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 HANDBOOK OF CLINICAL
NEUROLOGY

Series Editors

MICHAEL J. AMINOFF, FRANÇOIS BOLLER, AND DICK F. SWAAB

VOLUME 133

AMSTERDAM BOSTON HEIDELBERG LONDON NEW YORK OXFORD

PARIS SAN DIEGO SAN FRANCISCO SINGAPORE SYDNEY TOKYO
ELSEVIER
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Handbook of Clinical Neurology 3rd Series

Available titles
Vol. 79, The human hypothalamus: basic and clinical aspects, Part I, D.F. Swaab ISBN 9780444513571
Vol. 80, The human hypothalamus: basic and clinical aspects, Part II, D.F. Swaab ISBN 9780444514905
Vol. 81, Pain, F. Cervero and T.S. Jensen, eds. ISBN 9780444519016
Vol. 82, Motor neurone disorders and related diseases, A.A. Eisen and P.J. Shaw, eds. ISBN 9780444518941
Vol. 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed, eds. ISBN 9780444519009
Vol. 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed, eds. ISBN 9780444528933
Vol. 85, HIV/AIDS and the nervous system, P. Portegies and J. Berger, eds. ISBN 9780444520104
Vol. 86, Myopathies, F.L. Mastaglia and D. Hilton Jones, eds. ISBN 9780444518996
Vol. 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo, eds. ISBN 9780444518965
Vol. 88, Neuropsychology and behavioural neurology, G. Goldenberg and B.C. Miller, eds. ISBN 9780444518972
Vol. 89, Dementias, C. Duyckaerts and I. Litvan, eds. ISBN 9780444518989
Vol. 90, Disorders of consciousness, G.B. Young and E.F.M. Wijdicks, eds. ISBN 9780444518958
Vol. 91, Neuromuscular junction disorders, A.G. Engel, ed. ISBN 9780444520081
Vol. 92, Stroke – Part I: Basic and epidemiological aspects, M. Fisher, ed. ISBN 9780444520036
Vol. 93, Stroke – Part II: Clinical manifestations and pathogenesis, M. Fisher, ed. ISBN 9780444520043
Vol. 94, Stroke – Part III: Investigations and management, M. Fisher, ed. ISBN 9780444520050
Vol. 95, History of neurology, S. Finger, F. Boller and K.L. Tyler, eds. ISBN 9780444520081
Vol. 96, Bacterial infections of the central nervous system, K.L. Roos and A.R. Tunkel, eds. ISBN 9780444520159
Vol. 97, Headache, G. Nappi and M.A. Moskowitz, eds. ISBN 9780444521392
Vol. 98, Sleep disorders, Part I, P. Montagna and S. Chokroverty, eds. ISBN 9780444520067
Vol. 99, Sleep disorders, Part II, P. Montagna and S. Chokroverty, eds. ISBN 9780444520074
Vol. 100, Hyperkinetic movement disorders, W.J. Weiner and E. Tolosa, eds. ISBN 9780444520142
Vol. 101, Muscular dystrophies, A. Amato and R.C. Griggs, eds. ISBN 9780080450315
Vol. 102, Neuro-ophthalmology, C. Kennard and R.J. Leigh, eds. ISBN 9780444529039
Vol. 103, Ataxic disorders, S.H. Subramony and A. Durr, eds. ISBN 9780444518927
Vol. 104, Neuro-oncology, Part I, W. Grisold and R. Sofietti, eds. ISBN 9780444521385
Vol. 105, Neuro-oncology, Part II, W. Grisold and R. Sofietti, eds. ISBN 9780444535023
Vol. 106, Neurobiology of psychiatric disorders, T. Schlaepfer and C.B. Nemeroff, eds. ISBN 9780444520029
Vol. 107, Epilepsy Part I, H. Stefan and W.H. Theodore, eds. ISBN 9780444528988
Vol. 108, Epilepsy Part II, H. Stefan and W.H. Theodore, eds. ISBN 9780444528995
Vol. 109, Spinal cord injury, J. Verhaagen and J.W. McDonald III, eds. ISBN 9780444521378
Vol. 110, Neurological rehabilitation, M. Barnes and D.C. Good, eds. ISBN 9780444529015
Vol. 111, Pediatric neurology Part I, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444528919
Vol. 112, Pediatric neurology Part II, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444529107
Vol. 113, Pediatric neurology Part III, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444595652
Vol. 114, Neuroparasitology and tropical neurology, H.H. Garcia, H.B. Tanowitz and O.H. Del Brutto, eds.
ISBN 9780444534903
Vol. 115, Peripheral nerve disorders, G. Said and C. Krarup, eds. ISBN 9780444529022
Vol. 116, Brain stimulation, A.M. Lozano and M. Hallett, eds. ISBN 9780444534972
Vol. 117, Autonomic nervous system, R.M. Buijs and D.F. Swaab, eds. ISBN 9780444534910
Vol. 118, Ethical and legal issues in neurology, J.L. Bernat and H.R. Beresford, eds. ISBN 9780444535016
Vol. 119, Neurologic aspects of systemic disease Part I, J. Biller and J.M. Ferro, eds. ISBN 9780702040863
Vol. 120, Neurologic aspects of systemic disease Part II, J. Biller and J.M. Ferro, eds. ISBN 9780702040870
Vol. 121, Neurologic aspects of systemic disease Part III, J. Biller and J.M. Ferro, eds. ISBN 9780702040887
Vol. 122, Multiple sclerosis and related disorders, D.S. Goodin, ed. ISBN 9780444520012
Vol. 123, Neurovirology, A.C. Tselis and J. Booss, eds. ISBN 9780444534880
vi AVAILABLE TITLES (Continued)
Vol. 124, Clinical neuroendocrinology, E. Fliers, M. Korbonits and J.A. Romijn, eds. ISBN 9780444596024
Vol. 125, Alcohol and the nervous system, E.V. Sullivan and A. Pfefferbaum, eds. ISBN 9780444626196
Vol. 126, Diabetes and the nervous system, D.W. Zochodne and R.A. Malik, eds. ISBN 9780444534804
Vol. 127, Traumatic brain injury Part I, J. Grafman and A.M. Salazar, eds. ISBN 9780444528926
Vol. 128, Traumatic brain injury Part II, J. Grafman and A.M. Salazar, eds. ISBN 9780444635211
Vol. 129, The human auditory system: Fundamental organization and clinical disorders, G.G. Celesia
and G. Hickok, eds. ISBN 9780444626301
Vol. 130, Neurology of sexual and bladder disorders, D.B. Vodušek and F. Boller, eds. ISBN 9780444632470
Vol. 131, Occupational neurology, M. Lotti and M.L. Bleecker, eds. ISBN 9780444626271
Vol. 132, Neurocutaneous syndromes, M.P. Islam and E.S. Roach, eds. ISBN 9780444627025
 Foreword

We are proud to present for the first time a volume of the Handbook of Clinical Neurology devoted to autoimmune
neurologic disorders. The concept of antibody-associated encephalitis was first introduced in 1966 by Lord Brain. The
neurologic consequences of antibodies to acetylcholine receptors have been studied for some time but, in recent years,
a number of novel antibody-associated autoimmune neurologic disorders have been defined. The antibodies against
neural antigens, some paraneoplastic, are often specific to relatively well-defined syndromes and can be identified in
serum or cerebrospinal fluid.
The clinical features of autoimmune disorders of the nervous system include prominent neurologic and psychiatric
disturbances. These disorders, which constitute a rapidly emerging subspecialty, are reflected in the contents of the
present volume, which comprises 27 chapters, divided into three parts. Following the introductory first part, the second
deals with the basic principles of neurobiology and immunology, from the signaling molecules of the central nervous
system that are the targets of autoimmunity to animal models of autoimmune neurologic disorders. The third part
deals with the clinical, diagnostic, and therapeutic aspects of autoimmune neurologic and neuropsychiatric
disorders. The recent discovery of novel antibodies against targets on the neuronal surface that are often present
in patients with previously unexplained neuropsychiatric deficits is especially interesting, since such patients can
be successfully treated immunologically.
We are very fortunate to have as volume editors two distinguished scholars, Sean J. Pittock from the Mayo Clinic,
Rochester, USA, and Angela Vincent, from the John Radcliffe Hospital, University of Oxford, UK. They have assem-
bled an excellent international and multidisciplinary group of experts whom they have carefully guided in creating this
comprehensive book. We are grateful to them and to all the contributors.
This volume will be of interest not only to clinical neurologists and psychiatrists, but also to immunologists
and basic neuroscientists. A print version is available but interest is increasing in the electronic version of the
Handbook series, available on Elsevier’s Science Direct website, which facilitates its accessibility.
As always, it is a pleasure to thank Elsevier, our publisher – and in particular Michael Parkinson in Scotland and
Kristi Anderson and Mara E. Conner in San Diego – for their excellent assistance with the development and production
of this volume.
Michael J. Aminoff
François Boller
Dick F. Swaab
 Preface

