenomenon, with axons in two groups—normal or completely unable to conduct. However, if the safety margin for impulse conduction is impaired, normally innocuous fluctuations in membrane potential or in the amplitude or time course of the Na+ current at pathological nodes of Ranvier can make action potentials more difficult to generate. These changes can lead to conduction failure at those nodes. Membrane potential normally fluctuates due to physiological processes, such as activity and transient ischemia, and the time course of the Na+

Demyelinated axons may be able to conduct single impulses but be unable to conduct trains of impulses. This limitation can be measured as the “refractory period of transmission,” an index that is increased in demyelinated axons (McDonald and Sears, 1970; Smith, 1980; Felts et al., 1997) and in carpal tunnel syndrome (Gilliatt and Meer, 1990). In demyelinated rat axons, Bostock and Grafe (1985) established that the basis for “activity-dependent conduction block” is hyperpolarization at the blocking node. They induced conduction block in the impaired axons by stimulation at rates of 10–20 Hz (i.e., at rates that are within the physiological range). Secure conduction could be maintained by preventing the hyperpolarizing change in membrane potential that was produced by activity. In human subjects, a prolonged contraction involves a prolonged discharge of motor axons, Na+ ions accumulate inside the active axons, and the electrogenic Na+/K+ pump is stimulated to restore ionic balance across the membrane. The pump extrudes three Na+ ions and, in exchange, brings two K+ ions into the axon, and the resulting imbalance produces membrane hyperpolarization. The extent of hyperpolarization will be greater the stronger the effort and the longer the contraction, reflecting the greater impulse load placed on

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the axon. The current required to produce the same CMAP (i.e., the “threshold” for the CMAP), increases by ~40% following a maximal contraction lasting 1 min (Vagg et al., 1998; Kuwabara et al., 2002). This is likely to be physiologically important, even during submaximal contractions, dependent on their duration. Brief maximal contractions of 15-s duration will increase threshold by 10–15%, the important factor driving the hyperpolarization being the impulse load. The increase in threshold is accompanied by appropriate changes in supernormality and strength-duration properties: these indices are also measures of axonal excitability and are sensitive to changes in membrane potential. Together, the changes in threshold, supernormality and strengthduration properties indicate that the active axons have undergone hyperpolarization. In normal subjects, this degree of hyperpolarization will not jeopardize impulse conduction because, at each node of Ranvier, five times more current is generated than is required to produce an action potential (i.e., the safety margin is very high). When a disease process produces a variable lowering of the safety margin so that different axons span a range from those capable of secure conduction to those completely unable to conduct, there will be some axons able to conduct volleys at low rates (e.g., at 1 Hz), but unable to conduct if the axon is hyperpolarized by more physiological firing rates (10–20 Hz). In patients with multifocal motor neuropathy, an increase in “resting” conduction block can be precipitated by a maximal voluntary contraction (Kaji et al., 2000), though to demonstrate this, testing must occur proximal to the lesion site (Cappelen-Smith et al., 2000). Conduction block in motor axons also occurs in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) due to the voluntary contraction (Fig. 43.2; Cappelen-Smith et al., 2000). There is gradual recovery from conduction block as the activitydependent hyperpolarization lessens. If testing was performed before and after a maximal contraction of the test muscle it would detect not only “resting” conduction block (as in routine studies), but also its accentuation by axonal hyperpolarization. The necessary protocol is essentially the same as that when testing for neuromuscular transmission defects before and after a voluntary contraction, and the rationale is similar. 43.3.2. Release of ischemia Normal axons depolarize during ischemia, as the pump is paralyzed and K+ ions accumulate outside the

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axon. With release of ischemia, axons hyperpolarize as the pump is stimulated to restore ionic balance across the membrane and, following release of ischemia for 10 min, the increase in threshold is ~20%. This has proved sufficient to precipitate conduction block in patients with CIDP (Cappelen-Smith et al., 2002). Reassuringly, there was a similar relationship between the degree of conduction block in different subjects and the increase in threshold, whether the hyperpolarization was produced by activity or followed the release of ischemia. This finding is consistent with the view that the factor precipitating conduction block was axonal hyperpolarization in both cases.

