Vol 26.peripheral Nerve and Motor Neuron Disorders.2020

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OCTOBER 2020
VOL. 26 NO. 5 Peripheral Nerve and
Motor Neuron Disorders
Guest Editor: A. Gordon Smith, MD, FAAN
1128 Editor’s Preface

Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
1130 A Structured Approach to the Diagnosis of Peripheral Nervous

System Disorders
Zachary N. London, MD, FAAN
1161 Diabetes and Metabolic Disorders and the Peripheral

Nervous System
Christopher H. Gibbons, MD, MMSc, FAAN
1184 Guillain-Barré Syndrome

Kazim A. Sheikh, MBBS
1205 Chronic Inflammatory Demyelinating Polyradiculoneuropathy and

Its Variants
Kelly Gwathmey, MD
1224 Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies

Christopher J. Klein, MD, FAAN
1257 Peripheral Neuropathies Associated With Vasculitis and

Autoimmune Connective Tissue Disease
DENOTES CONTINUUM
Chafic Karam, MD
AUDIO INTERVIEW
1280 Peripheral Neuropathies Due to Vitamin and Mineral Deficiencies,
Toxins, and Medications
Nathan P. Staff, MD, PhD, FAAN
1299 Management of Neuropathic Pain in Polyneuropathy

Amanda C. Peltier, MD, MS; Derek Wood, MD
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1323 Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases
Colin Quinn, MD; Lauren Elman, MD
1348 Spinal Muscular Atrophy

Jessica Rose Nance, MD
1369 Peripheral Neuropathies Associated With Monoclonal

Gammopathies
Elie Naddaf, MD; Michelle L. Mauermann, MD, FAAN
PRACTICE ISSUES
1384 Test Utilization and Value in the Evaluation of

Peripheral Neuropathies
Brian C. Callaghan, MD, MS, FAAN
1392 Rising Drug Costs for Neurologic Diseases

Jason L. Crowell, MD; Ted M. Burns, MD
SELF-ASSESSMENT AND CME
1120 Learning Objectives and Core Competencies
1407 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
1409 Postreading Self-Assessment and CME Test
1421 Postreading Self-Assessment and CME Test—Preferred Responses
1431 Erratum
1432 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS
A. Gordon Smith, MD, FAAN Brian C. Callaghan, MD, MS, FAAN

Guest Editor Associate Professor of Neurology,
Professor and Chair of Neurology, University of Michigan,
Kenneth and Dianne Wright Ann Arbor, Michigan
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Distinguished Chair in Clinical

Relationship Disclosure: Dr Callaghan
and Translational Research serves on a scientific advisory board for
(Neurology), Virginia a Patient-Centered Outcomes Research
Institute grant, on the International Diabetes
Commonwealth University, Neuropathy Consortium board for the
Richmond, Virginia Peripheral Nerve Society, on the editorial
board of Neurology, and as a consultant
Relationship Disclosure: Dr Smith serves as for DynaMed. Dr Callaghan has received
a consultant for Alexion Pharmaceuticals, research/grant support from the American
Inc; Argenx; Disarm Therapeutics; Eidos Academy of Neurology, JDRF, the National
Therapeutics; and Regenesis Biomedical, Institutes of Health (R01 DK115687), and the
Inc. Dr Smith receives research/grant US Department of Veterans Affairs (Clinical
support from the National Institutes of Science Research and Development Merit
Health (U01NS095388, R01DK064814). I01CX001504) and provided consulting
services for medicolegal cases and the US
Unlabeled Use of Products/Investigational Vaccine Injury Compensation Program.
Use Disclosure: Dr Smith reports
no disclosure. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Callaghan reports
no disclosure.
Ted M. Burns, MD
Harrison Distinguished
Jason L. Crowell, MD
Professor of Neurology,
Neurologist, Beth Israel
University of Virginia,
Deaconess Medical Center,
Charlottesville, Virginia
Boston, Massachusetts;
Relationship Disclosure: Dr Burns reports Jerome H. Grossman MD
no disclosure.
Graduate Fellow, Harvard
Unlabeled Use of Products/Investigational Kennedy School, Cambridge,
Use Disclosure: Dr Burns reports Massachusetts
no disclosure.
Relationship Disclosure: Dr Crowell has
received fellowship support from Medtronic.
Unlabeled Use of Products/Investigational

Use Disclosure: Dr Crowell reports no disclosure.
1122 O C TO B ER 2 0 2 0

Lauren Elman, MD Kelly Gwathmey, MD
Associate Professor of Neurology, Assistant Professor of
Perelman School of Medicine at Neurology; Chief, Division of
the University of Pennsylvania, Neuromuscular Medicine,
Philadelphia, Pennsylvania Virginia Commonwealth
University, Richmond, Virginia
Relationship Disclosure: Dr Elman serves on
advisory boards for Biogen and Genentech, Relationship Disclosure: Dr Gwathmey
Inc, and receives publishing royalties from has served as a consultant for and
UpToDate, Inc. received personal compensation for
speaking engagements from Alexion
Unlabeled Use of Products/Investigational Pharmaceuticals, Inc.
Use Disclosure: Dr Elman discusses
the unlabeled/investigational use of Unlabeled Use of Products/Investigational
anticholinergics, clonazepam, levetiracetam, Use Disclosure: Dr Gwathmey discusses
mexiletine, mirtazapine, phenytoin, selective the unlabeled/investigational use of
serotonin reuptake inhibitors, steroids, and azathioprine, bortezomib, corticosteroids
tricyclic antidepressants for the treatment (methylprednisolone, prednisone),
of amyotrophic lateral sclerosis and other cyclophosphamide, cyclosporine,
motor neuron diseases. methotrexate, mycophenolate mofetil,
and rituximab for the treatment of
chronic inflammatory demyelinating
polyradiculoneuropathy and its variants.
Christopher H. Gibbons, MD,
MMSc, FAAN
Associate Professor of Neurology,
Chafic Karam, MD
Harvard Medical School,
Associate Professor, Department
Boston, Massachusetts
of Neurology, Hospital of the
Relationship Disclosure: Dr Gibbons has University of Pennsylvania,
received personal compensation for Philadelphia, Pennsylvania
serving as a scientific advisor for
Lundbeck and Theravance Biopharma Relationship Disclosure: Dr Karam has served
and as an associate editor for Autonomic as a deputy editor for Neurology and as a
Neuroscience: Basic and Clinical, consultant for Acceleron Pharma, Inc; Akcea
research/grant support from Grifols, Therapeutics; Alnylam Pharmaceuticals, Inc;
and publishing royalties from UpToDate, Inc. Argenx; Biogen; CSL Behring; and Sanofi
Dr Gibbons has held stock/stock options in Genzyme. Dr Karam has received personal
Cutaneous Neurodiagnostics, LLC, and has compensation for speaking engagements
given expert medical testimony. from Akcea Therapeutics; Alnylam
Pharmaceuticals, Inc; CSL Behring;
Unlabeled Use of Products/Investigational and Sanofi Genzyme and research/grant
Use Disclosure: Dr Gibbons reports support from Akcea Therapeutics and
no disclosure. Sanofi Genzyme.

Use Disclosure: Dr Karam discusses
the unlabeled/investigational use of
cyclophosphamide, immunoglobulin,
rituximab, and steroids in the treatment of
vasculitis and immune-mediated neuropathy
in rheumatologic disorders.
C O N T I N U U M J O U R N A L .C O M 1123

CONTRIBUTORS (CONTINUED)
Christopher J. Klein, MD, FAAN Michelle L. Mauermann,

Professor of Neurology, Mayo MD, FAAN
Clinic, Rochester, Minnesota Professor of Neurology,
Neuromuscular Division of
Relationship Disclosure: Dr Klein serves on
the clinical expert and therapy boards of the Neurology, Mayo Clinic College
Charcot-Marie-Tooth Association. Dr Klein of Medicine and Science,
has received personal compensation for
speaking engagements at the Neuropathic
Rochester, Minnesota
Pain Symposium and research/grant
Relationship Disclosure: Dr Mauermann
support from the Mayo Clinic Center for
serves on the editorial board of Mayo Clinic
Individualized Medicine.
Proceedings; receives research/grant
support from Alnylam Pharmaceuticals,
Inc, and Ionis Pharmaceuticals, Inc; and
Use Disclosure: Dr Klein reports
receives publishing royalties from Oxford
no disclosure.
University Press.

Use Disclosure: Dr Mauermann discusses
Zachary N. London, MD, FAAN the unlabeled/investigational use of IV
James W. Albers Collegiate immunoglobulin and rituximab for the
Professor of Neurology and treatment of IgM neuropathy.
Clinical Professor of Neurology,

University of Michigan Medical
School, Ann Arbor, Michigan Elie Naddaf, MD
Assistant Professor of
Relationship Disclosure: Dr London Neurology, Mayo Clinic College
has received personal compensation
for speaking engagements from the of Medicine and Science,
American Academy of Neurology, the Rochester, Minnesota
American Association of Neuromuscular &
Electrodiagnostic Medicine, the American Relationship Disclosure: Dr Naddaf reports
Clinical Neurophysiology Society, the no disclosure.
University of Pennsylvania, and the
University of Rochester. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Naddaf discusses
Unlabeled Use of Products/Investigational the unlabeled/investigational use of IV
Use Disclosure: Dr London reports immunoglobulin and rituximab for the
no disclosure. treatment of IgM neuropathy.

Assistant Professor of Neurology,
Johns Hopkins School of Medicine,
Baltimore, Maryland
Relationship Disclosure: Dr Nance receives
research/grant support from AveXis, Inc;
Biogen; Catabasis Pharmaceuticals, Inc;
Catalyst Pharmaceuticals, Inc; Cytokinetics,
Inc; Santhera Pharmaceuticals; and
Scholar Rock.

Use Disclosure: Dr Nance reports no
disclosure.
1124 O C TO B ER 2 0 2 0

Amanda C. Peltier, MD, MS Colin Quinn, MD
Associate Professor of Assistant Professor of Clinical
Neurology; Associate Professor Neurology, University of
of Medicine, Director of Pennsylvania, Philadelphia,
Cardiology, Heart and Vascular Pennsylvania
Institute, Vanderbilt University
Relationship Disclosure: Dr Quinn serves on
Medical Center, Nashville, advisory boards for Acceleron Pharma, Inc,
Tennessee and Amylyx Pharmaceuticals and as a
consultant for Amicus Therapeutics,
Relationship Disclosure: Dr Peltier serves Inc. Dr Quinn receives research/grant
as secretary of the International Diabetes support from Acceleron Pharma, Inc;
Neuropathy Consortium, on the board Amicus Therapeutics, Inc; and Amylyx
of directors of the American Autonomic Pharmaceuticals.
Society, and on advisory boards for Akcea
Therapeutics; Alnylam Pharmaceuticals, Unlabeled Use of Products/Investigational
Inc; and CSL Behring. Dr Peltier has received Use Disclosure: Dr Quinn discusses
personal compensation for speaking the unlabeled/investigational use
engagements from Akcea Therapeutics and of anticholinergics, clonazepam,
CSL Behring and research/grant support levetiracetam, mexiletine, mirtazapine,
from Akcea Therapeutics, CSL Behring, phenytoin, selective serotonin reuptake
and the National Institute of Neurological inhibitors, steroids, and tricyclic
Disorders and Stroke NeuroNEXT. antidepressants for the treatment of
amyotrophic lateral sclerosis and other
Unlabeled Use of Products/Investigational motor neuron diseases.
Use Disclosure: Dr Peltier discusses
the unlabeled/investigational use of
a-lipoic acid, amitriptyline, cannabidiol
oil, carbamazepine, nortriptyline, Kazim A. Sheikh, MBBS
oxcarbazepine, spinal cord stimulators,
Professor of Neurology,
valproic acid, and venlafaxine for the
treatment of neuropathic pain in McGovern Medical School,
polyneuropathy. University of Texas; Director,
Neuromuscular Program,
Houston Health Science
Center, Houston, Texas
Relationship Disclosure: Dr Sheikh serves
on the medical advisory board of the
GBS/CIDP Foundation International and on
the editorial board of Scientific Reports.
Dr Sheikh has received personal
compensation for speaking engagements
from CSL Behring and research/grant
support from the Department of Defense
(W81XWH-18-1-0422) and the National
Institute of Neurological Disorders and
Stroke (R21NS107961).

Use Disclosure: Dr Sheikh reports
no disclosure.

Nathan P. Staff, MD, Derek Wood, MD
PhD, FAAN Neurologist, UW Medicine–Valley
Associate Professor and Medical Center, Renton,
Consultant of Neurology, Mayo Washington
Clinic, Rochester, Minnesota
Relationship Disclosure: Dr Wood reports
Relationship Disclosure: Dr Staff serves as no disclosure.
an associate editor of Stem Cell Research
& Therapy and receives research/grant Unlabeled Use of Products/Investigational
support from BrainStorm Cell Limited; Use Disclosure: Dr Wood discusses the
Disarm Therapeutics; the National Institutes unlabeled/investigational use of a-lipoic acid,
of Health (R01 CA211887); Orion Therapeutics, amitriptyline, cannabidiol oil, carbamazepine,
LLC; and Regenerative Medicine Minnesota nortriptyline, oxcarbazepine, spinal cord
(RMM 11215 CT002). stimulators, valproic acid, and venlafaxine
for the treatment of neuropathic pain in
Unlabeled Use of Products/Investigational polyneuropathy.
Use Disclosure: Dr Staff reports
no disclosure.
Self-Assessment and CME Test Writers
Douglas J. Gelb, MD, PhD, FAAN D. Joanne Lynn, MD, FAAN

Professor of Neurology, Associate Dean for Student
University of Michigan, Life, Clinical Professor of
Ann Arbor, Michigan Neurology, The Ohio State
University College of Medicine,
Relationship Disclosure: Dr Gelb receives
royalties from MedLink, Oxford University Columbus, Ohio
Press, and UpToDate, Inc.
Relationship Disclosure: Dr Lynn receives
Unlabeled Use of Products/Investigational book royalties from Lippincott Williams
Use Disclosure: Dr Gelb reports & Wilkins and holds stock in Abbott
no disclosure. Laboratories; AbbVie Inc; Amgen Inc;
Bristol-Myers Squibb Company; CVS Health
Corporation; Express Scripts Holding
Company; General Electric; Merck & Co, Inc;
and Zimmer Biomet.

Use Disclosure: Dr Lynn reports no disclosure.
1126 O C TO B ER 2 0 2 0

EDITOR’S PREFACE
Disorders of Peripheral Nerves,

From Beginning to End
This issue of Continuum is devoted to the diagnosis and management

of the spectrum of neurologic diseases that involve the peripheral
nerves, from the anterior horn cells and sensory ganglions to the
most distal axons. To accomplish this monumental task, I am so
thankful that Dr A. Gordon Smith, Chair of the American Academy
of Neurology Education Committee and member of the Continuum Editorial Board,
accepted my invitation to serve as the guest editor for this issue, and I am so
appreciative of Dr Smith for his organization of such well-thought-out topics and for
bringing such remarkable experts on board.
The issue starts with the article by Dr Zachary N. vasculitis (whether isolated to the peripheral nervous
London, who provides his guide of how to approach system or part of a systemic process) and autoimmune
the categorization and diagnosis of peripheral connective tissue diseases. Dr Nathan P. Staff then
nervous system disorders, serving as a comprehensive discusses peripheral neuropathies that occur as a
introduction to the articles that follow in this issue. consequence of vitamin and mineral deficiencies,
Next, Dr Christopher H. Gibbons discusses the toxins, and medications, important causes of
pathophysiology, diagnosis, and management of the peripheral neuropathy that are potentially reversible
neuropathic disorders that occur because of diabetes if recognized early. Next, Drs Amanda C. Peltier and
and other metabolic disorders, the most common Derek Wood discuss the management of neuropathic
causes of neuropathy in our clinics. pain in polyneuropathy, a disabling symptom that
Dr Kazim A. Sheikh then reviews the can occur as a consequence of many of the variety of
pathophysiology, diagnosis, and most up-to-date causes of polyneuropathy discussed in this issue.
management considerations in Guillain-Barré The next articles discuss the disorders that involve
syndrome and its variants. Similarly, in the following dysfunction of the anterior horn cells. First, Drs Colin
article, Dr Kelly Gwathmey reviews the pathophysiology, Quinn and Lauren Elman review the diagnosis and
diagnosis, and current management options for chronic management of amyotrophic lateral sclerosis and
inflammatory demyelinating polyradiculoneuropathy other motor neuron diseases that predominantly
(CIDP) and its variants and includes a discussion of present in adults. Next, Dr Jessica Rose Nance reviews
the relatively recent concept of the nodopathies and spinal muscular atrophy, a previously untreatable
paranodopathies. disorder for which knowledge of the genetic
Next, Dr Christopher J. Klein discusses the underpinnings has led to recent and remarkable
evolving nomenclature, categorization, and clinical clinically beneficial therapeutic breakthroughs.
features of Charcot-Marie-Tooth disease and other In the final review article of the issue, Drs Elie
hereditary neuropathies. Dr Chafic Karam then Naddaf and Michelle L. Mauermann carefully review
reviews the diagnosis and management of peripheral the diagnostic investigations, implications, and
neuropathies that can occur in association with management of the not uncommon clinical situation
1128 OCTOBER 2020

in which peripheral neuropathies are associated with maximum of 20 hours toward the Self-Assessment
monoclonal gammopathies. Program (Section 3) of the Maintenance of
This issue is distinguished by having two Practice Certification Program of the Royal College of
Issues articles. In the first article, Dr Brian C. Physicians and Surgeons of Canada. Additional credit
Callaghan analyzes the practical and important can be obtained by listening to Continuum Audio
concept of test utilization and value in the interviews associated with this and other Continuum
investigation of peripheral neuropathies. In the issues, available to all subscribers, and completing
second article, Drs Jason L. Crowell and Ted M. tests on the Continuum Audio web platform or
Burns provide their informed analysis and opinions mobile app. Continuum Audio is also accredited by
regarding rising costs of drugs for neurologic the Royal College of Physicians and Surgeons of
diseases, including those of relevance to the topic of Canada.
this issue. We continue to invite all readers to try the new
After reading the issue and taking the Postreading Continuum mobile phone experience available at
Self-Assessment and CME Test written by Drs continpub.com/ConBeta. Using this intuitively built
Douglas J. Gelb and D. Joanne Lynn, readers may new mobile phone application, subscribers are able to
earn up to 20 AMA PRA Category 1 CreditsTM toward search, access, and read full Continuum articles,
self-assessment CME or, for Canadian participants, a including all text, tables, and figures, in an
easy-to-view format wherever they are and
whenever they want.
My sincere thank-you to Dr Smith for his
hands-on devotion to this complex issue through
The result under Dr Smith’s guest every step of the editorial process. The result under
Dr Smith’s guest editorship is an issue that will
editorship is an issue that will provide our readers with the knowledge and skills
provide our readers with the needed to diagnose and manage the many patients
knowledge and skills needed to we see with disorders affecting the peripheral
diagnose and manage … patients … nervous system from the nerve cell bodies to the
terminal axons and anywhere in between.
with disorders affecting the
peripheral nervous system from the —STEVEN L. LEWIS, MD, FAAN
EDITOR-IN-CHIEF
nerve cell bodies to the terminal
axons and anywhere in between. © 2020 American Academy of Neurology.
CONTINUUMJOURNAL.COM 1129

REVIEW ARTICLE

A Structured Approach
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
to the Diagnosis of
Peripheral Nervous
System Disorders
By Zachary N. London, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: Neuroanatomic localization and pattern recognition can
be used to diagnose both focal lesions and generalized disorders of the
peripheral nervous system. This article describes the nature and pattern of
sensory and motor deficits associated with lesions of specific spinal nerve
roots, plexus, or peripheral nerves. It also describes the patterns of
sensory and motor deficits that suggest multifocal or generalized disorders
of the motor neurons, sensory neurons, and peripheral nerves.
RECENT FINDINGS: The pattern of sensory and motor deficits may be used to
distinguish lesions of the peripheral nervous system from those of the
CITE AS:
central nervous system. The spinal roots, nerve plexus, and peripheral
CONTINUUM (MINNEAP MINN) nerves supply specific muscles and receive sensory input from distinctive
2020;26(5, PERIPHERAL NERVE AND cutaneous regions. Focal lesions of these structures therefore produce
MOTOR NEURON DISORDERS):
1130–1160. characteristic patterns of sensory and motor deficits. Multifocal or
generalized disorders of the peripheral nervous system may be
Address correspondence to distinguished by categorizing their sensory and motor involvement,
Dr Zachary N. London, 1324
Taubman Center, 1500 E Medical
proximal and distal predominance, and degree of symmetry. Serum tests,
Center Dr, Ann Arbor, MI 48109, CSF analysis, electrodiagnostic studies, MRI, ultrasound, nerve biopsy, and
zlondon@med.umich.edu. skin biopsy have unique roles in the diagnosis of suspected neuromuscular
RELATIONSHIP DISCLOSURE:
disorders.
Dr London has received personal
compensation for speaking SUMMARY: A structured approach to the diagnosis of nerve and motor
engagements from
the American Academy of neuron disorders can lead to hypothesis-driven diagnostic testing.
Neurology, the American Ancillary tests should be reserved for cases in which confirming or refuting
Association of Neuromuscular
a diagnosis will change patient management.
& Electrodiagnostic Medicine,
the American Clinical
Neurophysiology Society, the
University of Pennsylvania, and
the University of Rochester.
INTRODUCTION
T
UNLABELED USE OF he peripheral nervous system consists of the motor, sensory, and
PRODUCTS/INVESTIGATIONAL
autonomic neural elements that have extensions outside of the brain
USE DISCLOSURE:
Dr London reports no disclosure. and spinal cord. Motor neurons are located in the anterior gray matter
of the spinal cord and are often referred to as anterior horn cells. Their
© 2020 American Academy
axons traverse the nerve roots into the peripheral nerves and
of Neurology. communicate with the muscle at the neuromuscular junction. Sensory neurons
1130 OCTOBER 2020

are located in the dorsal root ganglia, which are located posteriorly just outside
the intervertebral foramina.
Dorsal and ventral roots travel through the intervertebral foramina and
fuse to form the spinal nerves. The anterior primary rami form the brachial
and lumbosacral plexus, which terminate in the peripheral nerves. Each of
these neuroanatomic structures is responsible for providing motor input to
specific muscles or receiving sensory input from specific areas in the
extremities or the afferent arcs of the deep tendon reflexes. When a patient
has right-sided focal weakness, the responsible lesion could be anywhere
along the motor pathway from the left motor cortex down through the
decussation at the medullary pyramids, in the corticospinal tracts, or in the
peripheral structures summarized above. For example, isolated weakness of
the right abductor pollicis brevis may be related to a central nervous system
(CNS) lesion or a peripheral lesion involving the C8 or T1 anterior horn cells,
corresponding ventral roots, lower trunk of the brachial plexus, medial cord of
the brachial plexus, median nerve, neuromuscular junction, or the muscle
itself. This list can be whittled down dramatically by adding a second clinical
abnormality, such as numbness over the palmar aspect of the right index
finger. The combination of those findings would make a right median
mononeuropathy significantly more likely than the other possible
localizations. This is the classic strategy of neuroanatomic localization; the
clinician uses the physical examination and a knowledge of functional
neuroanatomy to identify where the involved pathways overlap.
Disorders of the peripheral nervous system may be focal, multifocal, or
generalized, but the classic strategies of neuroanatomic localization work best
with focal lesions. In generalized disorders of the peripheral nervous system, the
innervations of individual muscles become less important than recognizing
patterns, such as whether the weakness and numbness are distal or proximal,
whether symptoms are symmetric between limbs, or whether cranial or
autonomic nerves are involved.
A rational approach to a patient with sensory or motor symptoms answers the
following questions about the clinical presentation:
u Does it localize to the CNS or to the peripheral nervous system?

u Can it localize to a single named peripheral nervous system structure?
u If it is multifocal or generalized:
◇ Does it involve sensory loss or weakness, or both?
◇ Is it primarily proximal or distal, or both?
◇ Is it symmetric or asymmetric?
u Is it acute or subacute in onset?
Often, the answers to these questions will narrow the differential diagnosis
enough so that the judicious use of ancillary testing can verify a specific
diagnosis.
CENTRAL OR PERIPHERAL NERVOUS SYSTEM

One of the first tasks of the clinician is to use the history and physical
examination to distinguish disorders of the peripheral nervous system from

APPROACH TO PERIPHERAL NERVOUS SYSTEM DISORDERS
disorders of the CNS. In addition to appreciation of upper motor neuron and

lower motor neuron signs on examination, a number of localization clues can be
useful in distinguishing central versus peripheral lesions (TABLE 1-1).
u Lesions in the brain and brainstem rarely cause pain. A notable exception is central
poststroke pain. This is a rare late effect of ischemic stroke, usually in the thalamus, and is
characterized by contralateral hyperalgesia and allodynia. The presence of pain with
neuropathic features (eg, burning, tingling, electric shock–like sensation) in the affected
limb(s) should prompt the examiner to consider a peripheral etiology.
u Hyporeflexia in a symptomatic limb suggests a peripheral lesion, whereas brisk reflexes in
a symptomatic limb suggest a central lesion.
u If all the signs and symptoms are in a single limb, both central and peripheral
localizations are possible. Hemibody symptoms suggest a central localization; no single
lesion in the peripheral nervous system can cause isolated symptoms affecting an
arm and leg on the same side of the body.
u If a patient has deficits in both strength and pain/temperature sensation in the same limb
and no other abnormalities, the lesion is either in the brain or the peripheral nervous
system, not in the spinal cord.
u Patients with ascending sensory loss in both lower extremities may have either a spinal
cord lesion or a polyneuropathy. Peripheral polyneuropathy causes length-dependent
symptoms and signs, so by the time the sensory loss spreads up above the knee, the
distal upper extremities are usually involved as well. Sensory loss that spreads up
from the feet to the groin or trunk without any upper extremity involvement is almost
always related to spinal cord pathology.
TABLE 1-1 Distinguishing Central From Peripheral Nervous System Lesions
Features Consistent With Any Central Nervous System Localization

◆ Brisk reflexes in an affected limb
◆ Increased tone in an affected limb
◆ Sensory or motor symptoms limited to two limbs on the same side of the body
◆ Weakness of extensors in the upper extremity
◆ Weakness of flexors in the lower extremity
Features Consistent With a Spinal Cord Localization
◆ Sensory loss in both legs with a sensory level on the trunk
◆ Decreased pinprick sensation on one side, weakness and diminished proprioception on the
other side
Features Consistent With a Peripheral Localization
◆ Axial or limb pain
◆ Diminished reflexes in an affected limb
◆ Weakness and diminished pain sensation in the same limb are not due to a spinal cord lesion
and are due to either a peripheral or brain/brainstem lesion
◆ Sensory loss that involves the hands and feet but not the trunk
1132 OCTOBER 2020

u Patients with upper extremity weakness due to a CNS lesion often have preferential KEY POINTS
involvement of the extensors, such as the triceps and wrist and finger extensor muscles.
Although rare, a proximal radial mononeuropathy could also affect these muscles. To rule ● The presence of
that out, it is useful to test the strength of the brachioradialis, which will be reduced in neuropathic pain in an
a proximal radial mononeuropathy but relatively spared (along with the other upper affected limb is more
extremity flexors) in a CNS lesion. suggestive of a peripheral
u Patients with leg weakness due to a CNS lesion often have preferential weakness of nervous system lesion than a
the flexors, such as the iliopsoas, hamstrings, and tibialis anterior. No single peripheral central nervous system
lesion could affect all of these muscles in isolation. lesion.
● Features that suggest a

central nervous system
FOCAL SYMPTOM PATTERN
lesion rather than a
The first question to ask is whether the sensory and motor signs and symptoms peripheral nervous system
can localize to a single named nervous system structure. The spinal nerve roots, lesion include a sensory
nerve plexus, and most peripheral nerves contain both afferent somatic sensory level on the trunk,
nerve fibers and efferent motor fibers. Lesions of these structures may cause hyperreflexia, hemibody
symptoms, weakness of
distinctive patterns of pain, sensory loss, and weakness. extensors in an arm, and
weakness of flexors in a leg.
Radiculopathy ● Neuralgic amyotrophy
A careful neurologic examination coupled with an understanding of the may appear to localize to
neuroanatomic functions of the spinal nerve roots may yield a very specific multiple nerves in the same
localization. TABLE 1-2 and TABLE 1-3 summarize the sensory and motor findings limb rather than a specific
part of the brachial plexus.
associated with lesions at each level.1 Sensory symptoms often precede motor
symptoms in cervical and lumbar radiculopathy. This should be considered in a
patient with axial and radicular pain who presents with a dermatomal pattern of
sensory loss.
The most common mechanisms of spinal nerve root compression are
intervertebral disk herniation and spondylosis.2 Less common causes include
synovial cysts, osteomyelitis and diskitis, vertebral fracture, bony malignant
disease, epidural hematoma, infectious radiculitis, or infiltrative disease of the
meninges. The presence of systemic symptoms may raise suspicion for some of
these less common mechanisms.
Plexopathy
The brachial and lumbosacral plexus are anatomically protected compared
to the spinal nerve roots but may be susceptible to trauma, structural
abnormalities, neoplastic infiltration, or inflammatory processes (TABLE 1-4
and TABLE 1-5).
Neuralgic amyotrophy (also known as idiopathic brachial plexitis or
Parsonage-Turner syndrome) is an uncommon disorder characterized by
subacute onset of pain, weakness, and sensory loss. Although it is usually referred
to as a plexopathy, neuralgic amyotrophy may present with multiple disparate
mononeuropathies in the same limb rather than dysfunction of a focal region of
the brachial plexus.3
Neurogenic thoracic outlet syndrome is a controversial and likely
overdiagnosed condition in which the lower trunk or C8 and T1 nerve roots are
injured or compressed by certain anatomic defects, such as an extra rib. It
presents with aching pain along the medial aspect of the upper extremity and
weakness of the intrinsic hand muscles.4
In patients with breast or lung cancer, the mechanisms of brachial plexopathy
include trauma during surgery, metastatic spread of tumor (which most

TABLE 1-2 Sensory, Motor, and Reflex Distributions of the Upper Extremity Rootsa
Principal Muscles Diminished

Structure Involved Sensory Distribution Reflexes
C5 root Rhomboidsb Lateral upper arm Biceps,
b brachioradialis
Supraspinatus
Infraspinatusb
Deltoidb
Brachioradialisb
Biceps
C6 root Supraspinatus Lateral forearm and hand, first Biceps,

two digits brachioradialis
Infraspinatus
Deltoid
Brachioradialisb
Triceps
Flexor carpi radialisb
Extensor carpi
radialisb
Pronator teresb
C7 root Tricepsb Centermost portion of the distal Triceps

b dorsal forearm and third digit
Flexor carpi radialis
Extensor carpi
radialisb
Pronator teresb
Extensor digitorumb
Flexor digitorumb
Flexor pollicis
longusb
C8 root Triceps Fourth and fifth digits and medial None

b hand
Extensor indicis
Flexor pollicis
longusb
Abductor pollicis
brevisb
Interosseib
T1 root Abductor pollicis Medial forearm None

brevisb
Interosseib
a
Modified with permission from London ZN.1 © 2019 American Academy of Neurology.
b
Muscle may be more prominently involved.
1134 OCTOBER 2020

commonly affects the lower trunk), and radiation injury. Tumor infiltration is
more likely to cause pain than radiation injury.5
Mononeuropathy
Most mononeuropathies occur at specific entrapment sites, regions where
specific nerves are relatively unprotected or susceptible to stretch or
compression due to day-to-day use or repetitive trauma. The most common
entrapment sites are the median nerve at the carpal tunnel, the ulnar nerve at
the elbow, the radial nerve at the spiral groove, and the fibular (peroneal)
nerve at the fibular head (TABLE 1-6 and TABLE 1-7).6 Most of these cause both
sensory and motor manifestations. Other causes of focal nerve injury include
acute trauma, ischemia, compression or invasion by tumor, infection, irradiation,
or injury due to cold.
Sensory, Motor, and Reflex Distributions of the Lower Extremity Rootsa TABLE 1-3

L2 root Iliopsoasb Anterior thigh None

b
Adductor longus
L3 root Iliopsoasb Medial thigh, knee Patellar

b
Quadriceps
Adductor longusb
L4 root Quadricepsb Medial lower leg Patellar

b
Adductor longus
Tibialis anterior
L5 root Gluteus mediusb Lateral lower leg, dorsal None

foot
Hamstrings
Tibialis anteriorb
Extensor digitorumb
Peroneus longusb
Tibialis posteriorb
S1 root Gluteus maximusb Posterior/lateral lower Ankle

b leg, plantar aspect of
Hamstrings
foot
Gastrocnemiusb
Peroneus longus
Extensor digitorum
Tibialis posterior
a
b

The most common mononeuropathies to cause a pure motor syndrome are

those that affect a nerve that does not have a sensory component. Examples
include the suprascapular nerve, the anterior interosseous nerve, or the posterior
interosseous nerve. Occasionally, entrapment of a mixed nerve, such as the ulnar
nerve or fibular (peroneal) nerve, may spare the fascicles involved in sensation.
In these cases, the distribution of the weakness is most helpful in localizing the
lesion. A pure motor syndrome that follows more of a myotomal pattern, with
denervation in the distribution of individual spinal roots, has been reported as a
complication of intrathecal chemotherapy or radiation therapy near the spinal
roots.7 In theory, injury or infiltration of the ventral spinal roots can cause a pure
motor radiculopathy, but this is rare.
TABLE 1-4 Sensory, Motor, and Reflex Distributions of the Upper Extremity Plexusa
Diminished
Structure Principal Muscles Involved Sensory Distribution Reflexes
Upper Supraspinatusb Lateral upper arm and forearm Biceps,

trunk b and first one to two digits brachioradialis
Infraspinatus
Deltoidb
Brachioradialisb
Bicepsb
Triceps
Pronator teres
Extensor carpi radialis
Lower Triceps Medial forearm and hand, None

trunk b fourth and fifth digits
Extensor digitorum
Extensor indicisa
Flexor digitorum
profundusb
Flexor pollicis longusb
Abductor pollicis brevisb
Interosseib
Middle Tricepsb Centermost portion of the Triceps

trunk b distal forearm and third digit
Extensor carpi radialisb
Pronator teresb
Extensor digitorumb
Flexor digitorumb
CONTINUED ON PAGE 1137
1136 OCTOBER 2020

Some peripheral nerves have no motor component. A focal lesion involving
one of these will result in isolated sensory loss in the distribution of that nerve.
Examples in the upper extremity include the superficial radial nerve and the
medial and lateral antebrachial cutaneous nerves. Examples in the lower
extremity include the lateral femoral cutaneous nerve, the saphenous nerve,
and the sural nerve. It is not uncommon for focal mononeuropathies of
mixed nerves to preferentially involve the sensory fascicles. A median
mononeuropathy caused by carpal tunnel syndrome, for example, commonly
presents with wrist pain and sensory loss in the palmar aspect of the first three
or four digits. Patients may not develop the characteristic thenar weakness
until late in the course of the disease.
CONTINUED FROM PAGE 1136
Diminished
Structure Principal Muscles Involved Sensory Distribution Reflexes
Lateral Bicepsb Lateral forearm, palmar hand Biceps
cord b and first three digits
Pronator teres
Flexor carpi radialisb
Flexor digitorumb
Medial Flexor digitorumb Medial forearm and hand, None

cord b fourth and fifth digits
Flexor pollicis longus
Abductor pollicis brevisb
Interosseib
Posterior Deltoidb Dorsal aspect of upper arm, Triceps,

cord b forearm, lateral hand, and the brachioradialis
Teres minor
first three digits
Brachioradialisb
Tricepsb
Extensor digitorumb
Extensor indicisb
a
b

MULTIFOCAL OR GENERALIZED SYMPTOM PATTERN

In patients with multifocal or generalized symptoms that appear to localize to the
peripheral nervous system, the next questions to ask are whether the symptoms
involve sensory loss or weakness, or both; whether they are proximal or distal, or
both; and whether they are symmetric or asymmetric (FIGURE 1-1).
MIXED SENSORY AND MOTOR SYMPTOM PATTERN

Most disorders of nerves, spinal roots, and plexus are characterized by both
sensory and motor involvement. The differential diagnosis can be narrowed
further by recognizing the pattern of signs and symptoms.
Proximal Asymmetric
Proximal asymmetric weakness and sensory loss are usually due to a
polyradiculopathy, polyradiculoneuropathy, or radiculoplexopathy. This pattern
is particularly suggestive of diabetic lumbosacral radiculoplexus neuropathy, also
known as diabetic amyotrophy, which presents with subacute progressive
asymmetric pain and weakness, most prominently affecting the proximal lower
extremity muscles. Most patients have superimposed weight loss and autonomic
dysfunction. The severity of the symptoms does not correlate with the severity of
the diabetes, and, in fact, glycemic dysregulation may be mild at the time of
diagnosis.8 For more information on diabetic lumbosacral radiculoplexus
neuropathy, refer to the article “Diabetes and Metabolic Disorders and the
Peripheral Nervous System” by Christopher H. Gibbons, MD, MMSc, FAAN,9 in
this issue of Continuum. Other causes of proximal asymmetric sensorimotor
symptoms include meningeal disorders, such as carcinoma, lymphoma,
sarcoidosis, or infections, which may infiltrate multiple nerves, roots, and
regions of the plexus.
TABLE 1-5 Sensory, Motor, and Reflex Distributions of the Lower Extremity Plexusa

Lumbar plexus Iliopsoas Anterior thigh, medial and Patellar

lateral thigh, medial lower leg
Quadriceps
Adductor longus
Lower Gluteus medius Posterior thigh, lateral lower Ankle

lumbosacral leg, all of foot
Gluteus maximus
plexus
Hamstrings
Tibialis anterior
Extensor digitorum
Peroneus longus
Tibialis posterior
Gastrocnemius
a
1138 OCTOBER 2020

Proximal and Distal Symmetric KEY POINTS
Peripheral nervous system disorders that involve proximal muscles are usually
● Injuries to nerve roots and
related to involvement of nerve roots (polyradiculopathy). Symmetric proximal mixed nerves, both of which
and distal involvement strongly suggests involvement of both nerve roots and contain both sensory and
the distal peripheral nerves (polyradiculoneuropathy). motor components, may
Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) presents present with pain or sensory
symptoms without
with acroparesthesia followed by symmetric ascending weakness and areflexia,
weakness.
usually developing over 1 to 2 weeks. The weakness usually affects proximal and
distal limb muscles symmetrically and may involve muscles involved in facial ● Chronic inflammatory
expression, speech, swallowing, neck flexion, breathing, and, occasionally, eye demyelinating
movements. Sensory loss is common but usually mild. Most patients report axial polyradiculoneuropathy
progresses for more than
and radicular pain. Patients often develop dysautonomia, characterized by sinus 8 weeks after symptom
tachycardia or labile blood pressure. Ninety percent of patients reach their nadir onset. Unlike acute
by 4 weeks.10 For more information on AIDP, refer to the article “Guillain-Barré inflammatory demyelinating
Syndrome” by Kazim A. Sheikh, MBBS,11 in this issue of Continuum. polyradiculoneuropathy, it is
generally not associated
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes with dysautonomia,
slowly progressive proximal and distal weakness, areflexia, and sensory loss. weakness of cranial
Progression continues for more than 8 weeks after symptom onset. Unlike AIDP, muscles, or dyspnea.
CIDP does not usually affect cranial nerves or muscles of respiration. For more
● Mononeuritis multiplex
information on CIDP, refer to the article “Chronic Inflammatory Demyelinating
affects named nerves but
Polyradiculoneuropathy and Its Variants” by Kelly Gwathmey, MD,12 in this not necessarily at the
issue of Continuum. common entrapment sites.
Proximal and Distal Asymmetric

The presence of significant asymmetry in a patient with prominent distal
weakness suggests a mononeuritis multiplex, which is defined by damage to at
least two named peripheral nerves, most often not at entrapment sites. The most
common mechanism is vasculitis, inflammatory destruction of the vasa
nervorum, and resultant ischemic nerve injury. The clinical course is usually
acute or stuttering, with significant pain and sensory and motor deficits in
discrete peripheral nerve distributions.13 Over time, mononeuritis multiplex may
affect so many nerves that the pattern becomes symmetric, a pattern referred to
as confluent mononeuritis multiplex.
Even when only one nerve is involved, the conditions that predispose patients
to mononeuritis multiplex should be considered if no evidence of trauma is
present, the involved nerve is not susceptible to entrapment, or the injury is not
at the common entrapment site (CASE 1-1).
Mononeuritis multiplex may occur in isolation (nonsystemic vasculitic
neuropathy) or may occur as a manifestation of eosinophilic granulomatosis
with polyangiitis, granulomatosis with polyangiitis, microscopic polyangiitis,
or polyarteritis nodosa. Other systemic inflammatory disorders, such as
rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus
(SLE) can predispose patients to mononeuritis multiplex.14 For more
information about vasculitic and other autoimmune axonal neuropathies,
refer to the article “Peripheral Neuropathies Associated with Vasculitis and
Autoimmune Connective Tissue Disease” by Chafic Karam, MD,15 in this issue
of Continuum.
Other causes of multiple mononeuropathies include lymphoma, diabetes,
hepatitis, or human immunodeficiency virus (HIV). Multifocal acquired
demyelinating sensory and motor neuropathy (MADSAM) is a rare variant of

CIDP that causes a chronic sensorimotor mononeuropathy multiplex with

involvement of individual nerves asymmetrically, distal more than proximal and
upper limbs more than lower limbs.16 Hereditary neuropathy with liability to
pressure palsies (HNPP) is an autosomal dominant disorder characterized by
recurrent painless mononeuropathies following compression or trivial trauma.17
Distal Symmetric
Distal symmetric involvement is consistent with a length-dependent
polyneuropathy. The differential diagnosis is based on the relative sensory and
motor involvement.
DISTAL SYMMETRIC POLYNEUROPATHY. The most common pattern of

generalized peripheral nerve dysfunction is aptly referred to as distal symmetric
polyneuropathy. This term is preferred over the less specific terms neuropathy,
peripheral neuropathy, and polyneuropathy, which are often used
interchangeably but fail to exclude focal or multifocal processes.
TABLE 1-6 Sensory, Motor, and Reflex Distributions of the Upper Extremity Nervesa

Dorsal scapular Rhomboidsb None None
b
Suprascapular Supraspinatus None None
b
Infraspinatus
Musculocutaneous Bicepsb Lateral forearm Biceps
Axillary Deltoid Lateral shoulder None
Radial
Superficial sensory nerve at None Dorsal hand and first three digits None
the wrist
Posterior interosseous Extensor digitorumb None None

b
Extensor indicis
At the spiral groove Brachioradialisb Dorsal hand and first three digits Brachioradialis
b
Extensor carpi radialis
Extensor digitorumb
Extensor indicisb
At the axilla Tricepsb Dorsal aspect of upper arm, forearm, lateral Brachioradialis,
b hand, and the first three digits triceps
Brachioradialis
Extensor digitorumb
Extensor indicisb
1140 OCTOBER 2020

Distal symmetric polyneuropathy is sensory predominant, with little or no
motor involvement until later in the course of the illness when patients may
have mild distal lower extremity weakness. Patients often experience
neuropathic pain, paresthesia, or sensory loss that starts in the toes and feet
because of length-dependent axonal injury. As the disease progresses, the
sensory symptoms move proximally. Around the time that sensory
abnormalities reach the knees, patients may also begin to experience
paresthesia, pain, or sensory loss in the fingertips. Sensory symptoms then
proceed proximally in the upper extremities. Loss of deep tendon reflexes
occurs in a length-dependent pattern. When present, motor involvement also
starts distally, with weakness of the toe flexor and extensor muscles. Atrophy
of the intrinsic foot muscles, such as the extensor digitorum brevis, may be
found before clinically significant weakness.
Patients with distal symmetric polyneuropathy may note mild sudomotor
dysfunction on directed questioning (reduced sweating in the feet or increased
sweating more proximally). However, more significant autonomic neuropathy,

Median
Anterior interosseous Flexor pollicis longusb None None

Flexor digitorum
profundus 1–2b
At the carpal tunnel Abductor pollicis Palmar first through third digits None
brevisb
At the elbow Pronator teresb Palmar hand and first through third digits None
b
Flexor digitorum
profundus 1–2b
Abductor pollicis
brevisb
Ulnar
At the wrist Interosseib Palmar aspect of fourth and fifth digits None
b
Interossei
At the elbow Flexor digitorum Medial hand, fourth and fifth digits None
profundus 4–5b
a
b

including orthostatic hypotension, prominent sexual dysfunction, or gastroparesis,

is unusual and suggests specific disorders (eg, diabetes or amyloidosis).
Most distal symmetric polyneuropathies have a chronic time course with slow
progression. Most patients with this pattern have diabetes, prediabetes, or
idiopathic neuropathy. Although uncommon, vitamin B12 deficiency and
paraproteinemia (monoclonal gammopathy) should be excluded in all patients.18
Other common causes of distal symmetric polyneuropathy include toxicity due
to specific chemotherapeutic agents and chronic alcohol use.18
Distal symmetric polyneuropathy with motor greater than sensory
involvement suggests a distinct differential diagnosis. The most common cause
of this pattern is Charcot-Marie-Tooth disease (CMT), also known as hereditary
motor sensory neuropathy. Other diagnostic clues for CMT include a young
age of onset, a positive family history, and high arches and hammer toes related
to long-standing atrophy of intrinsic foot muscles. For more information on
Charcot-Marie-Tooth disease, refer to the article “Charcot-Marie-Tooth Disease
TABLE 1-7 Sensory, Motor, and Reflex Distributions of the Lower Extremity Nervesa
Structure Principal Muscles Involved Sensory Distribution Diminished Reflexes
Femoral
Above inguinal ligament Iliopsoas Medial thigh and lower leg Patellar
Quadriceps
Below inguinal ligament Quadriceps Medial thigh and lower leg Patellar
Obturator Adductor longus Medial thigh None
Sciatic Hamstrings Lateral lower leg, all of foot Ankle

Tibialis anterior
Extensor digitorum
Peroneus longus
Tibialis posterior
Gastrocnemius
Fibular (peroneal)
Deep Tibialis anterior First dorsal webspace None

Extensor digitorum
Superficial Peroneus longus Lateral lower leg, dorsal aspect of foot None
Common Tibialis anterior Lateral lower leg, dorsal aspect of foot None
Extensor digitorum
Peroneus longus
Tibial Tibialis posterior Plantar aspect of foot Ankle

Gastrocnemius
a
1142 OCTOBER 2020

KEY POINTS
● Mononeuritis multiplex is
usually an axonal process,
but multifocal acquired
demyelinating sensory and
motor neuropathy and
hereditary neuropathy with
liability to pressure palsies
are multifocal demyelinating
neuropathies.
● Distal symmetric
polyneuropathy usually
begins to involve the distal
upper extremities around
the time that the lower
extremity sensory
symptoms progress to the
level of the knees.
● Clinical features that

should raise suspicion for a
hereditary cause of
neuropathy include young
age of onset, family history,
and high arches and
FIGURE 1-1 hammer toes.
A pattern recognition approach for multifocal or generalized sensory and motor symptoms.
In each of the nine squares, diagnoses at the top tend to be symmetric, whereas diagnoses at
the bottom tend to be asymmetric.
AIDP = acute inflammatory demyelinating polyradiculoneuropathy; ALS = amyotrophic lateral sclerosis;
CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CISP = chronic immune sensory
polyradiculoneuropathy; CMT = Charcot-Marie-Tooth disease; DADS = distal acquired demyelinating
symmetric neuropathy; DM1 = myotonic dystrophy type 1; FSHD = facioscapulohumeral dystrophy;
HNPP = hereditary neuropathy with liability to pressure palsies; IBM = inclusion body myositis; MADSAM =
multifocal acquired demyelinating sensory and motor neuropathy; MMN = multifocal motor neuropathy;
MND = motor neuron disease; NMJ = neuromuscular junction; PMA = progressive muscular atrophy; SMA =
spinal muscular atrophy.
and Other Hereditary Neuropathies” by Christopher J. Klein, MD, FAAN,19 in

this issue of Continuum.
Distal acquired demyelinating symmetric (DADS) neuropathy, a variant of CIDP,
is a rare cause of motor greater than sensory distal symmetric polyneuropathy.
DADS is a chronic inflammatory neuropathy characterized by symmetric distal
weakness and sensory loss, often with tremor.20 Many patients have an IgM
monoclonal gammopathy that binds to myelin-associated glycoprotein (MAG).
PURE MOTOR SYMPTOM PATTERN

Widespread weakness without significant sensory loss or pain localizes best to
disorders of the motor neurons, motor nerves, neuromuscular junctions, or the
muscles themselves. A summary of distinguishing features of pure motor
syndromes can be found in TABLE 1-8.
Proximal and Distal Symmetric

Proximal greater than distal symmetric weakness is usually due to a myopathy or,
less commonly, a disorder of neuromuscular junction transmission. Diagnostic

clues supporting a myopathy include myalgia, elevated serum creatine kinase,

and supportive EMG findings. Myasthenia gravis often causes ptosis, diplopia,
and dysarthria and dysphagia, although isolated limb weakness is rare.
Fatigability is a diagnostic clue, and electrodiagnostic studies and the presence of
anti–acetylcholine receptor antibodies confirm the diagnosis. Lambert-Eaton
myasthenic syndrome (LEMS) also causes proximal greater than distal weakness
with fatigue; other symptoms and signs of LEMS include reduced or absent
reflexes that augment following brief exercise and autonomic dysfunction
(particularly dry mouth). Cranial nerve involvement is uncommon. Although
transient improvement in strength is seen following brief exercise, most patients
subjectively report severe fatigue. Identification of antibodies reactive to
voltage-gated calcium channels and electrodiagnostic studies confirm the
diagnosis. Botulism is a syndrome in which the neurotoxin from the bacterium
Clostridium botulinum causes irreversible inhibition of acetylcholine release at the
presynaptic nerve terminals. Botulism presents with ocular and bulbar weakness
(usually with dilated poorly reactive pupils) that progresses to symmetric
descending flaccid paralysis throughout the trunk and extremities. Patients may
have blurry vision and paresthesia but rarely have true sensory loss. Symmetric
CASE 1-1 A 37-year-old woman with 6 months of fatigue, arthralgia, and chronic
cough presented to clinic 1 month after the sudden onset of right
footdrop and severe pain in her lower leg and foot. She had no history of
trauma to the leg or back.
On examination, she had severe weakness of right ankle dorsiflexion
but normal eversion and inversion strength. Sensation was diminished in a
patchy distribution in her feet, most prominently in a nummular area on
the dorsum of her right foot between the first and second toe. Nerve
conduction studies showed asymmetric sural sensory nerve action
amplitudes, lower on the left. The right fibular (peroneal) compound
muscle action potential (CMAP) amplitude was very low, without any
conduction slowing across the knee. Needle EMG showed active
denervation in the right tibialis anterior but was otherwise normal. Left
sural nerve biopsy showed endoneurial vessels with evidence of vessel
wall infarction and transmural infiltration by inflammatory cells.
COMMENT This patient had vasculitic mononeuritis multiplex. The initial clinical picture
was consistent with a focal mononeuropathy of the left deep fibular
(peroneal) nerve, which is not a common entrapment mononeuropathy.
The sudden onset, severe pain, bilateral sensory signs, and abnormal sural
nerve conduction studies further raised suspicion that this was the initial
presentation of mononeuritis multiplex, and the nerve biopsy confirmed
evidence of vasculitis. Additional serologic testing may have helped
determine if the patient’s weight loss, arthralgia, and cough were
manifestations of a systemic vasculitis, such as granulomatosis with
polyangiitis.
1144 OCTOBER 2020

motor neuronopathies also cause this pattern of weakness, although less
commonly than myopathies and neuromuscular junction disorders.
Rarely, CIDP may present with a pure motor syndrome characterized by
symmetric proximal and distal weakness without sensory loss or pain.
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuronopathy
that usually presents in infancy or childhood. It is a pure lower motor neuron
Multifocal or Generalized Pure Motor Syndromes TABLE 1-8
Localization/Disease Pattern of Weakness Distinguishing Clinical Features
Myopathy Proximal predominant greater than Variable

distal predominant or multifocal
Neuromuscular junction
Myasthenia gravis Eyelids, eye movements, face, bulbar Fatigability

with or without limb involvement
Lambert-Eaton myasthenic syndrome Lower extremity predominant Hyporeflexia potentiated by exercise,

dysautonomia
Motor neuron
Amyotrophic lateral sclerosis Limb or bulbar onset Upper motor neuron signs,
pseudobulbar affect, weight loss,
frontotemporal dysfunction
Brachial amyotrophic diplegia Bilateral proximal arms No progression to other body

segments for >12–18 months
Leg amyotrophic diplegia One or both legs No progression to other body

segments for >12–24 months
Spinal muscular atrophy Limb, bulbar and respiratory Autosomal recessive inheritance
pattern, infant or childhood onset
Spinal bulbar muscular Bulbar and proximal Face and tongue fasciculations,
atrophy (Kennedy gynecomastia, X-linked recessive
disease) inheritance pattern
Hirayama disease Unilateral or bilateral hand and forearm Young men, progresses for years then
stabilizes, minipolymyoclonus, cold
paresis
Infectious Segmental or generalized Acute or subacute onset, encephalitis,

signs of systemic infection
Paraneoplastic Segmental or generalized Subacute onset, association with

nonmotor paraneoplastic syndromes
Nerve
Multifocal motor neuropathy Distal upper extremity, weakness in the Weakness more than atrophy early in
distribution of individual nerves; no the course
bulbar or respiratory involvement
Pure motor chronic inflammatory Symmetric proximal and distal Reduced or absent reflexes
demyelinating polyradiculoneuropathy weakness; no bulbar or respiratory
(CIDP) involvement

disease, presenting with progressive limb, bulbar, and respiratory weakness

without spasticity or hyperreflexia. It is classified as type 1, 2, 3, or 4, depending
on the age of onset and expected rate of progression. Type 1 has the earliest
onset and most severe course, whereas type 4 is diagnosed after age 18 and
is not necessarily fatal. It is important to distinguish SMA (a condition for
which effective molecular therapy now exists) from other causes of isolated
childhood weakness, such as congenital myopathies, muscular dystrophies,
and congenital myasthenic syndromes. For more information on SMA, refer to
the article “Spinal Muscular Atrophy” by Jessica Rose Nance, MD,21 in this
issue of Continuum.
In an adult with progressive proximal and distal weakness, progressive
muscular atrophy should be suspected. Progressive muscular atrophy is a
degenerative motor neuron disease only involving lower motor neurons. Most
patients with this pattern eventually develop upper motor neuron signs,
consistent with amyotrophic lateral sclerosis (ALS). Rarely, patients with ALS
will present with bilateral proximal arm weakness without prominent upper
motor neuron involvement (known as brachial amyotrophic diplegia).
Spinal bulbar muscular atrophy (also known as Kennedy disease) is an
X-linked recessive trinucleotide repeat disorder that affects men between the
fourth and seventh decades of life. Spinal bulbar muscular atrophy is a pure
lower motor neuron disorder that has a predilection for the lower cranial nerves.
Patients often present with dysarthria more than dysphagia and fasciculations of
the tongue and lower face. Proximal limb weakness typically follows, along with
atrophy and hyporeflexia in the upper arms and hip girdle. It is slowly
progressive, with disability accumulating over many years or decades. The
genetic defect is in the androgen receptor gene, so patients often have systemic
features such as gynecomastia, impaired sexual function, or infertility.22
Diabetes mellitus is also common. Unlike ALS, a substantial proportion of
patients with spinal bulbar muscular atrophy also have a sensory neuropathy,
which may be clinical or subclinical. For more information on spinal bulbar
muscular atrophy, refer to the article “Amyotrophic Lateral Sclerosis and Other
Motor Neuron Diseases” by Colin Quinn, MD, and Lauren Elman, MD,23 in this
issue of Continuum.

Proximal and distal weakness that is asymmetric is usually due to a neurogenic
disorder, with the exception of inclusion body myositis, which presents
with asymmetric weakness that preferentially involves deep finger flexors
and knee extensor muscles. The most common cause of this pattern of
weakness is ALS.
ALS most often presents with progressive asymmetric painless weakness
affecting both proximal and distal muscles, although distal muscles are affected
first. ALS has a variable presentation, especially early in the course, and no
sensitive biomarker is available to identify the majority of cases. The time course
of symptoms, presence or absence of coincident upper motor neuron signs,
and pattern of weakness are the most useful clinical features for differentiating
ALS from other motor neuron disorders or mimics.
ALS is a progressive, invariably fatal, neurodegenerative disease. It is usually
sporadic, but familial cases are well described and some sporadic cases appear to
be associated with genetic mutations. Apoptosis of the lower motor neurons
1146 OCTOBER 2020

causes degeneration of the motor axons and denervation of the muscles supplied KEY POINTS
by those axons. This leads to fasciculations, weakness, and atrophy in the
● Spinal bulbar muscular
affected muscles. ALS presents with limb onset in about two-thirds of cases atrophy may cause
and bulbar onset in about one-third of cases.24 Weakness may begin fasciculations in the face or
asymmetrically but characteristically spreads to other limbs or regions of tongue, signs of androgen
the brain over months. ALS does not cause pain, but intermittent muscle deficiency (including
gynecomastia), and slowly
cramps are common. Patients often lose a significant amount of body weight,
progressive bulbar and
in part because of muscle loss and dysphagia. Involvement of the lower cranial proximal weakness.
motor nerves is common, but the motor neurons supplying the extraocular
muscles are spared. ● The pseudobulbar affect
Among the degenerative diseases that affect the lower motor neurons, ALS is seen in patients with
amyotrophic lateral
unique in that it also causes dysfunction of the upper motor neurons that run sclerosis represents
from the motor cortex through the brainstem and into the spinal cord dysregulation of emotional
corticospinal tracts. Involvement of the corticobulbar tracts can cause emotional output rather than a mood
lability, characterized by crying or laughing with minimal stimulus. This is disorder.
known as pseudobulbar affect and represents a dysregulation of motor output of ● Overt dementia is not
emotion rather than a mood disorder.25 Patients may note increased yawning. common in amyotrophic
Upper motor neuron involvement causes spasticity, which may present as limb lateral sclerosis, but up to
stiffness causing gait dysfunction and impaired mobility out of proportion to the half of patients will have
some impaired cognition or
weakness. Upper motor neuron signs that may be found on examination include
behavioral problems.
spastic dysarthria, spasticity in the limbs, hyperreflexia, frontal release signs
(such as a palmomental reflex), and primitive reflexes (such as Babinski and ● Brachial amyotrophic
Hoffman signs.) diplegia and leg
Impaired cognition and behavioral problems are common in ALS, with as amyotrophic diplegia
present with painless flaccid
many of 50% of patients having some form of frontotemporal dysfunction and weakness starting in one
15% of patients meeting strict criteria for frontotemporal dementia.26 body segment, which may or
Although ALS typically spreads to involve all limbs, regional variants have may not eventually progress
been described. Brachial amyotrophic diplegia is a pure lower motor neuron to involve other body
segments or cause upper
disorder that leads to progressive weakness limited to the upper extremities for at motor neuron pathology.
least 12 to 18 months. It may start asymmetrically, but most cases progress to
being symmetric. Brachial amyotrophic diplegia is characterized by early
proximal arm involvement, as opposed to typical ALS, in which weakness of the
intrinsic hand muscles may be noted first. The flail leg variant of ALS, also
known as leg amyotrophic diplegia, presents with pure lower motor neuron
involvement limited to one or both lower extremities for at least 12 to 24 months.
Both brachial amyotrophic diplegia and leg amyotrophic diplegia are associated
with atrophy and diminished or absent reflexes in the affected limbs. Both may
eventually progress to involve other body segments or upper motor neurons, at
which point the clinical picture may resemble classic ALS. Life expectancy is
generally greater in brachial amyotrophic diplegia and leg amyotrophic diplegia
than in patients who presented with a more rapid progression between body
segments. A minority of patients never develop weakness beyond a single body
segment, in which case the disease is disabling but may not be fatal.27 For more
information on ALS, refer to the article “Amyotrophic Lateral Sclerosis and
Other Motor Neuron Diseases” by Colin Quinn, MD, and Lauren Elman, MD,23
in this issue of Continuum.
Infectious motor neuronopathies also present with asymmetric proximal and
distal weakness. Poliomyelitis is an infection of the spinal cord caused by the
poliovirus. The poliovirus has a predilection for motor neurons, leading to acute
asymmetric and patchy flaccid paralysis with or without bulbar and respiratory

CASE 1-2 A 35-year-old man presented

with 2 years of left thumb
weakness that had not
improved following carpal
tunnel release surgery.
Following surgery, he
developed progressive
weakness of both hands and
had to quit his job scooping
ice cream. He did not have
any pain or sensory loss. FIGURE 1-2
On examination, he had no Nerve conduction studies showing partial
facial or bulbar weakness. conduction block with proximal stimulation in a
patient with multifocal motor neuropathy.
He had mild atrophy and a APB = abductor pollicis brevis; L = left; NCS = nerve
few fasciculations in his left conduction study.
thenar eminence, but Reprinted with permission from Russell JW, Zilliox LA,
Continuum (Minneap Minn).33 © 2014 American Academy
otherwise bulk appeared
of Neurology.
normal. Strength was 4/5 for
left elbow flexion, wrist
flexion, finger flexion, and
thumb abduction. He could not fully extend the third and fourth fingers
on the right hand. Otherwise, strength was full. Sensation was intact
throughout, and reflexes were diminished but not absent throughout.
Nerve conduction studies were significant for conduction block in
several upper extremity motor nerves (FIGURE 1-233). Active denervation
was seen in some of the intrinsic hand muscles on the left, and decreased
recruitment was seen in the left biceps and right finger extensors. GM1
ganglioside antibody testing was negative.
COMMENT This case highlights many of the classic features of multifocal motor
neuropathy (MMN), and how it can be differentiated from amyotrophic
lateral sclerosis (ALS). The patient presented with slowly progressive focal
asymmetric arm weakness without sensory symptoms. The weakness was
in the distribution of named nerves (left median and right radial) but with
variable weakness of different finger extensors, suggesting differential
fascicular involvement. A motor neuron disease such as ALS would more
typically present with a myotomal pattern of weakness. MMN does not
affect bulbar and facial muscles, whereas ALS eventually does. Patients
with ALS usually have significant atrophy and fibrillations in the clinically
affected muscles; the relative absence of these features suggests that
some of his weakness was caused by demyelination rather than axonal
loss. GM1 ganglioside antibodies are not sensitive, and a positive test is not
necessary to make the diagnosis of MMN in the correct clinical and
electrodiagnostic setting.
1148 OCTOBER 2020

weakness. The polio vaccine became available in 1955, and the disease has been KEY POINTS
eradicated in the United States. The last case of wild-type poliomyelitis that
● Systemic infections with
originated in the United States was in 1979, and the last time a traveler with polio West Nile Virus and specific
was identified in the United States was in 1993.28 In 2019, there were 176 cases of enteroviruses may cause a
wild-type polio worldwide.29 poliolike illness
A poliolike illness has been associated with West Nile virus infection. A small characterized by flaccid
paralysis with or without
percentage of patients with West Nile viremia will develop encephalitis, with
encephalitis.
or without an acute regional flaccid paralysis. Sensory loss in the affected limbs
is common. ● The extensor digitorum
Enterovirus D68 infections have been increasing worldwide since an outbreak brevis muscle may atrophy
in 2014. Although most patients only develop a mild respiratory illness, the virus in sensorimotor distal
symmetric polyneuropathy
is associated with acute flaccid myelitis in a minority of patients.30 but is often relatively spared
Very rarely, patients may develop a motor neuron disease as part of a in distal myopathies.
paraneoplastic syndrome, presenting with subacute-onset asymmetric upper
limb weakness, with or without upper motor neuron involvement.31 This may ● The weakness in
amyotrophic lateral
co-occur with nonmotor manifestations such as sensory neuronopathy. It is a sclerosis tends to follow a
difficult diagnosis to make because the clinical features are nonspecific, and myotomal pattern, whereas
patients often have no known tumor history at the time of presentation. the weakness in multifocal
motor neuropathy may be in
the distribution of specific
Distal Symmetric
peripheral nerves.
Distal symmetric weakness is most commonly due to hereditary motor
neuropathies. Axonal forms of CMT and juvenile forms of ALS have significant ● Early in the course of
phenotypic and genotypic overlap with hereditary spastic paraplegia.32 multifocal motor
Some myopathies, such as myotonic dystrophy type 1, primarily affect the neuropathy, patients may
have significant weakness
distal muscles. A careful sensory examination can usually distinguish a distal with little or no atrophy,
myopathy from a distal symmetric polyneuropathy. The extensor digitorum suggesting that the motor
brevis muscle is often weak and atrophic in sensorimotor neuropathy but axons are still intact.
relatively spared in most distal myopathies.
Distal Asymmetric
Distal asymmetric weakness should raise concern for ALS, particularly if reflexes
are preserved or brisk. Several other disorders cause distal asymmetric weakness
and should be excluded.
Multifocal motor neuropathy (MMN) is an acquired disorder of the motor
nerves presenting with progressive asymmetric limb weakness and characterized
by multifocal conduction block on nerve conduction studies. The underlying
mechanism is an immune attack at the nodes of Ranvier. It can easily be mistaken
for ALS, but it is important to distinguish between the two conditions because
MMN is a treatable and nonlethal condition. In MMN, the lesions are at the
level of the peripheral nerve rather than the cell body in the anterior horn cell,
so weakness and atrophy are more likely to follow a pattern of multiple
mononeuropathies rather than a myotomal pattern as would be seen in ALS.
For example, a patient with ALS who has interosseous weakness will likely also
have ipsilateral weakness of thumb abduction because both are derived
from the C8 and T1 nerve roots and have motor neurons in the same level of the
spinal cord. Patients with MMN often have differential weakness of muscles that
share a myotome but are supplied by different nerves or even different nerve
fascicles (CASE 1-2). Because MMN causes conduction failure at the nodes of
Ranvier, it may cause weakness out of proportion to atrophy, especially early in
the course of the disease.34 Typically, patients with MMN will have diminished

deep tendon reflexes in affected muscles and should not have bulbar or
respiratory involvement. For more information on MMN, refer to the article
“Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Its
Variants” by Kelly Gwathmey, MD,12 in this issue of Continuum.
Hirayama disease, or monomelic amyotrophy, is not a neurodegenerative
disease of the motor neurons but an unusual form of cervical myelopathy that has
a predilection for the motor neurons. Patients are often young men of Asian
descent. Forward displacement of the posterior cervical dural sac with neck
flexion causes cord compression or venous congestion that preferentially
damages the C7, C8, and T1 anterior horn cells on one or both sides (CASE 1-3).
Patients usually present with progressive painless weakness in the hand and
forearm, with sparing of the brachioradialis. Distinctive clinical manifestations
include cold paresis and an irregular tremor (minipolymyoclonus) with finger
extension. Weakness is progressive at first, but the disease plateaus within 5 years
and does not spread to other body segments.35
CASE 1-3 A 19-year-old man presented for evaluation of weakness in his right hand
that had slowly progressed over the previous 2 years. He was a casual
bodybuilder and had been able to maintain excellent muscle bulk
everywhere in his body other than the right forearm and hand. Recently,
he had noticed fasciculations in some of the intrinsic hand muscles. He
did not report any sensory loss or pain, other than a propensity for the
hand to cramp at night.
On examination, he had mild atrophy of the right hand and weakness of
all intrinsic hand muscles on the right, including the interossei and thumb
abductors. Electrodiagnostic testing showed low-amplitude median and
ulnar compound muscle action potentials (CMAPs). On needle EMG,
evidence of active denervation in the right abductor pollicis brevis, flexor
pollicis longus, first dorsal interosseus, and extensor indicis was seen.
MRI of the cervical spine showed focal atrophy of the cord from C5
through C7 vertebral levels. Dynamic MRI with the neck in flexion showed
the posterior dura with anterior displacement and compression of the
cord. The flow voids in the posterior epidural space during neck flexion
were exaggerated, and a crescent-shaped enhancing epidural space
extending from C4 to T2 was seen.
COMMENT Slowly progressive hand weakness in one limb could, in theory, be caused
by a single lesion of the C8 nerve root or lower trunk of the brachial plexus.
However, the lack of pain or sensory loss would be unusual and should
raise suspicion for focal injury to the lower cervical motor neurons. The
dynamic MRI findings described in this case are classic findings in Hirayama
disease, a rare juvenile-onset myelopathy with a predilection for the lower
cervical anterior horn cells. Although it is often known as monomelic
amyotrophy, a significant minority of patients eventually develop
symptoms in the contralateral arm.
1150 OCTOBER 2020

PURE SENSORY SYMPTOM PATTERN KEY POINTS
Sensory dysfunction without significant weakness localizes best to the spinal
● Hirayama disease
cord sensory tracts, the dorsal root ganglia, the sensory nerves, or small (monomelic amyotrophy)
unmyelinated nerves. Most clinically significant lesions will cause static sensory presents in young men with
loss in a fixed distribution. When patients present with episodic migrating unilateral or bilateral hand
paresthesia, a neurologic etiology is rarely identified. weakness that progresses
for years and then plateaus.
Proximal and Distal Symmetric ● Proprioception is often

The central projections of the sensory neurons travel through the dorsal columns involved early in disorders
and the spinothalamic tracts. Disruption of these tracts from trauma, disk affecting the dorsal columns
disease, infection, or toxic-metabolic syndromes leads to sensory loss and pain and late in disorders
affecting the peripheral
below the level of the lesion. A focal injury to the dorsal columns in the lower nerves.
parts of the spinal cord may affect the lower extremities only, mimicking a distal
symmetric polyneuropathy. If the cervical dorsal columns are disrupted, patients ● Patients with sensory
may report generalized sensory loss. Patients with cervical cord involvement neuronopathy may initially
appear weak on
may also report electric shock–like sensations traveling down their spines with confrontational testing but
neck flexion (the Lhermitte phenomenon). are able to generate full
Isolated dorsal column dysfunction may lead to impaired position sense and power when they look at the
two-point discrimination with relatively preserved pain sensation. This is helpful limb being tested.
in differentiating this condition from polyneuropathy, in which proprioception is
● Sensory neuronopathy
usually spared relative to other primary sensory modalities. may be idiopathic or
The dorsal columns are often involved as part of a more extensive myelopathy. associated with Sjögren
A careful history and motor examination may reveal bowel and bladder syndrome, a paraneoplastic
retention, hyperreflexia, or spasticity. syndrome, human
immunodeficiency virus, or
pyridoxine overdose.
All peripheral sensory nerves are derived from neurons located within the dorsal
root ganglia. Certain infectious, inflammatory, and metabolic disorders are known
to preferentially damage these sensory neurons. Because these conditions may
affect any dorsal root ganglion, the sensory loss does not conform to the typical
length-dependent pattern seen in most distal symmetric polyneuropathies. Sensory
loss may be asymmetric and may affect proximal areas before distal areas, including
the upper extremities, face, and trunk. Special sensory modalities may be affected,
and pain is common. The sensory loss in the limbs is often profound, leading to gait
and limb ataxia. Patients may have pseudoathetosis, adventitious movements of
their distal extremities caused by markedly impaired proprioception. The examiner
may initially note weakness on confrontational testing, but strength may normalize
when the patient looks at the limb that is being tested, using visual cues to overcome
their lack of proprioception. Deep tendon reflexes are reduced or absent.
This clinical presentation is strongly suggestive of a sensory neuronopathy but
is nonspecific as to cause. About 20% of cases occur as part of a paraneoplastic
syndrome associated with small cell lung cancer, lymphoma, adenocarcinoma, or
neuroblastoma.36 Paraneoplastic sensory neuronopathy tends to be rapidly
progressive and may co-occur with other paraneoplastic disorders. Other
etiologies include Sjögren syndrome, toxicity related to cisplatin or other
chemotherapies, pyridoxine overdose, or HIV infection, although in many cases
it is idiopathic.
Wartenberg migratory sensory neuritis, a poorly understood multifocal
sensory neuropathy, presents with sudden-onset fixed numbness of one or more
cutaneous nerves with or without preceding pain in the distribution of the

affected nerve(s). The cause of Wartenberg migratory sensory neuritis is

unknown. An autoimmune etiology has been suggested, but immunomodulatory
therapy does not appear to be beneficial.37
A small percentage of patients with small fiber neuropathy present with a
non–length-dependent syndrome of asymmetric proximal and distal pain and
loss of sensation to small fiber modalities (pain and temperature). In this case,
nerve conduction studies are normal, but diagnosis can be confirmed with skin
biopsies from proximal and distal sites stained with protein gene product 9.5 (PGP 9.5).
Multifocal sensory loss may also be related to rare inflammatory diseases such
as a chronic immune sensory polyradiculoneuropathy (CISP); chronic ataxic
neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl
antibodies (CANOMAD); and chronic ataxic neuropathy with anti–disialosyl
IgM antibodies (CANDA).38
Distal Symmetric
As discussed above, distal symmetric polyneuropathy is often sensory predominant
with no motor involvement until later in the course of the illness. Small fiber
polyneuropathy is a subset of distal symmetric polyneuropathy in which only the
small unmyelinated nerve fibers are impaired. These fibers carry pain and
temperature sensation as well as the autonomic fibers destined for the sweat glands
and viscera, so, by definition, patients have no somatic motor involvement. The
most distal nerves tend to be affected most, so symptoms usually begin in the toes or
balls of the feet and gradually spread proximally up the legs and eventually into the
hands. Patients may report a general sense of numbness in these areas or specifically
note an inability to distinguish temperatures or recognize painful stimuli. Painless
injuries may occur. Most patients report paresthesia and neuropathic pain. On
examination, patients will have decreased pain and thermal sensation, with
preserved position sense. Strength and deep tendon reflexes are generally spared.
Autonomic nerve dysfunction may cause decreased sweating in the affected areas.
Loss of autonomic vasomotor control may result in skin color changes, leaving the
TABLE 1-9 Neuromuscular Disorders That Present Acutely or Subacutely
Localization Examples of Disorders

Motor neuron Acute flaccid paralysis, paraneoplastic
Spinal root Disk herniation, varicella-zoster virus
Sensory neuron Paraneoplastic, Sjögren syndrome, pyridoxine toxicity
Plexus Idiopathic neuralgic amyotrophy, diabetic lumbosacral

radiculoplexus neuropathy
Nerve Direct nerve trauma, toxic (eg, chemotherapy or heavy metal-

induced), vasculitic mononeuritis multiplex, acute inflammatory
demyelinating polyradiculoneuropathy (AIDP) and variants
Neuromuscular junction Botulism
Muscle Inflammatory myopathies, rhabdomyolysis due to a metabolic

myopathy, toxic myopathies
1152 OCTOBER 2020

skin looking shiny, dry, and atrophic. Other autonomic symptoms, such as KEY POINT
gastroparesis, erectile dysfunction, or constipation, may occur.39
● The most useful screening
The differential diagnosis for small fiber or sensory predominant polyneuropathy laboratory tests for the
is broad. Some of the more common etiologies include diabetes mellitus, chronic workup of distal symmetric
alcohol use disorder, drug toxicity, and associated with paraproteinemia. polyneuropathy are tests for
diabetes or prediabetes,
serum lipids and
ACUTE OR SUBACUTE ONSET
cholesterol, a vitamin B12
Although the distribution of signs and symptoms is of paramount importance in level, and serum protein
categorizing peripheral nervous system disorders, the time course can narrow electrophoresis and
the differential diagnosis even further, especially if symptoms develop rapidly. immunofixation.
The only truly acute neuromuscular disorders are those related to trauma, such as
a peripheral nerve injury. Infectious, inflammatory, and toxic processes may
present subacutely, developing over hours to days. TABLE 1-9 provides examples
of subacute disorders organized by neuroanatomic localization.
DIAGNOSTIC TESTING
Blood tests, CSF analysis, electrodiagnostic studies, imaging, and tissue biopsy
all serve a situational role in the workup for sensory and motor symptoms.
The history and physical examination are paramount in the diagnosis of
neuromuscular disorders and inform the yield of specific diagnostic tests.
Blood Testing
The purpose of blood testing is to identify evidence of a systemic disorder
that may cause or put the patient at risk for a neuromuscular syndrome.
Mononeuropathy and radiculopathy are usually caused by local trauma;
therefore, blood testing is generally not indicated.
Distal symmetric polyneuropathy, on the other hand, is presumed to be the result
of a systemic process, although it is not always possible to identify the culprit.
Dozens of tests could, in theory, suggest an underlying cause, but only a select few
have a high enough yield to merit testing in all patients with a distal symmetric
polyneuropathy phenotype.40 The most useful test is a measure of serum glucose.
This may include a hemoglobin A1c, fasting glucose, or 2-hour oral glucose tolerance
test. It is controversial whether hemoglobin A1c values in the range suggestive of
prediabetes, impaired fasting glucose, and impaired glucose tolerance should be
considered abnormal in the workup of neuropathy.41 Patients with distal symmetric
polyneuropathy have a very high risk of having metabolic syndrome, so a fasting
cholesterol panel and serum triglycerides should also be checked. Serum protein
electrophoresis and serum immunofixation should be obtained to screen for
paraproteinemia, also known as monoclonal gammopathy. The immunofixation is
important because it may help identify low-level paraproteins that may be
overlooked on serum protein electrophoresis alone. The level of the paraprotein
correlates with risk of malignancy, but even low-level paraproteinemia may be
associated with neuropathy. A serum vitamin B12 level should be obtained; if the
value is borderline (above the lower limit of normal but lower than 500 pg/mL), a
serum methylmalonic acid level should be checked as well. Elevated levels may
suggest a functional vitamin B12 deficiency, even when the vitamin B12 level is
borderline. Up to 50% or more of patients with distal symmetric polyneuropathy
have prediabetes or diabetes, and even more have metabolic syndrome.42 The
serum protein electrophoresis and immunofixation are abnormal in 9%, and
vitamin B12 is abnormal in 3.6%.40 Little evidence is available to support the

routine testing of thyroid-stimulating hormone (TSH), erythrocyte sedimentation

rate, folate, antinuclear antibodies, Venereal Disease Research Laboratory
(VDRL), or other commonly employed blood tests. However, if patients have
systemic symptoms, rapid onset of neuropathy, motor predominance, or a
non–length-dependent pattern, a more thorough evaluation may be indicated.
If hereditary neuropathy is suspected, the clinical phenotype and
electrodiagnostic features can help the physician estimate the likelihood of specific
genetic abnormalities. However, the widespread availability of next-generation
sequencing panels that include both common (PMP22, MPZ, GJB1, and MFN2) and
uncommon mutations may obviate the need to choose individual genes to
sequence.18 X-linked Fabry disease is a treatable cause of small fiber neuropathy,
cardiovascular dysfunction, renal failure, and skin lesions. Men with Fabry disease
will have deficient α-galactosidase A in plasma and leukocytes. Female carriers can
identified by confirming elevated plasma lyso-Gb3 levels.43 In the absence of clinical
features other than small fiber neuropathy, the yield of molecular testing is low.44
Hereditary transthyretin (TTR) amyloidosis is an autosomal dominant multisystem
disease that can present with sensorimotor polyneuropathy. Since it is treatable,
some authors advocate for genetic testing early in the workup of neuropathy,
especially when patients have a family history, evidence of cardiovascular disease,
carpal tunnel syndrome, and prominent dysautonomia.45 Routine genetic testing of
patients with uncomplicated distal symmetric polyneuropathy is not recommended.
Mononeuritis multiplex and nontraumatic plexopathies are often associated
with systemic disease, but little consensus exists on which blood tests have the
highest yield. Studies may include a complete blood cell count, basic metabolic
panel, hemoglobin A1c, HIV, hepatitis panel, and autoimmune testing, including
antinuclear antibodies, erythrocyte sedimentation rate, C-reactive protein,
antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, complement
levels, and cryoglobulins.
If the history and examination suggest MMN, it is worthwhile to check for GM1
ganglioside antibodies. Anti-GM1 ganglioside antibodies are detected in at least 50%
of patients with MMN, and their presence is reasonably specific for this condition.34
Blood testing is usually nondiagnostic in demyelinating neuropathies. If the
time course and phenotype are suggestive of CIDP or DADS neuropathy, serum
protein electrophoresis and immunofixation should be obtained. If an IgM
paraprotein is identified, antibodies against MAG may verify the diagnosis of
DADS neuropathy. If an IgA or IgG paraprotein is identified, further workup
may be indicated to screen for POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome.
In patients with a phenotype suggestive of a sensory neuronopathy, the workup
should include paraneoplastic autoantibodies (especially anti-Hu antibodies),
anti–Sjögren syndrome A (SSA) and anti–Sjögren syndrome B (SSB) antibodies
to screen for Sjögren syndrome, and HIV testing. Pyridoxine levels should be
obtained if a clinical suspicion for toxicity exists. Serum protein electrophoresis,
immunofixation electrophoresis, and Gd1b antibody testing may be helpful in
this population to screen for the rare disorders CANOMAD and CANDA.46
Blood tests are generally low yield in the workup of motor neuron diseases,
with a few exceptions. Genetic testing may be considered in patients with ALS
and affected family members. In cases in which the diagnosis is uncertain or the
patient has signs of frontotemporal dementia, obtaining C9orf72 hexanucleotide
repeat testing may be helpful, even in patients without a clear-cut family history.
1154 OCTOBER 2020

Spinal bulbar muscular atrophy should be considered in a male patient with KEY POINTS
bulbar-predominant pure lower motor neuron weakness and signs of androgen
● Paraproteinemia may be
insensitivity. The diagnosis can be verified by identifying a CAG repeat associated with chronic
expansion on the androgen receptor gene. inflammatory demyelinating
polyradiculoneuropathy, is
CSF Testing common in patients with
distal acquired
CSF albuminocytologic dissociation is defined as a CSF protein concentration of
demyelinating symmetric
greater than 45 mg/dL with white blood cell count of less than 50 cells/mm3. In neuropathy, and is present
the correct clinical context, this finding is supportive of the diagnosis of AIDP. in most patients with
A 2019 study found the sensitivity of this finding to be 73.2% when CSF was POEMS (polyneuropathy,
organomegaly,
obtained an average of 13 days after symptom onset.47 During the course of the
endocrinopathy,
disease, early protein levels may correlate with disease severity. Normal CSF monoclonal plasma cell
results must be interpreted with caution. Some studies suggest that more than disorder, and skin changes)
50% of patients will have normal CSF levels within 1 to 2 weeks of symptom syndrome.
onset, and 12% of patients never show abnormalities.48 A significant pleocytosis
● The overreliance on
in a patient with AIDP suggests associated HIV. The primary use of CSF analysis modest CSF protein
in a patient suspected of AIDP is to exclude infectious diseases and malignancies. elevations is a common
The role of CSF albuminocytologic dissociation in the diagnosis of CIDP is reason for the overdiagnosis
even less clear. One of the most common reasons for the overdiagnosis of CIDP is of chronic inflammatory
demyelinating
putting too much stock in mildly to moderately elevated CSF protein levels.49 polyradiculoneuropathy.
Rather than using the standard upper limit of normal of 45 mg/dL, evidence
indicates that higher age-matched upper limits of normal should be implemented
(50 mg/dL for patients younger than 50 years of age and 60 mg/dL for patients
older than 50 years of age).50 In the absence of both clinical and electrodiagnostic
criteria that support the diagnosis of CIDP, an elevated CSF protein should not be
used to justify immunomodulatory treatment.51
Electrodiagnostic Testing
Electrodiagnostic testing is used to identify a wide range of neuromuscular
disorders. A complete electrodiagnostic evaluation includes two complementary
tests, nerve conduction studies and needle EMG. Nerve conduction studies are
most commonly performed by placing surface electrodes approximating the
location of the nerves beneath the skin. The nerve is stimulated in one location,
and a recording electrode detects a remote response over the surface of the nerve
or an associated muscle. Needle EMG involves inserting a thin needle into
skeletal muscles and recording the electrical activity within the muscle.
Using a combination of these techniques, the electrodiagnostic consultant can
identify and localize neuromuscular lesions to any level of the peripheral nervous
system, including the motor neuron, spinal root, plexus, sensory and motor
peripheral nerves, neuromuscular junction, and the muscle itself.
Electrodiagnostic studies can provide information about whether a process is
focal or generalized, whether a neuropathy is primarily axonal or demyelinating,
and whether nerve dysfunction is subacute or chronic.
Practically speaking, electrodiagnostic testing is more useful for some
diagnoses than others. It should be considered foundational for the diagnosis of
mononeuropathies, mononeuritis multiplex, demyelinating neuropathies,
sensory neuronopathy, plexopathies, disorders of neuromuscular junction
transmission, and motor neuron disorders.
Electrodiagnostic testing has some value in the diagnosis of radiculopathy. It
can determine the function of nerve roots and the chronicity of lesions and rule

out mimics such as mononeuropathy or plexopathy. However, conventional

electrodiagnostic tests can only examine the function of the motor roots. They
are less sensitive in patients with isolated pain and sensory symptoms, a common
clinical scenario.
Electrodiagnostic testing is probably overused in the workup of distal
symmetric polyneuropathy. Nerve conduction studies can identify and determine
the severity of large fiber axonal polyneuropathy but should be normal in pure
small fiber neuropathy.52 Knowing whether large fibers are involved in a distal
symmetric polyneuropathy often has no meaningful impact on patient
management. Thus, the role of electrodiagnostic testing in patients with isolated
distal symmetric numbness is unclear. For more information on the role of
electrodiagnostic testing in the evaluation of peripheral neuropathies, refer to the
article “Test Utilization and Value in the Evaluation of Peripheral Neuropathies”
by Brian C. Callaghan, MD, MS, FAAN,53 in this issue of Continuum.
Imaging
MRI of the cervical, thoracic, or lumbar spine is the preferred imaging modality for
visualizing the soft tissues and bony structures that comprise the neuraxis. It can
identify the most common space-occupying lesions that compress the exiting
nerve roots and abnormalities within the roots themselves. MRI may also show
hypertrophic or enhancing nerve roots in patients with demyelinating
polyradiculoneuropathies such as AIDP, CIDP, and CISP. Dynamic MRI of the
cervical spine can be diagnostic of Hirayama disease. The major limitation of
MRI of the spine is that potentially pathogenic changes, such as intervertebral
disk bulges and neuroforaminal stenosis, are found in a high proportion of
asymptomatic individuals.
Focused MRI of the brachial or lumbosacral plexus may have a role in
identifying neoplastic or infectious infiltration or structural lesions such as
neurogenic thoracic outlet syndrome. The clinical utility of MRI in the diagnosis
of motor neuron disease is unclear. Hyperintense signal along the corticospinal
tracts has been noted in patients with upper motor neuron–predominant
disease.54
Ultrasound is not a new technology, but its role in the diagnosis of
neuromuscular disorders has been expanding with the application of high-
frequency transducers and improved image processing. Ultrasound imaging
enables real-time morphologic evaluation of nerves and muscles. In the correct
clinical context, the finding of an enlarged cross-sectional nerve diameter is
sensitive, but not specific, for the nerve swelling associated with compression
mononeuropathy.55 Other sonographic features can be used to identify traumatic
peripheral nerve injury and demyelinating neuropathies.56 Ultrasound has been
used as an adjunct to EMG to identify fasciculations, decreased muscle thickness,
and increased muscle echo intensity and echo variance in patients with motor
neuron disease.57 Ultrasound is painless and thus is better tolerated than EMG.
Ultrasound is operator dependent and is limited by inadequate penetration,
which is problematic with patients who are obese or when assessing deeper
structures.58
Tissue Biopsy
In the correct clinical context, a nerve or skin biopsy may aid in the diagnosis of
polyneuropathy.
1156 OCTOBER 2020

NERVE BIOPSY. Nerve biopsy is most useful in the evaluation of mononeuritis KEY POINTS
multiplex. Systemic vasculitides that involve small to medium-sized arteries may
● Electrodiagnostic
affect epineurial vessels, resulting in asymmetric painful neuropathy. Serologic testing is an important part
testing, urinalysis, and body imaging may identify the underlying condition, of the workup for
obviating the need for biopsy to support the initiation of immunomodulatory mononeuropathies,
treatment. mononeuritis multiplex,
demyelinating neuropathy,
If a patient with mononeuritis multiplex has no systemic symptoms or all the
sensory neuropathy, and
tests for systemic vasculitis or inflammatory disorders are negative, a nerve motor neuron disease, but it
biopsy may be necessary to diagnose nonsystemic vasculitic neuropathy. is not sensitive for small
Pathologic findings include inflammation around and necrosis of the vessel walls. fiber polyneuropathy or
pure sensory radiculopathy.
Biopsy of a nearby muscle increases diagnostic sensitivity for vasculitis.
Nerve biopsy has limited utility in the diagnosis of CIDP. Pathologic changes are ● MRI of the spine can
often more extensive in proximal portions of peripheral nerves and may affect identify common causes of
motor nerves more than sensory nerves. At the time of biopsy, disease-specific radiculopathy and aid in the
features may have already disappeared. However, signs of demyelination are still diagnosis of chronic
inflammatory demyelinating
considered a supportive feature in the European Federation of Neurological polyradiculoneuropathy and
Societies/Peripheral Nerve Society criteria for CIDP.59 Hirayama disease but may
Electrodiagnostic testing can be used to identify a functionally impaired show degenerative changes
cutaneous nerve for biopsy. The most commonly biopsied nerves are the sural, of questionable significance
in both symptomatic and
radial, or superficial fibular (peroneal) nerves. Complications of nerve biopsy asymptomatic individuals.
include sensory loss, chronic pain, and wound infection. These are usually mild, but,
nonetheless, nerve biopsy should be avoided if the diagnosis can be made with ● Ultrasound imaging is
noninvasive testing. useful in the workup of
entrapment neuropathies
and has emerging
SKIN BIOPSY. Skin biopsy to indications in the workup of
directly measure epidermal fiber other neuromuscular
density has become increasingly disorders.
used to diagnose small fiber
● A nerve biopsy is the
polyneuropathy and determine if it diagnostic test of choice for
is length dependent or diffuse. A suspected nonsystemic
biopsy is taken from a distal and a vasculitic neuropathy. In the
proximal site in a lower extremity setting of known systemic
vasculitis, nerve biopsy
and the tissue is stained with an should only be performed if
antibody to PGP 9.5, a panaxonal demonstrating peripheral
marker (FIGURE 1-3). The primary nerve involvement will lead
usefulness of this test is when the to a change in
immunomodulatory
diagnosis of neuropathy is
treatment.
uncertain or if a non–length-
dependent small fiber neuropathy
is suspected. The test may be
overused in patients whose clinical
manifestations are consistent with
distal symmetric small fiber FIGURE 1-3
Skin biopsies from the distal leg stained with
polyneuropathy because the protein gene product 9.5 (PGP 9.5), a panaxonal
results only rarely lead to a change marker, demonstrate normal intraepidermal
in management. nerve fiber density (A) in an asymptomatic
Immunoglobulin light chain patient and reduced density (B) in a patient with
distal symmetric polyneuropathy. Arrows
amyloidosis is a rare but serious
designate normal epidermal axons. The bar
cause of small fiber–predominant represents 50 microns.
polyneuropathy, often with Figure courtesy of A. Gordon Smith, MD, FAAN.

dramatic dysautonomia. Although nerve and skin biopsy with Congo red staining
may demonstrate amyloid deposits, these deposits can be found in bone marrow,
salivary gland, or subcutaneous fat in 85% of affected patients.60
CONCLUSION
Focal lesions of the peripheral nervous system cause deficits that may be unique
to the involved neuroanatomic structure. Multifocal or generalized peripheral
nervous system disorders can be identified by the characteristic patterns of
sensory and motor involvement. Clinicians should use the history and physical
examination to inform the judicious use of diagnostic testing. Electrodiagnostic
studies, CSF analysis, and tissue biopsy are particularly useful in many clinical
settings but may be overused in other settings. The focus of testing should be to
confirm or refute suspected diagnoses when doing so is likely to impact patient
management.
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1160 OCTOBER 2020

Diabetes and Metabolic REVIEW ARTICLE

Disorders and the C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Peripheral Nervous
System
By Christopher H. Gibbons, MD, MMSc, FAAN
ABSTRACT
PURPOSE OF REVIEW: This
article provides an up-to-date review of the
manifestations of neuropathy seen in the setting of diabetes and other
metabolic disorders.
RECENT FINDINGS: Although a number of metabolic disorders cause or are

associated with peripheral neuropathy, the neuropathies associated with CITE AS:
glucose dysregulation make up the vast majority of cases. Recent CONTINUUM (MINNEAP MINN)
2020;26(5, PERIPHERAL NERVE AND
investigations have determined major differences in the neuropathies
associated with type 1 and type 2 diabetes. Neuropathy in type 1 diabetes is 1161–1183.
closely linked to glycemic control, whereas neuropathy in type 2 diabetes
is linked to dyslipidemia, central obesity, hypertension, insulin resistance, Address correspondence to
Dr Christopher Gibbons, Center
and glucose control. Although length-dependent axonal distal symmetric for Autonomic and Peripheral
polyneuropathy is the most common clinical presentation, diabetes is also Nerve Disorders, Beth Israel
associated with acute, asymmetric, painless, and autonomic neuropathies. Deaconess Medical Center,
1 Deaconess Rd, Palmer 111,
Boston, MA 02215,
SUMMARY: The prevalence of diabetes and metabolic syndrome is increasing cgibbons@bidmc.harvard.edu.
across the globe. The need to recognize and treat the wide array of clinical
manifestations of neuropathy detected in individuals with metabolic Dr Gibbons has received
disorders will continue to grow. As a consequence, an increasing number personal compensation for
serving as a scientific advisor for
of well-trained physicians who can manage these patients is needed. At Lundbeck and Theravance
present, treatment is largely focused on prevention and symptomatic Biopharma and as an associate
management. Investments into funding for both basic and clinical science editor for Autonomic
Neuroscience: Basic and
are necessary to bring novel therapeutic interventions into clinical practice. Clinical, research/grant support
from Grifols, and publishing
royalties from UpToDate, Inc.
Dr Gibbons has held stock/
INTRODUCTION stock options in Cutaneous
D
iabetes includes a group of disorders of abnormal carbohydrate Neurodiagnostics, LLC, and has
given expert medical testimony.
metabolism that result in hyperglycemia due to a range of conditions
that include impaired insulin secretion or insulin resistance, or both.1 UNLABELED USE OF
Type 2 diabetes is the most common form of diabetes (>90%) and is PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
characterized by increased insulin secretion in the setting of Dr Gibbons reports no
increasing peripheral insulin resistance. In contrast, type 1 diabetes is seen in 5% disclosure.
to 10% of cases of diabetes and is due to the autoimmune destruction of pancreatic
beta cells with subsequent insulin deficiency.1 Diagnostic criteria for type 1 and © 2020 American Academy
type 2 diabetes are reviewed in TABLE 2-1.2 It should be noted that a number of of Neurology.