Autoimmune neurology is one of the most exciting and rapidly evolving fields in contemporary neurology, and repre-
sents a new subspecialty driven mainly by discovery of novel neural (neuronal or glial)-specific autoantibodies and
their target antigens. Autoimmune disorders may affect every level of the nervous system, from cortex (epilepsy,
encephalopathy, dementia) to neuromuscular junction and muscle (myasthenia gravis, autoimmune myositis), and
are increasingly recognized as important and treatable causes of neurologic disease. Autoimmune neurology transcends
traditional borders of neurologic subspecialties and is relevant to behavioral neurology, epilepsy, neuro-infectious
disease, neuro-oncology, and neuromuscular (peripheral nerve, muscle, autonomic) and movement disorders.
The field is only beginning to find its footing as an independent subspecialty. International and national neurologic
societies now frequently offer educational courses and symposia that provide updates and overviews of what many
consider a complex and confusing constellation of conditions. This complexity is highlighted in the growing numbers
of publications relating to novel diagnostic biomarkers, their targets, mechanisms of action, and cancer and viral
associations, and new therapeutic options. As editors with a passionate interest in this area, who have worked collabo-
ratively in the past, we recognized that a comprehensive textbook on autoimmune neurology was absent from current
literature and we considered the international format of the Handbook series an ideal foundation for a first textbook in
this area.
Our goal was to provide an easy-to-read but comprehensive overview of this translational subspecialty. To do this
we brought together internationally recognized experts from Europe and North America and asked them to provide a
clear and concise overview in a clinically relevant context. We encouraged them to include a little history and back-
ground, but to mainly focus on recent publications. This they have done very effectively but the reader needs
to appreciate that this young field lacks standardized guidelines for diagnosis and treatment, and specific approaches
to diagnosis and treatment may differ from expert to expert and from institution to institution. There is, therefore,
a pressing need for multicenter studies on diagnostic algorithms and therapeutic management strategies.
The textbook is divided into three parts. The first part provides a brief but wide introduction to the field. The second
part includes basic science overviews of synaptic signaling molecules, the blood–brain barrier, immunology, cellular
and molecular outcomes of a targeted immune attack, neuronal and glial immunopathology, and animal models. We
hope that these chapters will provide a solid grounding to allow readers to begin to ask pertinent translational research
questions as they move into the clinical part. This third section, written by clinicians with expertise in diagnosis and
treatment of autoimmune neurologic disorders, is organized according to the nervous system level involved, starting
at the cerebral cortex and descending to muscle. The final chapter summarizes current approaches to immunotherapies
and some future prospects.
It remains a significant challenge and time commitment to write a book chapter. We sincerely thank our contrib-
utors for their help in making this book a reality. As editors we have tried to create a flow of concepts and ideas from
start to finish and very much appreciate our contributors’ flexibility with respect to changes, additions, and deletions
that were required to minimize overlap, avoid duplication, and maximize cohesion across the handbook.
We would like to acknowledge the many contributions of Ivan Roitt, Ian Simpson, Vanda Lennon, Jon Lindstrom,
Dan Drachman, Klaus Toyka, Andrew Engel, Ricardo Miledi, John Griffin and John Newsom-Davis and their
colleagues, who played essential roles in demonstrating the importance of autoantibodies in the peripheral nervous
system. Over the last 15 years the field has grown and widened considerably and that would not have been possible
without the major contributions of Vanda Lennon and Josep Dalmau. We very much appreciate the technical expertise
and help in transatlantic coordination of chapters and proof reviews provided by Mary Curtis, and help and support
provided by Dominica Luscombe. Finally, we thank our families for their support and patience in allowing us to
prepare and complete this volume.
Sean J. Pittock and Angela Vincent
 Contributors

R. Balice-Gordon D.A. Drubach

Department of Neuroscience, Perelman School of Department of Neurology, Mayo Clinic, Rochester,
Medicine at the University of Pennsylvania, MN, USA
Philadelphia, PA and Neuroscience and Pain Research
Unit, Pfizer, Inc., Cambridge, MA, USA E.P. Flanagan
Department of Neurology, Mayo Clinic, Rochester,
J. Bauer MN, USA
Center for Brain Research, Medical University Vienna,
Vienna, Austria M. Gorman
Department of Neurology, Boston Children’s Hospital
E.E. Benarroch and Harvard Medical School, Boston, MA, USA
Department of Neurology, Mayo Clinic, Rochester,
MN, USA S.R. Hinson
Departments of Laboratory Medicine/Pathology and
S.M. Benseler
Neurology, Mayo Clinic, College of Medicine,
Division of Rheumatology, Department of Paediatrics,
Rochester, MN, USA
Alberta Children’s Hospital, Alberta Children’s Hospital
Research Institute, Cumming School of Medicine,
M.Y. Hu
University of Calgary, Alberta, Canada
Department of Neurology, Yale School of Medicine,
New Haven, CT, USA
C.G. Bien
Epilepsy-Centre Bethel, Krankenhaus Mara, Bielefeld,
Germany S.R. Irani
Nuffield Department of Clinical Neurosciences, John
B.F. Boeve Radcliffe Hospital, Oxford, UK
Department of Neurology, Mayo Clinic, Rochester,
MN, USA A. Jain
Department of Neuroscience, Perelman School of
M. Bradl Medicine at the University of Pennsylvania,
Department of Neuroimmunology, Center for Brain Philadelphia, PA, USA
Research, Medical University Vienna, Vienna, Austria
C.J. Klein
J. Britton Department of Neurology, Mayo Clinic, Rochester,
Department of Neurology, Mayo Clinic, Rochester, MN, USA
MN, USA
B. Lang
E. Coutinho Neuroimmunology Group, Nuffield Department of
Nuffield Department of Clinical Neurosciences, John Clinical Neurosciences, John Radcliffe Hospital,
Radcliffe Hospital, Oxford, UK Oxford, UK

M.A.A.M. de Bruijn H. Lassmann

Department of Neurology, Erasmus University Medical Department of Neuroimmunology, Center for Brain
Center, Rotterdam, The Netherlands Research, Medical University Vienna, Vienna, Austria
xii CONTRIBUTORS
V.A. Lennon
Departments of Laboratory Medicine/Pathology and
Neurology, Mayo Clinic, College of Medicine,
Rochester, MN, USA
M. Lim
Children’s Neurosciences, Evelina London Children’s
Hospital at Guy’s and St. Thomas’ NHS Trust,
Kings Health Partners Academic Health Science
Centre, London and Nuffield Department of
Clinical Neurosciences, John Radcliffe Hospital,
Oxford, UK
C.F. Lucchinetti
Department of Neurology, Mayo Clinic, Rochester,
MN, USA
A. Mammen
National Institute of Arthritis and Musculoskeletal
and Skin Disorders, National Institutes of Health,
Bethesda, MD and Department of Neurology,
Johns Hopkins University School of Medicine,
Baltimore, MD, USA
A. McKeon
Departments of Neurology and Laboratory Medicine
and Pathology, Mayo Clinic, Rochester, MN, USA
K.L. Medina
Department of Immunology and Department of
Medicine, Mayo Clinic, Rochester, MN, USA
R.J. Nowak
Department of Neurology, Yale School of Medicine,
New Haven, CT, USA
B. Obermeier
Neuro/Immuno Discovery Biology, Biogen, Cambridge,
MA, USA
K.C. O’Connor
Department of Neurology, Yale School of Medicine,
New Haven, CT, USA
J. Palace
Department of Clinical Neurology, John Radcliffe
Hospital, Oxford, UK
P. Pettingill
Neurogenetics Group, Nuffield Department of
Clinical Neurosciences, John Radcliffe Hospital,
Oxford, UK
A. Petzold
The Dutch Expert Center for Neuro-ophthalmology,
VU University Medical Center, Amsterdam,
The Netherlands and Molecular Neuroscience,
UCL Institute of Neurology, London, UK
S.J. Pittock
Departments of Laboratory Medicine/Pathology
and Neurology, Mayo Clinic, College of Medicine,
Rochester, MN, USA
G.T. Plant
Moorfields Eye Hospital, The National Hospital for
Neurology and Neurosurgery and St. Thomas’ Hospital,
London, UK
B.F.Gh. Popescu
Department of Anatomy and Cell Biology and Cameco
MS Neuroscience Research Center, University of
Saskatchewan, Saskatoon, Canada
R.M. Ransohoff
Neuro/Immuno Discovery Biology, Biogen, Cambridge,
MA, USA
M.H. Silber
Center for Sleep Medicine and Department of
Neurology, Mayo Clinic College of Medicine,
Rochester, MN, USA
P. Stathopoulos
Department of Neurology, Yale School of Medicine,
New Haven, CT, USA
E. Strijbos
Department of Neurology, Leiden University Medical
Centre, Leiden, The Netherlands
M.J. Titulaer
Department of Neurology, Erasmus University Medical
Center, Rotterdam, The Netherlands
M. Twilt
Division of Rheumatology, Department of Pediatrics,
Aarhus University Hospital and Faculty of Medicine,
University of Aarhus, Aarhus, Denmark and Division
of Rheumatology, Department of Paediatrics, Alberta
Children’s Hospital, Alberta Children’s Hospital
Research Institute, Cumming School of Medicine,
University of Calgary, Alberta, Canada
A. Verma
Biomarkers and Experimental Medicine, Biogen,
Cambridge, MA, USA
 CONTRIBUTORS xiii
J. Verschuuren P. Waters
Department of Neurology, Leiden University Medical Neuroimmunology Group, Nuffield Department of
Centre, Leiden, The Netherlands Clinical Neurosciences, John Radcliffe Hospital,
Oxford, UK

A. Vincent S. Wong
Nuffield Department of Clinical Neurosciences, John Moorfields Eye Hospital and St. Thomas’ Hospital,
Radcliffe Hospital, Oxford, UK London, UK
Handbook of Clinical Neurology, Vol. 133 (3rd series)
Autoimmune Neurology
S.J. Pittock and A. Vincent, Editors
© 2016 Elsevier B.V. All rights reserved

Chapter 1

Introduction to autoimmune neurology

SEAN J. PITTOCK1* AND ANGELA VINCENT2
1
Departments of Laboratory Medicine/Pathology and Neurology, Mayo Clinic, College of Medicine, Rochester, MN, USA
2
Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK

Abstract
Considering the diversity and numbers of targets expressed on the estimated 500 billion glia and slightly
less numerous but more diverse neurons, if any channel, receptor or protein on such a cell can be the target
of the immune system, we need only imagine the possibilities. As those before us looked to the heavens
and ultimately walked on the moon, we need to recognize the potential implications of autoimmune
neurology – a new subspecialty in neurology that has truly launched! Its importance cannot be overstated
as many of the disorders now recognized as autoimmune are treatable and reversible, representing a shift
from the traditional view held by many in the lay and medical community that neurologists diagnose but
don’t treat! In this introductory chapter we provide a brief over-view of how the field developed, tabulate
the authors and contents of the individual topics covered in each chapter, and describe some of the
on-going challenges of the field.

Autoimmunity is a misguided immune response to

AUTOIMMUNE NEUROLOGY: A NEW
SUBSPECIALTY
Autoimmune neurology is a rapidly evolving new sub-
specialty in neurology driven mainly by discovery of
novel neural (neuronal or glial)-specific autoantibodies
directed at specific target antigens. Autoimmune neurol-
ogy intersects with many of the traditional subspecialties,
including cognitive and behavioral neurology (e.g., auto-
immune dementia and encephalopathy), movement
disorders (e.g., autoimmune chorea, myoclonus, and
ataxia), epilepsy (e.g., autoimmune epilepsy), neuro-
oncology (e.g., paraneoplastic neurologic disorders),
neuromuscular disorders (e.g., myasthenia gravis,
Lambert–Eaton syndrome), peripheral nerve (neuropa-
thies both somatic and autonomic, hyperexcitability dis-
orders), and demyelinating disorders (e.g., neuromyelitis
optica spectrum disorders). Despite their relative rarity,
the variety of clinical phenotypes and response to immu-
notherapies make the awareness of these diseases and
their diagnosis in patients particularly important.
the body’s own organs. Neurologic autoimmunity can
target virtually any structure within the central or periph-
eral nervous system and often in a highly specific way,
targeting a specific cell population (e.g., Purkinje cells
of the cerebellum, hippocampal neurons, or dorsal root
ganglia). As a general rule, antibodies targeting intracel-
lular proteins (nuclear and intracytoplasmic enzymes,
transcription factors, and RNA-binding proteins) serve
as markers of cytotoxic, neural peptide-specific,
T-cell-mediated injury and are generally poorly respon-
sive to immunotherapy (classic paraneoplastic syn-
dromes) (Albert et al., 1998). By contrast, antibodies
targeting plasma membrane proteins (neurotransmitter
receptors, ion channels, water channels, and channel-
complex proteins) may act as pathogenic effectors and
often imply immunotherapy responsiveness (Vincent
et al., 2011; Leypoldt et al., 2015).
Below, we include a brief overview of the field as it is
at the moment (late 2015), finishing with some specula-
tive and also cautionary comments.

