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 Neurobehavioral Toxicology Neurobehavioral And
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Studies on Neuropsychology Development and Cognition 1st
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Neurobehavioral Toxicology
STUDIES ON NEUROPSYCHOLOGY, NEUROLOGY,
AND COGNITION

Series Editor:
Linas Bieliauskas, Ph.D.
University of Michigan, Ann Arbor, MI, USA

Other titles in this series:

Fundamentals of Functional Brain Imaging: A Guide to the Methods and their
Applications to Psychology and Behavioral Neuroscience. Andrew C. Papanicolaou

Forensic Neuropsychology: Fundamentals and Practice. Edited by Jerry J. Sweet

Neuropsychological Differential Diagnosis. Konstantine K. Zakzanis, Larry Leach

and Edith Kaplan

Minority and Cross-Cultural Aspects of Neuropsychological Assessment. Edited by

F. Richard Ferraro

Ethical Issues in Clinical Neuropsychology. Edited by Shane S. Bush and

Michael L. Drexler

Practice of Child-Clinical Neuropsychology: An Introduction. Byron P. Rourke, Harry

van der Vlugt, and Sean B. Rourke

The Practice of Clinical Neuropsychology. A Survey of Practice and Settings. Edited by

Greg J. Lamberty, John C. Courtney, and Robert L. Heilbronner

Neuropsychological Rehabilitation: Theory and Practice. Edited by Barbara E. Wilson

Traumatic Brain Injury in Sports. An International Neuropsychological Perspective.

Edited by Mark R. Lovell, Ruben J. Echemendia, Jeffrey T. Barth, and
Michael W. Collins

Methodological and Biostatistical Foundations of Clinical Neuropsychology and

Medical and Health Disciplines. Edited by Domenic V. Cicchetti and Byron P. Rourke

A Casebook of Ethical Challenges in Neuropsychology. Edited by Shane S. Bush

Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives.

Volume I Foundations and Methods. Stanley Berent and James W. Albers

Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives.

Volume II Peripheral Nervous System. James W. Albers and Stanley Berent

Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives.

Volume III Central Nervous System. Stanley Berent and James W. Albers (2006)
Neurobehavioral Toxicology
Neurological and neuropsychological
perspectives
Volume I
Foundations and methods

Stanley Berent and James W. Albers

Neurobehavioral Toxicology Program,

Division of Neuropsychology,
Departments of Psychiatry and Neurology,
University of Michigan Medical School,
Ann Arbor, Michigan
First published 2005 by Taylor & Francis,
27 Church Road, Hove, East Sussex BN3 2FA
Simultaneously published in the USA and Canada
by Taylor & Francis
270 Madison Avenue, New York, NY 10016
Taylor & Francis is an imprint of the Taylor & Francis Group

This edition published in the Taylor & Francis e-Library, 2005.

“To purchase your own copy of this or any of Taylor & Francis or Routledge’s
collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.”

Copyright © 2005 Taylor & Francis

All rights reserved. No part of this book may be reprinted or
reproduced or utilised in any form or by any electronic, mechanical, or
other means, now known or hereafter invented, including photocopying
and recording, or in any information storage or retrieval system,
without permission in writing from the publishers.
The publisher makes no representation, express or implied, with regard
to the accuracy of the information contained in this book and cannot
accept any legal responsibility or liability for any errors or omissions
that may be made.
This publication has been produced with paper manufactured to strict
environmental standards and with pulp derived from sustainable
forests.
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
Berent, Stanley.
Neurobehavioral toxicology : neuropsychological and neurological
perspectives / Stanley Berent and James W. Albers.
p. cm.
Includes bibliographical references and index.
ISBN 1–84169–564–5 (hard cover)
1. Behavioral toxicology. 2. Neurotoxicology. I. Albers, James W.
(James Wilson) II. Title.
RA1224.B47 2005
616.8′0471–dc22
2004025284
ISBN 0-203-01469-3 Master e-book ISBN