43.3.3. Conduction block precipitated by changes in the Na+ current Conduction block is accentuated in some patients with CIDP during ischemia (Cappelen-Smith et al., 2002). Ischemia depolarizes axons and “depolarizing” conduction block is probably due to inactivation of Na+ channels. Inactivation is a normal process that has the effect of reducing the number of Na+ channels available for action potential generation. Presumably, the smaller action current would have then been insufficient to allow membrane potential to reach threshold (even though threshold is lower in depolarized axons). It is well known clinically that elevations in temperature can reveal or accentuate the deficits in patients with demyelinating diseases. The gating of ion channels is temperature-sensitive. When the duration of the action potential of single axons is prolonged by cooling, more current is passed at the node of Ranvier. Conversely, heating results in a briefer action potential, with a more rapid repolarization phase. The critical factor for action potential generation at the node of Ranvier is the time integral of the Na+ current, not just its amplitude, and this can be appreciated readily by considering axonal strength-duration properties. The threshold required to activate an axon is lower for stimuli of longer duration until rheobase is reached. Prolonging the action potential (e.g., by using scorpion venom) has been found to be capable of overcoming conduction block in demyelinated axons (Bostock et al., 1978), and this approach may have the potential for further pharmaceutical development. Conduction block can be

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Intensity (mA)

Stimulus 2

Stimulus 1

Amplitude (mV)

Fig. 43.2 Activity-dependent conduction block. Changes in the amplitude of the maximal compound muscle action potential (CMAP) in 2 symptomatic patients with chronic inflammatory demyelinating polyneuropathy (CIPD). Stimulus 2 was introduced immediately after the voluntary contraction and was 20% stronger than stimulus 1. The CMAPs were considered maximal because both stimuli produced CMAPs of the same amplitude. In A, the amplitude of the maximal CMAP was reduced to 55% of the pre-contraction level immediately after a maximal voluntary contraction for 1 min (open horizontal bar). In B, CMAP was decreased by 25%. From Cappelen-Smith et al. (2000), with permission from John Wiley & Sons, Inc.

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Stimulus 1

Amplitude (mV)

Intensity (mA)

Stimulus 2

precipitated in critically conducting demyelinated axons merely by elevating temperature (Rasminsky, 1973), thereby effectively reducing the current in the action potential. This does not occur in healthy nerves because, as mentioned earlier, the safety margin for impulse conduction at normal nodes is very high, ~5:1. 43.3.4. Testing for conduction block In testing for conduction block the intention is to demonstrate a pathological reduction in the amplitude and area of the CMAP when stimulating above and below the focus of pathology. The greater the distance between two stimulus sites the more dispersed the neu-

ral volley. Different degrees of conduction slowing can lead to phase cancellation between different motor unit action potentials (MUAPs) contributing to the CMAP and, thereby, a reduction in the size of the CMAP. Phase cancellation is less of a problem with CMAPs than with compound nerve potentials. This is because the duration of individual MUAPs is long (some 10–15 ms) while the action potentials of single axons are quite brief (1–2 ms). As a result, the dispersion of onset latencies over the tested nerve segment (only a few milliseconds) is small compared with MUAP duration but large compared with the axonal action potential. To avoid errors due to phase cancellation it is necessary to know the normal decrease in amplitude/area of the compound muscle or nerve potential for the length of the tested nerve segment. On