*Correspondence to: Sean J. Pittock, Departments of Laboratory Medicine/Pathology and Neurology, Mayo Clinic, College of
Medicine, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1-507-284-4836, E-mail: pittock.sean@mayo.edu
4 S.J. PITTOCK AND A. VINCENT
NEURAL ANTIBODIES RESULTING
FROM THE BODY’S IMMUNE RESPONSE
TO CANCER
From the 1960s onwards, immune-mediated peripheral
and brain disorders have been associated with systemic
tumors, often small cell lung carcinoma or gynecologic
or breast tumors (Table 1.1). Thus, to this day, autoim-
mune neurologic disorders are often assumed to be asso-
ciated with an overt or cryptic tumor. The consensus is
that a potentially effective antitumor immune response
is initiated by an antigen that is shared with the nervous
system (Giometto et al., 2010; McKeon and Pittock, 2011;
Iorio and Lennon, 2012; Rosenfeld and Dalmau, 2012).
This tumor-targeted immune response can be initiated
by intracellular onconeural proteins, often in the
nucleus, nucleolus cytoplasm (green triangle, Fig. 1.1)
of certain tumors. These antigens are presented to the
adaptive immune system by the tumor and immune
cell activation results. The antigens are also expressed

Table 1.1
Overview of neural antibodies and their associated neoplasms according to the nervous system level involved and neurologic
manifestation/syndrome

Level Syndrome/disorder Neural antibody (IgG) associations Neoplasm: frequency

Cerebral cortex Encephalitis (limbic)/ VGKC complex (LGI1) Thymoma, SCLC, other: <10%
encephalopathy VGKC complex (CASPR2) Thymoma: <40%
Autoimmune epilepsy NMDAR Ovarian teratoma: 50%
Autoimmune cognitive CRMP-5 (CV2) SCLC > thymoma: >90%
disorder/dementia ANNA-1 (Hu) SCLC > neuroblastoma: >80%
GABA R Lung, neuroendocrine: 50%
Ma2 Testicular, lung: >90%
Ma1 Breast, colon, parotid, lung: >90%
Amphiphysin Breast, SCLC: >90%
IgLON 5 (cognitive disorder/dementia) No tumor association known
AMPAR Lung, breast, thymoma: 70%
GAD65 Lung, neuroendocrine, thymoma: <10%
Diencephalon Hypothalamic dysfunction, Ma1, Ma2 (EDS, cataplexy) See above
EDS, narcolepsy/ VGKC complex (LGI1, CASPR2, other),
cataplexy, SIADH AQP4 Breast/lung/thymoma/carcinoid: <5%
Basal ganglia Chorea/dystonia/dyskinesia CRMP-5 (CV2) See above
GAD65
ANNA-1 (Hu),
VGKC complex (LGI1, CASPR2, other)
Amphiphysin
Cerebellum Cerebellar ataxia PCA-1 (Yo) Ovarian, breast, mullerian duct: >90%
Cerebellar degeneration PCA-Tr (DNER) Hodgkin’s lymphoma: >80%
ANNA-1 (Hu) See above
CRMP-5 (CV2)
mGluR-1 Hodgkin’s lymphoma: few cases
GAD65 See above
VGCC (PQ and N type) SCLC, other: 50%
Brainstem Brainstem encephalitis/ CRMP-5 (CV2) See above
encephalopathy ANNA-1 (Hu), OMS
Opsoclonus myoclonus ANNA-2 (Ri), OMS
(OMS)
Stiff-man syndrome (SMS) Amphiphysin
PERM Ma2
Ma1
GlyaR (SMS, PERM) Thymoma, lymphoma: 20%
AQP4 See above
GAD65 (SMS)
Spinal cord Myelopathy and myoclonus AQP4 See above
CRMP5 (CV2)
Amphiphysin
 INTRODUCTION TO AUTOIMMUNE NEUROLOGY 5
Table 1.1
Continued

Level Syndrome/disorder Neural antibody (IgG) associations Neoplasm: frequency

Peripheral Sensory neuronopathy and ANNA-1 (Hu) See above

nerves and sensorimotor CRMP-5 (CV2)
ganglia neuropathies. Peripheral Amphiphysin
nerve hyperexcitability Ganglionic AChR Breast, prostate, lung,
Autonomic neuropathies VGKC antibodies (CASPR2) gastrointestinal: <15%
(pandysautonomia or
limited)
Neuromuscular Myasthenia gravis Muscle AChR Thymoma: <20%
junction Lambert–Eaton syndrome VGCC (PQ type > N type) SCLC: 50%
SOX1 SCLC: >90%
Muscle Acute necrotizing myositis SRP54 Low risk
Dermatomyositis Anti TIF1g or NXP2 Adenocarcimoma: >70%

AChR, acetylcholine receptor; AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA, antineuronal nuclear anti-
body; AQP4, aquaporin-4; CASPR2, contactin-associated protein-like 2; CRMP-5 (CV2), collapsin response mediator protein 5; DNER, delta/
notch-like epidermal growth factor- receptor; EDS, Ehlers–Danlos syndrome; GABAR, gamma-aminobutyric acid receptor; GAD-65, glutamic
acid decarboxylase; GlyaR, glycine alpha receptor; IgLON5, immunoglobulin-like family member 5; LGI1, leucine-rich, glioma-inactivated 1;
mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartic acid receptor; NXP, nuclear matrix protein; PCA, Purkinje cell cytoplas-
mic antibody; PERM, progressive encephalomyelitis with rigidity and myoclonus; SIADH, syndrome of inappropriate antidiuretic hormone
secretion; SOX1, sex-determining region Y box 1 transcription factor; SRP, signal recognition particle; TIF, transcription intermediary factor;
VGCC, voltage gated calcium channel; VGKC, voltage-gated potassium channel. Lung cancer includes both small cell lung cancer (SCLC)
and nonsmall cell lung cancer, unless otherwise specified.

in neural cells (neurons or glia) and thus are coincidental SOME AUTOANTIBODIES TARGETING
targets. In many situations, the resulting cellular immu- INTRACELLULAR ANTIGENS ARE NOT
nity is thought to be responsible for neuronal destruction CLOSELY LINKED TO TUMORS
and permanent, irreversible disability. The specific anti-
When considering antibodies to intracellular antigens, it
bodies (humoral immunity), when directed against intra-
is important to mention glutamic acid decarboxylase
cellular antigens, are very unlikely to be causative, but
(GAD) antibodies. These are a biomarker for insulin-
remain an excellent biomarker for the presence of a
dependent diabetes mellitus, but also found, often at
tumor. In other cases, e.g., Lambert–Eaton myasthenic
very high titer, in patients with persistent neurologic dis-
syndrome, the immune response is directed towards
orders; these are frequently slowly progressive, chronic,
plasma membrane onconeural proteins (red diamonds,
and poorly responsive to immunotherapies. The diseases
Fig. 1.1) and the relevant antibodies are pathogenic.
associated with GAD antibodies are included in
In the majority of these patients, neurologic symp-
chapters on epilepsies and movement disorders because
toms precede the identification of a cancer, and identi-
their identification can point to an immunotherapy-
fication of one (or more) of the antibodies, which is
responsive disease in some patients. The possibility that
now available for most on a service basis, can be a very
these patients have other, potentially pathogenic anti-
useful biomarker for the presence of a specific tumor
bodies, has been raised and future studies may help
(Table 1.1). Because of the complexity of these diseases
to characterize better the GAD antibody-associated
and their treatments, however, close interaction with
conditions.
oncologists is required in the optimal management of
In addition, there are many disorders of other parts of
paraneoplastic neurologic disorders; surgery, radiation
the nervous system which are widely thought to be
therapy, and chemotherapy targeting the underlying
autoimmune-mediated but not yet associated with spe-
malignancy must be coordinated with appropriate
cific pathogenic antibodies. For instance, the antibodies
immunotherapy for the autoimmune neurologic disor-
in different forms of myositis, even though unlikely to
der. Stabilization of the neurologic condition should
be pathogenic since they are against intracellular anti-
be the aim, but these relatively rare patients do not
gens, are increasingly recognized to have clinical rele-
often get substantially better with immunotherapies
vance in diagnosis and therapeutic decision making.
(Rosenfeld and Dalmau, 2012).
6 S.J. PITTOCK AND A. VINCENT

Fig. 1.1. Immunopathogenic mechanisms of paraneoplastic and nonparaneoplastic (idiopathic) neural autoantibodies. In cases of
paraneoplastic autoimmunity, tumor-targeted immune responses are initiated by onconeural proteins expressed in the plasma
membrane (red diamond) or in the cytoplasm, nucleus, or nucleolus (green triangle) of certain tumors. These antigens are also
expressed in neural cells and thus are coincidental targets. Although there is evidence to support an analogous infectious-induced
mimicry in nonparaneoplastic autoimmunity (e.g., N-methyl-D-aspartic acid receptor (NMDAR) encephalitis after herpes simplex
virus encephalitis), the source of the initiating antigen remains elusive in most cases.
Antibodies targeting plasma membrane antigens are effectors of injury (red): antibodies (red) directed at neural cell plasma
membrane antigens (e.g., voltage-gated potassium channel complex, NMDA, alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA), gamma-aminobutyric acid-B (GABA-B) receptor) are effectors of cellular dysfunction or injury
through multiple effector mechanisms. These mechanisms include receptor agonist or antagonist effects, activation of the com-
plement cascades, activation of Fc receptors leading to antibody-dependent cell-mediated cytotoxicity (ADCC), and antigen inter-
nalization (antigenic modulation), thereby altering antigen density on the cell surface.
Antibodies targeting nuclear or cytoplasmic antigens are serum markers of a T-cell effector-mediated injury (green)
(Mohammad et al., 2014). Intracellular antigens (green triangles) are not accessible to immune attack in situ, but peptides derived
from intracellular proteins are displayed on upregulated major histocompatibility complex (MHC) class I molecules in a proin-
flammatory cytokine milieu after proteasomal degradation, and are then accessible to peptide-specific cytotoxic T cells. Antibodies
(green, e.g., antineuronal nuclear antibody-1 (ANNA-1), collapsin response mediator protein-5 (CRMP-5)) targeting these intra-
cellular antigens (green) are detected in both serum and cerebrospinal fluid, but are not pathogenic. In clinical practice, these anti-
bodies serve as diagnostic markers of a T-cell-predominant effector process. (From Diamond et al. (2009). Modified with
permission from Macmillan Publishers Ltd).