DIABETES AND METABOLIC DISORDERS
other forms of diabetes exist, including genetic defects in pancreatic beta cell
function, genetic defects in insulin activity, diseases that cause pancreatic
damage, endocrinopathies with diabetes as a component, chemical toxicities,
infections, immune-mediated disorders, and other genetic diseases.1 At present,
approximately 425 million people worldwide have a diagnosis of diabetes.3
OVERVIEW AND EPIDEMIOLOGY OF DIABETIC NEUROPATHIES

Neuropathy is one of the most prevalent, debilitating, and costly complications
of diabetes. More than 400 million people worldwide have diabetes, including
nearly 10% of Americans, highlighting the major potential health impacts both
individually and as a society.4 Diabetic neuropathy is one of the more challenging
disorders to recognize and treat because of the myriad clinical manifestations
that can occur. Because of the heterogeneity in symptoms and signs of
neuropathy, it is critical to define the potential involvement of neuropathy across
the nervous system and to understand the different pathophysiologic mechanisms
that may be involved across the types of diabetes and types of neuropathy.4–6
To distill this information into a digestible format, this article begins with a
general discussion of the pathophysiology of diabetes and neuropathy, with
subsequent sections focusing on the unique clinical manifestations of different
forms of neuropathy with attention to how a clinician can recognize and manage
each form. Uremic neuropathy is discussed separately.
Diabetic neuropathies encompass a broad range of conditions. The
neuropathies associated with diabetes generally fall into five categories:
u Length-dependent axonal polyneuropathy, the most common form; may be characterized

by differential injury to small-diameter unmyelinated axons, large myelinated axons, or both
u Acute diabetic neuropathies, including both radiculoplexus and treatment-induced
neuropathies
u Mononeuropathies involving individual cranial or peripheral nerves
u Autonomic neuropathies, which cause a range of symptoms depending on the end organ
involved
u An increase in risk for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)4–6
TABLE 2-1 American Diabetes Association Criteria for the Diagnosis of Diabetesa
Test Result
Fasting plasma glucose (FPG) Diabetes: FPG values ≥126 mg/dL (7.0 mmol/L)
Prediabetes: FPG values 100–125 mg/dL (5.6–6.9 mmol/L)
2-Hour oral glucose tolerance test Diabetes: 2-hour plasma glucose values of ≥200 mg/dL (11.1 mmol/L) during a 75-g
(OGTT) OGTT
Prediabetes: 2-hour plasma glucose values of 140–199 mg/dL (7.8–11.0 mmol/L) during
a 75-g OGTT
Glycosylated hemoglobin (A1c) Diabetes: A1c values ≥6.5% (48 mmol/mol)
Prediabetes: A1c values 5.7 to <6.5% (39–48 mmol/mol)
a
Data from the American Diabetes Association.2
1162 OCTOBER 2020

The epidemiologic data describing the neuropathies in diabetes are KEY POINTS
challenging to interpret, largely because of the varied clinical manifestations
● A number of
and the tendency for studies to investigate a particular neuropathy of interest manifestations of
(eg, length-dependent axonal neuropathy, cardiovascular autonomic neuropathy are seen in
neuropathy, or gastrointestinal autonomic neuropathy). Specific details of diabetes, including
epidemiology are provided within each of the neuropathy subsections of this length-dependent
neuropathy, acute
article, although several overarching themes are seen. It is important to
generalized or focal
recognize that both type 1 and type 2 diabetes carry a high risk of neuropathy neuropathies,
development, but they are distinct disorders.6 The underlying pathophysiology mononeuropathies, and
of neuropathy is different between the two. Neuropathy related to type 1 autonomic neuropathies.
diabetes is directly linked to glycemic control. Extensive literature has
● The risk of neuropathy in
established the clear connection between hyperglycemia and neuropathy type 1 diabetes is primarily
development in individuals with type 1 diabetes and that aggressive glycemic linked to glucose control,
control will reduce the risk of neuropathy development in the short term and whereas the risks of
carry significant long-term benefit.6 Optimal glycemic control in type 1 diabetes neuropathy in type 2
diabetes include glucose
reduces the relative risk of neuropathy development by 78%.4 In contrast, control, hyperlipidemia,
although still an important risk factor, hyperglycemia is much less important hypertension, abdominal
in the pathogenesis of neuropathy in type 2 diabetes. In type 2 diabetes, intensive obesity, low levels of
glycemic control only reduces the risk of neuropathy by 5% to 9%.4 Increasing high-density lipoproteins,
and tobacco use.
evidence indicates that individual components of the metabolic syndrome,
including hypertriglyceridemia, hypertension, abdominal obesity, low levels of ● Approximately half of
high-density lipoproteins, and tobacco use, are important determinants of patients with diabetic
neuropathy risk and progression.5,6 neuropathy have
neuropathic pain; however,
Type 1 diabetes accounts for approximately 5% to 10% of total cases of
it is important to recognize
neuropathy, although that number is decreasing over time as the magnitude of that the absence of pain
the public health epidemic of type 2 diabetes continues to grow. The does not rule out a
prevalence of neuropathy in the population of individuals with diabetes is neuropathy.
similar between those with type 1 and type 2 diabetes, ranging from 10% to
● Small unmyelinated axons
50% depending on how neuropathy is defined, although the onset is much are affected earlier than
earlier in disease duration in those with type 2 diabetes.4 The prevalence of large fibers in most cases of
neuropathy in a cohort of individuals with well-controlled type 2 diabetes axonal neuropathy in type 2
increased from 8% to 42% over 10 years; in contrast, in a cohort of individuals diabetes, so an examination
should always include
with poorly controlled type 2 diabetes, the prevalence of neuropathy increased testing for signs of small
from 0% to 68% over 4 years. fiber dysfunction (thermal or
Pain is a common comorbidity in diabetic neuropathy, seen in approximately pain sensation) as well as
30% of cases. Pain varies across the neuropathy phenotype but is most often large fiber function
(reflexes, vibration
seen in length-dependent and acute neuropathies. Risk factors for the
detection).
development of neuropathic pain in diabetic neuropathy are poorly understood,
but female sex and more advanced neuropathy are recognized risk factors.
Metabolic risk factors for pain include poor glycemic control, impaired renal
function, and elevated body mass index. For more information on the treatment
of neuropathic pain, refer to the article “Management of Neuropathic Pain in
Polyneuropathy” by Amanda C. Peltier, MD, MS, and Derek Wood, MD,7 in this
issue of Continuum.
DISTAL SYMMETRIC POLYNEUROPATHY OF DIABETES

Distal symmetric polyneuropathy (DSPN) is the most common clinical
presentation of neuropathy in diabetes. Accounting for roughly 50% to 75% of
cases of diabetic neuropathy,4 DSPN is the classic chronic and length-dependent
neuropathy associated with diabetes. Increasing evidence indicates that early

DSPN in type 2 diabetes (or even prediabetes) preferentially involves small

unmyelinated axons, frequently causing neuropathic pain, and gradually
progresses to more involvement of large myelinated axons over time.8
Longitudinal information gathered from DCCT (the Diabetes Control and
Complications Trial) and the EDIC (Epidemiology of Diabetes Interventions
and Complications) study show that approximately 20% of individuals with
type 1 diabetes develop DSPN after 20 years of diabetes and that glycemic control
is the major modifiable risk factor for disease progression.9 In contrast, 15% or
more of patients with type 2 diabetes have DSPN at the time of diagnosis,
a number that increases to 50% over 10 years.4 The risk factors for disease
progression in type 2 diabetes include glucose control, tobacco use, weight,
and lipid levels.4,6
The diagnosis of DSPN in diabetes is based on history, clinical examination
findings, and nerve conduction studies in select cases. The appropriate clinical
CASE 2-1 A 47-year-old woman with an 8-year history of type 2 diabetes and
chronically elevated glucose levels, with hemoglobin A1c values in the 8%
to 9% range, presented to her primary care doctor with an infection in the
bottom of her right great toe, with osteomyelitis. She did not routinely
seek preventive care and had not noticed the injury, so it was fairly
advanced by the time she sought medical attention. She was referred for
a neurologic consultation for evaluation of an acute asymmetric neuropathy
(the ulcer occurred only in the right foot, and she had never reported
neuropathy symptoms). She reported no symptoms of pain in either foot
and had not noticed anything wrong with her feet until she found the injury
on her toe. Upon direct questioning, she said she had not noticed the
sensation of the cold tile bathroom floor on her feet in many years.
On examination, she had normal strength, except for 4/5 strength at the
extensor hallucis longus bilaterally. She had reduced patellar and absent
ankle reflexes. Sensory examination revealed absent vibration, pinprick,
and temperature sensation at the great toes, with a graded increase in
sensation to the midshin of both legs. She had reduced proprioception in
the toes and reduced light touch in the feet. She also had loss of hair and
venous stasis changes in the lower limbs.
COMMENT This is a typical clinical presentation for a patient with a painless

length-dependent distal symmetric polyneuropathy in the setting of
diabetes. It is critical to screen patients with diabetes annually by history
and examination for evidence of neuropathy to detect the development of
neuropathy in a timely manner. In this case, education about foot care and
safety is critical, as is more aggressive treatment of glucose, lipids, and
blood pressure. Now that the patient is aware of the risks, she is more likely
to take an active role in her health care. Unfortunately, established distal
symmetric polyneuropathy is irreversible, so it is important to prevent
further neuropathy progression by aggressively addressing all modifiable
risk factors.
1164 OCTOBER 2020

evaluation for DSPN includes, but is not limited to, examination of muscle KEY POINTS
strength, deep tendon reflexes, and sensation (vibration, proprioception,
● The presence of atypical
thermal, pain, and light touch sensation). The presence of atypical features such features in a patient with
as significant asymmetry, an acute onset, or early motor involvement suggests a suspected distal symmetric
different neuropathy type or diagnosis and should prompt further diagnostic polyneuropathy, such as a
evaluation, including nerve conduction studies and EMG. Although DSPN is significant asymmetry, an
acute onset, or early motor
generally symmetric (by definition), symptoms may initially be reported in one
involvement, suggests a
limb and then gradually evolve into a symmetric pattern over time. However, a different neuropathy type or
significant asymmetry on neurologic examination is unusual and should prompt diagnosis and should
additional testing.4–6 prompt further diagnostic
evaluation, including nerve
The clinical features of the neuropathy typically reflect the underlying
conduction studies and
pathophysiology. The “dying back” neuropathy that occurs in the setting of EMG.
length-dependent axonal dysfunction due to metabolic disturbance presents as
numbness and positive sensory symptoms (paresthesia or neuropathic pain) in ● Nerve conduction studies
the most distal parts of the body first (eg, the feet) and then progresses up the leg and EMG are not required as
part of the routine diagnosis
as more proximal nerve fibers are damaged. Some patients present with pain in of distal symmetric
the distribution of the neuropathy (approximately 25% to 35%), whereas other polyneuropathy in diabetes
patients are asymptomatic (CASE 2-1). Unless routine neuropathy screening of unless atypical features are
patients with diabetes occurs, many patients may progress to an advanced present.
neuropathy and present with a complication (foot ulcer or injury) that could
● The diagnosis of distal
have been avoided. Patients with neuropathic pain in the setting of DSPN symmetric polyneuropathy
typically present much earlier in the disease course than those without pain. The provides a valuable
diagnosis of DSPN in diabetes can be classified as small fiber predominant, large opportunity to educate
patients on the health
fiber predominant, or mixed, depending on the combination of clinical
benefits of addressing risk
symptoms and signs.4–6 factors associated with
Although nerve conduction studies and EMG have traditionally been a neuropathy (glucose
component of the diagnosis of neuropathy, recent studies have questioned control, hyperlipidemia,
whether these results have changed clinical management.10 Neurophysiologic hypertension, tobacco use),
advocate for exercise, and
testing should be performed in individuals with atypical clinical presentations, in counsel on the importance
which the differential diagnosis still includes radicular, entrapment, or of proper foot care.
demyelinating neuropathies.
The management of DSPN in diabetes largely involves education about the
underlying problem. In many individuals, neuropathy may be the first
complication of diabetes, and this can be a wake-up call to the consequences
of unmanaged risk factors. The initial diagnosis of neuropathy offers an
opportunity to educate patients (and their treating physicians) about the need
to improve glycemic control, to more aggressively manage lipids and blood
pressure, and to counsel on tobacco cessation (in both type 1 and type 2
diabetes). Advocating for an increase in exercise is also a critical component
to successful treatment. Finally, all patients with DSPN should be counseled
on foot care to reduce the risk of foot ulceration or amputation. All patients
with diabetes should have protective sensation evaluated using a 10-gram
monofilament by applying the filament to the great toe until the filament
bends (FIGURE 2-1).11 Those unable to detect 7 of 10 applications are at
significantly elevated risk for painless injury and should be referred for
appropriate podiatric foot care. Patients should always wear hard-soled shoes
(to prevent stepping on something sharp or inadvertently injuring an
insensate foot), should make sure to check their feet at least once daily, and
should have a very low threshold for seeking medical attention in the setting
of a foot injury.

NEUROPATHY ASSOCIATED
WITH METABOLIC
SYNDROME AND
PREDIABETES
Prediabetes (impaired fasting
glucose or impaired glucose
tolerance) may precede the
diagnosis of type 2 diabetes by
several years. The American
Diabetes Association’s definition
of prediabetes is a hemoglobin
A1c level of 5.7% to 6.4%.12
Metabolic syndrome consists of
five components: glucose
dysregulation due to insulin
resistance (which includes the
diagnosis of prediabetes or
diabetes), elevated serum
triglycerides, reduced
high-density lipoprotein level,
central obesity, and
hypertension. In general, the
presence of three of the five
components of metabolic
syndrome is required for
diagnosis.12
At present, it is estimated
that more than 1 in 3 adults in
the United States and almost
1 billion people worldwide have
prediabetes.3,13 The prevalence of
FIGURE 2-1
The proper technique for testing pressure
neuropathy in prediabetes is
perception with the 10-gram monofilament. approximately 10%, and among
Patients should close their eyes while being individuals with otherwise
tested. The monofilament is placed perpendicular “idiopathic” neuropathy, the
to the skin (A) and pressure applied until the
monofilament bends (B). The monofilament
presence of prediabetes is
should be held in the bent position for 1 second approximately 25%.14,15 A
and then released. Testing sites include the first, growing body of literature links
third, and fifth metatarsal heads and the plantar metabolic syndrome with DSPN
surface of the distal hallux on each foot (C). Loss
risk. In many cases, a diagnosis
of ability to detect the monofilament at one or
more sites indicates neuropathy with a high risk of of DSPN can be made at the
foot ulceration. time of diagnosis of type 2
diabetes, strongly supporting
the evidence of ongoing
neuropathy development in the preceding years.12 The clinical manifestations
of DSPN in the setting of prediabetes and metabolic syndrome largely mirror
the clinical presentation of DSPN in type 2 diabetes, albeit at an earlier stage of
neuropathy severity. In most cases, patients have a length-dependent axonal
neuropathy that selectively targets small-diameter unmyelinated axons.
Clinically, this may present with small fiber sensory neuropathy that may be
1166 OCTOBER 2020

either painful or painless (CASE 2-2). A smaller number of patients may KEY POINT
present with autonomic dysfunction, primarily manifesting as reduced
● The risks associated with
cardiovagal function with a resting tachycardia and reduced exercise neuropathy development
tolerance. The reason that small unmyelinated fibers are more prone to exist in the prediabetes
damage has not been fully identified. state. The individual
components of the
metabolic syndrome,
PATHOPHYSIOLOGY OF DIABETIC NEUROPATHY
including glucose
At present, our understanding of the pathophysiology of diabetic neuropathy dysregulation/insulin
is incomplete, and the etiology is most likely multifactorial. Several putative resistance, dyslipidemia
mechanisms involving derangements of normal metabolic homeostasis, (hypertriglyceridemia and
low high-density lipoprotein
autoimmunity, and microvascular insufficiency have been implicated. The
level), central obesity, and
metabolic mechanisms that have been identified include the accumulation of hypertension, all contribute
glycation end products, oxidative and nitrosative stress, abnormal flux in to the risk of developing
calcium regulation, increased polyol pathway function, and mitochondrial distal symmetric
dysfunction. At the root of these metabolic derangements is inflammatory polyneuropathy.
stress on the system that has been linked to the growing role of dyslipidemia in
the development of neuropathy (particularly in type 2 diabetes) in addition to
hyperglycemia.5 Hyperglycemia and hyperlipidemia cause a combination of
inflammation, mitochondrial dysfunction, and oxidative stress that all result
in neuronal dysfunction, impaired axonal transport, and ultimately axonal
damage.6 Other potential pathways that contribute to neuropathy
development include the metabolism of sphingolipids into toxic
deoxysphingolipids.20 These various pathophysiologic mechanisms are
associated with damage to both peripheral sensory and autonomic neurons as
well as the supporting glial cells.5,6,19 For more complete information on the
pathophysiologic mechanism underlying the development of neuropathy,
several recent reviews of the pathophysiology of diabetic neuropathy have
been published.5,6,19
TREATMENT OF NEUROPATHIES IN DIABETES AND PREDIABETES

To date, no disease-modifying therapies have been approved for diabetic
neuropathy (or prediabetes-associated neuropathy). A string of significant
pharmaceutical failures in diabetic neuropathy has hampered further drug
development.21 However, treatment of modifiable risk factors has been shown to
limit disease progression in most patients.22 The major goals of care therefore
include reduction of modifiable risk factors such as hyperglycemia,
hyperlipidemia, hypertension, obesity, and tobacco use. The optimal types of
exercise and specific dietary recommendations that might improve outcomes are
not known at this time.
Dietary supplements have often been touted as effective treatments for
diabetic neuropathy. α-Lipoic acid has been investigated in a number of clinical
trials of diabetic neuropathy23; however, the benefits have been limited to
symptomatic relief, and it has not been shown to have any impact on disease
modification.24 Other dietary therapeutic interventions have been suggested but
have not demonstrated efficacy in clinical trials.
ACUTE DIABETIC NEUROPATHIES

The onset of an acute neuropathy in the setting of diabetes should suggest a small
number of potential causes. An asymmetric painful motor neuropathy often
suggests a lumbosacral radiculoplexus neuropathy (also known as diabetic

amyotrophy), whereas a length-dependent or generalized painful small fiber and

autonomic neuropathy might suggest complications of a rapid change in glucose
levels (treatment-induced neuropathy of diabetes).
Diabetic Lumbosacral Radiculoplexus Neuropathy

Commonly referred to as diabetic amyotrophy, diabetic lumbosacral
radiculoplexus neuropathy is a monophasic neuropathy that typically presents
over weeks to months, initially with asymmetric lower extremity pain, weakness,
and atrophy, often more prominent proximally.25 Although diabetic lumbosacral
radiculoplexus neuropathy has not been well studied due to its rarity and the
frequent delay in diagnosis, a 2019 study found the incidence to be approximately
CASE 2-2 A 53-year-old man presented for evaluation of a 4-month history of

painful tingling and lancinating pain in his toes, particularly at night. He
had been relatively healthy, with some mild hypertension and
hyperlipidemia.
On examination, his body mass index (BMI) was 31.3 kg/m2. He had
normal strength, reflexes, and coordination. Sensory examination
revealed intact proprioception, mildly decreased sensation to vibration
using a 128-Hz tuning fork (8 seconds at the great toes), and diminished
temperature and pinprick sensation in the feet. He also had some
thickened dry skin along the soles of the feet.
The clinical history and examination were consistent with small fiber
distal symmetric polyneuropathy. An initial laboratory workup showed
hemoglobin A1c of 5.9% and elevated total cholesterol (209 mg/dL) and
triglycerides (317 mg/dL). A 3-mm punch skin biopsy from the distal leg
demonstrated reduced intraepidermal nerve fiber density (FIGURE 2-2).
COMMENT This case illustrates a typical clinical presentation for a patient with a
painful small fiber distal symmetric polyneuropathy in the setting of
prediabetes and metabolic syndrome. Treatment should include exercise
and diet, with a goal of reducing insulin resistance and hyperglycemia. To
date, exercise programs that focus on cardiovascular exercise or a
combination of cardiovascular and resistance training exercises have
shown benefit in metabolic parameters and might reduce neuropathy
progression.16,17 Several small exercise studies have shown improvements
in pain and balance, although maintaining a long-term exercise program is a
significant hurdle.17,18 With obesity as a major risk factor for neuropathy
progression, a focus on weight loss has been of interest. To date, no
specific recommendations for dietary changes have been linked to
successful disease modification. Ongoing clinical trials with medical and
surgical weight loss are under way to determine potential impacts on
neuropathy progression.19 Close monitoring is needed for possible
progression to diabetes. Aggressive treatment of hyperlipidemia is also
recommended. Treatment of neuropathic pain should be considered if this
patient’s discomfort interferes with his activities of daily living.
1168 OCTOBER 2020

4.2 per 100,000 per year, suggesting that it is more common than other
immune-mediated neuropathies such as CIDP.26
Diabetic lumbosacral radiculoplexus neuropathy is most common in
middle-aged patients with type 2 diabetes and is more common in men than in
women. It is often associated with weight loss. The clinical presentation is
characterized by the relatively acute onset of severe unilateral burning pain in the
hip, thigh, or back that often spreads to the entire limb and contralaterally. After
the onset of pain, proximal weakness develops that can be quite debilitating.
Most patients require assistance with ambulation and aggressive pain
management.25,27 Sensory loss is not typically a major component of this process.
Neurophysiologic testing can be helpful in confirming involvement of the
FIGURE 2-2
Small fiber neuropathy. A punch skin biopsy is stained with protein gene product 9.5
(PGP 9.5), an axonal marker. A, No small unmyelinated nerve fibers are seen entering the
epidermal layers (the epidermis is the red tissue at the top). B, The usual appearance of a
normal skin biopsy, in which nerve fibers (green) pierce the epidermal layer.

lumbosacral roots, plexus, and nerves. Diabetic lumbosacral radiculoplexus

neuropathy may progress over months (in some cases as long as 18 months), with
another 12 to 24 months required for recovery. Unfortunately, recovery is
typically incomplete. Less commonly, patients may present with a symmetric
motor-only form.26,28
CASE 2-3 A 28-year-old woman with a 14-year history of type 1 diabetes with
historically poor glycemic control (hemoglobin A1c values in the 10% to 14%
range) but no symptoms of neuropathy and no other complications of
diabetes presented to the hospital with diabetic ketoacidosis due to a
urinary tract infection. Her family and providers met with her while she
was admitted to the hospital to encourage improved glucose control. She
started taking her insulin as prescribed after discharge from the hospital,
and her daily glucose readings improved.
Three weeks later, she presented to her primary care doctor with
severe burning pain in her hands and her legs with no associated
weakness or numbness. She had severe contact allodynia and
hyperalgesia in the distribution of the pain. Nerve conduction studies and
EMG ordered by her primary care physician were normal and she was
referred for a neurologic consultation.
At the time of her neurologic evaluation 6 weeks after hospitalization,
her hemoglobin A1c had decreased from 12.2% to 8.1%. On examination,
she had findings consistent with a length-dependent small fiber
neuropathy. She had normal strength, reflexes, and normal sensation to
vibration and proprioception. She had allodynia to light touch and
diminished pinprick and temperature sensation in her legs distally up to
midthigh and distally in her arms up to midforearm with areas of
hyperalgesia. Skin biopsies confirmed a severe small fiber neuropathy
with absent fibers at the distal leg, severely reduced at the distal thigh
but normal at the proximal thigh.
She was prescribed a tricyclic antidepressant, gabapentin, and an
agent for breakthrough pain. She had also developed proliferative
retinopathy during this time and required ophthalmologic intervention.
COMMENT Treatment-induced neuropathy of diabetes is seen in individuals with rapid

glycemic control on the background of chronic hyperglycemia. The severity
of the syndrome typically reflects the magnitude of change in the glucose
control. Treatment of the neuropathic pain can be challenging and typically
requires polypharmacy. As noted in this case, it may involve other
microvascular tissue beds, such as the eye and kidney, and both should be
monitored for disease progression. Diabetic anorexia, or diabulimia, is an
eating disorder characterized by the withholding of insulin to lose weight in
individuals with type 1 diabetes. It is a significant risk factor for
treatment-induced neuropathy and carries a very high morbidity and
mortality.32,33
1170 OCTOBER 2020

Unlike DSPN, diabetic lumbosacral radiculoplexus neuropathy is not directly KEY POINTS
related to hyperglycemia or metabolic syndrome. Pathologic data suggest it is
● The acute to subacute
caused by a microvasculitis resulting in ischemic nerve injury. Unlike patients onset of pain and weakness
with DSPN, patients with diabetic lumbosacral radiculoplexus neuropathy have in the hip and leg of an
generally better-than-average glycemic control. Despite the evidence of an individual with diabetes
immune basis, limited data are available regarding the potential efficacy of should raise suspicion for
diabetic lumbosacral
immunomodulatory treatment. A small randomized trial suggested that IV
radiculoplexus neuropathy.
methylprednisolone may help with neuropathic pain associated with diabetic Early recognition and
lumbosacral radiculoplexus neuropathy.29,30 Clinical trials are challenging intervention with IV
because patients with diabetic lumbosacral radiculoplexus neuropathy are often corticosteroids may improve
neuropathic pain and reduce
not appropriately diagnosed in the acute setting before the development of
the associated morbidity.
significant axonal injury. Although speculative, it is likely that early diagnosis
and prompt treatment could be of benefit. ● Treatment-induced
neuropathy of diabetes
Treatment-Induced Neuropathy of Diabetes should be suspected in an
individual with diabetes who
Previously known as insulin neuritis, or acute painful neuropathy, presents with the acute to
treatment-induced neuropathy of diabetes develops suddenly following rapid subacute onset of
improvement in glycemic control in the setting of chronic hyperglycemia. neuropathic pain in a
Treatment-induced neuropathy of diabetes may also be related to diabetic symmetric pattern that is
accompanied by
neuropathic cachexia, a disorder with overlapping clinical features, and is also predominantly small fiber
associated with weight loss.31 Treatment-induced neuropathy of diabetes is findings. A significant
characterized by the acute onset of neuropathic pain in a length-dependent or improvement in glycemic
generalized distribution, often with accompanying autonomic symptoms. The control that precedes the
development of pain is the
neuropathy predominantly involves small fiber sensory and autonomic nerve
clue to the diagnosis.
fibers (CASE 2-3). Treatment-induced neuropathy of diabetes is most
commonly seen after a significant treatment change in individuals with type 1
diabetes who have had chronic hyperglycemia or in individuals with newly
discovered type 2 diabetes with an unknown period of hyperglycemia
combined with an aggressive lowering of the hemoglobin A1c. Symptoms
typically begin 2 to 6 weeks after the change in glucose control, and
neuropathic pain can be very severe. Autonomic symptoms are sometimes
prominent, including orthostatic intolerance or hypotension, hyperhidrosis or
anhidrosis, early satiety, and erectile dysfunction, but they are frequently
overlooked given the severity of the neuropathic pain.31
Although the exact mechanism of treatment-induced neuropathy of diabetes
is unknown, one theory includes a relative hypoglycemic state resulting in
inadequate energy production by mitochondria and energy failure. Other
suspected mechanisms include an increase in proinflammatory cytokines and
resulting nerve fiber damage. Irrespective of the underlying mechanism,
longitudinal data suggest that complications associated with treatment-induced
neuropathy of diabetes can be profound if glycemic control is destabilized.34
Diabetic anorexia, also reported as diabulimia, is an eating disorder in
individuals with type 1 diabetes characterized by the withholding of insulin to
lose weight. Diabulemia is a significant risk factor for treatment-induced
neuropathy of diabetes and carries a very high rate of morbidity and mortality.
The severity of neuropathy in treatment-induced neuropathy of diabetes is
tied to the magnitude and rate of the change in hemoglobin A1c. Individuals
with the largest changes in glucose control have the largest region of body
involvement, the most severe pain, and the greatest symptoms of autonomic
dysfunction (FIGURE 2-3).

FIGURE 2-3
Treatment-induced neuropathy of diabetes. In this figure, the decline in the hemoglobin A1c is
shown along the x-axis, with the absolute risk of developing neuropathy shown along the
y-axis. With a greater change in the hemoglobin A1c, the risk of developing treatment-induced
neuropathy of diabetes increases. In addition, the clinical manifestations of neuropathy
tend to worsen, covering larger regions of the body with the larger change in hemoglobin A1c.
The red areas of the body are regularly involved, whereas the gray areas are sometimes
involved. With a modest change in the hemoglobin A1c of 2% to 3%, a distal small fiber
neuropathy may be the only manifestation.
In addition to the development of neuropathy, individuals who develop

treatment-induced neuropathy of diabetes also frequently have renal and retinal
involvement simultaneously, suggesting this is a diffuse microvascular process.
The majority of individuals with treatment-induced neuropathy of diabetes have
significant progression of proliferative retinopathy over a period of 12 months.
Renal function may decline, although increased microalbuminuria is the most
common manifestation.34,35
One of the most interesting findings in treatment-induced neuropathy of
diabetes is that a degree of neuropathy reversibility exists in some individuals
with type 1 diabetes. Although the neuropathy may not entirely resolve, in some
individuals with stable glucose control over several years, a trend in
improvement in nerve fiber density is noted by skin biopsy, neuropathy severity
as noted by examination score, and neuropathy pain scores. In contrast, in
patients with treatment-induced neuropathy of diabetes who continue to have
labile glycemic control with periods of poor control punctuated by significant
improvement in hemoglobin A1c, the neuropathy can be severe and
progressive.31,34 Unfortunately, because of the relatively small number of studies
on the topic, no clear consensus exists on how best to prevent or treat
treatment-induced neuropathy of diabetes. Based on the author’s experience
with the largest published cohort of individuals with treatment-induced
neuropathy of diabetes, avoiding dramatic improvements in hemoglobin A1c
1172 OCTOBER 2020

levels in individuals with chronic hyperglycemia is recommended (limiting KEY POINT
change to 1% reduction in the hemoglobin A1c per month). Management of
● The earliest clinical
treatment-induced neuropathy of diabetes should focus on managing manifestation of a diabetic
symptomatic pain while encouraging glucose stabilization at the current autonomic neuropathy is a
hemoglobin A1c level until symptoms begin to improve. resting tachycardia.
FOCAL NEUROPATHIES
Entrapment neuropathies, including median mononeuropathy at the wrist
(carpal tunnel syndrome), ulnar mononeuropathy at the elbow (cubital tunnel
syndrome), and fibular (peroneal) mononeuropathy at the fibular head are more
prevalent in individuals with diabetes when compared to the general
population.36 The clinical characteristics and electrodiagnostic features of the
entrapment neuropathies do not differ in diabetes, although they can be more
challenging to diagnose in the setting of an ongoing axonal neuropathy due to
diabetes.
AUTONOMIC NEUROPATHIES
Autonomic neuropathies encompass a diverse spectrum of clinical
manifestations because of the different organ systems involved. A major
difficulty in providing estimates of the prevalence of diabetic autonomic
neuropathy is the tendency to report autonomic dysfunction as it relates to the
organ system of interest. As a typical example, cardiovascular autonomic
neuropathy is a commonly measured study outcome in diabetes trials, but the
cardiovascular autonomic neuropathy results do not inform the investigator
about the presence or absence of gastrointestinal autonomic neuropathy (or any
other organ system involvement). Thus, rates of autonomic neuropathy may
range from less than 5% to greater than 70% depending on the organ system
studied and the testing paradigm employed. However, it is clear that
uncontrolled hyperglycemia over longer periods of time results in clinically
meaningful dysfunction of the autonomic nervous system.37
Diabetic Cardiovascular Autonomic Neuropathy

Diabetic cardiovascular autonomic neuropathy is of major clinical concern
because it is associated with a significant increase in both morbidity and
mortality.38 The clinical manifestations of cardiovascular autonomic neuropathy
may range from an increased resting heart rate to diminished heart rate response
to physiologic stress.4 As cardiovascular autonomic neuropathy becomes more
severe, orthostatic hypotension (defined as a fall in blood pressure of >20 mm Hg
systolic and 10 mm Hg diastolic) develops, which is the most severe and
debilitating form of cardiovascular autonomic neuropathy.37 The autonomic
dysfunction in cardiovascular autonomic neuropathy is due to denervation of the
vagus nerve, causing impaired heart rate variability and an increase in resting
heart rate and damage to peripheral efferent sympathetic vasomotor nerves that
control vasoconstriction, resulting in orthostatic hypotension. The end result of
cardiovascular autonomic neuropathy is diminished cardiac output, particularly
in association with exercise.39
The association between cardiovascular autonomic neuropathy in diabetes
and an increased rate of mortality is very high.40 Patients with diabetes who have
orthostatic hypotension in the setting of cardiovascular autonomic neuropathy
have a 5- to 10-year mortality range between 27% and 56%.4,6,37 The proposed

mechanisms for the increase in mortality include an absent or reduced

perception of myocardial ischemia, impaired hemodynamic response to
physiologic stressors (including surgery, infection, and anesthesia), QT interval
dispersion (the difference between maximum and minimum QT interval)
causing arrhythmias, imbalance between the sympathetic and parasympathetic
nervous system, and localized areas of myocardial ischemia with sympathetic
denervation and reinnervation.41
A number of treatments exist for the specific symptoms associated with
cardiovascular autonomic neuropathy. However, at present, no treatment
exists for the underlying disease, and no evidence has shown that symptomatic
therapy reduces the associated morbidity and mortality. As a consequence, the
primary goal is prevention of disease development and progression with
glycemic control and aggressive management of other features of metabolic
syndrome. A number of medications may cause or exacerbate orthostatic
hypotension, and they should be removed in the setting of orthostatic
hypotension (TABLE 2-2).
Gastrointestinal Autonomic Neuropathies in Diabetes

Gastrointestinal complications of diabetes include disorders of motility (slow or
fast transit) and the accompanying symptoms.
GASTROPARESIS. Gastroparesis is one of the most feared and challenging medical

complications of diabetes. Gastroparesis causes delayed transit of food (solids or
liquids) from the stomach into the small intestine; it is present in up to 50% of
individuals with diabetes.42–45 Many patients report postprandial fullness,
nausea, bloating, or vomiting, although some patients may be asymptomatic.
One of the more challenging aspects of gastroparesis is that it further complicates
glycemic control by causing a mismatch between glucose absorption and
administration of insulin. If insulin is taken with meals, delayed food absorption
can result in hypoglycemia with hyperglycemia later in the day. This mismatch
between food intake and insulin timing due to the gastroparesis results in a
TABLE 2-2 Impact of Medications and Other Agents on Autonomic Function
Autonomic Symptoms/Signs Potentially Causative Agents
Orthostatic hypotension Antidepressants, antihypertensive medications, α1-adrenoreceptor antagonists,

antiparkinsonian dopaminergic agents
Gastroparesis Opioids, clonidine, tricyclic antidepressants, calcium channel blockers, dopamine

agonists, muscarinic cholinergic receptor antagonists, glucagonlike peptide 1 (GLP-1)
agonists, phenothiazines, cyclosporine
Constipation Calcium channel antagonists, opioids, anticholinergic medications
Diabetic diarrhea Metformin, sorbitol-containing foods
Bladder dysfunction Anticholinergic agents, tricyclic antidepressants, calcium channel antagonists (impair
detrusor activity); α1-adrenoreceptor agonists (increase urethral sphincter tone),
α1-adrenoreceptor antagonists (decrease urethral sphincter tone)
Sexual dysfunction Antidepressants, antihypertensive medications, statins, antihistamines
1174 OCTOBER 2020

vicious cycle of worsening diabetes control resulting in more severe KEY POINTS
gastroparesis.
● Cardiovascular autonomic
Although symptoms of postprandial fullness are commonly noted in individuals neuropathy (particularly
with gastroparesis, objective assessment of gastroparesis severity is recommended. with orthostatic
The recommended diagnostic testing for gastroparesis is a gastric-emptying hypotension) is associated
study with scintigraphy. After a solid meal, 37% to 90% of food normally remains with significantly increased
mortality risk in patients
in the stomach after 1 hour. After 2 hours, this is reduced to 30% to 60%, and
with diabetes, with 5- to
typically 10% or less of food remains in the stomach after 4 hours. Food 10-year mortality rates
remaining in the stomach longer than expected suggests impaired gastric greater than 50%.
emptying (although certain medications can alter gastric emptying and should be
noted). Other causes for delayed gastric emptying should also be considered, ● Gastroparesis is a
common and disabling
including peptic ulcer, gastric obstruction, or other structural disorders. manifestation of diabetic
It should also be noted that although autonomic neuropathy plays an autonomic neuropathy, but
important role in the pathophysiology of gastroparesis, a separate and potentially the potential for
reversible component is directly related to hyperglycemia.46–48 Thus, if glucose symptomatic improvement
exists with better glycemic
control stabilizes, an improvement in gastroparesis may be seen that is not due to control.
any change in autonomic function.
Treatments for gastroparesis may require collaboration with a gastric motility ● Constipation may be a
expert. The first-line approach involves having patients eat smaller, more manifestation of diabetic
autonomic neuropathy but is
frequent meals. However, this strategy can further complicate glycemic control.
also frequently due to
Avoiding dietary fiber and fat is recommended. Removal of any offending medication. A careful review
medications (such as opioids, clonidine, tricyclic antidepressants, calcium of both prescribed and
channel blockers, dopamine agonists, muscarinic cholinergic receptor over-the-counter
medications may identify
antagonists, glucagonlike peptide 1 [GLP-1] agonists, phenothiazines, and
potential opportunities to
cyclosporine) should always be attempted (TABLE 2-2).49,50 Metoclopramide is improve symptoms.
the only US Food and Drug Administration (FDA)–approved agent for the
treatment of gastroparesis.46–48 However, it carries a host of serious
extrapyramidal side effects that limit its use, and duration of therapy beyond
5 days is not recommended.
CONSTIPATION. Although constipation is a common symptom in the general

population, it is particularly prevalent in diabetes, with up to 60% of patients
affected.51 Autonomic dysfunction can be due to several potential mechanisms,
but numerous potential medication effects can cause constipation in individuals
with diabetes. The patient’s medication list should be closely investigated, with
particular attention paid to the use of calcium channel antagonists, opioids, and
anticholinergic medications (TABLE 2-2).51 Constipation can be a challenge,
particularly if it occurs with gastroparesis because high-fiber diets and bulking
agents are contraindicated in gastroparesis.
DIARRHEA. Diabetic diarrhea is associated with autonomic neuropathy of the

gastrointestinal system, although the pathogenesis is frequently multifactorial.
Diabetic diarrhea is a disconcerting problem for people because it is typically a
profuse and watery diarrhea that usually presents during sleep. It is more
common in individuals with type 1 diabetes52 and is often associated with fecal
incontinence. Diabetic diarrhea may be reported in up to 20% of individuals with
diabetes. It may alternate with constipation or may persist as diarrhea for hours
at a time. Although the diagnosis in this case is typically made by history,
gastric-emptying studies may show either rapid or slow transit times and
therefore are not particularly helpful. Bacterial overgrowth is a common

comorbid complication. The differential diagnosis of diabetic diarrhea is

medication side effect (particularly metformin therapy in type 2 diabetes), foods
containing sorbitol (TABLE 2-2), exocrine pancreatic insufficiency, celiac disease,
or dysfunction of the bile salt metabolism pathway.37,52 Treatment focuses on
agents that reduce peristalsis, prolong transit time, and reduce fecal volume,
including loperamide, codeine, combination diphenoxylate and atropine, or
tincture of opium.53
Diabetic Urogenital Autonomic Neuropathy

Sexual dysfunction and bladder dysfunction are common urogenital
complications of diabetic autonomic neuropathy.
BLADDER DYSFUNCTION. In individuals with diabetes, involvement of the

bladder may occur as part of a progressive autonomic neuropathy and may result
in symptoms such as urinary frequency, urinary urgency, nocturia, and urinary
incontinence.52 Bladder symptoms are reported in up to 50% of individuals with
diabetes. However, objective evidence of bladder dysfunction may be seen in up
to 87% of individuals with type 1 diabetes. Bladder dysfunction may be a
consequence of damage to the autonomic and sensory afferent and efferent
fibers or of damage to the smooth muscle of the bladder or urothelial cell layer.
An overlap exists between symptoms linked to autonomic neuropathy and
urogenital symptoms attributed to central nervous system involvement, and
individuals with diabetes have risks for both.
One of the initial symptoms of autonomic neuropathy involving the bladder is
impaired sensation of fullness and dysfunction of the micturition reflex. As
neuropathy severity increases, detrusor activity is impaired, resulting in
increasing postvoid residuals, diminished urinary flow rates, and, ultimately,
urinary retention. With increasing retention, increasing bladder distention
eventually leads to urinary retention with overflow incontinence.37,52
Medications are a common cause of bladder dysfunction and should be
considered in the differential diagnosis of bladder dysfunction in diabetes.
Medications that impair detrusor activity include anticholinergic agents, tricyclic
antidepressants, and calcium channel antagonists (TABLE 2-2). Medications that
decrease urethral sphincter tone include the α1-adrenoreceptor antagonists,
which can cause urinary leakage; conversely α1-adrenoreceptor agonists can
increase urethral sphincter tone and result in urinary retention.37,52
The initial evaluation of a patient with diabetes with symptoms of urinary
dysfunction should include a review of medications for potential side effects
(TABLE 2-2), followed by a postvoid residual measurement by ultrasound. In
more complicated situations (ie, recurrent urinary tract infection or symptoms
suggestive of bladder outlet obstruction), a formal urodynamic study and
evaluation by urology are appropriate.
SEXUAL DYSFUNCTION. Diabetic autonomic neuropathy is a frequent cause of

sexual dysfunction in men and women. In women with diabetes, a reduction in
the vascular release of nitric oxide results in decreased vaginal relaxation and
painful intercourse.54 Diabetic neuropathy also leads to dysfunction of vaginal
exocrine glands, resulting in dryness and tissue irritation, further compounding
painful intercourse.55 As noted in a 2019 meta-analysis, the frequency of sexual
dysfunction in women was approximately 70% in women with type 2 diabetes, a
1176 OCTOBER 2020

twofold increase over age-matched women without diabetes.56 As with men, KEY POINTS
psychological factors also play a role in sexual function in women with diabetes,
● Diabetic diarrhea is often
and multifaceted clinical care addressing both physical and psychological factors profuse and watery; it
is necessary.55,56 frequently occurs at night
Erectile dysfunction is highly prevalent in men with diabetes, noted in up to with fecal incontinence.
75% of male patients.52 Although erectile dysfunction may be an early Medications should be
reviewed carefully because
manifestation of autonomic dysfunction, the underlying pathophysiology is a
identification and removal
combination of vascular, neurologic, and psychological factors. Medication side of offending medications
effects are also in the differential diagnosis for sexual dysfunction, and offending may improve symptoms.
medications should be removed, if possible (TABLE 2-2). One characteristic
feature of neurogenic and vascular erectile dysfunction is the gradual ● Bladder dysfunction is
common in diabetes and
decrease of morning erections combined with erectile failure during sexual often related to medication
stimulation; in contrast, erectile dysfunction associated with psychological side effects. As with other
onset is generally of more sudden onset, and morning erections are maintained. diabetic autonomic
In some cases of diabetic sympathetic nervous system dysfunction, neuropathies, offending
medications should be
ejaculatory failure may precede erectile dysfunction. Sympathetic nervous removed as the initial step in
system dysfunction can also lead to retrograde ejaculation due to impaired management.
bladder neck closure.57 Although a number of medications exist to treat
erectile dysfunction, they become less effective as neuropathy and vascular ● Sexual dysfunction is
common in both men and
disease worsen.
women with diabetes and
frequently is due to a
Sudomotor Function combination of
Sweat glands contain sympathetic cholinergic innervation and are necessary for psychological and physical
factors, both of which
proper homeostatic thermoregulation as well as skin health. Damage to
should be addressed.
sympathetic cholinergic nerves in a length-dependent fashion is a common
finding in individuals with diabetic neuropathy.52 The pattern of sudomotor ● Neuropathy involving the
dysfunction matches the distribution of the sensory neuropathy, typically sympathetic cholinergic
presenting in a stocking-and-glove distribution. Interestingly, patients do not nerves results in a
length-dependent region of
present with symptoms related to distal anhidrosis but instead report proximal anhidrosis, but patients
hyperhidrosis. The loss of distal sweating causes a compensatory proximal typically present with
hyperhidrosis to maintain thermoregulation; therefore, patients feel that they are complaints of proximal
sweating too much over their head and trunk. Management of this condition is hyperhidrosis.
challenging because sweat reduction can lead to hyperthermia, so treatments
focus on nonpharmacologic thermoregulation. Another classic finding in diabetic
neuropathy, although less common than distal anhidrosis, is gustatory sweating.
Sweat will appear over the face, head, neck, shoulders, and chest after eating;
although it is presumed to be related to nerve injury and aberrant reinnervation,
the pathophysiology has not been fully elucidated. Typical treatments range from
topical anticholinergic or aluminum-based agents to botulinum toxin
injections.58
Sudomotor dysfunction may present as the earliest clinical manifestation of
neuropathy and can be detected in very early diabetic neuropathy and in the
prediabetic/metabolic syndrome state. Clinical testing for sudomotor
dysfunction may involve different neurophysiologic tests of sweat function,
including the quantitative sudomotor axon reflex test (QSART),
thermoregulatory sweat testing, or other tests of sweat function. Testing
abnormalities must be differentiated from medication side effects, and without
proper thermal and humidity control, testing may be unreliable. It should be
noted that devices using electrochemical skin conductance that have been
heavily marketed for testing sweat function in neuropathy have had questions

raised about their utility because of serious problems in data reporting that
question the reliability and reproducibility of the results.59
Hypoglycemia-associated Autonomic Failure

Hypoglycemia-associated autonomic failure is a serious complication of
aggressive glycemic control. With a fall in glucose levels, the autonomic nervous
system is activated, including the sympathetic, parasympathetic, and
sympathoadrenal divisions. This results in a decrease in insulin secretion and an
increase in circulating glucagon, epinephrine, norepinephrine, pancreatic
polypeptide, cortisol, and growth hormone. With the fluctuation in hormone
levels, symptoms of autonomic activation are noted, including tremor,
palpitations, anxiety, diaphoresis, hunger, and paresthesia. With progressive
hypoglycemia, neuronal function declines and symptoms such as fatigue,
weakness, and dizziness occur, which progress to cognitive and behavioral
symptoms and finally to seizures in severe hypoglycemia.
A number of studies have identified an association between strict glycemic
control and a decreased counterregulatory response to hypoglycemia. As a result
of this diminished counterregulatory response, the perception of symptoms
associated with hypoglycemia is diminished, resulting in a lower threshold of
glucose at which future symptoms will occur. As the number of hypoglycemic
episodes increases, a vicious cycle of more severe and more frequent
hypoglycemia then develops.
A number of large longitudinal studies show that better glycemic control leads
to a reduction in the incidence of neuropathy, retinopathy, and nephropathy in
individuals with type 1 diabetes. However, in type 2 diabetes, the relationship
between glycemic control and the development of complications is not as clear.
A strong association exists between tight glycemic control and an increased
incidence of severe iatrogenic hypoglycemia. More recent studies have noted an
association between intensive glycemic control, hypoglycemic events, and an
increased rate of mortality. Although hypoglycemia has not been confirmed as
the cause of the increase in mortality in these studies, evidence was sufficient to
stop these ongoing trials prematurely.
Hypoglycemia and Cardiovascular Autonomic Function

During periods of recurrent hypoglycemia, the production of stimulating
hormones (eg, epinephrine, glucagon, adrenocorticotropic hormone [ACTH])
that result in the symptoms of hypoglycemia is decreased, thereby blunting the
responses to future episodes of hypoglycemia. In exposure to mild experimental
hypoglycemia in a controlled setting, cardiac vagal baroreflex sensitivity and
sympathetic adrenergic response to hypotension and orthostatic stress are
decreased.60 These changes in cardiovascular autonomic function persist for at
least 16 hours. These findings have direct clinical implications for patients with
diabetes who may have episodes of hypoglycemia. Recurrent episodes of
hypoglycemia lead to a blunted baroreflex response and may impair vagal
protection against arrhythmia and sudden death. Impaired parasympathetic
function (ie, cardiac vagal control) is also linked to higher mortality after
myocardial infarction.
Several studies have also linked hypoglycemia to abnormal cardiac
repolarization, manifesting as QT interval prolongation and QT dispersion on
ECG. It is unclear whether spontaneous hypoglycemia in individuals with
1178 OCTOBER 2020

diabetes results in the same degree of QT interval prolongation (although KEY POINTS
increases in up to 45 milliseconds have been reported in the setting of
● Recurrent hypoglycemia
spontaneous hypoglycemia). The potential pathophysiologic mechanisms blunts future autonomic
underlying the acute alterations in cardiac repolarization are not known. responses to low levels of
The long-term effects of hypoglycemia on nerve fiber structure and function glucose, creating a vicious
need to be more clearly identified, particularly as they relate to aggressive cycle of recurrent
hypoglycemia because of
glycemic control. At present, individuals with diabetes must walk a fine line
the body’s inability to sense
between the increased risk of complications with hyperglycemia and the low glucose levels.
increased risk of mortality with hypoglycemia.
● Recurrent hypoglycemia
DIABETES AND CHRONIC INFLAMMATORY DEMYELINATING is associated with an
increase in cardiovascular
POLYRADICULONEUROPATHY mortality, although the
CIDP is a heterogeneous immune-mediated condition of the peripheral nervous exact mechanism for the
system that may present in a progressive or relapsing-remitting fashion. CIDP increase in mortality is still
typically presents with the symmetric onset of proximal and distal sensory and under investigation.
motor symptoms. However, almost half of patients may present with an atypical ● It is controversial whether
disease with either focal or multifocal manifestations or more isolated motor or chronic inflammatory
sensory symptoms. CIDP is important to recognize because it is responsive to demyelinating
immunomodulatory treatment. The diagnosis of CIDP is based on a combination polyradiculoneuropathy
(CIDP) occurs more
of clinical features, supportive laboratory tests, and electrodiagnostic criteria. For
frequently in individuals
more information on CIDP, refer to the article “Chronic Inflammatory with diabetes; however,
Demyelinating Polyradiculoneuropathy and Its Variants” by Kelly Gwathmey, CIDP is widely
MD,61 in this issue of Continuum. overdiagnosed. A diagnosis
of CIDP in a patient with
A significant diagnostic dilemma exists in some patients with diabetes because
diabetes should be based on
of the overlapping clinical, electrodiagnostic, and laboratory features.62 typical clinical features, not
Individuals with significant axonal neuropathy in diabetes may have reduced on nerve conduction study
conduction velocities and elevated CSF protein. As a consequence, a debate is findings alone.
ongoing about whether an increased incidence of CIDP exists in patients with
diabetes. Some investigators argue that the numbers of patients with CIDP are
greater than that seen in the general population62; however, other investigators
suggest that the overlapping clinical, laboratory, and electrodiagnostic features
simply create an increased risk of misdiagnosis.63
A 2016 review of the literature reported that the prevalence of CIDP in
patients with diabetes was 9 times higher than in the general population.62 A
summary of the evidence for and against an association between CIDP and
diabetes has not provided a clear answer at this stage.63 A 2018 study examining
the utility of peripheral nerve ultrasound to distinguish between CIDP and
diabetic peripheral neuropathy demonstrated that individuals with CIDP had
larger cross-sectional nerve areas, a finding that might be valuable in
distinguishing between the two disorders.64 Future studies are required to
determine the relevance of this finding in clinical practice.
In clinical practice, a number of potential reasons to distinguish these
disorders exist, but the use of immunomodulatory therapy in a population of
individuals who will not benefit and could have complications from it is the
primary reason to ensure an accurate diagnosis. At present, motor nerve
conduction velocities less than 70% of the lower limit of normal, distal motor
latencies of greater than 150% of the upper limit of normal, and conduction block
in multiple nerves is highly specific for CIDP when detected within multiple
nerves.63 It is critical to remember that CIDP is a clinical diagnosis based on the
presence of proximal and distal weakness with areflexia. CIDP is widely

KEY POINTS overdiagnosed, in part because of overinterpretation of nerve conduction study

findings.65 In summary, there are no specific recommendations for the diagnosis
● Uremia is linked to an
increased risk of
and management of CIDP in diabetes, except that clear criteria should be
length-dependent followed to help confirm the individual diagnoses.
neuropathy but may improve
with dialysis or kidney UREMIA
transplantation.
Similar to the neuropathies seen in diabetes, neuropathy associated with uremia
● An acute optic may present with a variety of clinical manifestations, including a length-
neuropathy may also be dependent axonal neuropathy that is, in some cases, associated with slowed
seen in uremia and should be motor nerve conduction velocities in the demyelinating range. Typically seen
treated with hemodialysis with very low glomerular filtration rates, the clinical features typically suggest a
and corticosteroids.
slowly progressive length-dependent axonal neuropathy. Symptoms often
include paresthesia, burning pain, and cramps. Findings on neurologic examination
typically include reduced small and large fiber function, with motor weakness in
more advanced disease. In some cases, symptoms may improve with either kidney
transplantation or dialysis. Nerve conduction velocities often improve
posttransplantation, although there is minimal improvement in axon loss.66
One of the more unique clinical manifestations of uremic neuropathy is an
acute optic neuropathy. The pathophysiology of this manifestation is not well
understood, but it may be related to the accumulation of specific toxins in the
setting of uremia. Although data are relatively limited, treatment
recommendations include hemodialysis and the use of corticosteroids.67
CONCLUSION
Neuropathies associated with metabolic disorders are common. Diabetes and the
individual components of the metabolic syndrome make up the overwhelming
majority of all cases of neuropathy. The increasing frequency with which
diabetes and metabolic syndrome are detected in individuals around the world
suggests that an enormous number of individuals will develop neuropathy over
the next few decades. This will result in an increasing strain on health care
systems and the need for individuals who are able to effectively manage these
conditions. The neuropathies associated with diabetes include diverse clinical
manifestations that encompass chronic length-dependent axonal, focal, acute
focal, acute generalized, and autonomic neuropathies. The increasing prevalence
of diabetes and metabolic syndrome will cause even the rare manifestations of
diabetic neuropathy to be seen more regularly. The need for individuals with
expertise in this area should be a major focus for training across health care
systems. Funding of both basic and clinical investigations into treatments for
diabetic neuropathy is of critical importance given the impending influx of
diabetic neuropathies in aging populations.
USEFUL WEBSITES
INTERNATIONAL DIABETES FEDERATION IDF DIABETES AMERICAN DIABETES ASSOCIATION DIABETESPRO
ATLAS 9TH EDITION The American Diabetes Association’s DiabetesPro
The IDF Diabetes Atlas is an excellent resource for website provides practice guidelines resources,
information about the global impact of diabetes including standards of medical care in diabetes, and
with details about complications at a regional level. opportunities for continuing education.
diabetesatlas.org professional.diabetes.org/content-page/practice-
guidelines-resources
1180 OCTOBER 2020

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03741-6.

REVIEW ARTICLE

Guillain-Barré Syndrome
C O N T I N UU M A UD I O By Kazim A. Sheikh, MBBS
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article reviews the clinical features, diagnosis and
differential diagnosis, prognosis, pathogenesis, and current and upcoming
treatments of Guillain-Barré syndrome (GBS).
RECENT FINDINGS: GBS is an acute inflammatory neuropathic illness with

striking clinical manifestations and significant morbidity. A substantial
proportion of patients with GBS do not respond to current
immunomodulatory therapies (ie, plasma exchange and IV immunoglobulin
[IVIg]), highlighting the need for new therapies. Prognostic models that can
accurately predict functional recovery and the need for artificial
ventilation have emerged. These models are practical, and online
calculators are available for clinical use, facilitating early recognition of
patients with poor outcome and the opportunity to personalize
management decisions. Clinical and experimental studies have identified
innate immune effectors (complement, macrophage lineage cells, and
CITE AS:
CONTINUUM (MINNEAP MINN)
activating Fcγ receptors) as important mediators of inflammatory nerve
2020;26(5, PERIPHERAL NERVE AND injury. Two complement inhibitors are undergoing clinical testing for
efficacy in GBS.
1184–1204.
Address correspondence to SUMMARY: GBS is the most common cause of acute flaccid paralysis in the
Dr Kazim Sheikh, Department of United States and worldwide. New treatments for GBS have not emerged
Neurology, University of
Texas-Medical School at
since the 1990s. Our understanding of the pathogenesis of this disorder has
Houston, 6431 Fannin St, progressed, particularly over the past decade; as a result, new therapeutic
Houston, TX 77030, agents targeting different components of the complement cascade are at
Kazim.Sheikh@uth.tmc.edu.
advanced stages of clinical development.
Dr Sheikh serves on the medical
advisory board of the GBS/CIDP
Foundation International and on INTRODUCTION
T
the editorial board of Scientific he term Guillain-Barré syndrome (GBS) encompasses a group of
Reports. Dr Sheikh has received
personal compensation for
heterogeneous but related disorders of peripheral nerves that have
speaking engagements from CSL acute onset and almost always a monophasic course. GBS is often
Behring and research/grant postinfectious and usually paralytic, and a large body of inferred
support from the Department of
Defense (W81XWH-18-1-0422)
evidence supports the autoimmune nature of the syndrome. The
and the National Institute of two most common forms of GBS are acute inflammatory demyelinating
Neurological Disorders and polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy
Stroke (R21NS107961).
(AMAN). The incidence rate of GBS in the United States and Europe is
UNLABELED USE OF estimated to be 0.81 to 1.89 (median 1.1) cases per 100,000 person-years. The
incidence increases steadily with advancing age, and the disorder is
USE DISCLOSURE:
Dr Sheikh reports no disclosure. marginally more frequent in males than females.1 The lifetime risk of
developing GBS is 1 in 1000.
AIDP is the most common form of the disease in North America and Europe,
of Neurology. accounting for up to 90% of patients, whereas AMAN accounts for less than 10%.
1184 OCTOBER 2020

The relative incidence of AMAN is much higher in Asia, South America, and
Central America.2 These variations in incidence of AIDP and AMAN may reflect
differences in the immunogenetic repertoire and infectious pressures in different
geographic regions.
Most commonly used diagnostic criteria for GBS were developed at the
behest of the National Institute of Neurological Disorders and Stroke (NINDS)
in the context of the swine flu vaccine and GBS in 1976–1977.3 These criteria
are only relevant to major/paralytic forms of GBS; they have been reaffirmed4
and remain convenient for research and clinical use. Two clinical features
are requisite for the diagnosis of paralytic GBS: progressive muscle weakness
that must occur in more than one limb with relative symmetry on both
sides of the body and areflexia, implying loss of reflexes and/or hypoactive
reflexes. Features that strongly support, cast doubt upon, or rule out the
diagnosis of GBS are summarized in TABLE 3-1. The Brighton Collaboration
set forth diagnostic criteria that provide different levels of certainty for the
standardization of case definitions to improve vaccine safety.5 A limitation
of these criteria is the inclusion of a monophasic course that becomes
evident after follow-up, which limits their use in clinical diagnosis at the time
of presentation.
CLINICAL FEATURES
The diagnosis of GBS and related syndromes remains primarily clinical. Early
recognition is crucial because diagnostic tests such as nerve conduction studies
National Institute of Neurological Disorders and Stroke Diagnostic TABLE 3-1

Criteria for Guillain-Barré Syndromea
Features Required
for Guillain-Barré Features Supportive of Features That Rule
Syndrome Diagnosis Diagnosis Features Casting Doubt on Diagnosis Out Diagnosis
Progressive muscle Progression of Marked persistent asymmetry of History of hexacarbon

weakness of more weakness for weakness abuse
than one limb 2–4 weeks
Areflexia or Symmetric involvement Persistent bladder or bowel dysfunction Acute intermittent

hyporeflexia porphyria
Mild sensory symptoms or signs Severe bladder or bowel dysfunction at
onset Recent diphtheritic
Cranial nerve involvement
3 infection
>50 Leukocytes/mm in CSF
Recovery begins
Poliomyelitis,
2–4 weeks after nadir Presence of polymorphonuclear
botulism, toxic
leukocytes in CSF
Autonomic dysfunction neuropathy, functional
Sharp sensory level paralysis
Absence of fever
Central nervous system signs except in
Elevated CSF protein
Miller Fisher syndrome-Bickerstaff
brainstem encephalitis spectrum
disorders
CSF = cerebrospinal fluid.

a
Data from Asbury AK, Cornblath DR, Ann Neurol.4

GUILLAIN-BARRÉ SYNDROME
and CSF analysis may not be positive in the first week, and immune therapies
should be initiated as soon as possible. This section focuses on the clinical
features and diagnosis of GBS; subsequent sections discuss diagnostic testing
and therapies.
The clinical manifestations of GBS are diverse, reflecting various degrees
of injury to motor, sensory, and autonomic nerve fibers along the spinal roots
and cranial and peripheral nerves. The majority of patients with AIDP present
with sensory symptoms or pain (eg, backache, radicular painful paresthesia);
however, findings on sensory examination are less frequent. Although the
first symptoms are often sensory, AIDP is a predominantly motor
polyradiculoneuropathy characterized by acute progressive symmetric weakness
of proximal and distal muscles. The classic pattern of limb muscle weakness is
ascending, but weakness can start in proximal muscles. Rarely, the weakness can
be confined to the legs in the so-called paraparetic variant. These motor and
sensory symptoms are associated with reduced or absent deep tendon reflexes.
Approximately 25% to 30% of patients develop respiratory muscle weakness and
require mechanical ventilation.6 More than half of patients have cranial nerve
involvement, most commonly facial weakness, ophthalmoplegia, difficulty
swallowing, and altered taste. Dysautonomia of highly variable severity is seen in
the majority of patients and can manifest as reduced sinus arrhythmia, sinus
tachycardia, and other arrhythmias; labile blood pressure; orthostatic
hypotension; abnormal sweating; and pupillary abnormalities. Bladder and
bowel involvement can be seen, but if patients have severe sphincter dysfunction
at presentation, spinal cord or cauda equina disorders should be considered.
Among the axonal variants, the AMAN form of GBS is most common and is
characterized by motor findings with weakness typically beginning in the legs
but, in some patients, affecting arms or cranial muscles initially. Loss of deep
tendon reflexes corresponds to the severity of muscle weakness, likely reflecting
relative sparing of muscle afferent fibers (type Ia sensory fibers), which are
prominently affected in AIDP. A small proportion of Japanese patients with
AMAN are reported to have normal or exaggerated reflexes.7 Sensory
impairment is minimal, and autonomic involvement is less common than in
AIDP. The acute motor-sensory axonal neuropathy (AMSAN) subtype is a less
common8 and, in general, considered more severe form of axonal GBS.9 Patients
with AMSAN typically have severe involvement of sensory and motor nerve
fibers, a greater likelihood of autonomic involvement, and a poor prognosis.
Miller Fisher syndrome, the most common minor subtype of GBS, is
characterized by a triad of ophthalmoplegia, ataxia, and areflexia. Double
vision is the typical presenting symptom. In practice, facial and bulbar
weakness have been included as part of the syndrome. A significant
proportion of patients do not have the classic triad or have overlapping
features that are beyond the triad. Those who have features beyond the classic
triad have Miller Fisher syndrome–related disorder. An altered level of
consciousness or hyperreflexia with external ophthalmoplegia and ataxia
reflects central nervous system involvement indicative of Bickerstaff
brainstem encephalitis. It has been proposed that Miller Fisher syndrome–related
disorders are a clinical continuum of conditions with Bickerstaff brainstem
encephalitis on one end and Miller Fisher syndrome on the other. The inclusion
of Bickerstaff brainstem encephalitis under the rubric GBS is debated as clinically
discernible peripheral nerve involvement may not be obvious by bedside
1186 OCTOBER 2020

examination. Overlapping forms of Miller Fisher syndrome and AIDP can also KEY POINTS
be seen and are termed Miller Fisher syndrome–GBS overlap syndromes. Other
● Guillain-Barré syndrome
formes frustes of GBS include the pharyngeal-cervical-brachial variant and (GBS) encompasses a
acute autonomic neuropathy. Pure sensory neuropathies with an acute onset, spectrum of acute
a monophasic course (in the absence of systemic disorders) with either axonal neuropathic disorders, with
or demyelinating electrophysiology, or small fiber involvement may be muscle weakness being the
cardinal manifestation in the
viewed as part of the GBS spectrum.10
majority of patients. It is
GBS has a monophasic course in more than 95% of patients, and recurrence the most common cause of
has been reported in less than 5% of cases.11 About two-thirds of patients with acute flaccid paralysis in
GBS have an antecedent respiratory or diarrheal illness in the 4 to 6 weeks before the United States and
worldwide.
the onset of neurologic symptoms. By definition, the disease nadir is reached
within 4 weeks, although two-thirds of patients reach nadir within 14 days. The ● The National Institute of
progressive phase of the disease is followed by a highly variable static period Neurological Disorders and
before the onset of recovery (FIGURE 3-1). Recovery typically begins within 2 to Stroke diagnostic criteria for
4 weeks of nadir but can be delayed up to 6 months. The majority of patients paralytic GBS are simple and
practical for routine clinical
make a complete recovery over 6 to 12 months. use; the key features of the
Residual deficits affecting activities of daily living and quality of life are not criteria include symmetric
uncommon. The most common residual features include fatigue, pain, flaccid weakness,
paresthesia, and reduced muscle strength. Serious disability includes inability decreased deep tendon
reflexes, and exclusion of
to walk independently in approximately 20% of patients. Modern intensive alternative causes.
care has significantly reduced the mortality rate of GBS, but it remains 3% to
7% in recent series.8,12 Advanced age, severity of disease, mechanical ● Although the first
ventilation, pulmonary and cardiac complications, and systemic infections symptoms of acute
inflammatory demyelinating
increase the risk of mortality. Death can occur during the acute progressive
polyradiculoneuropathy
phase or during the recovery phase. Most deaths are attributed to cardiac (AIDP) are often sensory, it is
arrest secondary to autonomic disturbance, respiratory failure or infection, or primarily a motor
pulmonary embolism. polyradiculoneuropathy
causing symmetric
weakness of proximal and
INVESTIGATIONS distal muscles. The classic
Laboratory testing for the diagnosis of GBS includes nerve conduction studies pattern is of ascending
and EMG, CSF analysis, and serologic studies, if warranted. Nerve conduction weakness, but symptoms
studies and EMG, particularly relevant for paralytic forms, provide supportive may also begin proximally.
data by confirming the involvement of peripheral spinal roots and/or nerves to ● Of patients with GBS, 25%
differentiate between axonal and demyelinating subtypes and may provide to 30% will require
intubation because of
respiratory muscle
weakness or pharyngeal
muscle weakness (airway
protection); patients should
be closely monitored for the
need of mechanical
ventilation.
● Miller Fisher syndrome,

the most common minor
subtype of GBS, is
characterized by a triad of
ophthalmoplegia, ataxia,
and areflexia.
FIGURE 3-1
Three conceptualized stages in the monophasic course of a typical patient with Guillain-
Barré syndrome.

prognostic information by estimating the extent and location of axonal injury. A

single study around the time of admission may not be sufficient to accurately
discriminate between axonal and demyelinating variants, and serial studies may
be necessary, which are also required for prognostic information. Although serial
nerve conduction studies and EMG are useful diagnostically, they are not always
practical; at present, the treatment of axonal and demyelinating variants is
similar, and, as discussed below, useful clinical prognostic tools are available. The
main purpose of CSF analysis is to exclude other diagnoses. The utility of
antiglycan (ganglioside) serology for the diagnosis and management of GBS is
not established and, thus, is not necessary for routine clinical care of patients
with AIDP. The presence of specific antiganglioside antibodies can support the
diagnosis of minor variants or formes frustes of GBS, but, because of the
turnaround time of the results in the United States, these studies often do not
influence treatment decisions.
Nerve conduction studies are often normal early in the disease course,
although prolonged minimal F-wave latencies (or absent responses) reflecting
involvement of proximal nerve trunks or roots is a common finding during the
first week. A sural sparing pattern, in which the sural sensory response is
preserved but the upper limb sensory responses are absent or of reduced
amplitude, is another nerve conduction study finding that can be present early in
the course of AIDP. Other nerve conduction changes peak around 2 weeks after
symptom onset in the majority of patients.13 The typical demyelinating changes
on motor nerve conductions in AIDP include prolonged distal motor latencies,
reduced motor nerve conduction velocities, prolonged F-wave latencies (or
absent responses), increased temporal dispersion, and conduction blocks at
noncompressible sites. In contrast, axonal variants of GBS show decreased
compound muscle action potential (CMAP) amplitudes in AMAN and decreased
CMAP and sensory nerve action potential (SNAP) amplitudes in AMSAN in the
absence of typical demyelinating features except conduction block. Motor nerve
conduction changes mimicking reversible conduction block without temporal
dispersion can be seen in AMAN and can be a cause of confusion in classifying
TABLE 3-2 Guillain-Barré Syndrome Disability Scale Scoresa
Score Disability
0 Healthy
1 Minor symptoms or signs of neuropathy but capable of manual work/running
2 Able to walk 10 meters or more without support of a stick (cane) but incapable
of manual work/running
3 Able to walk 10 meters with a stick (cane), appliance, or support
4 Confined to bed or chair bound
5 Requiring assisted ventilation for at least part of the day
6 Death
a
Data from Hughes RA, et al, Lancet.22
1188 OCTOBER 2020

AMAN and AIDP early in the disease course. This feature is attributed to KEY POINTS
pathologic alterations at the nodes of Ranvier and is termed reversible
● An altered level of
conduction failure. Serial nerve conduction studies may be required to accurately consciousness or
distinguish between AMAN and AIDP as improvement in the conduction block hyperreflexia with external
in AMAN is not associated with the development of abnormal temporal ophthalmoplegia and ataxia
dispersion.14 reflects central nervous
system involvement
CSF analysis characteristically shows normal cell counts and elevated protein
indicative of Bickerstaff
levels, termed albuminocytologic dissociation. This feature is seen in more than brainstem encephalitis.
80% of patients after the first week.15 Lumbar puncture after initiation of IV Miller Fisher syndrome–
immunoglobulin (IVIg) therapy can be diagnostically challenging as IVIg can related disorders are
considered a clinical
increase CSF protein and white blood cell counts. In 10% to 15% of patients, a
continuum with Bickerstaff
mild (<50 cells/mm3) increase in white blood cell count can be present.16,17 CSF brainstem encephalitis on
cell counts greater than 50 cells/mm3 should raise suspicion for Lyme disease, one end and Miller Fisher
human immunodeficiency virus (HIV), cytomegalovirus, or an infiltrative syndrome on the other.
leptomeningeal process; an increased cell count may also raise suspicion for
● Residual symptoms after
paralytic rabies (in certain clinical settings) or poliomyelitis (in certain GBS are common and
geographic locations). include fatigue, pain,
Antiglycan antibodies (mostly antigangliosides) are the most commonly paresthesia, and reduced
recognized autoimmune markers in all forms of GBS. Gangliosides are sialic muscle strength.
acid–containing glycosphingolipids enriched in peripheral nerves.
● Nerve conduction studies
Antiganglioside antibodies are complement-fixing IgG isotypes (IgG1 and IgG3). and EMG provide
GM1, GD1a, GalNAc-GD1a, and GM1b gangliosides are implicated as target confirmation of an acute
antigens in AMAN. IgG anti-GM1 and anti-GD1a antibodies can be detected in up neuropathic process and
may differentiate between
to 50% to 60% of patients with AMAN in Japanese and northern Chinese
demyelinating and axonal
populations, respectively.18,19 The frequency of anti–GalNAc-GD1a and variants of GBS. They are
anti-GM1b antibodies in motor-predominant syndromes is 10% to 15%.20 often relatively normal early
Anti-GQ1b antibodies (often cross-reactive with GT1a) occur in more than 80% in the course; serial studies
of patients with Miller Fisher syndrome, providing the strongest association are often necessary and
may be useful for
between antibodies to a specific ganglioside and a GBS subtype.20 Antiglycan prognostication.
antibodies with various specificities (mostly LM1 and GM1) also occur in up to
25% to 30% of patients with AIDP.20 Recent studies have suggested that ● Partial motor nerve
antibodies to mixtures of gangliosides and other glycolipids can be correlated conduction block without
temporal dispersion may be
with different variants of GBS, but this does not substantially increase sensitivity seen in acute motor axonal
or positive reactivity.21 Antiganglioside antigen testing for GM1, asialo-GM1, neuropathy because of
GD1b, GD1a, GalNAc-GD1a, GT1a, and GQ1b is commercially available in the reversible conduction
United States. failure at the nodes of
Ranvier. Other
demyelinating features,
PROGNOSIS such as reduced conduction
A number of factors, including age (older than 40 years), preceding diarrhea, velocity and prolonged
short interval from onset to nadir of the disease, need for mechanical ventilation, minimal F-wave or distal
motor latencies, are absent.
high-grade deficits on the GBS disability scale (TABLE 3-222), and persistently low
CMAP amplitudes, are considered poor prognostic factors. Predictability of two ● CSF analysis typically
issues is of importance: the need for mechanical ventilation acutely (during the shows albuminocytologic
admission for GBS) and the long-term functional outcome (arbitrarily defined as dissociation. A mild
at 6 or more months after GBS onset). A Dutch group has developed validated pleocytosis (<50 cells/mm3)
can be seen in up to 10% to
clinical models with relatively high accuracy to predict the need for ventilation 15% of patients with GBS. A
and long-term functional outcome, and an online calculator is available.23 The pleocytosis of greater than
Erasmus GBS Respiratory Insufficiency Score (EGRIS) is based on the severity of 50 cells/mm3 suggests an
weakness (quantified as the Medical Research Council [MRC] sum score), the alternative diagnosis.
number of days between the onset of weakness and admission, and facial or

bulbar weakness; it allows prediction of the need for mechanical ventilation

during the first week after admission.6 This model can be used at the time of
admission to triage patients with a high EGRIS score to an intensive care unit
setting. The Modified Erasmus GBS Outcome Score (mEGOS) is a long-term
functional outcome model that is based on three parameters: age, severity of
weakness quantified as the MRC sum score, and the presence or absence of
preceding diarrhea.24 This model can be applied at the time of admission or
1 week after admission and predicts the probability of walking independently at
1, 3, and 6 months. The severity of weakness quantified by the MRC sum score is
a common denominator in these models and is emerging as an important variable
for predicting acute and long-term prognosis. Efforts are under way to correlate
the MRC sum score and serum neurofilament light chain levels (reflecting
cumulative axonal injury) with prognosis.
PATHOLOGY
The pathology of AIDP and axonal variants of GBS is well defined. AIDP is
characterized by demyelination and multifocal perivascular and endoneurial
T-cell infiltrations with patchy involvement of spinal roots and nerve trunks
and distal nerve segments.25 In some series, a proportion of cases showed
immunopathologic changes suggestive of antibody- and complement-mediated
demyelinating nerve injury.26 Macrophages are particularly prominent at sites
of extensive myelin breakdown and contain fragments of degenerating myelin,
and macrophage-mediated myelin stripping (contact-dependent injury) is
considered a hallmark of AIDP pathology (FIGURE 3-2).27 The spectrum of
pathologic changes in AIDP supports the role of T-cell– and antibody-mediated
immune injury, but the contribution of humoral and cellular mechanisms may
substantially vary in individual cases.
The pathology of AMSAN was initially described in Canadian patients who
had severe axonal degeneration in nerve roots and distal nerves without
inflammation or demyelination.9 The pathology of AMAN was characterized in a
series of ultrastructural and immunopathologic studies in patients from northern
China (FIGURE 3-3).27,28 These studies indicated a paucity of T-cell inflammation
and evidence of antibody and complement deposition. The earliest pathologic
changes were centered on motor nodes of Ranvier and included nodal
lengthening with distortion of paranodal myelin. This change was associated
with macrophages overlying nodes of Ranvier, which extended their processes
through the Schwann cell basal lamina covering the node and apposed the
axolemma. Macrophages then extended beneath the myelin terminal loops and
entered the periaxonal space, dissecting the axon from the adaxonal Schwann cell
plasmalemma and advancing into the internodal periaxonal space, where they
typically surrounded a condensed-appearing axon. This arrangement appeared
to be stable for some time, but the axon subsequently underwent wallerianlike
degeneration (contact-dependent injury). Immunohistology showed IgG and
C3d (membrane-bound cleaved product of C3) at the nodes of Ranvier initially
and later at paranodal and internodal axolemma.28 In some cases of AMAN, nodal
changes were not associated with significant axon degeneration; this restricted
nodal injury is believed to correlate with quick recovery in patients with AMAN,
in particular, those with reversible conduction failure.
In sum, the pathology of AIDP, AMAN, and AMSAN shares endoneurial
inflammatory effectors, including components of the innate immune system
1190 OCTOBER 2020

KEY POINTS
● Prognostic models for

GBS based on clinical
parameters, including
Medical Research Council
(MRC) sum score, which are
collected as part of
standard care, can reliably
predict the need for
mechanical ventilation in the
first week and functional
outcomes at 4 weeks to
6 months after admission.
● AIDP, acute motor axonal

neuropathy, and acute
motor-sensory axonal
neuropathy share common
pathologic features,
including activation of
components of the innate
immune system such as
complement activation and
upregulation of Fc receptors
for IgG (FcγRs). These are
promising therapeutic
FIGURE 3-2
targets.
Contact-dependent macrophage-mediated demyelination in acute inflammatory
demyelinating polyradiculoneuropathy (AIDP). A, Many large foamy (phagocytic)
macrophages (m) are associated with a myelinated nerve fiber undergoing demyelination ● It is believed that GBS is
along its length. Electron micrographs showing macrophage-mediated (M) myelin stripping at triggered by environmental
early (B) and advanced (C) stages. Axons labeled as A in panels B and C. exposures in genetically
Panel A modified with permission from Hafer-Macko C, et al, Ann Neurol.26 © 1996 American Neurological susceptible hosts.
Association.
Panels B and C modified with permission from Griffin JW, et al, Brain.27 © 1995 Oxford University Press.
(complement and macrophage lineage cells) that have upregulation of activating

FcγRs,29 and macrophages that induce contact-dependent Schwann cell/myelin
(AIDP) and axon (AMAN/AMSAN) injury. Detailed pathologic characterization
of AIDP and AMAN has prompted the development of new therapeutics
targeting innate immune effectors, particularly the complement cascade.
PATHOGENESIS
GBS is considered to be an autoimmune disorder. Autoimmune conditions are
characterized by an aberrant activation of the adaptive immune response, with
T cells and B cells reacting (independently or in concert) to tissue-specific
self-antigens in the absence of any direct microbial or tumor invasion of the
affected tissue(s), in this case, peripheral nerves. The precise mechanisms for the
development of GBS remain incompletely understood. There is general consensus
that GBS is triggered by environmental agents in genetically susceptible hosts. It
is likely that a single gene does not impart susceptibility to develop GBS but
that multiple genes are needed to induce aberrant immunity, and environmental
exposures may need to occur in a particular sequence, or in tandem, to provoke
autoimmunity. The genes that impart host susceptibility to develop GBS are not
firmly established. Additionally, random correct alignment of multiple genetic

FIGURE 3-3
Contact-dependent macrophage-mediated nodal and axonal injury in acute motor axonal
neuropathy (AMAN). A, Teased fiber preparations showing opsonization of the nodes of
Ranvier (arrows) of motor nerve fibers with C3d (membrane bound fragment of C3
component of complement). B, Teased fiber preparations showing that many motor fibers
had macrophages (stained for HAM-56 or HLA-DR) overlying and extending processes into
the nodes of Ranvier (arrows point to nodes of Ranvier). C, Electron micrograph showing
longitudinal myelinated motor nerve fiber with condensed axon (A) and adjacent
macrophage and its processes (M) that are separating it from overlying normal appearing
myelin. D, Electron micrograph showing cross sections of two adjacent fibers with different
levels of contact-dependent macrophage-mediated axon injury. The fiber on the left shows
a condensed axon (A) surrounded by periaxonal macrophage (M), whereas the fiber on the
right shows that the axon has degenerated and the macrophage (M) remains inside a
normal-appearing myelin sheath.
Panels A and B modified with permission from Hafer-Macko C, et al, Ann Neurol.28 © 1996 American
Neurological Association.
Panels C and D modified with permission from Griffin JW, et al, Brain.27 © 1995 Oxford University Press.
and environmental risk factors must occur in a correct sequence, with relatively
short latencies, before the development of an acute autoimmune disorder such
as GBS. Alternatively, multiple exposures, including possible infectious or
noninfectious events, occurring during a critical window when individuals are
more susceptible to them, are necessary to overcome tolerance. Breakdown of
self-tolerance (the unresponsiveness of the adaptive immune system to
self-antigens) is an important variable for the development of autoimmune
disorders such as GBS. Regulatory T cells function to maintain tolerance and
suppress other immune cells, such as B cells, T cells, and dendritic cells, to prevent
autoimmune disease. In human studies, the number of regulatory cells present
during the acute phase of GBS is decreased, and these cells are increased following
treatment.30,31 Stimulation or modulation of the immune system from a triggering
event can disrupt the balance needed to maintain immunologic homeostasis,
making the host susceptible to autoimmune disease. This complex construct
provides a potential explanation for the extreme rarity with which GBS develops
in an individual after exposure to common environmental triggers.
1192 OCTOBER 2020

Environmental and Other Triggers KEY POINTS
Infections of the gastrointestinal and upper respiratory tract are common triggers
● Campylobacter jejuni is
of GBS, and Campylobacter jejuni, a gram-negative rod, is the most common the most common trigger for
trigger of GBS (particularly for axonal forms), reported in 13% to 72% of patients GBS, particularly the axonal
in different series, with an overall prevalence estimated around 30%.32 C. jejuni forms, with an estimated
is one of the most common causes of bacterial gastroenteritis worldwide, but GBS prevalence of 30%.
However, the risk of GBS
is an extremely rare complication of this infection. It is estimated that less than
with C. jejuni infection is low
2 in 10,000 cases of C. jejuni infection develop GBS within a 2-month period.33 (less than 2 in 10,000).
The exact susceptibility factors of human host or attributes of C. jejuni that
determine whether GBS follows the infection are not known. Case control studies ● Noninfectious events,
have shown that upper respiratory tract infection caused by cytomegalovirus, including trauma,
vaccinations,
Epstein Barr virus, Mycoplasma pneumoniae, and Haemophilus influenzae are also immunosuppression, and
triggering events, as is nonrespiratory infection with hepatitis E. C. jejuni, M. pregnancy, may rarely
pneumoniae, and H. influenzae have been shown to express glycolipid antigens trigger GBS.
either by structural methods or by cross-reactive binding of antiglycolipid
antibodies in GBS sera. Cytomegalovirus can induce the expression of GM2
gangliosidelike antigens in cell cultures.
Recently, Zika virus, a mosquito-borne RNA flavivirus, was also identified as a
potential trigger for GBS; a French Polynesian study reported an increase in GBS
cases during a Zika virus outbreak in 2013-2014.34 Most post–Zika virus cases in
this series were AMAN, and a substantial proportion had antiglycan antibodies.
Similarly, post-Zika GBS was observed in South America during a major outbreak
in 2015-2016.35 Many patients with post-Zika GBS show a parainfectious rapid
disease onset.
In late 2019, an outbreak of illness caused by the novel coronavirus
SARS-CoV-2 was identified, and the disease was labeled COVID-19. In March
2020, the World Health Organization declared the illness a pandemic. A number
of neurologic complications have been reported in association with COVID-19
infections, and hypogeusia and hyposmia are perhaps the most common. A
number of case reports and series from China and Europe have also reported GBS
in association with COVID-19 infection, including demyelinating, axonal, and
Miller Fisher variants.36–38 CSF studies have generally shown albuminocytologic
dissociation and negative polymerase chain reaction (PCR) for COVID-19.36–38
Patients with GBS who present with fever, cough, hypogeusia, or hyposmia
should be tested for COVID-19. Moreover, there should be disease vigilance for
GBS in patients with COVID-19 infection, which could allow early initiation of
immune therapy.
Less common noninfectious triggering events for GBS include trauma,
vaccinations, immunosuppression, and pregnancy. In 1968, Arnason and Asbury39
reported a series of cases from Massachusetts General Hospital that developed
postsurgical polyneuritis after surgical trauma, and release of sequestered
peripheral nerve antigens was implicated as a trigger. A large 2018 French study
that examined the association of GBS and recent surgery using nationwide French
data concluded that GBS was moderately associated with any type of recent
surgery and more strongly associated with bone and digestive organ surgery.40
Rare sporadic cases of GBS have been described following a number of vaccines. In
1976, influenza vaccination was causatively implicated with exposure to the swine
flu vaccine, although subsequent surveillance found only one additional case of
GBS for every 1 million vaccines. The risk of developing GBS is much higher
following influenza infection than it is from vaccination.41 Patients who develop

their first attack of GBS within 6 to 8 weeks after any vaccination (postvaccination
cases) may be at particularly high risk and should not receive the same vaccine
again. The risk of relapse with influenza vaccination in patients who have
recovered from GBS not temporally associated with vaccination is extremely low.11
Individuals aged 65 or older and those with chronic serious disorders, including
chronic bronchitis and emphysema, are at increased risk of significant
complications from influenza and other infections, and age-appropriate
vaccinations should not be withheld unless a clear contraindication exists.
Molecular Mimicry
Antiganglioside antibodies are considered to be pathogenetically relevant to
AMAN and Miller Fisher syndrome, but the pathologic relevance of antiglycan
(except antigalactocerebroside) antibodies in AIDP is questioned because
relevant experimental data are lacking. Several lines of evidence support the
molecular mimicry hypothesis and pathogenicity of antiganglioside antibodies in
the axonal and Miller Fisher syndrome subtypes of GBS. Work over the past 3
decades has led to the hypothesis that postinfectious molecular mimicry is the
predominant pathophysiologic mechanism in GBS, particularly in Miller Fisher
syndrome and axonal variants, supported by the following key observations:
u C. jejuni enteritis is the most commonly recognized antecedent infection in GBS

u Different variants of GBS, particularly Miller Fisher syndrome and motor axonal variants,
are strongly associated with specific antiganglioside antibodies
u The lipooligosaccharides of C. jejuni isolates from patients with GBS carry relevant
gangliosidelike moieties
u Gangliosides, the purported target antigens, are enriched in nerve fibers
u Pathologic and immunopathologic studies in the axonal forms indicate antibody-mediated
axonal injury or dysfunction
u Active immunization animal studies have directly linked C. jejuni lipooligosaccharides to
the development of antiganglioside antibodies and neuropathy
u Passive transfer of antiganglioside antibodies can produce nodal and axonal injury in
experimental models that mimics the pathology seen in axonal GBS
Although the pathogenesis of AIDP is largely undetermined, evidence of

molecular mimicry exists in a small minority of patients with AIDP. A number of
patients develop GBS after M. pneumoniae infection. M. pneumoniae expresses
antigens that cross-react with galactocerebroside (GalC), a glycolipid that is
enriched in the myelin sheath of Schwann cells in peripheral nerves. These
patients have anti-GalC antibodies and commonly have the demyelinating/AIDP
form of GBS. Experimental animal studies demonstrate that immunization with
GalC and passive intraneural administration of anti-GalC antibodies produce
inflammatory demyelinating nerve pathology resembling the demyelination seen
in patients with AIDP.
Experimental and animal studies have attempted to define the immune
effectors that constitute the final common pathway of endoneurial inflammation
that mediates nerve injury in demyelinating and axonal variants in an effort to
identify therapeutic targets for drug development. That antigen specificity and
the nature of adaptive T-cell and B-cell autoimmune responses are not well
defined, particularly for AIDP. In contrast, strong evidence exists for the role
1194 OCTOBER 2020

of specific antiglycan antibodies in the pathogenesis of axonal and the Miller KEY POINTS
Fisher variants of GBS. Adaptive autoimmunity uses the powerful effector
● The risk of developing
functions of cells of the innate immune system, including monocytes/macrophages, GBS following influenza
to induce target tissue inflammation and injury in autoimmune disorders. infection is much higher than
Pathologic studies in demyelinating and axonal GBS indicate a central role for the risk of GBS following
macrophage populations (including contact-dependent injury), which are the vaccination. Patients who
develop GBS following
key components of the innate immune system and endoneurial inflammation.
influenza or any other
Recognizing all antigen-specific adaptive immune responses that initiate/orchestrate vaccine should not receive
nerve injury in autoimmune disorders such as GBS may not be necessary if the same vaccine again.
downstream innate immune effectors mediating nerve injury are identified.
Cumulatively, clinical and experimental studies have identified innate immune ● Postinfectious molecular
mimicry is the predominant
effectors that include classic complement pathway,42 macrophage-microglia pathophysiologic
lineage cells, and activating FcγRs43,44 as final common pathway(s) of mechanism in Miller Fisher
inflammatory nerve injury in GBS. syndrome and axonal
variants and in patients who
develop AIDP following
DIFFERENTIAL DIAGNOSIS AND OTHER ACUTE NEUROPATHIES Mycoplasma pneumoniae
The paralytic forms of GBS are relatively easy to recognize with a low probability infection.
of diagnostic confusion. The differential diagnosis for GBS is quite wide and
depends on the clinical subtype, patient’s age, and geographic locale. It includes ● Supportive and intensive
care remains the
central conditions such as encephalomyelitis and rhombencephalitis for Miller
cornerstone of management
Fisher syndrome–Bickerstaff brainstem encephalitis spectrum disorders. of patients with GBS during
Paralytic GBS can be confused with transverse myelitis or myelopathy early on, the acute phase of this
and clinicians should have a low threshold for spinal cord imaging. The monophasic illness, and
immune therapy with
differential diagnosis for paralytic GBS includes the following:
plasma exchange or IV
immunoglobulin (IVIg)
u Infections affecting anterior horn cells, including West Nile virus, enteroviruses (children hastens recovery.
more than adults), rabies (paralytic form), and polio (in appropriate geographic regions)
u Neuromuscular junction disorders, including myasthenic crisis and botulism (particularly
in young children)
u Acute severe myopathies, including immune-mediated necrotizing myopathies (eg, those
associated with antibodies against signal recognition particle and 3-hydroxy-3-
methylglutaryl-coenzyme A [HMG-CoA]) reductase, acute myositis, and rhabdomyolysis
u Periodic paralysis
u A number of other neuropathic and polyradiculopathic conditions that present acutely or
subacutely and can be confused with GBS (TABLE 3-3)
TREATMENT
Two immunomodulatory treatments, IVIg and plasma exchange, are used for the
treatment of GBS, but provision of multidisciplinary medical supportive care
remains the cornerstone of therapy during the acute phase to prevent
complications and facilitate recovery. All patients with GBS should be admitted
to a hospital with an intensive care unit, except for patients with very mild
disease who have reached a plateau phase or are already recovering. The
principles of GBS care include monitoring for major risks to avoid complications
arising from acute respiratory failure, dysautonomia, bulbar weakness,
progressive muscle weakness, and immobility. Close monitoring of forced vital
capacity, blood pressure, heart rate and rhythm, and bulbar function is necessary
to identify patients with deteriorating respiratory function or autonomic
instability or those at risk of aspiration who require intensive care. Close

monitoring of respiratory parameters and use of EGRIS should allow elective

(preemptive) intubation, which is less traumatic for patients and families and
less prone to complications. About one-third of patients require admission to an
intensive care unit. Important aspects of medical management include prevention
of nosocomial infections, prophylaxis for deep venous thrombosis, management
TABLE 3-3 Acute and Subacute Neuropathic Conditions With Features That Overlap
With Guillain-Barré Syndrome
Acute Radiculo/neuropathy Diagnostic Clues
Inflammatory/immune
Acute-onset chronic inflammatory demyelinating Progression >4 weeks or three treatment-related fluctuations in first
polyradiculoneuropathy (CIDP) 8 weeks
Vasculitic neuropathy Frequently asymmetric (can be confluent), predominantly axonal
Sensory ganglionitis Diffuse sensory loss, areflexia, pseudoathetosis, pseudoweakness (may

improve with visual compensation), posterior column degeneration on
MRI with latency of approximately 10 weeks
Intensive care unit setting
Critical illness neuropathy In the setting of sepsis or multiorgan failure, often ventilator
dependence, concomitant myopathy
Metabolic
Diabetes Frequently asymmetric (lumbosacral plexus), weight loss, history of

diabetes mellitus
Porphyria Axonal physiology, predominantly motor, psychiatric features,

abdominal pain, positive metabolic screen
Nutritional
Thiamine deficiency Often history of gastric bypass surgery, alcohol use disorder, vomiting,
acute weight loss, other B vitamins can be low, axonal
Infections
Human immunodeficiency virus (HIV) Early in infection, positive testing, CSF pleocytosis
Herpesviruses, including cytomegalovirus Often in setting of HIV, mixed myelopathic and radicular features, CSF
pleocytosis (polymorphonuclear leukocytes with cytomegalovirus),
polymerase chain reaction (PCR)
Lyme disease Radiculoneuritis, asymmetric, endemic area, tick bite, erythema

migrans, CSF pleocytosis, predominantly axonal
Toxic
Organophosphates Exposure to insecticides, occupation in plastic and petroleum

industries, axonal
Hexacarbons Occupational exposure or inhalant abuse of glues, lacquers, cleaning

solvents, axonal; secondary demyelinating changes including multifocal
motor conduction block can be seen
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
1196 OCTOBER 2020

of bowel and bladder dysfunction, pain management, early physical therapy and KEY POINTS
rehabilitation to avoid complications of immobility (including pressure ulcers), eye
● Randomized clinical trials
care in those with severe facial weakness, and psychosocial support. indicate that IVIg and plasma
Randomized clinical trials have shown the efficacy of plasma exchange up to exchange hasten recovery in
4 weeks after the onset of symptoms and IVIg within 2 weeks after onset in patients with GBS, and both
hastening recovery.45 All trials have used the GBS disability scale (TABLE 3-2) treatments were found to be
equally efficacious.
for enrollment and as the primary outcome measure. Patients with a GBS disability
score of 3 or higher were enrolled in these clinical trials, and an improvement of 1 ● Of patients with GBS
point on this scale at 4 weeks was considered treatment responsiveness. A standard treated with IVIg or plasma
dose of plasma exchange is to exchange 200 mL/kg to 250 mL/kg in four to five exchange in clinical trials,
sessions over 7 to 14 days. The clinical trials of IVIg administered a total of 2 g/kg 40% to 50% did not have a
clinical response (ie, did not
given over 4 to 5 days, although, in practice, this dose is sometimes administered meet primary end point),
over a shorter period in selected patients. Although head-to-head comparisons emphasizing the need for
of IVIg and plasma exchange in clinical trials have shown equivalent efficacy,45 new therapies.
IVIg is considered first-line treatment because of the ease of administration and
● Randomized controlled
widespread availability. In patients whose treatment is being initiated more than data indicate that
2 weeks after onset, it may be reasonable to consider plasma exchange, as clinical combination treatment with
trials have shown efficacy of this treatment in patients enrolled up to 4 weeks plasma exchange followed
after onset. Conceptually, early treatment is preferable as it could limit by IVIg is not superior to
treatment with IVIg or
endoneurial inflammation and nerve injury; data from North American46 and
plasma exchange alone, and
French Cooperative Group47 studies support this notion as the beneficial effects of anecdotal observations
plasma exchange were most marked in patients enrolled within 1 week after onset. indicate that combination
A large proportion of patients do not show significant response to initial treatment with IVIg followed
by plasma exchange is no
immunomodulatory treatment(s) and pose a special challenge as no
better than IVIg alone.
evidence-based recommendations are currently available for this group of Combination therapy is
patients. Randomized controlled trials indicate that 40% to 50% of patients did generally discouraged.
not improve significantly after plasma exchange or IVIg treatment, defined as
improvement by 1 or more points on the GBS disability scale at 4 weeks after ● No evidence- or
consensus-based
treatment (primary outcome measure).45 Two approaches are sometimes used for recommendations are
this group of patients. One is the use of combination therapy (ie, plasma exchange available for additional
followed by IVIg or, less commonly, IVIg followed by plasma exchange). The immunomodulatory
Plasma Exchange/Sandoglobulin GBS Trial compared plasma exchange followed treatments for patients with
GBS for whom initial IVIg or
by IVIg to either modality alone and found no significant differences in treatment plasma exchange treatment
groups, indicating that combination therapy is not superior to monotherapy has failed, and further
with either modality.48 Although IVIg followed by plasma exchange is supportive medical
counterintuitive (ie, the plasma exchange removes the previously infused management should be
tailored according to
circulating immunoglobulin), this approach is sometimes attempted in patients
individual needs in such
with severe disease who do not respond to IVIg alone. A small retrospective study cases.
examined this combination therapy and found that combination therapy was
not superior to IVIg alone.49 In general, the combination of IVIg and plasma
exchange, however sequenced, is discouraged. The second approach is the use
of high-dose or a second dose of IVIg in patients for whom the first IVIg
treatment has failed. This approach carries a risk of complications, and the ISID
(International Second IVIg Dose) study, a recently published observational study,
did not show better outcomes after a second IVIg course in GBS with poor
prognosis.50 A prospective randomized single-center trial examining whether a
second course of IVIg improves outcome is ongoing, and its results are awaited.
The author’s approach in such patients is to use a single treatment modality, early
tracheostomy and percutaneous endoscopic gastrostomy (if warranted), and early
discharge to a rehabilitation or long-term acute care facility (CASE 3-1).