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the other hand, if the distance between stimulus sites is too small, there can also be problems, and these are relevant to the technique of “inching.” The threshold of axons at the pathological site is generally quite high, such that stimulation there commonly generates action potentials not at that site but from nearby normal segments of the nerve. It is difficult to avoid this problem because supramaximal stimuli must be used to ensure that all axons are activated. In critically demyelinated axons, the degree of conduction block can be influenced by minor fluctuations in membrane potential in either direction or in the properties of the Na+ current. As discussed above, a number of physiological factors, such as activity, ischemia and its release and temperature, can alter conduction in impaired axons. There will be a detectable change in a patient’s deficit only if a significant number of axons are susceptible to such changes. It is commonly reported that conventional tests for conduction block do not correlate well with the difficulties that the patient experiences, and such studies are, therefore, of limited value in quantifying a patient’s response to treatment or in longitudinal studies. The sensitivity of testing for conduction block in demyelinating diseases would be improved by: (i) ensuring that the tested limb is warm, perhaps repeating studies after increasing core temperature; (ii) testing before and after a maximal voluntary contraction of the test muscle for 1 min; and (iii) testing before, during, and after ischemia of the limb produced by inflation of a sphygmomanometer cuff to 200 mm Hg for 10 min. The changes in excitability produced by voluntary activity and ischemia are quite long-lasting, and it is therefore recommended that testing after a voluntary contraction or with ischemia be performed on different days and not in the same visit. In all studies of conduction block, it is critical that the tested CMAPs are truly maximal. When a conditioning maneuver can produce axonal hyperpolarization, this should be taken into account. Given that a voluntary contraction can increase threshold at the test site by ~40%, it can be useful to alternate two unequal stimuli to be certain that the stimulus remains supramaximal when axons hyperpolarize. The first stimulus should be supramaximal and the second 20% stronger (Fig. 43.2; Cappelen-Smith et al., 2000, 2002). If the CMAPs evoked by two unequal stimuli are identical, it is likely that both stimuli were supramaximal. Activity can produce changes in the EMG waveform, largely due to slowing of the propagation velocity

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of muscle. This will produce changes in amplitude of the CMAP, and any such changes do not necessarily indicate conduction block in motor axons. The testing procedures discussed above are based on experiments on the thenar muscles, in which such changes are minimal. However, for other muscles (e.g., tibialis anterior) this may not be the case (Kuwabara et al., 2002). 43.4. Quantitative sensory testing Over the past 25 years, techniques of quantitative sensory testing (QST) have been gradually introduced into clinical practice and continue to be refined for the evaluation of peripheral nerve disorders. These assessments developed initially from a perceived need to provide information on small sensory nerve fiber function, which is not adequately assessed by conventional nerve conduction techniques. When used in conjunction with conventional techniques, QST may enable a more complete picture of sensory nerve function to be obtained. While criticisms remain concerning methodology, particularly related to issues of specificity, the tests are generally easy to perform, do not require much technical training on the part of the operator and are well tolerated by patients. Quantitative sensory techniques are psychophysiological. Unlike conventional sensory nerve conduction studies or evoked responses, both of which are independent of perceptual factors, all techniques of QST are very patient-dependent. The ability of QST to detect abnormality requires a high degree of patient alertness, concentration and cooperation throughout the test. While the stimulus used is an objective event, the response is subjective. Consequently, an abnormality detected by such testing may suggest nerve dysfunction in sensory pathways, but this can be anywhere from the receptor to the cortex and, more significantly, it could also result from lack of understanding of the test procedure. Provided that patient cooperation is full, the techniques of QST have been demonstrated to be sensitive in detecting sensory nerve dysfunction. Collectively, quantitative sensory studies deliver sensory stimuli (e.g., vibratory, thermal or painful) to activate distinct fiber types and pathways (Zaslansky and Yarnitsky, 1998). The rationale employed is that vibratory stimuli should activate large myelinated (Aβ)-fibers peripherally and the dorsal columns more centrally. Cold stimuli activate smaller myelinated (Aδ)-fibers, warm stimuli unmyelinated warm-specific C-fibers, and painful stimuli small myelinated and