Another example are disorders of the visual system PATHOGENIC AUTOANTIBODIES

which are very diverse and for which only a few defined
These are the antibodies on which this volume focuses.
antibodies currently exist. A comprehensive chapter on
Pathogenic antibodies in the peripheral nervous system
the visual system sets the scene for many future
have been known, of course, since the 1970s from the
discoveries.
 INTRODUCTION TO AUTOIMMUNE NEUROLOGY
seminal discoveries from Lindstrom, Drachmann, Engel,
and many others. Both myasthenia and Lambert–Eaton
syndrome have tumor-associated (thymoma or small cell
lung cancer) and nontumor-associated forms, but in
each case immunotherapies are highly effective. In the
1990s the discovery of ganglioside antibodies in some
forms of peripheral nerve disorders was another break-
through, although a direct effect of the antibodies was
more difficult to demonstrate, and treatment responses
are not always so easy to predict. Recently nodal proteins
have been identified in at least a small proportion of
patients with distinctive forms of chronic inflammatory
demyelinating polyneuropathy, and there is much more
to learn.
Even before the new era of autoimmune forms of
encephalitis (2000–current), there were hints that some
central nervous system disorders, as well as the well-
known neuromuscular and peripheral nerve diseases
mentioned above, were associated with specific anti-
bodies and might respond to immunotherapies. In partic-
ularly, some brain diseases overlapped with other
specialties. Patients with autoimmune thyroid or other
endocrinologic disorders commonly have coexisting
neurologic autoimmunity. In rheumatology, patients
with a personal or family history of organ- and
nonorgan-specific autoimmunity, such as systemic lupus
erythematosus, Sj€ ogren disease, and antiphospholipid
syndrome, may present with neurologic complications
of their connective tissue disease and commonly may
have other associated autoimmune neurologic disorders.
Of note, rheumatologists have extensive experience in
the use of a wide array of immunosuppressive medica-
tions that have applicability to autoimmune neurologic
disorders and these specialists have often been more will-
ing to use them in patients with neurologic involvement.
There is now an array of different antigenic targets
(e.g., leucine-rich, glioma-inactivated 1 (LGI1), alpha-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA), N-methyl-D-aspartic acid receptor (NMDA),
and gamma-aminobutyric acid (GABA) receptors) rec-
ognized as important in the differential diagnosis of
patients presenting with subacute neurologic syndromes.
Importantly, both children and adults of all ages can be
affected, making the recognition of these antibody-
associated syndromes of wide importance. Table 1.2 pro-
vides a brief synopsis of the contents of each chapter.
NEWASSOCIATIONS AND CHALLENGES
Which drug, how much, and for how long?
This young field of discovery has significant challenges
ahead, with so many unanswered questions. From a
treatment perspective, we need to begin to address basic
therapeutic questions: What drug? What dose? How long
7
to treat? Though these disorders are considered orphan
diseases, randomized controlled trials will be required
to better define appropriate therapeutic regimens. Some
of these disorders are monophasic illnesses and may
require short-lived immunotherapy. Some may actually
improve spontaneously.
Understanding immunopathogenesis will
lead to new therapies
Advanced serologic interpretive insights, coupled with
increased understanding of the pathogenic impact of
binding of neural antibodies to their targets will lead
to the discovery of novel therapeutic targets and open
up possibilities for repurposing of drugs already avail-
able, as well as the potential development of disease-
specific therapies. Repurposing of drugs used in related
fields, such as hematology and rheumatology, will allow
neurologists to accelerate the development of therapeu-
tics for previously devastating and incurable neurologic
conditions such as neuromyeltis optica (NMO), myasthe-
nia gravis, and chronic inflammatory demyelinating
polyneuropathy. This area will require further develop-
ment of animal models that directly model the disease
in question.
Toward a molecularly defined classification
This leads into another important challenge of how we
should classify or define these conditions. Should we
define them based on the molecular target or classify
according to specific clinical and radiologic criteria?
Many diverse disorders are now unified by a specific bio-
marker, and since many of the symptoms and signs
extend beyond their traditional clinical associations,
we suggest that a new terminology will be developed
consistent with an evolving nomenclature used in auto-
immune neurologic diseases that is molecular target-
defined. The term aquaporin-4 (AQP4) autoimmunity
is inclusive of the expanding systemic phenotype thus
far identified for NMO spectrum disorders. The absence
of AQP4 IgG might indicate an alternative diagnosis,
such as multiple sclerosis, another demyelinating
disorder, the presence of another antibody, or an indeter-
minate diagnosis. Similarly, the term autoimmune
NMDAR encephalitis has been used to define the
encephalopathy resulting from targeted attack of the
NMDAR by pathogenic IgGs. Such an approach to clas-
sification of inflammatory central nervous system dis-
eases does not infer, however, that similar syndromes
without that specific antibody do not exist. It does imply
that the clinical phenotype may be shared, although the
immunopathogenic mechanisms may differ (astrocyto-
pathy in AQP4 autoimmunity and oligodendrogliopathy
in myelin oligodendrocyte glycoprotein autoimmunity).
8 S.J. PITTOCK AND A. VINCENT
Table 1.2
Synopsis of contents of chapters
Authors and chapter title
Section 1. Introduction
1. Pittock and Vincent: Introduction to autoimmune neurology
Section 2. Basic neurobiology
2. Benarroch: Signaling molecules of the CNS as targets of
autoimmunity
3. Obermeier, Verma, and Ransohoff: The blood–brain barrier
4. Medina: Overview of the immune system
5. Jain and Balice-Gordon: Cellular, synaptic, and circuit
effects of antibodies in autoimmune CNS synaptopathies
6. Popescu and Lucchinetti: Immunopathology: autoimmune
glial diseases and differentiation from multiple sclerosis
7. Bauer and Bien: Neuropathology of autoimmune
encephalitides
8. Bradl and Lassmann: Neurologic autoimmunity:
mechanisms revealed by animal models
Summary of contents
A brief introduction and overview of the field of autoimmune
neurology from the editors’ perspectives
A very comprehensive and beautifully illustrated account of
how different ion channels and receptors regulate neuronal
excitability, the frequency and pattern of firing of action
potentials, and neurotransmitter release at synaptic
terminals. Some of these channels and receptors are already
known targets for antibodies, and others may be in the future
A detailed anatomic and functional description of the blood
brain barrier. Describes the importance of maintaining the
barrier, and the consequences of impaired structure, as well
as the formation and constituents of the cerebrospinal fluid,
influences of inflammation and hormonal regulation, and
possibilities for repair
Most neurologists need to revise and update their immunology
knowledge, and this chapter concentrates on describing what
needs to be known in the most concise and appropriate
manner. This will assist with improved understanding of the
subsequent chapters of the textbook, and defines the areas
most important for future treatments, particularly the B cells.
This builds on the preceding chapters to focus on cellular,
synaptic and circuit effects of antibodies, mainly
concentrating on molecular mechanisms by which antibody
binding results in disruption in synaptic transmission, with
particular emphasis on N-methyl-D-aspartic acid (NMDA)
receptor antibodies. A crucial questions of how the loss of
NMDA receptors alters circuit properties is far from
complete but, together with a better appreciation of disease
etiologies and both peripheral and central immune
mechanisms, should lead to a better understanding and more
targeted therapies in the future
A detailed account of the immunopathology of neuromyelitis
optica, which is now recognized as an antibody-mediated
autoimmune astrocytopathy. Systematic studies of biopsy
and autopsy tissues demonstrate how neuromyelitis optica
differs from multiple sclerosis, and the importance of
complement activation in the immunopathogenesis, which
was evident even before the discovery of aquaporin-4
antibodies. Further studies are detailing the contributions of
different cellular and molecular mechanisms
This chapter deals with the pathology and the pathogenetic
mechanisms involved in autoimmune neuronal diseases
associated with both intracellular and extracellular/
membrane antibody targets
A critical step in defining a disease as antibody-mediated is
showing that the autoantibodies can reproduce the cardinal
features of the disease in animals. Passive transfer of patient
antibodies to rodents is usually the first step but
comprehensive disease phenotypes are difficult to obtain.
Active immunization against the antigen of interest is usually
more effective – but not always – and can lead to a better
understanding of ongoing pathogenic mechanisms in a
 INTRODUCTION TO AUTOIMMUNE NEUROLOGY
Table 1.2
Continued
Authors and chapter title
9. Waters, Pettingill, and Lang: Detection methods for neural
autoantibodies
Section 3. Clinical: autoimmune neurologic diseases
10. Pittock and Palace: Paraneoplastic and idiopathic
autoimmune neurologic disorders: approach to diagnosis
and treatment
11. Irani and Vincent: Voltage-gated potassium channel–
complex autoimmunity and associated clinical syndromes
12. De Bruijn and Titulaer: Anti-NMDAR encephalitis and
other glutamate and GABA receptor antibody
encephalopathies
13. Britton: Autoimmune epilepsy
9
Summary of contents
chronic disease. This chapter provides a wide and critical
overview of what has been learnt from a variety of induced
and spontaneous models and describes some of the
challenges in their induction and interpretation
Laboratory methods are essential to detect the autoantibodies,
for clinical service and research. This chapter outlines the
methods in current use and the pros and cons of indirect
immunohistochemistry, western blot or line blot
technologies, cell-based assays, radioactive
immunoprecipitation assays, and enzyme-linked
immunosorbent assays with emphasis on optimizing their
clinical sensitivities and specificities
An approach to the diagnostic workup of a patient presenting
with a neurologic disease that is suspected to be immune-
mediated, either paraneoplastic or idiopathic. Emphasis on
the clinical, laboratory, and radiologic clues that should raise
suspicion for an autoimmune etiology, and the importance of
objective measures to provide pretreatment baselines against
which immunotherapy effects can be measured. Includes a
broad overview of the neurologic manifestations and the
spectrum of clinical, radiologic, and oncologic findings
associated with neural antibodies
The spectrum of disorders associated with antibodies has
expanded from the peripheral nervous system to include
disorders associated with pain, dysautonomia, and insomnia
(Morvan’s syndrome), a well-defined limbic encephalopathy
with prominent amnesia and seizures, and a highly distinctive
form of epilepsy termed faciobrachial dystonic seizures that
often precedes the limbic encephalitis and may be
antiepileptic drug-resistant. All respond to immunotherapies;
in Morvan’s syndrome a thymoma is common. The diversity
of these syndromes is partly explained by the fact that the
antibodies bind to different components of the voltage-gated
potassium channel (VGKC)–complex, notably leucine-rich
glioma-inactivated 1 (LGI1) and contactin-association protein
2 (CASPR2)
“Anti-NMDA receptor encephalitis” has become the major
topic in the field. This comprehensive overview of the clinical
phenotype, diagnostic evaluation, and therapeutic approach
to each of the disorders associated with antibodies to NMDA,
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA), and gamma-aminobutyric acid (GABA) A and
B receptors includes a thorough discussion of antibody
testing issues, and the authors’ preference for using
cerebrospinal fluid when possible. They also offer advice for
management of the patients within the clinical care setting
Autoimmune epilepsies can be defined as immunologically-
mediated disorders in which recurrent seizures are a primary
and persistent clinical feature. Seizures are the most overt
sign but less evident changes in behaviour or cognition need
to be considered. Clinical clues particularly imaging, EEG,
Continued
10 S.J. PITTOCK AND A. VINCENT
Table 1.2
Continued