CASE 3-1 A 36-year-old woman was admitted to the hospital with Guillain-Barré
syndrome (GBS) 3 days after the onset of neurologic symptoms. At
admission, she had proximal greater than distal weakness in her legs
more than her arms, areflexia, and distal sensory loss, and her forced
vital capacity was 2.83 L. She reported preceding diarrhea.
Her motor nerve conduction studies (see grid) were notable for
prolonged right median nerve distal latency, partial motor conduction
block in the right fibular (peroneal) nerve, and prolonged F-wave
latencies. Sensory nerve conduction studies (see grid) showed
inexcitable median and ulnar nerves, reduced radial evoked sensory
nerve action potential (SNAP) amplitude, and relatively preserved sural
SNAP, a pattern recognized as sural sparing, as shown in the test results.
CSF analysis showed no white blood cells, and protein was elevated at
51 mg/dL.
She was diagnosed with the acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) variant of GBS, and IV immunoglobulin
(IVIg) was administered for 5 consecutive days without any
complications. Her symptoms worsened after initiation of IVIg; she
became quadriplegic within 48 hours after admission while on IVIg
treatment, and her forced vital capacity dropped to less than 1 L,
requiring ventilatory support. No clinical improvement was seen 1 week
after completion of IVIg. Her family was extremely concerned about the
lack of responsiveness to IVIg. A number of options were considered,
including repeat electrical studies and lumbar puncture, nerve biopsy, a
second dose of IVIg, and plasma exchange. The multidisciplinary team
concluded that none of these approaches were evidence based and
decided to consider predictive modeling for GBS prognosis; they shared
this information with the patient and her family and instituted supportive
medical management. The patient’s Modified Erasmus GBS Outcome
Score (mEGOS) score was 10 at 7 days after admission, predicting a 40%
probability of walking independently at 3 months and 60% probability by
6 months.
The patient underwent tracheostomy and percutaneous endoscopic
gastrostomy and was transferred to a long-term acute care facility. Four
weeks later, the patient was on a tracheostomy collar without ventilator
support with mild recovery of proximal muscle function in the arms but
still confined to bed. Six months later, she was ambulating using a cane.
1198 OCTOBER 2020

Motor Nerve Conduction
Amplitude Conduction
Latency (Normal (Normal Velocity (Normal
Nerve and Site Range) Range) Segment Distance Range)
Median (right)
Wrist 4.6 ms (<3.9 ms) 7.1 mV (>6 mV) Abductor pollicis brevis-wrist NA NA
Elbow 9.5 ms 7.0 mV Wrist-elbow 240 mm 49 m/s (>49 m/s)
Ulnar (right)
Wrist 2.9 ms (<3.1 ms) 8.4 mV (>7 mV) Abductor digiti minimi-wrist NA NA
Below elbow 7.2 ms 7.4 mV Wrist-below elbow 235 mm 55 m/s (>49 m/s)
Above elbow 9.5 ms 6.3 mV Below elbow-above elbow 120 mm 52 m/s (>49 m/s)
Fibular (peroneal) (right)
Ankle 4.4 ms (<5.5 ms) 6.8 mV (>3 mV) Extensor digitorum brevis-ankle NA NA
Fibular head 10.7 ms 5.2 mV Ankle-fibular head 320 mm 51 m/s (>39 m/s)
Popliteal fossa 13.7 ms 5.1 mV Fibular head-popliteal fossa 100 mm 33 m/s
Tibial (right)
Ankle 4.9 ms (<5.8 ms) 4.6 mV (>4 mV) Abductor hallucis-ankle NA NA
NA = not applicable.
Sensory Nerve Conduction
Nerve and Onset Peak Latency Amplitude Conduction Velocity

Site Latency (Normal Range) (Normal Range) Segment Distance (Normal Range)
Median (right)
Wrist No No response No response Digit II-wrist 130 mm NA (>49 m/s)

response (<3.4 ms) (>20 μV)
Ulnar (right)
Wrist No No response No response Digit II-wrist 110 mm NA (>49 m/s)

response (<3.1 ms) (>12 μV)
Radial (right)
Forearm 2.1 ms 2.9 ms (<2.7 ms) 8 μV (>18 μV) Snuffbox-forearm 100 mm 48 m/s (>49 m/s)
Sural (right)
Lower leg 4.1 ms 4.8 ms (<4.5 ms) 8 μV (>6 μV) Ankle-lower leg 185 mm 46 m/s (>49 m/s)
CONTINUED ON
PAGE 1200

CONTINUED FROM
PAGE 1199
COMMENT A substantial proportion of patients with GBS deteriorate during or shortly
after treatment with IVIg or plasma exchange, and no evidence has shown
that combination therapy or repeat IVIg is helpful. Prognostic modeling is
practical for clinical use to make supportive management decisions in
such patients. In the past, some experts would prescribe additional IVIg
for patients who did not respond to a first dose because a study reported
that patients with large increments of serum IgG levels after standard IVIg
treatment (2 g/kg) recovered more quickly than those with smaller
increments.51 However, a second course of IVIg can be complicated by
anaphylaxis, acute kidney injury, thromboembolic events, or hemolytic
anemia. Further, the ISID (International Second IVIg Dose) study, an
observational study, did not show better outcomes after a second course
of IVIg in GBS with poor prognosis.50 It is prudent not to use a second dose
of IVIg in patients with GBS who do not respond to the first dose of IVIg
because of potential risks until evidence-based data are available to
support this treatment paradigm.
Treatment-related fluctuations, defined as worsening of at least 1 point on the

GBS disability scale after initial improvement or stabilization within 8 weeks
after disease onset,52 are another related aspect. Treatment-related fluctuations
can be seen in up to 10% of patients treated with IVIg or plasma exchange. No
evidence-based recommendations are available for patients with
treatment-related fluctuations, and general consensus is retreatment with the
original treatment modality as the preferred approach.
Although the incidence of GBS is slightly lower in children compared to
adults, the immunomodulatory treatment recommendations are similar.
Clinical trial data show that IVIg hastens total recovery.53 A total IVIg dose
of 2 g/kg can be administered over 2 days instead of a 5-day regimen with
the caveat that treatment-related fluctuations can be more common with a
shorter infusion paradigm.53 One trial compared IVIg with plasma exchange
in children requiring mechanical ventilation and found that overall
recovery was comparable, but plasma exchange was slightly superior in
shortening ventilatory support.54 Both plasma exchange and IVIg can be
used in pregnant women; however, IVIg is less likely to cause hemodynamic
instability.
Randomized controlled data do not exist for the use of immunotherapy
in minor variants of GBS, including Miller Fisher syndrome and related
disorders. Some anecdotal observations report beneficial effects of IVIg in the
treatment of minor variants. It is not unreasonable to err on the side of using
immunomodulatory treatments in patients with minor variants of GBS if the
treatment is unlikely to increase the risk of treatment-related adverse events,
because these cases reflect immune/inflammatory nerve injury, albeit restricted,
and some variants such as Miller Fisher syndrome have a propensity to spread
and involve limb muscles.
1200 OCTOBER 2020

Trends KEY POINT
An urgent need exists for new immunomodulatory treatments as a substantial
● Biologics targeting the
proportion of patients with GBS do not respond to current therapies. Emerging complement cascade are at
therapies with potential for GBS include complement and neonatal Fc receptor various stages of clinical
(FcRn) inhibitors and hypersialylated IVIg. The development of these therapies trials in GBS, and neonatal
is driven by current opinion favoring the role of IgG autoantibodies and innate Fc receptor (FcRn) inhibitors
(which can reduce IgG
immune effectors such as complement and activating FcγRs. Complement autoantibody burden) and
inhibitors are already in GBS clinical trials. Eculizumab, a humanized antibody modulators of FcγR are at
against complement component C5, has been studied in a small phase 2 trial in advanced stages of clinical
Japan as an add-on therapy with IVIg.55 This treatment was found to be relatively development with potential
applicability to GBS.
safe, and significantly more patients were able to run at 6 months in the
eculizumab-treated group compared to the placebo group, which was a
secondary outcome measure.56 A phase 3 trial is anticipated with this agent.
Another complement inhibitor, a humanized antibody against the C1q
component of complement is being studied in a phase 1b trial in the United States
as an add-on therapy with IVIg.57 This trial is currently recruiting.58 FcRn
functions to protect IgG from catabolism, and antagonism of this receptor
shortens the half-life of circulating pathogenic antineural autoantibodies, which
can reduce antibody-mediated nerve injury in experimental models relevant to
GBS.59 In this context, a number of FcRn inhibitors are at advanced stages of
clinical development for various indications, including chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP),60 and a rationale exists to
extend the use of these agents to GBS. Another novel agent currently in
human safety studies61 with potential to treat GBS is hypersialylated IgG, an
investigational glyco-modified product derived from commercially available
IVIg with an approximately tenfold enhanced anti-inflammatory activity
compared to IVIg.62 Preclinical studies indicate that sialylated IgG fractions have
tenfold more efficacy than IVIg in animal models of autoantibody-mediated
neuropathy relevant to GBS.63 Hypersialyated IgG likely works via modulation of
FcγR functions.
PATIENT SUPPORT AND EDUCATION

Patients with GBS and their families may benefit from community resources
and education. The GBS/CIDP Foundation International is a nonprofit
organization with the mission to support patients with GBS, CIDP, and related
conditions and their families. They are committed to education, research,
and advocacy.
CONCLUSION
GBS is the most common acute neuropathic illness requiring hospitalization,
which presents as acute flaccid paralysis in the majority of patients. Early diagnosis
and treatment are imperative. Medical supportive care, immunomodulatory
treatments, and prognostic modeling are vital components of acute management.
The need for more potent immunomodulatory therapies still exists, and ongoing
research promises to identify new disease-modifying treatments targeting relevant
immunopathomechanisms. The need of proregenerative therapies to enhance
nerve repair, particularly for patients with severe disease, axonal injury, and
residual deficits, is unmet.

USEFUL WEBSITES
GBS/CIDP FOUNDATION INTERNATIONAL IGOS GBS PROGNOSIS TOOL

The GBS/CIDP Foundation International website The IGOS GBS prognosis tool can be used to
provides information about Guillain-Barré syndrome estimate the prognosis of a patient with
and chronic inflammatory demyelinating Guillain-Barré syndrome.
polyradiculoneuropathy (CIDP), support for patients gbstools.erasmusmc.nl
and their families, news about advocacy, and
volunteer opportunities.
gbs-cidp.org
ACKNOWLEDGMENTS
Dr Sheikh is supported by the US Department of Defense (W81XWH-18-1-0422)
and the National Institute of Neurological Disorders and Stroke (R21NS107961).
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1204 OCTOBER 2020

Chronic Inflammatory REVIEW ARTICLE

Demyelinating C O N T I N U UM A U D I O
ONLINE
Polyradiculoneuropathy
and Its Variants

By Kelly Gwathmey, MD
ABSTRACT
PURPOSE OF REVIEW: Chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) and its variants comprise a group of
immune-mediated neuropathies with distinctive clinical presentations and
electrodiagnostic features. Prompt recognition of these treatable disorders CITE AS:
is mandatory as delays result in significant disability and morbidity. This CONTINUUM (MINNEAP MINN)
article highlights the clinical presentation, pathophysiology, diagnostic MOTOR NEURON DISORDERS):
evaluation, and treatment approach of these polyneuropathies. 1205–1223.
Address correspondence to
RECENT FINDINGS: Thespectrum of CIDP is expanding with the recent
Dr Kelly Gwathmey, Department
characterization of neuropathies associated with nodal and paranodal of Neurology, Virginia
antibodies. These neuropathies are distinguished by their unique Commonwealth University,
1101 East Marshall St, PO Box
presentations and are often refractory to IV immunoglobulin (IVIg) therapy. 980599, Richmond, VA 23298,
Subcutaneous immunoglobulins have recently been approved as a Kelly.Gwathmey@vcuhealth.
treatment option for CIDP and join corticosteroids, IVIg, and plasma org.
exchange as first-line treatment. RELATIONSHIP DISCLOSURE:

Dr Gwathmey has served as a
SUMMARY: CIDP is characterized by progressive symmetric proximal and consultant for and received
distal weakness, large fiber sensory loss, and areflexia, with clinical nadir speaking engagements from
reached more than 8 weeks after symptom onset. Autoimmune Alexion Pharmaceuticals, Inc.
demyelinating neuropathies fall on a continuum, with differences in the UNLABELED USE OF
type of nerve fibers affected and pattern of deficits. Distinguishing PRODUCTS/INVESTIGATIONAL
between typical CIDP and its variants allows for selection of the most USE DISCLOSURE:
Dr Gwathmey discusses the
appropriate treatment. unlabeled/investigational use of
azathioprine, bortezomib,
corticosteroids
(methylprednisolone,
INTRODUCTION prednisone),
I
n 1890, chronic inflammatory demyelinating polyradiculoneuropathy cyclophosphamide,
cyclosporine, methotrexate,
(CIDP) was first described by Eichhorst in a patient with a presentation
mycophenolate mofetil, and
similar to Guillain-Barré syndrome but with a chronic course.1 The term rituximab for the treatment of
chronic inflammatory polyradiculoneuropathy, which summarizes its clinical chronic inflammatory
demyelinating
and pathologic features, was later coined by Dyck and colleagues.2 Although polyradiculoneuropathy and its
CIDP is the most common chronic autoimmune neuropathy, the incidence and variants.
prevalence are quite low across epidemiologic studies. One 2019 meta-analysis
estimated the incidence rate to be 0.33 per 100,000 and the prevalence rate to be © 2020 American Academy
2.81 per 100,000.3 The diagnosis relies on the clinical presentation and of Neurology.

CIDP AND ITS VARIANTS
electrophysiologic and, in some cases, histopathologic evidence of acquired

demyelination, as well as exclusion of alternative causes of demyelination.
CLINICAL FEATURES
CIDP results in damage predominantly to peripheral nerve myelin, with the
heavily myelinated fibers the most susceptible to injury. Consequently, patients
present with numbness, weakness, and sensory ataxia. Half of patients are
considered to have typical CIDP, which manifests as symmetric proximal and
distal weakness, length-dependent loss of large fiber sensation, and areflexia
(CASE 4-1).4,5 The neuropathy progresses over several months, with clinical nadir
occurring after at least 2 months. The remaining patients have a CIDP variant
(TABLE 4-16–10). The course of CIDP may be monophasic, relapsing and
remitting, or chronically progressive.2,11 In up to 18% of patients, however, the
disease starts acutely, mimicking Guillain-Barré syndrome, and is termed
acute-onset CIDP.6,7 Although clinical nadir is reached within 2 months, patients
have a relapsing or progressive course that differentiates them from those with
Guillain-Barré syndrome.
CASE 4-1 A 65-year-old man presented with 1 year of progressive upper and lower
extremity weakness. He fell frequently and required a cane to ambulate.
He had also noticed a decline in manual dexterity, with difficulty
buttoning shirts and gardening. He denied any dysarthria, dysphagia, or
dyspnea. He had no significant medical comorbidities.
Examination revealed moderate generalized symmetric weakness of
the upper and lower extremities. Pinprick, temperature, and vibratory
sensation and proprioception were diminished in a length-dependent
pattern. Reflexes were diffusely absent. Electrodiagnostic studies
demonstrated a severe generalized primarily demyelinating
polyradiculoneuropathy with secondary axonal loss. CSF analysis
demonstrated a markedly elevated protein of 661 mg/dL with normal
white blood cell count of 1 cell/mm3.
The patient was started on prednisone 60 mg/d. Three months later,
he developed diabetes and had not clinically responded to the
prednisone. He received a loading dose of IV immunoglobulin (IVIg) of
2 g/kg over 5 days followed by 1 g/kg administered every 3 weeks, with
steady improvement in his weakness and sensory deficits.
COMMENT This patient’s history, examination, and electrodiagnostic and CSF studies
all support a diagnosis of chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP). This case illustrates the importance of
constant appraisal of treatment efficacy and potential side effects. This
patient experienced no improvement with corticosteroids and developed
severe side effects necessitating a change in therapy. For each of the
first-line treatments (immunoglobulins, corticosteroids, and plasma
exchange), only two-thirds of patients will respond. Therefore, changing
CIDP treatment is often necessary.
1206 OCTOBER 2020

Weakness is the most disabling CIDP symptom and results in impaired KEY POINTS
mobility, falls, and diminished manual dexterity. The presence of proximal
● One-half of patients with
muscle weakness is a diagnostic clue, even if less severe than distal weakness. chronic inflammatory
Postural tremor is a frequent accompanying clinical feature that may be demyelinating
debilitating and poorly responsive to CIDP treatment.12 Unlike in Guillain-Barré polyradiculoneuropathy
syndrome, cranial nerves are usually spared, although involvement of the facial (CIDP) have a typical
presentation of symmetric
and oculomotor nerves has been reported.13 In addition to weakness, most
proximal and distal
patients with CIDP report fatigue.14 Damage to heavily myelinated sensory nerve weakness, length-dependent
fibers results in impaired proprioception and sensory ataxia, whereas small nerve loss of large fiber sensation,
fiber dysfunction causing dysautonomia and neuropathic pain is less common. In and areflexia.
a minority of patients, respiratory impairment (which is much more common in
● Up to 18% of patients with
Guillain-Barré syndrome) has been described.15 CIDP will have an acute
onset that mimics
PATHOPHYSIOLOGY Guillain-Barré syndrome.
In contrast to Guillain-Barré syndrome, antecedent infections are rarely
● CIDP is differentiated
reported in CIDP. Although the exact pathophysiologic mechanisms are from Guillain-Barré
unknown, both cellular and humoral immunity likely play important roles.16 syndrome by a protracted
T cells and macrophages invade and strip the myelin lamellae supporting a time course, absence of
cellular immune response.17 Activation of T cells results in increased autonomic dysfunction, and
absence of respiratory
expression of IL-2 and tumor necrosis factor-α.18,19 Macrophages release toxic
impairment in most patients.
mediators that target peripheral nerves and phagocytose myelin.20 Antibodies
directed against peripheral nerve myelin protein P0 in some patients and ● All patients with
the response of patients to plasma exchange support the role of humoral suspected CIDP should be
immunity.21 screened for a monoclonal
gammopathy.
DIAGNOSTIC EVALUATION ● Albuminocytologic

Basic serum laboratory studies should be performed to exclude alternative or dissociation is expected on
confounding diagnoses, including hemoglobin A1c; complete blood cell count; CSF analysis in CIDP. The
presence of leukocytosis
electrolytes; liver, renal, and thyroid function studies; and vitamin B12 and raises suspicion for other
methylmalonic acid levels. All patients with possible CIDP must be screened conditions, such as
for a monoclonal gammopathy with serum and urine electrophoresis, neurosarcoidosis, human
immunofixation, and free light chains. In the presence of an IgM monoclonal immunodeficiency virus
(HIV), or carcinomatous
gammopathy, myelin-associated glycoprotein (MAG) antibodies should be
meningitis.
obtained. In those with IgG or IgA lambda monoclonal gammopathies, a skeletal
survey should be performed to rule out an osteosclerotic myeloma or ● The sural sparing pattern
plasmacytoma, and vascular endothelial growth factor (VEGF) level should be is an electrophysiologic
obtained to exclude POEMS (polyneuropathy, organomegaly, endocrinopathy, hallmark of CIDP and is
often found in addition to
monoclonal plasma cell disorder, and skin changes). For further discussion of other acquired
paraproteinemic neuropathies, refer to the article “Peripheral Neuropathies demyelinating features.
Associated With Monoclonal Gammopathies” by Elie Naddaf, MD, and Michelle
L. Mauermann, MD, FAAN,22 in this issue of Continuum. In those with poor
response to immunotherapy or with a strong family history, testing for inherited
neuropathies such as Charcot-Marie-Tooth disease and transthyretin familial
amyloidosis may be necessary.23,24
CSF analysis is usually not necessary, but, in certain cases of suspected CIDP,
it may be helpful. When collected, albuminocytologic dissociation (elevated
protein, normal leukocyte count) is anticipated. Elevated CSF protein is
significantly more common in typical and sensory CIDP than in multifocal
CIDP.25 While less than 10% of patients with CIDP may have a mild pleocytosis,
a CSF leukocyte count of greater than 50 cells/mm3 is very unusual and raises

concerns of lymphoma, leptomeningeal carcinomatosis, neurosarcoidosis, and

human immunodeficiency virus (HIV).26
Electrophysiologic evidence of acquired demyelination on nerve conduction
studies strongly supports the clinical diagnosis. Expected findings include
slowing of conduction velocities, prolongation of sensory and motor latencies,
prolonged F-wave latencies, partial motor conduction block, abnormal temporal
dispersion, and prolongation of blink reflexes. A unique finding of both acute
and chronic acquired demyelinating neuropathies is the predominant involvement
of the upper extremity sensory nerves with relative sparing of the sural nerve, the
so-called sural sparing pattern. In pure demyelinating neuropathies, EMG may
demonstrate only reduced recruitment of normal morphology motor unit
potentials. With secondary axonal degeneration, active denervation (positive
sharp waves and fibrillation potentials) and reinnervation (high-amplitude
long-duration polyphasic motor unit potentials) may be observed.
TABLE 4-1 Comparison of Features of Chronic Inflammatory Demyelinating

Polyradiculoneuropathy and Its Variants
Percentage of Chronic
Chronic Inflammatory Inflammatory
Demyelinating Demyelinating
Polyradiculoneuropathy Polyradiculoneuropathy
Variant Clinical Features Cases Treatment Response Notes
4
Typical chronic Symmetric 50% Immunoglobulins, Clinical nadir reached
inflammatory proximal and corticosteroids, plasma after 8 weeks
demyelinating distal weakness, exchange
polyradiculoneuropathy sensory loss,
(CIDP) areflexia
Acute CIDP Symmetric Up to 18%6,7 Immunoglobulins, Clinical nadir reached

proximal and distal corticosteroids, plasma before 8 weeks; may
weakness, sensory exchange mimic Guillain-Barré
loss, areflexia syndrome
Sensory CIDP Symmetric 5–15%5,8 Immunoglobulins, Distinguished from

sensory- corticosteroids, plasma idiopathic sensory
predominant exchange polyneuropathy by
presentation, early ataxia, younger
sensory ataxia, age, early upper
generalized extremity symptoms
hyporeflexia/
areflexia
Chronic immune sensory Sensory ataxia Unknown, very rare Immunoglobulins, Normal nerve
polyradiculopathy corticosteroids conduction studies;
(CISP) diagnosis relies on
somatosensory
evoked potentials,
CSF analysis, and MRI
abnormalities of
lumbar roots
1208 OCTOBER 2020

MRI studies, although often not performed, may demonstrate enlarged
enhancing nerve roots, plexus, and peripheral nerves.27,28 If concomitant central
nervous system demyelination is a concern, a brain MRI should be obtained.
Nerve ultrasound is emerging as a cost-effective imaging option in CIDP and
may serve as a potential biomarker. In treatment-naïve CIDP, focal enlargement
of the nerves is appreciated, whereas in chronic CIDP, the enlargement becomes
more confluent.29 Unlike axonal neuropathies, nerve enlargement in CIDP
affects primarily the proximal nerve segments (especially the median nerve) and
brachial plexus.30
Nerve biopsy is unnecessary in straightforward cases of CIDP. As CIDP
predominantly affects proximal mixed sensory and motor nerves, high-yield
targeted biopsy would entail greater morbidity than routine biopsy of a
cutaneous sensory nerve. Therefore, biopsy is reserved for those in whom a high
suspicion of an alternative diagnosis exists. When performed, biopsy often shows
Percentage of Chronic
Chronic Inflammatory Inflammatory
Demyelinating Demyelinating
Polyradiculoneuropathy Polyradiculoneuropathy
Variant Clinical Features Cases Treatment Response Notes
4,8,9
Motor CIDP Symmetric 4–10% Immunoglobulins; avoid May have
proximal and corticosteroids electrophysiologic
distal motor evidence of sensory
deficits involvement
Multifocal acquired Asymmetric distal 8–15%5,9 Immunoglobulins, May evolve into

demyelinating sensory more than corticosteroids, plasma typical CIDP
and motor neuropathy proximal sensory exchange
(MADSAM) and motor
deficits; affects
upper more than
lower extremities
Distal acquired Symmetric distal 2–10%9,10 With myelin-associated May be associated

demyelinating and more than glycoprotein (MAG) with an IgM
symmetric (DADS) proximal, sensory antibodies, treatment monoclonal
neuropathy more than motor ineffective although gammopathy; may
deficits; affects rituximab response have MAG antibodies;
lower more than reported in some series; considered
upper extremities without MAG antibodies, DADS-CIDP in the
response to absence of
immunoglobulins, monoclonal
corticosteroids, plasma gammopathy and
exchange MAG antibodies
CSF = cerebrospinal fluid; IgM = immunoglobulin M; MRI = magnetic resonance imaging.

histopathologic evidence of inflammatory cells infiltrating the endoneurium,

epineurium, and perivascular regions. With repeated demyelination and
remyelination, Schwann cell cytoplasmic processes stack, resulting in the typical
onion bulb formation.
Numerous recent publications have drawn attention to the high rate of
CIDP misdiagnosis.31 These diagnostic errors result in long-term use of
inappropriate treatments with extraordinary risk of adverse effects and cost to
the health care system. The source of these errors results primarily from
misinterpretation of electrodiagnostic studies and overinterpretation of
subjective response to IVIg infusions (TABLE 4-232). To prevent diagnostic
mistakes, particular attention should be paid to the clinical presentation and
adherence to published electrodiagnostic criteria for CIDP, the most widely
accepted of which is the European Federation of Neurological Societies/Peripheral
Nerve Society criteria (TABLE 4-333,34).35 With more than 15 different
published electrodiagnostic criteria for CIDP, the lack of a single universally
accepted criteria likely also contributes to diagnostic errors.36 Whereas nerve
conduction studies are an essential part of the diagnostic evaluation of CIDP, not
all patients meet formal criteria for CIDP; the presence of symmetric weakness
of all four limbs and proximal weakness in at least one limb in a patient with
possible CIDP has equivalent diagnostic sensitivity and specificity to nerve
conduction criteria.37
TREATMENT
CIDP treatment is initiated with one of three first-line therapies: immunoglobulins
(including IV and subcutaneous routes of administration), corticosteroids, or
plasma exchange; 50% to 70% of patients respond to one of these therapies.38 The
choice of treatment is tailored to the patient’s medical comorbidities, dosing
schedule, and, at times, availability of the product. The treatment approach
consists of induction therapy followed by maintenance therapy.
IVIg therapy was approved by the US Food and Drug Administration (FDA)
for treatment of CIDP in 2008. The initial dose, typically 2 g/kg, is divided over
2 to 5 days and followed by maintenance dosing of 1 g/kg administered every
3 weeks.33 Treatment for 6 weeks is recommended to assess for response before
switching to another therapy,39 and up to 12 weeks of treatment are necessary for
TABLE 4-2 Electrophysiologic Pitfalls Resulting in a Misdiagnosis of Chronic

Inflammatory Demyelinating Polyradiculoneuropathya
◆ Equivocal degrees of conduction velocity slowing in the axonal polyneuropathies

◆ Prolonged fibular (peroneal) nerve distal motor latency in the setting of reduced amplitude
◆ Mild conduction velocity slowing observed in motor neuron disease
◆ Conduction velocity slowing limited to sites of compression
◆ Slowing of sensory responses and amplitude-independent slowing in the context of diabetes
◆ Conduction velocity slowing and prolongation of distal latencies due to cold limb
temperatures
a
Data from Allen JA, et al, Muscle Nerve31 and Allen JA, Lewis RA, Neurology.32
1210 OCTOBER 2020

maximal benefit.40 Treatment response should be constantly assessed with the
goal to reduce the dose and frequency of the treatments and, if possible, taper the
IVIg entirely. Compared to the maintenance dose of 1 g/kg used in the ICE
(Immune Globulin Intravenous for Chronic Inflammatory Demyelinating
Polyneuropathy) trial, tailoring the regimen to the individual is noninferior
and more cost-effective.40,41 A phase 3 study of three different IVIg regimens
(0.5 g/kg, 1 g/kg, and 2 g/kg) every 3 weeks is ongoing; it is hoped that it will
establish the optimal maintenance dosing.42
Subcutaneous immunoglobulin (SCIg) therapy, approved by the FDA in
March 2018 for treatment of CIDP, is an appealing alternative to maintenance
IVIg for many patients given its lower incidence of systemic side effects. As it is
self-administered, patients also appreciate more autonomy. The PATH (Chronic
European Federation of Neurological Societies/Peripheral Nerve Society TABLE 4-3

Electrodiagnostic Criteria for Chronic Inflammatory Demyelinating
Polyradiculoneuropathya,b
Definite (at least one of the following):

◆ Motor distal latency prolongation ≥50% above upper limit of normal values (ULN) in two
nerves (excluding median neuropathy at the wrist from carpal tunnel syndrome), OR
◆ Reduction of motor conduction velocity ≥30% below lower limit of normal values (LLN) in two
nerves, OR
◆ Prolongation of F-wave latency ≥30% above ULN in two nerves (≥50% if amplitude of distal
negative peak compound muscle action potential [CMAP] <80% of LLN values), OR
◆ Absence of F waves in two nerves if the nerves have distal negative peak CMAP amplitudes
≥20% of LLN + ≥1 other demyelinating parameterc in ≥1 other nerve, OR
◆ Partial motor conduction block: ≥50% amplitude reduction of the proximal negative peak
CMAP relative to distal, if distal negative peak CMAP ≥20% of LLN, in two nerves, or in one
nerve + ≥1 other demyelinating parameterc in ≥1 other nerve, OR
◆ Abnormal temporal dispersion (>30% duration increase between the proximal and distal
negative peak CMAP) in ≥2 nerves, OR
◆ Distal CMAP duration (interval between onset of the first negative peak and return to
baseline of the last negative peak) increase in ≥1 nerve (median ≥6.6 ms, ulnar ≥6.7 ms,
peroneal ≥7.6 ms, tibial ≥8.8 ms)34 + ≥1 other demyelinating parameterc in ≥1 other nerve
Probable
◆ ≥30% amplitude reduction of the proximal negative peak CMAP relative to distal, excluding
the posterior tibial nerve, if distal negative peak CMAP ≥20% of LLN, in two nerves, or in one
nerve + ≥1 other demyelinating parameterc in ≥1 other nerve
Possible
◆ As in definite but in only one nerve
a
Modified with permission from Van den Bergh PYK, et al, Eur J Neurol.33 © 2010 The Authors. Journal
compilation © 2010 EFNS and Peripheral Nerve Society.
b
To apply these criteria, the median, ulnar (stimulated below the elbow), fibular (peroneal) (stimulate below
the fibular head), and tibial nerves on one side are tested. If criteria are not fulfilled, the same nerves are
tested at the other side and/or the ulnar and median nerves are stimulated bilaterally at the axilla and at
Erb’s point. Motor conduction block is not considered in the ulnar nerve across the elbow, and at least 50%
amplitude reduction between Erb’s point and the wrist is required for probable conduction block.
Temperatures should be maintained to at least 33°C (91.4°F) at the palm and 30°C (86°F) at the external
malleolus (good practice points).
c
Any nerve meeting any of the criteria (1 through 7).

Inflammatory Demyelinating Polyneuropathy and Treatment With

Subcutaneous Immunoglobulin) clinical trial was the pivotal phase 3 study that
randomly assigned patients with CIDP who were IVIg dependent to placebo,
0.2 g/kg 20% SCIg weekly, or 0.4 g/kg 20% SCIg weekly.43 The primary outcome
was the proportion of CIDP relapses or withdrawals from the study in each group
over the 24-week duration of the trial. Of the trial participants, 63% in the
placebo arm, 39% in the 0.2 g/kg arm, and 33% in the 0.4 g/kg arm met the
primary outcome (P=.0007). Both doses of SCIg were found to be efficacious and
well tolerated, supporting the use of SCIg as maintenance therapy in CIDP. A
small study of patients with CIDP who were treatment naïve compared SCIg to
IVIg and found them equally efficacious in terms of isokinetic muscle strength;
notably, improvement was earlier in the IVIg group at 2 weeks in contrast to
5 weeks in the SCIg group.44
Several corticosteroid regimens are used for induction therapy, including oral
prednisone (1 g/kg/d to 1.5 g/kg/d or alternate-day equivalent dose), dexamethasone
40 mg/d for 4 days every 4 weeks, or IV methylprednisolone 0.5 g one day each
week or for 4 consecutive days monthly.45 Comparison of these three regimens in
125 patients who were treatment naïve demonstrated that 60% of patients
improved and 61% of responders achieved remission; no differences between
treatments were seen in safety and efficacy.46 A large randomized controlled trial
investigating the additional benefit of IV methylprednisolone in combination
with IVIg for induction therapy is under way.47
Plasma exchange significantly improves clinical impairment and disability in
CIDP, but the benefit is short-lived. Five to ten exchanges of 50 mL/kg plasma
volume on alternate days are initiated within 2 to 4 weeks as induction therapy,
followed by one to two sessions every 3 to 4 weeks as maintenance therapy.
Given the logistic challenges of plasma exchange as maintenance therapy, it is
often considered for patients with CIDP refractory to IVIg and corticosteroids.
Many steroid-sparing immunosuppressant medications have been used in
CIDP, including mycophenolate mofetil,48 azathioprine, cyclophosphamide,
methotrexate, and cyclosporine. The data supporting the use of these drugs are
limited, as the existing trials were underpowered to demonstrate a significant
benefit.49 However, it is common clinical practice to use azathioprine or
mycophenolate mofetil in addition to corticosteroids to facilitate successful
tapering of the steroid dose, and pulse IV cyclophosphamide 1 g/m2 may be used
for patients with CIDP refractory to standard therapy.48,50 A 2018 study of
fingolimod failed to demonstrate efficacy.51 No clear guidance is available
regarding the treatment approach in refractory CIDP. Case reports and small
series exist that have used immunoadsorption, rituximab, and bortezomib in
refractory cases.52–54 Consideration of an alternative diagnosis is mandatory in
those with seemingly refractory disease.23
The treatment strategy in CIDP must be tailored to disease activity. The
Chronic Inflammatory Demyelinating Polyneuropathy Disease Activity Status
Tool (CDAS) allows for easy and reproducible classification of patients with
CIDP according to disease activity and treatment status. Among 106 patients
with CIDP followed for an average of 6.4 years, 11% were classified as
“cured,” 20% as in remission (defined as being stable off treatment for
<5 years), 44% had stable active disease that required ongoing treatment,
7% were improving on treatment following recent diagnosis, and 18% had
“unstable active disease” (either treatment refractory or treatment naïve).55
1212 OCTOBER 2020

Those with active disease may require dose escalation or switching therapies, KEY POINTS
whereas treatment tapering may be considered in those with inactive disease.
● Patients with suspected
Incorporation of validated clinical outcome measures should inform treatment CIDP do not require a
decisions. The standard outcome measures include manual muscle testing, the nerve biopsy if the
Inflammatory Neuropathy Cause and Treatment Disability Score (INCAT), electrodiagnostic findings
and handgrip strength.56 A newer instrument, the Inflammatory Rasch-built and clinical features are
consistent with an
Overall Disability Scale (I-RODS), demonstrates excellent responsiveness and
acquired demyelinating
correlates with objective measures of strength.57,58 Several disease-specific polyradiculoneuropathy.
validated quality-of-life instruments, such as the Inflammatory Neuropathy
Quality of Life Instrument (IN-QoL) and the Chronic Acquired Polyneuropathy ● More than 15 sets of
Patient-Reported Index (CAPPRI), can provide additional value to clinical diagnostic criteria for CIDP
have been published; the
assessments.59,60 most widely accepted is the
European Federation of
CIDP VARIANTS Neurological Sciences/
In contrast to “typical” CIDP, the CIDP variants do not conform to the expected Peripheral Nerve Society
criteria.
pattern of symmetric generalized weakness with length-dependent sensory
deficits. These polyneuropathies are characterized by sensory predominance ● The first-line treatments
(eg, sensory CIDP), motor predominance (eg, motor CIDP or multifocal motor for CIDP include
neuropathy [MMN]), asymmetry (eg, multifocal acquired demyelinating immunoglobulins (IV
and subcutaneous),
sensory and motor neuropathy [MADSAM]), or distal predominance (eg, distal
corticosteroids, and plasma
acquired demyelinating symmetric [DADS] neuropathy). exchange. Given the need for
long-term venous access and
Sensory CIDP limited facilities capable of
outpatient plasma exchange,
Approximately 5% to 15% of patients
in practice, plasma exchange
with CIDP have a pure sensory clinical is considered second- or
presentation but with electrophysiologic third-line treatment by many
evidence of demyelination on motor experts.
nerve conduction studies.61 Some of these
● Clinical trials suggest IV
patients will evolve into typical CIDP immunoglobulin (IVIg) can be
and develop weakness. Very few patients discontinued successfully
will have clinical and electrophysiologic without relapse in
involvement strictly isolated to the approximately 50% of
patients. The treating
sensory nerves. Sensory CIDP is physician should work
characterized by early ataxia, early toward reducing or
upper extremity involvement, diffuse discontinuing the IVIg if
hyporeflexia, cranial nerve involvement, possible.
and onset before the age of 55.62
● Use of clinically
Chronic immune sensory appropriate outcome
polyradiculopathy (CISP) represents a measures, such as disability
rare subtype of sensory CIDP. Patients scales and quality-of-life
present with prominent sensory ataxia. instruments, helps to inform
medical decision making in
The subtype was first reported in 2004; CIDP.
patients have sensory symptoms with
normal nerve conduction studies.63
Elevated CSF protein, enlarged and
enhancing nerve roots on lumbar MRI FIGURE 4-1
(FIGURE 4-1), and delayed somatosensory Sagittal postcontrast T1-weighted MRI
shows lumbar nerve root enhancement
evoked potentials are hallmarks. Patients (arrows) in a patient with chronic
with CISP may be treated successfully inflammatory sensory
with corticosteroids or IVIg. polyradiculoneuropathy.

Pure Motor CIDP

Pure motor CIDP appears to be a rare variant reported in only a few series,64 and
some patients have sensory nerve involvement on electrodiagnostic studies. In its
purest form, motor CIDP clinically and electrophysiologically spares the sensory
nerves, perhaps consistent with an expanded spectrum of MMN. Further
supporting this possibility, some patients with motor CIDP decompensate when
treated with corticosteroids, similar to in MMN.9
Multifocal Motor Neuropathy

MMN is a distinct chronic immune-mediated motor polyneuropathy that falls
outside of the CIDP rubric. Although historically categorized as a demyelinating
polyneuropathy, emerging evidence indicates that the characteristic partial
motor conduction block is due to anti-GM1 antibody–mediated conduction
failure at the node of Ranvier, suggesting MMN should be classified as a
nodopathy rather than a demyelinating syndrome.65 The immune-mediated
attack on the motor fibers of at least two peripheral nerves results in a multifocal
pattern. MMN typically presents with asymmetric distal upper extremity
weakness, with cramps and fasciculations manifesting in affected peripheral
nerve territories (CASE 4-2). In the differential diagnosis of motor neuron
diseases with the progressive painless weakness, patients with MMN lack upper
motor neuron signs. Cold paresis (increased weakness during cold) is also a
clinical hallmark (although this finding is common in other motor neuropathies,
such as monomelic amyotrophy). Conduction block of motor nerves causes
weakness without atrophy unless secondary axonal degeneration is present.
The electrophysiologic hallmark of MMN is demonstration of partial motor
conduction block at noncompressible sites. This is often difficult to demonstrate
on routine electrodiagnostic testing; alternative techniques, including
transcutaneous cervical root stimulation, transcranial magnetic stimulation, and
triple stimulation (which estimates the percentage of motor units discharged by
CASE 4-2 A 54-year-old man presented with progressive painless weakness of his
distal right arm, followed by his left foot. He denied any ocular, bulbar, or
sensory symptoms.
On examination, he had marked weakness of his right wrist and finger
extension and left foot dorsiflexion and eversion. Motor nerve
conduction studies demonstrated conduction block in several motor
nerves, with completely normal sensory responses. His CSF analysis
demonstrated a normal protein level. Anti-GM1 antibodies were negative.
COMMENT This patient’s multifocal weakness with electrophysiologic evidence of an

acquired demyelinating motor neuropathy is diagnostic of multifocal motor
neuropathy (MMN). Approximately 50% of patients with this pure motor
neuropathy lack the characteristic anti-GM1 antibodies. Also, unlike in
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), CSF
protein is often normal. This patient was started on IV immunoglobulin
(IVIg) with complete resolution of his neurologic deficits.
1214 OCTOBER 2020

transcranial electrical stimulation through electrical stimulation at three sites,
including the scalp, Erb’s point, and peripheral nerve), may be used.66
Significant titers of IgM antibodies directed toward GM1, a ganglioside on the
motor nerve axolemma at the node and Schwann cell paranode, are found in
40% to 60% of patients with MMN.66 Testing of GM1/galactocerebroside
complexes may increase the sensitivity to 70%.67 On MRI, T2 hyperintensity
and contrast enhancement of the brachial plexus is a common feature.68 Nerve
ultrasound demonstrating increased cross-sectional area of the median and
ulnar nerves may be more sensitive than MRI.69
The first-line treatment of MMN is IVIg, and most patients require long-term
treatment.70 For many patients, the effectiveness of IVIg declines several years
after initiation, usually in the setting of axonal degeneration.71 SCIgs are likely an
alternative in some patient populations.72 Most patients fail to respond to steroids
and may even deteriorate clinically.73 IV cyclophosphamide (1 g/m2 monthly for
six doses), with or without associated plasma exchange, may be an effective
strategy in some patients with IVIg-refractory MMN. Small uncontrolled studies
suggest individual patients may respond to B-cell depletion with rituximab,
although randomized clinical trials have not been performed.73
Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

MADSAM (ie, Lewis-Sumner syndrome or multifocal CIDP) is another variant
of CIDP that is differentiated from MMN by the involvement of sensory fibers.
Patients develop an insidious onset of gradually progressive, asymmetric, upper
A 72-year-old man had presented 4 years earlier with symmetric CASE 4-3
numbness and “heaviness” of both feet. Over time, this sensation had
ascended to the level of his knees. He also gradually developed
weakness affecting his distal upper and lower extremities and gait ataxia.
His electrodiagnostic studies at initial presentation revealed absent
sensory responses, extremely prolonged distal motor latencies (eg,
26.2 milliseconds for the right tibial compound muscle action potential
[CMAP]), and severely slowed conduction velocities without evidence of
conduction block. During initial evaluation of his neuropathy, an IgM
lambda monoclonal gammopathy and positive anti–myelin-associated
glycoprotein antibodies were identified.
Over the subsequent years, he was treated with IV immunoglobulin
(IVIg), plasma exchange, mycophenolate mofetil, and azathioprine.
Despite these treatments, he continued to gradually decline.
This patient’s diagnosis is distal acquired demyelinating symmetric (DADS) COMMENT

neuropathy with anti-MAG antibodies. He was initially misdiagnosed with
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP),
resulting in use of numerous therapies without clinical response. This is the
expected outcome as DADS with anti-MAG antibodies is classically
treatment refractory. Earlier recognition of his diagnosis would have
prevented years of expensive and futile treatments.

extremity weakness and numbness.74 Nearly half of patients with MADSAM

progress to typical CIDP. Cranial nerve involvement may occur, affecting the
optic, oculomotor, trigeminal, and facial nerves. Electrophysiologic and
histopathologic features resemble CIDP, and, similarly, three-fourths of patients
will have albuminocytologic dissociation on CSF analysis.75 Unlike MMN,
MADSAM is responsive to both corticosteroids and IVIg.
Distal Acquired Demyelinating Symmetric Neuropathy

DADS neuropathy is a CIDP variant causing symmetric distal-predominant
sensory or sensorimotor deficits resulting in ataxia. Weakness, if present, affects
the distal lower extremities. Action tremor may also be a feature. IgM
monoclonal gammopathy and MAG or sulfated glucuronyl paragloboside
antibodies are present in many patients with DADS.
Electrodiagnostic studies demonstrate acquired demyelination with extremely
prolonged distal motor and sensory latencies. In contrast to typical CIDP,
patients have disproportionate slowing of distal motor conductions with a
terminal latency index (distal nerve conduction distance/[proximal motor
conduction velocity distal motor latency]) ≤0.25, absence of conduction block,
TABLE 4-4 Nodo-Paranodopathies
Percentage of
Chronic Inflammatory
Demyelinating
Antibody Polyradiculoneuropathy
Target Clinical Features Casesa Target Treatment Response
Neurofascin Subacute onset, 5–10% Paranodal transmembrane Good response to
155 (NF155) symmetric motor more cell adhesion molecule rituximab and plasma
than sensory, sensory located on Schwann cell exchange; partial
ataxia, tremor (also of membrane response to
head/voice), distal- corticosteroids; IV
predominant; cranial immunoglobulin (IVIg)
neuropathies reported refractory
Neurofascin Subacute onset, 2% Axonal membrane protein Good response to

140 (NF140)/ symmetric sensory and involved in clustering of rituximab; partial
neurofascin motor, sensory ataxia, sodium channels located at response to IVIg and
186 (NF186) cranial neuropathies; the nodes of Ranvier; corticosteroids
nephrotic syndrome interacts with gliomedin
reported and neuronal cell molecules
Contactin-1 Subacute onset, 5% Paranodal, axonal cell Good response to

(CNTN1) symmetric motor more adhesion molecule rituximab; partial
than sensory, sensory response to
ataxia; nephrotic corticosteroids; IVIg
syndrome reported refractory
Contactin- Subacute onset, <1% Paranodal, axonal cell Good response to

associated symmetric distal- adhesion molecule rituximab; IVIg refractory
protein 1 predominant, severe
(CASPR1) neuropathic pain
a
Percentages of nodal and paranodal antibodies in CIDP taken from Pascual-Goñi E, et al, Curr Opin Neurol.79
1216 OCTOBER 2020

and absence of sural response.76 Histopathologic evidence of segmental
demyelination with IgM and complement deposits in the myelin sheaths and
widened outer myelin lamellae is seen. The response to immunotherapy in DADS
with anti-MAG antibodies remains suboptimal (CASE 4-3). Up to 50% of patients
with anti-MAG neuropathies have been reported to respond to rituximab in
some series, although no consensus exists on its use.77 Patients with DADS who
lack anti-MAG antibodies, however, may respond to IVIg, corticosteroids, and
plasma exchange.78
Nodopathies and Paranodopathies

Approximately 10% of patients with CIDP have autoantibodies directed to
paranodal or nodal antigens that represent a distinct entity classified as
nodo-paranodopathies.10 Testing for these pathogenic autoantibodies is
indicated in the context of unique clinical presentations (eg, subacute onset,
predominant tremor, distal predominant presentation, or sensory ataxia) and
often treatment-refractory polyneuropathy (TABLE 4-4,79 CASE 4-4).81
The targets of these autoantibodies in the paranodal region are three cell adhesion
molecules: contactin 1 (CNTN1) and contactin-associated protein 1 (CASPR1) in
A 40-year-old man presented to the hospital with a 3-week history of CASE 4-4
generalized weakness and distal-predominant sensory loss. His
examination was remarkable for weakness of most muscle groups in the 4/5
range, with a length-dependent loss of large fiber–mediated sensation. His
reflexes were unobtainable. His electrodiagnostic studies demonstrated
prolonged and absent F waves, multiple areas of partial motor conduction
block, and a sural sparing pattern on sensory nerve conduction studies. He
was diagnosed with Guillain-Barré syndrome and treated with 2 g/kg IV
immunoglobulin (IVIg). Despite this therapy, he continued to decline and
subsequently received plasma exchange before being discharged to a
rehabilitation hospital.
He was readmitted 1 week later with significant worsening and
had become quadriplegic and areflexic. Given his atypical course,
nodal and paranodal autoantibodies were tested, and an anti-neurofascin
155 (NF155) antibody was identified. He was started on rituximab, with
significant improvement in his function and only mild residual proximal
muscle weakness in his upper and lower extremities 3 months later.
This case of chronic inflammatory demyelinating polyradiculoneuropathy COMMENT

(CIDP) associated with the paranodal antibody NF155 illustrates an
important point. These rare forms of CIDP should be considered in the
setting of recurrent failures of first-line treatments such as plasma
exchange and IVIg. Additionally, nodo-paranodopathies often have a
subacute onset mimicking Guillain-Barré syndrome and must remain in the
differential if the patient’s course is atypical. This patient did not respond
adequately until treated with rituximab, a distinction that has recently been
highlighted in the literature.80

the axons and neurofascin 155 (NF155) in the myelin. These proteins form a
complex that assembles nodal voltage-gated sodium channels and juxtaparanodal
voltage-gated potassium channels (FIGURE 4-2).81 At the node of Ranvier,
autoantibodies target neurofascin isoforms 140 and 186 (NF140 and NF186).
These paranodal and nodal autoantibodies are of the IgG4 isotype.
Immunoglobulin response is achieved in only 40% of patients, and other
treatment considerations include rituximab, plasma exchange, and corticosteroids.
PROGNOSIS
The CIDP disease course varies dramatically from person to person. Over half of
patients will experience significant disability during their course, necessitating
either assistive devices to ambulate or becoming wheelchair dependent.82,83
Approximately 10% of patients will develop permanent disability or even
FIGURE 4-2
The node of Ranvier. This figure demonstrates the molecular components of the node of
Ranvier, paranode, and juxtaparanode. In the paranodal region, the cell adhesion molecules
contactin 1 (CNTN1), contactin-associated protein 1 (CASPR1), and neurofascin 155 (NF155)
may be targeted in some forms of chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP). At the node of Ranvier, neurofascin 186 (NF186) may be a target. Multiple other
important components of nodal and paranodal function are displayed that are relevant to
the pathophysiology and treatment of other autoimmune neuropathies, including
myelin-associated glycoprotein (MAG) in distal acquired demyelinating symmetric
(DADS) neuropathy and GM1 in multifocal motor neuropathy (MMN).
CASPR2 = contactin-associated protein 2; CNTN2 = contactin 2; Kv = voltage-gated potassium channel;
Nav = voltage-gated sodium channel; NrCAM = neuronal cell adhesion molecule.
Figure reprinted with permission from Querol L, et al, Nat Rev Neurol.81 © 2017 Wolters Kluwer Health, Inc.
1218 OCTOBER 2020

die,82–84 whereas up to 25% of patients may attain complete remission.84 Recent KEY POINTS
studies suggest that initial disability, older age at onset, F-wave latency, and
● Multifocal motor
reduced distal compound muscle action potential (CMAP) duration predict poor neuropathy may mimic
long-term outcome.85,86 amyotrophic lateral
sclerosis given its painless
progressive weakness, but it
is differentiated by its lack
CONCLUSION
of upper motor neuron signs
CIDP is the most common chronic autoimmune polyneuropathy, and its and electrophysiologic
diagnosis depends not only on a thorough examination but also on evidence of conduction
high-quality electrodiagnostic studies demonstrating unequivocal evidence of block on motor nerve
conduction studies.
acquired demyelination. Classically associated with gradually progressive
generalized weakness and sensory ataxia, nearly one-half of patients with ● Distal acquired
CIDP will have an atypical presentation, with the disease classified as a demyelinating symmetric
variant. Knowledge of these variants and their defining clinical and (DADS) neuropathy is often
electrodiagnostic characteristics enables clinicians to select the most associated with IgM
monoclonal gammopathy
appropriate treatment. Despite recent therapeutic advances, much remains and myelin-associated
unknown regarding the optimal treatment strategy. glycoprotein antibodies.
Patients with DADS are often
refractory to treatment.
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REVIEW ARTICLE

Charcot-Marie-Tooth
ONLINE
Disease and Other
Hereditary Neuropathies
By Christopher J. Klein, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of Charcot-Marie-Tooth
disease (CMT) and other inherited neuropathies. These disorders
encompass a broad spectrum with variable motor, sensory, autonomic,
and other organ system involvement. Considerable overlap exists, both
phenotypically and genetically, among these separate categories, all
eventually exhibiting axonal injury and neurologic impairment. Depending
on the specific neural and non-neural localizations, patients experience
varying morbidity and mortality. Neurologic evaluations, including
neurophysiologic testing, can help diagnose and predict patient
disabilities. Diagnosis is often complex, especially when genetic and
acquired components overlap.
RECENT FINDINGS:Next-generation sequencing has greatly improved genetic

CITE AS:
diagnosis, with many third-party reimbursement parties now embracing
CONTINUUM (MINNEAP MINN) phenotype-based panel evaluations. Through the advent of
2020;26(5, PERIPHERAL NERVE AND comprehensive gene panels, symptoms previously labeled as idiopathic or
1224–1256.
atypical now have a better chance to receive a specific diagnosis. A
definitive molecular diagnosis affords patients improved care and counsel.
Address correspondence to The new classification scheme for inherited neuropathies emphasizes the
Dr Christopher J. Klein, Mayo
causal gene names. A specific genetic diagnosis is important as
Clinic, 200 First St SW,
Rochester, MN 55905, considerable advances are being made in gene-specific therapeutics.
Klein.chistopher@mayo.edu. Emerging therapeutic approaches include small molecule chaperones,
antisense oligonucleotides, RNA interference, and viral gene delivery
Dr Klein serves on the clinical therapies. New therapies for hereditary transthyretin amyloidosis and
expert and therapy boards of Fabry disease are discussed.
the Charcot-Marie-Tooth
Association. Dr Klein has
received personal compensation SUMMARY: Comprehensive genetic testing through a next-generation
for speaking engagements at the sequencing approach is simplifying diagnostic algorithms and affords
Neuropathic Pain Symposium
and research/grant support from significantly improved decision-making processes in neuropathy care.
the Mayo Clinic Center for Genetic diagnosis is essential for pathogenic understanding and for gene
Individualized Medicine.
therapy development. Gene-targeted therapies have begun entering the
UNLABELED USE OF clinic. Currently, for most inherited neuropathy categories, specific
PRODUCTS/INVESTIGATIONAL symptomatic management and family counseling remain the mainstays of
USE DISCLOSURE:
Dr Klein reports no disclosure.
therapy.

of Neurology.
1224 OCTOBER 2020

KEY POINTS
INTRODUCTION
H
ereditary neuropathy encompasses a group of genetically ● Charcot-Marie-Tooth
heterogeneous disorders with a phenotypic spectrum spanning disease (CMT) is the most
from mildly symptomatic to severe disability. The most common common inherited
neuropathy but accounts for
form of mendelian-inherited neuropathy is Charcot-Marie-Tooth only a minority of the gene
disease (CMT), also called hereditary motor and sensory abnormalities among
neuropathy (HMSN). The prevalence of CMT ranges from 9.7 per 100,000 to inherited neuropathies.
82 per 100,000 persons.1 Although CMT is the most common category of
● Patients with inherited
inherited neuropathy, it accounts for only 118 of 853 inherited neuropathy entries
neuropathy often describe
found on the comprehensive catalog Online Mendelian Inheritance in Man. CMT their symptoms as subacute
is likely more prevalent because of de novo mutation mechanisms and high in onset, but foot and ankle
clinical penetrance. For example, PMP22 gene duplication, the most common abnormalities (hammer toes,
form of CMT, is caused by unequal sister chromatid exchange that is enhanced pes cavus, pes planus,
cavovarus) and shin and
by two large highly conserved DNA repeat domains that flank the gene. hand atrophy along with
Therefore, it is not uncommon for those affected to have no family history. needle EMG changes
Considering PMP22 duplications alone, large kindred studies have shown almost support the chronicity of
all affected persons will eventually develop clinical signs and symptoms. PMP22, disease course.
GJB1, MFN2, and MPZ mutations account for 90% of all CMT cases, each with ● The presence of ankle
reports of de novo occurrence.2 reflexes and normal
Patients with CMT present with slowly progressive muscle weakness and sensation in patients with
atrophy primarily affecting the distal extremities. Because most patients do not symmetric ankle weakness
raises the possibility of
have significant pain or sensory symptoms, clinical presentations may occur only
inherited distal myopathy or
after weakness affects activities of daily living. This sometimes leads patients to inherited distal hereditary
mistakenly provide a temporal course of subacute onset. Before children are motor neuron disease
brought to medical attention, they have often been labeled as being clumsy mimicking CMT. The genes
responsible for distal
or “slow in a foot race.” Foot and ankle abnormalities (hammer toes, pes cavus,
myopathy and progressive
pes planus, cavovarus) and shin and hand atrophy can assist in recognition of the muscular atrophy should be
chronic process (FIGURE 5-1). Thorough clinical evaluation and nerve conduction considered in next-
studies can help affirm the diagnosis, supported by a family history. Needle generation sequencing
EMG can also help determine chronicity when temporal course is in question panel testing for inherited
neuropathies.
as large motor unit potentials would not be found in a subacute process. The lack
of family awareness in up to two-thirds of families also increases difficulty
in diagnosis.
Non-CMT hereditary neuropathies have different clinical involvements
reflected in their names:
u Motor-only forms (hereditary motor neuropathy [HMN])

u Sensory-predominant forms (hereditary sensory and autonomic neuropathy [HSAN])
u Episodic attack forms (hereditary neuropathy with liability to pressure palsies [HNPP],
hereditary brachial plexus neuropathy [HBPN], also known as hereditary neuralgic
amyotrophy)
u Spastic forms (hereditary spastic paraplegia [HSP] with neuropathy, complicated HSP)
u Spinocerebellar forms with neuropathy (spinocerebellar ataxias [SCAs], dominant and
recessive)
u Metabolic neuropathies (inherited metabolic neuropathies)
u Mitochondrial neuropathy (mt-neuropathy)
It is important to emphasize that a considerable amount of overlap exists

phenotypically and genetically among these seemingly separate categories.

CMT AND OTHER HEREDITARY NEUROPATHIES
FIGURE 5-1
Muscular atrophy and bony changes can provide a clue of chronicity and inherited neuropathy.
A, Patient with Charcot-Marie-Tooth disease with first dorsal interosseous, shin, and calf
atrophy. B, Pes cavus (high arch) and hammer toes. C, Cavovarus (inward-turned ankle and
heel), foot deformities illustrated by line showing abnormal weight distribution, which
increases risk for lateral foot ulcers and musculoskeletal injuries.
Complicating this landscape further is the fact that some inherited myopathies
(eg, Miyoshi myopathy, GNE myopathy, myofibrillar myopathy)3 and certain
motor neuron disorders (eg, progressive muscular atrophy)4 can present with
symmetric lower motor neuron distal weaknesses, mimicking neuropathy.
Preserved ankle reflexes and no sensory loss are common in these disorders but
not in hereditary neuropathies. Neurophysiology cannot always separate these
disorders. Therefore, the decision whether to also test genes within these
categories should be considered.
EVOLVING CLASSIFICATION FOR INHERITED NEUROPATHIES

Each clinical and technologic advance in our understanding of inherited
neuropathies has led to changes in the classification. In 1886, Charcot and Marie
(in Paris) and Tooth (in London) described “peroneal muscular atrophy” as
slowly progressive distal weakness and muscle atrophy (ie, CMT). Soon after,
Déjérine and Sottas described “hypertrophic interstitial neuritis” with onset in
infancy or early childhood (ie, Déjérine-Sottas neuropathy). In 1968, Dyck and
Lambert5 identified two main electrophysiologic categories using motor nerve
conduction velocities: type 1 demyelinating (<38 m/s) and type 2 axonal (>38 m/s).
An intermediate form was subsequently introduced (with velocities of 35 m/s to
45 m/s). The ulnar motor forearm conduction velocity remains the most useful
conduction to distinguish primary axonal and demyelinating forms, including in
Déjérine-Sottas neuropathy, in which motor nerve conduction velocities are
frequently less than 15 m/s.
1226 OCTOBER 2020

As understanding of the genetic patterns and histopathologic and
neurophysiologic characteristics grew, so did the designated categories, and
HMSN was classified into types 1 through 7.6 Over the years, the term HMSN
has been interchangeably used with CMT. HMSN1 (CMT1) is an autosomal
dominant demyelinating form with uniformly slowed nerve conduction velocity
and gross nerve hypertrophy from diffuse myelin and fibroblast lamellae (onion
bulbs) on nerve biopsy (FIGURE 5-27); HMSN2 (CMT2) is an autosomal dominant
axonal predominant neuropathy showing normal to borderline slow nerve
conduction velocities with axonal atrophy. CMT3, initially synonymous with
HMSN3 or Déjérine-Sottas neuropathy, is now considered an early-onset severe
form recognized as caused by mutations in PMP22, MPZ, PRX, EGR2, and other
genes and no longer considered a separate category.8 Depending on the specific
gene mutations found, these patients now are classified as having HMSN1 (CMT1
autosomal dominant), HMSNX (CMTX X-linked), or HMSN4 (CMT4 autosomal
recessive). HMSN5 (CMT5) refers to HMSN associated with spastic paraplegia,
now called complicated HSP, HMSN6 (CMT6) refers to HMSN associated with
optic atrophy (mostly now understood to be mitochondrial), and HMSN7
(CMT7) refers to HMSN associated with retinitis pigmentosa (diverse genetic
causes). Currently, the terms HMSN5, HMSN6, and HMSN7 (CMT5, CMT6, and
CMT7) are largely not used in favor of gene cause designation. Additionally,
CMT4 does not correspond to HMSN4. HMSN4 was initially described as a
FIGURE 5-2
The pathologic findings of myelin lamella collagen thickening (onion bulbs) with PMP22
duplications differ from the mixed onion bulbs of chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP). Patients with PMP22 duplications tend to have slowed
conduction velocities without dispersion and potential conduction blocks as occur in CIDP.
Amp = amplitude; CMT1A = Charcot-Marie-Tooth disease type 1A; CV = conduction velocity;
Diff = difference; Dist = distance; DUR = duration; HMSN1A = hereditary motor and sensory neuropathy
type 1A; Lat1 = latency; Temp = temperature.
Reprinted with permission from Klein CJ, et al, Muscle and Nerve.7 © 2013 Wiley Periodicals, Inc.

recessively inherited, phytanic acid metabolic disorder (also known as Refsum

disease, PHYH) with childhood onset and systemic multiorgan involvement,
including ichthyosis, retinitis pigmentosa, and ataxia. HMSN4 (CMT4) instead
became the term of choice for all autosomal recessive demyelinating forms of
CMT. Within CMT types 1, 2 and 4, additional subclassifications were assigned
letters based on the specific causal gene and phenotype (eg, CMT1A, CMT1B).
This system worked well when the number of causal genes was limited.
However, recent technology accelerated the speed of gene discovery, and the
genetic causes have now exceeded the 26 letters of the alphabet, with the
identification of MORC2 taking the last letter of the alphabet as CMT2Z. Also, the
same gene can be associated with different CMT types; for example, MPZ has
been linked to the dominant demyelinating form (CMT1B), dominant axonal
forms (CMT2I/J), and Déjérine-Sottas neuropathy. Further complicating
classification is the fact that the same gene can transmit disease either
dominantly or recessively; for example, NEFL dominant mutations cause axonal
neuropathy CMT2E, whereas its recessive mutations lead to demyelinating
neuropathy CMT1F.
We are now in the era of next-generation sequencing, whereby hundreds of
genes can be sequenced simultaneously and inexpensively, driving changes in
the classification and ease of diagnosis of diverse inherited neuropathies. In 2015,
Mathis and colleagues9 proposed a new approach to include the gene name in the
nomenclature of inherited neuropathies. The same group recently modified their
nomenclature based on survey results from more than 300 physicians and
scientists who focus on peripheral nerve diseases. The new method uses three
modules for each disease category.10 The first module is the generic term (eg,
CMT-HMSN, distal HMN [dHMN], HSAN), the second module is the clinical
phenotype (Ax for axonal, De for demyelinating, In for intermediate), and the
third module is the mode of inheritance (autosomal dominant [AD], autosomal
recessive [AR], X-linked [XL]), followed by the causal gene name. The names of
causal genes are the key component of the new classification; a similar approach
has been proposed for other genetic disorders, such as hereditary ataxias.11 The
survey also indicated that the majority of peripheral nerve specialists favor this
new method, although some prefer an even simpler classification (eg, MPZ
neuropathy). Regardless, the evolution of the classification has increasingly
favored causal gene inclusions.
CLINICAL AND NEUROPHYSIOLOGIC DIAGNOSIS OF INHERITED

ETIOLOGY
Kindred (an aggregate of related people within a genetic study) evaluation can
be a critical step in identifying inherited neuropathies. However, conducting
kindred evaluation based on knowledge of the proband (the patient who
brings a family under genetic study) is far from straightforward as many
patients are unclear about the clinical phenotypes of family members. Within
the same kindred, the proband seeking attention may be severely affected,
whereas other family members may be asymptomatic and have only minimal
signs. When family history is not present or obvious, clinical examination of
family members is helpful but often impractical. The signs of a possible
genetic cause include high arches and hammer toes (FIGURE 5-1), an inverted
champagne bottle appearance of the legs, a history of frequent ankle sprains,
recurrent foot fractures during childhood, and inability to walk on heels and
1228 OCTOBER 2020

toes. For sensory-predominant forms, the presentation may include sensory KEY POINTS
loss with or without positive sensory symptoms (paresthesia or pain),
● Gene names are
recurrent acral paronychia, calluses, and ulcers. increasingly being included
Nerve conduction studies are useful in distinguishing between acquired and in the nomenclature of
inherited neuropathies. Autonomic testing (eg, orthostatic blood pressure, inherited disorders including
beat-to-beat heart rate, Valsalva heart rate, sweat production) can assist in inherited neuropathies.
differentiating CMT from HSAN or other inherited neuropathies, including
● Historical clues of
hereditary transthyretin amyloidosis, in which autonomic findings are common. inherited neuropathies
Inherited demyelinating neuropathies cause uniform conduction velocity should be sought, including
slowing, whereas acquired demyelinating neuropathies cause patchy slowing in frequent ankle sprains and
addition to partial conduction blocks and abnormal temporal dispersion foot fractures, recurrent
ingrown toenails
(FIGURE 5-2).12 However, exceptions do exist. Conduction abnormalities with (paronychia), and painless
CMTX-GJB1 mutations are often nonuniform with abnormal temporal foot ulcers.
dispersion and partial motor conduction blocks.13
Many factors, such as age, duration of disease, and severity of symptoms, also ● Prolonged blink R1
response latency greater
influence the results of nerve conduction studies. Nerve conduction velocity than 13 milliseconds,
increases through early childhood, reaches a plateau, and then slows with aging. regardless of severity or
This natural physiologic process complicates the interpretation of nerve age, suggests primary
conduction velocity results, especially when patients have very mild disease and demyelinating inherited
neuropathy.
are young or very old or have severe disease, creating ceiling and floor issues for
sensitivities by traditional nerve conduction responses. In patients with ● Patients with inherited
demyelinating neuropathy who have no significant clinical findings and have neuropathy are more
normal nerve conduction amplitudes or patients with severe demyelination in susceptible to clinical
which the ulnar motor amplitude is less than 0.5 mV, blink reflexes can declines from superimposed
acquired neuropathies such
distinguish primary demyelinating from axonal forms regardless of age. Blink R1 as diabetes and neurotoxic
latency prolongation (>13 milliseconds) strongly correlates with primary chemotherapy.
demyelinating inherited neuropathies.14
Nerve biopsy can be helpful in distinguishing inherited from acquired
chronic immune demyelinating polyradiculoneuropathy (CIDP) but should
only be used when acquired etiologies are being considered as a superimposed
diagnosis.15 CIDP causes multifocal onion bulbs and interstitial inflammation,
whereas inherited demyelinating neuropathy causes diffuse onion bulbs without
inflammation (FIGURE 5-2).16 In clinical practice, the most useful tool in
differentiating inherited from acquired neuropathies is still a careful history
and examination.
It is important to be aware that an acquired etiology of neuropathy may
superimpose onto an inherited neurologic defect. When patients present with
acute onset or rapidly progressive symptoms, the possibility of a hereditary
neuropathy should not be immediately dismissed.
Patients with inherited neuropathy are more susceptible to injury from
metabolic, toxic, and other nervous system insults, such as side effects from
chemotherapy.17 For example, when sudden worsening or repeated relapses
occur, superimposition of an inflammatory neuropathy on the hereditary
peripheral nerve disorder may be considered. Other common superimposed
processes with hypertrophic inherited neuropathies as in CMT1 are carpal tunnel
syndrome and lumbar spinal stenosis with activity-induced hand paresthesia and
pseudoclaudication, respectively. Inherited neuropathies are frequently
misdiagnosed as primary diabetic neuropathy. Unlike CMT, diabetic neuropathy
is sensory predominant (significant weakness is rare) and typically accompanied
by retinopathy or nephropathy.

AUTOSOMAL DOMINANT CMT DEMYELINATING NEUROPATHIES

Autosomal dominant demyelinating neuropathy (commonly referred as CMT1)
causes distal weakness and atrophy, reduced distal sensation, decreased deep
tendon reflexes, and variable foot and hand deformity.18 Motor and sensory
nerve conduction velocities are reduced, typically between 15 m/s and 38 m/s.
Usually, both distal motor latencies and F-wave latencies are prolonged,
indicating that conduction slowing is uniform along the length of the nerve.
Seven subtypes of CMT1 have been identified, with five causal genes (TABLE 5-1).
CMT1A is the most common form, accounting for more than 50% of all CMT
cases and approximately 70% of CMT1 cases.19 The onset of CMT1A is often
early, between 3 and 5 years of age. Patients can present with slow nerve
conduction velocities as early as during the first year of life, preceding the
development of signs and symptoms. Nerve biopsy (which is not required
clinically) reveals hypertrophic segmental demyelination and remyelination
appearing as onion bulbs.20 By the time of clinical presentation, all patients with
CMT1A have evidence of secondary axonal degeneration. Weakness and sensory
loss are likely the result of axonal degeneration rather than demyelination
(CASE 5-1).21 Patients with extremely slow motor nerve conduction velocities
have greater clinical severity compared with other affected persons.22
CMT1A is caused by mutations in the peripheral myelin protein 22 gene
(PMP22), most often a duplication, although point mutations may cause a similar
or more severe phenotype. PMP22 is a membrane glycoprotein and component
of the compact myelin sheet. It is mainly expressed in Schwann cells of the
peripheral nervous system. Although it makes up only 2% to 5% of total myelin,
TABLE 5-1 Charcot-Marie-Tooth Disease Autosomal Dominant Demyelinating

Neuropathy and Associated Phenotypes
Earlier Nomenclature
(OMIM Phenotype Number), Proposed New
Gene Inheritance Pattern Nomenclature Overlapping OMIM Phenotypes
PMP22 CMT1A (118220), AD CMT-De-AD-PMP22 CMT1E (118300), AD; Déjérine-Sottas (145900) AR, AD;
Roussy-Levy syndrome, (180800), AD
MPZ CMT 1B (118200), AD CMT-De-AD-MPZ CMT2I (607677), AD; CMT intermediate D (607791), AD;
Déjérine-Sottas (145900), AR, AD; neuropathy, congenital
hypomyelinating 2 (605253) AR, AD; Roussy-Levy syndrome
(180800), AD
LITAF CMT1C (601098), AD CMT-De-AD-LITAF None reported
EGR2 CMT1D (607678), AD CMT-De-AD-EGR2 Déjérine-Sottas (145900), AR, AD; neuropathy, congenital
hypomyelinating 1 (605253), AD, AR
PMP22 CMT1E (118300), AD CMT-De-AD-PMP22 CMT1A (118220), AD; Déjérine-Sottas (145900) AR, AD;
Roussy-Levy syndrome (180800), AD
NEFL CMT1F (607734), AD, AR CMT-De-AD-NEFL CMT2E (607684), AD
PMP2 CMT1G (618279), AD CMT-De-AD-PMP2 None reported
AD = autosomal dominant; AR = autosomal recessive; CMT = Charcot-Marie-Tooth disease; De = demyelinating; OMIM = Online Mendelian
Inheritance in Man.
1230 OCTOBER 2020

the amount of PMP22 in compact myelin is critical in the formation and
maintenance of compact myelin.23 It has been suggested that overexpression of
PMP22 leads to abnormal synthesis and functioning of myelin sheaths and
altered Schwann cell growth and differentiation,24 but the exact molecular
pathway of PMP22 protein overexpression remains unclear. Considerable
variability exists in the degree of neurologic deficits within families, even
between identical twins, suggesting that other external factors (eg, epigenetic
and environmental changes) modulate disease severity.25 The complexity of the
mechanism was further emphasized when levels of PMP22 on the intact myelin
were shown to be highly variable among patients with CMT1A, and no clear
correlation was seen between disease severity and PMP22 expression levels.25
Another major CMT gene, myelin protein zero (MPZ), is responsible for
CMT1B. MPZ is a component of compact myelin that is important in maintaining
myelin compaction and stability. CMT1A and CMT1B are usually clinically and
pathologically indistinguishable. Rarely, MPZ mutations also cause a late-onset
axonal neuropathy (CMT2J), with an age of onset between 30 and 50 years and
with variably slowed nerve conduction velocities but with axonal loss the main
finding. Some patients with CMT2J have pupillary defects (Adie pupil).
A 24-year-old man presented with the recent onset of tripping episodes. CASE 5-1
He walked at 10 months, and, although “not the best athlete,” he played
catcher on his high school baseball team. He had no family history of
similar symptoms in his parents, who accompanied him to the evaluation,
or his three brothers and two sisters.
His examination demonstrated marked high arches and hammering of
his toes, with inverted champagne bottle legs. He had mild steppage gait,
with distal weaknesses of foot and ankle dorsiflexors with mild
symmetric finger abduction weakness. He had mild sensory loss to light
touch and vibration in his distal toes but no loss of heat, pain, or cold
sensation. He denied any paresthesia or pain. Reflexes were absent in the
lower extremities and reduced at the brachioradialis.
His ulnar motor conduction velocity in the forearm was slowed to
24 m/s (normal >50 m/s) without abnormal temperature dispersion. His
parents’ nerve conduction velocities were normal. Focused genetic
testing for PMP22 duplication was positive in the patient but negative in
his parents.
This case is typical for PMP22 duplications, accounting for the most COMMENT
common inherited demyelinating neuropathy in North America. The
frequency of de novo PMP22 duplications, in part, leads to its common
occurrence within the population. The absence of a positive family history
should not dissuade from the diagnosis. The fact that this patient had five
siblings without affected status would argue against a recessive disorder,
which is more common in countries where consanguinity is common.
His obvious muscle atrophy in the ankles and hands argue against his
description of subacute onset.

AUTOSOMAL DOMINANT CMT AXONAL NEUROPATHIES

Axonal neuropathy (commonly referred to as CMT2) accounts for
approximately 30% of all genetically confirmed CMT cases.1 CMT2 is usually
characterized by reduced motor amplitudes, normal or near-normal nerve
conduction velocities, and loss of large myelinated nerve fibers and clusters of
regenerating nerve fibers on nerve biopsy, all indicating primary axonal
involvement.
TABLE 5-2 Charcot-Marie-Tooth Disease Axonal Neuropathy (A Through Z) and

Associated Phenotypes
Genea Inheritance Pattern Nomenclature Overlapping OMIM Phenotypes
MFN2 CMT2A (609260), AD, AR CMT-Ax-AD-MFN2 HMSN VIA (601152), AD

CMT-Ax-AR-MFN2
RAB7A1 CMT2B (600882), AD CMT-Ax-AD-RAB7A None reported
LMNA CMT2B1 (605588), AR CMT-Ax-AR-LMNA Cardiomyopathy, dilated, 1A (115200), AD; Emery-Dreifuss

muscular dystrophy2 (181350), AD; lipodystrophy type 2
(151660), AD
MED25 CMT2B2 (605589), AR CMT-Ax-AR-MED25 Basel-Vanagaite-Smirin-Yosef syndrome (616449), AR
TRPV4 CMT2C (606071), AD CMT-Ax-AD-TRPV4 Brachyolmia 3 (113500), AD; digital arthropathy-

brachydactyly (606835), AD; metatropic dysplasia
(156530), AD; scapuloperoneal spinal muscular
atrophy (181405), AD; spinal muscular atrophy, distal,
congenital nonprogressive (600175), AD;
spondylometaphyseal dysplasia, Kozlowski (184252), AD
NEFH CMT2CC (616924), AD CMT-Ax-AD-NEFH None reported
GARS1 CMT2D (601472), AD CMT-Ax-AD-GARS1 Neuropathy, distal hereditary motor, 5A (600794), AD
ATP1A1 CMT2DD (618036), AD CMT-Ax-AD-ATP1A1 Hypomagnesemia, seizures, and mental retardation 2

(618314), AD
NEFL CMT2E (607684), AD CMT-Ax-AD-NEFL CMT1F (607734) AR, AD
MPV17 CMT2EE (618400), AR CMT-Ax-AR-MPV17 Mitochondrial DNA depletion syndrome 6 (256810), AR
HSPB1 CMT2F (606595), AD CMT-Ax-AD-HSPB1 Neuropathy, distal hereditary motor, 2B (608634), AD
MPZ CMT2I (607677), AD CMT-Ax-In-AD-MPZ CMT1B (118200), AD; CMT intermediate D (607791), AD;
hypomyelinating (605253) AR, AD; Roussy-Levy syndrome
(180800), AD
MPZ CMT2J (607763), AD CMT-Ax-AD-MPZ CMT2 with hearing loss and pupillary abnormalities
GDAP1 CMT2K (607831), AD, AR CMT-Ax-AD-GDAP1, CMT4A (214400), AR; CMT, axonal, with vocal cord paresis
(607706) AR; CMT, intermediate type A, (608340), AR
CMT-Ax-AR-GDAP1
HSPB8 CMT2L (608673), AD CMT-Ax-AD-HSPB8 Neuropathy, distal hereditary motor 2A (15859), AD
1232 OCTOBER 2020

It is difficult to distinguish CMT2 from CMT1 based on history and
examination alone. Nerve conduction studies and genetic testing are required.
Motor nerve conduction velocities are generally greater than 38 m/s in CMT2.
The age of onset is usually later than in CMT1, often in the second or third decade
of life. However, CMT2 may present before 5 years of age with a more severe
phenotype.26 More than 30 subtypes and 33 causal genes have been identified in
CMT2 (TABLE 5-2), and 10 genes are linked to intermediate types (those with
Genea Inheritance Pattern Nomenclature Overlapping OMIM Phenotypes
DNM2 CMT2M (606482), AD CMT-Ax-In-AD-DNM2 CMTDIB (606482), AD; centronuclear myopathy 1, (160150),
AD; lethal congenital contracture syndrome 5 (615368), AR
AARS1 CMT2N (613287), AD CMT-Ax-AD-AARS1 Epileptic encephalopathy, early infantile, 29 (616339), AR
DYNC1H1 CMT2O (614228), AD CMT-Ax-AD-DYNC1H1 Spinal muscular atrophy, lower extremity-predominant 1

(158600), AD
LRSAM1 CMT2P (614436), AD, AR CMT-Ax-AD-LRSAM1 The original family was reported as CMT2G
CMT-Ax-AR-LRSAM1
DHTKD1 CMT2Q (615025), AD CMT-Ax-AD-DHTKD1 2-Aminoadipic 2-oxoadipic aciduria (204750), AR
TRIM2 CMT2R (615490), AR CMT-Ax-AR-TRIM2 Severe early-onset axonal neuropathy phenotype
IGHMBP2 CMT2S (616155), AR CMT-Ax-AD-IGHMBP2 Neuronopathy, distal hereditary motor, type VI (604320),
AR
MME CMT2T (617017), AD, AR CMT-Ax-AD-MME Spinocerebellar ataxia 43 (617018), AD
MARS1 CMT2U (616280), AD CMT-Ax-AD-MARS1 Interstitial lung and liver disease (615486), AR
NAGLU CMT2V (616491), AD CMT-Ax-AD-NAGLU Mucopolysaccharidosis IIIB (Sanfilippo B) (252920), AR
HARS1 CMT2W (616625), AD CMT-Ax-AD-HARS1 Usher syndrome 3B (614504), AR
SPG11 CMT2X (616668), AR CMT-Ax-AR-SPG11 Amyotrophic lateral sclerosis 5, juvenile (602099), AR;
spastic paraplegia 11 (604360), AR
VCP CMT2Y (616687), AD CMT-Ax-AD-VCP Amyotrophic lateral sclerosis 14, with or without
frontotemporal dementia (613954), AD; inclusion body
myopathy with early-onset Paget disease and
frontotemporal dementia 1 (167320), AD
MORC2 CMT2Z (616688), AD CMT-Ax-AD-MORC2 None reported
AD = autosomal dominant; AR = autosomal recessive; Ax = axonal; CMT = Charcot-Marie-Tooth disease; CMTDI = Charcot-Marie-Tooth disease
dominant intermediate; DNA = deoxyribonucleic acid; In = intermediate; OMIM = Online Mendelian Inheritance in Man.
a
Additional CMT2 genes without alphabet designation: DCAF8 (610100, AD, with giant axons), HINT1 (137200, AR, with neuromyotonia), MCM3AP
(618124, AR), PDXK (618511, AR, HMSN6C), SORD (618912, AR, sorbitol dehydrogenase deficiency).

nerve conduction velocities in an intermediate range) (TABLE 5-3). CMT2A is the

most common form and accounts for approximately 15% to 20% of CMT cases; it
is caused by mutations in the mitofusin 2 gene (MFN2). MFN2 is a membrane
protein that plays a central role in mitochondrial fusion.27 MFN deficiency
reduces mitochondrial mobility and leads to insufficient axonal transport of
mitochondria.28 Additional clinical features of CMT2A include optic atrophy,
hearing loss, vocal cord paralysis, and diaphragmatic weakness.
During the past decade, gene discovery has been accelerating, propelled by
next-generation technology.29 Despite this, the majority of patients with axonal
neuropathy showing classic CMT phenotypes do not have an identifiable
mutation. These patients tend to have an older age of onset, and increasing
evidence suggests that multiple variants of unclear significance in different genes
may account for “idiopathic neuropathy” or complex neuropathy phenotypes.30 It
is extremely challenging to determine the subtype of CMT2 based on clinical
presentation alone. Some specific signs and symptoms are associated with specific
genes. For example, CMT2C-TRPV4 causes vocal cord paralysis, CMT2B-RAB7A
is associated with prominent severe sensory loss with foot ulceration and
mutilation, and CMT2D-GARS1 causes prominent distal upper extremity
weakness. However, depending on the disease course, these signs may not be
clearly present at the time of examination. Furthermore, as more patients undergo
TABLE 5-3 Charcot-Marie-Tooth Disease Intermediate Neuropathy and Associated

Phenotypes
DNM2 CMTDIB (606482), AD CMT-In-AD-DNM2 CMT2I (607677), AD; centronuclear myopathy 1, (160150),
AD; lethal congenital contracture syndrome 5 (615368), AR
YARS1 CMTDIC (608323), AD CMT-In-AD-YARS1 None reported
MPZ CMTDID (607791), AD CMT-In-AD-MPZ CMT1B (118200), AD; CMT intermediate D (607791), AD;
hypomyelinating (605253) AR, AD; Roussy-Levy syndrome
(180800), AD
INF2 CMTDIE (614455), AD CMT-In-AD-INF2 Glomerulosclerosis, focal segmental, 5 (613237), AD
GNB4 CMTDIF (615185), AD CMT-In-AD-GNB4 None reported
NEFL CMTDIG (617882), AD CMT-In-AD-NEFL CMT1F (607734) AD, AR; CMT2E (607684), AD
GDAP1 CMTRIA (608340), AR CMT-In-AR-GDAP1 CMT4A (214400), AR; CMT2K (607831), AD, AR; CMT, axonal,
with vocal cord paresis (607706) AR; CMT, intermediate
type A, (608340), AR
KARS1 CMTRIB (613641), AR CMT-In-AR-KARS1 Deafness, type 89 (613916), AR
PLEKHG5 CMTRIC (615376), AR CMT-In-AR-PLEKHG5 Spinal muscular atrophy, distal, type 4 (611067), AR
COX6A1 CMTRID (616039), AR CMT-In-AR-COX6A1 None reported
AD = autosomal dominant; AR = autosomal recessive; CMT = Charcot-Marie-Tooth disease; DI = autosomal dominant intermediate; In = intermediate;
OMIM = Online Mendelian Inheritance in Man; RI = autosomal recessive intermediate.
1234 OCTOBER 2020

genetic testing, the clinical spectrum associated with each CMT mutation is KEY POINTS
expanding, with significant phenotypic variability and overlap among the many
● PMP22 duplications
subtypes of CMT2. account for approximately
70% of cases of primary
AUTOSOMAL RECESSIVE CMT NEUROPATHIES demyelinating neuropathy.
Autosomal recessive CMT is rare, comprising less than 10% of all cases. Recessive
● Mutations of MFN2 are
CMT is more prevalent in countries that have a high percentage of
the most common known
consanguineous marriages, where autosomal recessive neuropathy may account cause of primary axonal
for 30% to 50% of all CMT cases.31 In Western countries, patients with autosomal CMT.
recessive CMT often appear as isolated cases. Recessive CMT forms can be
demyelinating, axonal, or intermediate. Congenital amyelinating neuropathy, ● Not all patients with
inherited demyelinating
congenital hypomyelinating neuropathy, and recessive Déjérine-Sottas neuropathies have CMT;
neuropathy are included in this category. Patients with recessive CMT are some may have disorders
characterized by early onset, usually before the age of 3 years, and experience such as mitochondrial
rapid clinical progression that results in severe neuropathy, delayed motor neurogastrointestinal
encephalomyopathy or
milestones, and more marked distal limb deformities. The atrophy and weakness metachromatic
may progress to proximal limbs, especially the lower limbs, resulting in loss of leukodystrophy.
ambulation by the third decade of life in many patients. The neuropathies also
tend to be phenotypically complex, with more bulbar weakness and respiratory
involvement than dominant forms.
Molecular diagnosis in autosomal recessive CMT is challenging because of the
low mutation frequency and high genetic heterogeneity. The combination of
clinical characteristics and confirmed parental consanguinity are helpful to
identify a recessive genetic cause. Eight causal genes have been identified in
recessive CMT2 forms (TABLE 5-2), and 12 causal genes have been identified in
demyelinating forms (CMT4) (TABLE 5-4). The most severe CMT4 forms are
related to the myotubularin disorders (MTMR1 and SBF2) and are characterized
by prominent myelin redundancy with outfoldings and infoldings.
Demyelinating CMT4 often presents with severe secondary axonal loss; thus,
neurophysiologic examination may not be able to accurately measure motor
nerve conduction velocities, and blink R1 latency should be considered to
establish primary demyelination. Some CMT4 cases also present with vocal cord
paresis; bulbar, facial, and diaphragmatic weakness; and sensorineural deafness.
CMT4A-GDAP1 is one of the more common forms among this overall rare
group of neuropathies. Interestingly, GDAP1 mutations can also cause a recessive
axonal form (CMT2K), intermediate recessive CMT, and dominant CMT.
Patients with recessive GDAP1 mutations have reduced mitochondrial fission
activity, whereas patients with dominant GDAP1 mutations have impaired
mitochondrial fusion.32 Similar to MFN2, GDAP1 is a mitochondrial membrane
protein expressed in both Schwann cells and neurons as well as in various regions
of the central nervous system.
It is important to recognize that not all recessively inherited demyelinating
disorders are CMT. For example, mutations in TYMP (in mitochondrial
neurogastrointestinal encephalomyopathy [MNGIE]) and ARSA (in
metachromatic leukodystrophy) cause a demyelinating neuropathy that may be
the first manifestation of the disease.
X-LINKED CMT NEUROPATHIES

CMTX is the second most common form of HMSN, accounting for
approximately 10% to 15% all CMT cases. The majority of patients with CMTX

(approximately 90%) have mutations in GJB1 and are designated CMTX1.

Linkage studies have identified additional loci for X-linked CMTX2 through
CMTX5 (TABLE 5-5), but only the causal gene (PRPS1) for CMTX5 (Arts
syndrome) was recently identified. CMTX1 also affects females (ie, is X-linked
dominant), although males tend to be much more severely affected than females.
Patients with CMTX1-GJB1 present with progressive muscle atrophy and
weakness, with frequent falls in adolescence or early adulthood, areflexia,
sensory loss, and variable central nervous system involvement. Affected females
usually have a later onset or may even be asymptomatic despite mildly slowed
nerve conduction velocities. Nerve conduction studies usually show intermediate
nerve conduction velocities, mildly prolonged distal motor and F-wave latencies,
and distal axonal loss.
GJB1 encodes the gap junction protein connexin 32 (Cx32). Cx32 is expressed
in Schwann cells and oligodendrocytes and forms gap junctions in noncompact
myelin at the paranodal region and at the Schmidt-Lantermann incisures, playing
an important role in the homeostasis of myelinated axons. Mutant Cx32 fails to
form functional gap junctions. Males have lower conduction amplitudes in upper
TABLE 5-4 Charcot-Marie-Tooth Disease Autosomal Recessive Demyelinating

Neuropathy and Associated Phenotypes
GDAP1 CMT4A (214400), AR CMT-De-AR-GDAP1 CMT2K (607831), AR, AD; CMT, axonal, with vocal cord
paresis (607706) AR; CMT, intermediate, A (608340), AR
MTMR2 CMT4B1 (601382), AR CMT-De- AR-MTMR2 None reported
SBF2 CMT4B2 (604563), AR CMT-De-AR-SBF2 None reported
SBF1 CMT4B3 (615284), AR CMT-De-AR-SBF1 None reported
SH3TC2 CMT4C (601596), AR CMT-De-AR-SH3TC2 Mononeuropathy of the median nerve (613353), AD
NDRG1 CMT4D (601455), AR CMT-De-AR-NDRG1 None reported
EGR2 CMT4E (605253) AR, AD CMT-De-AR-EGR2 CMT1D (607678), AD; Déjérine-Sottas disease (145900), AD, AR
PRX CMT4F (614895), AR CMT-De-AR-PRX Déjérine-Sottas disease (145900), AR, AD
HK1 CMT4G (605285), AR CMT-Ax-AR-HK1 Neuropathy, hereditary motor and sensory, Russe type
(605285), AR; hemolytic anemia due to hexokinase deficiency
(235700), AR; retinitis pigmentosa 79, (617460), AD
FGD4 CMT4H (609311), AR CMT-De-AR-FGD4 None reported
FIG4 CMT4J (611228), AR CMT-De-AR-FIG4 Amyotrophic lateral sclerosis 11 (612577), AD; polymicrogyria,
bilateral temporooccipital (612691), AR; Yunis-Varon
syndrome (216340), AR
SURF1 CMT4K (616684), AR CMT-De-SURF1 Leigh syndrome, COX IV deficiency (256000), AR, mitochondrial
AD = autosomal dominant; AR = autosomal recessive; Ax = axonal; CMT = Charcot-Marie-Tooth disease; De = demyelinating; OMIM = Online
Mendelian Inheritance in Man.
1236 OCTOBER 2020

limb nerves. Although not required for diagnosis, nerve biopsy shows less
prominent onion bulbs (ie, rudimentary onion bulbs) compared to the large
onion bulbs seen in CMT1. It is likely that gap junction dysfunction causes
electrophysiologic conduction abnormalities at the paranodal level and
alterations of axonal Schwann cell interactions.
HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES

HSAN predominantly affects the sensory and autonomic nervous systems.
Overall, patients with HSAN have greater morbidity and mortality than those
with CMT. The characteristics of HSAN include progressive degeneration of
sensory and autonomic neurons, profound distal sensory loss, acral mutilation,
and variable autonomic and motor disturbances. To date, 15 genes have been
identified among eight types of HSAN (TABLE 5-6), but the genetic cause still
remains unresolved in approximately 70% of patients with HSAN. In contrast to
CMT/HMSN, in which large fiber sensory loss is predominant, patients with
HSAN have prominent small fiber sensory loss. Quantitative sensory testing
provides a diagnostic tool for measuring the small fiber sensory function of A
delta and C fibers, which is not possible by conventional electrodiagnostic
examination. Autonomic testing can be used to assess postganglionic small nerve
fiber function and define the specific sensory fiber involvement. In contrast to
CMT, all genetic categories of HSAN have measurable defects in sudomotor,
cardiovagal, or adrenergic function on autonomic testing.
HSAN1, which is dominantly inherited, is the most common form. Patients
with HSAN1 typically have lancinating leg pains, early-onset insensate foot
ulcers, and variable ankle and toe dorsiflexion weakness with large A-α fiber loss.
Nerve biopsies among these patients show pan–sensory fiber loss (A-α, C, and
Charcot-Marie-Tooth Disease X-linked Neuropathy and Associated TABLE 5-5

Phenotypes
CMTX Nomenclature
GJB1 CMTX1 (302800), XLD CMT-In-XLD-GJB1 None reported
AIFM1 CMTX4 (310490), XLR CMT-Ax-XLR-AIFM1 Combined oxidative phosphorylation deficiency 6 (300816),
XLR; Cowchock syndrome (310490), XLR; deafness, X-linked
5 (300614), XLR
PRPS1 CMTX5 (311070), XLR CMT-Ax-XLR-PRPS1 Arts syndrome (301835), XLR; deafness, X-linked 1 (304500),
XLR; gout, phosphoribosylpyrophosphate synthetase
I–related (300661), XLR; phosphoribosylpyrophosphate
synthetase superactivity (300661), XLR
PDK3 CMTX6, (300905), XLD CMT-Ax-XLD-PDK3 None reported
ATP7A Distal SMA3 (300489), XLR SMA3-Ax-XLR-ATP7A Menkes disease (309400), XLR; occipital horn syndrome
(304150), XLR
Ax = axonal; CMT = Charcot-Marie-Tooth disease; IN = intermediate; OMIM = Online Mendelian Inheritance in Man; XLD = X-linked dominant;
XLR = X-linked recessive.