ISBN 1-84169-564-5
Contents

Contents of Volumes II and III ix

From the Series Editor xvii
Acknowledgments xix
Disclosures xx

1 INTRODUCTION TO NEUROBEHAVIORAL TOXICOLOGY 1

Introduction 1
Some conceptual considerations 3
Neurotransmission 5
Neurotransmission and disease 7
Neurotoxicity 10
Common clinical neurobehavioral toxicology issues 11
Case presentations 12
Patient with progressive dementia 12
Patient with depression and suspected dementia 16
Importance of context with regard to toxic exposure 20
Exposure to a neurotoxicant in the context of a terrorist act
Comments 24

2 CLASSIFICATION AND MANAGEMENT OF

TOXICANT-RELATED INFORMATION 29
Introduction 29
Assessment and management of risk 30
Classification 32
Conclusion 47

3 CLINICAL AND CLINICAL RESEARCH CONSIDERATIONS 51

Introduction 51
Scientific method 52
Definition of the problem to be addressed 53
vi Contents
Hypothesis 53
Experiment 54
Analysis 59
Conclusions based on the scientific method 60
Special research considerations 61
Animal models 61
Additional issues related to sample selection 62
Protection of subjects in research 63
Bias 67
Masking and placebo controls 68
Evaluation of research claims regarding causality 69
Conclusion 73

4 CLINICAL APPROACHES 77
Introduction 77
Clinical neurology and clinical neuropsychology 78
The referral model 79
Managing the professional interaction 80
The clinical process 82
Some commonalities across fields 82
The need for objectivity 83
The need for an evidence-based approach to the clinical
process 85
Some general clinical attributes of neurotoxic disease 86
Other considerations 88
Determining abnormality 88
Patient motivation and attention 91
Psychopathology 92
Presence of third parties during a clinical evaluation 94
Effects of litigation 95
Summary 97

5 THE NEUROPSYCHOLOGICAL APPROACH 101

Introduction 101
Psychology and the specialty of clinical
neuropsychology 102
Brain and behavior 102
Clinical neuropsychology and its relationship to
neurobehavioral toxicology 105
Neuropsychological evaluation 106
The history 107
 Contents vii
The clinical interview 110
The psychometric examination 113
The neuropsychological method 116
Nature of neuropsychological data 116
Clinical evaluation of neuropsychological data 116
Psychometrics: basic technical considerations 120
Reliability 121
Validity 122
Other issues in test construction, selection, and
administration 126
Standardization 126
Normative data 127
Some additional comments on the neuropsychological
clinical approach 127
Developing the neuropsychological impression 127
Localizing the abnormality 129
Identifying general diagnostic categories 130
Use of additional neurodiagnostic testing to arrive at a final
neuropsychological diagnosis 130
Summary and conclusion 131

6 THE NEUROLOGICAL APPROACH 135

Introduction 135
The neurological approach 135
Foundations of clinical neurology as they relate to
neurobehavioral toxicology 136
Clinical neurology 138
Normal or abnormal 138
Clinical neurological evaluation 139
Clinical history 140
Clinical examination 142
Developing the neurological impression 156
Localizing the lesion 157
Establishing a differential diagnosis 163
Use of neurological symptoms 164
Use of neurological signs 165
Preliminary differential diagnosis 168
Neurodiagnostic testing 169
Psychometric tests as viewed by the neurologist 170
Electrodiagnostic evaluations 170
Conclusion 182
viii Contents
7 CRITIQUE OF RELEVANT CLINICAL TESTS 189
Introduction 189
Psychometric examination (neuropsychological testing) 191
Neuroimaging 193
Neurophysiological tests 199
Electroencephalogram (EEG) 200
Electromyography (EMG) 205
Other tests of neurological function 212
Summary 217

8 CAUSALITY 225
Introduction 225
Causality as invention 229
Science as a belief system 231
On the nature of scientific knowledge 233
Science and the legal system 233
The logical (rational) and the empirical 235
In Science 235
In clinical practice 240
Evidence-based medicine (EBM) 241
Conclusions 242