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unmyelinated fibers. Central transmission from these afferents involves spino-thalamic pathways. Whether such precise activation occurs is not clear. In practice it seems more likely that the different stimuli activate combinations rather than single types of receptors and fibers. 43.4.1. Methodology Algorithms for QST can be divided into two basic types: those based on “limits” and the alternative method of “levels” (Dyck et al., 1990, 1993; Yarnitsky and Sprecher, 1994; Yarnitsky, 1997). In the method of limits, stimuli of increasing intensity are delivered until the stimulus is perceived and indicated by a response from the patient. While this method is generally rapid, it incorporates a reaction time artefact. Using the alternative method of levels (“staircase” or “4–2–1”), stimuli of defined intensity are applied, with the patient indicating whether detection has occurred following each stimulus. This method is not adversely affected by the speed of the patient’s response, the corollary being that testing takes longer to complete and generally requires greater attention on the part of the patient. Due to the subjective nature of QST, normative data and test stability are critical. In particular, the environment in which the testing is undertaken and the instructions given to the patient must be strictly controlled, as must factors such as patient age, sex, ethnicity and patient motivation. The testing room must be quiet, instructions need to be standardized and the same examiner should undertake follow-up studies. A reproducible result is impossible without such a regimented approach to testing. There are little available data comparing the reproducibility of different testing systems and consequently normative values cannot be translated across the different testing systems. 43.4.2. Clinical utility QST has been used as a tool to investigate a number of peripheral nerve disorders, with the majority of studies concentrating on the endocrine and metabolic neuropathies. QST has been used in these disorders for the early diagnosis of neuropathy and as a tool for the assessment of therapeutic interventions in clinical trials. 43.4.2.1. Diabetes While QST abnormalities may be demonstrated for individual diabetic patients in the absence of clinically

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detectable neuropathy, prospective data demonstrating that such abnormalities will ultimately translate into the development of clinical neuropathy is lacking. Rather, the current consensus is that QST should not be used as the sole criterion for the diagnosis of diabetic neuropathy (Dyck et al., 1997; Shy et al., 2003). At the diagnostic level, QST is most useful when incorporated as part of a battery of investigations, including standard nerve conduction studies and heart rate variability testing in response to deep breathing, to support the findings of the clinical examination. QST has provided useful longitudinal data in studies documenting the natural history of diabetic neuropathy (Sosenko et al., 1993) and, in the clinical trial arena, thresholds have been measured and followed in patients, to compare the efficacy of different therapeutic interventions (Shy et al., 2003). Additionally, improvements in thermal and vibratory thresholds have both been demonstrated in diabetic patients adhering to strict blood sugar level control, further indicating the potential for QST as a patient monitoring technique (Service et al., 1983; Bertelsmann et al., 1987). 43.4.2.2. Uremic neuropathy Unlike diabetes that has the propensity to affect large and small fibers, uremia predominantly affects large myelinated fibers. Consequently, studies involving QST in uremic patients have concentrated primarily on vibratory perception. While a number of studies have demonstrated abnormalities in vibratory function in uremic patients (in some series estimated to be as high as 45% of patients studied), QST has not been shown to be more sensitive in detecting abnormality than standard nerve conduction studies (Nielsen, 1972; Tegner and Lindholm, 1985a, 1985b; Angus-Leppan and Burke, 1992). Nor have differences been shown in the natural history of sensory nerve function related to the different treatments for chronic renal failure (specifically peritoneal versus hemodialysis; Tegner and Lindholm, 1985b). 43.4.2.3. Small fiber neuropathy A difficult problem encountered by the clinical neurophysiologist is the assessment of patients with pain, in whom a small fiber neuropathy is suspected. QST studies using the thresholds for perception of thermal and vibratory stimuli have documented abnormalities in 82 and 60% of such patients respectively (Holland et al., 1997, 1998). However, such abnormalities were not correlated with measurements of mean