A-δ). Painless ulcerations leading to amputation of the limb are a frequent

complication of HSAN1.
HSAN2 through HSAN6 and HSAN8 have autosomal recessive inheritance
and are usually seen in consanguineous families. HSAN2 often manifests in
infancy with distal numbness and progressive loss of pain, temperature, and
touch sensation and loss of tendon reflexes, but autonomic complications are not
a prominent feature. HSAN2D, caused by mutations in the SCN9A gene that
encodes the voltage-gated sodium channel Nav1.7, causes congenital insensitivity
to pain. Mutations in this gene are dominantly inherited and may also cause
familial erythromelalgia, a condition characterized by distal severe burning
TABLE 5-6 Hereditary Sensory and Autonomic Neuropathy and Associated

Phenotypes
SPTLC1 HSAN1A (162400), AD HSAN-Ax-AD-SPTLC1 None reported
SPTLC2 HSAN1C (613640), AD HSAN-Ax-AD-SPTLC2 None reported
ATL1 HSAN1D (613708), AD HSAN-Ax-AD-ATL1 Spastic paraplegia 3A (182600), AD
DNMT1 HSAN1E (614116), AD HSAN-Ax-AD-DNMT1 Cerebellar ataxia, deafness, and narcolepsy (604121), AD
ATL3 HSAN1F (615632), AD HSAN-Ax-AD-ATL3 None reported
WNK1 HSAN2A (201300), AR HSAN-Ax-AR-WNK1 Pseudohypoaldosteronism, type IIC (614492), AD
RETREG1 HSAN2B (613115), AR HSAN-Ax-AR-RETREG1 None reported

(FAM134B)
KIF1A HSAN2C (614213), AR HSAN-Ax-AR-KIF1A Spastic paraplegia 30 (610357), AR
SCN9A HSAN2D (243000), AR HSAN-Ax-AR- SCN9A Epilepsy, generalized, with febrile seizures plus, type 7
(613863), AD; erythermalgia, primary (133020), AD;
febrile seizures, familial, 3B (613863), AD; insensitivity
to pain, congenital (243000), AR; paroxysmal extreme
pain disorder (167400), AD; small fiber neuropathy
(133020), AD
ELP1 HSAN3 (223900), AR HSAN-Ax-AR-ELP1 Also known as familial dysautonomia or Riley-Day

(IKBKAP) syndrome
NTRK1 HSAN4 (256800), AR HSAN-Ax-AR-NTRK1 Also known as insensitivity to pain, congenital, with
anhidrosis; medullary thyroid carcinoma, familial
(155240), AD
NGF HSAN5 (608654), AR HSAN-Ax-AR-NGF None reported
DST HSAN6 (614653), AR HSAN-Ax-AR-DST Epidermolysis bullosa simplex (615425), AR
SCN11A HSAN7 (615548), AD HSAN-Ax-AD-SCN11A Episodic pain syndrome, familial, 3, (615552), AD
PRDM12 HSAN8 (616488), AR HSAN-Ax-AR-PRDM12 None reported
AD = autosomal dominant; AR = autosomal recessive; Ax = axonal; CMT = Charcot-Marie-Tooth disease; De = demyelinating; In = intermediate;
OMIM = Online Mendelian Inheritance in Man.
1238 OCTOBER 2020

neuropathic pain associated with erythema, which is transiently improved by KEY POINTS
cooling. HSAN3-ELP1, also called familial dysautonomia or Riley-Day syndrome,
● Absence of male-to-male
occurs almost solely in individuals of eastern European Jewish ethnicity. HSAN3 transmission and females
manifests at birth and causes progressive prominent small fiber sensory loss, being more mildly affected
widespread autonomic disturbances, hyperhidrosis, and gastrointestinal than males within a family
dysfunction.33 Patients with HSAN4-NTRK1 typically present with absence of suggests CMTX1-GJB1, the
second most common form
responses to painful stimuli, decreased or absent sweating, recurrent episodes of
of CMT.
fever, and intellectual disability; nerve biopsies show a complete absence of
nonmyelinated fibers and loss of innervation of eccrine sweat glands by ● Patients with hereditary
sympathetic neurons.34 HSAN5-NGF has phenotypes similar to HSAN4, with sensory autonomic
severe reduction of nonmyelinated nerves and selective loss of myelinated neuropathy commonly have
pain, and some forms also
small-diameter fibers,35 but patients usually do not have intellectual disability. have gastrointestinal
HSAN6-DST is characterized by neonatal hypotonia, respiratory and feeding dysmotility, insensate
difficulties, severe autonomic abnormalities, lack of psychomotor development, injuries with amputations,
and mortality.36 and mortality from
respiratory and feeding
difficulties.
HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES
HNPP is dominantly inherited and results in recurrent compression or ● Patients with hereditary
entrapment neuropathies, with a superimposed length-dependent sensory- neuropathy with liability to
pressure palsies need to be
predominant neuropathy with prolonged motor distal latencies and slowed
recognized to avoid
sensory conductions.37 The genetic cause in the majority of patients with HNPP unnecessary decompressive
(80% to 90%) is a 1.5 Mb deletion of chromosome 17p11.2 encompassing the surgeries at points of
PMP22 gene region (the same gene responsible for CMT1A). The remaining 10% compression.
to 20% have microinsertions, microdeletions, and point mutations in PMP22,
leading to frameshift and nonsense mutations; therefore, it is important to
conduct both large deletion and sequencing analyses in patients who are affected.
HNPP is less common than CMT1A, but its exact prevalence is unknown. It is
estimated at 2 per 100,000 to 5 per 100,000 persons.38 The first attack generally
occurs in the second or third decade, although the age range extends from 2 to
70 years. Nerve biopsy of patients with HNPP shows focal thickenings of myelin
sheath, the so-called tomacula, which differ from the classic pathologic finding of
onion bulb formation in CMT1A. Attacks of usually painless focal weakness and
sensory loss recover with time. Although complete recovery is not typical, the
remaining symptoms improve. Studies show an inverse correlation between age
of onset and frequency of relapses, suggesting a poorer long-term prognosis for
those with earlier onsets.39–41 It is important to recognize this phenotype to avoid
unnecessary nerve decompressions (eg, wrist, elbow, knee), which are not
routinely beneficial. Patients typically also have distal symmetric polyneuropathy.
HEREDITARY BRACHIAL PLEXUS NEUROPATHY

HBPN, also known as hereditary neuralgic amyotrophy, is an autosomal
dominant recurrent painful neuropathy exhibiting incomplete penetrance.42
Patients have recurring attacks of acute, severe, debilitating shoulder and arm
pain before the age of 30 years. Early muscle atrophy is out of proportion to the
extent of nerve injury. Attacks involve the brachial plexus or its resultant nerves,
but in approximately 10% of cases, attacks involve the lumbosacral plexus, lower
cranial nerves, and phrenic nerves. Weakness typically begins 1 week after the
onset of pain. Pain is severe, and patients frequently present to the emergency
department. Patients are often unable to find a comfortable position and may
pace, and they frequently feel worse at night. Most patients gradually recover

TABLE 5-7 Distal Hereditary Motor Neuropathy and Associated Phenotypesa
Current Nomenclature
HSPB8 dHMN2A (158590), AD dHMN-Ax-AD-HSPB8 CMT2L (608673), AD
HSPB1 dHMN2B (608634), AD dHMN-Ax-AD-HSPB1 CMT2F (606595), AD
HSPB3 dHMN2C (613376), AD dHMN-Ax-AD-HSPB3 None reported
FBXO38 dHMN2D (615575), AD dHMN-Ax-AD-FBXO38 None reported
BSCL2 dHMN5A (600794), AD dHMN-Ax-AD-BSCL2 Encephalopathy, progressive, with or without

lipodystrophy (615924), AR; lipodystrophy, congenital
generalized, type 2 (269700), AR; silver spastic
paraplegia syndrome, (270685), AD
GARS1 dHMN5A (600794), AD dHMN-Ax-AD-GARS1 CMT2D (601472), AD
REEP1 dHMN5B (614751), AD dHMN-Ax-AD-REEP1 None reported
IGHMBP2 dHMN6 (604320), AR dHMN-Ax-AR-IGHMBP2 CMT2S (616155), AR
SLC5A7 dHMN7A (158580), AD dHMN-Ax-AD-SLC5A7 Myasthenic syndrome, congenital, 20, presynaptic

(617143), AR
DCTN1 dHMN7B (607641), AD dHMN-Ax-AD-DCTN1 Perry syndrome (168605), AD
SETX dHMN (also known as ALS4), dHMN-Ax-AD-SETX ALS4, juvenile (602433), AD; spinocerebellar ataxia
AD type 1 (606002), AR
TRPV4 dHMN8 or distal SMA (600175), dHMN8-Ax-AD-TRPV4 CMT2C (606071), AD; brachyolmia 3 (113500), AD; digital
AD arthropathy-brachydactyly (606835), AD; metatropic
dysplasia (156530), AD; parastremmatic dwarfism
(168400), AD; spondyloepiphyseal dysplasia,
Maroteaux (184095), AD; scapuloperoneal spinal
muscular atrophy (181405), AD; spondylometaphyseal
dysplasia, Kozlowski (184252), AD
WARS1 dHMN9 (617721), AD dHMN8-Ax-AD-WARS1 None reported
DYNC1H1 Distal SMA1 (158600), AD dSMA-Ax-AD-DYNC1H1 CMT2O (614228), AD
BICD2 Distal SMA2 dSMA2-Ax-AD-BICD2 None reported

(615290), AD
SIGMAR1 Distal SMA2 (605726), AR dSMA2-Ax-AR- SIGMAR1 Amyotrophic lateral sclerosis 16, juvenile (614373), AR
ATP7A Distal SMA3 (300489), XLR dSMA3-Ax-XLR-ATP7A Menkes disease (309400), XLR; Occipital horn
syndrome (304150), XLR
PLEKHG5 Distal SMA4 (611067), AR dSMA-Ax-AR-PLEKHG5 CMTRIC (615376), AR
DNAJB2 Distal SMA 5 (604139), AR dSMA-Ax-AR-DNAJB2 None reported
AD = autosomal dominant; AR = autosomal recessive; Ax = axonal; CMT = Charcot-Marie-Tooth disease; De = demyelinating; In = intermediate;
OMIM = Online Mendelian Inheritance in Man.
a
Distal spinal muscular atrophies share similar phenotypes with distal hereditary motor neuropathy.
1240 OCTOBER 2020

from pain, but motor recovery is often slow and incomplete, and some patients KEY POINT
are left with residual disabilities. Causal mutations or duplication of the SEPTIN9
● Family history, recurrent
gene on chromosome 17q25.3 have been linked to the susceptibility of developing episodes, and, possibly,
episodes of neuralgic amyotrophy in approximately half of patients with younger age of onset
HBPN.43,44 The pathogenic mechanisms of SEPTIN9 mutations are still unclear. distinguish hereditary
Patients with idiopathic neuralgic amyotrophy (Parsonage-Turner syndrome) brachial plexus neuropathy
from idiopathic neuralgic
present with the same clinical features as in HBPN, and no difference is seen in
amyotrophy (Parsonage-
the features of individual attacks. Family history, recurrent attacks, and, Turner syndrome).
possibly, younger age of onset help distinguish HBPN from idiopathic neuralgic
amyotrophy. SEPTIN9 mutation is often not found even for those with a clear
family history of HBPN, suggesting additional genetic causes remain to be
discovered.45 High-dose IV steroids may help reduce pain but do not stop
neurologic deficits from progressing. Anecdotally, prophylactic steroid
treatment may be helpful for patients with HBPN at the time of surgery and child
delivery as they have high likelihood of experiencing attacks at these times.46
DISTAL HEREDITARY MOTOR NEUROPATHY

dHMN is characterized by slowly progressive, symmetric, distal lower motor
neuron weakness with reduced or absent reflexes. Many forms of dHMN also
present with upper motor neuron features. Nerve conduction studies usually
show reduced motor amplitudes, suggesting chronic distal-predominant
denervation. A total of 19 causative genes have been described in dHMN or distal
spinal muscular atrophy (SMA), two disorders with very similar phenotypes
(TABLE 5-7). The majority of patients with dHMN (approximately 80%) still do
not have a molecular diagnosis. EMG is helpful to differentiate dHMN from distal
motor neuron disease and distal myopathy. Patients with distal motor neuron
disease or distal myopathy often have normal or slightly reduced motor nerve
conduction amplitudes with either markedly large motor units (motor neuron
disease) or small complex units (myopathy) on needle EMG.
By definition, sensory involvement is absent, although dHMN mutations can
have minor sensory involvements. Phenotypic overlap exists between dHMN
and CMT2, and mutations in some genes may cause either. dHMN2 is caused by
mutations in HSPB1 and HSPB8, and patients present during childhood or
adulthood. If sensory involvement is present, the disease is termed CMT2F (with
HSPB1 mutations) or CMT2L (with HSPB8 mutations). dHMN5 is characterized
by upper limb onset and caused by mutations in GARS1. If sensory involvement
is found, the disease is termed CMT2D. dHMN also shares similar phenotypes
with distal SMA and juvenile forms of amyotrophic lateral sclerosis, all of which
contributed to genetic diagnosis complexity.
COMPLEX HEREDITARY NEUROPATHIES

Peripheral neuropathy is present in many complex multisystem disorders that
affect both the central and peripheral nervous systems.47 In these complex
syndromes, peripheral neuropathy can either be one of the key symptoms or a
minor symptom that may be overshadowed by other manifestations.
Neuropathy may emerge later in the disease course or present as one of the
initial symptoms. Next-generation comprehensive panel sequencing can be a
good option for genetic diagnosis of these complex syndromic disorders, and,
because many of these conditions are treatable, inclusion of these genes in
CMT testing is favored.

Familial Amyloid Polyneuropathy

Familial amyloid polyneuropathies are a group of autosomal dominant
multisystem disorders causing tissue accumulation of fibril aggregates of
mutated precursor proteins of amyloid, including transthyretin (TTR),
apolipoprotein A1 (APOA1), and gelsolin (GSN). The most common cause is
mutations in TTR. Wild-type TTR can also be amyloidogenic, and it is one of the
most common causes of heart failure in older people, frequently with only very
mild neuropathy.48 Hereditary amyloidosis from TTR mutations (hereditary
transthyretin amyloidosis) typically manifests with length-dependent small fiber
sensorimotor polyneuropathy with loss of temperature and pain sensation,
life-threatening autonomic dysfunction with heart failure and cardiac
arrhythmias, and, sometimes, nephrotic disease (CASE 5-2). The clinical course,
penetrance, and age at onset vary significantly, even among patients with the
same mutation. The first identified TTR mutation (Val30Met) is still the most
common, but more than 100 amyloidogenic point mutations have been
identified. In people of Northern European descent, hereditary amyloidosis
from the Val30Met mutation typically presents late in the sixth decade of life,
whereas in Portuguese patients, it typically presents by the third decade. Oral
CASE 5-2 A 55-year-old man with diabetes with nephropathy without retinopathy
presented with insidious-onset ankle weakness and sensory loss with
foot ulcers over 2 years. He denied pain but did have foot paresthesia.
The patient believed his father developed cardiomyopathy in his late
sixties, and he died in his seventies.
On examination, he was unable to feel heat, pain, and light touch and
had foot and ankle weakness with an ulcer on his great toe. Orthostatic
blood pressure checks demonstrated a 20 mm Hg drop in systolic blood
pressure on standing.
The patient underwent focused gene panel testing of more than 20
genes associated with hereditary sensory and autonomic neuropathy and
mimic disorders, including TTR. He was found to have TTR mutation
Val122Ile and was started on patisiran, an RNA interference medication
designed to knock down mutated TTR and wild-type gene expression.
COMMENT Hereditary amyloid neuropathy from TTR mutations (hereditary

transthyretin amyloidosis) has a broad spectrum of phenotypes
(autonomic, motor, and sensory), some with cardiomyopathy and nephrotic
components more than others. The physicians who initially evaluated this
patient did not consider a genetic cause because of his diabetes diagnosis.
Diabetic neuropathy rarely causes weakness, and the presence of severe
neuropathy and nephropathy without retinopathy are red flags that
should prompt a thorough evaluation for an alternative explanation. The
presence of an autonomic neuropathy is another diagnostic clue. Up to 2%
of African Americans carry the Val122Ile TTR mutation (as seen in this
patient), which, for many, will only manifest with heart failure. It is likely that
his underlying diabetes contributed to worse neurologic involvement.
1242 OCTOBER 2020

administration of tafamidis meglumine, which prevents misfolding and deposition KEY POINTS
of mutated TTR, has been approved in European countries for neuropathy and
● Two drugs that knock
was recently approved in the United States for TTR cardiomyopathy. Two small down RNA expression of
oligonucleotide-based gene therapies, one small interfering RNA (patisiran) mutant and wild-type TTR
and one antisense (inotersen), are now approved by the US Food and Drug (patisiran and inotersen)
Administration (FDA) and are bringing hope to patients with what was previously have been recently
approved for hereditary
a uniformly fatal disorder.49 The gene knockdown has largely been possible
transthyretin amyloidosis
because the circulating function to carry vitamin A and thyroxine appears not to neuropathy.
be essential in adulthood. Liver transplantation, which has been the standard
therapy for patients with hereditary transthyretin amyloidosis, is likely to become ● Standard next-generation
less commonly used in light of these new molecular therapies and because patients sequencing cannot identify
nucleotide repeat expansion
still progress from wild-type TTR deposition following transplantation. Those mutations such as those
receiving a liver from a patient with hereditary transthyretin amyloidosis (the occurring in Friedreich
so-called domino liver transplantation) can also become affected.50 ataxia and cerebellar ataxia,
neuropathy, vestibular
areflexia syndrome
Hereditary Ataxias, Including Spinocerebellar Ataxias With Neuropathy (CANVAS).
Hereditary ataxias, including autosomal or X-linked dominant SCAs, are a large
group of genetically heterogeneous neurodegenerative disorders characterized
by slowly progressive cerebellar ataxia with nonataxia symptoms such as
oculomotor dysfunction, dysarthria, peripheral neuropathy, pyramidal and
extrapyramidal signs, and cognitive impairment. Axonal sensory neuropathy can
be a prominent presenting feature in common types (TABLE 5-8), and large fiber
sensory ataxia is typical in the most common recessive forms, such as Friedreich
ataxia (approximately 4 in 20,000 persons) and late-onset cerebellar ataxia,
neuropathy, vestibular areflexia syndrome (CANVAS, approximately 2 in
20,000 people).51 These two disorders and many other hereditary ataxias with
neuropathy are caused by repeat nucleotide expansions (trinucleotide,
tetranucleotide, pentanucleotide). These repeat expansions generally cannot be
identified by standard next-generation sequencing platforms (short read 150
base pairs); thus, developing a high-throughput method to sequence long repeat
expansions is still needed to fill the gap in genetic testing. For Friedreich
ataxia, simply looking for reduced levels of the frataxin protein is a sensitive
screening method.52
Complicated Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) encompasses a group of genetically
heterogeneous disorders that principally affect the central corticospinal tract and
dorsal columns. Patients with HSP present with progressive spasticity and
variable weakness and atrophy of the lower limbs. Compound motor action
potential (CMAP) amplitudes may be reduced in the lower extremities. HSP is
composed of a “pure” form with isolated spastic paraplegia and a “complicated”
form with other neurologic abnormalities. HSP with neuropathy is one of the
complicated HSP types, and peripheral neuropathy has been found in
approximately 15 to 20 complicated HSPs (TABLE 5-8). Given the high
phenotypic heterogeneity of HSP even within the same family, the classification
of HSP is increasingly based on genetics.
Lysosomal Storage Diseases

Lysosomal storage diseases are a group of disorders caused by mutations in
diverse lysosomal enzymes or proteins that lead to the accumulation of

undigested macromolecules within lysosomes. Several recessive disorders,

including Fabry disease, Krabbe disease, and metachromatic leukodystrophy,
have peripheral neuropathy as a major manifestation (TABLE 5-8). Fabry
disease is caused by mutations in the α-galactosidase-A gene GLA located on
the X chromosome, leading to accumulation of α-D-galactosyl moieties,
including globotriaosylceramide (Gb3) within multiple tissues. Patients
with Fabry disease (approximately 1 in 40,000 males in the population)
present with small fiber peripheral neuropathy that manifests initially with
paroxysmal burning pains in their hands and feet, often at a young age. They
may have many other clinical manifestations, including angiokeratomas (often
in a “bathing trunk” distribution), corneal and retinal defects, kidney disease,
TABLE 5-8 Examples of Complex Syndromes With Neuropathy
Causal Gene Disorder Descriptions (OMIM Phenotype Number) Neuropathy Presentation
FBLN5 Neuropathy with/without macular degeneration Demyelinating or axonal

(608895) with/without scoliosis, joint laxity, neuropathy
cutis laxa; can mimic Charcot-Marie-Tooth disease
FXN (repeat expansion) Friedreich ataxia (229300), AR Sensory predominant, axonal
RFC1 (repeat expansion) Late-onset cerebellar ataxia, sensory axonal Sensory predominant, axonal
neuropathy, vestibular areflexia syndrome
(CANVAS, 614575), AR
TTPA Ataxia with isolated vitamin E deficiency (277460), AR Sensory predominant, axonal
APTX Ataxia, early-onset, with oculomotor apraxia and Sensory predominant, axonal
hypoalbuminemia (208920), AR
SETX Spinocerebellar ataxia, AR, with axonal neuropathy Sensory predominant, axonal
(SCAN2, 606002), AR
SACS Spastic ataxia, Charlevoix-Saguenay type Sensorimotor with slowed

(SACS, 270550), AR nerve conduction velocities
SIL1 Marinesco-Sjögren syndrome (248800), AR Sensorimotor, axonal
ATM Ataxia-telangiectasia (208900), AR Sensory predominant, axonal
ATXN1, ATXN2, ATXN3, ATXN7, Spinocerebellar ataxia, AD, types 1, 2, 3, 7, 10, 12, 36; Sensory and/or motor, axonal
ATXN10, PPP2R2B, NOP56 (all repeat 14, 23, 27
expansions); PRKCG, PDYN, FGF14
SETX, VPS13D, SCYL1 Spinocerebellar ataxia, AR, types 1, 4, 21 Sensory and/or motor, axonal
KLC2 Spastic paraplegia, optic atrophy, and neuropathy Sensorimotor, axonal

(SPOAN, 609541), AR
ATL1, SPAST, ALDH18A1, KIF5A, RTN2, Spinocerebellar ataxia, AD, types 3A, 4, 9A, 10, 12, 17 Sensory and/or motor, axonal
BSCL2
SPG7, SPG11, ZFYVE26, SPART, Spinocerebellar ataxia, AR, types 7, 11, 15, 20, 26, 28, Sensory and/or motor, axonal
B4GALNT1, DDHD1, KIF1A, PNPLA6, 30, 39, 46, 55, 56
GBA2, C12ORF65, CYP2U1
1244 OCTOBER 2020

cerebrovascular and cardiovascular disease, and common gastrointestinal
disease. Death is common by the fifth decade. Because of the genetic complexity
of making the diagnosis, biochemical testing for either α-galactosidase in males
or its toxic byproduct globotriaosylsphingosine (lyso-Gb3) in females is
recommended before genetic sequencing. IV enzyme replacement with
agalsidase beta every 2 weeks has been shown beneficial.53 Recently, migalastat, a
daily administered oral chaperone therapy, was FDA approved for use in patients
with mutations that preserve the catalytic domain (approximately 50% of
patients). The small molecule binds the active domain of α-galactosidase and
“chaperones” it to lysozymes, prolonging its half-life and allowing enhanced
enzymatic activity.54
Causal Gene Disorder Descriptions (OMIM Phenotype Number) Neuropathy Presentation
CCT5 HSN with spastic paraplegia (256840), AR Severe sensory neuropathy
GBE1 Adult polyglucosan body disease (263570), AR Sensorimotor, axonal
PHYH Refsum disease (266500), AR Sensorimotor with normal or

slowed nerve conduction
velocities
ABCD1 Adrenoleukodystrophy (300100), XLR Sensorimotor, axonal
GLA Fabry disease (301500), XLR Painful sensory axonal and

small fiber neuropathy
TTR Amyloidosis, hereditary, transthyretin-related Painful sensorimotor

(105210), AD neuropathy, axonal, slowed
nerve conduction velocities
ARSA Metachromatic leukodystrophy (250100), AR Sensorimotor with normal or

velocities
GALC Krabbe disease (245200), AR Sensorimotor with normal or

velocities
ABCA1 Tangier disease (205400), AR High-density lipoprotein

deficiency, 1 (604091)
CYP27A1 Cerebrotendinous xanthomatosis (213700), AR Sensorimotor, axonal
MTTP Abetalipoproteinemia (200100), AR Sensory predominant, axonal
GAN Giant axonal neuropathy 1 (256850), AR Sensorimotor, axonal
HMBS Porphyria, acute intermittent (AIP) (176000), AR Motor predominant, axonal
AD = autosomal dominant; AR = autosomal recessive; XLR = X-linked recessive.

Mitochondrial Disorders
The extraordinary length and high energy demands of the axon heighten the
importance of proper mitochondrial function in nerves. Defects in mitochondrial
DNA maintenance and replication or defects in respiratory chain complex are
often associated with chronic axonal polyneuropathy. Multiple causal genes of
CMT are directly linked to mitochondrial dynamic function (eg, MFN2, GDAP1,
GARS1, PDK3, COX6A1). Peripheral neuropathy is a key symptom in many
complex mitochondrial disorders, such as mitochondrial neurogastrointestinal
encephalomyopathy (MNGIE) (CASE 5-3); sensory ataxic neuropathy,
dysarthria, and ophthalmoparesis (SANDO); and mitochondrial cerebellar
ataxia, renal failure, neuropathy, and encephalopathy (MCARNE) (TABLE 5-9).
When considering the mitochondrial plasmid genome (37 genes), it is important
to understand that the phenomenon of heteroplasmy may result in absence of
mutation discovery from lymphocyte blood DNA, and affected tissue sampling
may be required to identify the pathogenic mitochondrial mutation. Experience
in sequencing the mitochondrial genome in nerves is limited, but by choosing a
platform that sequences the available DNA with a high depth of coverage (>5000
times), the yield of making a genetic mitochondrial diagnosis is increased
regardless of the tissue source of DNA.55
CASE 5-3 A 14-year-old boy presented with new-onset unsteadiness and

incoordination. He had normal developmental milestones. He had a large
family, none of whom were affected by neuropathy.
On examination, he was thin but denied weight loss or gastrointestinal
symptoms. He had no muscle atrophy but had ankle weakness with
marked steppage gait and intrinsic hand muscle weakness with reduced
sensation in his distal extremities.
His nerve conductions were markedly abnormal, with ulnar motor
amplitude of 1.2 mV with forearm conduction velocity of 27 m/s
(normal >50 m/s). Blink R1 reflex was 14 milliseconds (normal
<12 milliseconds). PMP22 duplication analysis was negative, and an
expanded neuromuscular evaluation with over 200 genes was used to
identify a known pathogenic mutation in TYMP, the gene responsible for
mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
syndrome. A biochemical assay confirmed markedly elevated thymidine
and lactic acid levels. Within 1 year of the genetic diagnosis, he began
experiencing weight loss and gastrointestinal difficulty.
COMMENT Patients with MNGIE have marked demyelinating nerve conductions and
can present with neuropathy before the development of encephalopathy
and gastrointestinal difficulties. A more comprehensive gene panel
assisted in making the genetic diagnosis in this patient. Although this
patient’s mutation is a known pathogenic cause of MNGIE, use of a
biochemical confirmatory assay can help distinguish other metabolic
neuropathies in which variants of unclear significance are identified.
1246 OCTOBER 2020

UPDATED GENETIC DIAGNOSTIC APPROACHES IN INHERITED
NEUROPATHIES
The large number of causal genes in inherited neuropathy and their wide-ranging
cellular functions indicate that molecular pathways underlying inherited
neuropathy are extremely diverse, making diagnosis complicated (FIGURE 5-3).7
With over 800 entries for inherited neuropathies found on the Online
Mendelian Inheritance in Man website, choosing the best candidate gene is
challenging. This has necessitated a new approach compared to earlier
recommendations.56 Next-generation sequencing can redefine how inherited
neuropathy is diagnosed.29,57,58 The first diagnostic test for patients with
CMT1 should be testing for a PMP22 duplication. If testing is negative or if the
patient has a different form of CMT, a next-generation sequencing panel should
be considered; the ability to test larger, more comprehensive genetic panels in the
absence of PMP22 duplication presents a powerful new option (FIGURE 5-4). New
Mitochondrial Disorders With Neuropathy TABLE 5-9
Gene Gene Function Clinical Phenotype (OMIM Phenotype Number)
Neuropathy as a prominent symptom
MFN2 Mitofusin 2 CMT2A, HMSN V, HMSN VI
GDAP1 Ganglioside induced differentiation CMT2K, CMT4A

associated protein 1
MT-ATP6 MT-ATP synthase CMT2, dHMN
DHTKD1 Thiamine diphosphate-dependent 2-oxo CMT2Q

acid dehydrogenase
AIFM1 Mitochondrial FAD-dependent CMTX4

oxidoreductase
PDK3 Pyruvate dehydrogenase kinases CMTX3
Neuropathy as a key symptom
MT-ATP6 MT-ATP synthase Neuropathy, ataxia, and retinitis pigmentosa (NARP, 551500)
POLG DNA polymerase gamma Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
(SANDO, 607459); mitochondrial DNA depletion syndrome 4B
(MNGIE type, 613662)
TYMP Thymidine phosphorylase Mitochondrial DNA depletion syndrome 1 (MNGIE type, 603041)
TWNK TWINKLE mtDNA HELICASE Mitochondrial DNA depletion syndrome 7 (271245)
RRM2B Ribonucleotide reductase Mitochondrial DNA depletion syndrome 8B (MNGIE type, 612075)
SLC25A19 Mitochondrial thiamine pyrophosphate Thiamine metabolism dysfunction syndrome 4 (613710)

carrier
MT-ND5 NADH dehydrogenase subunit-5 Mitochondrial cerebellar ataxia renal failure neuropathy
encephalopathy (MCARNE)
CMT = Charcot-Marie-Tooth disease; dHMN = distal hereditary motor neuropathy; DNA = deoxyribonucleic acid; HMSN = hereditary motor and
sensory neuropathy; MNGIE = mitochondrial neurogastrointestinal encephalomyopathy; mtDNA = mitochondrial deoxyribonucleic acid.

KEY POINTS
● Enzyme replacement
therapy with recombinant
α-galactosidase was the
first available specific
treatment for Fabry disease.
Recently, migalastat, a new
drug using chaperone
therapy, was approved by
the US Food and Drug
Administration. Migalastat
is a small molecule drug that
stabilizes and facilitates
trafficking of rescuable
mutant forms of
α-galactosidase A protein,
partially restoring the
enzyme activity in
lysosomes.
● Next-generation
sequencing is simplifying
the genetic diagnosis of
inherited neuropathies.
FIGURE 5-3
Molecular targets of inherited neuropathy illustrate the diverse pathogenesis. The causal
genes for inherited neuropathies are essentially involved in every fundamental aspect of
cellular functions: Schwann cell cytoskeleton and myelin integrity (PMP22, MPZ, GJB1, SBF2),
axonal transport (KIF1A, DCTN1, HSPB1, DYNC1H1, NEFL, PRDM12), cytoskeletal stability
(HSPB1, FGD4, LMNA), endosomal vesicular transport (RAB7A, NDRG1, SH3TC2), transcription
regulation (EGR2), DNA methylation (DNMT1), protein translation (HARS1, GARS1, YARS1,
AARS1, BSCL2), divalent cation metabolism (TRPV4), unfolded protein response (VCP, HSPB1,
HSPB3, LMNA), mitochondrial dynamics (MFN2, GDAP1), endoplasmic reticulum formation
(ATL1, REEP1), membrane fusion (DNM2, SPG11, RAB7A), Ras protein signal transduction
(NTRK1, DNM2, FGD4, PLEKHG5), sphingolipid metabolism (SPTLC1, SPTLC2), Golgi body
structure (RETREG1), neurofilament organization (NEFL, NEFH), and others.
Reprinted with permission from Klein CJ, et al, Muscle and Nerve.7 © 2013 Wiley Periodicals, Inc.
1248 OCTOBER 2020

FIGURE 5-4
Algorithm for the genetic evaluation of inherited neuropathy in the era of next-generation
sequencing.
CMAP = compound muscle action potential; CMT = Charcot-Marie-Tooth disease; CMT1A = Charcot-Marie-
Tooth disease type 1A.
a
Disease-specific gene panels: expanded neuropathy (>190 genes); motor and sensory neuropathy, CMT
(>80 genes); hereditary motor neuropathy (>20 genes); hereditary sensory autonomic neuropathy
(>20 genes); metabolic neuropathies (>70 genes); mitochondrial neuropathy (>110 nuclear mitochondrial
genes, >20 mitochondrial genome genes); spastic paraplegia and neuropathy (>40 genes); hereditary
ataxia and neuropathy (>20 genes); hereditary brachial neuritis (SEPT9 duplication and point mutation analysis).
b
Includes genes responsible for inherited neuropathy, distal myopathy, distal motor neuron diseases, and
complex neuropathies (eg, hereditary transthyretin amyloidosis, Fabry-GLA).
informatics pipelines in next-generation sequencing allow duplication and

deletion identification in some laboratories previously not possible; however,
given the pretest probability of PMP22 duplications in CMT1, it is still best to
start with testing PMP22.57 Because the cost and size of next-generation
sequencing panels is no longer a major limiting factor, genes that can mimic
inherited neuropathy can also be studied through expanded neuromuscular
evaluation that includes distal myopathies and distal motor neuron or other
overlap syndromes (FIGURE 5-5 and CASE 5-4). With complex phenotypes,

KEY POINTS advancing to whole-exome

sequencing can be considered
● The accuracy of next-
generation sequencing
with appropriate genetic
testing correlates to the counseling.
depth of coverage of all Quality sequencing and
targeted genes represented analysis are essential with
in panel testing.
next-generation sequencing
● Foot and ankle surgeries because a large gene list can lead
should be reserved for to the identification of
patients for whom bracing numerous variants of unclear
for ankle stability has failed, significance. Interpretation
with tendon transfers
favored over joint fusions. requires an interdisciplinary
approach, with molecular
geneticists, clinicians,
FIGURE 5-5 bioinformatics experts,
Example phenotype-genotype overlaps between and biochemists working with
diverse inherited neuropathies and other clinicians. The quality of
neuromuscular diseases. Parentheses indicate next-generation sequencing is
genes not in the highlighted clinical classification
but with clinical overlap.
important, with a higher depth
ALS= amyotrophic lateral sclerosis; CMT= Charcot Marie of coverage (eg, how many
Tooth; DHMN= distal hereditary motor neuropathy; times any one region is
dSMA= distal spinal muscular atrophy; HMSN = hereditary
motor and sensory neuropathy; HSAN= hereditary sensory
sequenced) being linked to
autonomic neuropathy; HSP = hereditary spastic paraplegia. higher accuracy. Currently,
clinical laboratories should
confirm pathogenic findings by
Sanger sequencing, but as this technology continues to improve, this step may
not be needed in the future. Continued follow-up evaluation of variants of
unclear significance data on a yearly basis can help clarify the previously
unrecognized disease-causing nature of certain variants. Over time, the length
of variants of unclear significance lists is expected to decrease as population
reference databases continue to grow. Laboratory reports should provide
insight into the meaning of variants of unclear significance as related to
phenotypes and potential pathogenic implications. It is important to know
that ordering and interpreting next-generation sequencing require clinical
expertise to interpret the report at the patient care level to order additional
biochemical testing, confirm the pathogenicity, and conduct follow-up visits
with patients to discuss the impact of genetic diagnosis.29 Genetic counseling
before and after testing is important so patients understand the implications
of their testing.
MANAGEMENT AND SURVEILLANCE

Clinical involvement and severity are quite varied among patients with inherited
neuropathies, and tailored management is required. For some families, genetic
preimplantation counseling may be sought to select embryos without mutations,
thus ending the disease in subsequent family members.59 For CMT and dHMN,
the most common symptom is progressive weakness of the limbs, which can
have significant impact on employment and quality of life. Exercise is generally
encouraged, as studies have shown that daily endurance, stretching, and gripping
exercises help improve muscular strength in both upper and lower limbs, prevent
shortening of the Achilles tendons, and may slow the rate of progression in hand
1250 OCTOBER 2020

weakness.60,61 Various ankle-foot orthotic devices are available, and good fit is
essential for maximal benefit and reduced complications, including skin breakdown.
It is essential for patients to have long-term access to a trained orthotist. For those
with mild weakness, a lightweight (8-oz) well-fitting lace-up boot that extends at
least 6 inches above the ankle can be adequate for ankle stability. In patients with
HSAN, skin breakdown is a major issue, so vigilant daily inspection of the feet
should be emphasized to prevent early callus or ulcer formation from ill-fitting
shoes that could lead to amputations due to osteomyelitis. Even small sores need
major attention, and patients may need to stay off their feet.
Orthopedic surgery of the ankles and feet should generally be discouraged,
especially triple arthrodesis, or joint fusion. However, for patients with marked
cavovarus deformity (high arches and inward turning of the ankle) for whom
conservative orthosis and physical therapy interventions have failed, tibialis
posterior transfer and extensor hallucis longus transfer with calcaneal osteotomy
A 32-year-old man and his 26-year-old sister presented with an CASE 5-4
approximately 5-year history of gradually progressive weakness of their
ankles. Both were previously diagnosed with Charcot-Marie-Tooth
disease (CMT). Their parents and another sister were not affected. Both
patients had mild hand weakness that made it difficult to open jars.
Examination showed pes planus, an inverted champagne bottle
appearance of their legs, and ankle dorsiflexor weakness and plantar
flexor weakness and could not stand on heels or toes. They had mild
abduction weakness in intrinsic hand muscles and finger flexors. Reflexes
were normal. Sensation was reduced to light touch in the distal toes, with
normal vibration and heat pain sensation.
EMG study of the brother showed reduced motor amplitudes with
normal motor conduction velocities, and sural sensory amplitudes were
borderline normal at 6 mV. His needle EMG showed complex
long-duration motor unit potentials with both rapid and reduced
recruited motor units in clinically weak muscles. An expanded
neuromuscular genetic evaluation panel with more than 200 genes (CMT,
distal myopathy, and distal motor neuron genes) by next-generation
sequencing identified pathogenic compound heterozygote mutations in
GNE in both brother and sister, leading to the diagnosis of GNE myopathy.
The preservation of ankle reflexes and finger flexor weakness raised COMMENT
questions about the accuracy of the diagnosis of CMT. Many patients with
distal myopathy have mild sensory symptoms or signs; this should not
preclude consideration of a distal myopathy diagnosis. More than 30 genes
are associated with distal myopathy, including those with autosomal
recessive GNE. These red flags of possible distal myopathy should
encourage physicians to consider broader genetic testing. For many
patients with chronic myopathies, motor unit potentials can mimic those of
a primary neurogenic cause, further complicating diagnosis.

can be helpful.62–64 These surgeries improve ankle stability and can redistribute
weight, which is helpful in the prevention of skin ulcers and musculoskeletal
injury. For all patients with inherited neuropathy, careful monitoring of known
exacerbating factors, such as diabetes, chemotherapy, and trauma, is especially
important, as these superimposing factors can precipitate symptoms in patients
who are asymptomatic or cause an acceleration of disease progression. For
patients with systemic involvements, as in hereditary transthyretin amyloidosis
or mitochondrial disease, monitoring the heart for arrhythmia is essential as
pacemaker placement can be lifesaving. To provide the best care, the long-term
effort of a multidisciplinary team that includes a neurologist and other specialists
(eg, a genetic counselor, a physical therapist, and an otolaryngologist) is critical.
THERAPEUTIC DEVELOPMENTS
For most inherited neuropathies, current treatments remain symptomatic.
However, remarkable progress has been made in developing disease-modifying
therapies. Much of this effort has focused on CMT1A, given it is the most
common of these disorders. The therapeutic strategy for CMT1A aims to reduce
PMP22 expression. Several CMT transgenic rodent models that overexpress
PMP22 have been established to investigate different therapeutic strategies.
These mice showed typical CMT1 phenotypes, including hypomyelination and
demyelination in Schwann cells.65 Clinical trials of ascorbic acid and progesterone
antagonists using mouse models showed encouraging results, with decreased
PMP22 expression and improved neuropathy phenotypes.66 However, translating
the encouraging results from rodents to human clinical trials has not yet been
achieved,67,68 and no effective treatment for CMT1A is yet available. It was
reported that PMP22 levels actually fluctuate over time, which poses challenges
in using PMP22 dosage as a drug target.24 Recently, the level of intracellular
cyclic adenosine monophosphate-signal molecule (cAMP) has been found to
lower toxic PMP22 gene expression. A combination of baclofen, naltrexone, and
D-sorbitol (PXT3003) aimed to reduce cAMP has been investigated in a phase 2
trial,69 and a phase 3 clinical trial is ongoing.70
The recent successful application of gene replacement therapy by
adeno-associated virus 9 (AAV9) viral vectors for SMA has provided much
excitement for the therapeutic development of gene replacement therapy for
other neuromuscular diseases. Inherited neuropathies, especially recessive forms
with loss-of-function mechanisms, may be good candidates, as several viral
vectors have been shown to be efficient vehicles to deliver the wild-type gene to
replace the lost function of mutant protein. A 2016 study that used a lentiviral
vector to deliver GJB1 into adult GJB1-null mice achieved cell-specific expression
of the gene in up to 50% of Schwann cells in multiple lumbar spinal roots and
peripheral nerves.71 However, the potential off-target toxicity of the lentiviral
vector must be carefully evaluated. The AAV9 vector has been shown to be a safe
vehicle, with low off-target toxicity and strong tropism to spinal neurons. AAV9
could be an effective vector for neuropathy gene delivery, but the life span of the
AAV9 vector (episomal) in dividing cells may require repeated injections.
For autosomal dominant forms, a therapeutic strategy using RNA interference
to reduce the mutant protein with gain-of-function disease mechanisms is
making encouraging progress. This approach has been successful for hereditary
transthyretin amyloidosis, and similar mRNA knockdown approaches are
being evaluated in other inherited neuropathies.48 Antisense oligonucleotides
1252 OCTOBER 2020

targeting PMP22 mRNA to induce ribonuclease H (RNase-H)–facilitated
mRNA degradation has shown promising results in a preclinical trial study.
The level of rat PMP22 mRNA has been reduced by custom-designed antisense
oligonucleotides in the two different rodent models of CMT1A.72 However, this
approach needs careful dosage modulation as reduced PMP22 expression could
result in the PMP22 deletion phenotype of HNPP. The results of ongoing clinical
trials will provide more clarity on whether reducing PMP22 levels can improve
neuropathy symptoms. Another approach called “knock down and replace”
is also being explored. This approach combines small RNA targeting and viral
gene delivery methods to simultaneously knock down the mutated gene and
deliver a wild-type gene as the replacement. This approach holds potential for a
large number of dominantly inherited disorders. With such exciting progress
in gene therapy, many obstacles still exist, but obtaining a genetic diagnosis for
inherited neuropathy is more important than ever. It is predicted that efforts will
focus on those with devastating phenotypes and favorable risk-benefit profiles.
CONCLUSION
The phenotypic and genetic heterogeneity of inherited neuropathies has
continued to grow, blurring the lines of clinical categories. For this reason, the
gene names are emphasized in the new classifications. Next-generation
sequencing technology is simplifying the genetic testing algorithm, affording
ease in genetic diagnosis and accelerating new genetic discoveries and pathologic
understanding. Currently, for most patients with inherited neuropathy,
symptom management and genetic counseling will remain the mainstay of care
until safe, effective, and more widespread therapeutics become available.
USEFUL WEBSITE
ONLINE MENDELIAN INHERITANCE IN MAN
The Online Mendelian Inheritance in Man website
provides a comprehensive catalog of human genes
and genetic disorders.
omim.org
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2631–2642. doi:10.2106/JBJS.G.01356. with a combination of three repurposed drugs
(PXT3003) down-regulates Pmp22 over-expression
63 Lin T, Gibbons P, Mudge AJ, et al. Surgical
and improves myelination, axonal and functional
outcomes of cavovarus foot deformity in
parameters in models of CMT1A neuropathy.
children with Charcot-Marie-Tooth disease.
Orphanet J Rare Dis 2014;9:201. doi:10.1186/
Neuromuscul Disord 2019;29(6):427–436.
s13023-014-0201-x.
doi:10.1016/j.nmd.2019.04.004.
70 Attarian S, Vallat JM, Magy L, et al. An exploratory
64 Reilly MM, Pareyson D, Burns J, et al. 221st ENMC
randomised double-blind and placebo-controlled
International Workshop: Foot Surgery in
phase 2 study of a combination of baclofen,
Charcot-Marie-Tooth disease. 10-12 June 2016,
naltrexone and sorbitol (PXT3003) in patients
Naarden, The Netherlands. Neuromuscul Disord
with Charcot-Marie-Tooth disease type 1A.
2017;27(12):1138–1142. doi:10.1016/j.nmd.2017.09.005.
Orphanet J Rare Dis 2014;9:199. doi:10.1186/
65 Fledrich R, Stassart RM, Sereda MW. Murine s13023-014-0199-0.
therapeutic models for Charcot-Marie-Tooth
71 Kagiava A, Sargiannidou I, Theophilidis G, et al.
(CMT) disease. Br Med Bull 2012;102:89–113.
Intrathecal gene therapy rescues a model of
doi:10.1093/bmb/lds010.
demyelinating peripheral neuropathy. Proc Natl
66 Passage E, Norreel JC, Noack-Fraissignes P, et al. Acad Sci U S A 2016;113(17):E2421–E2429.
Ascorbic acid treatment corrects the phenotype doi:10.1073/pnas.1522202113.
of a mouse model of Charcot-Marie-Tooth
72 Zhao HT, Damle S, Ikeda-Lee K, et al. PMP22
disease. Nat Med 2004;10(4):396–401.
antisense oligonucleotides reverse
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Charcot-Marie-Tooth disease type 1A features in
67 Pareyson D, Reilly MM, Schenone A, et al. rodent models. J Clin Invest 2018;128(1):359–368.
Ascorbic acid in Charcot–Marie–Tooth disease doi:10.1172/JCI96499.
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double-blind randomised trial. Lancet Neurol 2011;
10(4):320–328. doi:10.1016/S1474-4422(11)70025-4.
1256 OCTOBER 2020

Peripheral Neuropathies REVIEW ARTICLE

Associated With C O N T I N U UM AUDIO
INTERVIEW AVAILABLE
ONLINE
Vasculitis and
Autoimmune Connective
Tissue Disease
By Chafic Karam, MD
ABSTRACT
CITE AS:
PURPOSE OF REVIEW: This articlediscusses peripheral neuropathies associated
with vasculitis (isolated or in the setting of systemic vasculitis) and 2020;26(5, PERIPHERAL NERVE AND
autoimmune connective tissue disease and provides a brief overview of MOTOR NEURON DISORDERS):
1257–1279.
their diagnostic evaluation and management.
RECENT FINDINGS: The classification of systemic vasculitic neuropathy and Dr Chafic Karam, 3303 S Bond
nonsystemic vasculitic neuropathy continues to evolve. Classification Ave, 18th Floor, Portland, OR
97239, chafickaram@gmail.com.
according to the presence of antineutrophil cytoplasmic antibodies and
their subtypes facilitates prognostication and management. Recent RELATIONSHIP DISCLOSURE:
Dr Karam has served as a deputy
research on antineutrophil cytoplasmic antibody–associated vasculitis has
editor for Neurology and as a
added to our understanding of its neurologic complications. The treatment consultant for Acceleron
of vasculitis is also evolving, and new nonsystemic vasculitic neuropathy Pharma, Inc; Akcea
Therapeutics; Alnylam
classification has impacted the treatment and management of this disorder. Pharmaceuticals, Inc; Argenx;
New classification criteria for Sjögren syndrome (which commonly causes Biogen; CSL Behring; and Sanofi
neurologic complications) facilitate accurate and timely diagnosis. Genzyme. Dr Karam has
received personal
compensation for speaking
SUMMARY: Vasculitis and autoimmune connective tissue disease are engagements from Akcea
underrecognized and treatable causes of peripheral neuropathy. Therapeutics; Alnylam
Pharmaceuticals, Inc; CSL
Furthermore, peripheral neuropathy may reveal an underlying Behring; and Sanofi Genzyme
rheumatologic or vasculitic disorder. Rapid recognition and treatment are and research/grant support
from Akcea Therapeutics and
essential. Familiarity with the diagnosis and treatment of neuropathies in Sanofi Genzyme.
the setting of connective tissue disease and vasculitis reduces morbidity
and, in some cases, mortality. UNLABELED USE OF
USE DISCLOSURE:
Dr Karam discusses the
INTRODUCTION unlabeled/investigational use of
cyclophosphamide,
V
asculitis and autoimmune connective tissue disease are immunoglobulin, rituximab, and
underrecognized and treatable causes of peripheral neuropathy. steroids in the treatment of
vasculitis and immune-
Rapid recognition and treatment are essential to reduce morbidity
mediated neuropathy in
and, in some cases, mortality. Peripheral neuropathy may be the rheumatologic disorders.
first manifestation of a rheumatologic or vasculitic disorder; thus,
neurologists must recognize the underlying processes so they can initiate the © 2020 American Academy
appropriate workup and start treatment urgently to reduce the risk of of Neurology.

VASCULITIS AND AUTOIMMUNE CONNECTIVE TISSUE DISEASE
irreversible neurologic damage. This article reviews the peripheral neuropathies

associated with vasculitis (isolated or associated with systemic vasculitis) and
autoimmune connective tissue disease and describes clinical phenotypes, the
appropriate workup, and treatment.
PERIPHERAL NEUROPATHY ASSOCIATED WITH VASCULITIS

The vasculitides are a heterogeneous group of autoimmune diseases caused by
inflammation in the blood vessel wall resulting in vascular injury, interruption of
blood flow, and subsequent ischemia and damage of affected organs. The 2012
International Chapel Hill Consensus Conference classified vasculitis according to
vessel size and the presence of antineutrophil cytoplasmic antibodies (ANCA).1
The Chapel Hill Consensus Conference also classified vasculitis associated with
systemic diseases (eg, rheumatoid arthritis [RA] and systemic lupus erythematosus
[SLE]) and vasculitis associated with other systemic disorders, including infections
(eg, hepatitis B or hepatitis C), drug exposure (eg, minocycline), and malignancy,
among others. The Peripheral Nerve Society has also published a classification
tailored to peripheral nerve vasculitis (TABLE 6-1).2 FIGURE 6-1 shows a simple
classification system that focuses on the most commonly encountered disorders.
TABLE 6-1 Classification of Vasculitides Associated With Neuropathya
Primary Systemic Vasculitides

◆ Small vessel vasculitis
◇ Microscopic polyangiitis
◇ Eosinophilic granulomatosis with polyangiitis
◇ Granulomatosis with polyangiitis
◇ Essential mixed cryoglobulinemia (non–hepatitis C)
◇ Henoch-Schönlein purpura
◆ Medium vessel vasculitis
◇ Polyarteritis nodosa
◆ Large vessel vasculitis
◇ Giant cell arteritis
Secondary Systemic Vasculitides
◆ Connective tissue disease
◇ Rheumatoid arthritis
◇ Systemic lupus erythematosus
◇ Sjögren syndrome
◇ Systemic sclerosis
◇ Dermatomyositis
◇ Mixed connective tissue disease
◆ Sarcoidosis
1258 OCTOBER 2020

Clinical Presentation
Clinical features suggestive of a vasculitic neuropathy include acute or subacute
painful multifocal sensory or sensorimotor neuropathy, an asymmetric distal
polyneuropathy with or without associated systemic features, and stepwise
progression (CASE 6-1). Some patients may have a relatively symmetric,
slowly progressive presentation, which can be misdiagnosed as an idiopathic
distal polyneuropathy. A careful review of systems, past medical history,
and current medications together with laboratory findings will help guide
clinicians to the correct diagnosis. On very rare occasions, fulminant vasculitic
neuropathy may mimic Guillain-Barré syndrome.
Diagnosis of Vasculitic Neuropathy

The diagnosis of a vasculitic neuropathy is based on recognition of the clinical
pattern and is supported by nerve conduction studies and neuropathology.
NERVE CONDUCTION STUDIES. Nerve conduction studies can demonstrate the

asymmetric or multifocal nature of the neuropathy, features that, at times, may
be difficult to appreciate on neurologic examination. When vasculitis is
◆ Behçet disease
◆ Infections
◇ Hepatitis B virus
◇ Hepatitis C virus
◇ Cytomegalovirus
◇ Leprosy
◇ Lyme disease
◇ Human T-cell lymphotropic virus type 1 (HTLV-1)
◆ Drugs
◆ Malignancy
◆ Inflammatory bowel disease
◆ Hypocomplementemic urticarial vasculitis syndrome
Nonsystemic/Localized Vasculitis
◆ Nonsystemic vasculitis neuropathy
◇ Nondiabetic lumbosacral radiculoplexus neuropathy
◇ Wartenberg migratory sensory neuritis
◆ Diabetic lumbosacral radiculoplexus neuropathy
◆ Localized cutaneous/neuropathic vasculitis
◇ Cutaneous polyarteritis nodosa
◇ Others
a
Modified with permission from Collins, MP, et al, J Peripher Nerv Syst.2 © 2010 Peripheral Nerve Society.

KEY POINTS
● Asymmetric signs or
symptoms or stepwise
progression, especially
when associated with
systemic symptoms, are
highly suggestive of
vasculitic neuropathy.
● Nerve conduction studies

done on opposite limbs,
even if asymptomatic, are
essential to demonstrate
asymmetry or multifocality,
which can be missed
clinically.
● Nerve biopsy is necessary

for a diagnosis of definite
vasculitis, but, because of
the patchy nature of the
disease process, a negative
biopsy does not rule out
vasculitis.
FIGURE 6-1
● Biopsy of a nearby muscle A simple classification system focusing on the most commonly encountered disorders
increases the diagnostic associated with vasculitic neuropathy.
yield of biopsy for ANCA = antineutrophil cytoplasmic antibody.
suspected vasculitic
neuropathy by about 15%.
suspected, it is imperative to test the opposite limb to demonstrate asymmetry.

Occasionally the neuropathy appears symmetric, especially in chronic cases
(confluent mononeuritis multiplex). Very rarely, areas of focal partial motor
conduction “block” due to acute focal ischemic nerve injury can be demonstrated.
Nerve conduction velocity is normal, and other features of demyelination are
lacking; conduction “block,” when present, is transient as wallerian degeneration
progresses.3 Nerve conduction studies can also help select a nerve affected by the
disease process for biopsy. Needle EMG can help approximate time and extent of
the injury and assess whether a superimposed myopathy is present.
PATHOLOGY. Tissue biopsy is necessary for the diagnosis of definite vasculitis.

A nerve biopsy may not always be necessary or preferred in systemic
vasculitis. For example, in a patient with ANCA-associated vasculitis, a kidney
or lung biopsy confirming the diagnosis is sufficient, especially when the
neuropathy pattern is suggestive of vasculitic neuropathy. Findings on nerve
biopsies are classified as possible, probable, or definite vasculitis (TABLE 6-2).2
Definite vasculitis consists of inflammation in the blood vessel wall and
vascular wall damage. Definite vasculitis can be further divided into active
or chronic. Appropriate staining is necessary to assess the etiology of vasculitis
in specific situations (eg, leprosy or lymphoma). Possible and probable
vasculitis can be determined by indirect signs suggestive of vasculitis. For
example, multifocal nerve fiber loss suggests ischemia, which is usually
caused by vasculitis. Hemosiderin deposits suggest that nerve hemorrhage
1260 OCTOBER 2020

has occurred, another indirect sign of vasculitis. A thrombosed blood vessel
with recanalization and neovascularization is suggestive of a remote or
chronic vasculitis.
The sensitivity of nerve biopsy for detecting vasculitis is less than 50%
because of the patchy nature of the disease. Combining a muscle biopsy with
the nerve biopsy modestly increases sensitivity by approximately 15%.4 In
general, an affected cutaneous sensory nerve, such as the sural, superficial
A 60-year-old man presented for neurologic consultation for weakness CASE 6-1
and numbness in his extremities. Six weeks before presentation he
developed a sudden left footdrop associated with numbness and a
painful prickling sensation. Within 1 week, he had developed similar
symptoms on the right side. A week later, he noticed weakness,
numbness, and pain in his right hand, which was followed 2 weeks later
by similar symptoms in his left hand. He had also lost 13.6 kg (30 lb)
unintentionally.
His physical examination was normal. His neurologic examination
showed diffuse, distal more than proximal, asymmetric weakness. Deep
tendon reflexes were absent at the ankles. He had sensory loss to all
modalities in the feet up to the knees and in the hands, and he needed
assistance to stand up from a seated position. He was unsteady and had
bilateral footdrop when walking.
Nerve conduction study and EMG showed multiple mononeuropathies
with subacute severe denervation. A sural nerve biopsy showed
lymphoplasmacytic inflammatory infiltrates involving the perineurial
small vessels disrupting the vascular smooth muscle and elastin layers.
The patient was admitted to the hospital urgently the next day for workup
and treatment.
Overnight, he developed double vision; a brain MRI and magnetic
resonance angiography (MRA) showed a left paramedian midbrain
infarction and circumferential vessel wall enhancement, and multifocal
areas of fusiform aneurysmal dilation were noted. Antineutrophil
cytoplasmic antibodies and hepatitis B test were negative. He was
started on IV methylprednisolone 1000 mg/d for 3 days, followed by oral
prednisone 60 mg/d. He was also started on IV cyclophosphamide
1000 mg once a month for 6 doses and oral azathioprine 200 mg/d.
Upon follow-up 6 months later, the patient was able to ambulate
independently but continued to have bilateral footdrop. Prednisone was
tapered down, and he continued the azathioprine.
The presentation of stepwise neuropathy seen in this patient is typical for COMMENT
polyarteritis nodosa. The angiographic findings and stroke differentiate
this case from nonsystemic peripheral nerve vasculitis. Stroke is a
complication of systemic vasculitis and may be missed in patients in whom
the predominant clinical picture is mononeuritis multiplex.

fibular (peroneal), or superficial radial, is biopsied. Biopsy of a nearby muscle

(eg, the peroneus brevis or medial gastrocnemius) is recommended.
The term microvasculitis is used when the vasculitis affects small-diameter
(<50 μm) blood vessels, including perineurial arterioles, endoneurial capillaries,
and venules. These blood vessels are composed of endothelial cells and pericytes.
Fibrinoid necrosis is not seen in microvasculitis. By definition, the term
microvasculitis is used when the blood vessel is disrupted by inflammatory cells,
TABLE 6-2 Diagnostic Criteria for Definite, Probable, and Possible Vasculitisa
Pathologically Definite
◆ Active lesion: nerve biopsy showing collection of inflammatory cells in vessel wall AND
one or more signs of acute vascular damage:
◇ Fibrinoid necrosis
◇ Loss/disruption of endothelium
◇ Loss/fragmentation of internal elastic lamina
◇ Loss/fragmentation/separation of smooth muscle cells in media (can be highlighted with
anti–smooth muscle actin staining)
◇ Acute thrombosis
◇ Vascular/perivascular hemorrhage
◇ Leukocytoclasia
◆ Chronic lesion: nerve biopsy showing collection of mononuclear inflammatory cells in
vessel wall AND one or more signs of chronic vascular damage with repair:
◇ Intimal hyperplasia
◇ Fibrosis of media
◇ Adventitial/periadventitial fibrosis
Pathologically Probable
◆ Pathologic criteria for definite vasculitic neuropathy not satisfied AND perivascular
inflammation accompanied by signs of active or chronic vascular damage OR perivascular/
vascular inflammation plus at least one additional class II or III pathologic predictor of
definite vasculitic neuropathy:
◇ Vascular deposition of complement, IgM, or fibrinogen by direct immunofluorescence;
◇ Hemosiderin deposits (Perls Prussian blue stain for iron);
◇ Asymmetric/multifocal nerve fiber loss or degeneration;
◇ Prominent active axonal degeneration; OR
◇ Myofiber necrosis, regeneration, or infarcts in concomitant peroneus brevis muscle
biopsy (not explained by underlying myopathy)
Pathologically Possible
◆ Pathologic criteria for definite or probable vasculitic neuropathy not satisfied AND
inflammation in vessel wall without other signs of definite vasculitic neuropathy OR one or
more signs of active/chronic vascular damage or pathologic predictors of definite vasculitic
neuropathy, without vessel wall or perivascular inflammation.
IgM = immunoglobulin M.
a
Modified with permission from Collins, MP, et al, J Peripher Nerv Syst.2 © 2010 Peripheral Nerve Society.
1262 OCTOBER 2020

which is always abnormal. It is important to differentiate microvasculitis from KEY POINT
a perivascular inflammatory cell collection not disrupting the blood vessel. The
● Laboratory testing is
latter is a nonspecific finding; however, perivascular inflammatory cell collection essential to determine
could be the only finding in very early vasculitis. These observations point to the whether vasculitis is
importance of a good history and examination and supportive blood testing secondary to a systemic
when making the diagnosis of vasculitic neuropathy.5 disorder or exposure that
may require different
management.
LABORATORY TESTING IN PATIENTS WITH VASCULITIS. Laboratory testing is
necessary in patients with suspected vasculitis to determine the type of vasculitis
(systemic, nonsystemic, or related to another disorder) and extent of other organ
involvement. The results have important implications for management and
prognosis. TABLE 6-3 lists suggested diagnostic tests.
PERIPHERAL NEUROPATHY ASSOCIATED WITH SYSTEMIC VASCULITIS

Systemic vasculitis affecting small or medium blood vessels can also involve the vasa
nervorum or nerve arterioles, causing neuropathy. Small vessel vasculitis is divided
into ANCA-associated vasculitis and immune complex vasculitis, which includes
cryoglobulinemic vasculitis. Nerve arterioles are also affected in medium blood
vessel vasculitis such as polyarteritis nodosa. Rarely, large vessel vasculitis can also
involve small and medium blood vessels. However, the rest of this discussion
focuses on the disorders that are most frequently associated with neuropathy:
ANCA-associated vasculitis, cryoglobulinemia, and polyarteritis nodosa.
ANCA-Associated Vasculitis
ANCA-associated vasculitis includes microscopic polyangiitis, granulomatosis
with polyangiitis, and eosinophilic granulomatosis with polyangiitis.1
ANCA are autoantibodies that target antibacterial proteins found in
neutrophils and monocytes, such as lysozyme, proteinase 3 (PR3), and
myeloperoxidase (MPO). ANCA induces vasculitis by directly activating
neutrophils. ANCA-associated vasculitis affects the capillaries, venules,
arterioles, and small arteries with very little to no immune deposits. Most cases of
microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic
granulomatosis with polyangiitis are ANCA positive. Significant overlap exists in
the clinical features of microscopic polyangiitis and granulomatosis with
polyangiitis. Patients with ANCA-associated vasculitis frequently have
constitutional symptoms, such as fever, weight loss, night sweats, fatigue, and
muscle aches. Involvement of the respiratory tract and kidneys is a hallmark of
the disease. Patients frequently have rapidly progressive glomerulonephritis,
which clinically presents with water retention, hypertension, foamy urine, and,
occasionally, hematuria. Granulomatous inflammation and asthma are not seen
in microscopic polyangiitis. Microscopic polyangiitis can cause alveolar
hemorrhage and pulmonary fibrosis.
In granulomatosis with polyangiitis, extravascular granulomatous
inflammation in the respiratory tract occurs, resulting in clinically evident sinus
and respiratory system involvement in many patients. Granulomatosis with
polyangiitis frequently causes pulmonary necrotizing granulomatous lesions that
appear as cavitation or nodular lesions on imaging. Patients typically have
sinonasal involvement and may have inflammatory eye disease. Many patients
develop leukocytoclastic vasculitis. Eosinophilic granulomatosis with
polyangiitis is accompanied by peripheral blood eosinophilia and asthma in

TABLE 6-3 Suggested Laboratory Testing When Suspecting Peripheral Nerve Vasculitis
Nerve conduction studies and EMG

Brain and spinal cord MRI/magnetic resonance angiography (MRA) or cerebral angiography if
central nervous system involvement is suspected
Chest x-ray or CT chest and abdomen in systemic vasculitis (especially in the setting of
antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis or sarcoidosis). A positron
emission tomography (PET) scan may be considered if malignancy is suspected
Laboratory testinga:
◆ Extractable nuclear antigen antibodies (which includes the following: anti-Ro [also called
anti-SSA], anti-La [also called anti-SSB], anti-Sm [anti-Smith antibody], anti-RNP
[antiribonucleoprotein], anti-Jo-1, anti-Scl70, anticentromere)
◆ ANCA (proteinase 3, myeloperoxidase)
◆ Erythrocyte sedimentation rate
◆ C-reactive protein
◆ Cryoglobulin
◆ Complete blood cell count with differential, kidney function tests
◆ Liver function tests
◆ Urinalysis
◆ Urine protein
◆ Serum protein electrophoresis/immunofixation electrophoresis
◆ Serum free light chain
◆ Hemoglobin A1c
◆ CCP
◆ C3
◆ C4
◆ Hepatitis C virus
◆ Hepatitis B virus
◆ Human immunodeficiency virus (HIV)
◆ Lyme disease
◆ Rheumatoid factor
◆ Antinuclear antibody
◆ dsDNA
◆ Nerve, muscle, kidney, pulmonary, skin, or salivary gland biopsy depending on organ
involvement
C3 = complement component 3; C4 = complement component 4; CCP = cyclic citrullinated peptide antibodies:

CT = computed tomography; dsDNA = double-stranded deoxyribonucleic acid; EEG = electroencephalography;
EMG = electromyography; MRI = magnetic resonance imaging; SSA = Sjögren syndrome A; SSB = Sjögren
syndrome B.
a
These tests can help determine whether vasculitis is associated with rheumatologic disorders, infection, or
malignancy and determine whether other organs are involved.
1264 OCTOBER 2020

addition to the extravascular granulomatous inflammation. Adult-onset asthma KEY POINTS
in a patient with a subacute asymmetric neuropathy or multifocal neuropathy
● Adult-onset asthma in a
strongly suggests eosinophilic granulomatosis with polyangiitis. Cardiac disease patient with a subacute
may be a rare severe manifestation. asymmetric neuropathy or
Peripheral neuropathy is common in ANCA-associated vasculitis and can multifocal neuropathy
be the first manifesting symptom of the disease. At least one-third of patients strongly suggests
eosinophilic granulomatosis
with ANCA-associated vasculitis have neuropathy. Patients with eosinophilic
with polyangiitis.
granulomatosis with polyangiitis are most likely to develop neuropathy. In one
study, among 955 patients with ANCA-associated vasculitis, 28% (269 of 955) had ● Testing for antineutrophil
neuropathy, which was more frequent in eosinophilic granulomatosis with cytoplasmic antibodies
polyangiitis (65%) than in microscopic polyangiitis (23%) or granulomatosis with (ANCA) in the setting of
vasculitis is essential to
polyangiitis (19%) (P<.001).6 Most patients had multifocal neuropathy or determine prognosis and
sensorimotor neuropathy. Sensory neuropathy was less frequent. Very rarely, appropriate treatment.
patients had isolated motor neuropathy. Patients with neuropathy had a higher
incidence of MPO-ANCA positivity; a diagnosis of eosinophilic granulomatosis ● In the rare instance
in which both
with polyangiitis; and skin, musculoskeletal, or cardiovascular involvement.6 myeloperoxidase and
Patients with ANCA-associated vasculitis may also rarely develop other proteinase 3 are positive in
autoimmune neuromuscular disorders, such as Guillain-Barré syndrome, chronic the same patient, drug-
inflammatory demyelinating polyradiculoneuropathy (CIDP), cranial induced vasculitis should
be suspected.
neuropathies, and myopathies.7
ANCA specificity to either MPO (usually perinuclear ANCA and typically
seen in microscopic polyangiitis or eosinophilic granulomatosis with
polyangiitis) or PR3 (usually cytoplasmic ANCA and typically seen in
granulomatosis with polyangiitis) has important implications (TABLE 6-4).8
ANCA-negative ANCA-associated vasculitis is used if the patient otherwise
fulfills the definition for an ANCA-associated vasculitis but tests negative
for ANCA.
Checking ANCA in patients with neuropathy not felt to be caused by vasculitis
is not recommended.9 ANCA positivity is not specific to ANCA-associated
vasculitis; it can be positive in patients with infections (eg, hepatitis C,
endocarditis, tuberculosis), inflammatory bowel disease, malignancy,
and other autoimmune diseases (eg, RA, SLE). In the rare instance in
which both MPO and PR3 are positive in the same patient, drug-induced
vasculitis should be suspected.10 A 2017 international consensus statement
recommended initial testing directly with immunoassays for PR3 ANCA
and MPO ANCA rather than indirect immunofluorescence assay.11 This
was driven by the large variability between indirect immunofluorescence
assay methods.12
Treatment of ANCA-associated vasculitis consists of induction therapy
followed by maintenance therapy. Without induction therapy, mortality is high,
even with corticosteroid therapy. Induction therapy is usually a combination of
corticosteroids (oral prednisone 60 mg/d or IV methylprednisolone 1 g every day
for 3 days, then weekly for 12 weeks with a subsequent taper) with pulse IV
cyclophosphamide (1 g/m2, dose adjusted based on nadir leukocyte counts, per
month for six doses or IV rituximab 375 mg/m2 weekly for four doses repeated
every 6 months).13 Less toxicity is seen with rituximab, and evidence suggests
that it is as effective or possibly more effective than cyclophosphamide in PR3
ANCA vasculitis.14 In severe disease or when the heart or central nervous system
is involved, cyclophosphamide may be preferred. Maintenance therapy
following induction consists of oral azathioprine (1 mg/kg/d to 2 mg/kg/d), oral

methotrexate (7.5 mg to 25 mg weekly), oral mycophenolate mofetil (1 g to 1.5 g

2 times a day), or IV rituximab (1 g every 4 to 6 months). Oral cyclophosphamide
is avoided if possible because of side effects, including leukopenia, alopecia,
infections, infertility, hemorrhagic cystitis, myelodysplasia, and neoplasms
(mainly bladder cancer).15 Future therapies may include C5a receptor inhibitors
such as avacopan (currently investigational).16
Polyarteritis Nodosa
Polyarteritis nodosa primarily affects small and medium-sized blood vessels.
Classification criteria were proposed by the American College of Rheumatology
for research purposes.17 Fulfilling three or more of the following 10 criteria is
suggestive of polyarteritis nodosa: weight loss greater than or equal to 4 kg
(8.8 lb), livedo reticularis, testicular pain or tenderness, myalgia, mononeuropathy
or polyneuropathy, diastolic blood pressure greater than 90 mm Hg, elevated
blood urea nitrogen or serum creatinine levels, presence of hepatitis B reactants
in serum, arteriographic abnormality, and presence of granulocyte or mixed
leukocyte infiltrate in an arterial wall on biopsy. These classification criteria were
adapted for clinical use as well, but they have low sensitivity and specificity.18,19
A 2008 diagnostic algorithm that suggests using positive and negative findings
yields about 70% sensitivity and 90% specificity.20 The positive findings include
hepatitis B virus antigen or DNA in serum, arteriographic anomalies, and
mononeuropathy or polyneuropathy. The negative findings include one or more
TABLE 6-4 Comparison of Clinical Features by Antineutrophil Cytoplasmic Antibodya
Proteinase 3 Antineutrophil Cytoplasmic

Antibody Myeloperoxidase Antineutrophil Cytoplasmic Antibody
Demographics 50–70 years of age 60–80 years of age
Geography Northern Europe, North America Southern Europe, Asia
Pathology Necrotizing vasculitis, granulomatous Necrotizing vasculitis, no granulomatous inflammation

inflammation
Renal Acute renal failure Kidney involvement is more common, more chronic injury
on biopsy
Respiratory More common; nodules, cavitation, and Less common; chronic lung fibrosis, peripheral
involvement central airway disease more specific to reticulation, honeycombing, and usual interstitial
proteinase 3 pneumonia more specific to myeloperoxidase
Upper airway More common; destructive lesions (nasal Rare

disease perforation, saddle nose)
Outcomes More likely to have resistant disease Worse long-term survival (more chronic injury)
Relapse rate Higher Lower
Treatment May respond better to rituximab than Similar response to rituximab and cyclophosphamide
cyclophosphamide
a
Modified with permission from Geetha D, Jefferson JA, Am J Kidney Dis.8 © 2019 National Kidney Foundation, Inc.
1266 OCTOBER 2020

of the following: presence of ANCA; asthma; ear, nose, and throat signs; KEY POINT
glomerulopathy; and cryoglobulinemia. This is based on the fact that patients with
● In polyarteritis nodosa,
polyarteritis nodosa generally do not have glomerulonephritis and ANCA testing for hepatitis B virus is
antibodies are negative.1,21 In addition to hepatitis B virus, other viral infections essential. Testing for ANCA
may be present. Neuropathy is seen in up to 70% of patients with polyarteritis is negative, and
nodosa and is more common in polyarteritis nodosa associated with hepatitis B glomerulopathy is not
present.
virus.22 Most patients also have systemic symptoms such as fever, weight loss,
myalgia, and arthralgia. Patients also frequently have cutaneous and
gastrointestinal manifestations and hypertension. Men frequently have testicular
involvement. Rarely, patients with polyarteritis nodosa have central nervous
system involvement, including stroke. The latter is thought to be usually related
more to thrombotic microangiopathy than to vasculitis.23 Angiography of the
visceral arteries can be highly suggestive of polyarteritis nodosa when arterial
saccular or fusiform microaneurysms coexisting with stenotic lesions are
demonstrated. Polyarteritis nodosa is usually a monophasic disease, with a relapse
rate of just under 20%. About 25% of patients die within 5 years of symptom onset.
Treatment is similar to ANCA-associated vasculitides, with induction therapy with
steroids and monthly IV cyclophosphamide for 6 to 12 months followed by
azathioprine or methotrexate (with dosages the same as those used in
ANCA-associated vasculitis, as discussed above). For polyarteritis nodosa
associated with hepatitis B virus, antiviral therapy and a short corticosteroid
treatment with plasma exchange should be used. Relapse is rare once hepatitis B
viremia is controlled.
Cryoglobulinemic Vasculitis
Cryoglobulinemia is caused by circulating immunoglobulins that precipitate at
cold temperature. Cryoglobulins are divided into three groups. Type I
cryoglobulins consist of isolated monoclonal immunoglobulin (usually IgM or
IgG). Type II cryoglobulins are mixed cryoglobulins with a monoclonal
component possessing antibody activity as well as polyclonal IgG. Type III
cryoglobulins are mixed polyclonal cryoglobulins that are usually
immunoglobulin–anti-immunoglobulin immune complexes.24 Not all patients
with cryoglobulinemia develop vasculitis. For example, up to 50% of patients
with hepatitis C virus have circulating cryoglobulins, but only 5% develop
vasculitis.25 Type I cryoglobulins are frequently associated with B-cell
lymphoproliferative disorders, such as monoclonal gammopathy of undetermined
significance (MGUS), Waldenström macroglobulinemia, chronic lymphocytic
leukemia, B-cell non-Hodgkin lymphoma, and multiple myeloma. Type II and
type III cryoglobulins can also be associated with lymphoproliferative
disorders but are mostly seen in patients with hepatitis C virus infection.
Patients with Sjögren syndrome, SLE, hepatocarcinoma, lymphoma, or
hepatitis B virus may also have cryoglobulinemia. Some cryoglobulinemias
are idiopathic. Patients with Sjögren syndrome and circulating cryoglobulins
have more pronounced systemic involvement and are at a higher risk of
developing lymphoma.26
Type II and type III cryoglobulins can engage with C1q on endothelial cells,
which promotes inflammatory cell recruitment resulting in vasculitis. Type I
cryoglobulins cause blood vessel occlusion and inflammation.27 The classic
triad of generalized weakness, palpable purpura, and diffuse joint pain is present
in up to 80% of patients. Peripheral neuropathy is present in more than half

of patients.28,29 The neuropathy is frequently distal and symmetric (CASE 6-2 and
CASE 6-3) but can also present as a multifocal neuropathy or as a small
fiber–predominant neuropathy.30 Other symptoms include livedo reticularis,
cutaneous ulcers, gangrene, Raynaud phenomenon, and glomerulonephritis.
Rarely, central nervous system manifestations may occur.31
On laboratory testing, antinuclear antibodies and rheumatoid factor may be
positive. Complement levels, especially C4, are typically low. Testing for
cryoglobulins requires that the blood sample be collected, stored, and centrifuged
at 37°C (98.6°F). The serum is then refrigerated at 4°C (39.2°F) for 72 hours
(preferably 7 days) to promote cryoprecipitation. If these steps are not followed
closely, the test may be falsely negative. Therapy for cryoglobulinemic
neuropathy requires treatment of the underlying cause in addition to symptom
management. If the symptoms are mild and an infection is detected, the infection
can be treated and immunosuppression may not be required (CASE 6-2). In
more severe cases, plasma exchange (generally every other day for five sessions)
or oral prednisone (60 mg/d), or both, followed by rituximab (two doses of 1 g
IV given 2 weeks apart or 375 mg/m2 weekly for 4 weeks) are indicated
(CASE 6-4).31,33
Other Causes of Systemic Vasculitic Neuropathy

Other causes of vasculitic neuropathy are rare but should be kept in mind, including
human immunodeficiency virus (HIV)–associated vasculitis (nerve large arteriole
CASE 6-2 A 67-year-old woman presented with a 12-month history of numbness,

tingling, and burning pain in her feet that, over time, had slowly spread to
her shins. She also had occasional shooting pain in her hands. Her
symptoms were associated with fatigue, but she denied weakness or
balance issues. When questioned, she recalled having a blood transfusion
when she was 12 years old.
Neurologic examination showed absent ankle deep tendon reflexes,
reduced pinprick sensation up to the midshin bilaterally, and slightly
reduced vibration sensation at the toes. Strength was normal.
Nerve conduction studies and EMG showed a mild, symmetric, distal
axonal peripheral neuropathy. Hepatitis C antibodies and cryoglobulins
were positive (type II cryoglobulinemia). She was started on elbasvir/
grazoprevir for hepatitis C and symptomatic treatment for neuropathy
symptoms. Her fatigue improved, and the neuropathy symptoms
remained stable. The patient continued to do well 3 years after hepatitis
C treatment.
COMMENT Careful review of systems and medical history may give clues to the
underlying cause of the neuropathy. Cryoglobulinemic vasculitic
neuropathy with mild symptoms caused by an infection may only require
treatment of the infection.
1268 OCTOBER 2020

A 55-year-old woman CASE 6-3
presented with fatigue,
anorexia, generalized
weakness, and diffuse pain
for 3 months. Her past
medical history was notable
for Sjögren syndrome
treated with 60 mg/d
oral prednisone.
On examination, she had
scattered erythematous
papules on both legs
extending to her thighs,
with hyperpigmentation of
the feet and shins extending
to midshin (FIGURE 6-2). She
had 1+ pitting edema and
mild weakness in toe
extension. Sensation to
pinprick, light touch, and
temperature was decreased
up to the knees, and
proprioception was
FIGURE 6-2
decreased in the toes.
Photographs of the patient in CASE 6-3. Scattered
Nerve conduction studies erythematous papules on both legs extending to
and EMG showed evidence thighs (A), with hyperpigmentation of the feet and
of a chronic, axonal, shins extending to midshin (B).
length-dependent
sensorimotor peripheral
neuropathy without significant asymmetry. Laboratory evaluation
showed pancytopenia, IgM kappa monoclonal protein with polyclonal
background, mildly elevated alkaline phosphatase, low albumin and
elevated total protein, elevated rheumatoid factor (more than
650 IU/mL), an erythrocyte sedimentation rate greater than 120 mm/h,
and a C-reactive protein of 22.5 mg/L (normal <10 mg/L). Renal function
was normal. Hepatitis B virus, hepatitis C virus, and human
immunodeficiency virus (HIV) were negative. Complement C3 was
normal, but C4 was low at 11 mg/dL (normal 16 mg/dL to 47 mg/dL).
Cryoglobulin screen was positive in 24 hours (type II). A sural nerve biopsy
showed chronic and active nerve arteriole vasculitis.
Patients with autoimmune connective tissue disease may develop COMMENT

secondary vasculitis. Cryoglobulinemic vasculitic neuropathy can be
secondary to Sjögren syndrome.

vasculitis), paraneoplastic vasculitis, sarcoidosis, Behçet disease, inflammatory

bowel disease, drug-related vasculitis (CASE 6-4), Lyme disease, and others.32
NONSYSTEMIC VASCULITIC NEUROPATHY

Vasculitic neuropathy may occur in isolation, without evidence of systemic
involvement. The classification of nonsystemic vasculitic neuropathy continues
to evolve. Current consensus divides nonsystemic vasculitic neuropathies into
the following syndromes: Wartenberg migratory sensory neuritis, postsurgical
inflammatory neuropathy, neuralgic amyotrophy (possibly), painful diabetic
radiculoplexus neuropathy (lumbosacral thoracic, cervical, or in combination),
CASE 6-4 A 17-year-old girl awoke with new-onset left arm pain with numbness and
weakness in the ulnar nerve distribution. She was taking minocycline for
acne. Eleven days after development of the left arm symptoms, she
developed numbness over the lateral aspects of the bilateral feet and
thighs as well as pain and numbness over the left dorsum of her hand.
One month later, she developed acute left leg weakness, nausea, and
vertigo, which prevented her from walking, and she presented to the
emergency department.
On examination, she had left arm and bilateral ankle dorsiflexion
weakness and reduced sensation in the left hand and both feet. Brain MRI
showed an acute right medial medullary ischemic stroke. Nerve
conduction studies and EMG showed an asymmetric axonal sensorimotor
peripheral neuropathy. Antinuclear antibody test was mildly positive
(1:160), and C-reactive protein was elevated (18.4 mg/L). A left superficial
radial nerve biopsy was consistent with necrotizing vasculitis (FIGURE 6-3).
Following the diagnosis of peripheral and central nervous system
vasculitis, minocycline was discontinued. The patient was started on IV
methylprednisolone and azathioprine.32 Upon follow-up 6 months later,
the patient’s pain and vertigo had resolved, and she was regaining
strength but had persistent numbness in her feet and left hand. The
methylprednisolone was tapered down, and she continued taking the
azathioprine.
COMMENT A careful review of medications may reveal the cause of vasculitis.

Minocycline and other medications have been implicated in systemic
vasculitis. Central nervous system complications may occur in systemic
vasculitis, as demonstrated in this patient. However, central nervous
system involvement may be overshadowed by the systemic symptoms
and, as in this case, the peripheral nerve vasculitis.
Case modified with permission from Baratta, JM, et al, Neurol Neuroimmunol Neuroinflamm.32
© 2015 American Academy of Neurology.
1270 OCTOBER 2020

painless diabetic radiculoplexus neuropathy, nonsystemic skin/nerve vasculitis,
and cutaneous polyarteritis nodosa.34 For more information on the diabetic
radiculoplexus neuropathies, refer to the article “Diabetes and Metabolic
Disorders and the Peripheral Nervous System” by Christopher H. Gibbons, MD,
MMSc, FAAN,35 in this issue of Continuum. Nonsystemic vasculitic neuropathies
can be recurrent/chronic or self-limiting.
Generalized Nonsystemic Vasculitic Neuropathy

Recurrent/chronic nonsystemic vasculitic neuropathy includes nonsystemic
skin/nerve vasculitis, cutaneous polyarteritis nodosa, and Wartenberg migratory
FIGURE 6-3
Nerve biopsies of the patient in CASE 6-4. A,
Hematoxylin and eosin (H&E) stain of the
superficial radial nerve demonstrates epineurial
nerve arteriole necrotizing vasculitis. Note the
inflammatory cells infiltrating and disrupting all
layers of the arteriolar wall and the fibrinoid
necrosis (arrows). B, Methylene blue stain of the
radial nerve demonstrates myelinated fiber
degeneration in the center of the fascicle that is
typical of ischemic changes (outlined ).
Reprinted with permission from Baratta, JM, et al, Neurol
Neuroimmunol Neuroinflamm.32 © 2015 American
Academy of Neurology.

sensory neuritis. As such, limited involvement of the muscle or skin may be

seen.2 Constitutional symptoms such as weight loss, fever, and malaise are rare.
Laboratory markers for vasculitis or a rheumatologic disorder are negative.
Most patients present with painful multifocal weakness and sensory loss.
Microvasculitis is a common underlying pathology. In nonsystemic vasculitic
neuropathy, the diagnosis is sometimes made clinically and without necessarily
doing a nerve biopsy. Furthermore, clinically probable vasculitic neuropathy
based on history and examination alone, without any laboratory tests, has been
recently proposed by the Brighton Collaboration (low level of certainty)36; this
definition is intended mainly for resource-poor countries. Delay in diagnosis is
common.37 Nonsystemic vasculitic neuropathy may need to be treated long term
and sometimes aggressively37 and may progress into systemic vasculitis. When
caught during the active phase of the disease, nonsystemic vasculitic neuropathy
should be treated with immunosuppression to reduce nerve damage, shorten the
disease course, and improve outcome.2 For treatment of nonsystemic vasculitic
neuropathy, the Peripheral Nerve Society recommends oral prednisone starting
at 1 mg/kg/d with a slow taper over 6 months. They suggest pulse IV
methylprednisolone in patients with severe, rapidly progressive nonsystemic
vasculitic neuropathy. If no response is seen, IV cyclophosphamide is
recommended. The group also suggests using maintenance therapy with
azathioprine or methotrexate for 18 to 24 months to reduce relapses.2
Wartenberg migratory sensory neuritis is a very rare form of multifocal sensory
neuropathy that is felt to be caused, at least in certain cases, by vasculitis.2 The
disease is characterized by sudden numbness and sometimes pain in the distribution
of one or multiple cutaneous nerves. Many patients have spontaneous full recovery,
suggesting a benign condition, whereas others have progressive disease and sensory
deficits.38 In general, no underlying cause is found. A nerve biopsy is usually not
required. When performed, it may show evidence of ischemia and inflammation.39
It is unclear if immunosuppression is helpful.
Self-limiting Nonsystemic Vasculitic Neuropathy

Self-limiting nonsystemic vasculitic neuropathies include postsurgical
inflammatory neuropathy, neuralgic amyotrophy (possibly), painful diabetic
and nondiabetic radiculoplexus neuropathy (lumbosacral, thoracic, cervical, or
in combination), and painless diabetic radiculoplexus neuropathy. Self-limiting
nonsystemic vasculitic neuropathies differ from the nonsystemic vasculitic
neuropathies discussed above in two ways. First, they usually fit a
well-recognized syndrome, and the diagnosis can be made clinically without a
nerve biopsy. Second, they are typically self-limiting, tend to improve on their
own, and tend not to recur. They can be divided into two groups: brachial
plexopathy and lumbosacral plexopathy.
BRACHIAL PLEXOPATHY. This group comprises the classic idiopathic neuralgic

amyotrophy (Parsonage-Turner syndrome), postsurgical inflammatory
neuropathy, and rare causes of significant upper extremity involvement in
diabetic radiculoplexus neuropathy. Idiopathic neuralgic amyotrophy or brachial
plexus neuritis is a common unilateral brachial plexopathy characterized by the
acute onset of pain in the shoulder region rapidly followed by paresthesia and
weakness in the shoulder and upper extremity. The deficit sometimes affects
only one nerve, such as in isolated phrenic neuropathy or anterior interosseus
1272 OCTOBER 2020

neuropathy, which can make diagnosis challenging. After a few weeks or months KEY POINTS
of progression, recovery gradually occurs but is not always complete. The
● Appropriate blood
diabetic form includes autonomic involvement and weight loss, is generally handling, including
bilateral, and can be associated with thoracic and lumbosacral radiculoplexus temperature control, is
neuropathies.40 Postsurgical inflammatory neuropathy can present as brachial essential for testing for
plexopathy, lumbosacral plexopathy, or multifocal neuropathy.41 Idiopathic cryoglobulinemia.
neuralgic amyotrophy is considered an inflammatory neuropathy but there is not
● In mild cases of
enough pathologic evidence that it is caused by vasculitis. However, the clinical cryoglobulinemic
progression is highly suggestive of a vasculitic neuropathy, and some rare nerve neuropathy associated
biopsies have demonstrated evidence of vasculitis.42,43 This has led some authors with infection,
to consider neuralgic amyotrophy as a possible form of nonsystemic vasculitic immunosuppression may
not be required when the
neuropathy.34 In both postsurgical inflammatory neuropathy and diabetic infection is treated
cervical radiculoplexus neuropathy, nerve biopsies have demonstrated adequately.
microvasculitis,40,41 and, in both conditions, a course of corticosteroids may
result in improved neuropathic pain.40,41 It is unclear whether the corticosteroids ● In nonsystemic vasculitic
neuropathy, systemic
halt the progression of the neuropathy, but for a suspected autoimmune brachial symptoms and signs are
plexopathy in its active phase, the author usually prescribes 1 g IV usually absent and serologic
methylprednisolone once per day for 3 consecutive days, then once weekly markers are negative.
for 5 weeks, followed by once every 2 weeks for 6 weeks, for a total of
● Different syndromes of
12 weeks in patients who are experiencing progressive disability at the time of
nonsystemic vasculitic
evaluation. A retrospective study of 50 patients with neuralgic amyotrophy neuropathy carry different
showed that compared to more than 200 historical controls, patients treated prognoses. The diagnosis is
with a short course of steroids had significantly better strength recovery and usually made clinically, and
pain relief.44 patients should be treated if
the disease is active.
LUMBOSACRAL PLEXOPATHY. This group comprises diabetic lumbosacral

radiculoplexus neuropathy (diabetic amyotrophy), painless diabetic
radiculoplexus neuropathy, nondiabetic radiculoplexus neuropathy, and
postsurgical inflammatory neuropathy (discussed above). Diabetic lumbosacral
radiculoplexus neuropathy typically develops acutely with severe burning pain
in the thigh, followed by weakness and atrophy of the lower extremity muscles.5,45
Most of the time the neuropathy spreads to the contralateral side. Patients
frequently have associated weight loss and dysautonomia. The painless form
is motor-predominant neuropathy, frequently symmetric with a slow
progression.46 The diabetic and nondiabetic lumbosacral radiculoplexopathies
are usually monophasic and progress over a period of 6 months on average before
they start to improve.47 The author often treats patients with significant pain and
progressive disability from these conditions with a short course of corticosteroids
as described above for the brachial plexopathy. Whether corticosteroids, IV
immunoglobulin (IVIg), or plasma exchange are helpful in improving outcomes
is unresolved.
PERIPHERAL NEUROPATHY IN AUTOIMMUNE CONNECTIVE TISSUE

DISEASE
Peripheral neuropathies associated with autoimmune connective tissue disease
are varied and often obscured by the symptoms of the primary disorder. If the
peripheral neuropathy becomes clinically significant, one should suspect
vasculitis or a dysimmune neuropathy such as CIDP or multifocal motor
neuropathy (MMN) with or without conduction block in the setting of
anti–tumor necrosis factor-α (TNF-α) therapy. Furthermore, the neuropathy

in chronic diseases can have other causes, such as diabetes, and should
not be attributed to the connective tissue disorder without appropriate
diagnostic evaluation. Common autoimmune connective tissue diseases and
the different types of neuropathies associated with these conditions are
discussed below.
Rheumatoid Arthritis
RA is a common, chronic systemic inflammatory disorder primarily affecting the
articular structures. Patients with RA typically present with arthritis in the hands
and prolonged morning stiffness. Joint erosion is seen on x-rays. Blood markers
include positive rheumatoid factor and anticitrullinated peptide antibodies and
elevated erythrocyte sedimentation rate and C-reactive protein. Peripheral
neuropathy in patients with RA, although common, is usually subclinical and
does not cause significant burden on the patient.48 Age appears to be a major
risk factor for neuropathy; RA severity, the presence of non-neurologic
extraarticular manifestations, and male sex are additional risk factors.49 Compression
neuropathies such as carpal tunnel syndrome are the most common form of
peripheral nervous system involvement in patients with RA. RA increases the risk
of carpal tunnel syndrome by at least twofold.50 Rarely, patients with RA develop
rheumatoid vasculitis with mononeuritis multiplex, which may be treated with
corticosteroids or more aggressive immunosuppression if the response is
inadequate.
Neuropathy in RA can be iatrogenic in nature. TNF-α inhibitors such as
infliximab, adalimumab, certolizumab, and etanercept are commonly used in the
treatment of RA. Studies have shown that patients exposed to TNF-α inhibitors
have a higher risk of peripheral neuropathy.51 Various types of neuropathies have
TABLE 6-5 American College of Rheumatology/European League Against Rheumatism

Classification Criteria for Primary Sjögren Syndromea,b
Item Weight/Score
Labial salivary gland with focal lymphocytic sialadenitis and focus score of 1 or more foci/4 mm2 3
Anti-SSA/Ro positive 3
Ocular staining score of 5 or more (or Van Bijsterveld Score 4 or more) in at least 1 eye 1
Schirmer test of 5 mm/5 min or less in at least 1 eye 1
Unstimulated whole saliva flow rate 0.1 mL/min or less 1
SSA = Sjögren syndrome A.

a
Modified with permission from Shiboski CH, et al, Arthritis Rheumatol.54 © 2016 The Authors.
b
The classification of Sjögren syndrome applies to any individual who meets the inclusion criteria, does not have any of the conditions listed as
exclusion criteria, and has a score of 4 or more when the weights from the five criteria items below are summed. These inclusion criteria are
applicable to any patient with at least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following
questions: (1) Have you had daily, persistent, troublesome dry eyes for more than 3 months? (2) Do you have a recurrent sensation of sand or gravel
in the eyes? (3) Do you use tear substitutes more than 3 times a day? (4) Have you had a daily feeling of dry mouth for more than 3 months? (5) Do
you frequently drink liquids to aid in swallowing dry food? or to any patient in whom there is suspicion of Sjögren syndrome from the European
League Against Rheumatism Sjögren Syndrome Disease Activity Index questionnaire (at least one domain with a positive item). Exclusion criteria
include prior diagnosis of any of the following conditions, which would exclude diagnosis of Sjögren syndrome and participation in Sjögren
syndrome studies or therapeutic trials because of overlapping clinical features or interference with criteria tests: history of head and neck
radiation treatment, active hepatitis C infection (with confirmation by polymerase chain reaction [PCR]), acquired immunodeficiency syndrome
(AIDS), sarcoidosis, amyloidosis, graft versus host disease, or IgG4-related disease.
1274 OCTOBER 2020

been reported with TNF-α inhibitors, including CIDP, MMN with or without KEY POINTS
conduction block, vasculitic neuropathy, small fiber neuropathy, and others.
● Tumor necrosis factor-α
Treatment depends on the type of neuropathy but generally requires stopping inhibitors, which are
the TNF-α inhibitor and, if symptoms do not improve or are severe, managing commonly used to treat
the neuropathy with immunosuppressant treatment (steroids or IVIg).52 rheumatoid arthritis, can
cause inflammatory
autoimmune neuropathies.
Systemic Lupus Erythematosus
SLE is a heterogeneous chronic autoimmune inflammatory disorder that can affect ● Patients with Sjögren
the skin, pleura, joints, kidneys, blood cells and coagulation factors, and the central syndrome frequently
or peripheral nervous system. SLE mainly affects woman of childbearing age. present to the neurologist
More than 95% of patients have a positive antinuclear antibody test. first because of peripheral
neuropathy.
Overt peripheral neuropathy in patients with SLE is rare. The most common
neurologic complications are central in origin and include headache, mood ● The presence of a
disorders, seizures, stroke, and myelitis. Peripheral nervous system involvement significant sensory
can also occur. One study that evaluated 1533 patients with SLE found that 14% neuropathy or dorsal root
ganglionopathy should
had peripheral neuropathy, but 40% of those were not directly related to SLE.53 prompt a thorough
Another study that evaluated 2097 patients with SLE found 5.9% had peripheral evaluation for Sjögren
neuropathy. Among these patients, the neuropathy was directly attributable to syndrome.
SLE in 66.7% of cases.53 The peripheral neuropathy seen in patients with SLE is
typically distal, length dependent, and mainly sensory. However, autonomic
neuropathy, Guillain-Barré syndrome, and CIDP have all been reported in
patients with SLE. As in RA, patients with SLE can rarely develop a vasculitic
neuropathy, which may be treated with corticosteroids or more aggressive
immunosuppression if the response is inadequate. Otherwise management of
peripheral neuropathy in SLE relies on the treatment of SLE and reducing general
risk factors for peripheral neuropathy.
Sjögren Syndrome
Sjögren syndrome is an autoimmune inflammatory disorder affecting exocrine
glands, such as the salivary and lacrimal glands, causing dry eyes and mouth.
Extraglandular manifestations can include disorders of the joints, muscles, lungs,
kidneys, and skin. A 2017 expert consensus based on three patient cohorts
suggested classification criteria based on the weighted sum of five items
(TABLE 6-5).54
Both the central and peripheral nervous systems can be affected in Sjögren
syndrome. Patients with Sjögren syndrome can develop a wide array of
peripheral nervous system manifestations, including distal symmetric
polyneuropathy, mononeuritis multiplex, sensory and autonomic neuropathy,
trigeminal mononeuropathies, and a dorsal root ganglionopathy.55 Dorsal root
ganglionopathy is a rare and disabling neuropathy in which the site of injury is
the primary sensory neurons located in the dorsal root ganglia. Patients
experience non–length-dependent panmodality sensory loss with sensory ataxia
and frequently neuropathic pain. Acquired sensory ganglionopathy should
always raise concerns for an autoimmune condition such as Sjögren syndrome or
a paraneoplastic syndrome with or without associated anti-Hu antibodies. Other
causes of sensory ganglionopathies include vitamin B6 toxicity and exposure to
platinum-based chemotherapy drugs. Patients with undiagnosed Sjögren
syndrome frequently present to the neurologist first because of neurologic
manifestations.56,57 Evaluation for Sjögren syndrome should be performed even
in the absence of sicca syndrome if the suspicion is high, as the neuropathy may

precede sicca syndrome.56 Serum antibodies may be negative as well; thus, minor
salivary gland biopsy is recommended in patients with clinical syndromes
strongly suggestive of Sjögren syndrome, including a significant sensory
neuropathy and autonomic neuropathy or a dorsal root ganglionopathy.
Vasculitis may be demonstrated in patients with a mononeuritis multiplex
pattern, but nonspecific perivascular lymphocytic infiltrates are commonly
observed in the spectrum of Sjögren syndrome neuropathies.55
Treatment of peripheral neuropathy in patients with Sjögren syndrome is
challenging. No randomized control trials have been conducted to support the
use of any specific medication. However, severe disabling neuropathies such as
sensory ganglionopathy and mononeuritis multiplex should be treated with
immunosuppression. Although randomized clinical trials for Sjögren syndrome
have been disappointing,58,59 several case series have shown benefit with IVIg,
steroids, or rituximab (which has also been the author’s experience).60,61
Systemic Sclerosis (Scleroderma)

Systemic sclerosis is a connective tissue disease associated with fibrotic tissue
change, skin thickening, microvascular abnormalities, positive antinuclear
antibodies, and anti-Scl70 antibodies. Clinically evident peripheral neuropathy is
rare in patients with scleroderma. Peripheral nerve abnormalities may be
detected more frequently with careful neurologic examination.62 As in other
rheumatologic disorders, patients can develop vasculitis and multifocal
neuropathy. Inflammatory myopathies are actually more common than
peripheral neuropathy in this population and should be suspected in all patients
with scleroderma reporting new weakness.63
CONCLUSION
Vasculitic neuropathy can be isolated or associated with systemic vasculitis.
Systemic vasculitis can be primary or secondary to associated medical conditions,
including infections or drug exposure. Careful medical history, review of
medications, and laboratory testing can help determine the nature of the
vasculitis, its prognosis, and treatment. In neuropathy associated with
connective tissue disease, it is important to rule out other causes of neuropathy,
such as diabetes or vitamin deficiency. On many occasions, neurologists will be
the first to evaluate patients with neuropathy related to these disorders; rapid
recognition, appropriate workup, and initiation of treatment can reduce
morbidity and, in some cases, mortality.
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REVIEW ARTICLE

ONLINE
Due to Vitamin and
Mineral Deficiencies,
Toxins, and Medications

By Nathan P. Staff, MD, PhD, FAAN
ABSTRACT
PURPOSE OF REVIEW: Vitamin and mineral deficiencies, neurotoxins, and,
particularly, prescription medications, are some of the most common
causes of peripheral neuropathy. Recognition and prompt treatment of
these neuropathies require a high index of suspicion and an accompanied
detailed history. This article provides a comprehensive approach and list of
items that must be considered in the setting of new-onset neuropathy.
RECENT FINDINGS: Although many of the neuropathies described in this article

have decreased in prevalence in developed countries because of public
health interventions and occupational/environmental regulations, new
causes for this class of neuropathy continue to be uncovered.
CITE AS: SUMMARY: The peripheral nervous system is susceptible to a broad array of
metabolic and toxic abnormalities, which most often lead to a length-
MOTOR NEURON DISORDERS): dependent sensory-predominant axonal peripheral neuropathy. A careful
1280–1298. history accompanied by recognition of multisystem clues can increase
recognition of these neuropathies, which is important as many have specific
Dr Nathan P. Staff, Mayo Clinic, treatments that may either improve the neuropathy or halt its progression.
200 First St SW, Rochester, MN
55905, staff.nathan@mayo.edu.
RELATIONSHIP DISCLOSURE: INTRODUCTION
D
Dr Staff serves as an associate eciphering the cause of a patient’s peripheral neuropathy is often a
editor of Stem Cell Research &
Therapy and receives
diagnostic challenge. Etiologies may range from things that are
research/grant support from common in the population (eg, diabetes, hereditary neuropathies)
BrainStorm Cell Limited, Disarm to things that are very rare, such as POEMS (polyneuropathy,
Therapeutics, the National
Institutes of Health (R01 CA211887); organomegaly, endocrinopathy, monoclonal plasma cell disorder,
Orion Therapeutics, LLC; and and skin changes) syndrome. It is critical that toxic and nutritional causes be
Regenerative Medicine systematically considered in the peripheral neuropathy differential diagnosis,
Minnesota (RMM 11215 CT002).
as identifying a specific underlying toxic or nutritional cause may lead to a cure
UNLABELED USE OF if recognized expeditiously.
USE DISCLOSURE:
To uncover a toxic or nutritional neuropathy, a careful history must be taken,
Dr Staff reports no disclosure. including medications, environmental exposures, hobbies, and alcohol consumption.
Determining the timing of neuropathy onset is also crucial. Most toxic neuropathies
should temporally coincide with the toxic exposure; if they do not, one must consider
of Neurology. an alternative diagnosis. A broader review of systems that pays particular attention to
1280 OCTOBER 2020

skin, nails, and hematologic and gastrointestinal systems may provide further insight KEY POINTS
because of the multiorgan involvement of many of these neuropathies (TABLE 7-11).
● A broad review of
systems that includes skin,
NUTRITIONAL DEFICIENCY–ASSOCIATED NEUROPATHIES nails, and hematologic and
Many different nutritional deficiencies may cause peripheral neuropathy. Often these gastrointestinal systems
neuropathies are associated with other signs and symptoms outside of the peripheral may provide clues to a
neuropathy caused by
nervous system that may provide clues to their etiology. Many nutritional
vitamin deficiencies or
deficiencies are now less common in the developed world because of better public toxins.
health and supplemented foods. Conversely, gastric bypass surgeries performed in
the developed world increase the risk of nutritional neuropathies; however, these ● Vitamin B12 deficiency
may be prevented with adherence to recommended supplements (FIGURE 7-1). secondary to inadequate
oral intake is uncommon,
Treatment guidelines for vitamin and mineral deficiencies are provided in TABLE 7-2.1 except in cases of a strict
vegan diet.
Vitamin B12
Vitamin B12 deficiency secondary to inadequate oral intake is uncommon, except ● Simultaneous onset of
sensory symptoms in the
in cases of a strict vegan diet. Most forms of vitamin B12 deficiency are due to poor hands and feet suggests
gastrointestinal absorption. Vitamin B12 has a complicated absorption pathway cervical cord pathology,
that starts with the production of intrinsic factor in the parietal cells of the which may be seen in
stomach.2 Intrinsic factor binds to vitamin B12 in the duodenum and is ultimately vitamin B12 or copper
deficiencies.
absorbed in the terminal ileum.
Specific causes of vitamin B12 deficiency can be viewed through the lens of this
absorptive pathway. Atrophic gastritis, gastric bypass, or prolonged proton
pump inhibitor use3 may lead to poor production of intrinsic factor and binding
of vitamin B12. In pernicious anemia, the parietal cells are attacked by the
immune system, which also leads to decreased intrinsic factor production.
Finally, poor absorption in the terminal ileum may occur in the setting of
inflammatory bowel disease (Crohn disease) or because of surgical resection.
Metformin use has also been associated with poor vitamin B12 absorption,4
highlighting the importance of not assuming all neuropathy in patients with
diabetes is due to their diabetes.4
Vitamin B12 deficiency leads to subacute combined degeneration of the spinal
cord. This typically presents clinically as sensory loss, paresthesia, and ataxia and
variably with cognitive deficits. One clue to this disorder is simultaneous onset of
sensory symptoms in the hands and the feet, which likely reflects the typical
cervical cord pathology that may be observed on MRI.5 On examination, these
patients often have mixed upper and lower motor neuron signs (absent ankle
reflexes with Babinski signs).
Neuropathy related to vitamin B12 deficiency is so well recognized that
testing for vitamin B12 deficiency is one of the few laboratory investigations
recommended in guidelines for the workup for neuropathy.6 Laboratory testing
for vitamin B12 deficiency should include both vitamin B12 and methylmalonic
acid levels. An elevated methylmalonic acid in the setting of a normal vitamin B12
level indicates cellular vitamin B12 deficiency. Autoantibodies to parietal
cells or elevated gastrin levels can help secure a diagnosis of pernicious
anemia. It is prudent to check for concomitant folate deficiency, as these
deficiencies often occur together. Given the combination of upper and lower
motor findings with cognitive deficits, imaging of the brain and spinal cord is
often performed. Cervical cord MRI may show T2 hyperintensity in the posterior
columns. Nerve conduction studies and EMG typically demonstrate an axonal
sensorimotor peripheral neuropathy.