Authors and chapter title Summary of contents

cerebrospinal fluid, and serologic features can suggest an

14. Flanagan, Drubach, and Boeve: Autoimmune dementia
and encephalopathy
15. Coutinho and Vincent: Autoimmunity in neuropsychiatric
disorders
16. Twilt and Benseler: Central nervous system vasculitis in
adults and children
17. McKeon and Vincent: Autoimmune movement disorders
18. Silber: Autoimmune sleep disorders
19. Flanagan: Autoimmune myelopathies
immune basis for seizures, sometimes in cases where no
specific antibody has been identified and other features are
not present. Other forms of epilepsy, such as Rasmussen’s
encephalitis, or associated with systemic autoimmune
diseases, and their treatments, are briefly reviewed.
Just as with epilepsies, there is growing recognition that some
forms of dementia and encephalopathies are likely to be
immunotherapy-responsive. Presentations vary, from acute
limbic encephalitis to acute or chronic disorders of cognition
mimicking neurodegenerative dementia. The importance of
bedside cognitive assessment and detailed neuropsychologic
testing is emphasized with a practical guide to recognition,
diagnosis, and management of patients for whom the
differential diagnoses may include Creutzfeldt–Jakob
disease, more insidious causes (Alzheimer’s disease, Lewy
body dementia, and frontotemporal dementia), primary and
secondary vasculitis, systemic lupus erythematosus, multiple
sclerosis, and even IgG4-related disease
This chapter focuses mainly on neuropsychiatric diseases as
seen by psychiatrists and the evidence from genetic
epidemiologic and immunologic studies that point towards an
autoimmune pathophysiology in some of the patients. The
authors also summarize the psychiatric manifestations in
patients with autoimmune forms of encephalitis, and discuss
how autoimmune central nervous system diseases might, in
some instances, be relevant to psychiatric disorders,
particularly schizophrenia and autism
Primary angiitis of the central nervous system (PACNS) is an
inflammatory brain disease targeting the cerebral blood
vessels, leading to a wide spectrum of features including
neurologic deficits, cognitive dysfunction, and psychiatric
symptoms. The authors provide a very useful discussion of
the differential diagnosis and differences between
angiography-positive and negative primary angiitis
This covers the broad clinical spectrum and diagnostic
evaluation of autoimmune movement disorders, and their
treatment, focusing on movement disorders, ataxias, and
hypokinetic or hyperkinetic disorders, and their associated
neural autoantibodies. It covers not only the classic
syndrome, stiff-person syndrome, and glycine receptor
antibody-associated forms, but also autoimmunity in
controversial areas such as those movement disorders
associated with streptococcal infections or celiac disease
Sleep disorders are another wide area where autoimmunity may
be highly relevant. This chapter reviews the different
manifestations associated with specific neural
autoantibodies and summarizes in more detail the evidence
that idiopathic narcolepsy is an autoimmune disease despite
the lack of a serum antibody biomarker
Primary autoimmune myelopathies can be antibody-mediated
(including aquaporin-4 autoantibodies), postinfectious,
 INTRODUCTION TO AUTOIMMUNE NEUROLOGY
Table 1.2
Continued
Authors and chapter title
20. Petzold, Wong, and Plant: Autoimmunity in visual loss
21. Hinson, Lennon, and Pittock: Autoimmune AQP4
channelopathies and neuromyelitis optica spectrum
disorders
22. McKeon and Benarroch: Autoimmune autonomic
disorders
23. Klein: Autoimmune-mediated peripheral neuropathies and
autoimmune pain
24. Verschuuren, Strijbos, and Vincent: Neuromuscular
junction disorders
25. Mammen: Autoimmune muscle disease
11
Summary of contents
paraneoplastic, and those thought to be immune-related but
not associated with any known specific antibody as in
multiple sclerosis and spinal cord sarcoidosis. A useful
overview of recent advances in this area and a practical
approach to the differential diagnosis and management of
these disorders are provided
An extensive overview of the literature on all forms of
autoimmune visual loss, from retinitis to optic neuritis,
providing a comprehensive differential diagnosis of
disorders and highlighting the importance of considering
immune mechanisms associated with systemic disease
Arguably the best-studied but not yet fully understood of the
new antibody-mediated diseases is neuromyelitis optica. This
covers in detail the immunobiology of aquaporin-4
autoimmunity and the continuing revision of neuromyelitis
optica spectrum disorder clinical diagnostic criteria. As the
spectrum broadens, the importance of highly specific assays
that detect pathogenic aquaporin-4-IgG targeting
extracellular epitopes of aquaporin-4 is emphasized.
Importantly, the treatment of this disease is leading the way
in the use of novel therapeutic agents in antibody-mediated
conditions
A number of different autoantibodies can lead directly or
indirectly to dysautonomia, and the role of the immune
system needs to be considered not only in neuropathies but
also in idiopathic forms. The direct effect of antibodies to
ganglionic acetylcholine receptors, calcium and potassium
channels can cause a variety of symptoms, whilst NMDAR,
glycine receptor, and dipeptidyl-peptidase-like protein
antibodies likely affect autonomic functions via
hypoathalamic-regulatory pathways. Therapeutic approaches
require both symptomatic and antibody-depleting therapies
Pain is another symptom that can be autoimmune. Immune-
mediated neuropathies have varied presentations with
different molecular and cellular antigenic targets. An
anatomic approach helps to understand the pathogenesis and
how the innate and adaptive immune systems interact to
result in these, sometimes underappreciated, conditions.
Treatments can reverse the symptoms and encourage
peripheral nerve regeneration
Disorders of the neuromuscular junction such as myasthenia
gravis and the Lambert–Eaton myasthenic syndromes, are
still paradigms for antibody-mediated diseases, and have the
advantage that they can be defined clinically and
physiologically, leading to recognition of early- and late-
onset forms as well as different antibodies, e.g., MuSK and
LRP4. Both symptomatic and immune treatments are
comprehensively discussed for this disease
Muscle diseases are often inflammatory and this provides a
comprehensive account of the epidemiology, clinical
presentation, and treatment of the autoimmune myopathies
and inclusion body myositis. This is an advancing field which
Continued
12 S.J. PITTOCK AND A. VINCENT
Table 1.2
Continued
Authors and chapter title
26. Lim and Gorman: Autoimmune neurologic disorders in
children
27. Hu, O’Connor, Pittock, and Nowak: Current and future
immunotherapy targets in autoimmune neurology
Recognition of such immunopathogenic differences will
likely be important as more individualized and mechanis-
tically targeted therapies become available. But these
considerations raise another question. How do we assess
sensitivity of antibody tests if the disease is only defined
by the presence of the antibody rather than the clinical
features?
Summary of contents
is defining a diverse family of diseases with recent
autoantibody discoveries that help to classify them, such as
antisynthetase autoantibodies, dermatomyositis
autoantibodies, immune-mediated necrotizing myopathy
autoantibodies, and autoantibody biomarkers of inclusion
body myositis and mixed connective tissue disease. Such a
complex area requires guidelines for the approach to myositis
autoantibody testing, and the different immunosuppressant
approaches that can be used
One of the exciting discoveries of the last 10 years is the
importance of considering specific forms of
encephalopathies and demyelinating diseases in children.
These include NMDAR antibody encephalitis and VGKC–
complex antibody-associated disorders that are often
immunotherapy responsive, but also a wide variety of other
syndromes, such as opsoclonus myoclonus syndrome and
Sydenham chorea, and those that are secondary to other
neuropsychiatric disorders, including systemic lupus
erythematosus and antiphospholipid syndromes. Epileptic
syndromes are particularly important, although antibody
markers are still rare in epilepsy, Rasmussen’s encephalitis,
as well as fever infection associated with refractory epilepsy
syndromes (FIRES). The authors also provide an overview of
antibodies associated with acquired demyelination
syndromes, including aquaporin-4 and myelin
oligodendrocyte glycoprotein antibodies, and provide some
insights into the role of inflammation in childhood
neurodegenerative disorders. Optimizing immunotherapies
and collaborations among clinicians and researchers are both
essential to facilitate recognition, standardization of care
paradigms with consistent definitions of “adequate” and
“insufficient” therapeutic responses, and assist in the
development of outcome measures that are appropriate in the
pediatric context
The standard acute and chronic immunotherapies are discussed
with a practical overview of their use in the clinic, including
mechanisms of action, dosing, monitoring, and side-effects.
The improved mechanistic understanding of the
immunopathology of the diseases described in this volume is
allowing the development of novel approaches to treatment
through new drug discovery or repurposing of drugs used in
other autoimmune conditions
Measuring and interpreting antibodies:
Predicting outcome and guiding therapeutic
decision making
This expanding group of diseases could not be recog-
nized without the development, in parallel, of autoanti-
body testing in serum and cerebrospinal fluid (CSF).
Another random document with
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that respect, we would like to inform them that all who believe that
the new Amendment has been or can be put in the Constitution by
governments, “seem to have lost sight of the people altogether in
their reasonings on this subject; and to have viewed” our national
and state governments, “not only as mutual rivals and enemies, but
as uncontrolled by any common superior in their efforts to usurp the
authorities of each other. These gentlemen must be here reminded
of their error. They must be told that the ultimate authority, wherever
the derivative may be found, resides in the people alone, and that it
will not depend merely on the comparative ambition or address of
the different governments, whether either, or which of them, will be
able to enlarge its sphere of jurisdiction at the expense of the other.”
(Fed. No. 46.) It contributes not a little to the importance of the
quoted statements that they were written by Madison, who also
wrote the real Fifth Article. They are his warning to the then
“adversaries of the Constitution.” They serve well as our warning to
the present adversaries of our Constitution, who assume and have
acted on the assumption that they can ignore its most important
factors whenever government desires to exercise or to grant a new
power to interfere with our individual freedom, although we have not
granted it but have reserved it to ourselves.
We might continue somewhat indefinitely the story of Senate Joint
Resolution 17 in the House of Representatives on that December
day of its passage therein. We would find, however, what we have
already seen of Webb and his colleagues there to be typical of all
they have said and all that they knew of basic American law. We
cannot leave that House on that day, however, without some
comment upon the final eloquent appeal made by Webb at the close
of his arduous labor to secure the passage of the Resolution.
To those, who have any knowledge in the matter, it is well known
that Christ preached the doctrine of free will and temperance, while
Mohammed laid down the law of prohibition. With great curiosity,
therefore, we have listened for years and still listen to the ceaseless
tirade coming from Christian churches where men style themselves
American “Crusaders” and denounce, in no temperate language, all
Americans who do not align themselves under the “Crescent” flag of
Mohammed and respect his Mohammedan command embodied in
the First Section of the Eighteenth Amendment. Our curiosity is not
lessened by the fact that their denunciation of those, who flatly deny
that the command itself is Christian, is always accompanied with an
equally temperate denunciation of those who dare to question their
Tory concept that governments in America can constitute new
government of men.
We have seen Webb, with a candor only equalled by ignorance,
frankly array himself with those who believe the Tory concept, that
the legislatures of the state citizens are “the only tribunal” in which
the national part of the Constitution of the American citizens can be
changed. To his credit, therefore, we find it a matter of record that,
with equal candor, he frankly arrays himself under the “Crescent” flag
of Mohammed and eloquently appeals to all other devotees “of the
great Mohammed” in support of the Mohammedan and un-Christian
precept embodied in the Eighteenth Amendment. That full justice
may be done his eloquence and his candor, these are his own words
on his immortal December 17, 1917: “During one of the great battles
fought by Mohammed, the flag was shot from the ramparts. A daring
and devoted soldier immediately seized it with his right hand and
held it back on the rampart. Immediately his right arm was shot off,
but, never faltering, he seized the flag with his left hand and that, too,
was instantly shot away whereupon with his bleeding stubs he held
the emblem in its place until victory came.
“With a zeal and a determination akin to that which animated this
devotee of the great Mahomet, let us wage a ceaseless battle and
never sheathe our swords until our constitutional amendment is
firmly adopted and the white banner of real effective prohibition
proudly floats over every courthouse and city hall throughout this, the
greatest nation upon earth.” (Congressional Record, Vol. 56, p. 469.)
 CHAPTER XVIII
THE TORY IN THE SENATE