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intra-epidermal nerve fiber density obtained from skin biopsy or with the clinical evaluation of severity. Despite this, when subsequent studies involving multiple modalities were assessed retrospectively, the majority (93%) of patients diagnosed with small fiber neuropathy demonstrated abnormalities in at least one type of QST procedure undertaken. This suggests that, as in diabetic patients, QST is most effective when multiple QST testing modalities are combined with other methods of neuropathy assessment (Tobin et al., 1999). Other pain syndromes including post-herpetic neuralgia, reflex sympathetic dystrophy and carpal tunnel syndrome have been investigated using QST techniques with mixed findings (Price et al., 1992; Goadsby and Burke, 1994; Rowbotham and Fields, 1996; Petersen et al., 2000). A recent consensus statement concluded that pain syndromes should not be diagnosed solely using QST techniques, again related to the issues of test sensitivity and specificity, as discussed earlier (Shy et al., 2003). 43.4.2.4. Toxic neuropathies Vibratory and thermal testing has shown benefit in the detection of neuropathy in alcoholic patients (Sosenko et al., 1991) and for the quantitation of sensory nerve damage in cancer patients treated with vincristine, taxol and cisplatin (Hansen et al., 1989; Postma et al., 1993; Chaudhry et al., 1994). 43.4.3. Summary While abnormalities in nerve function have been demonstrated for a number of peripheral nerve disorders using QST techniques, the lack of specificity of such findings has detracted from the overall clinical utility of these techniques. In addition, few longitudinal studies have been undertaken using the different QST assessments. As a “stand alone” test, QST has yet to establish itself for the investigation of patients with peripheral nerve disorders. However, when combined with other testing modalities and methods of assessment, the utility of QST increases and so therefore does its potential to contribute meaningfully to clinical practice in the future. It is likely that in patients with established deficits, QST will have an important role in longitudinal studies as a technique for measuring a clinically relevant response to therapy. This is because QST measures the clinically relevant parameter, sensation, something that routine nerve conduction does not really address.

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43.5. Power, fatigue and voluntary effort Most healthy subjects are rarely required to exert maximal voluntary power, and the sedentary citizen may well have motor units that have never discharged at the rates necessary to generate a tetanic contraction. Nevertheless, clinical testing assesses the maximal force that subjects can exert, usually against resistance provided by the examiner. The clinical impression that a contraction involves maximal effort or that it fatigues abnormally is based on largely subjective criteria, often said to be part of the skill-base that accumulates with experience. Many factors affect the maximal force output from a voluntarily contracting muscle, even when it can be certain that motivation and effort are maximal, such as age, gender, handedness, intercurrent illness, pain associated with the contraction (Graven-Nielsen et al., 2002; Jakobi and Rice, 2002). As a result there is wide variability of measures of strength in normal subjects and even on different occasions in the same subject. On the other hand, in patients who are losing strength, accurate measures of strength and fatigue are critical to documenting the progress of the disease and the response to therapy. Muscle strength can be measured under quasiisometric circumstances for virtually any muscle, which can be connected to a force transducer, but more usually for the elbow and wrist flexors and extensors, the knee extensors and ankle dorsi- and plantar flexors. With maximal efforts, it is impossible to restrict the contraction to only the test muscle group, and it is necessary to brace the limb and to fix the joint so that movement is minimal. It may also be necessary to stabilize the trunk. Healthy subjects usually generate similar forces in a sequence of three maximal efforts lasting 10–20 seconds, even though they often report greater effort in the later contractions. The greater effort is, however, not directed to the maximally contracting target muscle but to the activation of other muscles in the limb and throughout the body. Accordingly, measures of effort do not necessarily quantify the component of the supraspinal drive directed to the target muscle. The reproducibility of the measured maximal force is dependent on the reproducibility of measurement conditions: Is the joint angle such that the test muscle is at the optimal position on its length-tension curve? Is the fixation of the joint and limb standardized? Are the limb (and the trunk) braced so that only the force produced by the target muscle is detected by the force transducer?