PERIPHERAL NEUROPATHIES DUE TO DEFICIENCIES, TOXINS, AND MEDICATIONS
Replacement of vitamin B12 will typically halt progression of the subacute

combined degeneration; however, reversibility is typically less obvious. Because
most patients have poor gastrointestinal absorption, subcutaneous or IM
injection of 1 mg vitamin B12 is typically recommended at weekly intervals for
1 month and monthly thereafter (CASE 7-1), although 2018 data suggest that
high-dose oral replacement may be equivalent.7
TABLE 7-1 Systemic Involvement That May Provide Clues to the Etiology of a Peripheral
Neuropathy Due to Toxicity or Vitamin Deficiency
Central Nervous System

◆ Cognition
◇ Vitamin B12 deficiency
◇ Niacin deficiency (pellagra)
◇ Thiamine deficiency (Wernicke-Korsakoff syndrome)
◇ Lead toxicity
◇ Arsenic toxicity
◇ Mercury toxicity
◇ Disulfiram toxicity
◆ Cerebellum
◇ Vitamin E deficiency
◆ Corticospinal
◇ Copper deficiency
◆ Posterior column
Integument
◆ Skin
◇ Thiamine deficiency (beriberi)
◇ Lead toxicity
◇ Arsenic toxicityb
◇ Thallium toxicityc
◇ Silver toxicityd
◆ Nails
◇ Arsenic toxicitye
◇ Thallium toxicitye
1282 OCTOBER 2020

Copper
Elemental copper is absorbed in the stomach and duodenum. Acquired copper
deficiency may arise from inadequate intake, poor absorption, gastric surgery,
or zinc overuse, which causes deficiency by competitive absorption. Zinc
overuse from denture cream was once a common cause of copper deficiency;
however, most denture creams no longer contain zinc, and the incidence of this
Musculoskeletal System
◆ Muscle
◇ Vitamin E deficiencyf
Gastrointestinal System
◆ Intestines
◇ Lead toxicity
◇ Thallium toxicity
◆ Liver
Cardiovascular System
◆ Heart
◇ Thiamine deficiency (wet beriberi)
Renal System
◆ Kidney
Hematologic System
◆ Anemia
◇ Lead toxicity
◆ Pancytopenia
a
Modified with permission from Staff NP, Windebank AJ, Continuum (Minneap Minn).1 © 2014 American
Academy of Neurology.
b
Alopecia; melanosis with chronic exposure.
c
Alopecia.
d
Blue discoloration.
e
Mees lines.
f
Myopathy.

KEY POINTS cause has decreased significantly.

Zinc supplements are popular
● When investigating
vitamin B12 deficiency, it is
preventive treatments for viral
important to also consider upper respiratory tract infection
copper deficiency because and should be investigated in
the clinical picture can be the history.
very similar.
Copper deficiency mimics
● Vitamin B6 vitamin B12 deficiency, presenting
supplementation is only with clinical and pathologic
routinely recommended in evidence of a myeloneuropathy.8 It
the setting of isoniazid or is important to exclude copper
hydralazine treatment, in
which vitamin B6 deficiency deficiency in the workup of a patient
may occur. Otherwise, with sensory symptoms, ataxia, and
vitamin B6 supplementation mixed upper and lower motor
itself can cause a sensory neuron signs (eg, absent reflexes
neuropathy or sensory
ganglionopathy.
with Babinski signs). An axonal
length-dependent sensorimotor
peripheral neuropathy is seen on
nerve conduction studies, and
evidence of central slowing on
somatosensory evoked potentials is
also typically seen.9 Patients with
copper deficiency often also have
anemia and leukopenia. In the
appropriate clinical setting, serum
copper and zinc levels should
be tested.
The recommended replacement
therapy in copper deficiency is oral
FIGURE 7-1
elemental copper supplementation
Absorption of vitamins and minerals in the
gastrointestinal tract. of 8 mg/d for 1 week, 6 mg/d for
1 week, 4 mg/d for 1 week, and
then 2 mg/d thereafter. If the
underlying cause of copper
deficiency is reversed (ie, zinc overuse), the copper supplementation may be
halted once there has been documented repletion in 6 months. If the cause is
unclear, copper supplementation is recommended indefinitely. Reversibility
of neurologic damage is limited, with most patients reporting stabilization
of symptoms.
Vitamin E
Vitamin E is a fat-soluble vitamin that occasionally becomes deficient in the
setting of fat malabsorption (eg, from steatorrhea from cystic fibrosis or biliary
dysfunction). Vitamin E deficiency also occurs with the rare autosomal recessive
genetic disorders abetalipoproteinemia or ataxia with vitamin E deficiency,
which impair fat absorption. Vitamin E deficiency causes a large fiber peripheral
neuropathy with prominent cerebellar ataxia and areflexia with associated
Babinski signs (clinically similar to Friedreich ataxia). If fat malabsorption is
severe, replacement therapy with vitamin E is typically parenteral with
200 mg/d, but this may be switched to a high-dose oral formulation after
1284 OCTOBER 2020

correcting the primary cause of the deficiency. Genetic testing should be
considered when the cause for fat malabsorption is not evident.
Vitamin B6
Vitamin B6 deficiency is thought to primarily occur in the setting of isoniazid
therapy for tuberculosis. Vitamin B6 supplementation with isoniazid is standard
of care, which typically prevents deficiency from occurring. Vitamin B6 deficiency
due to poor oral intake is very uncommon. It presents as a sensory-predominant
axonal length-dependent peripheral neuropathy. Replacement therapy for
vitamin B6 deficiency is 50 mg/d orally, but this should only be given in
the setting of clear deficiency or during prolonged isoniazid or hydralazine
treatment.
The reason for caution with vitamin B6 supplementation is that peripheral
nerve damage from vitamin B6 can occur when it is taken in excess.10 Vitamin B6
toxicity occurs with excessive supplementation, typically more than 2 g/d, but
neuropathy from long-standing use of 50 mg/d has been reported. Of note,
vitamin B6 is present in many “nerve health” supplements that may be taken at
doses higher than recommended. Vitamin B6 toxicity causes direct damage to the
dorsal root ganglia sensory neurons and, in severe cases, may present as an
irreversible ganglionopathy that may worsen for weeks following
discontinuation of vitamin B6. In milder cases, reversibility is the rule (CASE 7-2).
Thiamine
Thiamine deficiency presents as either wet (heart failure) or dry (neuropathic)
beriberi syndrome. Fortunately, thiamine deficiency is rare in the developed
Vitamin Supplementation Recommendations in Symptomatic Vitamin TABLE 7-2

Deficienciesa
Confirmatory Length of Treatment/

Vitamin Testing Dosage/Route Comments Comments
Vitamin B12 Serum vitamin B12 1 mg IM/subcutaneous weekly Lifelong unless a Investigate for concomitant
(methylmalonic for 1 month, then monthly reversible cause is folate deficiency
acid) identified
Copper Serum copper Elemental copper (oral): Lifelong unless a Investigate for zinc excess
(ceruloplasmin, 8 mg/d for 1 week, 6 mg/d for reversible cause is
urine copper) 1 week, 4 mg/d for 1 week, identified
2 mg/d thereafter
Vitamin E Serum vitamin E Vitamin E (oral/IM): 200 mg/d Lifelong unless a

to 200 mg/kg/d depending on reversible cause is
severity and cause identified
Vitamin B6 Vitamin B6 50 mg oral daily Only necessary in High-dose vitamin B6

setting of isoniazid or supplementation causes
prolonged sensory neuropathy or
hydralazine treatment sensory ganglionopathy
IM = intramuscular.
a
Updated from Staff NP, Windebank AJ, Continuum (Minneap Minn).1 © 2014 American Academy of Neurology.

world outside of severe alcohol use disorder and malnutrition. The presentation
of dry beriberi may be either an axonal peripheral neuropathy (often with cranial
nerve involvement) or a polyradiculoneuropathy that mimics Guillain-Barré
syndrome.11 Thiamine deficiency can also present with Wernicke-Korsakoff
syndrome with anterograde amnesia.
It is important to replenish thiamine before administration of glucose
solutions, as glucose can severely exacerbate the thiamine deficiency (especially
in Wernicke-Korsakoff syndrome). This is typically delivered as 100 mg IV
thiamine, but higher doses may be used in the setting of confirmed
Wernicke-Korsakoff syndrome.
CASE 7-1 A 72-year-old woman presented with a 6-month history of progressive

unsteadiness while walking. She also described some tingling in her
hands and feet that began about a year earlier. She had been healthy
apart from occasional gastroesophageal reflux, for which she had been
taking a proton pump inhibitor.
Neurologic examination demonstrated loss of sensation to touch and
vibration in the hands and feet, with impaired proprioception at the great
toes and index fingers. She had trace ankle dorsiflexor weakness
bilaterally and was hyperreflexic at the knees with reduced reflexes at
the ankles. Babinski sign was present bilaterally.
MRI of her cervical spine revealed an area of longitudinal T2
hyperintensity in the posterior spinal cord without any associated
structural abnormalities (FIGURE 7-2). Nerve conduction study
demonstrated low-amplitude fibular (peroneal) and tibial compound
muscle action potentials (CMAPs). The sural sensory nerve action
potential (SNAP) was absent. The median and ulnar SNAP amplitudes
were reduced. Motor and sensory conduction velocities were normal,
and she had no conduction block or abnormal temporal dispersion.
Her serum copper was normal. Her vitamin B12 level was in the low
normal range at 224 ng/L (normal >180 ng/L). Her methylmalonic acid
level was elevated at 0.55 nmol/mL (normal <0.4 nmol/mL).
Because of the clinical scenario combined with an elevated
methylmalonic acid, a diagnosis of cellular vitamin B12 deficiency causing
subacute combined degeneration of the spinal cord and a concomitant
polyneuropathy was made, and the patient was started on IM vitamin B12
supplementation and physical therapy. At a 6-month follow-up visit, her
sensory symptoms were stable and she reported somewhat improved
steadiness on her feet.
1286 OCTOBER 2020

TOXIC NEUROPATHIES
Patients often raise the possibility that their peripheral neuropathy is due to a
toxic exposure. For a recent exposure with a known neurotoxic agent (eg,
paclitaxel), it may be easy to ascribe causality. On the other hand, with a
decades-old exposure (eg, toxic dust from living in New York during 9/11 or
Agent Orange exposure in Vietnam) in a patient with recent-onset neuropathy, it
can be difficult (or impossible) to assert any relation. From an epidemiologic
standpoint, the Bradford Hill criteria may be used as evidence to support a causal
association in the population.12 In the specific context of neurotoxicity,
Schaumburg13 narrowed this to five causation criteria (TABLE 7-3). Although
FIGURE 7-2
Sagittal (A) and axial (B) T2-weighted MRIs of the cervical spinal cord of a patient with
vitamin B12 deficiency. Arrows highlight the T2 hyperintensity within the
posterior spinal cord.
Causes for vitamin B12 deficiency include pernicious anemia, strict COMMENT
veganism, gastric bypass, prolonged antacid use, atrophic gastritis, or
diseases of the terminal ileum (eg, resection, Crohn disease). In this case,
use of a proton pump inhibitor resulting in atrophic gastritis may have
been the reason for poor vitamin B12 absorption. In the setting of a
myeloneuropathy, it is important to check both vitamin B12 and
methylmalonic acid because the vitamin B12 levels may be low normal or
only modestly reduced, as in this case. Serum copper was also checked
given the overlapping syndromes of vitamin B12 deficiency and copper
deficiency. The goal of vitamin B12 deficiency replacement therapy is to halt
progression. Improvement of myeloneuropathy is often minimal but may
be facilitated by physical therapy aimed at gait training.

these criteria may be helpful to guide the clinician, they do not encompass the
entire picture of neurotoxicity. For example, certain neurotoxins (eg, hexanes,
platinum chemotherapeutics) exhibit the coasting phenomenon, wherein the
neuropathy may actually worsen for weeks to months following cessation of the
exposure. Furthermore, it may be difficult to determine whether a neuropathy
is worsening or merely becoming more painful. In general, worsening of
neuropathy is better measured with negative symptoms, such as loss of sensation
and weakness, than it is with the positive symptoms of pain and paresthesia.
CASE 7-2 A 57-year-old man presented with a 3-month history of progressive

sensory symptoms, which he described as a buzzing and tingling
sensation starting in his feet that progressed over 1 week to his hands. He
felt like he was not quite as steady on his feet as before. He had no other
medical problems and did not take any prescribed medications, but he
did take a number of supplements. He also reported having a “couple of
beers” a day. He had no family history of neuromuscular disorders.
Neurologic examination revealed reduced sensation to all sensory
modalities. Strength was normal, and deep tendon reflexes were absent
at the ankles. When asked about his history of taking supplements, he
revealed taking four tablets of a daily nerve health supplement. Each
tablet included 50 mg vitamin B6, for a total daily dose of 200 mg.
Nerve conduction study demonstrated a low-amplitude sural sensory
nerve action potential (SNAP) but was otherwise normal. On laboratory
testing, his pyridoxal 5′-phosphate level was found to be elevated at
110 mcg/L (normal 5 mcg/L to 50 mcg/L). His fasting blood glucose was
120 mg/dL. The patient was told to stop taking the vitamin B6 supplement
and counseled to decrease his alcohol consumption. He was also
referred to his primary care physician for prediabetes management.
At his 3-month follow-up, the patient reported that his gait and
sensory symptoms initially continued to worsen for a few weeks after
cessation of vitamin B6 but then improved, and he had minor residual loss
of sensation on examination.
COMMENT This case illustrates a common scenario in which multiple possible causes
of peripheral neuropathy were present in a single patient. Given the rapid
improvement of symptoms following a few weeks of coasting (the
phenomenon in which a neuropathy may worsen for weeks to months
following termination of the inciting agent), it is most likely that the
vitamin B6 toxicity was the primary driver of this patient’s neuropathy.
Despite that, it is always important to mitigate other factors that could
play a role in a patient’s nerve health. In this case, recommendations were
made to limit the patient’s alcohol consumption and begin prediabetes
management. This case also demonstrates the importance of inquiring
about supplement use and examining the contents of multivitamins or
specific combination supplements patients may be taking.
1288 OCTOBER 2020

Finally, it is clear that the concept of causation is becoming more complex as our
understanding becomes more sophisticated. For example, how a given
neurotoxin may interact with a polygenic disease or epigenetic modifiers in a
specific patient would likely be difficult to assess at the bedside.14
Alcohol
A strong association exists between excess alcohol use and peripheral
neuropathy, and it is likely that alcohol overuse is one of the most common
causes of neuropathy. Although a recent survey study discovered that 26.4%
of adults reported binge drinking or heavy alcohol use in the past month,15 it can
be very challenging in the clinic to accurately assess the level of alcohol use.
Underreporting of alcohol use is rampant, and a high index of suspicion should
be employed. Other laboratory indications of alcohol overuse (elevated liver
function tests or red blood cell macrocytosis) may provide ancillary clues to
alcohol use, and, when uncovered, it is imperative to involve addiction specialists
early in the patient’s care.
Debate continues about whether the neuropathy associated with alcohol use
disorder is directly due to alcohol toxicity or primarily because of the poor
nutrition that is often seen in these patients.16,17 As stated above, alcohol abuse is
often associated with thiamine deficiency, which itself causes neuropathy.
Studies that have carefully documented adequate nutritional status in people
with alcohol use disorder have strongly suggested a separate role for alcohol-
induced neurotoxicity. Furthermore, alcohol-induced neuropathy has been
reported to have different clinical characteristics than nutrition-related
neuropathies and is more likely to be a painful small fiber neuropathy phenotype.
Because of the difficulties with its diagnosis, it is prudent to exercise caution
about quickly ascribing causality for alcohol use for a patient’s neuropathy in the
clinic, and other etiologies should be considered. On the other hand, given that it
is known that ethanol is toxic to in vitro dorsal root ganglia neurons,18 alcohol
moderation is recommended in anyone with peripheral neuropathy of any cause.
Renal Failure
Renal failure is a well-known cause of peripheral neuropathy, often referred to as
uremic neuropathy. With the advent of dialysis for renal failure, this has become
Causation Criteria for Identification of Neurotoxicitya,b TABLE 7-3
◆ Presence of the suspected agent is confirmed by history and either environmental or clinical
chemical analysis
◆ Severity and temporal onset of the condition are commensurate with duration and level of
exposure
◆ The condition is self-limiting, and clinical improvement follows removal from exposure
◆ Clinical features display a consistent pattern that corresponds to previous cases
◆ Development of a satisfactory corresponding experimental in vivo or in vitro model is
absolute proof of causation
a
Data from Schaumburg HH, Oxford University Press.13

less of a clinical problem. It is unclear the extent to which renal failure in the setting
of diabetes may synergistically worsen diabetic peripheral neuropathy (or vice
versa), although clinical experience suggests patients with diabetes who have
uremia, particularly those requiring dialysis, have a more severe neuropathy that
often exhibits distal weakness.19 It is important to consider other causes of
neuropathy in patients on chronic dialysis, as the uremic neuropathy in this setting
is typically a mild axonal sensorimotor peripheral neuropathy.
Heavy Metals
Exposure to several heavy metals has been shown to cause peripheral
neuropathy.20 Since these associations have been established, the incidence of
these toxic neuropathies has decreased because of changes in work safety and
public health. Classic heavy metal intoxications that lead to peripheral
neuropathy include lead, arsenic, thallium, and mercury. A high index of
TABLE 7-4 Occupational Exposures of Specific Toxinsa
Toxin Common Exposure Neuropathy Phenotype Treatment/Prognosis

Acrylamide (monomer, not Industrial (skin) Length-dependent sensorimotor Removal of exposure
polymerized form) peripheral neuropathy, acral results in near-complete
hyperhidrosis, dermatitis, ataxia, reversibility of
axonal peripheral neuropathy neurotoxicity
Allyl chloride Industrial (inhalation) Length-dependent sensorimotor Removal of exposure

peripheral neuropathy, axonal results in near-complete
peripheral neuropathy reversibility of neurotoxicity
Carbon disulfide Industrial (inhalation) Length-dependent sensorimotor Poor recovery

peripheral neuropathy, axonal
peripheral neuropathy,
encephalopathy (high doses)
Dimethylaminopropionitrile Industrial (inhalation) Urogenital dysfunction (and sacral Good recovery

(DMAPN) sensory loss), length-dependent
sensorimotor peripheral neuropathy,
axonal peripheral neuropathy
Ethylene oxide Industrial (inhalation) Length-dependent sensorimotor Good recovery

peripheral neuropathy, axonal
peripheral neuropathy,
encephalopathy
Hexacarbons (n-hexane and Industrial, inhalant Length-dependent sensorimotor Good recovery in mild
methyl n-butyl ketone) abuse peripheral neuropathy, occasionally cases, modest recovery in
severe (especially in inhalant abusers); more severe cases
coasting occurs; mixed axonal/
demyelinating peripheral neuropathy
Organophosphates Industrial, insecticides Occurs 1–3 weeks after exposure Good recovery only in very
(skin, inhalation, (after cholinergic syndrome), motor mild cases; if myelopathy
gastrointestinal) more than sensory peripheral present, poor recovery
neuropathy, corticospinal tract signs
a
1290 OCTOBER 2020

suspicion is often required for accurate diagnoses of these neuropathies, which KEY POINTS
may be tested via 24-hour urine collections (note that nontoxic organic arsenic
● Neuropathy due to
from seafood may be reported). Clinical clues that can be helpful for heavy metal thiamine deficiency has
intoxication include concomitant cognitive issues (lead, arsenic, mercury), many presentations,
alopecia and Mees lines (arsenic, thallium), and severe gastrointestinal upset including length-dependent
(lead, arsenic, thallium) (TABLE 7-1). The neuropathy phenotypes are varied. sensorimotor, cranial nerve,
and motor-predominant
Lead neuropathy is classically a motor-predominant upper extremity phenotype
polyneuropathy, all of which
(wrist-drop). Arsenic and thallium are often preceded by severe systemic illness may precede cognitive and
followed by either painful sensory neuropathy or a presentation similar to systemic symptoms.
Guillain-Barré syndrome.21,22 Whereas organic mercury does produce
paresthesia, its primary impact is from its fatal central nervous system toxicity. ● Establishing a causal link
between alcohol use and
Metal intoxication also occurs as either a contaminant or primary component neuropathy can be difficult
of nutraceuticals.23 Ayurvedic therapies are compounded products used in for a variety of reasons, but
traditional Indian medicine that may contain a combination of herbs, metals, it is recommended that all
minerals, and gems; approximately 20% of the products available on the internet patients with neuropathy
ingest minimal alcohol. Early
have been shown to contain metal (lead, mercury, or arsenic).24 Lead bullets referral to a chemical
may lead to intoxication either via chronically retained fragments or ingestion dependence specialist is
of wild game. Furthermore, rare reports exist of axonal peripheral neuropathy recommended when alcohol
associated with silver ingestion, which is available in colloidal forms purported use disorder is suspected.
to “kill pathogens.”25 Neuropathy due to silver intoxication is typically sensory
● Uremic neuropathy in the
predominant and is often accompanied by argyria, a bluish discoloration of setting of chronic dialysis is
the skin. typically a mild axonal
sensorimotor peripheral
neuropathy; other etiologies
Industrial Agents
should be considered if a
Similar to heavy metals, several industrial agents may cause peripheral severe neuropathy is
neuropathies,26 and their incidence has decreased following public health and encountered.
work safety responses to well-publicized outbreaks. In the developed world,
most exposures occur via personal use or small businesses for which regulations ● Intoxication from arsenic
or thallium is preceded by
are less stringent. Here again, a specific history that includes occupational and severe gastrointestinal
hobby exposure is imperative to detect these causes. Special note is made of illness, and the neuropathy
hexacarbons, which may cause intoxication either purposefully (inhalant abuse) may mimic Guillain-Barré
or from use in small machine shops for degreasing purposes. Hexacarbons cause syndrome.
a length-dependent sensorimotor neuropathy, which can be severe and
● Obtaining a detailed
associated with coasting. Further details about neurotoxic industrial agents are occupational and hobby
provided in TABLE 7-4. exposure history is critical
for discovering many toxic
neuropathies.
Medications
The most common cause of toxic neuropathy encountered in clinical practice is ● Medications may cause
medication exposure; many prescription medications have peripheral peripheral neuropathy in a
neuropathy as a potential side effect.27 The neuropathy may be predictably dose dose-dependent fashion or
dependent or idiosyncratic in onset. When these diagnoses are made, it is may be a rare idiosyncratic
reaction.
important to coordinate any possible medication changes with the prescribing
physician. If a medication is widely used, even an idiosyncratic neuropathy could
result in a significant public health impact. An example of this was recently
shown in the case of fluoroquinolone use, which is a rare cause of neuropathy
based on epidemiologic studies.28 A list of the currently used medications most
commonly associated with peripheral neuropathy is presented in TABLE 7-5.
Special consideration is made for neuropathies caused by neurotoxic
chemotherapy agents.29 Chemotherapy-induced peripheral neuropathy tends
to be axonal, sensory predominant, and dose dependent and occurs in

TABLE 7-5 Medications That Are Known to Cause Peripheral Neuropathya
Class and Drug Neuropathy Phenotype Comments
Anesthetic
Nitrous oxide Subacute combined Causes vitamin B12 deficiency

degeneration
Alcohol antagonist
Disulfiram Sensorimotor axonal
Antiarrhythmic
Amiodarone Sensorimotor axonal/

demyelinating
Procainamide Sensorimotor demyelinating Can mimic chronic inflammatory demyelinating

polyradiculoneuropathy (CIDP)
Antigout
Colchicine Mild sensory-predominant Myopathy usually more prominent; disrupts

axonal microtubules
Antihypertensive
Hydralazine Sensory-predominant axonal Rare except with prolonged high doses; prevented
with pyridoxine treatment
Antimicrobial
Chloramphenicol Mild painful sensory-

predominant axonal
Dapsone Motor-predominant axonal May mimic mononeuritis multiplex
Ethambutol Sensory-predominant axonal May also cause retrobulbar optic neuropathy
Fluoroquinolones Sensorimotor axonal Still controversial whether drug causes peripheral

neuropathy
Metronidazole Sensory-predominant axonal
Nitrofurantoin Sensorimotor axonal Can be severe, mimicking Guillain-Barré syndrome;

usually occurs in patients with renal impairment
Antineoplastic
Ado-trastuzumab emtansine Sensorimotor Antibody-drug conjugate
Brentuximab vedotin Sensorimotor
Epothilones (ixabepilone) Sensorimotor axonal
1292 OCTOBER 2020

Class and Drug Neuropathy Phenotype Comments
Eribulin mesylate Sensory-predominant axonal
Immune checkpoint inhibitors Polyradiculoneuropathy Often responsive to immunotherapy

(anti-PD1, anti–PD-L1, anti-CTLA4)
Platinum-based chemotherapy Sensory axonal/neuronopathy Cold-induced dysesthesia with oxaliplatin

(cisplatin, oxaliplatin, carboplatin)
Podophyllotoxins (etoposide, Sensorimotor axonal

teniposide)
Proteasome inhibitors Sensory-predominant axonal Carfilzomib less commonly causes peripheral

(bortezomib, carfilzomib) neuropathy; occasionally mimics mononeuritis
multiplex
Suramin Sensorimotor axonal/

demyelinating
Taxanes (paclitaxel, docetaxel) Sensorimotor axonal
Thalidomide, lenalidomide Sensory axonal
Vinca alkaloids (vincristine/ Sensorimotor axonal

vinblastine)
Antiseizure
Phenytoin Mild sensorimotor axonal
Antituberculosis
Isoniazid Sensory-predominant axonal Prevented with pyridoxine treatment
Immunosuppressant
Chloroquine Sensorimotor axonal/ Myopathy usually more prominent

demyelinating
Gold salts Sensorimotor axonal/

demyelinating
Leflunomide Painful sensory-predominant

axonal neuropathy
Nucleoside analogue reverse

transcriptase inhibitor
“D-drugs”: zalcitabine (ddC), Painful sensory axonal May have coasting; associated with elevated
didanosine (ddI), stavudine (d4T) lactate
a

more than 40% of patients

receiving neurotoxic agents.
Chemotherapy-induced
peripheral neuropathy is a leading
cause of drug dose reduction or
cessation, which may impact
survival in patients with cancer.
Furthermore, the lasting effects
of chemotherapy-induced
peripheral neuropathy can lead to
long-term morbidity, which can
relate to pain or gait instability.30,31
The main categories of agents
causing chemotherapy-induced
peripheral neuropathy are
platinates, taxanes, vinca
alkaloids, and proteasome
inhibitors (FIGURE 7-3).
Platinum-induced peripheral
neuropathy is seen in patients
receiving cisplatin, oxaliplatin, or
carboplatin.32 Carboplatin is less
neurotoxic than cisplatin or
oxaliplatin. Chronic platinum- FIGURE 7-3
Intracellular components of a peripheral sensory
induced peripheral neuropathy
nerve impacted by neurotoxic chemotherapy,
manifests as a sensory which leads to chemotherapy-induced peripheral
ganglionopathy with large fiber neuropathy.
sensory loss and sensory ataxia,
which is likely due to the toxic
effect of platinum DNA binding
in dorsal root ganglion sensory neurons. As mentioned earlier, an unusual feature
of platinum-induced neuropathy is the coasting phenomenon. Oxaliplatin is
unique in that is also causes acute cold-induced hyperalgesia, which likely arises
because of increased neuronal excitability via oxaliplatin’s effect on
voltage-gated sodium channels (CASE 7-3).
Taxanes and vinca alkaloids target the microtubules, which disrupts cell
mitosis but also frequently leads to chemotherapy-induced peripheral neuropathy.
Taxanes (paclitaxel, docetaxel, cabazitaxel) stabilize microtubule dynamics and
cause a dose-dependent length-dependent axonal sensory neuropathy.33
Paclitaxel, which is the most neurotoxic agent in this category, is also associated
with a diffuse acute pain syndrome in half of patients. The paclitaxel acute pain
syndrome is not clearly neuropathic but has been associated with the later
development of paclitaxel-induced neuropathy.34 Vinca alkaloids cause an
axonal sensorimotor peripheral neuropathy and are more likely to lead to
footdrop than the other neurotoxic chemotherapeutics, particularly when used
in younger populations.35 Vocal cord paralysis has also been reported more
frequently with vinca alkaloids.
Bortezomib and carfilzomib inhibit the proteasome, which is critical for
intracellular protein recycling. Proteasome inhibitors lead to a painful axonal
sensory neuropathy, which often may improve after medication withdrawal.36
1294 OCTOBER 2020

Bortezomib is more neurotoxic, but the effects have been shown to be less severe
when it is delivered subcutaneously.
Immune-mediated neuropathies are becoming more recognized with the
newer class of chemotherapeutics known as immune checkpoint inhibitors,
although they are not strictly neurotoxic.37 Ipilimumab targets the human
cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), leading to activation
of cytotoxic T-lymphocytic attacks on cancer cells. Cell death regulation of
immune cells is targeted via either the PD1 receptor (pembrolizumab and
nivolumab) or PD1 ligand (atezolizumab, durvalumab, avelumab).
Approximately 3% of patients develop neurologic side effects, including
peripheral and central nervous system disorders, some of which are
A 52-year-old woman was recently diagnosed with colon cancer and CASE 7-3
began a course of FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin)
regimen chemotherapy. She had no prior neuropathic symptoms but
developed unpleasant paresthesia that continued for 3 days following
her chemotherapy infusions. She underwent 12 cycles of FOLFOX every
2 weeks and had recurrent neuropathic symptoms with each infusion. She
said the dysesthesia was aggravated when her hands were cold and that
she even had dysesthesia in her throat when she drank cold liquids.
During the final cycles of chemotherapy, she began to develop loss of
sensation and gait unsteadiness that continued to worsen until 2 months
after her final infusion. The cold-induced dysesthesia ended following
her chemotherapy.
Neurologic examination 6 months after her final oxaliplatin infusion
demonstrated loss of sensation to touch, vibration, and joint position
sense in the toes, ankles, and fingers. Strength was normal, but she was
areflexic and tandem gait was impaired. Nerve conduction studies
demonstrated absent sural, median, and ulnar sensory nerve action
potentials (SNAPs). Blink responses and the remainder of the
electrodiagnostic testing were normal.
This case illustrates the two types of peripheral neurotoxicity caused by COMMENT
oxaliplatin. First, acute cold-induced dysesthesia may occur during the first
few days of each oxaliplatin infusion. During this period, it is possible to
demonstrate peripheral nerve hyperexcitability with peripheral nerve
excitability studies (a modified form of nerve conduction study that
quantitates threshold currents required for nerve action potential
generation). This type of neurotoxicity is exclusive to oxaliplatin and does
not occur with cisplatin or carboplatin. Later during oxaliplatin therapy, a
dose-dependent sensory ganglionopathy occurs that primarily manifests
as large fiber sensory loss and ataxia. Oxaliplatin, like other platinum
compounds, is known for causing a neuropathy that continues to worsen
for weeks to months after cessation of therapy. This phenomenon is
called coasting.

KEY POINTS life-threatening. Although neuromuscular junction defects or myopathies

are more common than neuropathies, chronic inflammatory demyelinating
● Coasting is a phenomenon
in which a neuropathy
neuropathies and vasculitic neuropathies have been observed in these
worsens for weeks to patients. Improvement of neurologic symptoms are reported with
months after the discontinuation of the chemotherapy and institution of immunotherapy
discontinuation of a toxic (steroids and/or IV immunoglobulin [IVIg]). Once the immune-related
agent. This is most often
neuromuscular disease is controlled, rechallenging with an immune
observed in chemotherapy-
induced peripheral checkpoint inhibitor is becoming a more common practice.
neuropathy due to
platinum-based BIOLOGICAL TOXINS
chemotherapy but can also A number of naturally occurring biological toxins act on the peripheral nervous
be seen in neuropathies due
system, which can lead to symptoms ranging from benign paresthesia to death.
to hexanes and vitamin B6
excess. Consuming fish contaminated with ciguatera toxin (produced by dinoflagellate
plankton) causes perioral paresthesia, metallic taste, and temperature-related
● Oxaliplatin causes dysesthesia. The toxin is concentrated in reef-dwelling fish, particularly
cold-induced dysesthesia. carnivorous species (eg, barracuda and grouper). A characteristic feature of
● Paclitaxel is associated
ciguatera toxin exposure is temperature inversion, resulting in cold objects being
with acute toxicity causing a perceived as very hot. The mechanism of action is modulation of sodium channel
pain syndrome that is not function.38 Mollusks contaminated with the dinoflagellate-produced saxitoxin or
clearly due to nerve brevetoxin B can cause paralysis when consumed.39 The puffer fish (fugu) is a
damage.
common item on sushi menus, but it must be carefully prepared to avoid the
● Patients with cancer are potentially fatal tetrodotoxin that is produced in its ovaries.
more commonly being Tick bites from Dermacentor andersoni, Dermacentor variabilis, or Ixodes
treated with immune- holocyclus can lead to a tick paralysis syndrome. This is most commonly seen in
checkpoint inhibitors, which
children and can cause paralysis and dysautonomia. Fortunately, removal of the
result in a neurologic
adverse event in 3% of tick leads to rapid reversal of symptoms.
patients. These neurologic When ingested, the fruit of the buckthorn plant (Karwinskia humboldtiana) of
adverse events include the southwest United States and Mexico produces a demyelinating neuropathy
central or peripheral syndrome that mimics Guillain-Barré syndrome.40
nervous system syndromes,
which may be
life-threatening.
CONCLUSION
Vitamin deficiencies, medications, and toxins are common causes of neuropathy
but can be difficult to diagnose. The list of agents that can lead to neuropathy is
very long, but most can be ruled out with a careful history, review of systems,
and physical examination. A high index of suspicion is crucial to uncovering
these etiologies, and quickly ascribing causality of a patient’s neuropathy to
concomitant diabetes, alcohol use, or family history of neuropathy can lead to a
tragic delay in diagnosis.
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32 Staff NP, Cavaletti G, Islam B, et al. 37 Psimaras D, Velasco R, Birzu C, et al. Immune
Platinum-induced peripheral neurotoxicity: from checkpoint inhibitors-induced neuromuscular
pathogenesis to treatment. J Peripher Nerv Syst toxicity: from pathogenesis to treatment.
2019;24 Suppl 2:S26–S39. doi:10.1111/jns.12335. J Peripher Nerv Syst 2019;24(suppl 2):S74–S85.
doi:10.1111/jns.12339.
33 Tamburin S, Park SB, Alberti P, et al. Taxane and
epothilone-induced peripheral neurotoxicity: 38 Pearn J. Neurology of ciguatera. J Neurol
from pathogenesis to treatment. J Peripher Nerv Neurosurg Psychiatry 2001;70(1):4–8. doi:10.1136/
Syst 2019;24 Suppl 2:S40–S51. doi:10.1111/jns.12336. jnnp.70.1.4.
34 Pachman DR, Qin R, Seisler D, et al. Comparison 39 Watkins SM, Reich A, Fleming LE, Hammond R.
of oxaliplatin and paclitaxel-induced neuropathy Neurotoxic shellfish poisoning. Mar Drugs 2008;
(Alliance A151505). Support Care Cancer 2016; 6(3):431–455. doi:10.3390/md20080021.
24(12):5059–5068. doi:10.1007/s00520-016-3373-1.
40 Calderon-Gonzalez R, Rizzi-Hernandez H.
Buckthorn polyneuropathy. N Engl J Med 1967;
277(2):69–71. doi:10.1056/NEJM196707132770204.
1298 OCTOBER 2020

Management of REVIEW ARTICLE
Neuropathic Pain in

C O N T I N U UM AUDIO
INTERVIEW AVAILABLE
Polyneuropathy
ONLINE
By Amanda C. Peltier, MD, MS; Derek Wood, MD
ABSTRACT
CITE AS:
PURPOSE OF REVIEW: Many polyneuropathies cause significant neuropathic CONTINUUM (MINNEAP MINN)
pain, resulting in substantial morbidity and reduced quality of life. 2020;26(5, PERIPHERAL NERVE AND
Appropriate management is crucial for maintaining quality of life for patients 1299–1322.
with painful polyneuropathies. The US Food and Drug Administration
(FDA) has only approved one new drug for painful diabetic neuropathy in the Address correspondence to
past decade, a topical capsaicin patch that was initially approved for the Dr Amanda C. Peltier, Vanderbilt
University Medical Center,
treatment of postherpetic neuralgia in 2009. Gabapentinoids and serotonin A-0118 Medical Center North,
norepinephrine reuptake inhibitors (SNRIs) continue to have an advantage in Nashville, TN 37232, Amanda.
safety profiles and efficacy. Other antiepileptic medications remain peltier@vumc.org.
second-line agents because of fewer studies documenting efficacy. RELATIONSHIP DISCLOSURE:

Dr Peltier serves as secretary for
the International Diabetes
RECENT FINDINGS: This
article reviews recent literature on complementary Neuropathy Consortium, on the
and pharmacologic therapies for the management of painful board of directors of the
polyneuropathies. Exercise has emerged as an important therapeutic tool American Autonomic Society,
and on advisory boards for
and may also improve the underlying polyneuropathy in the setting of Akcea Therapeutics; Alnylam
obesity, metabolic syndrome, and diabetes. Pharmaceuticals, Inc; and CSL
Behring. Dr Peltier has received
SUMMARY: The approach to management of painful polyneuropathies is speaking engagements from
multifactorial, using both pharmacologic and nonpharmacologic measures Akcea Therapeutics and CSL
Behring and research/grant
to improve pain severity and patient quality of life.
support from Akcea
Therapeutics; CSL Behring; and
the National Institute of
Neurological Disorders and
INTRODUCTION Stroke NeuroNEXT. Dr Wood
P
ainful polyneuropathy is one of the most common neurologic disorders reports no disclosure.
encountered by neurologists. The prevalence of polyneuropathy in the UNLABELED USE OF
general population is at least 4% and may be as high as 10% among PRODUCTS/INVESTIGATIONAL
those older than 40 years of age. A significant minority of these patients USE DISCLOSURE:
Drs Wood and Peltier discuss
have neuropathic pain, and it is estimated that up to 5% of Americans the unlabeled/investigational
have painful polyneuropathy.1–3 Diabetic polyneuropathy is the most common use of α-lipoic acid,
amitriptyline, cannabidiol oil,
cause of painful neuropathy in the world. Diabetic polyneuropathy affects 10% to
carbamazepine, nortriptyline,
50% of patients with diabetes, of which at least 20% have neuropathic pain.4 This oxcarbazepine, spinal cord
translates to more than 2.3 million affected patients in the United States alone. stimulators, valproic acid, and
venlafaxine for the treatment of
Chemotherapy-induced peripheral neuropathy, another common cause of painful neuropathic pain in
polyneuropathy, affects up to 30% of cancer survivors.5 Additional causes of polyneuropathy.
painful peripheral neuropathy include alcohol and other toxic substances,
nutritional deficiency, human immunodeficiency virus (HIV) infection, light © 2020 American Academy
chain and hereditary amyloidosis, and idiopathic (TABLE 8-1). of Neurology.

MANAGEMENT OF NEUROPATHIC PAIN IN POLYNEUROPATHY
EPIDEMIOLOGY AND IMPACT OF NEUROPATHIC PAIN

Twenty million Americans have chronic neuropathic pain.6 Causes include
painful polyneuropathies, postherpetic neuralgia, chronic back pain, spinal cord
injury, multiple sclerosis, and stroke. Postherpetic neuralgia and trigeminal
neuralgia affect 0.09% of the population. Painful diabetic polyneuropathy is
among the most common causes of neuropathic pain and is the most common
cause of painful polyneuropathy.7 Neuropathic pain more commonly affects
women than men (8% compared to 5.7%) and patients older than 50 years of
age.8 Neuropathic pain, including chemotherapy-induced peripheral
neuropathy, affects 20% to 50% of patients with cancer.9
The cost of pain in the United States is between $565 billion and $635 billion
each year, which is evenly split between medical costs and lost productivity.
Approximately $293 billion is due to direct costs of medical care, including
prescriptions, procedures, health care visits, and other health care expenditures.
Indirect costs are extrapolated from lost wages and productivity of patients with
pain and their caregivers.10 Chronic pain is associated with higher direct medical
costs than the most expensive major diagnoses, including cardiovascular disease
and cancer.10 Diabetic polyneuropathy alone is estimated to cost $11 billion to
$14 billion dollars annually.11,12 In Europe, the estimated annual costs per patient
for all neuropathic pain vary between €1939 and €3131 in direct costs and between
€7000 and €11,000 in indirect costs.13 Annual per patient costs in the United States
are $1600 to $7000 in direct costs and $6016 to $19,000 in indirect costs.14–16
Health care costs may be up to 3 times higher for patients with diabetic
polyneuropathy compared to controls and increase with opioid use.12,17 Because of
the imprecision in estimating the prevalence of chemotherapy-induced peripheral
neuropathy, it is difficult to estimate costs specific to neuropathy-related pain.
Multiple studies using a variety of assessment tools consistently indicate that
quality of life is significantly reduced for patients with neuropathic pain across all
domains.18,19 Medications used for neuropathic pain can affect cognition and
TABLE 8-1 Differential Diagnosis of Common Etiologies of Painful Neuropathies
◆ 丣Diabetic polyneuropathy
◆ 丣Monoclonal gammopathy–associated polyneuropathy
◆ 丣Chemotherapy-induced polyneuropathy (associated with taxanes, oxaliplatin, vincristine,
thalidomide, bortezomib)
◆ 丣Idiopathic small fiber polyneuropathy
◆ 丣Neuropathy associated with metabolic syndrome
◆ 丣Human immunodeficiency virus (HIV)–associated polyneuropathy
◆ 丣Hereditary sensory and autonomic neuropathies
◆ 丣Sjögren syndrome–associated polyneuropathy
◆ 丣Pyridoxine (vitamin B6) toxicity
◆ 丣Celiac neuropathy
◆ 丣Alcohol and other toxic neuropathies
◆ 丣Light chain and hereditary amyloidotic neuropathies
◆ 丣Nutritional deficiency neuropathies
1300 OCTOBER 2020

function. Neuropathic pain also affects sleep, mood, and other aspects of KEY POINTS
health.20,21 Neuropathic pain has a bidirectional relationship with sleep and
● Painful polyneuropathy is
mood.22 Pain leads to sleep disturbance in 60% to 80% of patients, and impaired one of the most common
sleep, in turn, leads to increased pain intensity and a higher risk of pain causes of neuropathic pain
catastrophizing (defined as magnification, rumination, and helplessness), and may affect up to 1 in 20
leading to reduced quality of life and poor overall health outcomes.23–25 Half of Americans.
patients with painful diabetic polyneuropathy have depression or anxiety, and
● Painful polyneuropathy is
one-fourth have both.26 associated with significantly
reduced quality of life and
PATHOGENESIS OF NEUROPATHIC PAIN increased health care costs,
Multiple mechanisms lead to neuropathic pain, many of which are centered as well as costs to society in
lost worker productivity.
on the dorsal root ganglion. Dorsal root ganglion cells are pseudounipolar
T-shaped cells with a bifurcated axon, one process extending into the ● Neuropathic pain leads to
periphery and the other centrally. Dorsal root ganglion neurons include those sleep disruption and vice
for myelinated Aβ and Aδ fibers and nonmyelinated C fibers, which are versa. Up to 80% of patients
with neuropathic pain have
arranged somatotopically in the ganglia. Myelinated axons terminate in sleep disturbance.
specialized receptors and C fibers in free nerve endings. Dorsal root ganglion
neurons can be cross-depolarized by excitation of neighboring dorsal root ● Half of patients with
ganglion cells within the same ganglion or cells within the substantia painful diabetic neuropathy
have depression or anxiety,
gelatinosa.27 A state of hyperexcitability and lack of inhibition by descending
and one-fourth have both.
central pathways is one of the main mechanisms of neuropathic pain arising
from polyneuropathy. Ectopic firing and central sensitization are thought ● Although the specific role
to be the main drivers of neuropathic pain.19 of SCN9A sequence variants
Evolving evidence suggests axonal and neuronal ion channels (particularly in the pathogenesis of small
fiber neuropathy is
voltage-gated sodium channels) play an important role in facilitating uncertain, voltage-gated
hyperexcitability in painful neuropathies. The role of the Nav1.7 voltage-gated sodium channels play an
sodium channel has received particular interest. Mutations in the Nav1.7 important role in
gene, SCN9A, cause both congenital insensitivity to pain and hereditary neuropathic pain, and
pharmacologic inhibition is a
erythromelalgia.28,29 Evidence is conflicting regarding the role of other SCN9A promising therapeutic
sequence variants in the etiology of small fiber neuropathy.30–32 Sodium Nav strategy.
channels 1.6, 1.8, and 1.9 have also been shown to have altered expression in
animal models of diabetic polyneuropathy, suggesting upregulation in
neuropathy leading to increased ectopic firing.33 Blocking axon potentials with
sodium channel blockers has been the putative action of multiple antiepileptic
drugs used in neuropathic pain, such as carbamazepine, oxcarbazepine,
lamotrigine, and lacosamide, and ongoing trials are exploring the utility of
sodium channel antagonists in patients with specific sodium channel
sequence variants.
The α2δ1 subunit of N-type calcium channels on C fibers in the superficial
dorsal horn of the spinal cord is the mechanistic target of gabapentinoids
(gabapentin and pregabalin). Binding of the gabapentinoids decreases
neurotransmitter release of norepinephrine, glutamate, and aspartate.34,35
Potassium channel expression is also altered in neuropathic pain, although this is
not a common pharmacologic target. While γ-aminobutyric acid (GABA) is
involved in neuropathic pain, few data support efficacy for GABA and GABA
transporter antagonists.36
PHARMACOLOGIC MANAGEMENT OF PAINFUL NEUROPATHY

Neuropathic pain is challenging to treat, and patients often need to try several
different agents alone or in combination before achieving a meaningful degree of

pain relief. Each medication should generally be tried at the maximal tolerated
dose for 6 to 8 weeks before determining treatment failure. Particular care should
be taken during dose titration to minimize the risk of side effects. Tricyclic
antidepressants and serotonin norepinephrine reuptake inhibitors (SNRIs) may
take several weeks to titrate to an effective dose.
Therapeutic development for painful neuropathy has been challenging. The US
Food and Drug Administration (FDA) has only approved one drug for painful
diabetic polyneuropathy in the past decade. An 8% topical capsaicin patch, which
was initially approved for the treatment of postherpetic neuralgia in 2009, was
approved for the new indication of painful diabetic polyneuropathy in July 2020.
Most studies of potential neuropathic pain agents focus on postherpetic neuralgia and
painful diabetic polyneuropathy, with few addressing idiopathic painful neuropathy.
The only FDA-approved medications for treatment of painful diabetic neuropathy
are pregabalin, duloxetine, tapentadol (which is only rarely used), and the capsaicin
patch. However, other medications may be effective and are used off-label.
The first steps in managing painful polyneuropathy are to quantify pain
severity and determine treatment goals. A common error is to confuse negative
symptoms, such as numbness or a feeling of walking on rocks or stumps or
wearing tight compression socks, with neuropathic pain. Although
CASE 8-1 A 73-year-old man with a past medical history of coronary artery disease
(status post–bypass surgery), osteoarthritis, and hypertension presented
for evaluation of burning pain in his feet and imbalance. He also reported a
separate tingling sensation throughout his legs with an associated urge to
move that preceded the onset of his neuropathic pain by several years. He
only noticed this sensation when he was in a recumbent position, and it
would improve with movement.
His body mass index was 32. Neurologic examination revealed severe
vibration loss in his feet with moderate loss at the knees and mild loss at
his hands. He had a distal gradient temperature loss to the midshins and
wrists bilaterally. Achilles reflexes were absent, and he had difficulty with
tandem gait.
His hemoglobin A1c was 5.9%. His vitamin B12 level was in the low-normal
range at 286 pg/mL. Serum protein electrophoresis and immunofixation
and ferritin were normal.
He was started on gabapentin and was counseled on dietary
modifications and exercise. He was also started on oral vitamin B12
supplementation. He experienced a moderate improvement in symptoms.
COMMENT This patient exhibited symptoms of both a painful sensory peripheral

polyneuropathy and restless legs syndrome (RLS). RLS may be primary or
may be seen in association with other neurologic disorders, such as
peripheral neuropathy. Distinguishing the features of RLS from peripheral
neuropathy can be challenging because of similarities in symptoms. This
case highlights the importance of selecting medications that may help both
RLS and neuropathic pain.
1302 OCTOBER 2020

uncomfortable, negative neuropathic symptoms will not respond to neuropathic KEY POINTS
pain agents. It is also important to educate patients that medications for
● No new medications for
neuropathic pain do not alter the natural history of neuropathy progression. The neuropathic pain have been
decision to begin a neuropathic pain agent for positive symptoms, such as approved in the past
tingling, burning, or pins and needles sensations, should be based on patients’ 10 years (although the
perception of severity and an understanding of their goals for treatment. For high-dose capsaicin patch
that was approved for
example, once informed that neuropathy is slowly progressive and that it rarely
postherpetic neuralgia in
leads to requirement for assistive devices to support ambulation, many patients 2009 was recently approved
opt to hold off on symptomatic treatment. Factors suggesting treatment is for use in painful diabetic
warranted include interference with sleep and activities of daily living. polyneuropathy in July
2020). The most commonly
Differentiating painful polyneuropathy from restless legs syndrome (RLS),
used medications are the
which may coexist with painful neuropathy, is important. Most pain medications gabapentinoids, which act
(except for gabapentinoids) are ineffective for RLS, and some agents (such as on α2δ calcium channels, and
tricyclic antidepressants) may worsen it (CASE 8-1). medications that increase
Setting realistic treatment expectations is essential. Complete pain relief is norepinephrine at the
synapse.
typically not a realistic goal. Use of pain scores and visual analog scales may be
helpful in quantifying pain for follow-up visits. Gabapentinoids (gabapentin ● Each neuropathic pain
and pregabalin), tricyclic antidepressants, and SNRIs are the first-line medication should generally
treatments for painful neuropathy. The authors typically advocate using either a be tried at the maximal
tolerated dose for 6 to
gabapentinoid or an SNRI as first-line treatment, as these have the most evidence 8 weeks before concluding
available and most are now available in a generic form. Therapeutic choices it is ineffective.
should be personalized based on the patient’s pain profile, comorbid medical
conditions, and medication side effects. Identification of appropriate ● Differentiating painful
polyneuropathy from
expectations in timing of relief is also important. SNRIs typically require longer
restless legs syndrome
to take effect. Knowing when to refer a patient to a multidisciplinary pain (RLS), which may coexist
clinic is important. Referral should be considered for patients with greater pain with painful neuropathy, is
severity, those for whom first-line neuropathic agents have failed, and those important as most pain
with significant mental health comorbidities or pain catastrophizing. medications (with the
exception of the
Specific classes of neuropathic pain agents are reviewed below. Many patients gabapentinoids) are
require more than one agent to achieve meaningful pain relief. Unfortunately, ineffective for RLS, and
few head-to-head data comparing these medications are available. some agents (such as
tricyclic antidepressants)
may worsen RLS.
First-line Neuropathic Pain Agents
Clinical evidence for pharmacologic therapies for neuropathic pain is discussed ● Setting realistic treatment
in the sections that follow. TABLE 8-237 and TABLE 8-3 summarize therapies and expectations for pain
their level of evidence. The therapies discussed have high-quality clinical trial management is essential.
Complete pain relief is
data, high-level recommendations from professional societies such as the typically not a realistic goal.
American Academy of Neurology (AAN), and FDA approval providing the
rationale for their designation as first-line therapies. ● Gabapentin is absorbed in
the intestine via an
GABAPENTINOIDS. Gabapentinoids were initially developed as analogues of the active-transport mechanism
and displays nonlinear
inhibitory neurotransmitter GABA to treat epilepsy. After producing significant pharmacokinetics with
improvement in neuropathic pain, they were discovered to block the α2δ subunit saturable absorption and
of voltage-gated calcium channels in the dorsal horn of the spinal cord. decreased bioavailability at
higher doses.
GABAPENTIN. In 1994, gabapentin was approved for the treatment of epilepsy, but
today it is more widely used as a first-line treatment for neuropathic pain.
Gabapentin may be started at a daily dose of 900 mg/d divided into three doses,
although it is frequently started at a lower dose. The dose is then titrated based on
clinical response to a maximum of 3600 mg/d. Gabapentin is absorbed in the

intestine via an active-transport mechanism and displays nonlinear

pharmacokinetics with saturable absorption and decreased bioavailability at
higher doses. Bioavailability of oral doses of gabapentin decrease as the dose
goes up, from 80% of 100 mg to 27% of 1600 mg. Peak serum concentration
occurs at 3 hours.38 Therefore, a typical dosing scheme would titrate up to doses
TABLE 8-2 First-line Medications for the Treatment of Painful Diabetic Neuropathya
American Academy
Typical Dose of Neurology Level of
Medication Range Common Side Effects Recommendation Notes
Gabapentin 300–1200 mg Sedation, weight gain, B Adjust dose in patients
3 times a day peripheral edema with renal dysfunction
Pregabalin 150–600 mg/d in Sedation, weight gain, A Adjust dose in patients

two to three peripheral edema with renal dysfunction;
divided doses Schedule V controlled
substance
Tricyclic 10–25 mg at Anticholinergic: dry B Avoid in patients with

antidepressants (eg, bedtime; titrate up mouth, constipation, history of prior suicide
amitriptyline, to maximum of orthostatic attempt; obtain ECG if
nortriptyline) 150 mg/d hypotension, urinary titrating to high doses or
retention, sedation; if on concomitant QTc
weight gain prolonging drugs; also
avoid in individuals with
specific cardiac
conductance
abnormalities
Duloxetine 30 mg/d to 60 mg Nausea, dizziness, B Avoid in patients with

2 times a day increased blood hepatic dysfunction
pressure, hyperhidrosis and in patients with a
glomerular filtration rate
lower than 30 mL/min;
60 mg 2 times a day has
not been shown to be
more effective than
60 mg/d
Venlafaxine Immediate release: Nausea, dizziness, B Extended-release

37.5 mg/d to increased blood formulation may be
225 mg/d in two to pressure, hyperhidrosis better tolerated and less
three divided likely to be associated
doses once higher with a withdrawal
than 37.5 mg/d syndrome on
discontinuation
Extended release:
37.5 mg/d;
increase in 37.5 mg
increments to total
daily dose of
225 mg/d
ECG = electrocardiogram.
a
Data from Bril V, et al, Neurology.37
1304 OCTOBER 2020

of 900 mg maximum per dose 3 to 4 times a day. Very little increase in efficacy KEY POINT
occurs over 3600 mg daily.
● Gabapentin and
Gabapentin acts on the α2δ subunit of presynaptic voltage-gated calcium pregabalin have similar
channels, leading to inhibition of these channels and modulation of efficacy, although patients
neurotransmitter release. The name gabapentin is a misnomer as the drug has may respond to, or tolerate,
no effect on GABA receptors. Gabapentin is non–protein bound and does not one and not the other.
Gabapentin displays
undergo hepatic metabolism. It is renally excreted unchanged with a half-life
nonlinear pharmacokinetics
of 5 to 9 hours.39 The dosage should be adjusted based on creatinine clearance. with saturable absorption
Gabapentin enacarbil is an extended-release form. It was shown to be superior to and decreased
placebo in reducing daily pain on an 11-point Likert scale.40 Gabapentin has bioavailability at higher
doses, which may favor the
a Level B recommendation from the AAN’s evidence-based guideline on the
use of pregabalin.
treatment of painful diabetic neuropathy.37
Gabapentin is generally well tolerated and is often the first medication tried for
painful neuropathy based on long-standing clinician experience, limited drug
interactions, easy titratability, good tolerability, and low cost. The most common
reason for discontinuing the medication is sedation or ineffectiveness. Other
potential adverse effects include peripheral edema and weight gain. An
encephalopathy with positive and negative myoclonus may be observed in cases of
gabapentin toxicity and typically occurs in the setting of renal dysfunction. In
response to the opioid epidemic, numerous states have enacted legislation making
gabapentin a controlled substance because of concern that gabapentin may
potentiate the effects of opioids.
PREGABALIN. Like gabapentin, pregabalin also acts on the α2δ subunit of

voltage-gated calcium channels. The FDA approved pregabalin in 2004 for the
treatment of epilepsy, postherpetic neuralgia, and painful diabetic neuropathy.
It is typically started at 150 mg/d in two to three divided doses and is titrated
based on clinical response to a maximum dose of 300 mg/d to 600 mg/d. Unlike
gabapentin, pregabalin has linear pharmacokinetics, with greater than 90%
bioavailability regardless of dose.38 Like gabapentin, it is renally excreted
unchanged, and the dose should be adjusted based on creatinine clearance.
Although pregabalin’s half-life allows for dosing 2 times a day, some patients feel
a wearing off and benefit from dosing 3 times a day.
Several Class I studies have demonstrated the superiority of pregabalin over
placebo for the treatment of painful diabetic neuropathy. A randomized
double-blind placebo-controlled study demonstrated a statistically significant
decrease in mean pain score for pregabalin 300 mg/d compared to placebo,
although 10% of patients in the pregabalin group withdrew from the study
because of adverse effects.41 In another study of patients with painful diabetic
neuropathy, pregabalin 300 mg/d did not differ from gabapentin enacarbil
(1200 mg/d to 3600 mg/d) and neither drug differed from placebo.42 Pregabalin
is the only medication to receive a Level A recommendation from the AAN’s
evidence-based guidelines on the treatment of painful diabetic neuropathy.37
Some patients for whom gabapentin has failed because of tolerability or
efficacy issues may have a better response with pregabalin or vice versa, although
medications from other classes should be tried first. The side effect profile of
pregabalin is similar to gabapentin. As of 2019, pregabalin is available as a generic
formulation, which will likely help mitigate cost issues previously associated with
the drug. Pregabalin is a Schedule V controlled substance (the lowest risk level
among the FDA drug schedules).

TRICYCLIC ANTIDEPRESSANTS. The tricyclic antidepressants were originally

synthesized in the 1950s and act to inhibit norepinephrine and serotonin reuptake.
They also act as antagonists at histamine and muscarinic cholinergic receptors,
producing a characteristic side effect profile. The two most commonly used tricyclic
antidepressants for painful polyneuropathy are amitriptyline and nortriptyline.
These tricyclic antidepressants should be started at a low dose (10 mg to 25 mg) at
bedtime, increased by 10 mg/d to 25 mg/d every 7 to 14 days to a maximum dose of
75 mg/d to 150 mg/d, although many patients are able to achieve pain relief at lower
doses. An ECG should be obtained when titrating to higher doses or if starting a
tricyclic antidepressant in combination with other QTc-prolonging drugs.
Amitriptyline 75 mg/d was shown to be superior to placebo in patients with
diabetic and nondiabetic painful polyneuropathy, with 67% of patients on
amitriptyline having improvement.43 Tricyclic antidepressants have a Level B
recommendation from the AAN’s evidence-based guideline on the treatment of
painful diabetic neuropathy.37
The most common adverse effects of tricyclic antidepressants are sedation and
anticholinergic effects. Nortriptyline may be less sedating than amitriptyline.
Common anticholinergic effects include dry mouth, constipation, orthostatic
hypotension, urinary retention, and blurred vision. Cognitive impairment may
also be seen, particularly in individuals with underlying cognitive dysfunction.
Caution should be exercised when initiating tricyclic antidepressants in elderly
individuals or those with preexisting cognitive or autonomic dysfunction
as they may be more susceptible to anticholinergic side effects. Tricyclic
antidepressants should be avoided in patients with severe depression or
history of suicide attempt, as intentional overdose may cause a fatal cardiac
dysrhythmia. Slow upward titration can mitigate some adverse effects, especially
sedation. The authors typically increase weekly or every two weeks to
improve tolerability.
TABLE 8-3 Multimodal Options for Painful Polyneuropathy Treatment
Complementary/
Pharmacologic Therapies Nonpharmacologic Therapies Exercise
First-level therapies Pregabalin, duloxetine, α-Lipoic acid 600 mg/d Aerobic exercise 4
(clinically proven with gabapentin h/wk at 50–85%
placebo-controlled studies, FDA maximum heart
approved, Level A and B rate
evidence-based recommendations)
Second-level therapies Tricyclic antidepressants, Levomefolate/Schizochytrium/ Balance exercises

(smaller studies, prospective studies venlafaxine, valproate, pyridoxal phosphate/ to decrease fall
without placebo control, greater side lidocaine patches methylcobalamin, B vitamin risk, tai chi
effects) supplements (avoiding excess
vitamin B6), spinal cord stimulation
Third-level therapies Topiramate, lacosamide, Acupuncture Yoga

(anecdotal, case studies) oxcarbazepine,
lamotrigine, mexiletine
FDA = US Food and Drug Administration.
1306 OCTOBER 2020

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS. SNRIs block reuptake of KEY POINTS
both serotonin and norepinephrine. Their specific effects on norepinephrine
● The two most commonly
reuptake are thought to increase descending pain inhibitory pathways used tricyclic
converging on the dorsal horn in the spinal cord. Their number needed to treat antidepressants for painful
correlates with norepinephrine reuptake inhibition.44 polyneuropathy are
amitriptyline and
nortriptyline.
DULOXETINE. Duloxetine acts to inhibit the reuptake of serotonin and
norepinephrine. It was the first drug approved by the FDA for the treatment of ● Caution should be
diabetic peripheral neuropathy in 2004. The standard dose is 60 mg once a day, exercised when initiating
although it may be initiated at 30 mg/d for the first week if tolerability is a tricyclic antidepressants in
concern. Although it can be dosed up to 120 mg/d in two divided doses, doses elderly individuals or those
with preexisting cognitive or
higher than 60 mg/d are not thought to confer additional benefit and are autonomic dysfunction as
associated with increased side effects.45 Duloxetine should be avoided in patients they may be more
with hepatic impairment and in patients with impaired renal function susceptible to
(glomerular filtration rate lower than 30 mL/min). anticholinergic side effects,
and their use should be
A multicenter double-blind randomized placebo-controlled trial in patients with avoided in patients with
painful diabetic neuropathy compared duloxetine at 60 mg/d and 60 mg 2 times severe depression or history
a day with placebo.46 The primary end point was mean change from baseline on of suicide attempt because
a 24-hour average pain score. Duloxetine at 60 mg/d and 60 mg 2 times a day of the risk of intentional
overdose.
was associated with a statistically significant improvement compared to placebo.
Of patients in the duloxetine 60 mg 2 times a day group, 12.1% discontinued ● Duloxetine may be a
treatment because of adverse effects compared to only 4.3% in the 60 mg/d particularly good agent for
group and 2.6% in the placebo group. Nausea is the most common adverse effect. patients with painful
diabetic neuropathy with
Fatigue, increased sweating, decreased libido, and hypertension are other possible
comorbid depression,
side effects. A risk of serotonin syndrome exists if used in combination with other anxiety, or fibromyalgia.
serotonergic medications (eg, tricyclic antidepressants, selective serotonin
reuptake inhibitors [SSRIs], tramadol). Duloxetine may be a particularly good
choice for patients who also have depression/anxiety or fibromyalgia.
VENLAFAXINE. Venlafaxine is another drug within the SNRI class that has been
shown to be beneficial for the treatment of neuropathic pain. It is available in
both an immediate-release and an extended-release formulation. The
immediate-release formulation is started at 37.5 mg/d to 75 mg/d and can
be titrated to 225 mg/d. Doses greater than 37.5 mg/d should be given in two
or three divided doses. The extended-release formulation is given as a
once-daily dose and can be started at 37.5 mg/d to 75 mg/d and increased by
37.5 mg every 1 to 2 weeks if needed. The extended-release formulation is
often preferred because of ease of use, less severe discontinuation syndrome
on stopping the drug, and less dizziness and nausea at initiation of therapy. In
patients with renal or hepatic impairment, the daily dose should be reduced
accordingly.
Venlafaxine extended-release formulation has shown benefit in the treatment
of painful diabetic neuropathy compared to placebo, with a 32% reduction
(75 mg) and 50% reduction (150 mg to 225 mg) on a visual analog pain intensity
scale compared to 27% in the placebo group.47 Like duloxetine, venlafaxine has
a Level B recommendation from the AAN’s evidence-based guideline on the
treatment of painful diabetic neuropathy.37
The side effect profile of venlafaxine is similar to duloxetine. Patients taking
the immediate-release formulation should be advised against stopping the drug
abruptly because of the risk of precipitating a withdrawal syndrome.

Second-line Neuropathic Pain Agents

Many patients with painful polyneuropathy do not adequately respond to first-line
agents. Evidence supports the utility of a number of other treatments that may be
used as second-line agents.
ANTIEPILEPTIC DRUGS. Valproic acid was shown to have efficacy in the management
of painful diabetic neuropathy compared to placebo48,49; however, limited studies
involved a small number of patients and were done at the same single center. Valproic
acid has many side effects, including weight gain, thrombocytopenia, pancreatitis,
tremor, sedation, and hair loss, and thus it is less likely to be used when considering a
second-line agent for neuropathy. Reports are conflicting regarding the efficacy of
oxcarbazepine for the treatment of painful diabetic polyneuropathy. Although several
studies have failed to show benefit, patients in one study of oxcarbazepine initiated at
300 mg/d and titrated to a maximum of 1800 mg/d had a significantly larger decrease
in the mean change on a visual analog scale pain score compared to placebo.50
Hyponatremia is a well-known adverse effect. Carbamazepine has also been used for
chronic pain but has not been shown to be effective over placebo. It can also cause
hyponatremia and significant bone marrow depression.51
Topiramate has also been investigated for use in painful diabetic
polyneuropathy. Topiramate titrated up to 400 mg/d or the maximum tolerated
dose was shown to be modestly superior to placebo in pain reduction on a visual
analog scale score over 12 weeks.52 Topiramate has several adverse effects,
including fatigue, cognitive dysfunction, and extremity paresthesia; it may also
trigger depressive episodes in some individuals. It should be avoided in patients
with a history of nephrolithiasis. Weight loss is a well-known side effect of
topiramate, and its use as a treatment for neuropathic pain in patients with
metabolic syndrome is actively being investigated. An ongoing multicenter
clinical trial of topiramate as a potential disease-modifying agent for neuropathy
associated with metabolic syndrome based on its effects on weight and
insulin sensitivity is ongoing using the NeuroNEXT trial network.53
Several studies have failed to demonstrate a benefit for use of lamotrigine in
the treatment of painful diabetic polyneuropathy. However, post hoc analysis in
one study of patients who reached a dose of 400 mg/d demonstrated a
statistically significant mean reduction in pain intensity score from baseline to
19 weeks compared to placebo.54–56
MEXILETINE. Mexiletine is a sodium channel blocker that has also been studied
for the treatment of neuropathic pain. It is typically prescribed for myotonia and
arrhythmias. In a placebo-controlled study, it did not provide pain relief greater
than placebo.57
TOPICAL LIDOCAINE AND CAPSAICIN. Topical agents may add symptomatic relief
and have the advantage of minimal side effects.58 Topical lidocaine is available
in both an ointment and patch form. Lidocaine can be a useful adjunctive therapy
in patients whose pain is well localized to the distal extremities.59,60 It has been
best studied in postherpetic neuralgia as the pain is in a more localized area. As the
neuropathy progresses and becomes more proximal, topical lidocaine becomes less
useful because of more area needing coverage. One strategy is to apply lidocaine
patches at night before bed as patients with neuropathic pain tend to notice their
pain more at night. Lidocaine patches should be used for a maximum of 12 hours
1308 OCTOBER 2020

on, followed by 12 hours off, and up to three patches may be used at a time. KEY POINTS
Lidocaine has been shown to be more useful as an add-on therapy.
● Despite a lower
Topical capsaicin has also been studied in postherpetic neuralgia and diabetic efficacy compared to
neuropathic pain and has Level B evidence.37 Capsaicin is a transient receptor gabapentinoids and
potential cation channel subfamily V member 1 (TRPV1) agonist. At low doses and serotonin norepinephrine
with brief exposure, it causes a burning sensation (capsaicin is the active ingredient in reuptake inhibitors,
antiepileptic drugs and
hot peppers). With a high dose or repeated exposure, it causes epidermal axonal mexiletine may still be worth
degeneration, which is the putative mechanism of action. The new capsaicin a trial in some patients with
patch approved by the FDA has a higher concentration of capsaicin (8%), and up refractory pain.
to four patches can be applied at a time, which will last for up to 3 months.61
● Topical agents (such as
Application must take place in the clinic in a well-ventilated area. The provider
lidocaine patches or cream)
applying the patch should wear nitrile gloves to prevent skin exposure. During are of modest efficacy but
the clinical trials, participants had lidocaine cream applied before putting on may add symptomatic relief
patches to minimize pain and discomfort from the patches. When using in selected patients with
neuropathic pain and have
low-dose topical capsaicin cream for neuropathic pain, patients must be warned
the advantage of minimal
that they will experience a period of burning discomfort with initiation of side effects.
therapy and that gloves should be worn during administration to avoid
inadvertent exposure to sensitive areas (eg, eyes). Previously, most experts used ● Opioid analgesics,
topical capsaicin sparingly and mainly for patients with tactile allodynia in a including tramadol, should
not be used as first- or
localized region. It is unclear how effective the new patch will be in clinic. second-line medications for
neuropathic pain and should
OPIOID ANALGESICS. Opioid analgesics (including tramadol) should not be used only be considered in severe
as first- or second-line medications for neuropathic pain and should only be and refractory cases when
considered in severe and refractory cases when all other options have failed. all other options have failed.
In general, referral to a pain
Oxycontin was shown to be effective in a placebo-controlled study and in clinic is recommended if
subsequent studies.62,63 Morphine was shown to have efficacy in combination opioid therapy is being
with other medications, such as gabapentin and pregabalin, in additional considered.
studies.64,65 Other opioids have not been as well studied but presumably have
similar benefits. Given the long-term safety and medicolegal implications of
prescribing opioid analgesics and that they are not recommended as first- or
second-line agents, it is advisable to refer these patients to a pain clinic for
initiation and management of opioid therapy because of the complexities
involved.66
Tramadol has a mixed mechanism of action. Tramadol is both a μ-opioid receptor
agonist and an SNRI. Tramadol has been studied in several trials, including trials for
pain in diabetic polyneuropathy and postherpetic neuralgia, and was found to be
effective compared to placebo.67,68 Tramadol is dosed starting at 25 mg and can be
increased to 50 mg administered up to every 6 hours, with a maximum of 400 mg/d.
Long-acting tramadol should not be increased to higher than 300 mg/d.
Tapentadol has a similar mechanism to tramadol in that it not only has weak
μ-opioid receptor agonism but also has norepinephrine reuptake inhibitor
activity. Initial studies of tapentadol showed minimal efficacy over placebo.69
However, studies with extended-release tapentadol showed a greater than 30%
decrease in pain in the majority of patients with painful diabetic peripheral
neuropathy.70,71 It was also studied in cancer pain in an open-label study and
chronic low back pain.72,73 Its weak efficacy makes it a third-line option. It is
dosed starting at 50 mg, increasing to 100 mg up to every 4 to 6 hours with a
maximum of 1600 mg/d.
Opioid-induced hyperalgesia is a significant phenomenon that is thought to be
caused by neuroplastic changes and sensitization to μ-opioid receptors and

nociceptor toll-like receptor 4 (TLR4), which may arise from opioid activation
of mast cells, microglia, and other cells in the peripheral and central nervous
systems.74–76 It was first described in 1945 and is different from tolerance, which
occurs over time and requires gradually escalating dosages to maintain the
same level of analgesia. Opioid-induced hyperalgesia causes patients to have
increased pain and diffuse allodynia that is often different than their initial pain
manifestation.74 Although opioid-induced hyperalgesia may be more common with
higher-potency opioids, tramadol has also been reported to cause opioid-induced
hyperalgesia, making it a concern for lower-potency opioids as well.77 The treatment
is to recognize opioid-induced hyperalgesia when it occurs, taper opioids, and then
determine whether it is safe to restart opioid treatment (CASE 8-2).
Other medicines studied for neuropathic pain include dihydroergotamine
(a treatment for migraine), which is a 5-HT1 receptor agonist that may improve
pain in rat models,78 and memantine, an anti–N-methyl-D-aspartate (NMDA)
receptor antagonist used for dementia. Memantine has been studied in seven
CASE 8-2 A 67-year-old woman with type 2 diabetes presented with a 20-year
history of painful neuropathy symptoms. She was taking pregabalin,
oxcarbazepine, metaxalone, paroxetine, and tramadol and had been on
opioids for years, which were recently transitioned to fentanyl patches.
She had subjectively good pain control, and her hemoglobin A1c had been
maintained at 6.1%. Her main symptoms were memory issues and
dizziness.
At her appointment, she was slow to respond and had small pupils. She
had severe sensory loss to above the knees to both pin and vibration and
distal weakness of toe extensors and finger abductors. Deep tendon
reflexes were absent in the legs.
The decision was made to start tapering and weaning off her
medications because of concern for polypharmacy as she was exhibiting
poor balance, confusion, and sedation. She was weaned off
oxcarbazepine and metaxalone first because of the suspicion that they
were most likely related to side effects. At the next visit, discussion
about her opioid use was productive and she agreed to wean off opioids
given concern regarding the risk of opioid-induced hyperalgesia and
multiple side effects. She was slowly tapered off fentanyl over the next
several months with good results and fewer memory issues.
COMMENT Recognition of medication side effects and stepwise elimination or

decrease in dosage of medicines to avoid side effects is important.
Recognition of opioid tolerance and opioid-induced hyperalgesia is crucial,
although management of this situation is often difficult in practice and
avoidance of opioids is recommended. Many patients with refractory pain
are reluctant to reduce dosages, and education on this issue may take more
than one visit. For this reason, if a patient’s pain is refractory to multiple
medications, consideration of the use of opioids is best referred to an
experienced pain specialist and avoided as much as possible.
1310 OCTOBER 2020

trials, with only two showing benefit over placebo.79 Ketamine and amantadine KEY POINT
have also been studied, with mixed results.79 Ketamine, an anesthetic NMDA
● Opioid-induced
receptor antagonist, is commonly added to topical compounded creams for hyperalgesia causes
neuropathic pain but has not shown any clinical efficacy in topical form.80 patients to have increased
pain and diffuse allodynia
SUPPLEMENTS AND OTHER ALTERNATIVE TREATMENTS FOR that is often different than
their initial pain
NEUROPATHIC PAIN
manifestation.
Patients often seek complementary and alternative treatments for neuropathic
pain in polyneuropathy for multiple reasons. Some patients are fearful or
suspicious of pharmacologic therapies, and some may have had significant side
effects or incomplete efficacy. Some therapies have been advertised with
minimal clinical data. α-Lipoic acid is the best studied supplement, but other
commonly used supplements with some clinical studies are also discussed below.
α-Lipoic Acid
α-Lipoic acid is an antioxidant that has shown symptomatic benefit for patients
with painful diabetic polyneuropathy.81 It is most commonly used as an
adjunctive therapy or as a second-line agent. It may also be suggested to patients
who are averse to conventional pharmacotherapeutics and prefer a nutraceutical
option. α-Lipoic acid has been studied in several large studies with conflicting
evidence. The ALADIN III (Treatment of Symptomatic Diabetic Polyneuropathy
With the Antioxidant Alpha-Lipoic Acid: A 7-month Multicenter Randomized
Controlled Trial) study showed an improvement in Neuropathy Impairment
Score but not in Total Symptom Score.82 The SYDNEY 2 (Assessment of Efficacy
and Safety of Thioctic Acid in the Oral Treatment of Symptomatic Diabetic
Neuropathy) trial compared orally administered α-lipoic acid (600 mg/d,
1200 mg/d, or 1800 mg/d) to placebo. The primary outcome measure was change
in baseline Total Symptom Score. All three doses were found to be superior to
placebo in pain relief and Neuropathy Symptoms and Change Score, although
mean Total Symptom Score did not differ between treatment groups.81,83 The
NATHAN 1 (Assessment of Efficacy and Safety of Thioctic Acid in the Oral
Treatment of Diabetic Polyneuropathy [Stage 1 or 2]) study suggested that
patients with fewer comorbidities (eg, hypertension, cardiovascular disease, and
obesity) were more likely to improve in Neuropathy Impairment Score-Lower
Limbs.84,85 The most common adverse effects are acid reflux and nausea, but in
the authors’ experience, α-lipoic acid tends to be discontinued more often
because of ineffectiveness than because of tolerability issues.
Cannabidiol and Cannabis-derived Treatments

Cannabinoids have become a popular pharmacotherapy in many neurologic
disorders, such as multiple sclerosis, epilepsy, and Parkinson disease.
Cannabinoids bind to cannabinoid receptors, predominantly CB1 in the brain but
also TRPV1, peroxisome proliferator-activated receptor γ (PPARγ), GABA
receptors, and calcium channels.86 Many patients report anecdotal improvement
with the use of cannabidiol, whether taken orally or used as an ointment.2
A Cochrane Review evaluated 16 placebo-controlled studies of cannabinoid
products, including cannabidiol oil, tetrahydrocannabinol (THC) and
cannabidiol oronasal spray, nabilone (synthetic mimic of THC), inhaler herbal
cannabis, and plant-derived THC. The number needed to benefit was calculated
to be 20 because of small differences between placebo and cannabis products to

decrease pain by a significant amount (28% in the cannabis group reported a

meaningful decrease in pain compared to 22% in the placebo group).87 Most
studies were of low quality with possible bias and small numbers.87 The side
effects of cannabis products include dizziness, sedation, hypotension, and ataxia.
Adverse effects may be worse in the elderly because of slower metabolism and
increased fat percentage.88 In addition, cannabis interacts with other commonly
used medications for neuropathic pain, such as valproic acid.89 Because of
current legal and regulatory concerns as well as insufficient data regarding its
efficacy in the treatment of painful diabetic polyneuropathy, the use of cannabis
cannot currently be recommended outside of an investigational setting. When
counseling patients about cannabidiol products, clinicians should emphasize that
well-designed clinical trials are lacking and that potentially significant side
effects may occur.
Other Supplements
Deficiencies of multiple B vitamins (most notably vitamins B1, B6, and B12) are
known to cause polyneuropathy.90,91 Metformin, a hypoglycemic agent
commonly used in diabetes, is also known to decrease vitamin B12 absorption,
potentially exacerbating existing diabetic polyneuropathy. A branded multi–B
vitamin supplement (levomefolate/Schizochytrium/pyridoxal phosphate/
methylcobalamin) has shown some efficacy in diabetic polyneuropathy.92,93
However, it is simply folate, vitamin B6, and B12, and costs up to $136 for
30 capsules, which is substantially more expensive compared to buying similar
supplements over the counter. In addition, the vitamin B6 component may
also increase risk for hypervitaminosis B6–associated toxicity, leading to
worsening sensory neuropathy/ganglionopathy. In the authors’ opinion, other
multivitamins that are marketed specifically to patients with neuropathy are also
expensive and provide no value beyond that of inexpensive over-the-counter
alternatives.
Additional supplements that have been advertised as potentially helpful
include acetyl-L-carnitine, a supplement thought to enhance mitochondrial
activity, which has been shown to improve diabetic polyneuropathy in animal
models.94 Curcumin has been anecdotally shown to improve neuropathy and
neuropathic pain, with some evidence in animal studies,95–97 and nutmeg and
St. John’s wort have also been shown to have some improvement in neuropathic
pain.98 Lion’s mane (Hericium erinaceus) may improve neuroregeneration and
increase nerve growth factor, with some nociceptive activity.99,100 Fish oil, which
contains omega-3 fatty acids,101,102 has also been touted for neuropathic pain
based on a study in rats.101 Clinical trial data are lacking, and the efficacy of fish
oil has not been established.
PSYCHIATRIC TREATMENT FOR REFRACTORY NEUROPATHIC PAIN

Specific studies of antidepressants not affecting norepinephrine reuptake, such
as SSRIs, have shown they are not specifically efficacious in the treatment of
neuropathic pain. However, they are still useful for underlying major depression,
which may exacerbate neuropathic pain.103 In addition, individualized treatment
of depression is important, and cognitive therapy can be a useful tool in
multidisciplinary pain clinics.104 Evaluation of the risk of suicide is important in
patients with refractory neuropathic pain as many treatments have a possible
effect of increased suicidality. Patients on opioid therapy are especially at risk for
1312 OCTOBER 2020

overdose, and increased monitoring is necessary to avoid it. Anecdotally, KEY POINTS
neuropathic pain that is refractory to multiple agents may be an indication of
● High-quality clinical trial
coexistent depression; screening for depression may lead to improved pain data supporting the use of
management. The use of SNRIs can be especially helpful with coexistent cannabinoids for
depression neuropathic pain are
lacking, and side effects are
common. Their use outside
NONPHARMACOLOGIC TREATMENT OF NEUROPATHIC PAIN
of clinical trials is
Many patients inquire about or try alternative treatments for neuropathic pain discouraged.
when pharmacologic treatments are insufficient or not tolerated or if they are
interested in complementary medicine. The literature on exercise and other ● Recognition and
nonpharmacologic therapies is summarized below. Most of these therapies individualized treatment of
depression is important,
have the same drawbacks of limited or absence of placebo-controlled rigorous and cognitive therapy can
clinical trials as do many of the pharmacologic treatments and supplements be a useful tool in
summarized. multidisciplinary pain
clinics.
Exercise ● Given the multiple health
Exercise is a largely overlooked treatment modality, but growing literature benefits of exercise and
documenting its efficacy in improving chronic neuropathic pain and improvement in other
potentially improving some etiologies of neuropathic pain make it a promising parameters of health,
exercise should be highly
therapeutic option for both neuropathic and non-neuropathic pain.105 It has
encouraged in all
been primarily studied in diabetic polyneuropathy and neuropathy associated patients with painful
with metabolic syndrome and prediabetes.106,107 Animal exercise studies polyneuropathy.
show that exercise increases dorsal root ganglion production of multiple
neurotrophic factors, including brain-derived neurotrophic factor and nerve
growth factors, and decreases proinflammatory cytokines such as tumor necrosis
factor-α and IL-1β.108,109 In addition to improving pain, exercise may improve
the underlying neuropathy among patients with metabolic syndrome,110 likely
by improving insulin sensitivity and multiple metabolic factors, including
dyslipidemia.110,111
The specific type and amount of exercise necessary to result in improved pain
and neuropathy is uncertain, as is the relative importance of associated dietary
counseling. Moderate aerobic exercise in addition to strength training has been
studied in supervised and unsupervised settings and has shown improvement in
pain and objective parameters of neuropathy.112,113 Tai chi and other balance
exercises may improve fall risk, but outcome measures have not included pain, so
it is undetermined whether they also improve pain control.114 Yoga may help
with chronic pain but has not been studied specifically in neuropathic pain
populations.115 Given the multiple health benefits of exercise, including
improvement in other parameters of health, exercise should be highly
encouraged in all patients with painful polyneuropathy. The authors typically
recommend 30 minutes of moderate-intensity exercise daily, using whatever
modality the patient most enjoys and can sustainably tolerate.
Spinal Cord Stimulation

The premise of spinal cord stimulation is that electrical stimulation of nerve roots
or dorsal columns via a surgically placed electrode in the epidural space would act
as a gate and block pain perception without ablation. Electrical stimulation is
produced by a radio-controlled device to modulate anesthesia. Two trials of
spinal cord stimulation have shown at least short-term benefits in painful
diabetic polyneuropathy,116,117 with some patients experiencing durable

improvement.118 Long-term cost-effectiveness is unclear compared to

pharmacologic treatments as the short-term cost is relatively high and not all
patients benefit long term.119,120 Significant risk exists, and complications are
possible, including infection, damage to the nerve roots or cord during surgical
placement, and hardware failures. In addition, patients are unable to get future
MRIs after placement, and pain relief decreases over time. This treatment
modality may be an option in patients with refractory pain or in those who are
intolerant to multiple medications, but only in the hands of experienced
surgeons and well-trained personnel. In general, spinal cord stimulation should
only be recommended following a thorough evaluation in a multidisciplinary
pain clinic.
Acupuncture
Acupuncture is an established treatment for pain in China and other Asian
countries, but placebo-controlled studies are limited. Acupuncture’s mechanism
of action is not well established, although it has been theorized to either affect
descending pain control pathways or to decrease neuroinflammation.121 In one
study, acupuncture was shown to be associated with improved glycemic
control.122 A Cochrane Review found insufficient evidence to support or refute
acupuncture’s efficacy for neuropathic pain.123 Although most studies were
small and many had significant methodologic limitations, several suggest some
benefit in diabetic polyneuropathy and chemotherapy-induced peripheral
neuropathy.123–126 In the United States, access to acupuncture is limited in many
nonurban settings. The authors offer acupuncture as an option for patients with
pain that is refractory to multiple medications and those who are interested in
alternative therapies. Not all insurance plans cover acupuncture, so a discussion
regarding cost is important. However, this has changed significantly in the past
10 years, and Medicare and other private insurers may now cover to a limited
number of visits.
AN ALGORITHMIC APPROACH TO NEUROPATHIC PAIN MANAGEMENT

Most patients with painful polyneuropathy should be started on either a
gabapentinoid or an SNRI as a first-line agent, although the choice of agent
should be based on patient comorbidities. Patients with associated RLS may
benefit from the dual action of gabapentinoids, whereas a patient with symptoms
of associated depression may benefit more from an SNRI such as duloxetine or
venlafaxine. After appropriate titration to a maximally tolerated dose, the patient
should be reevaluated in 6 to 8 weeks for efficacy and consideration of a second
or alternative agent or treatment approach (TABLE 8-2 and TABLE 8-3). Many
patients require more than one agent for effective treatment.65 Typically, if a
gabapentinoid is started first, a tricyclic antidepressant or SNRI would be added
second and vice versa. Tricyclic antidepressants are typically not started as
first-line agents because of significant side effects in the elderly, but they may be
reasonable first-line agents in younger patients (eg, in a younger patient with
significant insomnia) (CASE 8-3).
All patients should be counseled regarding the positive effects of exercise.
Many patients with painful polyneuropathy are resistant to exercise and worry it
will make pain worse. Also, many patients with diabetic polyneuropathy may
be sedentary, morbidly obese, and have joint symptoms that may limit exercise
choices. Working with patients on finding affordable and realistic goals of
1314 OCTOBER 2020

exercise and access to exercise equipment can be a challenge. However, if they
exercise, many patients will see that it improves pain and overall quality of life.
If combination therapy is not helpful and patients have tolerated appropriate
dose escalation without improvement, complementary agents (such as α-lipoic
acid) and other second-line agents or nonpharmacologic treatments (such as
acupuncture) should be considered. If pain continues to be refractory and trials
of even third-line agents are unsuccessful, referral to a multidisciplinary pain
clinic is helpful. A multidisciplinary pain clinic can evaluate for possible
treatment using spinal cord stimulation, opioids, or other treatments beyond the
scope of this review (TABLE 8-3).
A 52-year-old woman presented with a 3-year history of burning pain and CASE 8-3
tingling in her feet associated with a severe pruritic sensation. She had a
past medical history of hypertension, hypertriglyceridemia, obstructive
sleep apnea, and anxiety. She reported that she had been taking vitamin B
supplements for years.
Physical examination revealed a blood pressure of 136/85 mm Hg and a
body mass index of 32.2 (class 1 obesity). Excoriations on the feet were
observed related to intense scratching, and she had a distal gradient
temperature loss to the ankles and wrists bilaterally. Distal vibratory
sensation and deep tendon reflexes were intact.
Her laboratory workup revealed a vitamin B6 level elevated to 4 times
the upper limit of normal (20 nmol/L to 125.0 nmol/L).
All extraneous sources of vitamin B6, including supplements, were
discontinued. She was started on gabapentin but was unable to tolerate it
because of daytime sleepiness and cognitive fog. She was then switched
to duloxetine, which helped somewhat, but she was unable to tolerate
doses higher than 30 mg/d because of hyperhidrosis. Low-dose
pregabalin was later added and cautiously titrated up given her prior
sensitivity to gabapentin. She tolerated this regimen well.
This case illustrates several important points, including the importance of COMMENT
trialing different medications within the same class (eg, gabapentin and
pregabalin) as well as selecting medications to target underlying
comorbidities. In this case, a serotonin norepinephrine reuptake inhibitor
(SNRI) was used to target comorbid anxiety. Additionally, the patient had
reported pruritus, which highlights an often-overlooked symptom. Pruritus
can be neuropathic in nature and seen in the setting of small fiber
neuropathy. Her examination findings of distal temperature loss with intact
vibratory sensation and reflexes is suggestive of a predominately small
fiber process. Finally, it is not uncommon for patients with painful
polyneuropathy to have multiple different risk factors or causes. This
patient had metabolic syndrome and an elevated pyridoxine (vitamin B6)
level, each of which can cause a painful small fiber neuropathy. Patients
with an established cause for polyneuropathy, including diabetes, should
also be carefully evaluated for other potential etiologies.