When our present Constitution was before the people of America,

waiting their approval or rejection, Madison and Hamilton published
their series of essays, now known as The Federalist. It is not our
intent to dwell upon the knowledge of American basic law shown by
these two men. Elsewhere our Supreme Court has paid its deserved
tribute to The Federalist as an authority of the greatest weight in the
meaning of our Constitution. At this moment, we desire to mention
one remarkable quality which makes those essays unique among
arguments written in the heat of a great political controversy. They
were written to urge that human beings create a great nation and
grant some enumerated powers to interfere with their own freedom.
They were written when other great leaders were opposing that
project with the utmost ability and eloquence. These opponents, as
is the custom with men in any heated controversy, denounced the
project and its advocates. The abuse of both project and advocates
has probably never been exceeded in America. Yet it is one
remarkable quality of the arguments of Madison and Hamilton, in
The Federalist, that they themselves never leave the realm of reason
and fact and law, or descend to irrelevant abuse of those who differ
in opinion with them.
We, who have lived through the last five years in America, can
truthfully say that the advocates of the new constitution of
government, the Eighteenth Amendment, have made their essays
and speeches and arguments notable for the same quality, by its
utter absence.
Because fact would interfere with the making of their new
Constitution, they have changed fact. Because law meant that
government could not constitute their government of the people, they
have stated law which has never been law in America since 1776.
Because reason would prevent the achievement of their purpose,
they have appealed to irrelevant abuse of those who dared to differ
in opinion with them.
In view of these known facts, we average Americans shall not be
surprised when we read the record of the Senate on its own proposal
that government should exercise a power not delegated to interfere
with individual freedom. Fresh from the reading of the record in the
House, we shall not be surprised to find that the Senate also ignored
the most important factors in the Tenth Amendment and the Fifth
Article, “the people” in the one, and the mention of the people’s
exclusive ability to make national Articles in the other.
When his proposing Resolution came before the Senate on July
30, 1917, Senator Sheppard quickly made clear his mental attitude
on the relation of government to human beings. Whenever a sincere
Tory has voiced himself on that matter, it has always been inevitable
that he betray the thought that human beings are the assets of the
State and not its constituent members. As Madison said, “We have
all known the impious doctrine of the Old World, that people were
made for kings and not kings for the people.” In the country or in the
mind where that doctrine prevails, it is held to be the right and the
privilege of government to see that the people, like the other assets
of the State, are kept in good condition so that all property of the
State may have its greatest economic value in the market of the
world.
And so we find Sheppard, through all his opening support of the
new constitution of government based on the Tory doctrine, making
clear the necessity that our government keep that asset, which is the
citizens of America, in good physical condition like any other
machine that may be in America.
“In an age of machinery and of business transactions on a scale
more enormous and complicated than ever before, the clear eye, the
quick brain and the steady nerve are imperatively demanded.
Society today is more dependent upon the man at the machine than
at any previous period. We are coming to understand that the engine
of the body must have the same care as the engine of the aeroplane,
the battleship, the railway train, the steamship or the automobile; that
the trade in alcohol is a form of sabotage which the human machine
cannot endure; that it is no more to be tolerated than would be the
business of making and selling scrap iron to be dropped into the
delicate and complex machinery of modern manufacture,
transportation and commerce.” (Congressional Record, Vol. 55, p.
5550.)
After this admirably accurate appreciation of the relation of our
American government to the asset which is ourselves, Sheppard
then proceeded to teach us (who have just lived through the
education of the American human beings who made the
Constitution) the real facts of that making, as he knows them.
He is advocating that our only American government should ask
the legislative governments of the states, which are not the
governments of American citizens, directly to interfere with our
individual freedom and to grant to themselves and to our only
government future power to interfere therewith on a matter not
enumerated in the First Article. Naturally, as real fact would make
manifest the absurdity of such proposal, he states that, when the
Constitution was made, “by votes of the Southern States the power
to amend the federal Constitution was vested in three fourths of the
states.” Undoubtedly he meant us to understand that the Constitution
(through whose real making we have just lived) was made by the
states and that the Southern States granted to the legislatures of
three fourths of the states the omnipotent ability over the human
beings of America, which those human beings themselves had
denied to the English king and his legislature. That he meant us so
to understand we shall learn to a certainty in a moment. Meanwhile,
let us note how inadvertently he states part of the truth, while
omitting all reference to the part thereof which would make his own
proposal the clear absurdity which it was.
We note his reference to that part of the Fifth Article which
mentions the ability of three fourths of the state legislatures to
amend the federal Constitution. Because we have lived through the
days of the real American leaders, we recall that our Constitution is
both federal and national and that state legislatures always had
ability to make federal Articles and never had ability to make national
ones. We also remember that those state legislatures were
permitted, by the people who made our Constitution, to retain some
of the ability they had and were given no new ability. We also
remember that the Fifth Article mentions their existing ability to make
federal Articles and prescribes, as the command of the people of
America, that a “Yes” from three fourths of them shall validly make a
change in the federal part of our dual Constitution. For which reason,
with somewhat of amusement, we note Sheppard’s inadvertent
accuracy of statement, when he says that three fourths of the state
legislatures may amend the federal Constitution. With our
knowledge, we do not care what he meant or intended that others
should understand. We know that nothing has been more definitely
settled in America, since 1776, than that legislative governments
never can make a national Article or change our national
Constitution.
We now come to that part of Sheppard’s oration in which he
makes certain his remarkable “knowledge” that our Constitution was
made by the states—which are political entities—and not by the
people of America. With a complacency requisite in one who
advocates that unique constitution of a new kind of government in
America, government of the people by government without authority
from the people, we find him quoting from Calhoun of 1833 the
doctrine that the states made the Constitution. “In this compact they
have stipulated, among other things, that it may be amended by
three fourths of the states; that is, they have conceded to each other
by compact the right to add new powers or to subtract old, by the
consent of that proportion of the states, without requiring, as would
otherwise have been the case, the consent of all.” (Congressional
Record, Vol. 55, p. 5553.)
The history of America from May 29, 1787, to July 30, 1917, was
clearly a sealed book to Sheppard of Texas on that later day.
On May 30, 1787, at Philadelphia, Randolph of Virginia offered the
three Resolutions, which proposed that the people of America create
a nation and absorb into their national system the federal union
which had been made by the states. The first resolution was to
express the sentiment of the convention “that the union of states
merely federal will not accomplish the objects”; the second was to
express the sentiment that “no treaty or treaties among the whole or
part of the states, as individual sovereignties, would be sufficient”;
and the third was to express the sentiment “that a national
government ought to be established, consisting of the supreme
legislative, executive, and judiciary.”
The work of that Philadelphia Convention was carried to a
successful conclusion on the basis of those sentiments. When their
proposed Constitution had been worded, it was sent to and made by
the one people of America, not by the states.
The Constitution of the United States was ordained and
established, not by the states in their sovereign capacities,
but emphatically, as the Preamble of the Constitution
declares, by the “people of the United States.”
So declared Justice Story, from the Bench of the Supreme Court,
as far back as the decision of Martin v. Hunter’s Lessee, 1 Wheat.
324. As Story was an associate of Marshall on that Supreme Court,
and as he is recognized as one of the greatest exponents of our
Constitution, we average Americans prefer his knowledge to that of
Sheppard even when the latter does quote from Calhoun.
Furthermore, in an unbroken line of decisions, extending over the
entire period of more than a century of whose history Sheppard
knows naught, the Supreme Court has insistently proclaimed the
same fact, namely, that the people of America—not the states—
made our Constitution.
“It is no longer open to question that by the Constitution a
nation was brought into being, and that that instrument was
not merely operative to establish a closer union or league of
States.” (Justice Brewer, in the Supreme Court, Kansas v.
Colorado, 206 U. S. 46.)
Indeed, many men before Sheppard have attempted to deny that
fact. History, however, records no successful denial. As Sheppard
states, the words of Calhoun were from his reply to Webster in 1833.
In the history of a century, all a sealed book to Sheppard, Haine also
asserted, against Webster, the belief of Calhoun and Sheppard as to
what were the facts of the making of our Constitution. We average
Americans, in an earlier chapter herein, have read Webster’s
statement as to what were the facts of that making. Having lived,
ourselves, through the days when the Americans did make their own
Constitution, we agree wholly with Webster and the Supreme Court
and know that the states had no part whatever in its actual making.
Over fifty years ago, however, it became absolutely immaterial,
except for academic purposes, what might be the personal beliefs of
ourselves or Calhoun or Haine or Sheppard or Webster. Shortly after
the middle of the last century, the Southern States, just as unwilling
as Sheppard in 1917 to accept the unalterable decision of the
Supreme Court that our Constitution is not a compact between
states, appealed to the only tribunal to which there is any appeal
from that Court, the tribunal of civil war. Even Sheppard must know
the result of Gettysburg, the surrender forever of any claim that the
Constitution is a compact between the states. Even Sheppard must
some time have heard the echo of Lincoln’s appeal, at Gettysburg,
that government of the people, by them and for them, should not
perish from the earth. Even Sheppard must recognize, whether or
not he wish to do so, how successfully the American people, whose
predecessors made the Constitution, answered that appeal of
Lincoln and intend to keep our government a government of the
people, by them and for them, instead of a Sheppard government of
the people, by governments without authority from the people.
We average Americans, however, do not question the wisdom of
Sheppard in quoting the repudiated claim of Calhoun, so long as
Sheppard and his colleagues intended to continue their effort to
impose upon us the new constitution of a new kind of American
government, which is their Eighteenth Amendment. If he and they
were to find anywhere citations in support of the ability of
governments in America to exercise and to grant undelegated power
to interfere with human freedom, to what source could he or they go
for such citations? Their proposition depended wholly for its validity
upon the Tory concept of the relation of government to its assets and
subjects, the people. And, in the five volumes of the records of the
conventions of the Americans, in the two volumes of The Federalist,