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43.5.1. Central versus peripheral fatigue and estimations of voluntary effort In the literature, “peripheral” fatigue refers to processes occurring within the muscle, and “central” fatigue refers to a loss of power due to a loss of neural drive to the muscle. As a result, central fatigue does not necessarily imply a disorder within the central nervous system; it can occur with peripheral nerve disorders producing conduction block in motor axons, e.g., multifocal motor neuropathy (Kaji et al., 2000) and chronic inflammatory demyelinating polyneuropathy (Cappelen-Smith et al., 2000), as discussed earlier under Section 43.2. Merton (1954) introduced the technique of twitch interpolation to distinguish central fatigue (neural) from peripheral fatigue (muscle). A maximal stimulus delivered to the nerve innervating a contracting muscle will generate an increment in force only if some motor units in the contracting muscle are not discharging sufficiently to produce a fused tetanus. The activation of the motor axons will result in a maximal compound EMG potential, but this will not produce a significant force increment if all motor units are firing at rates sufficient to produce fusion of their twitch contractions. Recently there has been renewed interest in this technique and some refinements have been introduced (Hales and Gandevia, 1988; Allen et al., 1995, 1998; Taylor et al., 1996), but the underling principle remains essentially the same. In healthy subjects, the size of the interpolated twitch decreases as the strength of the background voluntary contraction increases (Merton, 1954), the relationship being approximately linear (Fig. 43.3). Healthy subjects can contract the biceps brachii such that an interpolated stimulus produces no additional twitch force (or only 2–5% of the control twitch force). As a result, the effort put into the contraction can be estimated as: (100 − [interpolated twitch force*100/control twitch force] as a %). In this calculation, the resting twitch contraction force is an inadequate control because the contraction potentiates the resting twitch, producing an increase in area of the CMAP of >20% (for intrinsic muscles of the hand). The potentiation persists for some time after the contraction, so that a supramaximal stimulus delivered 5 seconds after relaxation may provide an adequate control for twitches evoked during the contraction (Allen et al., 1995).

Fig. 43.3 Twitch interpolation and effort. In the upper panel, the responses evoked by supramaximal stimuli (at arrow) over biceps brachii at different levels of voluntary torque (prestimulus contraction level set to zero). As voluntary torque increases, the response evoked by the stimulus decreases, and the time to peak of the evoked response shortens. The largest response (control twitch) was evoked from the completely relaxed muscle when there was zero voluntary torque. In this example, no response is evoked by the stimulus at maximal voluntary torque. The lower panel plots voluntary torque versus torque evoked by single and paired stimuli for a single subject. At high voluntary torques, there is a region where voluntary torque increases but little torque is evoked from the biceps brachii (i.e., >60 Nm or >75% MVC). This suggests that biceps brachii is near-maximally activated during voluntary maximal elbow flexion at approximately 85% MVC. From Allen et al. (1998), with permission from John Wiley & Sons, Inc.

More recently, some groups have delivered strong interpolated stimuli to the motor cortex during and after fatiguing contractions to define the mechanisms of central fatigue and any possible failure of cortical drive (Brasil-Neto et al., 1993; McKay et al., 1995, 1996; Gandevia et al., 1996; Taylor et al., 1996; Sacco et al., 1997, 2000; Taylor and Gandevia, 2001). In addition, strong electrical stimuli have been delivered across the mastoids to activate corticospinal axons directly at the decussation of the pyramids (Gandevia