POSTSCRIPT 247

Subject index 249

Contents of Volume II

9 CLINICAL AND ELECTRODIAGNOSTIC

EVALUATIONS OF THE PERIPHERAL NERVOUS SYSTEM
Examination of the peripheral nervous system
Clinical examination in selected conditions
Electromyography (EMG) examination
Developing the differential diagnosis using clinical and EMG
results
Sources of error
Summary

10 INDUSTRIAL AND ENVIRONMENTAL AGENTS

Selected presentations
Acrylamide
Arsenic
Botulinum Toxin
Carbon Disulfide
Elemental mercury
Lead
Organophosphorus compounds
Thallium
Trichloroethylene
Summary

11 MEDICATIONS AND SUBSTANCES OF ABUSE

Selected presentations
Cisplatin
Colchicine
Dapsone
Disulfiram
x Contents
Ethyl alcohol
n-Hexane
Lipid-lowering medications (HMG-CoA reductase
inhibitors)
nondepolarizing neuromuscular blockade and
corticosteroids
Nitrofurantoin
Penicillamine
l-Tryptophan
Vaccination – A/New Jersey (swine flu) vaccine
Summary

12 CONDITIONS WHICH SOMETIMES MIMIC

PERIPHERAL NERVOUS SYSTEM DISEASE
The influence of aging on clinical and electrodiagnostic
examinations
Neurologic examination
Electrodiagnostic examination
The influence of anthropometric factors on the clinical and
electrodiagnostic examinations
Neurologic examination
Electrodiagnostic examination
Nerve biopsy results
Physiologic or emotional conditions producing symptoms
suggestive of neuromuscular disease
The influence of normal physiology on the nervous
system
Functional or psychological factors
Non-neurologic conditions suggestive of peripheral
neuropathy or myopathy
Symptoms due to connective tissue or skin
Vascular disorders
Metabolic/endocrine disorders mimicking neuropathy
Disorders of the spinal cord and nerve roots mimicking
peripheral neuropathy
Conditions suggesting myopathy or defective neuromuscular
transmission
Case presentation
Summary
 Contents xi
13 CONSEQUENCES OF AN INCOMPLETE
DIFFERENTIAL DIAGNOSIS
Case presentations
Lead-exposed painter with arm weakness
Patient with acute sensory loss and ethylene oxide
exposure
Patient with an acute reaction to an organophosphorus
pesticide
A woman with silicone breast implants and diffuse
neuromuscular symptoms
Husband and wife with mushroom poisoning
Patient with acute abdominal pain and neuropathy
Chemist with myelopathy and neuropathy
Machinist with suspected solvent-induced toxic
neuropathy
Summary

14 ISSUES AND CONTROVERSIES INVOLVING THE

PERIPHERAL NERVOUS SYSTEM EVALUATION
Neurotoxic peripheral neuropathies: Typical and atypical
distributions
Symmetry versus multifocal presentations
Proximal versus distal presentations
Upper extremity more than lower extremity
distributions
Possible explanations for atypical neurotoxic
distributions
Subclinical toxic neuropathy
Subclinical neuropathy identified on electrodiagnostic
testing
Delayed effect neurotoxicity
Identifying a normal study: Adequacy of the clinical and
electrodiagnostic results
What is normal?
Issues involving interpretation of the EMG evaluation
What if the electrophysiology results are normal?
Patients with small fiber polyneuropathy
Establishing causation in clinical neurotoxicological
investigations
Inadvertent or unrecognized confounding due to selection
bias
xii Contents
Potential misinterpretation of results due to
pseudocausation
Adverse effects inferred by correlational analyses
Controversial neurotoxic disorders involving the peripheral
nervous system
Summary

POSTSCRIPT VOLUME II

APPENDIX TO VOLUME II

Subject index
Contents of Volume III

15 INDUSTRIAL AND ENVIRONMENTAL AGENTS

Selected presentations
Carbon monoxide
Lead in adults
Lead in children
Organic mercury
Pesticides
Solvents
Summary

16 MEDICATIONS AND SUBSTANCES OF ABUSE

Selected presentations
Anti-convulsants
Amphetamines
Corticosteroids
Cyclosporine
Ethyl alcohol
Hypnotics and sedatives
Lithium
Pain medications (opioids)
Psychotropic medications
Toluene
Summary