and in over two hundred volumes of American decisions in the
Supreme Court, he and they knew that no single citation of authority
could be found to support the idea that we Americans are “subjects”
and not citizens. In the face of such a situation, he and they had but
a choice between the repudiated claims of Calhoun and Haine or the
concepts of Lord North and his associates in the British Parliament
of 1775. We average Americans know what choice we would have
made, under such circumstances. For which reason we are not
surprised to find Sheppard, after his remarkable quotation from
Calhoun, continuing on to say that the states “by reserving to
themselves the unqualified and exclusive right of amendment kept
intact their sovereign capacity in so far as the organic law of the
nation was concerned.” (Congressional Record, Vol. 55, p. 5553.)
With the Supreme Court, we have always known and we still
know, despite Sheppard, that the people of America did all the
reserving that was done and which the Tenth Amendment merely
declared had been done. We note, with intent to remember, how
clearly Sheppard demonstrated his total ignorance of the most
important factor in that Tenth Amendment, “the people,” and of the
most important factor in the Fifth Article, the mention of the reserved
exclusive ability of the people themselves, assembled in their
“conventions,” to amend or change or add any national Article in
their Constitution.
As we go on with his oration of that July day, we find him insisting,
as we found the House insisting on a later day, that the states and
their legislative governments are all the protection to our individual
liberties which the American people were able to attain by the efforts
of those remarkable years from 1775 to 1790. Curiously enough, that
insistence is mentioned in the same breath in which he suggests that
we, the citizens of America, have some rights, evidently in the nature
of privileges which a government confers on its subjects. This is
what he has to say: “In refusing the people the right to appeal to the
only tribunal having power of amending, the tribunal of the states, for
the redress of what they consider one of the most terrible grievances
in the republic, Congress would deny to them one of the most sacred
of all rights, the right of petition.”
 Why should the supreme legislature not deny that right of petition
to us, if the inferior state legislatures, who are not governments of
the citizens of America, claim power to deny us any right they
please, as they do by their supposed Eighteenth Amendment to our
Constitution?
But we waste time on this Sheppard. Let him say his own farewell
to us; the citizens of America, in his closing words of July 30, 1917.
As Webb, in the House, closed with his eloquent appeal to every true
Mohammedan, we naturally find Sheppard closing with his appeal to
whatever Tory sentiment believes that the same most important
factor in the Tenth Amendment and the Fifth Article should be equally
ignored.
“At the close of this debate we will have an opportunity to enable
the states to exercise their highest function—the right to shape, alter,
and develop the federal Constitution. They are the proper tribunal to
decide the fate of this Amendment. They compose the mightiest
array of free commonwealths united in a federated whole the world
has ever seen.... If there is anything in the Amendment subversive of
their liberties and their welfare, they can be trusted to condemn it.
Let not Congress assume to judge for them. Let Congress discharge
its preliminary task of submission and stand aside. Let it put in
motion the referendum provided by the national organic law—the
method of amendment the states themselves established when they
created the Constitution. Let the states perform the duty which
remains the sole instance of their sovereignty over the federal
government itself.” (Congressional Record, Vol. 55, p. 5554.)
If it were still 1833, if there never had been a Gettysburg or an
Appomattox, could Calhoun himself have done better? If there never
had been the Statute of 1776 or an American Revolution to make it
the basic law of America, could any Tory peer in the Westminster
Parliament of 1775 have been more zealous to see that the states
themselves—which are mere political entities—should determine
whether there was anything in the Eighteenth Amendment
“subversive of their liberties and their welfare?” If there is, “they can
be trusted to condemn it.” Let our “Congress discharge its
preliminary task of submission and stand aside.” What if there is
anything in the Amendment subversive of our liberties and our
welfare? Why should we be trusted with the opportunity to condemn
it, the opportunity which we reserved exclusively to ourselves by the
most important factors in the Tenth Amendment and the Fifth Article?
Why should we remember that Jefferson, also from a Southern
State, penned the Statute of 1776 in which the American people
commanded that no government acquire power over people except
from people and not from governments? Why should we remember
that Pendleton, also from the South, while actually engaged with all
the rest of the American people in making the First Article, referred
to it and asked, “Who but the people can delegate powers? What
have the state governments to do with it?” Why should we remember
that Wilson, in the previous December, that of 1787, said of our
Constitution, “Upon what principle is it contended that the sovereign
powers reside in the state governments? The proposed system sets
out with a declaration that its existence depends upon the supreme
authority of the people alone? How comes it, sir, that these state
governments dictate to their superiors—to the majesty of the
people?” Why should we remember that Webster, answering Hayne
and Calhoun, said, also speaking of our Constitution, “While the
people choose to maintain it as it is—while they are satisfied with it,
and refuse to change it—who has given, or who can give, to the
state legislatures a right to alter it, either by interference,
construction, or otherwise?... Sir, the people have not trusted their
safety, in regard to the general constitution, to these hands. They
have required other security and taken other bonds.” (4 Ell. Deb.
508.)
It is true that these earlier Americans have clearly in mind the most
important factor in both the Tenth Amendment and the Fifth Article.
But it must not be forgotten that Pendleton and Wilson and the
Americans of that day, in making our Constitution, in constituting a
new government and giving to it some powers over the freedom of
human beings, were acting entirely outside any written law except
the Statute of ’76. Is not their example a sound precedent for those
who are now constituting a new government of Americans and giving
it power over their freedom, for those who made the Eighteenth
Amendment and those who upheld its validity? What if the makers of
the new government are themselves government? If governments
choose to act outside of all written law and to ignore that part thereof
which is the important factor of the Tenth Amendment and the Fifth
Article, are these governments not emulating the example of the
American people in 1787? True, these American people did act in
strict conformity to the Statute of 1776, and this modern constitution
of new government by government is not in conformity with that
Statute. But was not that Statute itself the revolt of human beings
against government? If human beings, by successful revolt against
government, could change themselves from subjects to citizens, why
cannot government, by successful revolt against human beings,
change them from citizens to subjects?
If, however, Sheppard and Webb and those of their Tory faith insist
that the new constitution of government is in our Constitution, and
put there validly, under claimed grant from us to state governments
of omnipotence over American citizens, we, on our part, know that
their claim is without the slightest support. Moreover, our knowledge
in that respect is knowledge of indisputable legal fact. That the fact
would be equally indisputable, even if our Constitution was a
compact between states, as Calhoun did claim, and as Sheppard
does claim, we can clearly demonstrate even to Sheppard himself.
Our education with the earlier Americans, who changed their status
from that of subject to citizen, has taught us all we need for that
demonstration.
Let us assume, what Sheppard asserts, that the states made the
Constitution, that it is a compact between states. Sheppard is a
Texan. If our Constitution is a compact between states, the State of
Texas is one of the parties to that compact. We ask Sheppard
whether he and the other Texans are the State of Texas or whether
the legislative government in Texas is the State of Texas? If he
answers that the Texas legislature is the State of Texas, we proceed
no further. That answer will be his frank confession that the Texan is
a subject of the Texas government and not a citizen or member of
the Texas State.
 On the other hand, if he answers that the human beings of Texas
are the State of Texas, we do proceed further. We proceed along the
most definitely settled legal principle in America. If the human beings
in Texas are its citizens and constitute its State, the constitution of
Texas is their creation and the legislature of Texas is the creature of
that constitution. From the Texans, through the creation which is their
constitution, that legislature derives its every power over the human
beings in Texas and cannot have any such power except by grant
from those human beings themselves. That is the law of Texas,
settled by hundreds of decisions in Texas and America. Now, if our
American Constitution is a compact between the State of Texas—the
human beings in Texas—and the other states—the human beings in
the other states—how comes it that the mere creature of the Texans,
without power over them except from them, can, by combination with
other servant legislatures outside Texas, give to itself and to other
governments outside Texas a new power to interfere with the
freedom of the human beings in Texas?
We are rather afraid that Sheppard and those of his faith, even
assuming that our Constitution is a compact between states, have
entirely overlooked the legal fact that a government is not the State
in America. We are rather afraid that they have reverted to what
Madison called “the impious doctrine of the Old World,” namely, that
the government is the State and the human beings are its asset and
its property. We are rather afraid that they agreed with the concept of
Louis of France, expressed in his famous “I am the State.”
On no other basis can we explain their complete ignorance of the
one important factor in the Tenth Amendment and the Fifth Article,
“the people” of America, who, assembled in their “conventions,” as
mentioned in the Fifth Article, are the citizens of America and
compose the State or Nation of America.
We average Americans, in the light of our education, reading the
record of that July 30 in our Senate, would have thought, were it not
for one fact, that every senator was using the expurgated edition of
the Constitution, which Webb later used in the House, and which
omits entirely from the Fifth Article the words, “by conventions in
three fourths of” the states. Were it not for that one fact our thought
would have been justified. We know that the proposition of
Sheppard, embodied in his Senate Resolution No. 17, was that the
proposed new Article should be referred to the tribunal of the state
legislative governments. We know, and we have quoted his own
statement, which is the basis of that knowledge, that he held that
legislative tribunal to be “the only tribunal having power of amending”
our Constitution. We know that he held this legislative tribunal to be
“the proper tribunal to decide the fate of this Amendment.” We know
his confidence that this legislative and government tribunal has “the
right to shape, alter, and develop” our Constitution, ordained and
established by the citizens of America. His conviction, in this respect,
is stamped indelibly on our mind, because it came in such sharp
conflict with our knowledge that all Americans of an earlier day held
that every national Article, like the First Article and the supposed
Eighteenth Amendment, must be referred to that other tribunal, the
only tribunal competent to make such Articles where men are
citizens and not subjects, the tribunal of the American citizens
themselves, the tribunal mentioned in the Fifth Article in the words
“by conventions in three fourths of” the states in America.
We know, therefore, inasmuch as neither Sheppard nor any
senator but one apparently knew of the existence of that other and
supreme tribunal or of the presence of those words in the Fifth
Article, that all senators save that one must have been using an