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et al., 1999), producing an interpolated twitch of central origin but one which bypasses cortical processing. In a refinement designed to address problems associated with transcranial magnetic stimulation, Magistris et al. (1998) introduced a triple stimulation technique, in which CMAPs of abductor digiti minimi were recorded to a transcranial stimulus followed by supramaximal stimuli delivered to the wrist and at Erb’s point. The collision created by appropriately timed stimuli effectively eliminated the influences of desynchronization of motor unit activity and repetitive firing of motor units. Magistris et al. (1998) have shown that transcranial stimuli can excite virtually all motoneurons in the hypothenar pool, and their technique has since been used to study the motor cortical contributions to fatigue (Andersen et al., 2003). 43.5.2. Twitch interpolation in neurological disorders If weakness results from loss of peripheral nerve axons, the strength of a maximal voluntary contraction will be reduced, but an interpolated stimulus to the motor nerve will not generate an abnormal increment in force. If there is conduction block, delivering the interpolated twitch below the site of the lesion will produce an abnormal force increment. With weakness due to a central nervous system disorder, stimulation to the peripheral nerve will generate an interpolated twitch even when effort is maximal, much as occurs with a healthy subject who is not exerting maximal effort. In other words, interpolated peripheral nerve stimuli cannot distinguish between a deliberate (or psychogenic) failure of central drive and a cortical, subcortical or spinal lesion preventing the translation of maximal effort into maximal drive onto the motoneurone pool. 43.5.3. Problems with twitch interpolation Apart from the issues raised above, there are two important issues that must be considered when using twitch interpolation. (1) The stimulus to motor axons innervating the contracting muscle must be supramaximal. This is because active axons hyperpolarize significantly, even after contractions as brief as 15 sec (Vagg et al., 1998). The extent of hyperpolarization depends on the impulse load and, for the thenar muscles, reaches 40% with maximal efforts lasting 1 min. Failure to exceed the threshold for all

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axons innervating the contracting muscle will reduce the size of the interpolated twitch and may create the erroneous impression that greater effort was used. (2) Strong stimuli may encroach on the innervation of other muscles that could influence the measured force. For example, intense stimuli over the motor point of biceps brachii are used to generate a maximal contraction of elbow flexors (Allen et al., 1995, 1998), but such stimuli may also activate the radial innervation of triceps brachii, such that the recorded force will be the resultant of two opposing contractions (Awiszus, 1998; Burke and Gandevia, 1998). 43.6. Tests of spinal reflex function during voluntary effort The motoneuron pool can be caused to discharge reflexly by muscle afferent volleys (see Chapter 10 by Valls-Solé and Deuschl) or by cutaneous afferent volleys (e.g., the RA II and RA III responses of Hugon, 1973). More complex patterns of reflex action can be revealed if the stimuli are delivered during a background contraction of the test muscle because, if the on-going EMG is full-wave rectified before averaging, inhibitory influences can be demonstrated. The advantages of using reflexes in the assessment of peripheral nerve or segmental pathology are: (1) The full-reflex arc can be explored, including the most proximal segments of afferent and efferent axons. Proximal segments are notoriously difficult to assess adequately, whether by SEPs (see below) or MEPs. (2) The same motoneuron pool can be accessed by inputs that traverse different peripheral nerves or different posterior roots. For example, the thenar muscles (C8/T1) can be accessed by volleys in muscle afferents (C8/T1) or by cutaneous afferent volleys from the thumb and index finger (C6/C7). (3) The input–output relationship for spinal reflexes differs from that for cerebral SEPs, such that tests of reflex function have greater sensitivity in peripheral nerve disorders. For the SEP, weak afferent inputs can produce SEPs of normal size: if the afferent volley is ~50% of maximum, the SEP will be >90% of maximum; the SEP is less < 50% of maximum only when the afferent volley is 10–20% of maximum (Gandevia and Burke, 1984). On the other hand, a