KEY POINT It is very important to explore sleep disturbances, depression, and anxiety
with every patient. Those with comorbid depression may benefit from an
● An algorithmic approach
that integrates
SNRI, and independent therapy for associated sleep and mood disorders may
pharmacologic and be necessary.
nonpharmacologic therapy Analysis of failure of neuropathic pain treatment is important. Failure is
with specific attention to commonly due to lack of appropriate dose escalation (without adverse side effects),
comorbid sleep and mood
inadequate treatment duration (ie, less than 6 weeks), or side effects related to the
disorders is the most
effective approach to specific agent used. Sometimes, patients discontinue a medication due to symptoms
neuropathic pain that may not be related to the agent. Retrial at a lower dose with slower titration can
management. be helpful, especially in patients for whom multiple agents have failed. Screening for
coexistent conditions such as depression, RLS, and other conditions that may
impede success is helpful (FIGURE 8-1127).128,129
CONCLUSION
Management of painful polyneuropathies is challenging and often requires
multiple strategies. An urgent need exists for additional therapeutic
development, including clinical trials that enroll patients with idiopathic and
other forms of painful neuropathy such as chemotherapy-induced peripheral
neuropathy. The largest contribution in recent literature has been the
demonstration of exercise as a therapeutic strategy for neuropathic pain. Further
FIGURE 8-1
An algorithmic approach to neuropathic pain management.
ALA = α-lipoic acid; Rx = prescription; SNRIs = serotonin norepinephrine reuptake inhibitors;
TCAs = tricyclic antidepressants.
Modified with permission from Bates D, et al, Pain Med.127 © 2019 Oxford University Press.
1316 OCTOBER 2020

work needs to be done in demonstrating the optimal type and dose of exercise.
An algorithmic approach that integrates pharmacologic and nonpharmacologic
therapy with specific attention to comorbid sleep and mood disorders is the most
effective approach to neuropathic pain management. Patients with severe or
refractory neuropathic pain may benefit from a referral to a multidisciplinary
pain clinic.
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125 Rowin J. Integrative neuromuscular medicine:
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1322 OCTOBER 2020

Amyotrophic Lateral REVIEW ARTICLE

Sclerosis and Other C O N T I N U UM A U D I O
ONLINE
Motor Neuron Diseases

By Colin Quinn, MD; Lauren Elman, MD
ABSTRACT
PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic
approach, and treatments available for amyotrophic lateral sclerosis (ALS)
and other motor neuron diseases. The article also provides an update on CITE AS:
the genetics and pathophysiology of ALS. CONTINUUM (MINNEAP MINN)
RECENT FINDINGS: ALS remains a clinical diagnosis without a unique 1323–1347.
biomarker. The areas of greatest progress include a large expansion in the
number of genes associated with familial and sporadic ALS. The discovery Address correspondence to
of these genes, along with other work, has provided a deeper understanding Dr Colin Quinn, University of
Pennsylvania, 3400 Spruce St,
of the mechanisms of motor neuron failure in ALS. Areas of particular Philadelphia, PA 19104,
interest include the role of transactive response DNA-binding protein 43 and colin.quinn@uphs.upenn.edu.
other RNA-processing proteins in the development of disease. RELATIONSHIP DISCLOSURE:
Dr Quinn serves on advisory
SUMMARY: ALS remains a relentlessly progressive disorder with an elusive boards for Acceleron Pharma,
Inc, and Amylyx
core pathophysiology. The current mainstay of treatment remains Pharmaceuticals and as a
symptom management and palliation, particularly in the setting of a consultant for Amicus
multidisciplinary clinic. The future holds potential for targeted therapies Therapeutics, Inc. Dr Quinn
receives research/grant
based on an ever-evolving understanding of the pathophysiology of both support from Acceleron
familial and sporadic ALS. Pharma, Inc; Amicus
Therapeutics, Inc; and Amylyx
Pharmaceuticals. Dr Elman
serves on advisory boards for
Biogen and Genentech, Inc, and
INTRODUCTION receives publishing royalties
M
otor neuron diseases include a variety of acquired and from UpToDate, Inc.
inherited neurodegenerative conditions that entirely or
UNLABELED USE OF
predominantly injure motor neurons. Amyotrophic lateral PRODUCTS/INVESTIGATIONAL
sclerosis (ALS) is the most common of these diseases and will USE DISCLOSURE:
be the focus of much of this discussion. Drs Quinn and Elman discuss the
unlabeled/investigational use of
The motor neuron system is composed of upper and lower motor neurons. anticholinergics, clonazepam,
Upper motor neurons reside in the primary motor cortex of the brain, and their levetiracetam, mexiletine,
mirtazapine, phenytoin,
axons comprise the corticobulbar tract (connecting to the brainstem) and the
selective serotonin reuptake
corticospinal tract (connecting to the spinal cord). Lower motor neurons, also inhibitors, steroids, and tricyclic
referred to as alpha motor neurons or anterior horn cells, are located in motor antidepressants for the
treatment of amyotrophic
nuclei in the brainstem or the anterior gray matter of the spinal cord. Their axons lateral sclerosis and other motor
connect to muscles of the bulbar region or limbs. Injury to the motor neuron neuron diseases.
system results in loss of voluntary muscle function that may affect limb, bulbar,
and/or respiratory function, with the specific symptoms depending on which © 2020 American Academy
part of the motor pathway is affected. of Neurology.

ALS AND OTHER MOTOR NEURON DISEASES
Since the earliest descriptions of the clinical and pathologic features of ALS by
Jean-Martin Charcot in the 1870s, our understanding of the underlying
pathophysiology of the disease has expanded enormously. Still, a unifying causal
theory remains elusive. This article describes the clinical features of ALS; outlines
an approach to diagnostic evaluation; reviews the latest understanding of the
genetics, pathology, and pathophysiology of the disease; and discusses current
management approaches. It also reviews variants of ALS and some motor neuron
disorders that can mimic features of ALS. Specific cases are used to highlight
relevant discussion points.
EPIDEMIOLOGY
The global incidence of ALS is 2 per 100,000 to 3 per 100,000, which leads to a
prevalence of 4 per 100,000 to 5 per 100,000.1,2 Historically, certain areas have
seen a higher disease concentration, including the island of Guam, the Kii
Peninsula of Japan, and others.3 People of non-European descent are thought to
possibly have a lower relative risk of the disease.3 The lifetime risk of ALS in the
United States and Europe is 1 in 350 for men and 1 in 400 for women,3
demonstrating the male predominance of this disease, which is generally higher
at younger ages of onset.4 Risk of ALS increases with age until the eighth decade,
with an average age of onset in the late fifties and early sixties.2,5 Familial ALS,
defined as ALS in which there are multiple affected family members, accounts
for approximately 10% of cases; the remaining 90% are sporadic. Even in
sporadic cases, the overall disease risk attributable to genetics approaches 60%,
with the remaining 40% of risk related to environmental factors.6 Uncovering
the identity of individual environmental risk factors has been extraordinarily
challenging. Epidemiologic evidence suggests high levels of physical
fitness/athleticism7,8 and slimness7,9,10 increase ALS risk. Since Lou Gehrig was
diagnosed with ALS, professional athletics and ALS have been associated. More
recently, focus has been on increased risk in players of soccer11 and American
football,12 raising the question of whether this is because of the sport activity, the
genetic ability to participate in the sport, head or other trauma experienced
during play, or other factors such as pesticides on the field. Although this
question still remains unresolved, emerging data suggest that professional sports
with concussive risk (eg, American football and soccer) carry the highest relative
risk of ALS compared to professional sports without concussive risk and
nonprofessional sports with and without concussive risk.13 An association also
exists between having served in the US military and developing ALS.14,15 In
addition to athletes and military personnel, other occupations with risks
associated with ALS include veterinarian, hairdresser, and power-production
plant operator.16 Some evidence exists that exposure to certain organic
solvents and pesticides may pose a slightly increased risk of ALS.17 The
contribution of smoking to the risk of ALS is quite unclear, as some studies
have indicated a risk whereas others have not,18–21 and a clear dose-response
has not been demonstrated.22 Other suggested environmental risk factors for
ALS, including exposure to heavy metals,17 cyanotoxins,23 and electric shock,24
have not held up under statistical scrutiny. Evidence of spatial clustering is
limited. Most reports are anecdotal and likely better explained by chance. A
large Finnish study examined spatial relationships at birth and death and
found two clusters of disease, although the underlying etiology of these
clusters was not clear.25
1324 OCTOBER 2020

CLINICAL FEATURES KEY POINTS
ALS is a heterogeneous disease with a variety of potential clinical phenotypes;
● The incidence of
however, all presentations have at their core a progressive decline in physical amyotrophic lateral
function due to weakness or spasticity without equivalent sensory loss or sclerosis (ALS) has remained
pain. Some patients also experience changes to emotional expression or constant at around 2 per
cognitive abnormalities. 100,000 per year to 3 per
100,000 per year and is
slightly higher in men than
Motor Features in women.
Approximately 70% of patients with ALS present with weakness of the limbs,
which is typically asymmetric and distal at onset. Twenty-five percent of ● Of patients with ALS, 90%
patients present with bulbar symptoms, which manifest as difficulty have sporadic disease and
10% have familial ALS, which
speaking, chewing, or swallowing (CASE 9-1). A small minority of patients follows an autosomal
have respiratory onset, and less than 1% present with diffuse fasciculations dominant pattern of
and a wasting syndrome. Extraocular movements are spared until late-stage inheritance.
disease. The progressive nature of symptoms is a critical component to
● Patients with ALS
diagnosis. Symptoms begin insidiously in an affected region and progress in typically have a combination
that region as spread to other regions also occurs. Of note, some patients with of upper motor neuron and
ALS will describe “sudden” onset or stepwise symptoms, but careful review of lower motor neuron signs
their history will typically reveal progressive symptoms before the loss of a that affect multiple
segments of the body.
particular functional ability.
The symptoms and signs of ALS can be broadly classified as upper motor
neuron or lower motor neuron and can also be classified by the segment of
the body in which they occur. Upper motor neuron weakness is caused by loss
of downgoing inhibition in the corticobulbar and corticospinal tracts and leads
to increased tone and spasticity, slowness of movement, increased tendon
reflexes, and the presence of pathologic reflexes. Lower motor neuron
weakness is caused by damage to the anterior horn cell or its axon and results
in pure motor weakness, reduced reflexes, muscle atrophy, fasciculations, and
cramps. The electrophysiologic features of lower motor neuron injury are
discussed in the diagnostic evaluation section below. In the bulbar segment,
these symptoms and signs can manifest as dysarthria and dysphagia, along
with facial weakness. Upper motor neuron, or spastic, dysarthria is
characterized by slow and strained speech, often with spastic dysphonia.
Lower motor neuron, or flaccid, dysarthria is characterized by weakness of
lingual, facial, and palatal muscles causing imprecise, breathy, and hypernasal
speech. Laryngospasm and involuntary cheek or tongue biting are additional
bulbar upper motor neuron symptoms. Facial weakness and dysphagia often
lead to sialorrhea and difficulty managing secretions. Brisk and pathologic
reflexes that may be found in the bulbar segment include the jaw jerk,
palmomental signs, and facial reflexes. The presence of a mixed spastic and
flaccid dysarthria is almost always indicative of ALS. Upper motor neuron and
lower motor neuron signs in the limbs are described above and may
particularly cause imbalanced gait when present in the legs. Cramps may
frequently occur in the limbs, thoracic region, and neck and are often
brought about by activity that causes contraction and shortening of the
involved muscle. Respiratory insufficiency is typically thought to be
caused preferentially by lower motor neuron dysfunction of the diaphragm
and accessory muscles of respiration26 resulting in shortness of breath,
orthopnea, sleep-disordered breathing, paradoxical breathing,27 and reduced
vocal volume.

Pseudobulbar Affect
Pseudobulbar affect is a disorder of emotional expression that is caused by
disruption of corticopontocerebellar pathways.28,29 Patients describe laughing or
crying that is not under voluntary control and is out of proportion to their
internal emotional state; excessive yawning may also be a feature of this
syndrome. Pseudobulbar affect is not specific to ALS but, when present in the
setting of progressive weakness, can point to a neurogenic cause for the
weakness, thus distinguishing it from other neuromuscular disorders.
Cognitive Features
Cognitive abnormalities have been described in ALS for more than a century.30
In the past 30 years, multiple observational studies have suggested that up to
one-half of patients with ALS have neuropsychological abnormalities, most
commonly manifesting as executive dysfunction.31–33 A smaller population of
patients with ALS (5% to 15%) have frank frontotemporal dementia (ALS-FTD).34
CASE 9-1 A 67-year-old man presented with an 8-month history of progressive

slurring of speech. Over the same period of time, he had noted weakness
of his left hand but denied numbness. He had also experienced muscle
cramping in his hands and legs. When asked, he said that he had been
crying spontaneously, which was unusual for him.
Neurologic examination revealed mixed spastic and flaccid dysarthria
and frequent yawning. He had fasciculations of the tongue, upper arms,
and thighs and atrophy of the tongue and left hand (FIGURE 9-1) but no clear
atrophy elsewhere. Proximal arm and lower extremity strength were
normal, but he had weakness of the left greater than right finger
extensors and intrinsic hand muscles. A jaw jerk was present, and arm
and leg reflexes were brisk (3+). Hoffman sign was present on the right.
Plantar responses were extensor. Sensation was preserved.
MRI of the brain and cervical and thoracic spine was unremarkable.
Sensory and motor nerve conduction studies in the right arm and leg were
normal. Needle EMG revealed fasciculation potentials in multiple arm
and leg muscles. Fibrillation potentials and positive sharp waves were
seen in the right and left triceps and intrinsic hand muscles, left distal leg
muscles, and left thoracic paraspinals. Large motor units with reduced
recruitment were seen in the left hand and multiple left leg muscles.
1326 OCTOBER 2020

Most patients with ALS-FTD present with the behavioral variant of FTD,
demonstrating disinhibition, lack of empathy, poor initiation, and impaired
executive functioning (CASE 9-2), although disorders of language production
manifesting as the nonfluent/agrammatic variant of primary progressive aphasia
have also been reported.34,35 Conversely, approximately 15% of patients who
present with FTD will develop ALS.36,37 Common tools for evaluation include the
Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and the ALS Cognitive
Behavioral Screen (ALS-CBS).38,39
DIAGNOSTIC EVALUATION AND DIFFERENTIAL DIAGNOSIS

To date, no single diagnostic test is available for ALS. Diagnosis is based on the
combination of historical features, examination findings, and electrophysiologic
features and the exclusion of other potential causes for these findings. The
symptoms described by patients with ALS are detailed above. On examination, a
combination of upper motor neuron and lower motor neuron signs is expected,
FIGURE 9-1
Photographs of the patient in CASE 9-1 with amyotrophic lateral sclerosis. A, Atrophy of the
tongue. Atrophy of the hand is worst in the lateral ulnar (B, first dorsal interosseous) and
median (C, abductor pollicis brevis) innervated muscles, commonly referred to as split
hand syndrome.
This patient had bulbar-onset amyotrophic lateral sclerosis (ALS). The COMMENT
examination and EMG showed signs of lower motor neuron involvement in the
bulbar, cervical, thoracic, and lumbosacral body segments. Additionally, the
examination showed signs of upper motor neuron involvement affecting
the bulbar, cervical, and lumbosacral regions. No signs of a structural cause for
upper motor neuron pathology were seen on MRI. In the absence of any
alternative explanation for these findings, the criteria for a diagnosis of ALS
was met (Revised El Escorial: clinically definite).

although, in the authors’ experience, approximately 15% of patients present with

isolated lower motor neuron findings and a significantly smaller portion (4%)
present with isolated upper motor neuron findings (unpublished data from the
Penn Integrated Neurodegenerative Diseases Database 2007–2020, data
reviewed May 8, 2020).
The revised El Escorial40 and Awaji41 criteria are common diagnostic criteria
used for the clinical diagnosis of ALS (FIGURE 9-2). It is important to note that
these are classification criteria and not a measure of disease severity. Although a
classification of clinically definite ALS does, on average, carry a worse prognosis
than clinically possible ALS, one patient may be minimally disabled with
clinically definite ALS and another may die, never having moved beyond a
classification of clinically possible ALS. Staging systems that aim to inform
disease progression and prognosis have also been proposed and are starting to
gain ground and acceptance. The King’s staging system classifies ALS into stage 1,
symptom onset (involvement of first region); stage 2A, diagnosis; stage 2B,
involvement of second region; stage 3, involvement of third region; stage 4A,
CASE 9-2 A 58-year-old woman was brought into clinic by her daughter, who
described her mother as having had 1 year of progressive difficulty
walking and behavioral changes. She noted that her mother had always
been kind and interested in her daily life, but over the past year she had
stopped asking about her grandchildren. Her eating habits had changed,
and she had gained 15 pounds because of excessive daily consumption of
butter pecan ice cream. The patient became angry when asked about
these changes, which was unusual for her. The patient’s father had died
of symptoms consistent with amyotrophic lateral sclerosis (ALS), and her
paternal grandmother struggled with dementia before her death.
On examination, the patient was pleasant but disinhibited. She
repeatedly asked about the examiner’s marital status. She was oriented
to time and place. Her motor examination revealed atrophy of the distal
right greater than left leg. Rare fasciculations were seen in her legs. Gait
demonstrated right greater than left footdrop. Reflexes were 3+ at the
knees with crossed adductors and absent at the ankles. Palmomental
signs were present bilaterally.
MRI of the brain was unremarkable. EMG revealed diffuse active
denervation and chronic reinnervation in the legs. An ALS gene panel
revealed a chromosome 9 open reading frame (C9orf72) gene repeat
expansion.
COMMENT This patient has familial ALS frontotemporal dementia (ALS-FTD) in the
setting of a C9orf72 repeat expansion. She has abnormalities on
examination and EMG consistent with ALS. Her behavioral changes are
consistent with impaired executive function and disinhibition and strongly
suggest a behavioral variant of FTD. Her family history indicates a
dominantly inherited disorder causing dementia or ALS, or both. Mutations
in C9orf72 are the most common cause of familial ALS and ALS-FTD.
1328 OCTOBER 2020

FIGURE 9-2
Revised El Escorial and Awaji diagnostic criteria for amyotrophic lateral sclerosis (ALS).
EMG = electromyography.
Data from Ludolph A, et al, Amyotroph Lateral Scler Frontotemporal Degener40 and Nodera H, et al, Brain Nerve.41
need for gastrostomy; and stage 4B, need for noninvasive ventilation.42 The ALS
Milano-Torino staging system starts at stage 0 with symptoms but no loss of
independence and includes stages 1 through 4 for loss of independence in a
number of domains derived from the ALS Functional Rating Scale–Revised
(ALSFRS-R) (swallowing, walking/self-care, communicating, and breathing);
stage 5 represents death.43 The two staging systems are considered to be
complementary and are now included in some clinical trials.44
For patients with a history of progressive weakness and an examination
revealing diffuse upper motor neuron and lower motor neuron findings, the
diagnostic evaluation can be focused. Nerve conduction studies and EMG should
be performed. Nerve conduction studies typically demonstrate preservation of
sensory responses with normal or reduced motor amplitudes. As comorbid
sensory polyneuropathy may occur, abnormal sensory responses should not
exclude the diagnosis of ALS and should be considered in proportion to the motor
findings. Motor responses are often preserved in early or slowly progressive ALS
because of collateral sprouting of the remaining motor neurons. Needle EMG
should demonstrate signs of active denervation (fibrillation potentials and
positive sharp waves) along with chronic denervation in multiple myotomes.
Limited electromyographic abnormalities with upper motor neuron examination
findings may be seen in early or upper motor neuron–predominant disease;
however, this should prompt consideration of an alternative etiology of upper
motor neuron involvement with a coexistent lower motor neuron injury (eg,
cervical radiculomyelopathy). The authors recommend MRI of the neuraxis at
and rostral to the lowest level of upper motor neuron findings. For example, a
patient with brisk upper and lower extremity reflexes would require imaging of
the brain and cervical and thoracic spine to exclude an alternative explanation for
these findings.
In addition to electrodiagnostic evaluation and neuroimaging, limited
further testing may be required to exclude particular diagnoses in certain clinical
scenarios (TABLE 9-1). In patients with isolated findings of diffuse weakness,
a broad differential should be considered, including myopathy, a defect

in neuromuscular junction transmission, polyradiculopathy, or a motor-

predominant polyneuropathy. A myopathy is typically excluded by the
presence of fasciculations, the pattern of weakness (distal and asymmetric), the
degree of creatine kinase elevation (typically <1000 U/L in ALS), and the lack of
myopathic findings on needle EMG. At times, myopathic processes, such as
fascioscapulohumeral muscular dystrophy and inclusion body myositis, may be
asymmetric, but in these instances the overall pattern of weakness typically
suggests the underlying diagnosis. Some myopathies have modest creatine kinase
elevations or have a “neurogenic appearance” on needle EMG (both are common
with inclusion body myositis). Rarely, it may be necessary to resort to muscle
biopsy to confirm a neurogenic process.
TABLE 9-1 Amyotrophic Lateral Sclerosis Mimicsa
Diagnosis Diagnostic Clue Confirmatory Testing
Lower motor neuron predominant/weakness
Benign fasciculations Acute onset, widespread, no weakness EMG does not demonstrate
denervation or chronic reinnervation
(and often does not show
fasciculations)
Inclusion body myopathy Weakness of deep finger flexors and Myopathic EMG, plus NT5C1A antibody
quadriceps (helpful when present), muscle biopsy
findings
Multifocal motor neuropathy (MMN) Nerve (rather than myotome) pattern Partial motor conduction block on
with conduction block with asymmetric upper extremity nerve conduction studies, positive
predominance anti-GM1 antibodies
Neuralgic amyotrophy Pain at onset, involvement of named Nerve conduction studies and EMG
nerves, self-limited course findings, MRI with and without contrast
of the involved plexus
Monomelic amyotrophy Young male with asymmetric hand and MRI findings
(Hirayama disease) distal forearm weakness and atrophy,
self-limited course
Spinal bulbar muscular atrophy Slow progression, facial twitching, Absent sural sensory responses, CAG
(Kennedy disease) tremor, sensory neuropathy, evidence of repeat expansion in the androgen
androgen insensitivity (eg, gynecomastia, receptor gene
testicular atrophy)
Motor-predominant Charcot-Marie- Symmetric and distal onset, young age of Nerve conduction studies
Tooth disease (CMT)/distal spinal onset, slow progression demonstrating abnormal sensory nerve
muscular atrophy action potential (SNAP) amplitudes and
(in CMT type 1) evidence of
demyelination; positive genetic testing
for CMT
Post–severe denervation (postpolio) History of distant polio or other severe Giant motor unit action potentials on
syndrome nerve injury with recovery followed by EMG
slow progression of weakness in the
distribution of prior polio symptoms;
muscle pain is common
1330 OCTOBER 2020

Nerve conduction studies should demonstrate sparing of sensory nerves/
neurons. Sensory involvement that maps to the regions of weakness should
suggest an acquired (eg, vasculitis) or inherited (eg, familial amyloid)
polyneuropathy. Careful assessment of motor responses should be performed to
assess for demyelinating features (distal latencies >30% prolonged, conduction
velocity <70% normal, or conduction block), which, if present, suggest an
acquired demyelinating neuropathy such as chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP) or multifocal motor neuropathy
(MMN). For more information on CIDP and MMN, refer to the article “Chronic
Inflammatory Demyelinating Polyradiculoneuropathy and Its Variants” by Kelly
Gwathmey, MD,45 in this issue of Continuum. If MMN is suspected on the basis of
Diagnosis Diagnostic Clue Confirmatory Testing
Upper motor neuron predominant
Nutritional myeloneuropathies Sensory (predominantly dorsal column) Abnormal sensory nerve conduction
deficits, sensory neuropathy studies, vitamin B12 or copper
deficiency, dorsal column
abnormalities on MRI
Hereditary spastic paraparesis Young onset, family history, slow Positive hereditary spastic paresis
progression, predominantly leg genetic screen
involvement
Adrenomyeloneuropathy Sensory neuropathy, with or without Abnormal sensory nerve conduction

adrenal insufficiency, X-linked (females studies, ABCD1 mutation
may still be affected)
Late-onset Tay-Sachs disease Cerebellar ataxia/atrophy, psychiatric HEXA mutations

features, Ashkenazi descent (recessive)
Polyglucosan body disease Distal sensory loss, neurogenic bladder, White matter changes on MRI, GBE1
cerebellar ataxia, cognitive deficits mutations
Human immunodeficiency virus (HIV) Extended history of HIV; MRI may be HIV positive
myelopathy unremarkable
Multiple sclerosis Sensory and sphincter involvement, MRI findings, CSF findings
relapsing-remitting course (some)
Mixed lower motor neuron/upper motor neuron
Cervical radiculomyelopathy Sphincter involvement, pain, sensory Foraminal and canal stenosis on MRI
symptoms/level (should be rostral to highest upper
motor neuron examination findings)
CSF = cerebrospinal fluid; EMG = electromyography; MRI = magnetic resonance imaging.

a
The diagnoses in this table largely assume the presence of significant amyotrophic lateral sclerosis features that may confuse clinicians. Many of
these diagnoses are quite rare and do not warrant individual investigation unless additional features as described in the Confirmatory Testing
column are present. More common disorders considered when examining a patient with painless weakness are discussed in the article text and
not addressed in this table.

electrodiagnostic testing or by the involvement of specific named nerves,

anti-GM1 antibodies should be checked, although the sensitivity of this test is
about 50%.46 In the setting of preserved sensory responses with diffuse EMG
abnormalities and no upper motor neuron findings, an immune (eg, CIDP,
sarcoid), infectious (eg, varicella-zoster virus, cytomegalovirus, West Nile virus,
Lyme disease), or neoplastic (eg, lymphomatous or carcinomatous)
subarachnoid process should be sought by collecting CSF. Men with a lower
motor neuron syndrome with abnormal sensory responses on nerve conduction
studies should be tested for spinal bulbar muscular atrophy (Kennedy disease)
with testing for a CAG repeat expansion in the androgen receptor gene,
especially in the setting of slowly progressive disease, infertility, and
gynecomastia. If prominent cerebellar or psychiatric symptoms are present,
HEXA gene testing is appropriate to exclude adult-onset Tay-Sachs disease.
Human immunodeficiency virus (HIV) may rarely be associated with an
ALS-like syndrome (known as HIV-associated motor neuron disease). Because
reports exist of patients with this syndrome having a response to antiretroviral
therapy,47 HIV testing should be part of the diagnostic evaluation in patients who
are at risk.
Isolated upper motor neuron examination findings should prompt careful
examination of the neuraxis, with MRI performed to exclude structural causes
of upper motor neuron injury. Nutritional causes of myelopathy, including
vitamin B12 and copper deficiency, should be excluded. Infectious causes of
chronic myelopathy include human T-cell lymphotropic virus types 1 and 2
(HTLV-1/HTLV-2) and HIV vacuolar myelopathy; these should be sought in
the appropriate setting. Stiff person syndrome can present as an upper motor
neuron phenotype and can be investigated with anti–glutamic acid
decarboxylase (GAD) antibodies. In patients with slowly progressive
symptoms predominantly in the legs, genetic evaluation for hereditary spastic
paraparesis (HSP) should be performed whether or not the patient has a
family history of similar issues. In patients with isolated clinical upper motor
neuron signs, nerve conduction studies and EMG are useful tools to confirm
the absence of sensory involvement and to look for subclinical lower motor
neuron abnormalities on the needle study. In patients with predominant
upper motor neuron clinical findings but sensory involvement on nerve
conduction studies, testing of the ABCD1 gene should be performed to
exclude adrenomyeloneuropathy.
Once the diagnosis of ALS is established, careful reassessment should be
routinely performed in follow-up visits to ensure that any new symptoms or
signs remain consistent with the diagnosis of ALS and do not suggest an
alternative diagnosis.
AMYOTROPHIC LATERAL SCLEROSIS BIOMARKERS

Currently, no nonclinical biomarkers are used in standard practice for
diagnosis (beyond exclusion of other etiologies) or tracking of disease
progression, although several have demonstrated some promise, particularly
in predicting prognosis and disease progression. These include body fluid
markers (eg, neurofilament light chain and phosphorylated neurofilament
heavy chain, cystatin C, transthyretin, p75 neurotrophin receptor
extracellular domain, miR-451, monocyte chemoattractant protein-1),48
electrophysiologic measures (eg, electrical impedance myography, motor unit
1332 OCTOBER 2020

number estimation), and imaging techniques (eg, MRI, positron emission KEY POINTS
tomography [PET]). Specific biomarkers have been developed for certain
● Frontotemporal dementia
forms of familial ALS, including CSF superoxide dismutase 1 (SOD1) levels in occurs in 5% to 15% of
familial ALS due to SOD1 mutations. Development of biomarkers is critical for patients with ALS, and a
drug development, particularly given the heterogeneity of the clinical features larger proportion of patients
of ALS.49,50 will have subtle findings of
personality change or
executive dysfunction.
PATHOLOGY
The name amyotrophic lateral sclerosis is reflective of the original pathologic ● The diagnostic evaluation
features described by Charcot. Along with muscle atrophy (amyotrophy) due of ALS does not need to be
to denervation, he noted scarring and hardening (sclerosis) of the lateral extensive in the setting of
the appropriate clinical
portions of the spinal cord, the location of the corticospinal tracts. Microscopic history and physical
evaluation of the motor cortex and anterior horns of the spinal cord reveals examination, although it is
loss of motor neuron cell bodies (FIGURE 9-3) and signs of neuroinflammation. imperative to exclude all
Classic pathologic features of ALS also include Bunina bodies, small treatable conditions.
eosinophilic cytoplasmic inclusions found in the cytoplasm of surviving motor ● MRI should be performed
neurons in nearly all types of ALS; however, their significance has not yet at the lowest level of upper
been explained.51 Potentially more mechanistically relevant are the motor neuron findings and
ubiquitinated cytoplasmic inclusions that contain transactive response above in patients with
suspected ALS.
DNA-binding protein 43 (TDP-43), which are present in nearly all patients
with ALS (FIGURE 9-4).52 First described in a landmark article in 2006, ● Isolated upper motor
TDP-43 intracytoplasmic inclusions represent the pathologic link between the neuron examination findings
should prompt careful
examination of the neuraxis,
with MRI performed to
exclude lesional causes of
upper motor neuron injury.
FIGURE 9-3
Hematoxylin and eosin (H&E) stains of the lumbar spinal cord in a healthy individual and in
a patient with amyotrophic lateral sclerosis. In the spinal cord of a healthy individual,
numerous motor neurons are visible at low-power and high-power magnification. In a
patient with amyotrophic lateral sclerosis, a paucity of motor neuron cell bodies is seen at
the same magnifications.

FIGURE 9-4
Transactive response DNA-binding protein 43 (TDP-43) immunohistochemistry of the lumbar
spinal cord in a patient with amyotrophic lateral sclerosis. Sections were stained using an
antibody that recognizes phosphorylated TDP-43 and counterstained with hematoxylin for
nuclei (blue). The immunostain demonstrates cytoplasmic and neuritic TDP-43 inclusions
affecting motor neurons (brown). Panel A is at slightly lower magnification and shows neuronal
cell body TDP-43 pathology and neuritic pathology; panel B emphasizes cell body inclusions.
Figure courtesy of John L. Robinson, MS.
phenotypes of ALS and FTD; their discovery heralded the genetic link that was
discovered shortly thereafter.
GENETICS
ALS is most commonly a sporadic disease, with no family history in 90% of
patients. Approximately 10% of patients have a family history (familial ALS),
which is typically dominant; over the past 30 years, this population has been
extensively explored, with a goal of explaining the genetic underpinnings of their
disease and leveraging this knowledge to a greater understanding of the
underlying mechanisms of cell death in all forms of ALS.
In 1993, SOD1 mutations were the first genetic cause of familial ALS to be
described. SOD1 mutations account for approximately 20% of familial ALS.
Whereas the mutation was initially thought to cause oxidative damage in the
setting of haploinsufficiency, further study demonstrated a dominant negative
effect of the most common SOD1 mutations.53 As no other familial ALS
mutations were discovered for 15 years after SOD1, this gene became the primary
model for ALS genetics through the mid-2010s; however, concerns have been
raised that SOD1 pathophysiology may be distinct because of some unique
features of SOD1-mediated ALS pathology (discussed later in this article).
In 2008, after a prolonged period without major gene discoveries in ALS, a
family with dominant ALS was identified with a common mutation in the
TARDBP gene. Although an uncommon cause of familial ALS (approximately
4%), the discovery of the TARDBP mutation was an important turning point
because it linked a gene mutation to the most common pathologic feature seen in
ALS (TDP-43 inclusions), and it marked the beginning of a decade of discovery
of new genes associated with familial ALS (FIGURE 9-5). TDP-43 plays a critical
role in RNA processing, and this pathway has become a central focus in the
pathogenesis of ALS (refer to the pathophysiology section below).
1334 OCTOBER 2020

KEY POINTS
● Gene discovery for ALS

has accelerated remarkably
over the past decade,
leading to improved
understanding of ALS
pathophysiology that will
ideally result in targeted
therapies in the near future.
● SOD1 mutations were the

first genetic mutations
discovered in familial ALS.
However, SOD1 pathology is
distinct from the pathology
seen in the majority of ALS
cases.
FIGURE 9-5
Timeline of amyotrophic lateral sclerosis (ALS) gene discovery. The discovery of genes
associated with familial and sporadic ALS has rapidly increased over the past 20 years. Most
of the genes identified are associated with familial ALS, with C9orf72 representing the largest
proportion, followed by SOD1 and then TDP-43 and FUS. Some genes listed are ALS risk
factors (ATXN2, C21orf2, MOBP, and SCFD1) or possible disease modifiers (SARM1). STMN2
mutations have not been found in familial ALS, but missplicing of STMN2 RNA appears to be
important in ALS pathophysiology. The size of the circles is proportionate to the contribution
of each gene to the overall population of familial ALS.
Data courtesy of Robert H. Brown Jr, DPhil, MD.
Soon after the discovery of the TARDBP mutation, another gene involved in RNA
processing was found to be a cause of familial ALS. Mutations in the fused in sarcoma
(FUS) gene are an uncommon cause of familial ALS (<5%) but are important because
of the similarity between FUS and TARDBP function, although, interestingly,
FUS-related familial ALS lacks TDP-43 pathology.54,55 Additionally, FUS mutations
are more commonly seen in patients with early-onset ALS and should be considered
in any patient presenting with ALS in the second or third decade of life.54
The most significant discovery in ALS genetics of the past decade is the
location of a mutation on C9orf72. An important locus on chromosome 9 was
initially identified by a genome-wide association study performed in Finland,56
which is an ideal geographic region for study because of a high incidence of ALS
and relative genetic homogeneity. Later work revealed a hexanucleotide repeat
expansion (GGGGCC) in the noncoding region of C9orf72, causing an autosomal
dominant form of familial ALS.57,58 Expansions of at least 30 repeats are
associated with ALS, FTD, or ALS-FTD. Expansions in C9orf72 explain 40% of
familial ALS in a European ALS population and nearly 10% of sporadic ALS.59 Of
note, the contribution of C9orf72 expansions in non-European populations may
be different. For example, a study of 59 Japanese patients with familial ALS
revealed C9orf72 expansion in less than 4% of families.60 The penetrance of the
mutation nears 100%. Patients who are going to develop ALS do so at a younger
age than those who develop FTD. Spinal onset tends to occur at a younger age
than bulbar onset, and males also tend to have a younger onset; this pattern holds

true whether the mutation is inherited or sporadic.61 Approximately 50% of

people with C9orf72 expansions will develop C9orf72-associated disease by age
60, and nearly 100% are symptomatic by 80 years of age.59
PATHOPHYSIOLOGY
A unifying theory of ALS pathophysiology remains elusive and may ultimately
prove unobtainable. The multiple potential pathways that may play a role in ALS
pathophysiology are reviewed below. These pathways likely interact and may
vary in importance in individual patients with ALS.
C9orf72 Mutations
As the most common cause of familial ALS, mutations in C9orf72 are of
significant interest as they promise to inform our understanding of ALS
pathophysiology. Both loss-of-function and toxic gain-of-function
mechanisms have been proposed. Although C9orf72 protein function is not
entirely elucidated, it appears to be related to membrane trafficking. Patients
with expansions in the hexanucleotide repeat region of C9orf72 produce less
mRNA and C9orf72 protein than patients with a standard number of repeats
(<30), which suggests haploinsufficiency. Through repeat-associated
non-AUG (RAN) translation, the expanded hexanucleotide repeat region can
produce multiple dipeptide repeat proteins that form cytosolic aggregations.
The functional significance of the pre-mRNA and dipeptide repeat proteins
generated by the repeats is not clear, although concern exists that pre-mRNA
may occupy nuclear binding proteins required for proper splicing of other
mRNAs.62,63
Impaired Protein Processing

Cytosolic aggregation of misfolded proteins and impaired protein degradation
processes are features of nearly all neurodegenerative conditions. Similarly,
multiple mutant proteins associated with the development of ALS form
potentially pathogenic intracellular aggregations. SOD1, the first gene associated
with ALS, has a dominant negative effect likely due to the accumulation of
misfolded mutant proteins with direct toxic effect on cellular function and
indirect effects through impairment of cellular degradation of proteins in
proteasomes and autophagolysosomes. Aggregations of wild-type SOD1 protein
have also been noted in patients with sporadic ALS. Other protein mutations seen
in rare cases of familial ALS, including ubiquilin 2, valosin-containing protein,
and optineurin, are associated with impaired protein degradation.
Impaired RNA Processing

With the discovery of cytoplasmic TDP-43 inclusions in ALS, RNA processing
became a major area of focus in ALS pathogenesis. TDP-43 is a DNA/RNA-
binding protein involved in transcription, RNA splicing, and transport and is
usually exclusively located in the nucleus. The discovery of displaced cytoplasmic
TDP-43 raised concern for either a loss of nuclear TDP-43 function in RNA
processing or a toxic effect of TDP-43 cytoplasmic aggregates, or a combination
of the two. More recent evidence has suggested that altered nuclear RNA splicing
may impact critical proteins involved in axonal function. Specifically, altered
stathmin-2 splicing may result in early truncation and loss of full-length protein,
which is essential for axon stability and regeneration.64 FUS is another
1336 OCTOBER 2020

RNA-binding protein associated with ALS, further supporting the notion of RNA KEY POINTS
processing as an important pathway in ALS neurodegeneration.55
● Hexanucleotide repeat
expansions in C9orf72 are
Cellular Abnormalities and Failure the most common cause of
Numerous signs of cellular abnormalities in ALS are difficult to categorize as familial ALS.
either primary issues or downstream consequences of neurodegeneration from
● No single cause of ALS
one of the mechanisms discussed above. These include neuronal hyperexcitability,
has been determined,
endoplasmic reticulum stress, mitochondrial failure, cytoskeletal abnormalities, although multiple critical
impaired axonal transport, axonal retraction, and synaptic failure.53 pathways in motor neuron
degeneration have been
Immune Dysregulation/Inflammation identified. Of particular
current interest are
The role of the immune system and immunomodulatory therapy in ALS has long abnormalities in RNA
been debated. Clear evidence exists of immune activation in ALS and a processing.
relationship between proinflammatory states and faster disease progression.
Activated microglia and macrophages are found in the motor cortex and spinal ● Cytoplasmic transactive
response DNA-binding
cords of patients with ALS and are typically absent in controls.65 Microglia are the protein 43 (TDP-43)
resident immune cells of the central nervous system and may have a inclusions are a hallmark of
proinflammatory (M1) or anti-inflammatory (M2) influence on the immune ALS pathology in the vast
response.66 Proinflammatory cytokines (eg, IL-6)67 and lower numbers of majority of patients.
regulatory (compared to cytotoxic) T cells are associated with faster disease
● No curative therapy has
progression.68 Despite these findings, multiple trials of immunosuppression, been identified for ALS. The
including corticosteroids with azathioprine,69 cyclophosphamide with IV mainstay of treatment is
immunoglobulin (IVIg),70 and a posttransplant regimen of immunosuppression multidisciplinary care and
(basiliximab, tacrolimus, mycophenolate mofetil, and prednisone)71 have palliative symptom
management.
failed to show a significant effect on ALS disease progression in humans.
Nonetheless, current approaches to reduce the proinflammatory state (eg, ● The oral drug riluzole is
masitinib,72 tocilizumab73) or encourage an anti-inflammatory/proregulatory the most widely used
state (eg, rapamycin,74 T–regulatory cell infusions plus IL-275) are in active or disease-modifying agent in
ALS and has a well-
planned human trials. Mesenchymal stem cells, which may have a variety of established, albeit modest,
trophic effects on motor neurons, also appear to have an impact on inflammatory effect on survival.
markers, which may predict response to this therapy.76
● Edaravone is an IV
disease-modifying agent
MANAGEMENT
that slowed the rate of
Currently, ALS has no cure. A few disease-modifying options with limited functional decline in a small
efficacy are available. Much of the focus of ALS care centers on multidisciplinary number of select ALS
management of symptoms. patients with early, diffuse,
and rapidly progressing
disease. However, a prior
Disease-Modifying Therapies trial in a broader population
Despite decades of clinical trials involving numerous agents with varying was negative and questions
mechanisms of action, only two disease-modifying agents are currently available, remain regarding its long-
both of which have modest effects on disease outcomes. Riluzole, an inhibitor term effectiveness in the
general ALS population.
of neuronal glutamatergic transmission, was first approved in 1995 after
demonstrating a 12% increase in 1-year survival in subjects treated with 50 mg
2 times a day compared to subjects treated with placebo.77 Repeated studies of
riluzole have consistently demonstrated a modest survival benefit averaging
3 months.78 Edaravone, which is an intravenously administered free radical
scavenger that reduces oxidative stress in the setting of cellular injury, was
approved in 2017 based on a small study of Japanese patients with early, diffuse,
and rapidly progressive ALS. In this population, a 33% reduction in the decline of
the ALS Functional Rating Scale–Revised (ALSFRS-R) was seen over the course

of 6 months.79 A prior trial in a broader ALS population failed to demonstrate this

effect. A number of questions remain about edaravone’s efficacy, including
whether it is effective in the general ALS population, whether it provides benefit
beyond 6 months, and whether its efficacy is long lasting.80 A post hoc analysis of
an extension trial in which some patients had delayed initiation of edaravone (24
weeks after the start of the trial) found that no benefit was seen with delayed
edaravone even in the group that was expected to benefit the most from the drug
(clinically definite ALS, forced vital capacity >80% predicted, score ≥2 on all
ALSFRS-R items).81
Care of the Patient With Amyotrophic Lateral Sclerosis

Nonpharmaceutical interventions have also demonstrated benefit in ALS.
Specifically, patients receiving multidisciplinary care report better quality of life
and longer survival,82,83 and patients receiving early noninvasive ventilation have
slower decline in respiratory weakness and prolonged survival compared to
untreated cohorts.84–86 Optimal outpatient care involves having patients with
ALS attend a multidisciplinary clinic every 3 months, in which body mass index
and forced vital capacity are carefully tracked. Recommendations regarding
TABLE 9-2 Symptom Management in Amyotrophic Lateral Sclerosis
Symptom Nonpharmacologic Management Pharmacologic Management
Bulbar segment
Dysarthria Early voice banking, augmentative communication None

devices
Dysphagia/weight Alteration of food consistencies, behavioral None

loss strategies for eating (small bites, chin tuck), offer
feeding tube placement
Weak cough Insufflator-exsufflator, aggressive secretion None

management
Sialorrhea Suction device, radiation therapy Tricyclic antidepressants, anticholinergics,

botulinum toxin injection to the salivary glands
Thickened Ensure adequate hydration Guaifenesin, nebulized medications (saline bullets,

secretions albuterol with acetylcysteine)
Laryngospasm Botulinum toxin to laryngeal adductor muscles, Clonazepam

tracheostomy
Jaw clenching/ Bite guard Clonazepam, baclofen, botulinum toxin injection

biting to specific muscles
Pseudobulbar None Dextromethorphan HBr/quinidine sulfate,

affect selective serotonin reuptake inhibitors (SSRIs),
tricyclic antidepressants
Limb-related
Weakness Energy conservation, bracing and adaptive None

equipment
1338 OCTOBER 2020

nutrition, use of equipment and mobility devices, and respiratory interventions
should be discussed and support offered to patients and caregivers.87,88 ALS is
associated with substantial morbidity, and treatment of the symptoms of ALS is a
critical focus of multidisciplinary care (TABLE 9-2).
AMYOTROPHIC LATERAL SCLEROSIS VARIANTS

The classic definition of ALS is a combination of upper motor neuron and lower
motor neuron dysfunction affecting multiple segments of the body, which is
reflected in the Revised El Escorial and Awaji criteria. If the disease is limited by
body segment or limited to either upper motor neuron or lower motor neuron
disease, a variant should be considered.
Progressive bulbar palsy is a rare syndrome in which disease is limited to the
bulbar segment. It most often presents in older women, and the prognosis can be
quite good if early intervention with feeding tube placement and secretion
management is implemented.89 Flail arm, also known as brachial amyotrophic
diplegia, involves slowly progressive loss of arm function, which is often initially
asymmetric and proximal. Flail leg, also known as leg amyotrophic diplegia, is
also slowly progressive and asymmetric but may be proximal or distal at onset.
Symptom Nonpharmacologic Management Pharmacologic Management
Spasticity Stretching regimen Oral centrally acting muscle relaxants (baclofen,

tizanidine), benzodiazepines, gabapentin,
intrathecal baclofen via pump, botulinum toxin
injection to specific muscles
Cramps Stretching/position change Mexiletine, phenytoin, levetiracetam
Contractures Splints in neutral for wrists/fingers and ankles None
Respiratory
Respiratory Noninvasive positive pressure ventilation, invasive Morphine for air hunger
insufficiency ventilation
Other
Cognitive- Caregiver education regarding presence of Low-dose SSRIs, low-dose trazodone, low-dose
behavioral cognitive-behavioral issues atypical antipsychotics (olanzapine, quetiapine,
impairment aripiprazole)a
Depression Counseling Antidepressant medications
Anxiety Meditation, biofeedback Buspirone, antidepressants with anxiolytic

indication (SSRIs, serotonin norepinephrine
reuptake inhibitors [SNRIs]), benzodiazepines
Insomnia Sleep hygiene Melatonin, sedative hypnotics, trazodone,

mirtazapine
Anorexia Offer feeding tube placement Megestrol, dronabinol, mirtazapine, steroids
a
Atypical antipsychotics carry a US Food and Drug Administration (FDA) black box warning for increased mortality in older individuals with
dementia.

Both flail arm and flail leg are considered regional variants of ALS and portend a
better prognosis than “classic” ALS. Over time, a certain proportion of patients
with flail arm or flail leg will progress to more widespread disease, but the factors
that predict progression and the exact proportion of patients that convert to
widespread disease remain somewhat unclear.90
Progressive muscular atrophy occurs when clinical disease is limited to the
lower motor neuron, at least for an extended period of time at disease onset. One
series showed that patients with progressive muscular atrophy are more likely to
be male and older at disease onset and survive longer91; however, in another series,
no difference between males and females was seen and progressive muscular
atrophy life expectancy was shorter than in ALS.92 By approximately 5 years after
onset, 22% of patients will have upper motor neuron features of disease, and the
disease is then considered ALS with lower motor neuron onset. Neuropathologic
studies indicate that at least a significant portion of patients diagnosed in life as
having progressive muscular atrophy have upper motor neuron pathology.92–94
The majority of patients with progressive muscular atrophy have TDP-43
pathology, although a significant minority demonstrate FUS pathology.94
Primary lateral sclerosis is a slowly progressive disorder with prolonged
survival that remains isolated to the upper motor neuron for at least 4 years from
onset. Primary lateral sclerosis typically has onset around age 50, most often
begins in the legs, and frequently involves the bulbar region. Recent consensus
CASE 9-3 A 20-year old man presented to a neuromuscular clinic with 24 months of
progressive asymmetric hand weakness and atrophy. He denied
preceding trauma, pain, or sensory loss. His medical history was
unremarkable. He stated that his symptoms had started in the right hand
and progressed to involve his left hand within several months.
Examination revealed atrophy in the right thenar and hypothenar
eminences and asymmetric weakness in muscles of the C8-T1 myotomes
(wrist extensors, finger flexors, finger abductors, and thumb abductors
all grade 3 on the right and 4 on the left). The rest of the neurologic
examination was normal.
Nerve conduction studies revealed reduced motor amplitudes in the right
ulnar and median nerves with normal sensory responses. Needle EMG
demonstrated severe chronic denervation in muscles innervated by the
C8/T1 nerve roots and mild to moderate chronic denervation in the triceps
bilaterally, worse on the right; the legs and thoracic paraspinal muscles
were normal. MRI of the cervical spine in the neutral position revealed the
loss of normal cervical lordosis but no disk herniation or cord signal change.
MRI with flexion of the neck showed slight enlargement and diffuse
enhancement within the posterior epidural space from C5 through C7-T1,
with small flow voids seen on the T2-weighted sequences (FIGURE 9-6).
COMMENT This patient has monomelic amyotrophy (Hirayama disease). His weakness
can be expected to stop progressing and not spread beyond its current
extent. He was advised to avoid prolonged neck flexion.
1340 OCTOBER 2020

diagnostic criteria include categories of diagnostic certainty based on duration of
isolated upper motor neuron signs as well as the requirement of the absence of
lower motor neuron signs and alternative explanations.95 Clinical cases of both
primary lateral sclerosis and progressive muscular atrophy with the genetic
mutations seen in ALS have been diagnosed.
AMYOTROPHIC LATERAL SCLEROSIS MIMICS

A number of disorders that phenotypically may resemble ALS are reviewed in
the section on differential diagnosis. Diagnostic differentiation can be difficult
because of the lack of definitive testing available for ALS. The most commonly
encountered mimics and their differentiating features are presented in TABLE 9-1.
Two disorders that have classically (although perhaps not completely correctly)
been considered motor neuron disorders, monomelic amyotrophy and spinal
bulbar muscular atrophy, are discussed in more detail here.
Monomelic Amyotrophy
Originally described in the Japanese population and also called Hirayama disease,
monomelic amyotrophy most commonly presents with asymmetric arm
weakness in young men around the age of 20. It typically involves the C8/T1
musculature, although some involvement of C7-innervated muscles may be seen;
progression occurs over the course of 2 to 5 years (CASE 9-3). The diagnosis is
FIGURE 9-6
Imaging of the patient in CASE 9-3 with monomelic amyotrophy (Hirayama disease). A, Sagittal
T2-weighted MRI of the cervical spine in a neutral position is fairly unremarkable. B, Sagittal
T2-weighted MRI with neck flexion shows enlargement of the posterior epidural space
from C5 to T1 (arrows).

KEY POINTS made on the basis of history, the classic clinical findings, and findings on cervical
MRI, including dynamic flexion. Imaging findings include mild to moderate
● The presence of isolated
lower motor neuron or
atrophy of the lower cervical cord, loss of posterior dural attachment on neutral
upper motor neuron images, forward displacement of the posterior dural sac and flattening of the cord
abnormalities should with flexion, and prominent posterior epidural venous plexus.96–98 These MRI
broaden the differential findings are supportive of the proposed pathophysiologic mechanism of forward
diagnosis but does not
displacement of the dura with flexion leading to compression of the spinal cord
preclude an ALS diagnosis.
with resultant ischemia of the anterior horn cells at C8 and T1.98 This may stem
● Monomelic amyotrophy from insufficient growth of the dura relative to the vertebral column during
presents in young men with puberty,98 which would explain the age of onset; this phenomenon is more
atrophy of one or both arms, prevalent in young men, which explains the male preponderance of monomelic
typically in the lower
cervical myotomes. The amyotrophy. Additionally, this points to an ischemic mechanism of anterior horn
diagnosis is typically cell loss, which is borne out by the few pathologic samples available.99 Thus,
confirmed by findings on although the disease was originally believed to be a self-limited degenerative
cervical MRI, including motor neuron disease, it is probably best thought of as an ischemic
dynamic flexion
demonstrating forward
poliomyelopathy. Management of monomelic amyotrophy is typically
displacement of the dura. conservative. Cervical collar therapy and avoidance of prolonged forward neck
Although the cause of injury flexion has been recommended during the early or rapidly progressive phase of
is not certain, the most disease.100 Surgical intervention may rarely be indicated.101,102
common theory is
microvascular disturbance
due to compression with Spinal Bulbar Muscular Atrophy
resultant ischemia of the Also called Kennedy disease, spinal bulbar muscular atrophy is an X-linked CAG
anterior horn cells at trinucleotide repeat disorder caused by a mutation in the androgen receptor
C8 and T1.
gene. Neurodegeneration is caused by a toxic gain of function that occurs in the
● Spinal bulbar muscular setting of ligand (testosterone and dihydrotestosterone) binding to the mutant
atrophy is a rare cause of receptor.103,104 Men with disease usually present as adults with fasciculations,
motor neuropathy but cramps, tremor, elevated creatine kinase (less than 1000 U/L), and weakness.
should be considered in men Onset of weakness most commonly occurs in the bulbar region, followed by the
with lower motor neuron
disease, sensory neuropathy lumbosacral region and then the cervical region.105 Dysphagia with poor
on nerve conduction nutritional status may become an important medical concern; neuromuscular
studies, predominant bulbar respiratory failure is rare in spinal bulbar muscular atrophy but can occur.
symptoms, and facial Symptoms of androgen insensitivity, including infertility and gynecomastia,
twitching. It is caused by an
X-linked trinucleotide
are common. Measurement of hormone levels shows elevations in testosterone,
repeat disorder in the free testosterone, dihydrotestosterone, and estradiol and decreased
androgen receptor gene. androstenedione.105 Decreased sensation, often modest and subclinical, and
Neurodegeneration is due to abnormal sensory nerve conduction studies are found in the majority of those
a toxic gain of function that
occurs in the setting of
affected. As in other trinucleotide repeat diseases, repeat length inversely
ligand (testosterone and correlates with age of onset106; repeat length also predicts results of sensory and
dihydrotestosterone) motor nerve conduction studies.107 Attempts to treat spinal bulbar muscular
binding to the mutant atrophy with antiandrogens have not yet been a clear success.108,109 Because of
receptor.
known low concentrations of insulinlike growth factor 1 (IGF-1) in patients
with spinal bulbar muscular atrophy, studies of IGF-1 mimetics remain
under way.110
CONCLUSION
Motor neuron diseases, particularly ALS, remain devastating disorders without
substantial disease-modifying treatments. ALS diagnosis remains clinical based
on upper motor neuron and lower motor neuron symptoms and signs.
Encouraging biomarker development has occurred in the past decade, although
1342 OCTOBER 2020

this is largely focused on prognosis and progression rather than diagnosis. Gene
discovery in familial ALS has expanded our understanding of the affected
pathways resulting in cellular degeneration. Still, a unifying theory of motor
neuron degeneration or a distinct categorization of different disease types by
pathophysiology remains elusive. The next decade should bring further advances
in our understanding of ALS pathophysiology along with treatments that take
advantage of new drug delivery mechanisms and target both specific familial
subtypes and common pathways in sporadic disease.
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REVIEW ARTICLE

Spinal Muscular Atrophy
C O N T I N UU M A UD I O By Jessica Rose Nance, MD
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of the pathophysiology
and clinical presentations of spinal muscular atrophy (SMA) and reviews
therapeutic developments, including US Food and Drug Administration
(FDA)–approved gene-targeted therapies and mainstays of supportive
SMA care.
RECENT FINDINGS:Over the past decades, an understanding of the role of

SMN protein in the development and maintenance of the motor unit and
the intricate genetics underlying SMA has led to striking developments in
therapeutics with three FDA-approved treatments for SMA, one targeting
SMN1 gene replacement (onasemnogene abeparvovec-xioi) and two others
enhancing SMN protein production from the SMN2 gene (nusinersen and
risdiplam). These therapies are most effective in infants treated at younger
ages, and improvement is most striking in babies treated as neonates.
Despite improvements in motor function, patients (especially those treated
at older ages) continue to experience significant weakness and require
continued close monitoring of respiratory and orthopedic symptoms.
CITE AS: SUMMARY: Striking therapeutic advancements have changed the clinical
CONTINUUM (MINNEAP MINN) course of SMA dramatically, although supportive care continues to play an
important role in patient care.
1348–1368.
Address correspondence to INTRODUCTION

Dr Jessica Rose Nance, The Johns
S
Hopkins Hospital, David M. pinal muscular atrophy (SMA) is an autosomal recessive disease of the
Rubenstein Child Health Building, lower motor neurons characterized by progressive weakness and
200 N Wolfe St, Suite 2158;
muscle atrophy. It is caused by a homozygous deletion/mutation in
Baltimore, MD 21287,
jnance6@jhmi.edu. the survival motor neuron 1 (SMN1) gene on chromosome 5q13. The
disease phenotype is broad. Before the availability of SMA therapies,
Dr Nance receives research/
the disease was classified into groups by age of symptom onset and motor
grant support from AveXis, Inc; milestones achieved,1 and, although approved therapies change the
Biogen; Catabasis developmental trajectory, this grouping remains helpful for general
Pharmaceuticals, Inc; Catalyst
Pharmaceuticals, Inc; prognostication and is still used for defining cohorts in clinical trials. Patients
Cytokinetics, Inc; Santhera with type 1 (SMA1) have severe weakness, with onset at younger than 6 months
Pharmaceuticals; and of age, and never achieve the ability to sit independently. Patients with type 2
Scholar Rock.
(SMA2) have milder weakness presenting before 18 months of age and are able to
UNLABELED USE OF sit but never achieve the ability to walk independently. Patients with type 3
USE DISCLOSURE:
(SMA3) have weakness in childhood and are able to ambulate. Patients with type
Dr Nance reports no disclosure. 4 (SMA4) have milder adult-onset weakness. The disease severity is influenced
by a variable copy number of a second paralogous SMN2 gene.2
With an incidence of 1 per 10,000 and a carrier frequency of 1 in 50, SMA is
of Neurology. one of the most common recessively inherited diseases.3 The most common form
1348 OCTOBER 2020

of the disease, SMA1, is one of KEY POINTS
the most common genetic causes
● Spinal muscular atrophy
of death in children. In the late (SMA) is a progressive motor
1800s, Werdnig4 and Hoffmann5 neuron disease caused by
first described the histopathologic mutations/deletions in the
features in infants with severe survival motor neuron 1
(SMN1) gene. It has a broad
progressive weakness and
phenotypic spectrum and is
respiratory failure resulting in classified into categories
early death. The muscle based on age of onset,
pathology is characterized by motor milestone
achievement, and copy
groups of round atrophic fibers
number of the paralogous
and clusters of relatively FIGURE 10-1
SMN2 gene.
Hematoxylin and eosin (H&E) staining of skeletal
hypertrophic myofibers
muscle in spinal muscular atrophy showing
(FIGURE 10-16). grouped atrophy and clusters of relatively
● SMA type 1 (SMA1) is the
Over the decades since its first most common form of SMA
hypertrophic myofibers.
and is characterized by
description, the ability to provide Reprinted with permission from Pestronk A, Neuromuscular
onset of weakness in the
Disease Center.6
supportive care in the form of first few months of life.
ventilatory, nutritional, and Without disease-modifying
orthopedic interventions improved therapy, babies with SMA1
never achieve the ability to
patient longevity and comfort, yet the prognosis remained dismal. Babies with SMA1 sit independently, and the
never achieved the motor milestone of sitting and had a rapidly progressive course of average time to death or
weakness and respiratory failure resulting in death before 2 years of age without requirement for permanent
chronic pulmonary and nutritional interventions. This all changed in 2016 with the US ventilation for an infant
with untreated SMA1 is
Food and Drug Administration (FDA) approval of the first of three therapies for
13.5 months.
SMA, all of which increase SMN protein production. The first approved treatment
was nusinersen, an antisense oligonucleotide targeted at the SMN2 mRNA and
dosed intrathecally every 4 months for life.7 The second approved therapy was
onasemnogene abeparvovec-xioi, an adeno-associated virus 9 (AAV9)–mediated
SMN1 gene replacement given intravenously as a single dose.8 The third therapy,
risdiplam, a small molecule targeting SMN2 mRNA splicing, is given as a daily oral
medication and was recently approved by the FDA in August 2020. These medications
improve survival, decrease the need for respiratory intervention, improve motor
function significantly, and allow some patients with SMA to achieve motor
milestones never before observed in the disease. Improvements are most striking
when treatment is delivered to infants, especially in neonates treated with
nusinersen or onasemnogene abeparvovec-xioi before the onset of overt
symptoms of weakness. This motivates diagnosis and treatment as early as
possible, especially in babies with SMA1 or SMA2, for whom these interventions
have the largest impact. Despite the significant impact of these therapies on the
disease course, many patients experience significant weakness, necessitating
continued close monitoring and provision of respiratory, nutritional, orthopedic,
and rehabilitative interventions.
GENETICS AND PATHOPHYSIOLOGY

Our understanding of the molecular genetics underlying SMA has improved
significantly over the past few decades. A basic familiarity with these advances is
necessary to understand the variability in disease phenotype and the targets of
current therapeutic approaches (FIGURE 10-2). The SMN1 gene on chromosome
5q13 encodes the SMN protein.9 Humans and higher primates also have a variable
copy number of a paralogous SMN2 gene, which significantly differs from SMN1

SPINAL MUSCULAR ATROPHY
FIGURE 10-2
Genetic mechanism for spinal muscular atrophy (SMA). A, Region of interest in the SMN
gene on chromosome 5q13 showing the deleted SMN1 gene and variable copy number of
SMN2 gene. In the absence of the SMN1 gene, motor neuron survival depends upon a
diminished amount of SMN protein that can be produced from the mutated SMN2 gene.
The majority of SMN2 mRNA lacks exon 7 (Δ7-SMN) and produces a protein product that
is degraded. Exon 7 is included in a minority of transcripts (FL-SMN) that produce functional
SMN protein. B, The severity of the SMA phenotype can generally be predicted by the
SMN2 copy number and is inversely related to the patient’s number of copies.
DNA = deoxyribonucleic acid; FL-SMN = full-length SMN mRNA. mRNA = messenger ribonucleic acid.
Data from Feldkötter M, et al, Am J Hum Genet.2
because of a C to T change in the splicing region of exon 7 that reduces splicing

efficiency.10 This results in exclusion of exon 7 in the majority of mRNA
transcripts produced from the SMN2 gene and subsequent degradation of the
abnormal protein.11 Thus, only a minority of SMN2 mRNA transcripts include
exon 7 and are able to produce normal protein. Normally, the level of SMN protein
that is required to maintain lower motor neurons can be achieved in individuals with
at least one copy of the SMN1 gene. In SMA, however, both SMN1 copies are absent,
usually because of deletion, although in about 5% of cases because of a point
mutation. Thus, motor neuron survival becomes dependent on an insufficient
amount of SMN protein that can only be produced by an individual’s SMN2 copies.
Individuals with more copies of SMN2 produce more SMN protein and thus have a
milder phenotype.2,12 With this understanding, SMN1 gene replacement and
augmentation of protein production from the SMN2 gene were seen as important
targets in the development of SMA therapeutics.
The absence of sufficient levels of SMN protein leads to lower motor neuron
death, resulting in progressive weakness and skeletal muscle atrophy in individuals
with SMA. However, the exact role of SMN protein in the motor neuron remains
unknown. On a molecular level, SMN protein is expressed in all cells, but motor
neurons are the most severely affected by reduced levels.13 The primary role of
SMN protein is thought to involve assembly of small nuclear ribonuclear protein
(SnRNP) complexes required for pre-mRNA splicing.14 At least some SMN protein
is required for life, as demonstrated by multiple animal models (which lack SMN2
1350 OCTOBER 2020

genes) in which SMN knockout is lethal, either embryonically or very early in KEY POINT
life (Caenorhabditis elegans,15 Drosophila,16 zebrafish,17 mouse18). That a complete
● In SMA, both copies of
lack of SMN protein in humans is embryonically lethal is supported by the absence the SMN1 gene are absent.
of reported cases of patients lacking both SMN1 and SMN2 genes. Introduction of a Thus, motor neuron survival
human SMN2 transgene into the homozygous mutant Smn-/- mouse avoids is dependent on the number
embryonic lethality, and, similar to in human disease, an increase in the number of SMN2 copies. Patients
with SMA with more SMN2
of SMN2 copies produces increasingly milder phenotypes with later onset of
copies have a milder
symptoms in a dose-dependent fashion.19 phenotype.
Development of a mouse model recapitulating human disease has been vital to
investigating the role of SMN protein in maintenance of motor neurons and the
motor circuit. Selective motor neuron loss in the mouse model has the same pattern
seen in humans, in which motor neurons innervating axial and proximal limb
muscles are affected more severely and earlier compared to those innervating distal
muscles.20 In the presence of reduced levels of SMN protein, motor neuron death
and dysfunction in motor neuron synapses in the anterior horn of the spinal cord are
seen.20 At the same time, inadequate SMN levels disrupt neuromuscular junctions
and are associated with impaired development, atrophy, and denervation of
myofibers (FIGURE 10-321).22,23 Similar findings are noted on autopsy of human
patients with SMA.24 Increasing SMN expression in the early postnatal period in
severely affected mice ameliorates the phenotype, but later restoration of SMN
expression is ineffective, suggesting that high levels of SMN protein are especially
important during embryonic and early postnatal development.25 Autopsy studies of
SMN protein levels in human control and SMA tissues also suggest the importance
of SMN protein during gestational and neonatal stages of motor neuron
FIGURE 10-3
Inadequate SMN protein levels disrupt several interactions within the motor unit.
MN = motor neuron; NMJ = neuromuscular junction.
Reprinted from Tisdale S, Pellizzoni L, J Neurosci.21 © 2015 The Authors.

development.26 Thus, in both mouse models and human patients, SMN protein
appears to play a role in both embryonic development of the motor unit and in the
maintenance of motor neurons postnatally and throughout life.
CLINICAL PRESENTATION
Over time, the classification of SMA has evolved based on a clinical understanding
of SMA, including the age of onset of weakness and the degree of motor milestone
achievement (TABLE 10-1). Along this continuum of disease, weakness is more
rapidly progressive in patients with earlier-onset disease, whereas weakness can
be relatively stable in patients with adult-onset disease. Available therapies have
had a striking impact on the clinical course of the disease, but the classification
continues to be useful in allowing clinicians to provide prognostic information to
patients and their families and to anticipate the individual patient’s needs. This
classification also plays an important role in stratifying patients in clinical trials.
Spinal Muscular Atrophy Type 1

The majority of individuals affected with SMA present in infancy with muscle
weakness and delay or absence of early motor milestones. An infant with SMA1
shows symptoms in the first few months of life and, before the approval of
gene-targeted therapies, was never able to achieve a sitting position
(FIGURE 10-4A27). The majority never gained head control or rolled over.
Neurologic examination of an untreated symptomatic infant reveals a
nonencephalopathic infant with diffuse proximally predominant muscle
weakness and diffusely decreased muscle tone and bulk. Deep tendon reflexes
TABLE 10-1 Classification of Spinal Muscular Atrophy by Typea
Spinal SMN2 Lifespan

Muscular Age of Maximum Motor Copy Without
Atrophy Type Onset Milestone Number Intervention Other Clinical Features
0 <1 week No milestones 1 <1 month Congenital weakness, severe joint

achieved contractures, neonatal respiratory failure
1 2–6 months Never sits 2, 3 <2 years Early proximal weakness, areflexia, tongue
fasciculations, respiratory failure and swallowing
dysfunction, scoliosis, joint contractures
2 6–18 months Sits independently 3, 4 >2 years Proximal weakness, tongue fasciculations,
tremor, respiratory muscle weakness, scoliosis,
joint contractures
3A <3 years Walks 3, 4 Adult Often loses ability to walk in later childhood or
independently early adulthood, tremor, scoliosis
3B 3–21 years Walks 3, 4 Adult Often maintains walking into adulthood, tremor,
independently scoliosis
4 >21 years Walks 4 or Adult Mild proximal weakness

independently more
a
Type is based on age of onset and motor milestone achievement.
1352 OCTOBER 2020

FIGURE 10-4
Clinical features differentiating spinal muscular atrophy (SMA) types. A, Baby with SMA type 1
showing diffuse weakness, prominent frog-leg posturing, and bell-shaped chest. B, Siblings
with SMA type 2 are able to sit. Note diffusely decreased muscle bulk and prominent joint
contractures. C, Patient with SMA type 3 is able to stand and walk. Note decreased muscle
bulk, joint contractures, and scoliosis.
Panel A reprinted with permission from Oskoui M, et al.27 © 2018 Academic Press.
Panel B reprinted with permission from Angelini C.30 © 2018 Springer International Publishing Switzerland.
Panel C reprinted with permission from reprinted from Crawford TO.31 © 2018 Academic Press.
are absent. Early on, muscles of facial expression are strong, but bulbar weakness
and tongue fasciculations are a common finding. Over time, scoliosis and joint
contractures develop. Weakness is often accompanied early on by respiratory
muscle weakness, and patients have a characteristic bell-shaped chest. Because
of respiratory failure and bulbar weakness with swallowing dysfunction,
untreated infants require respiratory and nutritional interventions in the first
year or two to prolong life. Without disease-modifying therapy, babies with
SMA1 are expected to die or require permanent ventilation by the average age
of 13.5 months.28 The majority of patients with SMA1 possess two copies of the
SMN2 gene (FIGURE 10-2B).2,29

A smaller proportion of patients with SMA are classified as having SMA2. These
individuals typically present between 6 and 18 months of age with diffuse
weakness, decreased muscle bulk, and absent reflexes (FIGURE 10-4B30). Tongue
fasciculations and a fine motor tremor are common. Without therapy, patients
with SMA2 achieve the ability to sit but never ambulate independently, and they
may lose the ability to sit independently as they age. Swallowing and respiratory
function decline over time, and, although individual patients with SMA2 may
have a normal life span, they are vulnerable to respiratory infections and may
require ventilatory support at some point. Respiratory function worsens as
scoliosis develops and progresses, and spinal fusion surgery is helpful in some
patients. Joint contractures can also limit the function and comfort of these
patients. Therapies ameliorate these features, especially when delivered earlier in
the course of the disease. The majority of patients with SMA2 possess three copies
of the SMN2 gene (FIGURE 10-2B).2,29


Patients with SMA3 present in later childhood (between the ages of 18 months
and 21 years) and all will achieve the ability to walk independently, although gait
stability is often impaired and many may lose the ability to walk later in life
(FIGURE 10-4C31). Weakness is primarily proximal. The phenotypic spectrum is
broader for this type, as patients will sit and walk with varying degrees of
weakness throughout childhood and adulthood. SMA3 has been further
subdivided into type 3a (with symptom onset before 3 years of age) and type 3b
(with symptom onset after 3 years of age). Those with SMA3b are more likely to
continue to walk independently after 20 years of age.1 Therapy, especially when
delivered early, ameliorates features of the disease. Patients with SMA3 have a
normal life expectancy. The majority of patients with SMA3 have three or four
copies of the SMN2 gene (FIGURE 10-2B)2,29
Other Types of Spinal Muscular Atrophy

Rarely, patients with SMA may present at the opposite ends of the disease
spectrum. Infants with SMA type 0 (SMA0) develop weakness prenatally and
are born with arthrogryposis multiplex congenita and severe respiratory failure.
They cannot breathe on their own and do not typically survive past 6 months of
age. They commonly have one copy of SMN2. Patients with SMA4 present in
adulthood, usually with varying degrees of leg weakness. They have a normal life
span. The SMN2 copy number is greater than four in the majority of these
patients (FIGURE 10-2B).2,29
TABLE 10-2 Evaluations to Measure Motor Function Status in Patients With Spinal
Muscular Atrophy
Test
Scale Name Scoring Duration Examples of Functions Evaluated Target Population
Hammersmith Infant 8 items 20 min Head control, sitting, grasping, Infants 2–24 months, spinal
Neurological Examination kicking, rolling, crawling, standing, muscular atrophy (SMA) types
Section 233 walking 1 and 2
Hammersmith Functional 33 items 20 min Rolling, sitting, lying to sitting, SMA types 2 and 3
Motor Scale Expanded34 kneeling, kneeling to standing, (24 months to adult)
squatting, jumping, stair climb/
descent
Children’s Hospital of 16 items 20 min Head control, rolling, gross motor Neonates and infants with
Philadelphia Infant Test of functions of upper and lower SMA type 1
Neuromuscular Disorders35 limbs, axial strength/tone
Revised Upper Limb 19 items 10 min Upper limb gross and fine motor SMA types 2 and 3 (3 years to
Module36 functions adulthood)
Motor Function Measure37,38 Adult: 32 20 min Upper and lower limb gross and General neuromuscular
items fine motor functions, rolling, lying disorders (3–64 years)
to sitting, sitting to standing,
Child: 20
running, hopping
items
6-Minute Walk Test39 Distance in 6 min Walk as fast as possible along a SMA type 3
meters 25-m loop for 6 minutes
1354 OCTOBER 2020

FOLLOWING DISEASE ACTIVITY IN SPINAL MUSCULAR ATROPHY KEY POINT
In addition to recognition of the importance of the SMN2 copy number in
● The majority of patients
predicting SMA type, the development and validation of additional measures with SMA type 1 possess two
of motor neuron function have facilitated disease monitoring and have been SMN2 gene copies. Those
instrumental as end points in SMA clinical trials. Electrophysiologic with SMA type 2 usually
modalities are used to evaluate the extent of muscle denervation and can have three copies, those
with SMA type 3 have three
quantify changes in motor unit numbers over time in SMA. Compound muscle
or four copies, and patients
action potential (CMAP) amplitude provides a measure of the number of with SMA type 4 typically
intact motor neurons supplying a given muscle. CMAP amplitudes decrease as have more than four copies.
weakness progresses in infants, and the maximum CMAP amplitude is lower Those with SMA type 0,
which presents with
in patients with an SMN2 copy number less than three and in those with more
arthrogryposis multiplex
decreased motor function.32 Standard EMG measuring voluntary motor unit congenita and severe
action potential amplitudes and durations as well as the pattern of recruitment respiratory failure, typically
can also help to evaluate and follow the degree of muscle denervation in have one copy.
patients with SMA.
Several different motor function scales are used to measure SMA disease
activity across multiple ages and SMA types (TABLE 10-233–39). A basic familiarity
with these scores is useful in evaluating clinical trial data and in assessing
therapeutic response to molecular therapies (a practice that may be required for
prior authorization for insurance). Some of these functional outcome measures are
specifically validated for SMA, and others are validated for patients with
neuromuscular disorders in general. The Hammersmith Functional Motor Scale
Expanded (HFMSE) is an SMA-specific scale validated to assess disease
progression in patients with SMA2 or SMA3.34,40 It has 33 items scored on a scale of
0 to 2, with a score range of 0 to 66; a higher number indicates more advanced
motor function. The Hammersmith Infant Neurological Examination Section 2
(HINE-2) is used to evaluate infants with SMA1.33 It is an eight-item scale, with a
score of 0 to 5 for each activity. The Children’s Hospital of Philadelphia Infant Test
of Neuromuscular Disorders (CHOP-INTEND) is validated for infants and young
children with SMA1.35 It includes 16 motor activities graded on a scale of 0 to 4,
with a maximum score of 64.
Respiratory failure is a significant cause of morbidity and mortality in young
patients with SMA, but pulmonary function testing is difficult and unreliable in
this age group. Therefore, the amount of time until chronic respiratory support
is required (defined as either invasive or noninvasive respiratory intervention
for 16 or more hours per day for more than 14 days or tracheostomy) is a useful
outcome measure for respiratory failure in SMA clinical trials.7,8
Neurofilament proteins represent an emerging area of biomarker
development in patients with SMA. Neurofilament proteins are intermediate
filaments expressed specifically in neurons and are the dominant component
of the motor axon cytoskeleton.41 They are heteropolymers composed of
neurofilament light, medium, and heavy chains. Neurofilament proteins are
released into the extracellular space following axonal damage, and
neurofilament light chains and phosphorylated neurofilament heavy chains
are measurable in the blood and CSF.42 Neurofilament proteins have been
studied as biomarkers of disease activity in several other neurodegenerative
diseases, including amyotrophic lateral sclerosis, Alzheimer disease, and
multiple sclerosis, with mixed results.43 Evaluation of neurofilament protein
levels in patients with SMA receiving SMN-dependent genetic therapies
demonstrate a striking decrease following treatment, thus representing a

potentially powerful biomarker for following SMA disease activity and

response to therapy.44
SMN–DEPENDENT THERAPIES
An understanding of the genetic mechanisms of SMA, together with
development of validated outcome measures assessing degrees of weakness and
developmental delay, was instrumental in the success of the three FDA-approved
therapies targeting gene expression in SMA.
Nusinersen
In December 2016, the FDA approved nusinersen, an antisense oligonucleotide that
promotes the inclusion of exon 7 during splicing of SMN2 RNA. The medication
is given intrathecally, initially with four loading doses (the first three loading doses
every 14 days and the fourth loading dose given 30 days after the third dose)
followed by maintenance dosing every 4 months. The pivotal ENDEAR (A Study to
Assess the Efficacy and Safety of Nusinersen [ISIS 396443] in Infants With Spinal
Muscular Atrophy) trial enrolled infants with SMA1 who were younger than
6 months of age.45 At final analysis, 50% of treated infants demonstrated
improvement in motor milestones (as measured by the HINE-2), compared to 0%
in the control group. Additional studies in neonates (NURTURE [A Study of
Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically
Diagnosed and Presymptomatic Spinal Muscular Atrophy] trial)46 and in older
patients with SMA2 or SMA3 (EMBRACE [A Study to Assess the Safety and
Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular
Atrophy] trial)47 were also encouraging. The most striking finding in the nusinersen
trials was that the improvement in function was most impressive in babies treated at
younger ages. This was further supported in the ongoing open-label NURTURE
trial, in which asymptomatic neonates with two or three copies of SMN2 began
treatment at the age of 6 weeks or younger. Thus far, all are alive and breathing
independently after 2.9 years of follow-up (average age 34.8 months).46
Importantly, at an age at which we expect to see decreased motor milestone
development, these subjects demonstrated a striking improvement in motor
function, with 100% able to sit, 92% walking with support, and 88% walking
independently. The rationale behind this improvement is that asymptomatic babies
have a population of motor neurons that can be rescued and thus have greater
capacity to experience a more normal developmental trajectory. This is in contrast to
symptomatic infants and older patients who already manifest significant weakness
because they have lost a critical population of motor neurons and are in a slower
phase of decline. This is consistent with mouse and human data suggesting that
higher levels of SMN are most important during gestational and neonatal stages of
motor development.
No side effects have been identified related to nusinersen itself, but
complications associated with intrathecal administration have been reported,
including low-pressure headaches and pain at the injection site. Intrathecal
administration is a straightforward procedure in many patients with SMA, and in
younger and weaker children, it can be done without anesthesia. The clinician
may opt for sedation or general anesthesia in older and stronger children to
improve comfort and ease of administration. In older children and adults with
significant scoliosis or spinal fusion, involvement of interventional radiology
with fluoroscopy or CT guidance may be helpful. In some of these patients with
1356 OCTOBER 2020

spinal fusion, a lumbar laminectomy may help to further optimize access to KEY POINTS
the spinal canal. Although it is too early to know the long-term outcomes in
● In December 2016, the
patients treated presymptomatically and the drug is not a cure for those treated US Food and Drug
after symptom onset, nusinersen certainly offers significant hope for those Administration approved
with a disease without any previous interventions to slow the progression of nusinersen as the first
weakness. The observation that treatment is most helpful when given early in therapy for SMA. An
antisense oligonucleotide,
presymptomatic infants emphasizes the need to identify these babies early to
nusinersen targets increased
expedite treatment. In many states, SMN genotyping is now included in efficiency of inclusion of
newborn screening programs, as discussed in greater detail below. exon 7 during splicing of
SMN2 RNA.
Onasemnogene Abeparvovec-xioi
● Neonates with SMA with
In May 2019, the FDA approved onasemnogene abeparvovec-xioi for patients two or three SMN2 copies
younger than 2 years of age with all types of SMA. Onasemnogene treated with nusinersen
abeparvovec-xioi is an AAV9-delivered SMN1 gene replacement therapy that is before the onset of
administered as a single weight-based IV dose. symptoms demonstrate
striking improvement in
The pivotal trial for onasemnogene abeparvovec-xioi enrolled 12 babies with motor function, with the
predicted SMA1 phenotype (two copies of SMN2), who each received open-label large majority able to walk
therapy administered before 6 months of age.48 Response to therapy was independently.
compared to a natural history cohort and unaffected cohort. Compared to
● Onasemnogene
untreated natural history cohort patients with SMA1 who never achieve the
abeparvovec-xioi is an
ability to sit, at 24 months posttreatment, 92% sat unassisted for 5 seconds or adeno-associated virus
more and 75% achieved sitting for 30 seconds or more. Survival free of 9–mediated SMN1 gene
respiratory intervention was also significantly improved in the treated infants. replacement therapy given
as a single IV dose. It is
Similar to nusinersen, the impact of therapy was greater in patients treated at
indicated for patients of all
younger ages and with fewer symptoms. SMA types who are 2 years
In clinical trials, elevated liver enzymes and elevated platelets were observed. of age or younger at the
Liver function, however, was not affected. Additionally, some patients exhibited time of dosing. Similar to
elevated troponin I levels without changes in heart function, and the clinical nusinersen, the impact of
therapy is greatest in
significance of this finding is not understood. Because of concerns for liver patients treated at a younger
toxicity, patients should be treated with systemic corticosteroids equivalent to age and greater in those with
oral prednisolone 1 mg/kg/d for 30 days. The dose may be tapered over the next three SMN2 copies than in
28 days if liver function testing (specifically aspartate transaminase [AST], alanine those with two copies.
transaminase [ALT], bilirubin, and prothrombin time) remains unremarkable.
The prevalence of exposure to and development of antibodies against AAV9,
and thus the AAV9 vector, is relatively low compared to other adeno-associated
virus types.49 Special consideration of this is required in newborns before
onasemnogene abeparvovec-xioi treatment. Given concern for reduced vector
transduction at the time of treatment, consideration of neutralizing antibodies
passively transferred to the affected neonate across the placenta or in breast milk
is important. A baseline anti-AAV9 antibody titer should be measured before
infusion. If titers are greater than 1:50, the titer should be rechecked again no
more than 2 weeks later. Because 2 weeks could represent a period in neonatal
development during which a delay in treatment could make a significant
difference in the outcome, this interval should be determined with consideration
of SMA type and the rate of progression of weakness, favoring checking sooner in
patients with SMA1 with more rapid progression. It should be noted that no
specific data are available regarding the level of IgG antibodies that could inhibit
onasemnogene abeparvovec-xioi vector transduction, and the titer of less than
1:50 was a conservative choice during the clinical trials.50 Although breast-
feeding was prohibited in the onasemnogene abeparvovec-xioi trials based on

the theoretical risk of anti-AAV9 antibody transfer, no clear evidence indicates

that IgA antibodies transferred in this way could inhibit vector transduction.50
Thus, the decision of whether or not to hold off on breast-feeding during the
pretreatment and immediate posttreatment periods should be considered in
the context of its potential impact on the therapy compared to the impact of
short-term use of infant formula. A discussion between the provider and the
family is recommended.
To monitor for toxicity, a series of laboratory tests are recommended over the
weeks after dosing. ALT, AST, bilirubin, and prothrombin time should be
checked before infusion, weekly for the first month, then every other week for
the second and third months, until the results are normal. Platelets and troponin I
should be measured before infusion and weekly for the first month. Platelets
should then be followed every other week and troponin I monthly for the second
and third months.
The nonreplicating AAV9 viral capsid taken up by motor neurons exists as an
episome and is not diluted because motor neurons do not divide. Little theoretical
risk exists for the therapy to impact caregivers or those who interact closely with
patients in the short or long term. Based on viral shedding testing during the
clinical trial, caregivers should use protective gloves when coming into direct
contact with patient feces and use good hand hygiene for approximately 60 days
after the injection.50 This is especially true for caregivers or mothers with potential
or known pregnancies as the effect of onasemnogene abeparvovec-xioi on the
developing fetus is unknown. Additionally, it is not known if this exposure to the
vector is sufficient to induce an antibody response in a seronegative mother who
is at risk of future pregnancies with a fetus affected with SMA.
Risdiplam
In August 2020, the FDA granted approval for risdiplam, a small molecule
therapy that increases splicing efficiency at exon 7 in the SMN2 mRNA, thus
increasing the amount of functional protein that can be produced in the absence
of SMN1.51 Risdiplam is approved as a daily oral medication for patients with
SMA of all types ages 2 months and older. In an open-label clinical trial involving
patients with SMA1 aged 1 to 7 months, 41% were able to sit unsupported for at
least 5 seconds following 12 months of treatment and 90% were alive without
permanent ventilation by at least 15 months of age.52 Patients with type 2 or type 3
SMA between the ages of 2 and 25 years treated with risdiplam for 12 months
demonstrated a significant improvement in gross motor performance, including
upper limb functions, compared to those treated with placebo.52
The medication so far has been well tolerated in trials, with the most common
side effects in patients with SMA1 being upper respiratory tract infection,
pneumonia, cough, and vomiting. Patients with SMA2 or SMA3 more commonly
experienced fever, diarrhea, and rash. None of the side effects reported in the
trials necessitated discontinuation of therapy.52 At the time of this writing,
no additional information regarding safety monitoring recommendations is
available.
SMN-INDEPENDENT THERAPIES
The absence of SMN protein affects multiple components of the motor unit, and
these components are also targets for therapeutic development. Two therapies
targeting muscle growth and function in SMA are currently in clinical trials.
1358 OCTOBER 2020

Promotion of Muscle Growth KEY POINTS
Because muscle atrophy is such a prominent feature in neuromuscular disorders,
● Risdiplam was approved
targeting enhancement of muscle cell growth is an attractive therapeutic in August 2020 and is a daily
approach. Myostatin is an endogenous protein that limits muscle cell growth. oral small molecule therapy
Several trials of antibodies targeted against activation of myostatin’s active form that increases production of
have been unsuccessful.53 SRK-015 is an antimyostatin antibody that differs from full-length SMN protein
from the SMN2 mRNA. After
previous forms in that it targets the latent form of the protein and prevents its
12 months, nearly half of
activation in muscle.54 Preclinical animal studies of the compound demonstrated infants with SMA type 1
target engagement and showed increased function and weight. The compound is treated first between 1 and
currently in phase 2 studies in patients with SMA2 and SMA3. 7 months of age were able to
sit supported for at least
5 seconds. Older individuals
Enhancement of Muscle Function with SMA type 2 or SMA
Improvement in the efficiency of muscle force generation is also a target for type 3 treated with risdiplam
therapeutic development. Reldesemtiv (formerly CK-2127107) is an activator of also showed improvement in
fast skeletal muscle troponin, which has demonstrated increased force of motor function compared to
a placebo-controlled group.
contraction in healthy subjects.55 Phase 2 testing in patients with SMA1, SMA2,
and SMA3 demonstrated increased distance in the 6-Minute Walk Test and ● Response to nusinersen,
improvement in respiratory function compared to controls.56 onasemnogene
abeparvovec-xioi, and
risdiplam therapies is more
DIAGNOSIS AND MANAGEMENT striking when they are
Before the approval of SMN-dependent therapies, confirmation of a genetic delivered during the first
diagnosis of SMA occurred after onset of weakness, when babies or children with months of life. Early
motor delays were identified and tested by clinicians who suspected the disease treatment of SMA type 1
enables patients to achieve
based on the classic clinical features described above. Because these treatments
motor milestones never
work best in children before the onset of symptoms, the challenge is now to identify before possible. Some
and diagnose patients much earlier in the disease course. Despite these therapeutic patients with SMA type 1
advances, the response often remains incomplete, and the types of supportive treated within the first weeks
of life are able to walk.
care that have been a mainstay of SMA treatment in the past remain important.
● Although striking
Early Diagnosis Through Newborn Screening and Maternal Carrier Screening improvement in motor
With commercial availability of nusinersen, onasemnogene abeparvovec-xioi, and milestone achievement is
risdiplam and clear evidence of improved outcomes with treatment in the neonatal seen in patients with
SMA after treatment
period, the challenge of identifying babies as early as possible arises (CASE 10-1). with nusinersen,
The Recommended Uniform Screening Panel recently added SMA as a standard onasemnogene
disease, which means that states are legally required to test for SMA as part of their abeparvovec-xioi, or
standard newborn screening. Thus, states are currently ramping up their programs risdiplam, they still
experience significant
(FIGURE 10-5).57 It is important to note that newborn screening for SMA includes weakness.
only testing of the SMN1 gene. SMN2 copy number must be ordered by the clinician
evaluating the baby. Additional efforts to identify prenatal cases are also under way, ● Clinical trials are
with the American College of Obstetrics and Gynecology officially recommending currently evaluating agents
that promote muscle growth
that SMA screening be offered to all women who are pregnant or considering
(antimyostatin antibody) and
pregnancy.58 enhance muscle function (an
Although patients are able to be identified within the first week of life through activator of fast skeletal
newborn screening, a time gap remains before they can receive medication muscle troponin).
because insurance authorization is required for these very expensive
medications. Before the approval of risdiplam, to justify insurance coverage and
timely approval in this critical population, key opinion leaders presented an
algorithm regarding treatment recommendations for gene-targeted therapies in
individuals with SMA identified through newborn screening.59 The consensus is
that all newborns with two, three, or four copies of SMN2 (especially those in

whom an SMA type 1 or type 2 phenotype is expected) should receive immediate

therapy with either onasemnogene abeparvovec-xioi or nusinersen. In patients
with five or more copies (who are expected to develop an SMA type 4
phenotype), treatment can be deferred with close monitoring for symptom
development.59 A summary of tests recommended for monitoring symptom
onset in patients with five or more copies of SMN2 is presented in TABLE 10-3.
Given that SMA carrier screening and SMA newborn screening are not yet
widespread in the United States or around the world, a significant number of
patients are not identified at birth. In these patients, the physician’s suspicion
should be roused in patients with a clinical history and examination features as
described in TABLE 10-1. Genetic testing for the SMN1 mutation and SMN2 copy
number is available from several commercial laboratories. In older patients with
SMA who were not diagnosed by newborn screening, the decision to treat is
based upon the presence of symptoms as defined in TABLE 10-3. In states and
CASE 10-1 A pediatric neurologist received a phone call from the state health
department reporting the newborn screening identification of a 5-day-
old baby girl with spinal muscular atrophy (SMA). The provider scheduled
an appointment with the baby and her parents the next day.
On initial examination in the clinic on day of life 6, the baby was
bright-eyed and well appearing, with normal muscle bulk. She was
feeding well and breathing comfortably with antigravity strength in all
four extremities. She had head lag on pull to sit and slight slip-though on
vertical suspension, but both findings were within the broad range of
normal limits for the baby’s age. Tendon reflexes were absent. Although
the baby’s examination was nearly normal, because of the highest
prevalence, the phenotype was most likely SMA type 1. After a
discussion, the family wished to pursue onasemnogene abeparvovec-xioi
therapy, so the SMN2 copy number and absence of anti–adeno-
associated virus 9 (AAV9) antibody titer had to first be confirmed before
proceeding. While waiting for these results, the provider began the prior
authorization for onasemnogene abeparvovec-xioi therapy. The SMN2
copy number returned 4 days later with two copies of SMN2, and the
family returned for results disclosure.
At follow-up examination 4 days later, the provider noted some very
mild paradoxical breathing and increased head lag. Although still having
antigravity strength, the baby moved less in proximal muscle groups and
felt “less sturdy” in the provider’s arms. The examination was now more
consistent with an SMA type 1 phenotype.
Onasemnogene abeparvovec-xioi is expensive and prior authorization
is complicated, but with progression of weakness, the provider pushed
urgently for approval. Additional time was required to establish the
institution’s protocol regarding the administration of gene therapy. Final
insurance authorization and institutional approval for treatment was
achieved 3 weeks after the last visit. At that point, the baby had
progressed mildly in weakness and hypotonia.
1360 OCTOBER 2020

countries in which these therapies are approved and newborn screening is
widespread, the population of symptomatic untreated patients is expected to decline.
Nusinersen Versus Onasemnogene Abeparvovec-xioi Versus Risdiplam

The decision of which drug to offer patients depends on several factors. All three
drugs are commercially approved for all types of SMA, and, so far, they appear to
have similar efficacy. The age of the patient is an important consideration.
Whereas nusinersen is approved for all ages, onasemnogene abeparvovec-xioi is
approved for treatment of individuals before their third birthday. Because
risdiplam is not approved for babies younger than 2 months of age, very early
symptomatic newborns and those diagnosed presymptomatically through
newborn screening will be eligible only for nusinersen or onasemnogene
abeparvovec-xioi. For these very young individuals, it is important to discuss the
mode of therapy with parents/guardians. For many, the single IV dose of
Oral prednisolone 1 mg/kg was started on day of life 29, and

onasemnogene abeparvovec-xioi treatment was delivered on day 30. The
baby did well, with mild elevation in liver transaminases during the first
2 weeks after dosing that subsequently resolved. Prednisolone was weaned
without problems. She was followed closely over the next months and had
no significant progression of weakness. At her 8-month follow-up, she had
gained head control. She could not raise arms above her head but could
reach for toys in front of her and sit with support at both hips.
This case highlights that although newborn screening allows earlier COMMENT
diagnosis of SMA, barriers to early treatment still exist. Even if the SMA
type is suspected based on examination, the SMN2 copy number must be
determined to confirm the expected phenotypic trajectory. Additionally,
the process of insurance authorization and establishing an institutional
protocol for treatment can, in some cases, take weeks. This is valuable time
during which degenerating motor neurons could potentially be rescued by
therapy. Many institutions have already treated children with some of
these therapies and have an institutional policy for treatment. For those
that do not but anticipate treating patients, proactively getting a treatment
policy in place will save time. Because of the expense, each new insurance
authorization is challenging and requires persistent attention, especially in
cases in which the patient is declining.
The case also highlights that even with early therapy and gain of
measurable milestones that would otherwise not be attained, treated
children can still have considerable weakness. In the case of this patient,
onasemnogene abeparvovec-xioi effectively changed the early course
from an SMA type 1 to an SMA type 2 or type 3 phenotype. This patient will
need close monitoring for respiratory dysfunction, contractures, and
scoliosis, and she may need a wheelchair at some point. It is thus important
that even patients who are treated early receive continued follow-up with
an experienced provider in a clinic equipped to care for patients with SMA.