17 CONDITIONS ASSOCIATED WITH OR WHICH

SOMETIMES MIMIC TOXIC-INDUCED CENTRAL
NERVOUS SYSTEM DISEASE
The influence of aging on the clinical and psychometric
examinations
xiv Contents of Volume III
Psychological or emotional conditions producing symptoms
suggestive of central nervous system disease
Anxiety disorders
Mood disorders
Somatoform disorders
Other psychological/psychiatric considerations
Neurological or medical conditions associated with or
mimicking toxic-induced central nervous system disease
Dementia
Headache
Hepatic encephalopathy
Hypothyroidism
Hypoxic encephalopathy
Parkinson’s disease and Parkinsonism
Summary

18 CONSEQUENCES OF AN INCOMPLETE
DIFFERENTIAL DIAGNOSIS

Selected presentations
Child with behavioral and learning problems attributed to
lead
Depression in a chronic medical condition
Neurobehavioral complaints attributed to “black mold”
Patient with cognitive symptoms attributed to dental
amalgams
Patient with history of head injury
Patient with neurobehavioral complaints attributed to diet
drugs
Patient with presumed arsenic-induced neurotoxicity
Solvent exposed mechanic with dementia
Solvent exposed machinist with behavioral and neurological
complaints
Summary

19 ISSUES AND CONTROVERSIES INVOLVING THE

CENTRAL NERVOUS SYSTEM EVALUATION

The complexity of the neurobehavioral evaluation

Patient with toxic exposure but multiple explanations for his
complaints
Illustrative case
 Contents of Volume III xv
Factors influencing the evaluation
Individual differences
Other considerations that influence or even explain the
patient’s complaints and examination findings
Approaching a differential diagnosis from a neurobehavioral
perspective
The role of neuropsychological testing in the examination
The importance of ancillary test results
The importance of the patient history and interview
Establishing causation in clinical neurotoxicological
investigations
Controversial neurotoxic disorders involving the central
nervous system
Summary

POSTSCRIPT VOLUME III

APPENDIX TO VOLUME III

Subject index
From the Series Editor

I am particularly proud to introduce the first of our three volume series

Neurobehavioral Toxicology, Neurological and Neuropsychological Perspec-
tives. Previous texts regarding the behavioral effects of exposure to neuro-
toxins have generally been written from somewhat narrowed perspectives,
either purely from a medical and neurological standpoint or from a psycho-
logical and neuropsychological focus. In either case, either the importance of
psychological measurement has been de-emphasized or the accurate identifi-
cation of underlying neurophysiological mechanisms has been neglected. It
was the purpose of this series to produce a collaborative, state-of-the-art
product addressing the impact of neurotoxic exposure on behavior.
Both Dr. Berent and Dr. Albers are professors at the University of
Michigan and are board certified respectively in Clinical Neuropsychology
and in Neurology. Both have published extensively in the area of
neurotoxicology, among others, and they approach their subject with a
refined expertise based on extensive clinical and research experience. They
have collaborated extensively over the years and the fruits of their labors are
evident in this series.
Volume I, Foundations and Methods, serves as an introduction to the
field. Quite often clinicians may approach the subject of neurobehavioral
toxicology in a manner which does not do justice to the methods of classi-
fication and appreciation of toxin-related information, appropriate inter-
pretation and integration of clinical and research findings, and a genuine
appreciation for the contributions of neuropsychology and neurology to the
formulation of case impressions. This volume approaches each of these areas
in detail, ending with an extensive treatment of how to establish whether
causality exists between neurotoxic exposure and apparent behavioral
consequences. Too often, both clinicians and researchers have fallen prey to
making causal inferences from toxic exposure to behavior without appreciat-
ing neurological underpinnings of their subject, the power and limitations of
behavioral measures, or even the logic of the process of inference. Volume I
serves to provide the background from which the clinical and thought process
regarding neurobehavioral toxicology can be rationally engendered, either
in appreciating research reports or appraising and interpreting individual
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