expurgated edition of the Fifth Article.
On that July 30 we find Senator Ashurst making plain that he has
our edition of our Constitution. He said, “When our federal
Constitution was written in 1787, two methods of amending were
provided; and, unless I am mistaken, it was the first written
constitution in history which provides for two methods of
amendment.” This brief and simple mention of that significant fact, in
relation to the Fifth Article, seems to have been the only cognizance
of the fact itself, in the Senate of that day or in the entire subsequent
history of the Eighteenth Amendment, even in the great litigations
about it in which were arrayed against one another the most
renowned “constitutional” lawyers in America. So far as would
appear from the Senate record, no knowledge of the amazingly
important effect of that Fifth Article mention of two distinct powers
(one limited and then existing in government and the other unlimited
and then and now existing in the American people) to make future
Articles was acquired in the Senate or afterward, from the fact itself
or from Ashurst’s allusion to the fact.
Back at Philadelphia in 1787, Gerry, always Tory in his mental
attitude to government and human being, realized fully the amazing
importance of this Fifth Article mention of the two then existing
powers to make Articles, the limited power of legislative
governments to make federal Articles (which had made all the
federal Articles of 1781) and the unlimited and exclusive power of
the people themselves to make national Articles, which had been
exercised to make the national Articles in each existing state
constitution, and which the Philadelphia Convention had already
ascertained and held was the only power competent to make such
Articles as their own proposed First Article and the Eighteenth
Amendment. While the Philadelphia Convention had been
discussing and deciding that their proposed Constitution, because of
its First Article, the real constitution of government, must be referred
to the people, Gerry had always opposed that decision. He had
always fought to have that First Article sent to government, to have
its grants of power over the freedom of men made by government to
government. When, therefore, the closing business day of that
Convention was reached on September 15, 1787, he made his final
and consistent Tory effort that citizens should be asked to make a
Fifth Article which would change them back again to the subjects
they had been in 1775. That effort was his motion of September 15
to strike from the Fifth Article, as we know it, the words “or by
conventions in three fourths of” the states. He knew, as we know, by
reason of our education with the Americans who defeated his effort,
that those words are the Fifth Article mention of the then existing
only ability in America which then could or now can make such
Articles as the original First Article or as the supposed Eighteenth
Amendment. He knew, as we average Americans now know, that,
only if such mention were stricken from that Fifth Article, could any
future possible claim be made that legislative governments have
ability to exercise or to grant undelegated power to interfere with
individual freedom. With the important object in mind, that he secure
some foundation for such claim in the future, he made his motion to
strike that mention of our exclusive power from that Fifth Article. As
we average Americans know, his effort to have a convention even
propose such a Fifth Article to “a people better acquainted with the
science of government than any other people in the world” was
beaten by the decisive vote of 10 to 1.
The proposal of the Eighteenth Amendment by government to
government was the attempt of our servant American government to
reverse the result of that vote of September 15, 1787. The action of
the state legislative governments in America upon that proposed
Eighteenth Amendment was an action depending entirely for its
validity upon a recount of that vote and the assumption that the
convention did strike out that mention of our exclusive power to
make national Articles and that the Fifth Article went to the American
people and was made by them without that mention in it. For which
very obvious reasons, we average Americans do not understand
how the fact, to which Ashurst made brief allusion on July 30, 1917,
was not the basis of every attack made in the Supreme Court by
many of the most renowned “constitutional” lawyers in America,
when they did assail the validity of that Eighteenth Amendment.
It is difficult to pick out the one most remarkable thing in the
complete story of the last five years. Yet we are inclined to believe
that, from a certain point of view, the one most remarkable thing is
the absolute failure of even one of those renowned lawyers to
appreciate or know or mention the fact and its decisive effect upon
the alleged validity of the Amendment they challenged, the fact that
the Fifth Article does name two future makers of Articles, the
governments which could and did make the federal Articles of 1781,
but which neither could nor did make the First Article of 1787 or the
Eighteenth Amendment of 1917, and the citizens of America, who
could and did make the First Article of 1787 and who alone can
make but have not made the Eighteenth Amendment.
Even Ashurst seems to have known that it was remarkable, unique
in history, for the Fifth Article to name two different makers of future
Articles. It is amazing that the imperative reason for this naming of
two makers, distinct and different in their ability to make, never
suggested itself to any of the renowned lawyers of 1920, even
though they knew the dual nature, national and federal, of our
Constitution. It is amazing when we realize that the Supreme Court,
in 1819, had stated, as an obvious thing, that, when the First Article
(granting power to interfere with the freedom of men) was proposed,
the legal “necessity of referring it to the people, and of deriving its
powers directly from them, was felt and acknowledged by all.” It is
amazing when the same Supreme Court in 1907 had authoritatively
repeated that statement: “The powers the people have given to the
general government are named in the Constitution, and all not there
named, either expressly or by implication, are reserved to the people
and can be exercised only by them or upon further grant from them.”
However, we average Americans, still pursuing the history of
America to learn when we again became “subjects,” will later herein
consider the litigation about the Eighteenth Amendment. So far as
the Senate is concerned, we leave it on December 18, 1917, the day
on which it finally proposed that legislative governments make the
Eighteenth Amendment, whose Second Section was exactly of the
same nature as the First Article, namely, an Article of the kind which
the Philadelphia Convention of 1787 had known never could be
made by legislative governments in America. In that Senate, as in
the House, the public record discloses no American who did not
ignore the most important factor in the Tenth Amendment and the
Fifth Article, no American who knew the legal necessity of deriving,
directly from the people themselves, every power to interfere with the
individual freedom of the people.
So far as history tells the tale, in the legislatures of the states, that
legal necessity was “known and acknowledged” by none. There were
many therein, as there were many in the later court litigations, who
opposed the making on the ground of its unwisdom. There were also
many, again as in the later litigations, who contended that there
should be no interference with the freedom of American citizens, as
such, except on the matters enumerated in the First Article. But,
neither in our own American legislature nor in these state
legislatures, as in the later litigations, was there one who knew the
only legal and maintainable ground for that belief, the legal fact, as
the Philadelphia Convention found it, that only the American people
could validly grant government power to interfere with their individual
freedom, and the legal fact that the American people, constituting
their government, kept the legal situation, in that respect, exactly as
the Philadelphia Convention found it, by the most important factors in
the Tenth Amendment and the Fifth Article.
The amazing haste with which the ratifying legislatures exercised,
for the first time in America, this imaginary power to interfere with the
individual freedom of the American citizens is a matter of history. The
manner in which that legislative exercise of imaginary government
power over subjects was secured in many states is something with
which we are all familiar. We desire, however, to emulate the
example set by Madison and Hamilton in The Federalist, so far as
judgment can restrain the honest indignation of citizens, when
government undertakes to make them “subjects.” Therefore we
leave it entirely to those who uphold the validity of the supposed new
Amendment to substitute irrelevant matter, mostly personal abuse
that is harmless in view of its source, for the sound legal arguments
in support of validity, which they can never find until the Statute of
’76 is repealed and our constitutions of government are so changed
that we cease to be citizens and become the subjects our ancestors
were in 1775.
For those who would like to look upon all American governments
as model exemplars of American respect for American law and
American constitutions, the date of the proposal in December, 1917,
and the quickness of ratification and the manner in which ratification
was largely secured, are all matters most unpleasant to contemplate.
Even now the most sincere advocate of the new Amendment never
speaks of it without unwittingly showing his chagrin at the general
knowledge that it was proposed and passed by governments when
millions of the citizens of those governments were fighting and were
armed to fight for human liberty, and that even governments would
never have dared to pass it except at that particular time.
These facts, however, reflect only on the virtue of the Amendment.
They have no bearing upon its validity. We average Americans are
interested now only in that claimed validity. We know that, if it is
valid, we have become subjects, that we are no longer citizens. We
are seeking to find out when and how that change was made in our
relation to all governments in America. Beginning on July 4, 1776,
we have come down to December 18, 1917. We have found
ourselves, on that day, still citizens. We know that our servant
legislature at Washington made a proposal on that day, which was
legally absurd, unless we had already become subjects. We have
listened carefully to what they had to say, in support of that proposal,
and have ascertained that they neither knew nor understood the
most important factor in our Tenth Amendment and Fifth Article, by
which our ancestors kept their own and our status as citizens. We
know that the state legislatures could not change that status.
Therefore we now simply note the fact that, in 1918, some of them
ratified the proposal on the basis that all of us were their subjects.
We know that our own government at Washington has acted,
whenever it felt disposed to enforce the supposed new command
against us and not to disobey it openly itself, as if we were the
subjects of those ratifying legislatures.
We know also that in 1920, after more than a year of exhaustive
study of our history and our Constitution and our laws by hundreds of
our most eminent lawyers, all working for one object, the legal
demonstration of the invalidity of the new Amendment, a chosen
number of the most renowned “constitutional” lawyers in America
appeared in the Supreme Court and orally argued against validity
and filed the briefs against validity which were the result of this
concentrated effort. We know also that, in that court, on behalf of our
own government and on behalf of those other governments which
that government has proclaimed to be the supreme dictator in
America, there also appeared another chosen array of the most
renowned “constitutional” lawyers, in the forefront being a former
justice of that court, now the American Secretary of State. This latter
array appeared to demonstrate how and when, since 1790, our own
status was changed from citizen to subject and the collective
legislatures of some of the states were substituted for ourselves as
possessors of the supreme constitutional will in America.
 We average Americans, therefore, to complete our education, now
turn to the arguments of these lawyers and to their briefs, with
somewhat of chagrin at our own unaided ability to ascertain the
“when” and “how” we became subjects and our Constitution, in its
national Articles and aspect, became the creature of legislative
governments, although the American people originally created it to
be the master of all governments.