KEY POINTS
● Increased need exists for

early diagnosis of SMA,
which drives the inclusion of
SMA testing in newborn
screening programs and the
promotion of female carrier
testing in pregnant women.
● All newborns with two,

three, or four copies of
SMN2 (especially those in
whom an SMA type 1 or type
2 phenotype is expected)
should receive immediate
therapy with either
onasemnogene
abeparvovec-xioi or
nusinersen. In patients with
five or more copies (who are
expected to develop an
SMA type 4 phenotype), FIGURE 10-5
treatment can be deferred Status of spinal muscular atrophy newborn screening programs in the United States as of
with close monitoring for August 2020.
symptom development. Reprinted with permission from curesma.org.57 © 2020 Cure SMA.
onasemnogene abeparvovec-xioi may be preferable to repeated dosing of

nusinersen by lumbar puncture every 4 months over a lifetime. Parents and
guardians, however, should be aware that elevation of liver enzymes in the weeks
after onasemnogene abeparvovec-xioi dosing could represent liver inflammation
that may become severe in rare cases, and close monitoring by the treating
physician is important. In rare patients in whom baseline liver enzymes or
anti-AAV9 antibody titers are elevated, nusinersen may be preferable. An open-
label trial evaluating risdiplam in patients with SMA treated first between birth
and 6 weeks is currently ongoing.52 For infants 2 months and older, daily oral
risdiplam may be presented as an additional option.
For individuals 3 years of age and older, nusinersen and risdiplam are the
approved options. Although no side effects to nusinersen itself have been
identified, the repeated lumbar punctures required for nusinersen treatment can
have procedure-related side effects. In addition, many children require general
anesthesia for comfort during the procedure, and individuals with severe
scoliosis may require repeated radiation exposure to be dosed by interventional
radiology under fluoroscopy or CT guidance.
Clinical trials of risdiplam have identified no significant treatment-limiting
side effects; however, this drug lacks the longer-term postmarketing safety
analysis that is available for nusinersen. For patients in whom repeat lumbar
punctures with or without anesthesia and radiation exposures are undesirable,
daily oral risdiplam is the appropriate alternative. In conversations involving
older patients with childbearing potential who are considering either risdiplam or
nusinersen, it should be mentioned that the effects of both drugs on fertility and
fetal development are unknown.
Also unknown are the effects of using these medications in combination.
While the idea of increasing total SMN protein production from both SMN1 and
1362 OCTOBER 2020

SMN2 simultaneously using onasemnogene-abeparvovec-xioi with either
nusinersen or risdiplam is appealing, organized trials have not yet been
conducted to establish safety or efficacy. Similarly, no data are yet available to
suggest that risdiplam and nusinersen used together are more efficacious in
increasing SMN protein production from the SMN2 gene than either drug alone.
Although early efficacy and safety data appear to be comparable between
risdiplam and nusinersen, decisions about switching from one drug to another
should be made cautiously at this early juncture. Additional trials to evaluate
these kinds of treatment scenarios are anticipated or under way.
Because of the extraordinary cost of these medications, challenges associated
with prior authorization for insurance coverage may also play an important role
in treatment decisions. In the United States, nusinersen is priced at $125,000
dollars per dose, costing $750,000 in the first year and then $375,000 per year for
the duration of the patient’s life. This does not include additional costs required
for intrathecal medication administration, for example, in the operating room
Summary of Tests Used to Monitor Patients With ≥5 SMN2 Copies for TABLE 10-3
Whom Treatment Is Not Initiated Immediatelya
Level of Change/Results Which Would Prompt Appropriate Age of

Test or Outcome Measure Initiation of Treatment Patient for Test
EMG/nerve conduction studies Any active or chronic neurogenic change All
Compound muscle action potential Below normative values for an age-matched child All
(CMAP)
Myometry Decrease in extent of muscle contraction ≥4 years
Physical examination/reflexes Any of the following: loss of reflexes, failure to meet or All
regression in ability to perform motor milestones,
proximal weakness, and weakness in trunk righting/
derotation
Children’s Hospital of Philadelphia A failure to gain motor functions with age in keeping with Infants
Infant Test of Neuromuscular normal development OR a drop in total score from
Disorders previous assessment
Hammersmith Infant Neurological A failure to gain motor functions with age in keeping with Infants
Examination normal development OR a drop in total score from
previous assessment
Hammersmith Functional Motor Scale A failure to gain motor functions with age in keeping with ≥2 years
Expanded normal development OR a drop in total score from
previous assessment
6-Minute Walk Test A failure to gain motor functions with age in keeping with ≥5 years
normal development OR a drop in total score from
previous assessment
Bayley Scales of Infant and Toddler A failure to gain motor functions with age in keeping with Infants/toddlers
Development normal development OR a drop in total score from (recommended 1 to
previous assessment 42 months)
EMG=electromyography.
a
Modified with permission from Glascock J, et al, J Neuromuscul Dis.59 © 2020 IOS Press and the Authors.

with anesthesia. The single weight-based IV dose of onasemnogene abeparvovec-

xioi costs $2.1 million. Daily oral risdiplam pricing is also weight-based, with a
maximum cost of $340,000 per year for the duration of the patient’s life. Paying
for these kinds of medications individually or in combination may place a
significant burden on the country’s health care systems.
Continued Importance of Supportive Therapy

Despite the remarkable advances in treatment, many patients continue to
experience significant weakness,45,48 and the complications of SMA, although
ameliorated by these therapies, continue to cause morbidity and mortality.
The mainstays of supportive therapy, which have been employed and refined
over decades of SMA care, continue to play a vital role in treatment of the
respiratory, nutritional, and orthopedic vulnerabilities experienced by
patients with SMA.
PULMONARY MANAGEMENT. The risk of pulmonary dysfunction in SMA is

related to hypoventilation and decreased ability to maintain a clear airway in
the setting of primarily intercostal respiratory muscle weakness (it is not known
why the diaphragm remains relatively spared until late in the disease). Because
worsening respiratory status correlates with worsening weakness, assessment
and management of pulmonary dysfunction in SMA can be considered
differently based not on SMA type but on the patient’s ability to sit or walk.60
Assessments should be performed at least every 6 months, with a low threshold
for obtaining a sleep study if any concern for nocturnal hypoventilation exists.
Airway clearance methods, such as oral suctioning, pulmonary physical therapy,
and cough assist, should be instituted early in nonsitting patients who are
particularly weak. Noninvasive ventilatory methods or tracheostomy should be
considered early in symptomatic patients depending on the preference of the
patient or parents (depending on age). This is also true of patients with the ability
to sit and walk, although less need exists for intermittent or continuous ventilatory
support in these stronger patients. Respiratory muscle weakness and impaired
airway clearance make both nonsitting and sitting patients with SMA especially
vulnerable to pulmonary infections, including aspiration pneumonia.
Standard immunizations are indicated, with annual influenza and
pneumococcal vaccinations. Annual respiratory syncytial virus vaccination is
indicated for infants with SMA. Of note, for infants treated with glucocorticoids
after treatment with onasemnogene abeparvovec-xioi, the provider may
consider delaying some immunizations during the immunosuppressed period.50
NUTRITIONAL MANAGEMENT. Bulbar muscle weakness can be a significant

problem for individuals with SMA, especially those who are unable to sit. In
nonsitting and sitting patients, a baseline barium swallow study is recommended
shortly after the time of diagnosis; aspiration risk should be followed closely,
especially if concerns exist for choking with feeds or progressive cough
weakness.60 Enteral feeding may safely provide nutrition to help protect against
aspiration pneumonia in these patients. Enteral feeding may also be necessary in
weaker patients with SMA1 or SMA2, in whom limitation of mouth opening
caused by contracture of the masseter muscle may limit oral feeding.
REHABILITATIVE AND ORTHOPEDIC MANAGEMENT. Rehabilitative management of

patients with SMA should focus on accommodating weakness and promoting
1364 OCTOBER 2020

mobility to improve patients’ engagement and minimize the orthopedic KEY POINTS
complications of progressive weakness.61 Positioning and bracing are especially
● The efficacy of
important for both sitting and nonsitting patients to avoid worsening nusinersen, onasemnogene
contractures and scoliosis. Slowing of progressive joint contractures is helpful in abeparvovec-xioi, and
motor function and independence. Spinal fusion can play an important role in risdiplam appears to be
patient comfort and preservation of respiratory function. equivalent. Decisions
between the medications
should be based on the
patient’s age and discussion
CONCLUSION of mode of delivery and side
Striking advances in understanding of the pathophysiology and genetics of SMA, effects with the patient or
the patient’s parents or
along with improved understanding of the disease’s natural history and
guardians.
validation of meaningful outcome measures, have created a clinical and research
environment for the development of successful gene-targeted therapies. With ● Clinical trials evaluating
the approval of nusinersen, onasemnogene abeparvovec-xioi, and risdiplam, the the potential benefits of
prognosis of SMA is now more hopeful, especially in very young babies with combination treatments
with SMN1- and SMN2-
SMA1, who, with early treatment, are able to attain even the earliest motor enhancing therapies are
milestones never before possible. Despite these advances, children and adults anticipated or currently
with SMA continue to have varying degrees of weakness that require under way.
accommodation. Many are still vulnerable to pulmonary failure and orthopedic
● The extraordinary cost of
complications. Additional improvement upon current gene-targeted therapies
SMN-targeted therapies
requires early identification and treatment and may require refinement of the may complicate the process
dose or dosing interval. The combination of SMN1 replacement and SMN2- of obtaining prior insurance
enhancing therapy may provide additional benefit, but currently there is no authorization.
definite evidence for this. Furthermore, although not yet approved, the potential
● Supportive therapy,
exists that the addition of non-SMA–specific therapies targeting muscle growth including pulmonary,
and function may improve outcomes. Despite the progress in disease-modifying nutritional, and
therapies, continued symptomatic management with close respiratory, rehabilitative management,
nutritional, and orthopedic care is vital to the success of these treatments. plays a vital role in the
treatment of SMA since
many patients continue to
experience significant
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41 Petzold A. Neurofilament phosphoforms:
53 Mariot V, Joubert R, Hourdé C, et al.
surrogate markers for axonal injury, degeneration
Downregulation of myostatin pathway in
and loss. J Neurol Sci 2005;233(1):183–198.
neuromuscular diseases may explain challenges
doi:10.1016/j.jns.2005.03.015.
of anti-myostatin therapeutic approaches.
42 Yuan A, Rao MV, Veeranna, Nixon RA. Nat Commun 2017;8(1):1859–1858. doi:10.1038/
Neurofilaments and neurofilament proteins in s41467-017-01486-4.
health and disease. Cold Spring Harb Perspect
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43 Bridel C, van Wieringen WN, Zetterberg H, et al. 2019;28(7):1076–1089. doi:10.1093/hmg/ddy382.
Diagnostic value of cerebrospinal fluid
55 Andrews JA, Miller TM, Vijayakumar V, et al.
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systematic review and meta-analysis. JAMA
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56 Day J. Update of CY 5021: a phase 2 clinical trial of
44 Darras BT, Crawford TO, Finkel RS, et al.
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muscular atrophy. Ann Clin Transl Neurol 2019;
spinal muscular atrophy. Paper presented at:
6(5):932–944. doi:10.1002/acn3.779.
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45 Finkel RS, Mercuri E, Darras BT, et al. Nusinersen Dallas, TX.
versus sham control in infantile-onset spinal
57 McCall S. Newborn screening for spinal muscular
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1723–1732. doi:10.1056/NEJMoa1702752.
sma/. Updated May 11, 2020. Accessed August 3,
46 De Vivo DC, Bertini E, Swoboda KJ, et al. 2020.
Nusinersen initiated in infants during the
58 Committee on Genetics. Committee opinion no.
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the phase 2 NURTURE study. Neuromuscul
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47 Mercuri E, Darras BT, Chiriboga CA, et al.
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59 Glascock J, Sampson J, Connolly AM, et al. 60 Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis
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61 Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis
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doi:10.1016/j.nmd.2017.11.005.
1368 OCTOBER 2020

Peripheral Neuropathies REVIEW ARTICLE

Associated With C O N T I N U UM A U D I O
ONLINE
Monoclonal
Gammopathies
By Elie Naddaf, MD; Michelle L. Mauermann, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: Neurologists commonly evaluate patients with a
monoclonal gammopathy and peripheral neuropathy. As both monoclonal
gammopathy and peripheral neuropathy are common in the general
population, their coexistence may, in some instances, be purely coincidental.
However, monoclonal gammopathies or underlying lymphoplasmacytic
disorders can affect the peripheral nervous system by various mechanisms.
This article discusses how to approach patients with monoclonal
gammopathy and peripheral neuropathy, highlighting clinical and laboratory CITE AS:
clues that may aid in establishing a diagnosis in a timely manner. CONTINUUM (MINNEAP MINN)
RECENT FINDINGS: From a hematologic standpoint, a monoclonal gammopathy
1369–1383.
may be of undetermined significance or can be associated with an
underlying myeloma, lymphoplasmacytic lymphoma, or amyloidosis. Each Address correspondence to
of these conditions can cause peripheral neuropathy, with varying clinical Dr Elie Naddaf, Mayo Clinic,
200 First St SW, Rochester,
and electrodiagnostic profiles. Treatment usually consists of treating the MN 55905, Naddaf.Elie@
underlying hematologic disorder. IgM-associated peripheral neuropathy mayo.edu.
may not require treatment from a hematologic standpoint, and only RELATIONSHIP DISCLOSURE:
anecdotal evidence exists for the use of immunotherapy in such patients. Dr Naddaf reports no
Therefore, treatment should be determined on a case-by-case basis. disclosure. Dr Mauermann
serves on the editorial board of
Mayo Clinic Proceedings;
SUMMARY: Evaluating for an association between a monoclonal gammopathy receives research/grant
and a peripheral neuropathy in a patient depends on the monoclonal support from Alnylam
Pharmaceuticals, Inc, and Ionis
gammopathy subtype and the clinical and electrodiagnostic Pharmaceuticals, Inc; and
characteristics of the peripheral neuropathy. receives publishing royalties
from Oxford University Press.
UNLABELED USE OF
USE DISCLOSURE:
INTRODUCTION
Drs Naddaf and Mauermann
N
eurologists commonly evaluate patients with a monoclonal discuss the unlabeled/
gammopathy and peripheral neuropathy. Both peripheral investigational use of IV
immunoglobulin and rituximab
neuropathy and monoclonal gammopathy are relatively common in for the treatment of IgM
the general population: peripheral neuropathy has an estimated neuropathy.
overall prevalence of 1.66% to 3.9% in the US population, whereas
monoclonal gammopathy occurs in about 3.2% of individuals older than 50 years © 2020 American Academy
of age and in more than 5% of individuals older than 70 years of age.1–3 Both of Neurology.

PERIPHERAL NEUROPATHIES WITH MONOCLONAL GAMMOPATHIES
peripheral neuropathy and monoclonal gammopathy affect men more than

women, with increasing incidence with age. Therefore, the coexistence of a
monoclonal gammopathy and peripheral neuropathy in a particular patient is
commonly coincidental. Alternatively, the peripheral neuropathy could be
related to the monoclonal gammopathy by various underlying mechanisms:
abnormal cell proliferation in which a monoclonal gammopathy is the sign of an
underlying lymphoproliferative disorder directly involving nerves; high protein
burden and protein deposition as seen in amyloidosis; or immune-mediated via
autoantibody activity, activation of complement pathway, or secretion of
cytokines.4 This article details the clinical phenotype, relevant laboratory
findings, and electrodiagnostic profile of peripheral neuropathies associated with
monoclonal gammopathy, including myeloma, and highlights how to use this
information to adopt a practical clinical approach to patients presenting with a
peripheral neuropathy and a monoclonal gammopathy.
MONOCLONAL GAMMOPATHY
Plasma cells are mature B cells, able to secrete antibodies or immunoglobulins.
Immunoglobulins are made of two heavy chains and two light chains. Each
plasma cell produces a specific immunoglobulin with a single type of heavy chain
and a unique antigen-binding site. Therefore, serum normally contains a vast
repertoire of polyclonal antigen-specific antibodies. This results in a wide-based
curve in the gamma globulin range on serum protein electrophoresis.
Occasionally, proliferation of a single plasma cell clone occurs, resulting in the
secretion of a monoclonal immunoglobulin, referred to as a monoclonal
protein or monoclonal gammopathy. A monoclonal gammopathy is visible as a
spike on top of the wide-based curve on serum protein electrophoresis and is
referred to as an M-spike, in which M stands for monoclonal (FIGURE 11-1).
For unclear reasons, IgD and IgE monoclonal gammopathies are extremely
rare; therefore, neurologists will mainly encounter monoclonal gammopathies
of the IgG, IgA, or IgM heavy chain subtypes and either kappa or lambda light
chain subtypes. It is also possible for the monoclonal gammopathy to be light
chain only.
According to the International Myeloma Working Group, serum protein
electrophoresis, serum immunofixation, and quantification of free light chains in
the serum should be sufficient to screen for a monoclonal gammopathy, with a
sensitivity of more than 97%.5 Patients with high suspicion for amyloidosis
should also have 24-hour urine protein electrophoresis and immunofixation;
24-hour urine testing should also be obtained in all patients with abnormal serum
testing as part of the workup.
Significance of a Monoclonal Gammopathy

As a monoclonal gammopathy indicates the presence of an underlying clonal
plasma cell disorder, the significance from a hematologic perspective varies,
ranging from benign to a malignant lymphoplasmacytic disorder. When the
proliferation of plasma cells in the bone marrow or the amount of secreted
monoclonal protein reaches a certain threshold, it can result in end organ
damage, making the monoclonal gammopathy of hematologic significance.
Otherwise, a “benign” monoclonal gammopathy is referred to as a monoclonal
gammopathy of undetermined significance (MGUS). To be labeled as MGUS, a
monoclonal gammopathy has to have a low clonal burden as reflected by a low
1370 OCTOBER 2020

KEY POINTS
● The coexistence of a
monoclonal gammopathy
and peripheral neuropathy
in an individual patient is
often coincidental.
● A monoclonal
gammopathy has
undetermined significance
from a hematologic
standpoint when the patient
has a low serum monoclonal
protein level (<3 g/dL), less
than 10% plasma cells in the
bone marrow, and less than
500 mg/24 hour of M protein
in the urine) and no evidence
of end organ damage.
FIGURE 11-1
Monoclonal gammopathy representation. A, In normal state, antibodies of different colors ● Whereas a monoclonal
result in a wide-based curve on serum protein electrophoresis. B, Proliferation of a purple gammopathy may be of
clone results in a spike on top of the wide-based curve on serum protein electrophoresis, undetermined significance
representing the monoclonal spike. from a hematologic
standpoint, it may still be of
clinical significance from a
serum monoclonal protein level (<3 g/dL), less than 10% plasma cells in the bone neurologic standpoint.
marrow, and less than 500 mg M protein in the urine per 24 hours. In addition,
the patient should have no evidence of end organ damage as expressed by the
acronym CRAB (hypercalcemia, renal failure, anemia, or bone lesions). Whereas
myelomas are rare, MGUS is common. Although benign, MGUS carries an
inherent lifelong risk of progression into a lymphoplasmacytic malignancy of
about 1% per year.6 Therefore, MGUS often requires continued monitoring.
Furthermore, despite being of undetermined significance from a hematologic
standpoint, MGUS can be associated with a wide spectrum of disorders spanning
multiple organs and tissues, including the kidney, skin, and peripheral nervous
system, hence the newly introduced term a monoclonal gammopathy of
clinical significance.4
Monitoring of Monoclonal Gammopathy of Undetermined Significance

Once a monoclonal gammopathy is detected, the patient should be referred
to a hematologist or an internist for further investigation and to determine
the need for long-term monitoring. The three main high-risk factors for
progression into a lymphoplasmacytic malignancy are IgM subtype, M-spike
greater than or equal to 1.5 g/dL, and abnormal serum free light chain ratio.6,7
The presence of one of these risk factors should prompt further investigation
to rule out an underlying malignancy, including a bone marrow biopsy in
patients with all subtypes and the addition of a skeletal survey in patients with
IgG and IgA subtypes. All patients with MGUS should have a repeat evaluation
with complete blood cell count, serum protein electrophoresis, free light
chains, and calcium and creatinine levels in 6 months and on a yearly basis
thereafter. For patients with no high-risk factors, it is unclear whether
routine monitoring adds any benefit as the risk of progression into a
lymphoplasmacytic malignancy is low, about 7% over 20 years.6,8,9

Clinical Approach to a Monoclonal Gammopathy

The clinical approach to peripheral neuropathies associated with monoclonal
gammopathy is detailed in FIGURE 11-2. When a monoclonal gammopathy is
detected in a patient with peripheral neuropathy, the first step is to categorize it
based on the monoclonal protein type (IgM, non-IgM, light chain). The next step
is to assess for associated symptoms, signs, and laboratory abnormalities that
would suggest an underlying lymphoplasmacytic disorder, in collaboration with
hematology or the primary care physician. In general, systemic symptoms such
as B symptoms (eg, fever, weight loss, night sweats), abnormalities in other cell
lineages (eg, anemia, thrombocytopenia, thrombocytosis), or high M protein
level should prompt evaluation for an underlying lymphoplasmacytic disorder.
Distinctive clinical and electrodiagnostic features of the neuropathy (eg,
prominent autonomic involvement, rapid progression, motor weakness,
demyelination on nerve conduction studies) should also prompt further study.
Peripheral neuropathies of recent onset should be approached with caution, as
patients may not yet display all the characteristics of a certain paraproteinemic
neuropathy.
FIGURE 11-2
Algorithmic approach to evaluating patients with a monoclonal gammopathy and peripheral
neuropathy.
CRAB = hypercalcemia, renal failure, anemia, or bone lesions; IgM = immunoglobulin M; POEMS =
polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes.
a
The presence of marked autonomic failure with any type of monoclonal gammopathy should raise
suspicion for amyloidosis.
1372 OCTOBER 2020

From a practical standpoint, monoclonal gammopathies can be classified into KEY POINTS
three categories: IgM, non-IgM, and light chain. IgM MGUS can progress into
● IgM peripheral
Waldenström macroglobulinemia and, rarely, IgM myeloma. IgG and IgA neuropathy usually presents
(non-IgM) MGUS can progress into multiple myeloma or osteosclerotic with progressive sensory
myeloma, and light chain MGUS can progress into light chain myeloma. All loss resulting in gait ataxia,
MGUS subtypes can progress into amyloidosis. with no to minimal weakness
(distal acquired
IgM-Associated Disorders [DADS] phenotype).
IgM is the most common monoclonal gammopathy subtype encountered in
patients with peripheral neuropathy, whereas IgG is the most common in the ● IgM peripheral
general population.10 Furthermore, IgM is the only MGUS subtype that has been neuropathy, distal acquired
definitively associated so far with a peripheral neuropathy without an underlying (DADS) phenotype, is a
hematologic malignancy or amyloidosis. Therefore, adopting a systematic demyelinating neuropathy
approach to evaluate patients with peripheral neuropathy and a monoclonal with characteristic
gammopathy, especially in the case of IgM, is of utmost importance. prolongation of motor
distal latencies on
electrodiagnostic testing.
IgM MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE. IgM-
associated peripheral neuropathy most commonly presents as progressive
sensory loss in the feet resulting in marked gait ataxia and can occasionally
be associated with tremor. Patients usually have no to minimal weakness;
when weakness occurs, it is mainly of toe extension.11 This is also referred to
as distal acquired demyelinating symmetric (DADS) neuropathy. Less
commonly, patients may present with more prominent weakness affecting
proximal and distal muscles in addition to the sensory loss, representing a
polyradiculoneuropathy mimicking chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP).
On nerve conduction studies, IgM neuropathy is classically demyelinating,
with preferential involvement of the distal nerve segments manifesting with
prolonged motor distal latencies. Sensory responses are often absent.
Approximately 50% of patients have antibodies to myelin-associated
glycoprotein (MAG); hence, the neuropathy is sometimes called anti-MAG
neuropathy. However, no difference in clinical phenotype, course, or severity of
the neuropathy is known between patients who are seropositive and patients
who are seronegative.12
When patients present with sensory symptoms predominantly affecting small
fiber modalities without significant large fiber involvement and lack of
demyelinating features on nerve conduction studies, it is more likely that the
presence of IgM MGUS is coincidental. Although this is the typical phenotype for
chronic idiopathic axonal peripheral neuropathy, the presence of an MGUS
should still prompt exclusion of amyloidosis in the right clinical context, such as
in patients presenting with rapidly progressive neuropathy or marked systemic
or autonomic symptoms.
Only anecdotal evidence exists to support the use of immunotherapy in IgM
neuropathy, as most clinical trials showed no benefit or only marginal benefit.13
Rituximab can be considered on a case-by-case basis. Patients with short disease
duration, rapid progression, or significant weakness may benefit from a
treatment trial.14 The authors offer treatment to all patients with the
polyradiculoneuropathy phenotype, as distinguishing it from CIDP can be
challenging. The authors try IV immunoglobulin (IVIg) first followed by
rituximab for nonresponders.

WALDENSTRÖM MACROGLOBULINEMIA. Waldenström macroglobulinemia is

by definition an IgM lymphoplasmacytic lymphoma. In its classic form,
Waldenström macroglobulinemia–associated peripheral neuropathy has similar
clinical presentation to IgM neuropathy, with progressive length-dependent
sensory loss, gait ataxia, and minimal weakness. Occasionally, Waldenström
macroglobulinemia–associated peripheral neuropathy may present as a
polyradiculoneuropathy mimicking CIDP (CASE 11-1). However, patients with
Waldenström macroglobulinemia may also report systemic symptoms of weight
CASE 11-1 A 79-year-old man presented with a 6-month history of progressive

symptoms that began with imbalance. He then developed diffuse
weakness in upper and lower limbs, which led to multiple falls and
inability to get up off the floor. He described decreased sensation below
his knees and elbows with burning pain in his feet. He had a 24-year
history of an IgM monoclonal gammopathy, found during a workup for
anemia. A bone marrow biopsy 10 years earlier showed less than 10%
plasma cells.
Neurologic examination demonstrated symmetric distal more than
proximal upper and lower limb weakness. He was areflexic, had loss of
vibration and proprioception to the ankles, and was unable to walk on his
heels or toes. He had a positive Romberg sign, and tandem gait was
markedly impaired. Nerve conduction studies and EMG demonstrated a
demyelinating polyradiculoneuropathy with evidence of slowed
conduction velocities, motor conduction blocks, temporal dispersion,
and prolongation of F-wave latencies. Ganglioside and myelin-associated
glycoprotein (MAG) antibodies were negative. The M-spike had
increased to 3.2 g/dL. Lumbar puncture demonstrated 2 white blood
cells/mm3 and a protein level of 161 mg/dL.
The patient underwent a bone marrow biopsy, which showed
low-grade B-cell lymphoma with plasmacytic differentiation consistent
with smoldering Waldenström macroglobulinemia. Before the diagnosis
of Waldenström macroglobulinemia, the patient had tried IV
immunoglobulin (IVIg) and dexamethasone with minimal improvement.
Rituximab 375 mg/m2 weekly for 4 weeks provided marked clinical
improvement, and he continued on maintenance infusions every 3 months
for 1 year. The patient remained stable afterward without needing further
rituximab infusions.
COMMENT The chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

phenotype associated with Waldenström macroglobulinemia or IgM-
associated neuropathy may be indistinguishable from classic CIDP but may
not respond to traditional treatment such as IVIg and corticosteroids.
Rituximab may be a very effective treatment in these patients. This case
also demonstrates that monoclonal gammopathies require long-term
follow-up because of the risk of evolution to a lymphoplasmacytic
malignancy; this risk is highest for IgM.
1374 OCTOBER 2020

loss, night sweats, and fatigue. Patients with Waldenström macroglobulinemia can KEY POINTS
also have hepatosplenomegaly, dysautonomia, and other organ involvement. On
● Waldenström
electrodiagnostic testing, Waldenström macroglobulinemia neuropathy can be macroglobulinemia–
either axonal or demyelinating. Demyelination is observed in one-third of patients associated peripheral
and, when present, is predominantly distal.15 On laboratory testing, unlike in IgM neuropathy can look similar
neuropathy, patients with Waldenström macroglobulinemia can have associated to IgM peripheral
neuropathy but with more
anemia, thrombocytopenia, cryoglobulinemia, and significantly greater level of IgM
prominent systemic
monoclonal gammopathy.15 All these distinctive features constitute red flags that symptoms and cytopenias.
should prompt further investigation, including a bone marrow biopsy, in patients
presenting with an IgM monoclonal gammopathy and peripheral neuropathy. ● Chemotherapy-induced
Less commonly, patients with Waldenström macroglobulinemia may also peripheral neuropathy is the
most common neuropathy
have peripheral nerve involvement from neurolymphomatosis, vasculitis, or type encountered in
cryoglobulinemia.16 A non–length-dependent or multifocal pattern and the multiple myeloma.
presence of significant pain should raise concern for an infiltrative or vasculitic
process; however, the lack thereof does not necessarily rule these processes out.
Peripheral nerve imaging (MRI or ultrasound) and nerve biopsy may be needed
in such cases.
Treatment of Waldenström macroglobulinemia neuropathy consists mainly of
treating the underlying lymphoproliferative disorder.
OTHER IgM-ASSOCIATED DISORDERS. CANOMAD (chronic ataxic neuropathy,

ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies) is
a rare peripheral neuropathy resembling Miller Fisher syndrome but chronic
rather than acute. Patients may have ataxia, ophthalmoplegia, bulbar weakness,
and facial numbness, although not all patients have all the components of this
syndrome. CANOMAD is defined by the presence of IgM antibodies reacting
principally with disialosyl epitopes (usually anti-GD1b; sometimes with
cross-reactivity against other disialosyl gangliosides, including GQ1b), and
approximately half of patients have cold agglutinins. CANOMAD can be treated
with IVIg or rituximab.17
IgM deposition neuropathy, in which IgM immunoglobulins deposit within
the nerve (mimicking amyloidosis), is extremely rare.18,19
Non–IgM-Associated Disorders
IgG and IgA monoclonal gammopathy can be associated with underlying
myeloma or amyloidosis, both of which may present with their neurologic
manifestations. However, no clear association between IgG and IgA MGUS and
peripheral neuropathy has been established. Therefore, in the absence of
underlying multiple myeloma, osteosclerotic myeloma, or amyloidosis, the
presence of an IgG or IgA monoclonal gammopathy in a patient with a peripheral
neuropathy is more likely to be coincidental.
MULTIPLE MYELOMA. Multiple myeloma is a plasma cell malignancy of the bone

marrow. The cardinal features of multiple myeloma are hypercalcemia, renal
failure, anemia, and bone pain. The most frequent neurologic complication is
compressive radiculopathy. Chemotherapy-induced peripheral neuropathy is
the most frequent cause of neuropathy in multiple myeloma, often due to
treatment with bortezomib or thalidomide.20,21 Peripheral neuropathy is
reported in 5% to 20% of patients with untreated multiple myeloma; however,
this may be an overrepresentation as studies have not rigorously excluded

alternative causes.22–24 The mechanism of the neuropathy is not well elucidated,

and it is clear that some cases are due to secondary amyloid deposition. The
neuropathy in multiple myeloma without amyloid has been described as
length-dependent sensorimotor, sensory, or motor predominant. Patients with
secondary amyloidosis may present with carpal tunnel syndrome and may
later develop prominent dysesthesia, dissociated sensory loss with predominant
loss of pain and thermal discrimination, autonomic dysfunction, or, rarely,
painless weakness without autonomic dysfunction. Nerve conduction studies
show a predominantly axonal length-dependent sensorimotor peripheral
neuropathy. Treatment of multiple myeloma neuropathy consists mainly of
treating the underlying plasma cell disorder, balancing the risk of neurotoxicity
associated with these agents.
POEMS (POLYNEUROPATHY, ORGANOMEGALY, ENDOCRINOPATHY,

MONOCLONAL PLASMA CELL DISORDER, AND SKIN CHANGES) SYNDROME.
POEMS syndrome is a rare multisystem paraneoplastic syndrome due to an
underlying plasma cell neoplasm. Diagnostic criteria have been established for
the diagnosis of POEMS.25 The required major criteria include a monoclonal
plasma cell proliferative disorder and polyneuropathy. Patients must also meet
one other major criterion, which includes elevated vascular endothelial growth
factor (VEGF), the presence of Castleman disease (angiofollicular lymph node
hyperplasia), or sclerotic bone lesions.26 Minor criteria include organomegaly,
endocrinopathy, characteristic skin changes, papilledema, extravascular volume
overload, and thrombocytosis. These features are not universally present,
especially at disease presentation, which leads to marked delays in diagnosis. In
fact, 60% of patients in some series were initially diagnosed with CIDP.27 VEGF
is the cytokine that correlates best with disease activity. It is expressed in many
tissues and is known to target endothelial cells; it induces rapid and reversible
increase in vascular permeability and may be important in angiogenesis.28
The neuropathy in POEMS syndrome often begins distally in the lower
limbs with weakness and sensory loss and can progress rapidly to a
polyradiculoneuropathy with proximal and distal weakness and areflexia
(CASE 11-2). The distal weakness is often severe, with bilateral footdrop and
distal leg atrophy. Pain is often present and is a helpful feature to distinguish
POEMS from CIDP.27 Nerve conduction studies often support a primarily
demyelinating length-dependent sensorimotor peripheral neuropathy or diffuse
polyradiculoneuropathy. The demyelination is often uniform throughout the
nerve; conduction block and temporal dispersion are less common but can occur.30
Autonomic involvement is uncommon, apart from erectile dysfunction, which
may be related to hypogonadism. Nerve biopsy demonstrates demyelination and
axonal degeneration and an increase in epineurial microvessels.31
The monoclonal protein in POEMS syndrome is lambda light chain–restricted
in more than 95% of patients.28 An elevated platelet count is present in more than
half of patients with POEMS, compared to in 1% to 2% of patients with CIDP.32
VEGF levels greater than 200 pg/mL in plasma and greater than 1920 pg/mL in
serum are helpful markers for POEMS syndrome.33,34 As patients with POEMS
commonly have an endocrinopathy (hypogonadism, hyperprolactinemia,
hypothyroidism, glucose intolerance, or adrenal insufficiency), screening via a
comprehensive laboratory workup is warranted and should include the following
tests: total and bioavailable testosterone, follicle-stimulating hormone, luteinizing
1376 OCTOBER 2020

hormone, estradiol (in women), prolactin, thyroid-stimulating hormone (TSH), KEY POINTS
free thyroxine, fasting glucose, cortisol, and adrenocorticotropic hormone
● POEMS (polyneuropathy,
(ACTH).35,36 Osteosclerotic lesions occur in approximately 95% of patients but organomegaly,
can be confused with benign bone lesions. They can also be lytic rather than endocrinopathy,
sclerotic in appearance. Whole-body low-dose CT is more sensitive than plain monoclonal plasma cell
x-ray in detecting small sclerotic lesions and can also show other features of the disorder, and skin changes)
neuropathy can mimic
disease, such as hepatosplenomegaly, adenopathy, or effusions, including ascites.37
chronic inflammatory
Treatment for POEMS syndrome is directed at the underlying clonal plasma demyelinating
cell disorder and is based on the extent of plasma cell infiltration. The neuropathy polyradiculoneuropathy
is reported to stabilize or improve with various systemic therapies, including (CIDP) as associated
features may be easily
autologous stem cell transplantation.38
overlooked.
Light Chain–Associated Disorders ● The presence of

A light chain–only MGUS is less common and carries the lowest risk of thrombocytosis in a patient
with CIDP should prompt
progression into a malignancy.39 However, a light chain–only monoclonal
evaluation for underlying
gammopathy can be associated with immunoglobulin light chain (AL) POEMS.
amyloidosis and light chain multiple myeloma. Multiple myeloma–associated
neuropathy is discussed in the section on non–IgM-associated disorders above. ● Any type of monoclonal
gammopathy can be
associated with amyloidosis.
IMMUNOGLOBULIN LIGHT CHAIN AMYLOIDOSIS. Although the most common
type of monoclonal gammopathy associated with AL amyloidosis is light chain ● Among all patients
only and lambda restricted, all types of monoclonal gammopathy can be the with paraproteinemic
precursor of AL amyloidosis. AL amyloidosis is a systemic disorder in which disorders, patients with
insoluble misfolded light chains deposit into various tissues, including immunoglobulin light chain
(AL) amyloidosis appear
peripheral nerves, which occurs in up to 20% of patients.40 Therefore, the sickest and may display
patients may present with a wide spectrum of symptoms, including cardiorespiratory,
cardiorespiratory, gastrointestinal, genitourinary, and systemic symptoms. gastrointestinal,
Among all patients with paraproteinemic disorders, patients with AL genitourinary, and systemic
symptoms at presentation.
amyloidosis appear the sickest, with nearly half of them reporting weight loss
and fatigue (CASE 11-3).41 Whereas early on in the disease course AL amyloid ● Most commonly, patients
neuropathy predominantly affects small fibers, it is very rare for patients with with AL amyloidosis with
amyloid neuropathy (5%) to present with a pure small fiber sensory neuropathy, peripheral nerve
involvement present with
and patients who do, usually have associated generalized autonomic failure,
generalized autonomic
distinguishing them from patients with idiopathic small fiber sensory failure and a painful length-
neuropathy.42 The majority of patients (about two-thirds) present with dependent sensory and
generalized autonomic failure and a painful length-dependent sensory and motor peripheral
neuropathy.
motor peripheral neuropathy.42 The remainder of patients may present with a
similar phenotype but without pain, with pure autonomic failure, or with large ● The majority of patients
fiber peripheral neuropathy without autonomic involvement.42 Diagnostic with AL amyloidosis are not
findings of periorbital or facial purpura, hepatomegaly, and macroglossia are autologous stem cell
seen in a minority of patients. AL amyloid neuropathy should be considered in transplantation eligible at
diagnosis; hence, early
patients with nephrotic range proteinuria, heart failure with preserved ejection diagnosis is important.
fraction, unexplained hepatomegaly, or diarrhea.
On electrodiagnostic testing, amyloid neuropathy is classically a
length-dependent sensory and motor predominantly axonal peripheral
neuropathy. In the minority of patients with a pure small fiber sensory
neuropathy, electrodiagnostic testing may be normal.
The diagnosis of AL amyloidosis requires demonstration of amyloid
deposition in tissue. A surrogate biopsy site, such as abdominal fat pad, bone
marrow, minor salivary glands, or skin, is usually attempted first given the less

invasive nature of the procedure. A combined abdominal fat pad and bone
marrow biopsy can detect amyloid deposition with a sensitivity of 85%.43 If these
are negative and the clinical suspicion remains high, then a biopsy from an
affected organ or tissue, such as the peripheral nerves, should follow. Once
amyloid is detected, amyloid subtyping should follow, preferably via mass
spectrometry.44 As monoclonal gammopathies are common in the general
population, ruling out hereditary transthyretin amyloidosis in these patients is
CASE 11-2 A 39-year-old man presented with a 3-month history that began with
swelling in his feet and difficulty lifting his left leg while getting into his
truck. The symptoms had progressed to include proximal and distal leg
weakness and sensory loss that ascended to his knees. He reported
progressive imbalance and required a walker upon presentation. He also
had bouts of severe abdominal pain and reported erectile dysfunction.
General examination demonstrated lower extremity edema, flushing,
and hypertrichosis (FIGURE 11-3). He had palpable axillary and inguinal
adenopathy and hepatosplenomegaly. Neurologic examination showed
diffuse weakness more pronounced distally, worse in the lower limbs. He
was hyporeflexic in the upper limbs and areflexic in the lower limbs.
Sensation was reduced to vibration, joint position, and pinprick below the
knees, and he had a positive Romberg sign.
Laboratory studies demonstrated
thrombocytosis (platelet count
1,349,000 cells/mm3, normal
<317,000 cells/mm3). He had no
monoclonal protein on serum or urine
protein electrophoresis and
immunofixation. He had elevated
kappa light chains (2.39 mg/dL,
normal range 0.33 mg/dL to
1.94 mg/dL) and lambda light chains
(8.47 mg/dL, normal range
0.57 mg/dL to 2.63 mg/dL), with
normal kappa to lambda ratio (0.28,
normal range 0.26 to 1.65). His
testosterone was reduced.
Electrodiagnostic studies
demonstrated an axonal greater than
demyelinating length-dependent
peripheral neuropathy without
evidence of conduction block or
temporal dispersion. Lumbar
puncture was remarkable for a
FIGURE 11-3 protein level of 235 mg/dL. CT of the
Hypertrichosis in the patient in CASE 11-2. abdomen and pelvis demonstrated
1378 OCTOBER 2020

crucial.45 For more information on transthyretin amyloidosis, refer to the article
“Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies” by
Christopher J. Klein, MD, FAAN,46 in this issue of Continuum.
The treatment of choice for AL amyloidosis is autologous stem cell
transplantation for eligible patients. However, the majority of patients (75% to
80%) are ineligible at time of diagnosis and are therefore treated with
chemotherapy.47
moderate splenomegaly with three nonspecific bone lesions felt to

be benign.
Initial treatment with IV immunoglobulin (IVIg) 2 g/kg divided over
4 days for a diagnosis of chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) provided no clinical improvement.
Further evaluation with positron emission tomography (PET) CT showed
an expansile lytic lesion in the right ilium and right midhumerus and
prominent fludeoxyglucose (FDG)-avid right axillary lymph nodes. His
vascular endothelial growth factor (VEGF) level was markedly elevated
(700 pg/mL, normal <96.2 pg/mL). Bone marrow biopsy demonstrated
20% lambda light chain restricted plasma cells.
He was diagnosed with POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma cell disorder, and skin changes)
syndrome. The patient was started on chemotherapy (ixazomib,
lenalidomide, and dexamethasone), followed by an autologous stem cell
transplant (conditioned with melphalan), with subsequent stabilization of
his neuropathy.
This case demonstrates several important features of POEMS syndrome. COMMENT

Serum monoclonal protein studies may be negative. The kappa to lambda
light chain ratio is normal in up to 80% of patients, despite elevation in
lambda free light chains.29 Approximately half of patients with POEMS
have thrombocytosis compared to less than 2% of patients with CIDP,
which should raise the suspicion of this diagnosis.32 Patients with POEMS
often do not have conduction block or temporal dispersion despite other
demyelinating features on nerve conduction studies.

CASE 11-3 A 67-year-old man presented with a 4-month history of unsteady gait and
orthostasis. In the preceding 3 years, he had noted nonbloody watery
diarrhea and a 54.4-kg (120-lb) weight loss. At presentation, he required a
walker for ambulation. He reported lightheadedness upon standing that
had progressed to syncope on multiple occasions. He had a 5-year
history of diabetes managed on metformin but had no nephropathy or
retinopathy.
On examination, his supine blood pressure was 116/70 mg Hg, and his
blood pressure after standing for 5 minutes was 90/60 mm/Hg, with no
significant change in his heart rate. Pupillary reflexes and motor
examination were normal; ankle reflexes were reduced. He had sensory
loss to vibration, touch, and pinprick in the feet. Tandem gait was
unsteady.
Laboratory studies showed a hemoglobin A1c of 4.8% and the presence
of an IgG lambda monoclonal protein (0.4 g/dL) with elevated kappa
(2.21 mg/dL, normal range 0.33 mg/dL to 1.94mg/dL) and lambda
(3.30 mg/dL, normal range 0.57 mg/dL to 2.63 mg/dL) light chains with
normal kappa to lambda ratio (0.67, normal range 0.26 to 1.65).
Electrodiagnostic testing demonstrated a chronic sensorimotor axonal
polyradiculoneuropathy. An autonomic reflex screen showed severe
postganglionic sympathetic sudomotor, cardiovagal, and cardiovascular
adrenergic failure (FIGURE 11-4). Subcutaneous fat aspirate demonstrated
congophilic amorphous deposits that were further assessed with liquid
chromatography tandem mass spectrometry and confirmed as AL
lambda-type amyloid.
Treatment with systemic chemotherapy was initiated
(cyclophosphamide, bortezomib, and dexamethasone), with stabilization
of the patient’s peripheral neuropathy and persistence of the orthostatic
intolerance and diarrhea.
COMMENT This case illustrates that weight loss is the most common symptom of light
chain amyloidosis at presentation. Generalized autonomic failure is
common in amyloidosis, and orthostatic hypotension is present in 11% of
patients at diagnosis.40 This case also emphasizes the importance of
considering alternative causes of a sensory and autonomic neuropathy in a
patient with well-controlled diabetes without nephropathy or retinopathy.
1380 OCTOBER 2020

FIGURE 11-4
Autonomic reflex screen of the patient in CASE 11-3. A, Quantitative sudomotor axon reflex
test (QSART) shows length-dependent postganglionic sympathetic sudomotor dysfunction
in sweat output of the forearm (red line), distal leg (green line), and foot (yellow line);
sudomotor function in the proximal leg (blue line) is spared. B, Heart rate response to deep
breathing shows markedly reduced heart rate response (green line with multicolored
arrowheads shows maximum and minimum heart rate) to deep breathing (blue line),
indicating marked cardiovagal dysfunction. C, Valsalva maneuver response shows
cardiovagal dysfunction with markedly reduced Valsalva ratio (black bars indicate initiation
of Valsalva; green line with arrowheads shows maximum and minimum heart rate) and
cardiovascular adrenergic dysfunction as shown by systolic (red line), mean arterial
(pink line), and diastolic (yellow line) blood pressure measurements with absent late
phase II (asterisk) as well as absent phase IV overshoot and slowed blood pressure
recovery time (number sign). D, Tilt-table testing (black bars indicate tilt up and tilt down)
shows orthostatic hypotension. Red line indicates systolic blood pressure measurement,
pink line indicates mean arterial blood pressure measurement, and yellow line indicates
diastolic blood pressure measurement. Heart rate response (green line) is also reduced.

CONCLUSION
The clinical approach to a peripheral neuropathy in the setting of a monoclonal
gammopathy should be guided by the monoclonal gammopathy subtype and the
clinical and electrodiagnostic phenotype of the peripheral neuropathy. Such
patients greatly benefit from a multidisciplinary approach in collaboration with
hematology. Determining the nature of the relationship between the monoclonal
gammopathy and the peripheral neuropathy is crucial to guide treatment
decisions and for prognosis.
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doi:10.1182/blood-2011-06-362392.

PRACTICE ISSUES

Test Utilization and Value
ONLINE
in the Evaluation of
By Brian C. Callaghan, MD, MS, FAAN
ABSTRACT
Peripheral neuropathies can be classified as typical or atypical. Patients
with atypical neuropathy have one or more of the following features:
acute/subacute onset, non–length dependence, motor predominance, or
asymmetry. This classification is important because it informs the appropriate
CITE AS: diagnostic evaluation of this highly prevalent condition. The evaluation of a
typical peripheral neuropathy, also known as distal symmetric
MOTOR NEURON DISORDERS): polyneuropathy, requires a thorough history, neurologic examination, and
1384–1391. focused laboratory testing. Electrodiagnostic testing and MRI account for
the majority of costs but rarely lead to changes in diagnosis or management.
Dr Brian Callaghan, 109 Zina These costs are increasingly being passed on to patients, especially those
Pitcher Pl, 4021 BSRB, Ann Arbor, with high-deductible health plans. In contrast, patients with atypical
MI 48104, bcallagh@med.umich.
edu.
neuropathy require more extensive testing, including electrodiagnostic
tests. These tests are much more likely to lead to the use of disease-
RELATIONSHIP DISCLOSURE: modifying therapies in these patients compared to in those with typical
Dr Callaghan serves on a
scientific advisory board for a
peripheral neuropathy. This article describes two cases to illustrate the
Patient-Centered Outcomes appropriate diagnostic workup of those with typical or atypical neuropathy.
Research Institute grant, on the
International Diabetes
Neuropathy Consortium board
for the Peripheral Nerve Society, CASE 1
on the editorial board of
Neurology, and as a consultant
A 60-year-old man presented for an outpatient neurology consultation with
for DynaMed. Dr Callaghan has numbness, tingling, and pain in his feet. His symptoms started 3 years earlier
received research/grant support in his toes and slowly and steadily spread to his midshins with no involvement
from the American Academy of
Neurology, JDRF, the National of his hands. His symptoms were symmetric, and he denied weakness. He had
Institutes of Health (R01 a past medical history of hyperlipidemia and hypertension but did not have
DK115687), and the US diabetes or significant alcohol consumption. No one in his family had a
Department of Veterans Affairs
(Clinical Science Research and diagnosis of neuropathy or similar symptoms.
Development Merit I01CX001504) Neurologic examination revealed normal strength, absent Achilles
and provided consulting services
for medicolegal cases and the US
reflexes, decreased pinprick sensation below the knees, and 3 seconds of
Vaccine Injury Compensation vibration sensation at the toes.
Program.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL DISCUSSION
T
USE DISCLOSURE:
Dr Callaghan reports no
he patient in CASE 1 presented with symptoms and signs of a typical
disclosure. distal symmetric polyneuropathy. No atypical features such as
acute/subacute onset, non–length dependence, motor predominance,
© 2020 American Academy or asymmetry were present (PRACTICE FIGURE 1).1,2 The patient did
of Neurology. not have a condition known to cause neuropathy, such as diabetes or
1384 OCTOBER 2020

alcohol use disorder. In cases of
distal symmetric polyneuropathy,
the most important components
of the diagnostic evaluation are
the history and neurologic
examination.3 Laboratory tests
add slightly to the diagnostic yield,
whereas electrodiagnostic tests
and MRIs are rarely needed. Nerve
biopsies are not needed because of
the low diagnostic yield and high
morbidity associated with these
procedures. Testing for this
patient should include a glucose
tolerance test, vitamin B12 level,
serum protein electrophoresis
with immunofixation, complete
blood cell count, and
comprehensive metabolic panel.
History and Examination

As in most clinical conditions, the
history and examination are
essential in determining the PRACTICE FIGURE 1
underlying cause of a distal Diagnostic algorithm for distal symmetric
polyneuropathy. Testing for distal symmetric
symmetric polyneuropathy. Distal
polyneuropathy is based on whether atypical
symmetric polyneuropathy can be features are present and whether a known cause
caused by a lengthy list of is already established based on the history and
conditions, including, but not neurologic examination. Most cases of distal
symmetric polyneuropathy require limited
limited to, diabetes, prediabetes,
diagnostic testing.
alcohol use disorder, nutritional EMG = electromyography.
deficiencies, paraproteinemias, Modified with permission from Callaghan BC, et al, JAMA.1
medications, chronic kidney © 2015 American Medical Association.
4
disease, and genetic causes. Most
of these conditions are diagnosed or suspected by taking a thorough medical,
family, and social history. Idiopathic neuropathy accounts for at least one-fourth
of distal symmetric polyneuropathies and increases greatly after the age
of 40.3,5–8 The lack of recognition of the high prevalence of idiopathic distal
symmetric polyneuropathy likely drives unnecessary testing. Community-
based neurologists are able to diagnose the underlying cause of distal
symmetric polyneuropathy in 64% of cases before further diagnostic testing.3
Laboratory Testing
Laboratory testing is important to attempt to diagnose the underlying cause of
distal symmetric polyneuropathy in those in whom the history does not lead to
a clear etiology. The American Academy of Neurology (AAN) guideline
supports testing for hyperglycemia and vitamin B12 deficiency, testing for
a monoclonal gammopathy with a serum protein electrophoresis with
immunofixation, complete blood cell count, and comprehensive metabolic
panel (PRACTICE FIGURE 1).9

TEST UTILIZATION AND VALUE IN PERIPHERAL NEUROPATHIES
Testing for hyperglycemia is the most important diagnostic step, as

diabetes and prediabetes are the most common causes of distal symmetric
polyneuropathy.3,6,7,10,11 Hemoglobin A1c and fasting glucose can be used to test
for hyperglycemia, but a glucose tolerance test has a higher sensitivity.11 Since
the diagnosis of diabetes or prediabetes is important to the management of
patients with distal symmetric polyneuropathy, using the most sensitive test is
essential. Vitamin B12 level is one of the few tests with a yield higher in distal
symmetric polyneuropathy than expected in the general population, and
vitamin B12 deficiency has been associated with worsening neuropathy.12,13
Vitamin B12 replacement is inexpensive and has the potential to improve
neuropathy and prevent further worsening, highlighting the need for this test.
The prevalence of a monoclonal gammopathy (abnormal serum protein
electrophoresis with immunofixation) is 10% in patients with otherwise
idiopathic neuropathy, which is much greater than in population-based
studies.14 These tests have the potential to uncover monoclonal gammopathies
that may indicate underlying malignancy or may be the precursor to future
malignancy. Complete blood cell counts and comprehensive metabolic panels
do not have great evidence to support their use, but the majority of
neurologists would order them, based on a national survey.15 In contrast,
rheumatologic tests (such as an antinuclear antibody test) and
thyroid-stimulating hormone (TSH) do not have a higher yield in those with
distal symmetric polyneuropathy compared to those without neuropathy.16
Previous studies have also demonstrated that more extensive laboratory testing
does not increase the yield and that repeat testing is not helpful.13,17,18 The AAN
guideline–recommended tests are also the tests most likely to change clinical
management.3 Guideline-supported diagnostic tests are not just a starting point
but are usually the only tests needed for patients presenting with typical distal
symmetric polyneuropathy.
Electrodiagnostic Testing
Nerve conduction studies and EMG enable clinicians to determine the pattern of
nerve injury and whether underlying axon loss or primary demyelination is
present. However, these tests rarely change the pretest diagnosis or management
of patients with distal symmetric polyneuropathy.3 In a study of 458 patients,
only two patients had a change in diagnosis (from distal symmetric
polyneuropathy to “no neuropathy”) and no patients had a change in
management based on these tests. Interestingly, the chance of patients
undergoing an electrodiagnostic test is highly dependent on which neurologist
they see and not on other demographic or clinical factors.3 These results have led
to a position statement from the American Diabetes Association stating that
routine electrodiagnostic tests are not needed in patients with diabetes and distal
symmetric polyneuropathy unless atypical features are present, the diagnosis is
unclear, or another etiology is suspected.19 Which neuropathy patients would
benefit from these tests is unclear, but it would likely be those with atypical
features. An editorial has criticized this work based on four studies that reported
a different yield of electrodiagnostic studies.20 However, the largest study
with the most rigorous study design came to the same conclusion that
electrodiagnostic tests are not routinely needed in those with distal symmetric
polyneuropathy of clear cause.3,21 Two of the other studies focused on all tertiary
electrodiagnostic referrals and only included a small number of patients with
1386 OCTOBER 2020

distal symmetric polyneuropathy, which limits making any conclusions about
the value of electrodiagnostic testing in patients with distal symmetric
polyneuropathy.22,23 One other small study did not have a clear definition of
distal symmetric polyneuropathy and provided minimal details of what
constituted a change in management.24 Therefore, the current evidence does not
support routine electrodiagnostic tests in the evaluation of distal symmetric
polyneuropathy. Defining the exact scenarios that warrant testing requires
further studies, but the answer to whether all patients with distal symmetric
polyneuropathy should have electrodiagnostic tests is probably not.25
MRI
MRI of the neuraxis can help determine the cause of peripheral nervous system
lesions, especially with localizations such as polyradiculopathies, plexopathies,
and radiculoplexus neuropathies (PRACTICE FIGURE 2).26 However, the yield of
PRACTICE FIGURE 2
Diagnostic algorithm for atypical distal symmetric polyneuropathy. Testing for atypical distal
symmetric polyneuropathy is based on the localization of nerve injury from the nerve
conduction study and EMG. Most cases of atypical distal symmetric polyneuropathy require
extensive diagnostic testing.
Abs = antibodies; AMA = antimitochondrial antibody; ANA = antinuclear antibody; ANCA = antineutrophil
cytoplasmic antibody; ASMA = antismooth muscle antibodies; BJS = Bence Jones screen; CBC = complete
blood cell count; COMP = comprehensive metabolic panel; CRP = C-reactive protein; CXR = chest x-ray;
dsDNA = double-stranded deoxyribonucleic acid; EMG = electromyography; ESR = erythrocyte sedimentation
rate; FLC = free light chain; GM1 = ganglioside M1; HIV = human immunodeficiency virus; HTLV = human T-cell
lymphotropic virus; MRI = magnetic resonance imaging; RF = rheumatoid factor; SPEP/IF = serum protein
electrophoresis/immunofixation; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B; UA = urinalysis;
UPEP/IF = urine protein electrophoresis/immunofixation; VEGF = vascular endothelial growth factor;
WNV = West Nile virus.
Reprinted with permission from Callaghan BC, et al, JAMA Neurol.26 © 2015 American
Medical Association.

MRI is extremely low in those with distal symmetric polyneuropathy.3 One large
study demonstrated that none of the 458 patients with distal symmetric
polyneuropathy had a change in etiologic diagnosis or management after MRI
despite almost 30% of the patients receiving these tests.3,27 Despite the low yield,
MRIs of the neuraxis are ordered frequently, even in a survey that presented a
vignette with classic distal symmetric polyneuropathy symptoms, signs, and the
label of distal symmetric polyneuropathy to neurologists and primary care
physicians.15,27,28 These findings have led to a Choosing Wisely recommendation
from the American Association of Neuromuscular and Electrodiagnostic
Medicine that states that physicians should not order an MRI of the spine or
brain for those with only peripheral neuropathy.29 MRI should be reserved for
presentations consistent with polyradiculopathies, plexopathies, and
radiculoplexus neuropathies.
Cost
The cost of the diagnostic evaluation of distal symmetric polyneuropathy is
largely driven by electrodiagnostic tests and MRIs.30 These tests account
for 88% of the total diagnostic expenditures. The costs of the evaluation and
management (E/M) by neurologists and other physicians and the few
laboratory tests are quite small by comparison. In 2016, the mean estimated
reimbursements were $1076 for electrodiagnostic tests, $1265 for MRI,
and $253 for the physician visit (E/M) (unpublished data using the Clinformatics
Datamart, OptumInsight, Eden Prairie, Minnesota). Whereas out-of-pocket
costs for these diagnostic tests were previously quite small, they have risen
dramatically over the past 15 years. With deductibles rising, these costs are
now substantial for the approximately 40% of patients in commercial insurance
plans who pay out-of-pocket costs. The median out-of-pocket cost for these
patients is $230 for electrodiagnostic tests, $204 for MRI, and $40 for the
physician evaluation.
Policy Implications
The most valuable aspect of the diagnostic evaluation of peripheral neuropathy is
the physician visit (E/M service). However, the US Centers for Medicare &
Medicaid Services (CMS) recently proposed grouping E/M levels 2 through 5 and
later proposed grouping levels 2 through 4. This policy would have adversely
impacted neurologists more than any other specialty since neurology is
largely an E/M-based specialty and neurologists more frequently use
level 4 and 5 codes than any other specialist.31,32 One likely reason that
this policy proposal did not go into effect was the AAN’s advocacy on this
topic in conjunction with other medical societies. In contrast to E/M, CMS
substantially reduced reimbursement for nerve conduction studies in 2013,
which led to decreased use of nerve conduction studies much more so than
use of EMG, which did not experience the same change in reimbursement.33
Furthermore, non-neurologists drastically reduced nerve conduction
study use. These results demonstrate that the magnitude of reimbursement
affects diagnostic test utilization. Incentivizing value in the care of patients
with distal symmetric polyneuropathy would likely require higher payments
for services that are more likely to lead to changes in management, such as
physician visits, compared to payments for other diagnostic tests that are
often not needed.
1388 OCTOBER 2020

CASE 2
A 60-year-old man presented for an outpatient neurologic consultation
with numbness, tingling, and pain in his right foot more than his left foot. He
had a past medical history of hyperlipidemia and hypertension but did not
have diabetes or significant alcohol consumption. The symptoms had
started 4 weeks earlier in his right foot and 1 week earlier in his left foot. He
stated that his right foot was also weak.
Neurologic examination revealed right dorsiflexion strength of 4/5 and
left plantar flexion strength of 4+/5; he was otherwise strong. He had an
absent left Achilles reflex with 2+ reflexes elsewhere; decreased pinprick
sensation in the dorsum of the right foot, the right lateral leg, and the sole
of the left foot; and 3 seconds of vibration sensation at the right toe and
7 seconds at the left toe.
DISCUSSION
The patient in CASE 2 presented with symptoms and signs of an atypical
peripheral neuropathy. The atypical features included a subacute onset, motor
predominance, and asymmetry. In contrast to CASE 1, the diagnostic evaluation
should consist of electrodiagnostic studies to further localize the nerve injury and
to evaluate for demyelinating features. Possible localizations include multiple
mononeuropathies, non–length-dependent neuropathy, polyradiculopathy,
and radiculoplexopathy, each of which requires specific diagnostic tests
(PRACTICE FIGURE 2).4 The most likely localization from this presentation is
multiple mononeuropathies given the pattern of sensory deficits in the
distribution of specific nerves (right fibular [peroneal] and left tibial), and the
most likely diagnosis is a vasculitic neuropathy, also known as mononeuritis
multiplex. For more information on mononeuritis multiplex, refer to the article
“Peripheral Neuropathies Associated With Vasculitis and Autoimmune
Connective Tissue Disease” by Chafic Karam, MD,34 in this issue of Continuum.
After electrodiagnostic testing, tests that are often needed for the investigation of
vasculitic neuropathy include antinuclear antibody, antineutrophil cytoplasmic
antibody (ANCA), rheumatoid factor, Sjögren syndrome A (SSA)/Sjögren
syndrome B (SSB), double-stranded DNA, cryoglobulins, human
immunodeficiency virus (HIV), hepatitis B and C serologies, urinalysis, chest
x-ray, complete blood cell count, comprehensive metabolic panel, and a nerve
biopsy. In contrast to the evaluation of patients with distal symmetric
polyneuropathy, these evaluations are likely to lead to treatment with a
disease-modifying therapy. In the case of ANCA-positive vasculitic neuropathy,
rituximab induction and maintenance has been shown to be effective at
preventing relapse.35,36
CONCLUSION
Typical peripheral neuropathies are much more common than atypical
peripheral neuropathies. The diagnostic evaluation can be quite extensive for
atypical peripheral neuropathies and should be limited for those with typical
peripheral neuropathies; all patients require a complete history, neurologic
examination, and simple laboratory tests, with more extensive testing, such as
electrodiagnostic tests and MRIs, reserved for atypical presentations or special

situations. Costs, including patient out-of-pocket costs, should be considered to

ensure maximum value in the diagnostic evaluation of peripheral neuropathy.
ACKNOWLEDGMENT
The author would like to thank Raymond Price, MD, for his editorial assistance.
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172(2):127–132. doi:10.1001/archinternmed.2011.1032.

PRACTICE ISSUES
Rising Drug Costs for
Neurologic Diseases

ONLINE
By Jason L. Crowell, MD; Ted M. Burns, MD
ABSTRACT
The cost of prescription drugs in the United States is rising like never
before and has led to an inflection point where clinicians must consider the
potential financial damage to the patient and to society related to the more
expensive drugs available. Many of the highest-priced drugs are approved
as orphan drugs, a legally defined status providing additional benefits to
pharmaceutical companies that is intended to incentivize therapeutic
development for rare diseases. The Orphan Drug Act has been a great
success since it was enacted in 1983, resulting in the development of many
innovative, life-changing, and even lifesaving drugs; however, high drug
prices place patients at risk for personal bankruptcy, prescription
abandonment, and higher rates of hospitalization. These negative
consequences have become more widespread and severe because some
companies exploit pricing via the market exclusivity granted to them under
the provisions of the Orphan Drug Act. As more and more companies
develop these drugs, the cost to society increases as does the capacity to
tolerate unjustified prices. The societal effects of drug pricing must be
considered through the prism of opportunity costs; that is, what benefit is
lost by choosing to spend on one thing instead of another. Clinical- and
economic-based analyses from independent groups such as the Institute
CITE AS:
for Clinical and Economic Review can help physicians understand the value
2020;26(5, PERIPHERAL NERVE AND of drugs (ie, the benefits relative to cost). When prescribing a high-priced
MOTOR NEURON DISORDERS): medication, clinicians should discuss the drug’s value and the associated
1392–1406.
opportunity cost with patients and have an open discussion about patients’
Address correspondence to ability to financially tolerate the treatment.
Dr Jason Crowell, Beth Israel
Deaconess Medical Center,
330 Brookline Ave, KS406, Boston
MA 02215, jcrowell@hks.harvard.
edu.
INTRODUCTION
T
he cost of prescription drugs in the United States has skyrocketed over
RELATIONSHIP DISCLOSURE: the past decade. The drug-pricing problem is complex and involves
Dr Crowell has received
fellowship support from many stakeholders, including those who profit from the complexity
Medtronic. Dr Burns reports no and opaqueness of the system. More than ever, extreme or predatory
disclosure. pricing threatens access to care, negatively impacts our health care
UNLABELED USE OF system, and hurts our society. Patients and taxpayers (ie, almost everyone)
PRODUCTS/INVESTIGATIONAL shoulder the cost via insurance premiums and copays, taxes, cost shifting, rationing,
USE DISCLOSURE:
Drs Crowell and Burns report no
and reallocation of resources. In 2014, the sources of payment for outpatient
disclosures. prescription drugs were Medicare, Medicaid, and other public payers, 42% (taxes);
employee-sponsored private health insurance, 40% (premiums, costs passed on to
consumers); out-of-pocket, 15%; and other third-party payers, 3%.1,2 Between
of Neurology. 2013 and 2015, net spending in the United States on prescription drugs rose 20%.2
1392 OCTOBER 2020

Nearly one in four Americans reports difficulty affording their medicines.3 Of
working-age Americans with health insurance, 20% have problems paying
medical bills, and premiums and medical bills are a leading cause of personal
bankruptcy.4 Lowering the costs of prescription drugs—not insurance for
patients with preexisting conditions, Medicare spending, or funding
medical research—led polling as Americans’ top health concern in an August
2019 poll.5
In 2017, the United States spent $334 billion on prescription drugs, an amount
that is, per capita, 47% more than Canada and 160% more than the
United Kingdom, and it is increasing at a faster rate in the United States than in
other countries.6,7 The prices of the 20 drugs with the highest gross revenues
were 3 times higher in the United States than in the United Kingdom.8 As a
percentage of the US gross domestic product, health care has grown significantly
in the past 20 years (now representing 18% of the gross domestic product). In this
context, it is remarkable that the proportion of health care dollars spent on drugs
has also grown, from 7% in the 1990s to 12% in 2017.9,10
Medications for neurologic conditions are some of the most expensive in all of
medicine. In 2013, the Medicare Part D program that pays for outpatient
prescription medications spent $5 billion on drugs prescribed by neurologists;
this was the third-highest payout among the medical specialties (behind internal
medicine and family medicine).11 In 2017, Medicare Part D spent $2.52 billion on
pregabalin alone, placing it seventh on the list of total spending for all outpatient
prescriptions purchased.12 (For comparison, in 2016, Medicare spent $1.4 billion
for all neurologists’ services and procedures through Part B.13) Not only are the
total costs of these drugs increasing, but the out-of-pocket costs patients pay are
rising dramatically as well.14,15 The cost of multiple sclerosis drugs is often quoted
as an example of the drug pricing problem. Between 2004 and 2016, the monthly
mean out-of-pocket cost for a multiple sclerosis drug increased almost 2000%,
from $15 to $309.14
The bulk of spending on prescription drugs in the United States is on
brand-name drugs, those without a generic alternative. Only 10% of
prescriptions filled are for brand-name drugs, yet they account for 78% of the
total cost of prescription medications.16 The market exclusivity afforded to
brand-name manufacturers, which translates into more profits for the
drugmaker and pharmacy benefit manager and higher prices for consumers, is
protected in the United States.8 Most brand-name drugs are protected from
generic competitors for 5 to 7 years after receiving approval from the US Food
and Drug Administration (FDA), although a drug’s intellectual property patent
can extend this protection even longer.17,18
When the period of exclusivity expires, generic drugs rapidly enter the market
and drug prices fall, at least in theory. However, brand-name manufacturers
frequently work out deals with generic manufacturers in exchange for their delay
in bringing a generic drug to market, a dubious process known as pay-for-delay.19
Another method for brand-name manufacturers to artificially extend their
monopoly is a process known as evergreening; the pharmaceutical company might
apply for a patent extension by making perfunctory changes to the drug that,
although meeting the threshold for new intellectual property, do not change the
effect of the drug.20 These “innovative” pricing practices are accompanied by
little to no actual biopharmaceutical innovation. Fortunately, when market
competition is allowed to take place, the benefits are clear: when just two

RISING DRUG COSTS FOR NEUROLOGIC DISEASES
competing generic drugs enter a market, the average relative price for the drug
falls to 52% of the brand-name price.21
THE EXTRAORDINARY COSTS OF ORPHAN DRUGS

Another reason neurologic drugs (and, in particular, drugs for neuromuscular
disorders) are so expensive is because many of them treat rare diseases and, thus, are
approved by the FDA under an orphan drug designation (PRACTICE TABLE 122–31).
The Orphan Drug Act of 1983 incentivizes drug development for diseases
affecting fewer than 200,000 patients in the United States.32 It provides
drug manufacturers with 7 years of market exclusivity, tax credits, and access to
grants and accelerated approval pathways.33 The 7-year market exclusivity
period differs from traditional patent law in that it does not begin until the drug
is granted FDA approval. The Orphan Drug Act has successfully incentivized
companies to develop treatments for patients with rare diseases, resulting in
many new innovative and effective drugs that likely would not otherwise exist.
This success has come at a price, in large part because companies continue to test
the boundaries of what price will be tolerated for a drug with orphan drug status.
Between 1998 and 2017, the average cost per year for an orphan drug increased
from $7136 to $186,758, an increase of over 2500%. On average, orphan drugs are
5 times more expensive per patient than non–orphan drugs.34
How to pay for all of these drugs, including those destined to soon enough
emerge from the drug development pipeline, is a huge challenge because rare
PRACTICE TABLE 1 Cost of Orphan Drugs for Peripheral Nervous System Disordersa
Drug Disorder Average US List Price
Edaravone Amyotrophic lateral sclerosis $145,524/year23
Riluzole Amyotrophic lateral sclerosis $1800–$8400/year24
Immunoglobulin Chronic inflammatory demyelinating $47,854/year25

polyradiculoneuropathy (CIDP)
Deflazacort Duchenne muscular dystrophy $81,400/year26
Eteplirsen Duchenne muscular dystrophy $1,002,000/year26
Dichlorphenamide Hypokalemic/hyperkalemic periodic paralyses $109,500/year27
3,4-Diaminopyridine (3,4 DAP) Lambert-Eaton myasthenic syndrome $375,000/year28
Eculizumab Myasthenia gravis, acetylcholine receptor antibody positive $678,000/year29
Nusinersen Spinal muscular atrophy $750,000 for the first year;

$375,000/year thereafter30
Onasemnogene Spinal muscular atrophy Onetime infusion $2,125,00030

abeparvovec-xioi
Patisiran Hereditary transthyretin amyloidosis $345,000/year31
Inotersen Hereditary transthyretin amyloidosis $300,000/year31
a
Data from the National Institutes of Health Genetic and Rare Diseases Information Center.22
1394 OCTOBER 2020

diseases are cumulatively common; approximately 7000 have been identified. In
the United States, a disease is defined as rare when it affects fewer than 200,000
Americans. Using this definition, 25 million to 30 million Americans have a rare
disease. In 2017, total spending on orphan drugs in the United States was $43
billion (a $16 billion increase in spending compared to 2013) (PRACTICE FIGURE 1).35
It is reasonable to predict that without a significant course correction that
prohibits or curbs ever-increasing pricing, the overall cost will eventually reach
unsustainable numbers.
The privilege of establishing a drug’s price may be abused in many ways. One
way is to simply charge much more for the drug than its value. This practice
occurs with both newly approved drugs and approved or off-label drugs already
on the market. Determining the value of newly approved orphan drugs is
complex and is discussed later in this article. When a drug is priced significantly
higher than its estimated value, its price is not justified and the financial burden
it places on our society is unnecessary. Some businesses charge remarkably high
prices for existing, once-inexpensive generic drugs after conducting clinical trials
and obtaining FDA approval. By seeking FDA approval for an existing,
inexpensive, effective, yet-unapproved drug, the company can receive 7 years of
exclusivity through the Orphan Drug Act. Because no regulatory authority is
engaged in drug pricing decisions, the company can charge whatever high price
it likes until the exclusivity and patent protection period ends and generic
competition allows patients to get back essentially the same drug they had
previously been taking at a much lower price. One example is a new
reformulation of 3,4-diaminopyridine (3, 4-DAP) that was recently approved for
Lambert-Eaton myasthenic syndrome (LEMS) at an annual list price of $375,000.28
Other companies might repackage an existing and inexpensive drug that is
under approval for another condition so they can get 7 years of exclusivity for the
new indication and charge an unjustifiable price for the old drug with a new
PRACTICE FIGURE 1
Spending on orphan drugs in the United States.
Reprinted with permission from IQVIA Institute for Human Data Science.35 © 2018 IQVIA Inc.

indication. In a 2015 Senate Special Committee on Aging hearing on drug prices,

Senator Susan Collins (R, Maine) said, “For many decades, federal policy has
sought to strike the right balance between maintaining the incentives needed to
promote innovation and the development of new drugs and keeping medicines
affordable. That balance we have struck never anticipated companies acquiring
off-patent drugs and then jacking up their prices to enormous heights, and doing
so, as one executive essentially put it, ‘because I can.’”36
Orphan drug status, with its attendant higher prices, can also be achieved
through the creation of a Trojan application, sometimes with an assist from
salami slicing. A Trojan application is one seeking FDA approval for a single rare
disease, knowing full well that the drug will also be used for other off-label
indications if it is approved. Rituximab is one example of this practice. Although
it was initially approved for follicular B-cell lymphoma, it is now used to treat
dozens of conditions, including several immune-mediated neuromuscular
disorders. As the name implies, salami slicing refers to the act of “cutting up” a
bigger common disease (ie, one affecting more than 200,000 Americans) into
smaller rare diseases (ie, ones affecting less than 200,000 Americans) for the
purpose of an orphan drug approval. This allows the drug to gain the benefits of
orphan drug designation (eg, exclusivity, tax breaks, and accelerated approval)
and the benefits of the market when it is used for other subforms or variants of
the more common condition. Thus, a salami-sliced disease can be used for a
Trojan application. Seven of the top 10 best-selling drugs in the United States in
2014 came on the market with an orphan designation, illustrating both that the
Orphan Drug Act is no longer being used solely to incentivize the industry to
develop drugs for conditions with poor economic potential and the remarkable
revenue-generating potential of these questionable maneuvers.37
Some of the newest and most expensive drugs in neurology—including
near-miraculous treatments for children with spinal muscular atrophy (SMA)—
are included in this class of orphan drugs. For example, nusinersen, an antisense
oligonucleotide, was approved in 2016 and has an initial cost of $750,000,
followed by $375,000 each year thereafter. This was followed in 2019 by
onasemnogene abeparvovec-xioi, a onetime adenovirus-delivered gene therapy
for SMA with a price tag of $2,125,000.30 Unlike Trojan applications or salami
slicing, these drugs represent a substantial innovative advance in therapeutics.
However, it is important that all drugs, particularly those with such a high price
tag, be carefully evaluated for the value they provide (ie, the benefits relative to
the cost of therapy).
DISTRIBUTIVE JUSTICE AND OPPORTUNITY COST

Practicing neurology is challenging, but the bioethics of what we do every
day are most often straightforward. We usually practice with ease three
principles of bioethics: beneficence (do good), patient autonomy (the patient
has decision-making autonomy, within reason), and nonmaleficence (cause
no harm, or the least harm possible, with our actions). The fourth pillar of
bioethics, distributive justice (the fair distribution of limited resources), has
played a less prominent role in clinical decision making. However, rising
health care costs, including a dramatic rise in drug costs, has been damaging
to many individuals, our system, and society. Because of the financially
toxic costs of some drugs, physicians and the public they serve must now
incorporate the notion of distributive justice and the related economic concept
1396 OCTOBER 2020

of opportunity cost (what benefit is lost by choosing to spend on one thing
instead of another) into their clinical decision making.
CASE
A 58-year-old man with amyotrophic lateral sclerosis presented to a
multidisciplinary clinic wondering if he should start edaravone and
dextromethorphan/quinidine sulfate, two drugs he and his family had
recently read about on the internet. Since his diagnosis 3 months earlier, he
had been taking and tolerating riluzole, but he had begun to experience
symptoms of mild pseudobulbar affect, which he found embarrassing. The
treating neurologist, patient, and family discussed the efficacy, safety,
tolerability, convenience, and cost of edaravone and dextromethorphan/
quinidine sulfate.
DISCUSSION
The patient in this case is an amalgam of many patients the authors care for in
their amyotrophic lateral sclerosis clinic. The two drugs were chosen for
discussion because they are both very expensive but arguably of only modest
benefit. Whether or not to recommend either drug lacks a straightforward
answer and illustrates the tensions between considerations of efficacy and cost.
Edaravone has been shown to provide slight slowing of disease progression in a
narrow subset of patients, albeit unnoticed by the individual patient, at a cost of
approximately $150,000 annually in the United States. The other drug is a
combination formulation of two previously inexpensive drugs,
dextromethorphan (an already-existing over-the-counter cough medicine) and
quinidine (an inexpensive generic antiarrhythmic agent). Despite its humble
beginnings, the combination formulation of dextromethorphan/quinidine
sulfate was priced at approximately $15,000 annually following its FDA approval
a decade ago. Furthermore, off-label less expensive alternatives exist for
pseudobulbar affect (eg, generic antidepressants).
The discussion around and decision making involved in adding these two
drugs to a patient’s regimen are complex and best done thoughtfully and in
a trusting relationship. Any tactful discussion on the merits of prescribing
edaravone, in particular, should probably not occur at the time of diagnosis, a
time when patients and families should not be discussing societal concerns or the
details of the limited value of an extremely expensive drug. When the time is
right, these treatment decisions should follow an honest and open discussion of
efficacy, safety, tolerability, convenience, and cost. When patients and family
are fully informed by a trusted ally (the treating neurologist), it has been our
experience that most ultimately decline the disease-modifying edaravone and,
for symptoms of pseudobulbar affect, first try an inexpensive off-label
alternative to dextromethorphan/quinidine sulfate. When asked why they made
the decisions they did, the authors’ personal experience has been that most
patients point out the drugs’ limited values and significant expense to society.
Extreme drug pricing has created a moral dilemma for physicians who also
view this problem at a health care system and societal level. Although it would be
wonderful, we simply do not have unlimited resources to spend on drugs. What
value for a drug—its quality or benefit per cost—will we accept? As the clinicians

recommending and prescribing these high-priced medications, it is our

responsibility to ensure our patients understand the drug’s value and its potential
to induce financial toxicity, to both the individual patient and our society. This is
no different than our responsibility to educate our patients about a drug’s
efficacy, safety, tolerability, and convenience.
In most other countries, opportunity cost is factored into policy-level decision
making, usually by governmentally funded health technology assessment
entities, such as the United Kingdom’s National Institute for Health and Care
Excellence(NICE). However, in the United States, opportunity cost has been a
lower priority. To illustrate opportunity cost, consider how society might spend
$1.5 million for health care. This amount is the total annual operating budget for
the free clinic in Charlottesville, Virginia, which provides clinic visits, drugs, and
diagnostic tests, including imaging, for 3500 working poor residents (Mohan
Nadkarni, MD, cofounder and board member of the Charlottesville Free Clinic,
email, June 8, 2020). This same amount is also what it now costs to treat four
adults with LEMS each year with a recently FDA-approved version of 3,4-DAP,
a drug that was once available in a slightly different formulation from another
pharmaceutical manufacturer free of charge. (The original drug is now available
with an FDA indication for pediatric LEMS.1,38) The wildly different value
provided to society in return for the $1.5 million is created by the generosity of
those involved in the free clinic combined with the extraordinarily high price of
the new formulation, which is based on a drug that had been remarkably
inexpensive and available for more than 3 decades before the new formulation’s
2018 FDA approval. As taxpayers and others experience rising costs and financial
toxicities, clinicians must become more literate in the concept of opportunity
cost. Clinicians must be able to identify drugs that are priced unfairly and create
otherwise avoidable opportunity cost injustices. By doing so, clinicians can help
achieve a more just distribution of the health care dollar and mitigate the damage
caused by unjustifiably high drug prices.
FINANCIAL TOXICITY
The term financial toxicity was initially used to describe the adverse impact of
extremely expensive cancer therapeutics on a patient resulting from direct or
indirect costs.39 In the same way that a pharmacologic side effect profile may
influence the selection of a drug for a specific patient with specific comorbidities,
a drug’s risk of financial toxicity may similarly influence the decision of whether
to prescribe it or not. And, in the same way that traditional toxicity of a drug may
result in lifelong health effects, so too can the financial toxicity of a drug produce
lifelong consequences. Many are left to face difficult decisions about what their
medicine is worth to them. Nearly 15% of poor Americans report splitting pills or
skipping doses altogether to avoid the effects of financial toxicity.40 Nearly one in
three Medicare beneficiaries report taking fewer doses of medicine than
prescribed as a way to reduce costs.41 Other consequences include negative
mental health from personal financial stress, job immobility, predatory lending,
bankruptcy, more visits to the emergency department, higher rates of
hospitalization, and even higher death rates.41 Patient access to expensive drugs
is threatened by their high costs. Clinicians need to know that most patients are
not comfortable broaching the subject of financial hardships related to their
medical care; thus, patients should be asked during their clinic visits to discuss
these harmful consequences.
1398 OCTOBER 2020

Over the past decade, the pharmaceutical industry has devised ways to spread
the financial toxicity of drug costs—especially orphan drugs—to society rather
than to any individual patient, thereby lessening the likelihood of any bad press
from egregious examples of an individual’s financial ruin or lack of access. One
increasingly common way to do this is through patient or prescription assistance
programs. Not-for-profit organizations often donate to these programs while
simultaneously accepting the bulk of their funding from pharmaceutical
companies with a vested interest in that same market of patients. In 2017 to 2019,
eight pharmaceutical companies collectively paid over $840 million to settle
allegations that they paid kickbacks to patients through charitable foundations.42
Ultimately, by dispersing extravagant drug costs (including out-of-pocket costs)
to all of society, we all experience the effects of financial toxicity, albeit in less
noticeable ways such as higher taxes, premiums, deficits, and debt.
Consequently, clinicians must recognize that financial toxicity impacts both
individual patients requiring expensive treatment and our health care system and
society. Knowing what your patient pays out-of-pocket is no longer enough.
Clinicians must also know the list price of the drugs they prescribe, because these
costs, when unjustifiably high, are unnecessarily toxic to all of us, especially those
living paycheck to paycheck.
A NEW WAY TO THINK ABOUT VALUE

Playwright George Bernard Shaw once said, “A government that robs Peter to
pay Paul can always depend on the support of Paul.” Countless legislative
proposals have been discussed in recent years to address the rising costs of drugs,
including capping the annual increase in drug prices to the rate of inflation,
indexing the price of drugs to international prices, or modifying/eliminating
rebate programs. Yet the pharmaceutical industry remains the top lobbying force
in Washington, spending more than $100 million annually to support
drugmakers, drug wholesalers, pharmacy benefit managers, and other
stakeholders, creating headwinds against reform.43
There is a growing consensus that any successful solution will depend on
estimating and agreeing on the actual value of a drug.44–47 The Institute for
Clinical and Economic Review (ICER) is an independent and nonpartisan
research organization and a leader in evaluating the clinical and economic
value of prescription drugs in the United States.48 ICER conducts rigorous
analyses of available clinical data and publicly convenes key stakeholders,
including patients, clinicians, companies, private insurers, and the
government, to translate evidence into policy recommendations that lead to a
more just and efficient health care system. ICER’s drug assessment reports
establish a value-based price benchmark, estimating how each drug should be
priced to appropriately reflect long-term improved patient outcomes. Reports
also evaluate the potential short-term budget impact of new drugs to alert
stakeholders to situations in which short-term costs may strain health system
budgets and lead to patient access restrictions.49 It is important to distinguish
true value based assessments from pricing models that are value based in
name only. For example, some drugmakers offer outcome-based contracts
to payers in which an amount of money is returned if a certain clinical
outcome is not achieved. Such payment models may have the appearance of
providing value but, in fact, allow the manufacturer to overprice the drug
from the outset.50

One of the ways ICER provides information about a drug’s value (defined as
benefit per cost) is through cost-effectiveness analysis. To determine the
incremental benefit provided by a drug, ICER uses the quality-adjusted life year
(QALY) as the standard of measurement, which accounts for both quality and
quantity of life.49 One QALY represents one additional year of life with perfect
health, whereas an additional year of life with only 50% health represents 0.5
QALY. To compare cost-effectiveness from drug to drug, a cost threshold per
QALY gained is specified as the benchmark. ICER uses a cost-effectiveness
threshold of $100,000 to $150,000 per QALY. For example, a drug that costs $1
million and provides 10 QALYs meets this cost-effectiveness threshold and is a
high-value drug, its high price notwithstanding. For (presymptomatic) SMA,
ICER recently determined a value-based price benchmark for onasemnogene
abeparvovec-xioi would range from $1.2 million to $2.1 million.51 As debate exists
regarding the appropriate benchmark-specific cost-effectiveness threshold,
ICER provides a list of threshold prices depending on the benchmark chosen
(PRACTICE TABLE 2). Admittedly, certain information may be difficult to capture
in a simple QALY cost-effectiveness analysis; for example, a drug’s benefit may
yield significant societal benefit that is not reflected in any one individual’s
quantity or quality of life (ICER also incorporates these and other variables in its
reports). Nevertheless, by referencing each drug’s price to the QALY gained, a
drug’s value becomes more salient.
On the September 23, 2019, Neurology Podcast, A. Gordon Smith, MD, FAAN,
and Steven D. Pearson, MD, MSc, the founder and president of ICER, discussed
the influence of ICER and clinicians on drug companies when establishing
prices for expensive drugs.52 For example, before announcing the price of
onasemnogene abeparvovec-xioi for SMA, the manufacturer discussed publicly
the potential for a list price in the range of $4 million to $5 million. Meanwhile,
ICER reported a value-based price benchmark for onasemnogene
abeparvovec-xioi in the range of $1.2 million to $2.1 million. The manufacturer
PRACTICE TABLE 2 Threshold Prices for Onasemnogene Abeparvovec-xioi in Type 1 Spinal

Muscular Atrophya,b
Per Quality-Adjusted
Life Year Per Life Year Gained
Threshold Price at $50,000 NA NA
Threshold Price at $100,000 $310,000 $710,000
Threshold Price at $150,000 $899,000 $1,498,000
Threshold Price at $200,000 $1,488,000 $2,287,000
a
Reprinted with permission from Institute for Clinical and Economic Review (ICER).51 © 2019 Institute for
Clinical and Economic Review.
b
Threshold prices are based on a onetime cost per onasemnogene abeparvovec-xioi.
1400 OCTOBER 2020

later announced a list price of $2.1 million. When asked about the influence of
ICER’s report, Dr Pearson said:
I think it did influence their thinking. It certainly was in the first sentence
of the justification for the price that the CEO put out with the launch.
Now, I’m not suggesting that that happens all the time, but I do think
again that it’s an important part of the landscape. Clinical experts
equally have a tremendously important role to play, because I do know
that in the spreadsheets that they look at behind closed doors at the
manufacturers, one of the biggest columns is “clinical expert pushback”
and if they think that clinical experts are going to blanch at the price or
react negatively, that factors into their thinking too.52
The decision of how to set a fair price for a drug is further complicated by the
discrepancy between the private individual benefit of a drug and its societal
benefit. In economics, this discrepancy is referred to as an externality—a benefit
(or harm) that is not accounted for in the cost of the individual good. Bees are a
classic example of a positive externality.53 To the beekeeper, bees are only as
valuable as the honey they produce. However, this narrow perspective ignores
the value bees provide to surrounding farms by pollinating nearby crops. The
societal benefit, or value, provided by the bees is thus much greater than the sum
of the value of their honey. With this concept in mind, consider patisiran, a drug
approved in 2018 for the treatment of hereditary transthyretin amyloidosis.
Hereditary transthyretin amyloidosis is a progressive hereditary disease caused
by misfolding of the transthyretin protein, resulting in deposition in peripheral
nerves, the heart, and other organs, eventually causing death. When patisiran
was approved in 2018 for treatment of hereditary transthyretin amyloidosis, it
was the first disease-specific treatment for patients with this condition as well as
the first FDA-approved drug in a new class of drugs that work through RNA
interference.54 RNA-interference drugs such as patisiran can control gene
expression by inducing cleavage of target messenger RNA, thus inhibiting the
production of a specific protein.55 In clinical trials, patients treated with patisiran
experienced functional improvement (ability to walk), improvement in neuropathy
symptoms, and better quality of life than patients treated with placebo.31 At
$345,000 per year, the price set for patisiran by its manufacturer, ICER’s long-term
cost-effectiveness analysis concluded a cost of $850,000 per QALY gained.31 Clearly,
this far exceeds the benchmark threshold price used by ICER of $100,000 to
$150,000 per QALY gained. Thus, for patisiran to reach this benchmark would
require either significant gains in QALYs or a significant reduction in cost. As can
be seen in PRACTICE FIGURE 2, the probability that patisiran is cost-effective at
the manufacturer’s price is essentially zero, from a societal perspective, until one
QALY gained is considered to be worth at least $500,000 per year.31
But does patisiran only provide value for those patients with hereditary
transthyretin amyloidosis treated with the drug? Or is it possible that the
advances of this remarkable new class of gene-silencing drugs will benefit other
patients with different disorders amenable to RNA-interference therapy?
Returning to the previous analogy, bees are more valuable than the honey they
produce. And so, once we recognize that the societal benefit of patisiran is greater
than the sum of its benefits to individual patients, how do we reward this
external value? If producers are not rewarded for the benefit their good provides

PRACTICE FIGURE 2
Cost-effectiveness acceptability curve for patisiran versus best supportive care from the
modified societal perspective.
QALY = quality-adjusted life year.
Reprinted with permission from Institute for Clinical and Economic Review (ICER).31 © 2018 Institute for Clinical and
Economic Review.
to society (ie, the positive externality), they will underproduce the good.
Economists would tell us that to encourage the production of a good that
provides a positive externality, we should subsidize its production,
rewarding the producer for the benefit the good provides society. In
other words, the “fair” price for a drug—fair to the investors and
researchers for their scientific contributions that will benefit manifold
patients with other diseases—may be greater than the value that the drug
provides for its intended patients. Determining when a drug produces a
positive externality and the societal value of such an externality is challenging
but necessary. One sure way to stifle the development of new treatments for
our patients is to undervalue truly innovative drugs and the decades of
research that stand behind them.
CONCLUSION
Much of the focus of this article has been on the ultra-high-priced drugs and
potential cures for a broken system. But what about today, with drug prices being
what they are? How do we translate drug pricing literacy into good decision
making, first and foremost for our patients and, secondarily, for the health of
society? Even with a thorough understanding of a drug’s value, many
patient-specific variables make it extremely challenging to know if any given
drug is the best value for the patient sitting on the examination table. Treatment
decision making has never been more difficult. Advocating for our patients has
also never been more challenging. Nevertheless, the authors of this article
suggest a few steps we can take:
1 Know and discuss the cost of the treatments in our armamentarium, including for
orphan drugs. Learn the wholesale acquisition cost (list price) of the drug and share this
information with the patient. Whereas the net price is the actual price paid and is
1402 OCTOBER 2020

often less because of rebates and discounts, it is much more difficult to find the net
price than the list price, and these numbers may not differ that greatly (eg, net price might
be 10% to 20% less than list price).
2 Warn patients that drugs may cause financial toxicity and encourage patients to share
any difficulty they might encounter with filling any prescription. This goes for all drugs
prescribed, not just any orphan drug or other expensive drug. Ask about financial toxicity
at every clinic visit. Find out what patients pay in copays and deductibles. Ask patients
how they deal with these financial challenges (eg, do they sometime leave prescriptions
unfilled or split the dose?). Point out that there might be less burdensome treatment
alternatives or less expensive pharmacies. Get help from a social worker or pharmacist.
Patients have a lot to teach clinicians.
3 Within reason, know any value analyses of an expensive drug. Nonprofit organizations
such as ICER exist to help providers understand the value of drugs.56,57 Consider
an overpriced drug as one with a price that greatly exceeds the drug’s value. This can
be determined by reading ICER reports or learning the history of the drug’s price. For
example, many old drugs have experienced price hikes over the past decade
without the support of new clinical evidence; these are overpriced drugs.
4 Distinguish overpriced drugs (price that far exceeds estimated value) from drugs with
high—but fair—prices. When appropriate, discuss drug value with individual patients,
such as when a patient expresses interest in the societal impact of drug costs (distributive
justice and opportunity cost) or when a patient is at risk for suffering from high out-of-
pocket costs. Focus on advocating for fixes for the overpriced drugs rather than all
expensive drugs.
5 Advocate for fair drug prices. Concerns may be expressed in many ways (eg, editorials,
letters to the editor, letters to elected representatives in Congress, lectures, and other
teaching sessions). Express displeasure with drugs that are overpriced. The American
Academy of Neurology (AAN) recognizes the importance of the drug pricing issue; in 2018,
the AAN’s Neurology Drug Pricing Task Force produced a report outlining specific
recommendations.58 The AAN and other subspecialty organizations frequently offer
advocacy opportunities for clinicians to meet with lawmakers and advocate for their
patients (Neurology on the Hill and the Palatucci Advocacy Leadership Forum are good
examples). Support organizations that advocate for fair drug prices, such as the AAN
and ICER.
Given the rising cost of drugs, financial toxicity is increasingly common and
underreported. Our patients deserve to pay (and the pharmaceutical industry
deserves to receive) a fair price for their medications—a price that reflects the
benefit these medications provide to patients and society. It is our responsibility to
learn and help our patients know the value of the drugs we prescribe.
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conditions. Institute for Clinical and Economic
46 Robinson JC, Howell S, Pearson SD. Value-based
Review. icer-review.org/wp-content/uploads/
pricing and patient access for specialty drugs.
2017/02/ICER_Assessing-the-Value-of-Drugs-
JAMA 2018;319(21):2169–2170. doi:10.1001/
for-Rare-Conditions_051017.pdf. Published May
jama.2018.5367.
47 Naci H, Kesselheim AS. Specialty drugs—a
35 IQVIA Institute for Human Data Science. Orphan
distinctly American phenomenon. N Engl J Med
Drugs in the United States: Growth Trends in Rare
2020;382(23):2179–2181. doi:10.1056/NEJMp1909513.
Disease Treatments. iqvia.com/-/media/iqvia/
pdfs/institute-reports/orphan-drugs-in-the- 48 Institute for Clinical and Economic Review.
united-states-growth-trends-in-rare-disease- icer-review.org/about/. Accessed July 29, 2020.
treatments.pdf?_=1575565762648. Published
October 2018. Accessed June 8, 2020.
Overview of the ICER value assessment
36 United States Senate. Senate aging committee framework and update for 2017–2019. icer-
holds 1st hearing on off-patent Rx drug price review.org/wp-content/uploads/2018/03/ICER-
spikes. www.aging.senate.gov/press-releases/ value-assessment-framework-update-FINAL-
senate-aging-committee-holds-1st-hearing-on- 062217.pdf. Accessed July 29, 2020.
off-patent-rx-drug-price-spikes-. Published
50 Kaltenboeck A, Calsyn M, Frederix GWJ, et al.
December 9, 2015. Accessed July 29, 2020.
Grounding value-based drug pricing in
37 Daniel MG, Pawlik TM, Nickles Fader AN, et al. population health. Clin Pharmacol Ther 2020.
The Orphan Drug Act: restoring the mission to doi:10.1002/cpt.1741.
rare diseases. Am J Clin Oncol 2016;39(2):210–213.
doi:10.1097/COC.0000000000000251.
Spinraza and Zolgensma for spinal muscular
38 Burns TM, Smith GA, Allen JA, et al. Editorial by atrophy: effectiveness and value. icer-review.
concerned physicians: unintended effect of the org/wp-content/uploads/2018/07/ICER_SMA_
orphan drug act on the potential cost of 3,4- Final_Evidence_Report_052419.pdf. Published
diaminopyridine. Muscle Nerve 2016;53(2): April 3, 2019. Updated May 24, 2019. Accessed
165–168. doi:10.1002/mus.25009. July 29, 2020.