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reflex response has a threshold, and once that threshold has been exceeded, the reflex discharge grows in proportion to the afferent volley. 43.6.1. Testing reflex function This discussion will focus on the H-reflex, and the methods that can be used to extend testing to multiple muscles in the upper and lower limbs. However, similar principles can be adopted for testing cutaneo-muscular reflexes and for testing the reflex effects of Ia afferents on heteronymous motoneuron pools (Miller et al., 1995a, 1995b; Meunier et al., 1996). The H-reflex depends on a spinal monosynaptic pathway, but its mechanisms are not as simple as may at first seem. While the excitatory input responsible for the H-reflex is from homonymous group Ia afferents, the afferent volley contains group Ib afferents, and it is impossible to restrict the stimulus to only afferents from the muscle being tested (e.g., only to muscle afferents from soleus when testing the soleus H-reflex) (Burke et al., 1983). The size of the H-reflex is limited by postsynaptic inhibition from the Ib component of the volley and possibly by recurrent inhibition from low-threshold motoneurons (see Pierrot-Deseilligny et al., 1981; Burke et al., 1984; Marchand-Pauvert et al., 2002), both of which can curtail and attenuate the Ia EPSP. Indeed, the group I EPSP is quite short (~1–2 ms in soleus of human

subjects; Burke et al., 1984), and the reflex discharge commonly involves only a small percentage of the motoneuron pool. H-reflexes can be recorded from most limb muscles, though special techniques, such as post-stimulus time histograms of the discharge of single motor units, may be required to demonstrate that the discharge is of reflex origin when the reflex arc is very short. The reflexes tested routinely in our laboratories are listed in Table 43.1. 43.6.2. Rest and voluntary contraction Conduction through spinal reflex pathways is commonly tested using the H-reflex in subjects who are at rest. Arguably, it would be more revealing to perform such studies during a voluntary contraction because the reflex circuitry was presumably designed to assist movement not relaxation.The effects of a voluntary contraction on reflex function are summarized in Table 43.2. Performance of a weak voluntary contraction potentiates the H-reflex by raising the motoneuron pool to firing threshold. This lowers the threshold for a reflex response but produces little change, if any, in reflex latency. In addition, the descending drives reduce the inhibitory effects of Ib afferents in the test volley and this enhances the reflex response for any given afferent input (Burke et al., 1984; MarchandPauvert et al., 2002). H-reflexes may then be recorded reliably for some muscles from which they cannot be

Table 43.1 H-reflexes in routine diagnostic practice Present at rest Soleus, Vastus Lateralis and Flexor Carpi Radialis (when stimulus rate is 0.3 Hz) For these muscles, absence at rest but presence during a contraction usually means reduced afferent input or low central excitability Reflexes tested in routine diagnostic studies C5/6 Biceps Brachii C6 Extensor Digitorum Communis C6/7 Flexor Digitorum Communis C8/T1 Abductor Pollicis Brevis L(2)3/4 Vastus Lateralis L4/5 Tibialis Anterior S1 Soleus NB: good reflex in peroneus longus (care with TA) Capricious reflexes Abductor Digiti Minimi Brachioradialis Triceps Brachii

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Table 43.2 Effects of voluntary contraction Raises motoneurone excitability ● reflexes are obtainable when motoneurone excitability to Ia inputs is low at rest (e.g., tibialis anterior, abductor pollicis brevis) ● reflexes are obtainable when the afferent input is weak * deliberately, so that there is a small M-wave (e.g., biceps brachii) * in pathology ● it focuses the reflex on the contracting muscle ● it allows heteronymous reflexes to become demonstrable (e.g., median-to-biceps; femoral-to-soleus and TA) ● reflex responses need to be averaged to define latency accurately ● allows stimulus rates of 2 or 3 Hz without discomfort ● does not alter latency significantly

recorded at rest (e.g., tibialis anterior, extensor carpi radialis and abductor pollicis brevis), and the lower threshold for the reflex may allow reflex onset to be clearly delineated from the M-wave, because the lower stimulus intensity produces a smaller M-wave (Burke et al., 1989). This may be useful with more proximal muscles, such as the quadriceps femoris muscles, flexor and extensor carpi radialis and biceps brachii (Fig. 43.4). In healthy subjects at rest, the H-reflex can be recorded from soleus on stimulation of the tibial nerve, from quadriceps femoris on stimulation of the femoral nerve and from flexor carpi radialis (FCR) on stimulation of the median nerve, provided that a low stimulus repetition rate (