52 American Academy of Neurology. Neurology 55 Coelho T, Adams D, Silva A, et al. Safety and
podcast. Update on drug pricing with Gordon efficacy of RNAi therapy for transthyretin
Smith. September 23, 2019. neurology.aan. amyloidosis. N Engl J Med 2013;369(9):819–829.
libsynpro.com/website/ms-and-vaccine- doi:10.1056/NEJMoa1208760.
practice-guideline. Released September 23,
56 Freund D, Choi J. Is ICER NICEr?
Pharmacoeconomics 2018;36(4):385–386.
53 Meade JE. External economies and doi:10.1007/s40273-018-0617-6.
diseconomies in a competitive situation.
57 Roland D. Obscure model puts a price on good
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health—and drives down drug costs. The Wall
doi:10.2307/2227173.
Street Journal. wsj.com/articles/obscure-
54 US Food and Drug Administration. FDA approves model-puts-a-price-on-good-healthand-drives-
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press-announcements/fda-approves-first-its-
58 American Academy of Neurology. AAN task force
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tackles high neurology drug pricing. aan.com/
disease. Published August 10, 2018. Accessed
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2018/. Published November 2018. Accessed
July 29, 2020.
1406 OCTOBER 2020

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Postreading
SELF-ASSESSMENT
AND CME
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and CME Test
By Douglas J. Gelb, MD, PhD, FAAN; D. Joanne Lynn, MD, FAAN
PERIPHERAL NERVE AND MOTOR NEURON DISORDERS

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Canadian participants can claim a maximum of 20 hours per issue (credits
are automatically calculated).

POSTREADING TEST
ARTICLE 1: A STRUCTURED APPROACH TO THE DIAGNOSIS OF PERIPHERAL

NERVOUS SYSTEM DISORDERS
1 A lesion of which of the following peripheral nerves would be most

likely to result in a pure sensory syndrome with no motor
manifestations?
A common fibular (peroneal)

B deep fibular (peroneal)
C obturator
D saphenous
E superficial fibular (peroneal)
2 In a patient with monomelic amyotrophy (Hirayama disease), which

of the following muscles is likely to be strongest?
A abductor digiti minimi

B brachioradialis
C extensor digitorum
D first dorsal interosseous
E flexor pollicis longus
3 A mononeuropathy of which of the following nerves would be

expected to cause a pure motor syndrome?
A axillary
B obturator
C posterior interosseous
D tibial
E ulnar
4 Which of the following neuropathic conditions presents with a

proximal and distal asymmetric pattern of involvement?
A acute inflammatory demyelinating polyradiculoneuropathy (AIDP)

B brachial amyotrophic diplegia
C Charcot-Marie-Tooth disease
D chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
E vasculitic neuropathy
1410 OCTOBER 2020

ARTICLE 2: DIABETES AND METABOLIC DISORDERS AND THE PERIPHERAL
NERVOUS SYSTEM
5 Which type of peripheral neuropathy is most common in patients with

diabetes?
A acute diabetic radiculoplexopathy

B autonomic neuropathy
C length-dependent axonal polyneuropathy
D mononeuropathy
E treatment-induced neuropathy of diabetes
6 What risk factor for neuropathy is most important to control in

type 1 diabetes?
A abdominal obesity
B hyperglycemia
C hypertension
D hypertriglyceridemia
E low high-density lipoprotein levels
7 A 62-year-old man with type 2 diabetes develops the acute onset of

burning pain in his right hip and low back that spreads to involve the
whole leg and then to the left hip and leg. Over several weeks, he also
develops significant proximal weakness to the point that he ambulates
with a cane. This is associated with a 13.6-kg (30-lb) weight loss. EMG
shows involvement of lumbosacral roots, plexus, and nerves. What is
the most likely pathophysiology of this neuropathy?
A abnormal sphingolipid metabolism

B inflammation secondary to dyslipidemia
C microvasculitis
D mitochondrial dysfunction
E oxidative stress
8 Which of the following autonomic neuropathic complications of

diabetes is associated with the highest mortality?
A bladder dysfunction
B gastroparesis
C gustatory sweating
D obstipation
E orthostatic hypotension

POSTREADING TEST
ARTICLE 3: GUILLAIN-BARRÉ SYNDROME
9 In a patient for whom the diagnosis of acute inflammatory

demyelinating polyradiculoneuropathy (AIDP) is being considered
because of progressive sensory and motor symptoms over several
days, which of the following features would most likely suggest an
alternate diagnosis?
A back pain at onset of symptoms

B bilateral facial weakness
C lightheadedness when standing from a seated position
D onset of weakness in proximal muscles
E severe urinary sphincter dysfunction at onset of symptoms
10 One week after hospitalization for Guillain-Barré syndrome, which of

the following parameters has the most value in predicting the
probability that a patient will be able to walk independently in
6 months?
A CSF protein level

B deep fibular (peroneal) distal motor latency
C oxygen saturation level
D serum antiganglioside antibody titer
E severity of weakness
11 A 58-year-old man began having trouble walking 2 days ago, and it has
progressed to the point where he cannot ambulate unassisted. He has
also started to experience diplopia. On examination, he can only
abduct each eye 20 degrees, and he is unable to move his left eye up or
down. He has diffuse truncal and appendicular ataxia, and he is
areflexic. Antibodies to which of the following gangliosides are likely
to be present in his serum?
A Ga1NAc-GD1a
B GD1a
C GM1
D GM1b
E GQ1b
1412 OCTOBER 2020

ARTICLE 4: CHRONIC INFLAMMATORY DEMYELINATING
POLYRADICULONEUROPATHY AND ITS VARIANTS
12 A unique finding of both acute and chronic demyelinating

polyneuropathies is predominant involvement of the upper extremity
sensory nerves with relative sparing of which of the following nerves?
A axillary
B lateral plantar
C saphenous
D sural
E ulnar
13 A 58-year-old man presents with progressive painless weakness in a

distal greater than proximal pattern. Electrophysiologic studies
demonstrate an asymmetric multifocal process. CSF analysis
demonstrating elevated protein and a pleocytosis should raise concern
for which of the following?
A amyotrophic lateral sclerosis

B chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
C infectious or neoplastic polyradiculitis
D multifocal acquired demyelinating sensory and motor neuropathy
(MADSAM)
E multifocal motor neuropathy (MMN)
14 A 50-year-old man develops progressive generalized weakness and

distal-predominant sensory loss of subacute onset consistent with
chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP). Clinical features include tremor and sensory ataxia. His
electrophysiologic studies demonstrate prolonged and absent F
waves, multiple areas of partial motor conduction block, and a sural
sparing pattern. Blood work for monoclonal gammopathy and
anti–myelin associated glycoprotein (MAG) antibodies are negative.
He has not responded to IV immunoglobulin (IVIg), corticosteroids,
or plasma exchange. What additional tests should be obtained?
A anti–tissue transglutaminase antibodies

B endomysial antibodies
C ganglioside GD1b antibody
D ganglioside GM1 antibody
E nodal and paranodal antibodies

POSTREADING TEST
15 Which of the following differentiates multifocal motor neuropathy

(MMN) from amyotrophic lateral sclerosis?
A asymmetric weakness
B conduction block
C cramps
D fasciculations
E lack of pain
ARTICLE 5: CHARCOT-MARIE-TOOTH DISEASE AND OTHER HEREDITARY

NEUROPATHIES
16 Which of the following features would be the most compelling

evidence that a patient with peripheral polyneuropathy has an
acquired demyelinating neuropathy rather than a hereditary
demyelinating neuropathy?
A absence of affected family members

B absent ankle reflexes
C ankle plantar flexion weakness
D patchy slowing and abnormal temporal dispersion on nerve
conduction studies
E ulnar motor conduction velocity less than 38 m/s
17 Charcot-Marie-Tooth disease is most often caused by mutations in the

gene for which of the following proteins?
A connexin 32
B mitofusin 2
C myelin protein zero
D peripheral myelin protein 22
E voltage-gated sodium channel Nav1.7
18 Deletions in the gene responsible for Charcot-Marie-Tooth disease

type 1A can cause which of the following hereditary conditions?
A abetalipoproteinemia
B familial erythromelalgia
C hereditary brachial plexus neuropathy
D hereditary neuropathy with liability to pressure palsies (HNPP)
E phytanic acid deficiency
1414 OCTOBER 2020

19 A US Food and Drug Administration (FDA)–approved antisense
oligonucleotide is available for which of the following
hereditary conditions?
A cerebrotendinous xanthomatosis
B Fabry disease
C giant axonal neuropathy 1
D Tangier disease
E transthyretin amyloidosis
ARTICLE 6: PERIPHERAL NEUROPATHIES ASSOCIATED WITH VASCULITIS

AND AUTOIMMUNE CONNECTIVE TISSUE DISEASE
20 Which of the following disorders is classified as a medium vessel

vasculitis?
A eosinophilic granulomatosis with polyangiitis

B giant cell arteritis
C granulomatosis with polyangiitis
D microscopic polyangiitis
E polyarteritis nodosa
21 Which of the following disorders should be considered when a

patient’s serum is positive by immunoassay for both myeloperoxidase
and proteinase 3 antineutrophil cytoplasmic antibody autoantibodies?
A drug-induced vasculitis
B eosinophilic granulomatosis with polyangiitis
C essential mixed cryoglobulinemia
D microscopic polyangiitis
E vasculitis associated with rheumatoid arthritis
22 Which of the following characteristics in combination with other

findings support a diagnosis of polyarteritis nodosa?
A adult-onset asthma
B antineutrophil cytoplasmic antibody antibodies
C cryoglobulinemia
D glomerulopathy
E serum positive for hepatitis B virus antigen

POSTREADING TEST
23 A 64-year-old man presents with generalized weakness, palpable

purpura, diffuse joint pain, and peripheral neuropathy. The
neuropathy is distal and symmetric. Which of the following disorders
is most likely to present with this constellation of symptoms?
A cryoglobulinemic vasculitis
C giant cell arteritis
D granulomatosis with polyangiitis
E microscopic polyangiitis
24 A 29-year-old woman presents with a mononeuritis multiplex type

neuropathy that has progressed over 3 months. She has experienced
constitutional symptoms of weight loss, fatigue, and diffuse muscle
aches over this time. Approximately 6 months ago, she was diagnosed
with new-onset asthma. Myeloperoxidase antineutrophil
cytoplasmic antibody test is positive. Which of the following is the
most likely diagnosis?
A cryoglobulinemic vasculitis
C microscopic polyangiitis
D mixed connective tissue disease
E polyarteritis nodosa
ARTICLE 7: PERIPHERAL NEUROPATHIES DUE TO VITAMIN AND MINERAL

DEFICIENCIES, TOXINS, AND MEDICATIONS
25 Metformin can cause reduced absorption of which of the following

nutrients?
A copper
B vitamin B1 (thiamine)
C vitamin B6 (pyridoxine)
D vitamin B12 (cobalamin)
E vitamin E (α-tocopherol)
26 Excessive intake of which of the following nutrients can cause a

sensory ganglionopathy?
A copper
B vitamin B1 (thiamine)
C vitamin B6 (pyridoxine)
D vitamin B12 (cobalamin)
E vitamin E (α-tocopherol)
1416 OCTOBER 2020

27 A motor-predominant upper extremity phenotype is most common
with neuropathy due to which of the following toxins?
A arsenic
B cisplatin
C lead
D paclitaxel
E thallium
28 Cold-induced hyperalgesia can be a manifestation of toxicity from

which of the following medications?
A amiodarone
B bortezomib
C colchicine
D isoniazid
E oxaliplatin
29 A 58-year-old woman developed severe nausea, abdominal pain,

and diarrhea 4 hours after returning from a seafood restaurant. Two
days later, she began to notice that when she touched cold objects,
they felt unbearably hot. She most likely ingested which of the
following toxins?
A brevetoxin
B ciguatoxin
C saxitoxin
D scombrotoxin
E tetrodotoxin
ARTICLE 8: MANAGEMENT OF NEUROPATHIC PAIN IN POLYNEUROPATHY
30 Which of the following symptoms is suggestive of opioid-induced

hyperalgesia in the setting of increased pain despite treatment with
escalating opioid doses?
A acral paresthesia
B diffuse allodynia
C hyperhidrosis
D migratory erythema
E urticaria

POSTREADING TEST
31 A 45-year-old man with painful diabetic peripheral neuropathy

would like to try something to alleviate his pain but prefers a
nutraceutical option. Which of the following agents has the most
evidence of symptomatic benefit for painful diabetic neuropathy in
clinical studies?
A α-lipoic acid
B curcumin
C evening primrose
D ginkgo biloba
E omega-3 fatty acids
ARTICLE 9: AMYOTROPHIC LATERAL SCLEROSIS AND OTHER MOTOR

NEURON DISEASES
32 Patients with amyotrophic lateral sclerosis are most likely to develop

symptoms of which of the following disorders?
A behavioral variant frontotemporal dementia

B limbic-predominant age-related transactive response
DNA-binding protein 43 encephalopathy
C logopenic variant primary progressive aphasia
D progressive nonfluent aphasia
E semantic variant primary progressive aphasia
33 Mutations in which of the following genes are the most common cause
of familial amyotrophic lateral sclerosis?
A C9orf72
B FUS
C SOD1
D TARDBP
E VCP
34 A 56-year-old man with diffuse weakness and fasciculations,

prominent facial twitching, and gynecomastia should be tested for
mutations in the gene for which of the following?
A androgen receptor
B insulin like growth factor-1 (IGF1)
C progranulin
D survival of motor neuron 1, telomeric (SMN1)
E vascular endothelial growth factor (VEGF)
1418 OCTOBER 2020

ARTICLE 10: SPINAL MUSCULAR ATROPHY
35 The majority of individuals affected with spinal muscular atrophy

have which type?
A spinal muscular atrophy type 0

B spinal muscular atrophy type 1
C spinal muscular atrophy type 2
D spinal muscular atrophy type 3
E spinal muscular atrophy type 4
36 What is the therapeutic action for onasemnogene abeparvovec-xioi

for the treatment of spinal muscular atrophy?
A deletion of SMN2 exon 7

B enhancement of SMN protein production
C gene replacement of SMN1
D improved transcription of SMN1 gene
E promotion of muscle growth
37 What is the route of administration for nusinersen?
A inhalation
B intramuscular
C intrathecal
D intravenous
E oral
ARTICLE 11: PERIPHERAL NEUROPATHIES ASSOCIATED WITH

MONOCLONAL GAMMOPATHIES
38 A 59-year-old man has had progressively worsening balance

problems over the past year. He also reports numbness in his hands
and feet, clumsiness of his hands, and fluctuating double vision, all of
which have gradually progressed. His examination is notable for
marked limitation of eye movements in all directions, impaired
vibration and position sensation in all limbs with a distal-to-proximal
gradient, truncal and appendicular ataxia, and areflexia. Testing
reveals an IgM gammopathy. The antibodies are most likely to be
directed against which of the following?
A gangliosides with a disialosyl epitope

B N-methyl-D-aspartate (NMDA) receptors
C vascular endothelial growth factor (VEGF)
D voltage-gated calcium channels
E voltage-gated potassium channels

POSTREADING TEST
39 A 50-year-old woman began to experience numbness, tingling, and

weakness in her feet 3 months ago, and it rapidly progressed to the
point where she now has severe weakness in all limbs, bilateral
footdrop, and calf atrophy. Her examination is notable for skin
hyperpigmentation and hypertrichosis, hepatomegaly,
lymphadenopathy, diffuse weakness, distal sensory loss, and
areflexia. Electrodiagnostic studies are consistent with demyelinating
polyradiculoneuropathy. Serum protein electrophoresis reveals an
IgG lambda M protein. Which of the following blood tests is most
likely to be abnormal?
A angiotensin-converting enzyme
B antiphospholipid antibodies
C rheumatoid factor
D tissue transglutaminase antibodies
E vascular endothelial growth factor (VEGF)
40 Which of the following is the most common cause of polyneuropathy

in patients with multiple myeloma?
A autoantibodies
B chemotherapy
C diffuse compression of peripheral nerves
D diffuse infiltration of peripheral nerves
E diffuse ischemia of peripheral nerves
1420 OCTOBER 2020

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment
and CME Test—Preferred
Responses
By Douglas J. Gelb, MD, PhD, FAAN; D. Joanne Lynn, MD, FAAN
PERIPHERAL NERVE AND MOTOR NEURON DISORDERS

Following are the preferred responses to the questions in the Postreading
Self-Assessment and CME Test in this Continuum issue. The preferred
response is followed by an explanation and a reference with which you
may seek more specific information. You are encouraged to review the
responses and explanations carefully to evaluate your general
understanding of the article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon completion of the Postreading Self-Assessment and

CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS: This

program is an Accredited Self-Assessment
Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the University of Calgary Office of Continuing Medical
Education and Professional Development. Canadian participants should
visit MAINPORT (www.mainport.org) to record learning and outcomes.
Canadian participants can claim a maximum of 20 hours per issue (credits
are automatically calculated).
ARTICLE 1: A STRUCTURED APPROACH TO THE DIAGNOSIS OF PERIPHERAL

NERVOUS SYSTEM DISORDERS
1 The preferred response is D (saphenous). The saphenous nerve has no motor

component, so a focal lesion of the saphenous nerve results in a pure sensory
syndrome. Lesions of mixed nerves can also cause pure or predominantly
sensory syndromes, especially in the early stages, in situations in which
preferential involvement of sensory fascicles exists. For more information, refer

POSTREADING TEST—PREFERRED RESPONSES
to page 1137 of the Continuum article “A Structured Approach to the Diagnosis of

Peripheral Nervous System Disorders.”
2 The preferred response is B (brachioradialis). Patients with monomelic

amyotrophy (Hirayama disease) primarily have involvement of muscles
innervated by the C7, C8, and T1 roots, resulting in progressive painless
weakness in the hand and forearm, with sparing of the brachioradialis muscle,
which derives its innervation from the C5 and C6 roots. For more information,
refer to page 1150 of the Continuum article “A Structured Approach to the
Diagnosis of Peripheral Nervous System Disorders.”
3 The preferred response is C (posterior interosseous). Most mononeuropathies

will be associated with both sensory and motor manifestations. The most
common mononeuropathies to cause a pure motor syndrome are those involving
nerves without sensory components, such as the posterior interosseous,
anterior interosseous, or suprascapular nerves. Occasionally, entrapment or
other pathologic processes involving a mixed nerve will result in a pure motor
presentation because of preferential sparing of fascicles serving sensation. For
more information, refer to page 1136 of the Continuum article, “A Structured
Approach to the Diagnosis of Peripheral Nervous System Disorders.”
4 The preferred response is E (vasculitic neuropathy). Mononeuritis multiplex

generally presents with significant initial asymmetry affecting multiple individual
nerves in both distal and proximal distributions. Vasculitis and other systemic
inflammatory disorders, lymphoma, diabetes, and viral infection are common
causes of multiple mononeuropathies. Acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) most often present as symmetric distal and
proximal distributions. Charcot-Marie-Tooth disease would be expected to
present in a distal symmetric pattern and brachial amyotrophic diplegia in a
proximal symmetric pattern. For more information, refer to page 1139 of the
Continuum article, “A Structured Approach to the Diagnosis of Peripheral
Nervous System Disorders.”
ARTICLE 2: DIABETES AND METABOLIC DISORDERS AND THE PERIPHERAL

NERVOUS SYSTEM
5 The preferred response is C (length-dependent axonal polyneuropathy). The

most common type of diabetic neuropathy is length-dependent axonal
polyneuropathy, which can predominantly affect small-diameter or
large-diameter axons, or both. This type of neuropathy accounts for
approximately 50% to 75% of cases of diabetic neuropathy. Mononeuropathies are
common, and diabetes causes nerves to be more vulnerable to compression.
Autonomic neuropathies are not uncommon and may have multiple different
1422 OCTOBER 2020

manifestations. Acute diabetic radiculoplexopathies and treatment-induced
neuropathy are relatively uncommon neurologic manifestations of diabetes. For
more information, refer to page 1162 of the Continuum article “Diabetes and
Metabolic Disorders and the Peripheral Nervous System.”
6 The preferred response is B (hyperglycemia). For type 1 diabetes, the risk of

neuropathy is directly linked to glycemic control. Optimal glycemic control in
type 1 diabetes reduces the relative risk of development of neuropathy by
almost 80%. In contrast, tight glycemic control is much less effective at reducing
the risk of development of neuropathy in type 2 diabetes, and other individual
components of the metabolic syndrome appear to contribute significantly to
the overall risk. For more information, refer to page 1163 of the Continuum article
“Diabetes and Metabolic Disorders and the Peripheral Nervous System.”
7 The preferred response is C (microvasculitis). This case is most consistent with

diabetic lumbosacral radiculoplexus neuropathy or diabetic amyotrophy. This
entity is notable for severe pain starting in one lower limb and frequently
progressing to the other associated with the development of proximal weakness
and relative sparing of sensory functions. It is often associated with weight loss.
The underlying pathophysiology has been shown to be a microvasculitic process
causing ischemic nerve injury. It typically progresses over months and takes 1 to
2 years for incomplete recovery to occur. For more information, refer to
page 1171 of the Continuum article “Diabetes and Metabolic Disorders and the
Peripheral Nervous System.”
8 The preferred response is E (orthostatic hypotension). Diabetic cardiovascular

autonomic neuropathy includes manifestations of increased resting heart rate,
diminished heart rate response to physiologic stress, decreased cardiac output,
and orthostatic hypotension. Related to vagus nerve denervation, diabetic
cardiovascular autonomic neuropathy is associated with increased mortality,
especially when orthostatic hypotension is present. For more information, refer
to page 1173 of the Continuum article “Diabetes and Metabolic Disorders and the
Peripheral Nervous System.”
ARTICLE 3: GUILLAIN-BARRÉ SYNDROME
9 The preferred response is E (severe urinary sphincter dysfunction at onset of

symptoms). Most patients with acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) present with back pain, radicular pain, painful
paresthesia, or other sensory symptoms. Cranial nerve symptoms, including
facial weakness, are common. Orthostatic hypotension and other features of
autonomic dysfunction may also occur in AIDP. Although ascending weakness is
the classic pattern, the weakness may start proximally. Severe sphincter
dysfunction at presentation is unusual and suggests the possibility of spinal

cord, conus medullaris, or cauda equina dysfunction. For more information, refer
to page 1186 of the Continuum article “Guillain-Barré Syndrome.”
10 The preferred response is E (severity of weakness). A functional outcome

model based on age, the presence or absence of preceding diarrhea, and
severity of weakness (quantified using the Medical Research Council [MRC]
sum score) predicts the probability of walking independently at 1, 3, and
6 months. For more information, refer to page 1190 of the Continuum article
“Guillain-Barré Syndrome.”
11 The preferred response is E (GQ1b). This patient has ophthalmoparesis, ataxia,

and areflexia, the classic triad of the Miller Fisher variant of Guillain-Barré
syndrome. More than 80% of patients with Miller Fisher syndrome have
anti-GQ1b antibodies in their serum. For more information, refer to page 1189 of
the Continuum article “Guillain-Barré Syndrome.”
ARTICLE 4: CHRONIC INFLAMMATORY DEMYELINATING

POLYRADICULONEUROPATHY AND ITS VARIANTS
12 The preferred response is D (sural). The presence of the sural sparing pattern
on electrophysiologic studies is a hallmark of chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP) and other acquired primary
demyelinating neuropathies. For more information, refer to page 1208
of the Continuum article “Chronic Inflammatory Demyelinating
Polyradiculoneuropathy and Its Variants.”
13 The preferred response is C (infectious or neoplastic polyradiculitis). Chronic

inflammatory demyelinating polyradiculoneuropathy (CIDP) and most of its
variants are associated with a CSF albuminocytologic dissociation with
elevated protein but normal cell count or a normal profile as in multifocal
CIDP. A significant CSF pleocytosis should raise concern for the possibility
of an infectious or neoplastic cause of symptoms such as human
immunodeficiency virus (HIV), lymphoma, or leptomeningeal carcinomatosis.
For more information, refer to page 1207 of the Continuum article “Chronic
Inflammatory Demyelinating Polyradiculoneuropathy and Its Variants.”
14 The preferred response is E (nodal and paranodal antibodies).

Approximately 10% of patients with chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) will have autoantibodies directed against
paranodal or nodal antigens. These nodo-paranodopathies should be
suspected if the presentation includes distal-predominant presentation,
sensory ataxia, prominent tremor, and poor response to the usual beneficial
treatments. Some patients with this variant have been observed to respond
1424 OCTOBER 2020

to rituximab. For more information, refer to page 1217 of the Continuum article
“Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Its Variants.”
15 The preferred response is B (conduction block). Multifocal motor neuropathy

(MMN) generally presents as a painless asymmetric progressive weakness
associated with cramps and fasciculations. These findings are also common in
amyotrophic lateral sclerosis. However, conduction block in multiple nerves is
the hallmark of MMN. For more information, refer to page 1214 of the Continuum
article “Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Its
Variants.”
ARTICLE 5: CHARCOT-MARIE-TOOTH DISEASE AND OTHER HEREDITARY

NEUROPATHIES
16 The preferred response is D (patchy slowing and abnormal temporal

dispersion on nerve conduction studies). Inherited demyelinating neuropathies
usually cause uniform slowing of conduction velocities, although exceptions
exist. In contrast, patchy slowing, partial or total conduction blocks, and
abnormal temporal dispersion are common in acquired demyelinating
neuropathies. Patients with inherited neuropathies often have no affected
family members because of de novo mutations. Areflexia, weakness of ankle
dorsiflexion and plantar flexion, and slow conduction velocities are typical of
both inherited and acquired demyelinating neuropathies. For more information,
refer to page 1229 of the Continuum article “Charcot-Marie-Tooth Disease and
Other Hereditary Neuropathies.”
17 The preferred response is D (peripheral myelin protein 22). The most common
form of Charcot-Marie-Tooth disease (CMT) is type 1A, which accounts for
approximately 70% of all CMT1 cases and more than 50% of all CMT cases.
CMT1A is caused by mutations in the gene for peripheral myelin protein 22. For
more information, refer to page 1230 of the Continuum article “Charcot-Marie-
Tooth Disease and Other Hereditary Neuropathies.”
18 The preferred response is D (hereditary neuropathy with liability to pressure

palsies [HNPP]). In most patients with HNPP, the genetic cause is a deletion in
the gene for peripheral myelin protein 22, the same gene responsible for
Charcot-Marie-Tooth disease type 1A (CMT1A). For more information, refer to
page 1239 of the Continuum article “Charcot-Marie-Tooth Disease and Other
Hereditary Neuropathies.”
19 The preferred response is E (transthyretin amyloidosis). Two small

oligonucleotide-based gene therapies have been approved by the US Food and
Drug Administration (FDA) for transthyretin amyloidosis. One (patisiran) is a small

interfering RNA, and the other (inotersen) is an antisense oligonucleotide. For

more information, refer to page 1243 of the Continuum article “Charcot-Marie-
Tooth Disease and Other Hereditary Neuropathies.”
ARTICLE 6: PERIPHERAL NEUROPATHIES ASSOCIATED WITH VASCULITIS

AND AUTOIMMUNE CONNECTIVE TISSUE DISEASE
20 The preferred response is E (polyarteritis nodosa). Polyarteritis nodosa

is a vasculitis that affects medium blood vessels such as arterioles. Polyarteritis
nodosa is one of the vasculitides that is most frequently associated with
neuropathy. For more information, refer to page 1258 of the Continuum article
“Peripheral Neuropathies Associated With Vasculitis and Autoimmune
Connective Tissue Disease.”
21 The preferred response is A (drug-induced vasculitis). Antineutrophil

cytoplasmic antibody (ANCA) positivity is common in multiple types of
vasculitis, including those associated with infections, inflammatory bowel
disease, and other autoimmune diseases. ANCA specificity to myeloperoxidase
is typically seen in microscopic polyangiitis and eosinophilic granulomatosis
with polyangiitis. Proteinase 3 specificity is typically seen in granulomatosis with
polyangiitis. If positivity for both myeloperoxidase and proteinase 3 is present,
then drug-induced vasculitis should be suspected. For more information, refer
to page 1265 of the Continuum article “Peripheral Neuropathies Associated
With Vasculitis and Autoimmune Connective Tissue Disease.”
22 The preferred response is E (serum positive for hepatitis B virus antigen). The
American College of Rheumatology classification criteria require that patient
presentations fulfill three or more of 10 criteria for the identification of
polyarteritis nodosa vasculitis patients for research purposes. The presence of
hepatitis B virus antigen is one characteristic supportive of a diagnosis of
polyarteritis nodosa. Antineutrophil cytoplasmic antibody antibodies,
glomerulopathy, adult-onset asthma, and cryoglobulinemia are generally not
present in patients with polyarteritis nodosa. For more information, refer to
page 1266 of the Continuum article “Peripheral Neuropathies Associated With
Vasculitis and Autoimmune Connective Tissue Disease.”
23 The preferred response is A (cryoglobulinemic vasculitis). The majority of

patients with cryoglobulinemia present with the classic triad of generalized
weakness, palpable purpura, and diffuse joint pain. Associated neuropathy may
occur in several different forms: distal and symmetric, small fiber predominant,
or multifocal neuropathy. Diagnosis requires careful testing for cryoglobulins,
and treatment must be focused at the underlying causative condition. For more
information, refer to page 1267 of the Continuum article “Peripheral
1426 OCTOBER 2020

Neuropathies Associated with Vasculitis and Autoimmune Connective Tissue
Disease.”
24 The preferred response is B (eosinophilic granulomatosis with polyangiitis).

This presentation of subacute multifocal neuropathy with adult-onset asthma is
most consistent with eosinophilic granulomatosis with polyangiitis. Eosinophilic
granulomatosis with polyangiitis is accompanied by peripheral blood
eosinophilia and extravascular granulomatosis, which can affect multiple
organs. Patients with neuropathy have a high incidence of myeloperoxidase
antineutrophil cytoplasmic antibody positivity. For more information, refer to
page 1265 of the Continuum article “Peripheral Neuropathies Associated with
Vasculitis and Autoimmune Connective Tissue Disease.”
ARTICLE 7: PERIPHERAL NEUROPATHIES DUE TO VITAMIN AND MINERAL

DEFICIENCIES, TOXINS, AND MEDICATIONS
25 The preferred response is D (vitamin B12 [cobalamin]). Long-term metformin

use has been associated with poor absorption of vitamin B12 (cobalamin). For
more information, refer to page 1281 of the Continuum article “Peripheral
Neuropathies Due to Vitamin and Mineral Deficiencies, Toxins, and
Medications.”
26 The preferred response is C (vitamin B6 [pyridoxine]). Vitamin B6 toxicity

causes direct damage to dorsal root ganglion sensory neurons.
For more information, refer to page 1285 of the Continuum article “Peripheral
Medications.”
27 The preferred response is C (lead). Lead toxicity classically produces a

neuropathy with a motor-predominant upper extremity phenotype. For more
information, refer to page 1290 of the Continuum article “Peripheral
Medications.”
28 The preferred response is E (oxaliplatin). Toxicity from cisplatin, oxaliplatin, or

carboplatin manifests as a sensory ganglionopathy; in addition, oxaliplatin causes
acute cold-induced hyperalgesia, which is probably due to increased neuronal
excitability resulting from oxaliplatin’s effect on voltage-gated sodium
channels. For more information, refer to page 1293 of the Continuum article
“Peripheral Neuropathies Due to Vitamin and Mineral Deficiencies, Toxins, and
Medications.”

29 The preferred response is B (ciguatoxin). Ciguatoxin (ciguatera toxin) is

produced by a dinoflagellate and concentrated as it moves up the food chain
to reef-dwelling fish, such as barracuda, grouper, and snapper. It produces
gastrointestinal symptoms and a neuropathy, which often has the distinctive
feature of temperature inversion, in which cold objects are perceived as very
hot. For more information, refer to page 1296 of the Continuum article
“Peripheral Neuropathies Due to Vitamin and Mineral Deficiencies, Toxins, and
Medications.”
ARTICLE 8: MANAGEMENT OF NEUROPATHIC PAIN IN POLYNEUROPATHY
30 The preferred response is B (diffuse allodynia). Opioid-induced hyperalgesia

should be considered when patients report worsening pain rather than
improvement with opioid treatment and experience diffuse allodynia. The
underlying mechanisms are thought to involve neuroplastic changes and opioid
activation of immune cells with resultant sensitization of opioid receptors. For
more information, refer to page 1310 of the Continuum article “Management of
Neuropathic Pain in Polyneuropathy.”
31 The preferred response is A (α-lipoic acid). α-Lipoic acid is an antioxidant that

has been shown to provide greater symptomatic relief compared to placebo
for patients with painful diabetic neuropathy, although several large clinical
trials have yielded conflicting evidence. α-Lipoic acid is generally well tolerated
and is a good option for use as second-line or adjunctive therapy and for
patients who are averse to conventional pharmacotherapeutics. Anecdotal
reports of improvement in neuropathy symptoms exist for curcumin. For more
information, refer to page 1311 of the Continuum article “Management of
Neuropathic Pain in Polyneuropathy.”
ARTICLE 9: AMYOTROPHIC LATERAL SCLEROSIS AND OTHER MOTOR

NEURON DISEASES
32 The preferred response is A (behavioral variant frontotemporal dementia). Of

the 5% to 15% of patients with amyotrophic lateral sclerosis who have frank
frontotemporal dementia, the majority have the behavioral variant. For more
information, refer to page 1326 of the Continuum article “Amyotrophic Lateral
Sclerosis and Other Motor Neuron Diseases.”
33 The preferred response is A (C9orf72). Hexanucleotide expansions in the

noncoding region of C9orf72 are the most common cause of familial
amyotrophic lateral sclerosis, accounting for 40% of familial cases in a European
amyotrophic lateral sclerosis population. For more information, refer to
1428 OCTOBER 2020

page 1335 of the Continuum article “Amyotrophic Lateral Sclerosis and Other
Motor Neuron Diseases.”
34 The preferred response is A (androgen receptor). Spinal bulbar muscular

atrophy, an X-linked disorder caused by a trinucleotide repeat expansion in the
androgen receptor gene, typically presents in adulthood. It is characterized by
weakness, fasciculations, prominent facial twitching, and symptoms of
androgen sensitivity, including gynecomastia and reduced fertility. Most
patients also have sensory nerve involvement. For more information, refer to
page 1330 of the Continuum article “Amyotrophic Lateral Sclerosis and Other
Motor Neuron Diseases.”
ARTICLE 10: SPINAL MUSCULAR ATROPHY
35 The preferred response is B (spinal muscular atrophy type 1). Spinal muscular
atrophy (SMA) type 1 is the most common form of SMA and represents
approximately 60% of infants born with a SMA genotype. Infants affected with
SMA type 1 present in the first few months of life with muscle weakness and
delay or absence of early motor milestones. For more information, refer to
page 1352 of the Continuum article, “Spinal Muscular Atrophy.”
36 The preferred response is C (gene replacement of SMN1). Approved

by the US Food and Drug Administration (FDA) in 2019, onasemnogene
abeparvovec-xioi is an adeno-associated virus 9–delivered SMN1 gene
replacement therapy administered as a single IV dose. Clinical trials
demonstrated therapeutic benefits, including attainment of ability to sit
unassisted for at least 5 seconds in 92% of treated infants and improved
survival free of respiratory intervention. For more information, refer to
page 1357 of the Continuum article, “Spinal Muscular Atrophy.”
37 The preferred response is C (intrathecal). Nusinersen is an antisense

oligonucleotide that improves the inclusion of exon 7 during splicing of the SMN2
gene and is dosed intrathecally every 14 days for the first three loading doses,
followed by a dose 1 month later and then every 4 months for life. For more
information, refer to page 1363 of the Continuum article, “Spinal Muscular Atrophy.”
ARTICLE 11: PERIPHERAL NEUROPATHIES ASSOCIATED WITH MONOCLONAL

GAMMOPATHIES
38 The preferred response is A (gangliosides with a disialosyl epitope). This

patient’s clinical presentation, with gradually progressive sensory loss, ataxia,

and ophthalmoparesis, is typical of CANOMAD (chronic ataxic neuropathy,

ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies)
syndrome. For more information, refer to page 1375 of the Continuum article
“Peripheral Neuropathies Associated With Monoclonal Gammopathies.”
39 The preferred response is E (vascular endothelial growth factor [VEGF]). This

patient has polyneuropathy, organomegaly, monoclonal gammopathy, and skin
changes, four of the features of POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma cell disorder, and skin changes)
syndrome. Most patients with this syndrome have levels of VEGF that are more
than 5 times normal values. For more information, refer to page 1376 of the
Continuum article “Peripheral Neuropathies Associated With Monoclonal
Gammopathies.”
40 The preferred response is B (chemotherapy). Chemotherapy-induced

peripheral neuropathy is the most frequent cause of polyneuropathy in
multiple myeloma. For more information, refer to page 1375 of the Continuum
article “Peripheral Neuropathies Associated with Monoclonal Gammopathies.”
1430 OCTOBER 2020

ERRATUM
In the June 2020 issue of Continuum

(Neurology of Systemic Disease, Vol. 26, No. 3), the

following error occurred:
In “Obstetric and Gynecologic Disorders and the

Nervous System” by Mary Angela O’Neal, MD
(Continuum: Lifelong Learning in Neurology
2020:26:623), the statistic is incorrectly stated in the
sentence, “In a large study from the author’s
institution over a 10-year period, cerebral venous
thrombosis occurred in 17% of pregnancies.” The
corrected sentence is shown below:
In a large study from the author’s institution over a

10-year period, cerebral venous thrombosis was
found to be the etiology in 17% of pregnancy-related
strokes.
O’Neal MA. Obstetric and gynecologic disorders and the nervous
system. Continuum (Minneap Minn) 2020;26(3, Neurology of Systemic
Disease):611–631. doi:10.1212/CON.0000000000000860.

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives ◆ Describe how to evaluate patients presenting with

peripheral neuropathy and a monoclonal gammopathy
Upon completion of this Continuum: Lifelong and screen for an underlying lymphoplasmacytic
Learning in Neurology Peripheral Nerve and Motor disorder
Neuron Disorders issue, participants will be
◆ Perform an evidenced-based and cost-effective
able to: diagnostic evaluation for patients with typical and
atypical peripheral neuropathy
◆ Distinguish between focal, multifocal, and generalized
disorders of the peripheral nervous system using ◆ Discuss the importance of fair drug prices, the
the history, neurologic examination, and carefully concept of opportunity cost, and the ways that
selected tests expensive drugs can impact patients and society and
explain the basic concepts underlying clinical and
◆ Diagnose and manage peripheral neuropathies related economic analyses to estimate the value of drugs
to diabetes and other metabolic disorders
◆ Diagnose Guillain-Barré syndrome and its subtypes,

treat patients using immunomodulatory and Core Competencies
supportive therapies, and use existing prognostication This Continuum: Lifelong Learning in Neurology
tools to advise patients and their families about the
likelihood and degree of recovery Peripheral Nerve and Motor Neuron Disorders
issue covers the following core competencies:
◆ Identify, diagnose, and treat the spectrum of chronic
acquired demyelinating polyradiculoneuropathies ◆ Patient Care
◆ Recognize, diagnose, and treat patients with inherited ◆ Medical Knowledge

neuropathies
◆ Practice-Based Learning and Improvement
◆ Diagnose and manage the spectrum of peripheral
neuropathies associated with autoimmune connective ◆ Interpersonal and Communication Skills
tissue disease and vasculitis
◆ Professionalism
◆ Diagnose and manage peripheral neuropathies due
to vitamin and mineral deficiencies, toxins, and
◆ Systems-Based Practice
medications
◆ Discuss current pharmacologic and nonpharmacologic

therapies for the management of painful
polyneuropathy
◆ Describe clinical patterns, diagnostic evaluation,

and management strategies in amyotrophic lateral
sclerosis and discuss current advances in its genetics
and pathophysiology
◆ Explain the underlying genetics and pathophysiology

of spinal muscular atrophy, differentiate between
its clinical phenotypes, appropriately prescribe
the US Food and Drug Administration–approved
therapeutics, and provide supportive care
1120 O C TO B ER 2 0 2 0

LIST OF ABBREVIATIONS
Peripheral Nerve and Motor Neuron Disorders IgA Immunoglobulin A

IgD Immunoglobulin D
IgE Immunoglobulin E
IgG Immunoglobulin G
AAN American Academy of Neurology IgG4 Immunoglobulin G4
AAV9 Adeno-associated virus 9 IgM Immunoglobulin M
ACTH Adrenocorticotropic hormone IM Intramuscular
AIDP Acute inflammatory demyelinating polyradiculoneuropathy IV Intravenous
ALS Amyotrophic lateral sclerosis IVIg Intravenous immunoglobulin
ALSFRS-R ALS Functional Rating Scale–Revised
LEMS Lambert-Eaton myasthenic syndrome
ALT Alanine transaminase
MADSAM Multifocal acquired demyelinating sensory
AMAN Acute motor axonal neuropathy and motor neuropathy
AMSAN Acute motor-sensory axonal neuropathy MAG Myelin-associated glycoprotein
ANCA Antineutrophil cytoplasmic antibody MCARNE Mitochondrial cerebellar ataxia, renal failure,
AST Aspartate transaminase neuropathy, and encephalopathy
CANDA Chronic ataxic neuropathy with anti-disialosyl mEGOS Modified Erasmus GBS Outcome Score
IgM antibodies
MGUS Monoclonal gammopathy of undetermined
CANOMAD Chronic ataxic neuropathy, ophthalmoplegia, significance
IgM paraprotein, cold agglutinins,
and disialosyl antibodies MMN Multifocal motor neuropathy
CANVAS Cerebellar ataxia, neuropathy, vestibular MNGIE Mitochondrial neurogastrointestinal
areflexia syndrome encephalomyopathy
CHOP- Children’s Hospital of Philadelphia Infant Test of MPO Myeloperoxidase
INTEND Neuromuscular Disorders MRA Magnetic resonance angiography
CIDP Chronic inflammatory demyelinating MRC Medical Research Council
polyradiculoneuropathy MRI Magnetic resonance imaging
CISP Chronic immune sensory polyradiculopathy mRNA Messenger ribonucleic acid
CMAP Compound muscle action potential NINDS National Institute of Neurological Disorders and Stroke
CMS Centers for Medicare & Medicaid Services NMDA N-methyl-
-methyl-D-aspartate
CMT Charcot-Marie-Tooth disease PCR Polymerase chain reaction
CNS Central nervous system PET Positron emission tomography
CSF Cerebrospinal fluid PGP 9.5 Protein gene product 9.5
CT Computed tomography
POEMS Polyneuropathy, organomegaly, endocrinopathy,
DADS Distal acquired demyelinating symmetric [neuropathy] monoclonal plasma cell disorder, and skin changes
dHMN Distal hereditary motor neuropathy PR3 Proteinase 3
DNA Deoxyribonucleic acid QALY Quality-adjusted life year
DSPN Distal symmetric polyneuropathy QSART Quantitative sudomotor axon reflex test
ECG Electrocardiogram; electrocardiography
RA Rheumatoid arthritis
EGRIS Erasmus GBS Respiratory Insufficiency Score
RLS Restless legs syndrome
E/M Evaluation and management
RNA Ribonucleic acid
EMG Electromyography
SANDO Sensory ataxic neuropathy, dysarthria,
FDA US Food and Drug Administration and encephalopathy
FDG Fludeoxyglucose
SCA Spinocerebellar ataxia
FTD Frontotemporal dementia
SCIg Subcutaneous immunoglobulin
GABA γ-Aminobutyric acid
SLE Systemic lupus erythematosus
GAD Glutamic acid decarboxylase
SMA Spinal muscular atrophy
GBS Guillain-Barré syndrome
SNAP Sensory nerve action potential
H&E Hematoxylin and eosin
SNRI Serotonin norepinephrine reuptake inhibitor
HBPN Hereditary brachial plexus neuropathy
HFMSE Hammersmith Functional Motor Scale Expanded SPEP Serum protein electrophoresis
HINE-2 Hammersmith Infant Neurological Examination Section 2 SSA Sjögren syndrome A
HIV Human immunodeficiency virus SSB Sjögren syndrome B
HMN Hereditary motor neuropathy SSRI Selective serotonin reuptake inhibitor
HMSN Hereditary motor and sensory neuropathy TDP-43 Transactive response DNA-binding protein 43
HNPP Hereditary neuropathy with liability to pressure palsies THC Tetrahydrocannabinol
HSAN Hereditary sensory and autonomic neuropathy TNF-a Tumor necrosis factor-a
HSP Hereditary spastic paresis TSH Thyroid-stimulating hormone
HTLV-1 Human T-cell lymphotropic virus type 1 TTR Transthyretin
HTLV-2 Human T-cell lymphotropic virus type 2 VDRL Venereal Disease Research Laboratory
ICER Institute for Clinical and Economic Review VEGF Vascular endothelial growth factor
© 2020 American Academy of Neurology.

Peripheral Nerve and Motor

Neuron Disorders
Article 1: A Structured Approach to the
Diagnosis of Peripheral Nervous
System Disorders
Zachary N. London, MD, FAAN. Continuum (Minneap Minn). October 2020;
26 (5 Peripheral Nerve and Motor Neuron Disorders):1130–1160.
ABSTRACT
PURPOSE OF REVIEW:
Neuroanatomic localization and pattern recognition can be used to diagnose both focal lesions
and generalized disorders of the peripheral nervous system. This article describes the nature and
pattern of sensory and motor deficits associated with lesions of specific spinal nerve roots, plexus,
or peripheral nerves. It also describes the patterns of sensory and motor deficits that suggest
multifocal or generalized disorders of the motor neurons, sensory neurons, and peripheral nerves.
RECENT FINDINGS:
The pattern of sensory and motor deficits may be used to distinguish lesions of the peripheral
nervous system from those of the central nervous system. The spinal roots, nerve plexus, and
peripheral nerves supply specific muscles and receive sensory input from distinctive cutaneous
regions. Focal lesions of these structures therefore produce characteristic patterns of sensory
and motor deficits. Multifocal or generalized disorders of the peripheral nervous system may be
distinguished by categorizing their sensory and motor involvement, proximal and distal
predominance, and degree of symmetry. Serum tests, CSF analysis, electrodiagnostic studies,
MRI, ultrasound, nerve biopsy, and skin biopsy have unique roles in the diagnosis of suspected
neuromuscular disorders.
SUMMARY:
A structured approach to the diagnosis of nerve and motor neuron disorders can lead to
hypothesis-driven diagnostic testing. Ancillary tests should be reserved for cases in which
confirming or refuting a diagnosis will change patient management.
KEY POINTS
• The presence of neuropathic pain in an affected limb is more suggestive of a peripheral nervous system
lesion than a central nervous system lesion.

• Features that suggest a central nervous system lesion rather than a peripheral nervous system lesion include
a sensory level on the trunk, hyperreflexia, hemibody symptoms, weakness of extensors in an arm, and
weakness of flexors in a leg.
• Neuralgic amyotrophy may appear to localize to multiple nerves in the same limb rather than a specific part
of the brachial plexus.
• Injuries to nerve roots and mixed nerves, both of which contain both sensory and motor components, may
present with pain or sensory symptoms without weakness.
• Chronic inflammatory demyelinating polyradiculoneuropathy progresses for more than 8 weeks after
symptom onset. Unlike acute inflammatory demyelinating polyradiculoneuropathy, it is generally not
associated with dysautonomia, weakness of cranial muscles, or dyspnea.
• Mononeuritis multiplex affects named nerves but not necessarily at the common entrapment sites.
• Mononeuritis multiplex is usually an axonal process, but multifocal acquired demyelinating sensory and
motor neuropathy and hereditary neuropathy with liability to pressure palsies are multifocal demyelinating
neuropathies.
• Distal symmetric polyneuropathy usually begins to involve the distal upper extremities around the time that
the lower extremity sensory symptoms progress to the level of the knees.
• Clinical features that should raise suspicion for a hereditary cause of neuropathy include young age of onset,
family history, and high arches and hammer toes.
• Spinal bulbar muscular atrophy may cause fasciculations in the face or tongue, signs of androgen deficiency
(including gynecomastia), and slowly progressive bulbar and proximal weakness.
• The pseudobulbar affect seen in patients with amyotrophic lateral sclerosis represents dysregulation of
emotional output rather than a mood disorder.
• Overt dementia is not common in amyotrophic lateral sclerosis, but up to half of patients will have some
impaired cognition or behavioral problems.
• Brachial amyotrophic diplegia and leg amyotrophic diplegia present with painless flaccid weakness starting
in one body segment, which may or may not eventually progress to involve other body segments or cause
upper motor neuron pathology.
• Systemic infections with West Nile Virus and specific enteroviruses may cause a poliolike illness
characterized by flaccid paralysis with or without encephalitis.
• The extensor digitorum brevis muscle may atrophy in sensorimotor distal symmetric polyneuropathy but is
often relatively spared in distal myopathies.
• The weakness in amyotrophic lateral sclerosis tends to follow a myotomal pattern, whereas the weakness in
multifocal motor neuropathy may be in the distribution of specific peripheral nerves.
• Early in the course of multifocal motor neuropathy, patients may have significant weakness with little or no
atrophy, suggesting that the motor axons are still intact.
• Hirayama disease (monomelic amyotrophy) presents in young men with unilateral or bilateral hand weakness
that progresses for years and then plateaus.
• Proprioception is often involved early in disorders affecting the dorsal columns and late in disorders
affecting the peripheral nerves.
• Patients with sensory neuronopathy may initially appear weak on confrontational testing but are able to
generate full power when they look at the limb being tested.
• Sensory neuronopathy may be idiopathic or associated with Sjögren syndrome, a paraneoplastic syndrome,
human immunodeficiency virus, or pyridoxine overdose.
• The most useful screening laboratory tests for the workup of distal symmetric polyneuropathy are tests for
diabetes or prediabetes, serum lipids and cholesterol, a vitamin B12 level, and serum protein electrophoresis
and immunofixation.
• Paraproteinemia may be associated with chronic inflammatory demyelinating polyradiculoneuropathy, is
common in patients with distal acquired demyelinating symmetric neuropathy, and is present in most
patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder,
and skin changes) syndrome.

• The overreliance on modest CSF protein elevations is a common reason for the overdiagnosis of chronic
inflammatory demyelinating polyradiculoneuropathy.
• Electrodiagnostic testing is an important part of the workup for mononeuropathies, mononeuritis multiplex,
demyelinating neuropathy, sensory neuropathy, and motor neuron disease, but it is not sensitive for small
fiber polyneuropathy or pure sensory radiculopathy.
• MRI of the spine can identify common causes of radiculopathy and aid in the diagnosis of chronic
inflammatory demyelinating polyradiculoneuropathy and Hirayama disease but may show degenerative
changes of questionable significance in both symptomatic and asymptomatic individuals.
• Ultrasound imaging is useful in the workup of entrapment neuropathies and has emerging indications in the
workup of other neuromuscular disorders.
• A nerve biopsy is the diagnostic test of choice for suspected nonsystemic vasculitic neuropathy. In the
setting of known systemic vasculitis, nerve biopsy should only be performed if demonstrating peripheral
nerve involvement will lead to a change in immunomodulatory treatment.
Article 2: Diabetes and Metabolic

Disorders and the Peripheral
Nervous System
Christopher H. Gibbons, MD, MMSc, FAAN. Continuum (Minneap Minn). October
2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1161–1183.
ABSTRACT
PURPOSE OF REVIEW:
This article provides an up-to-date review of the manifestations of neuropathy seen in the
setting of diabetes and other metabolic disorders.
RECENT FINDINGS:
Although a number of metabolic disorders cause or are associated with peripheral neuropathy,
the neuropathies associated with glucose dysregulation make up the vast majority of cases.
Recent investigations have determined major differences in the neuropathies associated with
type 1 and type 2 diabetes. Neuropathy in type 1 diabetes is closely linked to glycemic control,
whereas neuropathy in type 2 diabetes is linked to dyslipidemia, central obesity, hypertension,
insulin resistance, and glucose control. Although length-dependent axonal distal symmetric
polyneuropathy is the most common clinical presentation, diabetes is also associated with
acute, asymmetric, painless, and autonomic neuropathies.
SUMMARY:
The prevalence of diabetes and metabolic syndrome is increasing across the globe. The need to
recognize and treat the wide array of clinical manifestations of neuropathy detected in individuals
with metabolic disorders will continue to grow. As a consequence, an increasing number of
well-trained physicians who can manage these patients is needed. At present, treatment is largely
focused on prevention and symptomatic management. Investments into funding for both basic
and clinical science are necessary to bring novel therapeutic interventions into clinical practice.
KEY POINTS
• A number of manifestations of neuropathy are seen in diabetes, including length-dependent neuropathy,
acute generalized or focal neuropathies, mononeuropathies, and autonomic neuropathies.

• The risk of neuropathy in type 1 diabetes is primarily linked to glucose control, whereas the risks of
neuropathy in type 2 diabetes include glucose control, hyperlipidemia, hypertension, abdominal obesity, low
levels of high-density lipoproteins, and tobacco use.
• Approximately half of patients with diabetic neuropathy have neuropathic pain; however, it is important to
recognize that the absence of pain does not rule out a neuropathy.
• Small unmyelinated axons are affected earlier than large fibers in most cases of axonal neuropathy in type 2
diabetes, so an examination should always include testing for signs of small fiber dysfunction (thermal or pain
sensation) as well as large fiber function (reflexes, vibration detection).
• The presence of atypical features in a patient with suspected distal symmetric polyneuropathy, such as a
significant asymmetry, an acute onset, or early motor involvement, suggests a different neuropathy type or
diagnosis and should prompt further diagnostic evaluation, including nerve conduction studies and EMG.
• Nerve conduction studies and EMG are not required as part of the routine diagnosis of distal symmetric
polyneuropathy in diabetes unless atypical features are present.
• The diagnosis of distal symmetric polyneuropathy provides a valuable opportunity to educate patients on the
health benefits of addressing risk factors associated with neuropathy (glucose control, hyperlipidemia,
hypertension, tobacco use), advocate for exercise, and counsel on the importance of proper foot care.
• The risks associated with neuropathy development exist in the prediabetes state. The individual components
of the metabolic syndrome, including glucose dysregulation/insulin resistance, dyslipidemia
(hypertriglyceridemia and low high-density lipoprotein level), central obesity, and hypertension, all
contribute to the risk of developing distal symmetric polyneuropathy.
• The acute to subacute onset of pain and weakness in the hip and leg of an individual with diabetes should
raise suspicion for diabetic lumbosacral radiculoplexus neuropathy. Early recognition and intervention with
IV corticosteroids may improve neuropathic pain and reduce the associated morbidity.
• Treatment-induced neuropathy of diabetes should be suspected in an individual with diabetes who presents
with the acute to subacute onset of neuropathic pain in a symmetric pattern that is accompanied by
predominantly small fiber findings. A significant improvement in glycemic control that precedes the
development of pain is the clue to the diagnosis.
• The earliest clinical manifestation of a diabetic autonomic neuropathy is a resting tachycardia.
• Cardiovascular autonomic neuropathy (particularly with orthostatic hypotension) is associated with
significantly increased mortality risk in patients with diabetes, with 5- to 10-year mortality rates greater
than 50%.
• Gastroparesis is a common and disabling manifestation of diabetic autonomic neuropathy, but the potential
for symptomatic improvement exists with better glycemic control.
• Constipation may be a manifestation of diabetic autonomic neuropathy but is also frequently due to
medication. A careful review of both prescribed and over-the-counter medications may identify potential
opportunities to improve symptoms.
• Diabetic diarrhea is often profuse and watery; it frequently occurs at night with fecal incontinence.
Medications should be reviewed carefully because identification and removal of offending medications may
improve symptoms.
• Bladder dysfunction is common in diabetes and often related to medication side effects. As with other
diabetic autonomic neuropathies, offending medications should be removed as the initial step in
management.
• Sexual dysfunction is common in both men and women with diabetes and frequently is due to a combination
of psychological and physical factors, both of which should be addressed.
• Neuropathy involving the sympathetic cholinergic nerves results in a length-dependent region of anhidrosis,
but patients typically present with complaints of proximal hyperhidrosis.
• Recurrent hypoglycemia blunts future autonomic responses to low levels of glucose, creating a vicious cycle
of recurrent hypoglycemia because of the body’s inability to sense low glucose levels.
• Recurrent hypoglycemia is associated with an increase in cardiovascular mortality, although the exact
mechanism for the increase in mortality is still under investigation.

• It is controversial whether chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) occurs
more frequently in individuals with diabetes; however, CIDP is widely overdiagnosed. A diagnosis of
CIDP in a patient with diabetes should be based on typical clinical features, not on nerve conduction
study findings alone.
• Uremia is linked to an increased risk of length-dependent neuropathy but may improve with dialysis or kidney
transplantation.
• An acute optic neuropathy may also be seen in uremia and should be treated with hemodialysis and
corticosteroids.
Article 3: Guillain-Barré Syndrome

Kazim A. Sheikh, MBBS. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the clinical features, diagnosis and differential diagnosis, prognosis,
pathogenesis, and current and upcoming treatments of Guillain-Barré syndrome (GBS).
RECENT FINDINGS:
GBS is an acute inflammatory neuropathic illness with striking clinical manifestations and
significant morbidity. A substantial proportion of patients with GBS do not respond to current
immunomodulatory therapies (ie, plasma exchange and IV immunoglobulin [IVIg]), highlighting
the need for new therapies. Prognostic models that can accurately predict functional recovery
and the need for artificial ventilation have emerged. These models are practical, and online
calculators are available for clinical use, facilitating early recognition of patients with poor
outcome and the opportunity to personalize management decisions. Clinical and experimental
studies have identified innate immune effectors (complement, macrophage lineage cells, and
activating Fcγ receptors) as important mediators of inflammatory nerve injury. Two complement
inhibitors are undergoing clinical testing for efficacy in GBS.
SUMMARY:
GBS is the most common cause of acute flaccid paralysis in the United States and worldwide.
New treatments for GBS have not emerged since the 1990s. Our understanding of the
pathogenesis of this disorder has progressed, particularly over the past decade; as a result, new
therapeutic agents targeting different components of the complement cascade are at advanced
stages of clinical development.
KEY POINTS
• Guillain-Barré syndrome (GBS) encompasses a spectrum of acute neuropathic disorders, with muscle
weakness being the cardinal manifestation in the majority of patients. It is the most common cause of acute
flaccid paralysis in the United States and worldwide.
• The National Institute of Neurological Disorders and Stroke diagnostic criteria for paralytic GBS are simple
and practical for routine clinical use; the key features of the criteria include symmetric flaccid weakness,
decreased deep tendon reflexes, and exclusion of alternative causes.
• Although the first symptoms of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) are
often sensory, it is primarily a motor polyradiculoneuropathy causing symmetric weakness of proximal
and distal muscles. The classic pattern is of ascending weakness, but symptoms may also begin
proximally.

• Of patients with GBS, 25% to 30% will require intubation because of respiratory muscle weakness or
pharyngeal muscle weakness (airway protection); patients should be closely monitored for the need of
mechanical ventilation.
• Miller Fisher syndrome, the most common minor subtype of GBS, is characterized by a triad of
ophthalmoplegia, ataxia, and areflexia.
• An altered level of consciousness or hyperreflexia with external ophthalmoplegia and ataxia reflects central
nervous system involvement indicative of Bickerstaff brainstem encephalitis. Miller Fisher syndrome–related
disorders are considered a clinical continuum with Bickerstaff brainstem encephalitis on one end and Miller
Fisher syndrome on the other.
• Residual symptoms after GBS are common and include fatigue, pain, paresthesia, and reduced muscle
strength.
• Nerve conduction studies and EMG provide confirmation of an acute neuropathic process and may
differentiate between demyelinating and axonal variants of GBS. They are often relatively normal early in the
course; serial studies are often necessary and may be useful for prognostication.
• Partial motor nerve conduction block without temporal dispersion may be seen in acute motor axonal
neuropathy because of reversible conduction failure at the nodes of Ranvier. Other demyelinating features,
such as reduced conduction velocity and prolonged minimal F-wave or distal motor latencies, are absent.
• CSF analysis typically shows albuminocytologic dissociation. A mild pleocytosis (<50 cells/mm3) can be
seen in up to 10% to 15% of patients with GBS. A pleocytosis of greater than 50 cells/mm3 suggests an
alternative diagnosis.
• Prognostic models for GBS based on clinical parameters, including Medical Research Council (MRC) sum
score, which are collected as part of standard care, can reliably predict the need for mechanical ventilation
in the first week and functional outcomes at 4 weeks to 6 months after admission.
• AIDP, acute motor axonal neuropathy, and acute motor-sensory axonal neuropathy share common
pathologic features, including activation of components of the innate immune system such as complement
activation and upregulation of Fc receptors for IgG (FcγRs). These are promising therapeutic targets.
• It is believed that GBS is triggered by environmental exposures in genetically susceptible hosts.
• Campylobacter jejuni is the most common trigger for GBS, particularly the axonal forms, with an estimated
prevalence of 30%. However, the risk of GBS with C. jejuni infection is low (less than 2 in 10,000).
• Noninfectious events, including trauma, vaccinations, immunosuppression, and pregnancy, may rarely
trigger GBS.
• The risk of developing GBS following influenza infection is much higher than the risk of GBS following
vaccination. Patients who develop GBS following influenza or any other vaccine should not receive the same
vaccine again.
• Postinfectious molecular mimicry is the predominant pathophysiologic mechanism in Miller Fisher syndrome
and axonal variants and in patients who develop AIDP following Mycoplasma pneumoniae infection.
• Supportive and intensive care remains the cornerstone of management of patients with GBS during the acute
phase of this monophasic illness, and immune therapy with plasma exchange or IV immunoglobulin (IVIg)
hastens recovery.
• Randomized clinical trials indicate that IVIg and plasma exchange hasten recovery in patients with GBS, and
both treatments were found to be equally efficacious.
• Of patients with GBS treated with IVIg or plasma exchange in clinical trials, 40% to 50% did not have a clinical
response (ie, did not meet primary end point), emphasizing the need for new therapies.
• Randomized controlled data indicate that combination treatment with plasma exchange followed by IVIg is
not superior to treatment with IVIg or plasma exchange alone, and anecdotal observations indicate that
combination treatment with IVIg followed by plasma exchange is no better than IVIg alone. Combination
therapy is generally discouraged.
• No evidence- or consensus-based recommendations are available for additional immunomodulatory
treatments for patients with GBS for whom initial IVIg or plasma exchange treatment has failed, and further
supportive medical management should be tailored according to individual needs in such cases.

• Biologics targeting the complement cascade are at various stages of clinical trials in GBS, and neonatal Fc
receptor (FcRn) inhibitors (which can reduce IgG autoantibody burden) and modulators of FcγR are at
advanced stages of clinical development with potential applicability to GBS.
Article 4: Chronic Inflammatory

Demyelinating Polyradiculoneuropathy
and Its Variants
Kelly Gwathmey, MD. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral
ABSTRACT
PURPOSE OF REVIEW:
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and its variants comprise a
group of immune-mediated neuropathies with distinctive clinical presentations and
electrodiagnostic features. Prompt recognition of these treatable disorders is mandatory as
delays result in significant disability and morbidity. This article highlights the clinical
presentation, pathophysiology, diagnostic evaluation, and treatment approach of these
polyneuropathies.
RECENT FINDINGS:
The spectrum of CIDP is expanding with the recent characterization of neuropathies associated
with nodal and paranodal antibodies. These neuropathies are distinguished by their unique
presentations and are often refractory to IV immunoglobulin (IVIg) therapy. Subcutaneous
immunoglobulins have recently been approved as a treatment option for CIDP and join
corticosteroids, IVIg, and plasma exchange as first-line treatment.
SUMMARY:
CIDP is characterized by progressive symmetric proximal and distal weakness, large fiber
sensory loss, and areflexia, with clinical nadir reached more than 8 weeks after symptom onset.
Autoimmune demyelinating neuropathies fall on a continuum, with differences in the type of
nerve fibers affected and pattern of deficits. Distinguishing between typical CIDP and its
variants allows for selection of the most appropriate treatment.
KEY POINTS
• One-half of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have a typical
presentation of symmetric proximal and distal weakness, length-dependent loss of large fiber sensation,
and areflexia.
• Up to 18% of patients with CIDP will have an acute onset that mimics Guillain-Barré syndrome.
• CIDP is differentiated from Guillain-Barré syndrome by a protracted time course, absence of autonomic
dysfunction, and absence of respiratory impairment in most patients.
• All patients with suspected CIDP should be screened for a monoclonal gammopathy.
• Albuminocytologic dissociation is expected on CSF analysis in CIDP. The presence of leukocytosis raises
suspicion for other conditions, such as neurosarcoidosis, human immunodeficiency virus (HIV), or
carcinomatous meningitis.
• The sural sparing pattern is an electrophysiologic hallmark of CIDP and is often found in addition to other
acquired demyelinating features.

• Patients with suspected CIDP do not require a nerve biopsy if the electrodiagnostic findings and clinical
features are consistent with an acquired demyelinating polyradiculoneuropathy.
• More than 15 sets of diagnostic criteria for CIDP have been published; the most widely accepted is the
European Federation of Neurological Sciences/Peripheral Nerve Society criteria.
• The first-line treatments for CIDP include immunoglobulins (IV and subcutaneous), corticosteroids, and
plasma exchange. Given the need for long-term venous access and limited facilities capable of outpatient
plasma exchange, in practice, plasma exchange is considered second- or third-line treatment by many experts.
• Clinical trials suggest IV immunoglobulin (IVIg) can be discontinued successfully without relapse in
approximately 50% of patients. The treating physician should work toward reducing or discontinuing the
IVIg if possible.
• Use of clinically appropriate outcome measures, such as disability scales and quality-of-life instruments,
helps to inform medical decision making in CIDP.
• Multifocal motor neuropathy may mimic amyotrophic lateral sclerosis given its painless progressive
weakness, but it is differentiated by its lack of upper motor neuron signs and electrophysiologic evidence of
conduction block on motor nerve conduction studies.
• Distal acquired demyelinating symmetric (DADS) neuropathy is often associated with IgM monoclonal
gammopathy and myelin-associated glycoprotein antibodies. Patients with DADS are often refractory
to treatment.
• Autoantibodies directed toward paranodal and nodal antigens are present in approximately 10% of cases of
CIDP; these cases have unique clinical presentations and are often IVIg refractory.
• Patients with nodal and paranodal autoantibodies may respond to rituximab as the autoantibodies are of the
IgG4 isotype.
Article 5: Charcot-Marie-Tooth Disease

and Other Hereditary Neuropathies
Christopher J. Klein, MD, FAAN. Continuum (Minneap Minn). October 2020;
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of Charcot-Marie-Tooth disease (CMT) and other inherited
neuropathies. These disorders encompass a broad spectrum with variable motor, sensory,
autonomic, and other organ system involvement. Considerable overlap exists, both
phenotypically and genetically, among these separate categories, all eventually exhibiting
axonal injury and neurologic impairment. Depending on the specific neural and non-neural
localizations, patients experience varying morbidity and mortality. Neurologic evaluations,
including neurophysiologic testing, can help diagnose and predict patient disabilities. Diagnosis
is often complex, especially when genetic and acquired components overlap.
RECENT FINDINGS:
Next-generation sequencing has greatly improved genetic diagnosis, with many third-party
reimbursement parties now embracing phenotype-based panel evaluations. Through the advent
of comprehensive gene panels, symptoms previously labeled as idiopathic or atypical now have
a better chance to receive a specific diagnosis. A definitive molecular diagnosis affords patients
improved care and counsel. The new classification scheme for inherited neuropathies
emphasizes the causal gene names. A specific genetic diagnosis is important as considerable

advances are being made in gene-specific therapeutics. Emerging therapeutic approaches
include small molecule chaperones, antisense oligonucleotides, RNA interference, and viral
gene delivery therapies. New therapies for hereditary transthyretin amyloidosis and Fabry
disease are discussed.
SUMMARY:
Comprehensive genetic testing through a next-generation sequencing approach is simplifying
diagnostic algorithms and affords significantly improved decision-making processes in
neuropathy care. Genetic diagnosis is essential for pathogenic understanding and for gene
therapy development. Gene-targeted therapies have begun entering the clinic. Currently, for
most inherited neuropathy categories, specific symptomatic management and family counseling
remain the mainstays of therapy.
KEY POINTS
• Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy but accounts for only a
minority of the gene abnormalities among inherited neuropathies.
• Patients with inherited neuropathy often describe their symptoms as subacute in onset, but foot and ankle
abnormalities (hammer toes, pes cavus, pes planus, cavovarus) and shin and hand atrophy along with needle
EMG changes support the chronicity of disease course.
• The presence of ankle reflexes and normal sensation in patients with symmetric ankle weakness raises the
possibility of inherited distal myopathy or inherited distal hereditary motor neuron disease mimicking CMT.
The genes responsible for distal myopathy and progressive muscular atrophy should be considered in
next-generation sequencing panel testing for inherited neuropathies.
• Gene names are increasingly being included in the nomenclature of inherited disorders including inherited
neuropathies.
• Historical clues of inherited neuropathies should be sought, including frequent ankle sprains and foot
fractures, recurrent ingrown toenails (paronychia), and painless foot ulcers.
• Prolonged blink R1 response latency greater than 13 milliseconds, regardless of severity or age, suggests
primary demyelinating inherited neuropathy.
• Patients with inherited neuropathy are more susceptible to clinical declines from superimposed acquired
neuropathies such as diabetes and neurotoxic chemotherapy.
• PMP22 duplications account for approximately 70% of cases of primary demyelinating neuropathy.
• Mutations of MFN2 are the most common known cause of primary axonal CMT.
• Not all patients with inherited demyelinating neuropathies have CMT; some may have disorders such as
mitochondrial neurogastrointestinal encephalomyopathy or metachromatic leukodystrophy.
• Absence of male-to-male transmission and females being more mildly affected than males within a family
suggests CMTX1-GJB1, the second most common form of CMT.
• Patients with hereditary sensory autonomic neuropathy commonly have pain, and some forms also have
gastrointestinal dysmotility, insensate injuries with amputations, and mortality from respiratory and feeding
difficulties.
• Patients with hereditary neuropathy with liability to pressure palsies need to be recognized to avoid
unnecessary decompressive surgeries at points of compression.
• Family history, recurrent episodes, and, possibly, younger age of onset distinguish hereditary brachial plexus
neuropathy from idiopathic neuralgic amyotrophy (Parsonage-Turner syndrome).
• Two drugs that knock down RNA expression of mutant and wild-type TTR (patisiran and inotersen) have been
recently approved for hereditary transthyretin amyloidosis neuropathy.
• Standard next-generation sequencing cannot identify nucleotide repeat expansion mutations such as those
occurring in Friedreich ataxia and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).
• Enzyme replacement therapy with recombinant α-galactosidase was the first available specific treatment for
Fabry disease. Recently, migalastat, a new drug using chaperone therapy, was approved by the US Food and

Drug Administration. Migalastat is a small molecule drug that stabilizes and facilitates trafficking of rescuable
mutant forms of α-galactosidase A protein, partially restoring the enzyme activity in lysosomes.
• Next-generation sequencing is simplifying the genetic diagnosis of inherited neuropathies.
• The accuracy of next-generation sequencing testing correlates to the depth of coverage of all targeted genes
represented in panel testing.
• Foot and ankle surgeries should be reserved for patients for whom bracing for ankle stability has failed, with
tendon transfers favored over joint fusions.
Article 6: Peripheral Neuropathies

Associated With Vasculitis and
Autoimmune Connective Tissue Disease
Chafic Karam, MD. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve
and Motor Neuron Disorders):1257–1279.
ABSTRACT
PURPOSE OF REVIEW:
This article discusses peripheral neuropathies associated with vasculitis (isolated or in the
setting of systemic vasculitis) and autoimmune connective tissue disease and provides a brief
overview of their diagnostic evaluation and management.
RECENT FINDINGS:
The classification of systemic vasculitic neuropathy and nonsystemic vasculitic neuropathy
continues to evolve. Classification according to the presence of antineutrophil cytoplasmic
antibodies and their subtypes facilitates prognostication and management. Recent research on
antineutrophil cytoplasmic antibody–associated vasculitis has added to our understanding of its
neurologic complications. The treatment of vasculitis is also evolving, and new nonsystemic
vasculitic neuropathy classification has impacted the treatment and management of this
disorder. New classification criteria for Sjögren syndrome (which commonly causes neurologic
complications) facilitate accurate and timely diagnosis.
SUMMARY:
Vasculitis and autoimmune connective tissue disease are underrecognized and treatable causes
of peripheral neuropathy. Furthermore, peripheral neuropathy may reveal an underlying
rheumatologic or vasculitic disorder. Rapid recognition and treatment are essential. Familiarity
with the diagnosis and treatment of neuropathies in the setting of connective tissue disease and
vasculitis reduces morbidity and, in some cases, mortality.
KEY POINTS
• Asymmetric signs or symptoms or stepwise progression, especially when associated with systemic
symptoms, are highly suggestive of vasculitic neuropathy.
• Nerve conduction studies done on opposite limbs, even if asymptomatic, are essential to demonstrate
asymmetry or multifocality, which can be missed clinically.
• Nerve biopsy is necessary for a diagnosis of definite vasculitis, but, because of the patchy nature of the
disease process, a negative biopsy does not rule out vasculitis.
• Biopsy of a nearby muscle increases the diagnostic yield of biopsy for suspected vasculitic neuropathy by
about 15%.

• Laboratory testing is essential to determine whether vasculitis is secondary to a systemic disorder or
exposure that may require different management.
• Adult-onset asthma in a patient with a subacute asymmetric neuropathy or multifocal neuropathy strongly
suggests eosinophilic granulomatosis with polyangiitis.
• Testing for antineutrophil cytoplasmic antibodies (ANCA) in the setting of vasculitis is essential to determine
prognosis and appropriate treatment.
• In the rare instance in which both myeloperoxidase and proteinase 3 are positive in the same patient,
drug-induced vasculitis should be suspected.
• In polyarteritis nodosa, testing for hepatitis B virus is essential. Testing for ANCA is negative, and
glomerulopathy is not present.
• Appropriate blood handling, including temperature control, is essential for testing for cryoglobulinemia.
• In mild cases of cryoglobulinemic neuropathy associated with infection, immunosuppression may not be
required when the infection is treated adequately.
• In nonsystemic vasculitic neuropathy, systemic symptoms and signs are usually absent and serologic markers
are negative.
• Different syndromes of nonsystemic vasculitic neuropathy carry different prognoses. The diagnosis is usually
made clinically, and patients should be treated if the disease is active.
• Tumor necrosis factor-α inhibitors, which are commonly used to treat rheumatoid arthritis, can cause
inflammatory autoimmune neuropathies.
• Patients with Sjögren syndrome frequently present to the neurologist first because of peripheral neuropathy.
• The presence of a significant sensory neuropathy or dorsal root ganglionopathy should prompt a thorough
evaluation for Sjögren syndrome.
Article 7: Peripheral Neuropathies Due to

Vitamin and Mineral Deficiencies, Toxins,
and Medications
Nathan P. Staff, MD, PhD, FAAN. Continuum (Minneap Minn). October 2020; 26 (5
Peripheral Nerve and Motor Neuron Disorders):1280–1298.
ABSTRACT
PURPOSE OF REVIEW:
Vitamin and mineral deficiencies, neurotoxins, and, particularly, prescription medications, are
some of the most common causes of peripheral neuropathy. Recognition and prompt treatment
of these neuropathies require a high index of suspicion and an accompanied detailed history.
This article provides a comprehensive approach and list of items that must be considered in the
setting of new-onset neuropathy.
RECENT FINDINGS:
Although many of the neuropathies described in this article have decreased in prevalence in
developed countries because of public health interventions and occupational/environmental
regulations, new causes for this class of neuropathy continue to be uncovered.
SUMMARY:
The peripheral nervous system is susceptible to a broad array of metabolic and toxic
abnormalities, which most often lead to a length-dependent sensory-predominant axonal
peripheral neuropathy. A careful history accompanied by recognition of multisystem clues can

increase recognition of these neuropathies, which is important as many have specific treatments
that may either improve the neuropathy or halt its progression.
KEY POINTS
• A broad review of systems that includes skin, nails, and hematologic and gastrointestinal systems may
provide clues to a neuropathy caused by vitamin deficiencies or toxins.
• Vitamin B12 deficiency secondary to inadequate oral intake is uncommon, except in cases of a strict vegan diet.
• Simultaneous onset of sensory symptoms in the hands and feet suggests cervical cord pathology, which may
be seen in vitamin B12 or copper deficiencies.
• When investigating vitamin B12 deficiency, it is important to also consider copper deficiency because the
clinical picture can be very similar.
• Vitamin B6 supplementation is only routinely recommended in the setting of isoniazid or hydralazine
treatment, in which vitamin B6 deficiency may occur. Otherwise, vitamin B6 supplementation itself can cause
a sensory neuropathy or sensory ganglionopathy.
• Neuropathy due to thiamine deficiency has many presentations, including length-dependent sensorimotor,
cranial nerve, and motor-predominant polyneuropathy, all of which may precede cognitive and systemic
symptoms.
• Establishing a causal link between alcohol use and neuropathy can be difficult for a variety of reasons, but it
is recommended that all patients with neuropathy ingest minimal alcohol. Early referral to a chemical
dependence specialist is recommended when alcohol use disorder is suspected.
• Uremic neuropathy in the setting of chronic dialysis is typically a mild axonal sensorimotor peripheral
neuropathy; other etiologies should be considered if a severe neuropathy is encountered.
• Intoxication from arsenic or thallium is preceded by severe gastrointestinal illness, and the neuropathy may
mimic Guillain-Barré syndrome.
• Obtaining a detailed occupational and hobby exposure history is critical for discovering many toxic
neuropathies.
• Medications may cause peripheral neuropathy in a dose-dependent fashion or may be a rare idiosyncratic
reaction.
• Coasting is a phenomenon in which a neuropathy worsens for weeks to months after the discontinuation of a
toxic agent. This is most often observed in chemotherapy-induced peripheral neuropathy due to
platinum-based chemotherapy but can also be seen in neuropathies due to hexanes and vitamin B6 excess.
• Oxaliplatin causes cold-induced dysesthesia.
• Paclitaxel is associated with acute toxicity causing a pain syndrome that is not clearly due to nerve damage.
• Patients with cancer are more commonly being treated with immune-checkpoint inhibitors, which result in a
neurologic adverse event in 3% of patients. These neurologic adverse events include central or peripheral
nervous system syndromes, which may be life-threatening.
Article 8: Management of Neuropathic

Pain in Polyneuropathy
Amanda C. Peltier, MD, MS; Derek Wood, MD. Continuum (Minneap Minn). October
2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1299–1322.
ABSTRACT
PURPOSE OF REVIEW:
Many polyneuropathies cause significant neuropathic pain, resulting in substantial morbidity and
reduced quality of life. Appropriate management is crucial for maintaining quality of life for

patients with painful polyneuropathies. The US Food and Drug Administration (FDA) has only
approved one new drug for painful diabetic neuropathy in the past decade, a topical capsaicin
patch that was initially approved for the treatment of postherpetic neuralgia in 2009.
Gabapentinoids and serotonin norepinephrine reuptake inhibitors (SNRIs) continue to have an
advantage in safety profiles and efficacy. Other antiepileptic medications remain second-line
agents because of fewer studies documenting efficacy.
RECENT FINDINGS:
This article reviews recent literature on complementary and pharmacologic therapies for the
management of painful polyneuropathies. Exercise has emerged as an important therapeutic
tool and may also improve the underlying polyneuropathy in the setting of obesity, metabolic
syndrome, and diabetes.
SUMMARY:
The approach to management of painful polyneuropathies is multifactorial, using both
pharmacologic and nonpharmacologic measures to improve pain severity and patient quality
of life.
KEY POINTS
• Painful polyneuropathy is one of the most common causes of neuropathic pain and may affect up to 1 in
20 Americans.
• Painful polyneuropathy is associated with significantly reduced quality of life and increased health care
costs, as well as costs to society in lost worker productivity.
• Neuropathic pain leads to sleep disruption and vice versa. Up to 80% of patients with neuropathic pain have
sleep disturbance.
• Half of patients with painful diabetic neuropathy have depression or anxiety, and one-fourth have both.
• Although the specific role of SCN9A sequence variants in the pathogenesis of small fiber neuropathy is
uncertain, voltage-gated sodium channels play an important role in neuropathic pain, and pharmacologic
inhibition is a promising therapeutic strategy.
• No new medications for neuropathic pain have been approved in the past 10 years (although the high-dose
capsaicin patch that was approved for postherpetic neuralgia in 2009 was recently approved for use in
painful diabetic polyneuropathy in July 2020). The most commonly used medications are the gabapentinoids,
which act on α2δ calcium channels, and medications that increase norepinephrine at the synapse.
• Each neuropathic pain medication should generally be tried at the maximal tolerated dose for 6 to 8 weeks
before concluding it is ineffective.
• Differentiating painful polyneuropathy from restless legs syndrome (RLS), which may coexist with painful
neuropathy, is important as most pain medications (with the exception of the gabapentinoids) are ineffective
for RLS, and some agents (such as tricyclic antidepressants) may worsen RLS.
• Setting realistic treatment expectations for pain management is essential. Complete pain relief is typically
not a realistic goal.
• Gabapentin is absorbed in the intestine via an active-transport mechanism and displays nonlinear
pharmacokinetics with saturable absorption and decreased bioavailability at higher doses.
• Gabapentin and pregabalin have similar efficacy, although patients may respond to, or tolerate, one and not
the other. Gabapentin displays nonlinear pharmacokinetics with saturable absorption and decreased
bioavailability at higher doses, which may favor the use of pregabalin.
• The two most commonly used tricyclic antidepressants for painful polyneuropathy are amitriptyline and
nortriptyline.
• Caution should be exercised when initiating tricyclic antidepressants in elderly individuals or those with
preexisting cognitive or autonomic dysfunction as they may be more susceptible to anticholinergic side
effects, and their use should be avoided in patients with severe depression or history of suicide attempt
because of the risk of intentional overdose.

• Duloxetine may be a particularly good agent for patients with painful diabetic neuropathy with comorbid
depression, anxiety, or fibromyalgia.
• Despite a lower efficacy compared to gabapentinoids and serotonin norepinephrine reuptake inhibitors,
antiepileptic drugs and mexiletine may still be worth a trial in some patients with refractory pain.
• Topical agents (such as lidocaine patches or cream) are of modest efficacy but may add symptomatic relief in
selected patients with neuropathic pain and have the advantage of minimal side effects.
• Opioid analgesics, including tramadol, should not be used as first- or second-line medications for
neuropathic pain and should only be considered in severe and refractory cases when all other options have
failed. In general, referral to a pain clinic is recommended if opioid therapy is being considered.
• Opioid-induced hyperalgesia causes patients to have increased pain and diffuse allodynia that is often
different than their initial pain manifestation.
• High-quality clinical trial data supporting the use of cannabinoids for neuropathic pain are lacking, and side
effects are common. Their use outside of clinical trials is discouraged.
• Recognition and individualized treatment of depression is important, and cognitive therapy can be a useful
tool in multidisciplinary pain clinics.
• Given the multiple health benefits of exercise and improvement in other parameters of health, exercise
should be highly encouraged in all patients with painful polyneuropathy.
• An algorithmic approach that integrates pharmacologic and nonpharmacologic therapy with specific
attention to comorbid sleep and mood disorders is the most effective approach to neuropathic pain
management.
Article 9: Amyotrophic Lateral Sclerosis

and Other Motor Neuron Diseases
Colin Quinn, MD; Lauren Elman, MD. Continuum (Minneap Minn). October 2020;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the clinical features, diagnostic approach, and treatments available for
amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The article also provides an
update on the genetics and pathophysiology of ALS.
RECENT FINDINGS:
ALS remains a clinical diagnosis without a unique biomarker. The areas of greatest progress
include a large expansion in the number of genes associated with familial and sporadic ALS. The
discovery of these genes, along with other work, has provided a deeper understanding of the
mechanisms of motor neuron failure in ALS. Areas of particular interest include the role of
transactive response DNA-binding protein 43 and other RNA-processing proteins in the
development of disease.
SUMMARY:
ALS remains a relentlessly progressive disorder with an elusive core pathophysiology. The
current mainstay of treatment remains symptom management and palliation, particularly
in the setting of a multidisciplinary clinic. The future holds potential for targeted therapies
based on an ever-evolving understanding of the pathophysiology of both familial and
sporadic ALS.

KEY POINTS
• The incidence of amyotrophic lateral sclerosis (ALS) has remained constant at around 2 per 100,000 per year
to 3 per 100,000 per year and is slightly higher in men than in women.
• Of patients with ALS, 90% have sporadic disease and 10% have familial ALS, which follows an autosomal
dominant pattern of inheritance.
• Patients with ALS typically have a combination of upper motor neuron and lower motor neuron signs that
affect multiple segments of the body.
• Frontotemporal dementia occurs in 5% to 15% of patients with ALS, and a larger proportion of patients will
have subtle findings of personality change or executive dysfunction.
• The diagnostic evaluation of ALS does not need to be extensive in the setting of the appropriate clinical
history and physical examination, although it is imperative to exclude all treatable conditions.
• MRI should be performed at the lowest level of upper motor neuron findings and above in patients with
suspected ALS.
• Isolated upper motor neuron examination findings should prompt careful examination of the neuraxis, with
MRI performed to exclude lesional causes of upper motor neuron injury.
• Gene discovery for ALS has accelerated remarkably over the past decade, leading to improved
understanding of ALS pathophysiology that will ideally result in targeted therapies in the near future.
• SOD1 mutations were the first genetic mutations discovered in familial ALS. However, SOD1 pathology is
distinct from the pathology seen in the majority of ALS cases.
• Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial ALS.
• No single cause of ALS has been determined, although multiple critical pathways in motor neuron
degeneration have been identified. Of particular current interest are abnormalities in RNA processing.
• Cytoplasmic transactive response DNA-binding protein 43 (TDP-43) inclusions are a hallmark of ALS
pathology in the vast majority of patients.
• No curative therapy has been identified for ALS. The mainstay of treatment is multidisciplinary care and
palliative symptom management.
• The oral drug riluzole is the most widely used disease-modifying agent in ALS and has a well-established,
albeit modest, effect on survival.
• Edaravone is an IV disease-modifying agent that slowed the rate of functional decline in a small number of
select ALS patients with early, diffuse, and rapidly progressing disease. However, a prior trial in a broader
population was negative and questions remain regarding its long-term effectiveness in the general ALS
population.
• The presence of isolated lower motor neuron or upper motor neuron abnormalities should broaden the
differential diagnosis but does not preclude an ALS diagnosis.
• Monomelic amyotrophy presents in young men with atrophy of one or both arms, typically in the lower
cervical myotomes. The diagnosis is typically confirmed by findings on cervical MRI, including dynamic
flexion demonstrating forward displacement of the dura. Although the cause of injury is not certain, the most
common theory is microvascular disturbance due to compression with resultant ischemia of the anterior horn
cells at C8 and T1.
• Spinal bulbar muscular atrophy is a rare cause of motor neuropathy but should be considered in men with
lower motor neuron disease, sensory neuropathy on nerve conduction studies, predominant bulbar
symptoms, and facial twitching. It is caused by an X-linked trinucleotide repeat disorder in the androgen
receptor gene. Neurodegeneration is due to a toxic gain of function that occurs in the setting of ligand
(testosterone and dihydrotestosterone) binding to the mutant receptor.

Article 10: Spinal Muscular Atrophy
Jessica Rose Nance, MD. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of the pathophysiology and clinical presentations of spinal
muscular atrophy (SMA) and reviews therapeutic developments, including US Food and Drug
Administration (FDA)–approved gene-targeted therapies and mainstays of supportive SMA care.
RECENT FINDINGS:
Over the past decades, an understanding of the role of SMN protein in the development and
maintenance of the motor unit and the intricate genetics underlying SMA has led to striking
developments in therapeutics with three FDA-approved treatments for SMA, one targeting
SMN1 gene replacement (onasemnogene abeparvovec-xioi) and two others enhancing SMN
protein production from the SMN2 gene (nusinersen and risdiplam). These therapies are most
effective in infants treated at younger ages, and improvement is most striking in babies treated
as neonates. Despite improvements in motor function, patients (especially those treated at older
ages) continue to experience significant weakness and require continued close monitoring of
respiratory and orthopedic symptoms.
SUMMARY:
Striking therapeutic advancements have changed the clinical course of SMA dramatically,
although supportive care continues to play an important role in patient care.
KEY POINTS
• Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by mutations/deletions in the
survival motor neuron 1 (SMN1) gene. It has a broad phenotypic spectrum and is classified into categories
based on age of onset, motor milestone achievement, and copy number of the paralogous SMN2 gene.
• SMA type 1 (SMA1) is the most common form of SMA and is characterized by onset of weakness in the first
few months of life. Without disease-modifying therapy, babies with SMA1 never achieve the ability to sit
independently, and the average time to death or requirement for permanent ventilation for an infant with
untreated SMA1 is 13.5 months.
• In SMA, both copies of the SMN1 gene are absent. Thus, motor neuron survival is dependent on the number of
SMN2 copies. Patients with SMA with more SMN2 copies have a milder phenotype.
• The majority of patients with SMA type 1 possess two SMN2 gene copies. Those with SMA type 2 usually have
three copies, those with SMA type 3 have three or four copies, and patients with SMA type 4 typically have
more than four copies. Those with SMA type 0, which presents with arthrogryposis multiplex congenita and
severe respiratory failure, typically have one copy.
• In December 2016, the US Food and Drug Administration approved nusinersen as the first therapy for SMA. An
antisense oligonucleotide, nusinersen targets increased efficiency of inclusion of exon 7 during splicing of
SMN2 RNA.
• Neonates with SMA with two or three SMN2 copies treated with nusinersen before the onset of symptoms
demonstrate striking improvement in motor function, with the large majority able to walk independently.
• Onasemnogene abeparvovec-xioi is an adeno-associated virus 9–mediated SMN1 gene replacement therapy
given as a single IV dose. It is indicated for patients of all SMA types who are 2 years of age or younger at the
time of dosing. Similar to nusinersen, the impact of therapy is greatest in patients treated at a younger age
and greater in those with three SMN2 copies than in those with two copies.

• Risdiplam was approved in August 2020 and is a daily oral small molecule therapy that increases production
of full-length SMN protein from the SMN2 mRNA. After 12 months, nearly half of infants with SMA type 1
treated first between 1 and 7 months of age were able to sit supported for at least 5 seconds. Older
individuals with SMA type 2 or SMA type 3 treated with risdiplam also showed improvement in motor function
compared to a placebo-controlled group.
• Response to nusinersen, onasemnogene abeparvovec-xioi, and risdiplam therapies is more striking when
they are delivered during the first months of life. Early treatment of SMA type 1 enables patients to achieve
motor milestones never before possible. Some patients with SMA type 1 treated within the first weeks of life
are able to walk.
• Although striking improvement in motor milestone achievement is seen in patients with SMA after treatment
with nusinersen, onasemnogene abeparvovec-xioi, or risdiplam, they still experience significant weakness.
• Clinical trials are currently evaluating agents that promote muscle growth (antimyostatin antibody) and
enhance muscle function (an activator of fast skeletal muscle troponin).
• Increased need exists for early diagnosis of SMA, which drives the inclusion of SMA testing in newborn
screening programs and the promotion of female carrier testing in pregnant women.
• All newborns with two, three, or four copies of SMN2 (especially those in whom an SMA type 1 or type 2
phenotype is expected) should receive immediate therapy with either onasemnogene abeparvovec-xioi or
nusinersen. In patients with five or more copies (who are expected to develop an SMA type 4 phenotype),
treatment can be deferred with close monitoring for symptom development.
• The efficacy of nusinersen, onasemnogene abeparvovec-xioi, and risdiplam appears to be equivalent.
Decisions between the medications should be based on the patient’s age and discussion of mode of delivery
and side effects with the patient or the patient’s parents or guardians.
• Clinical trials evaluating the potential benefits of combination treatments with SMN1- and SMN2- enhancing
therapies are anticipated or currently under way.
• The extraordinary cost of SMN-targeted therapies may complicate the process of obtaining prior insurance
authorization.
• Supportive therapy, including pulmonary, nutritional, and rehabilitative management, plays a vital role in the
treatment of SMA since many patients continue to experience significant weakness.
• Rehabilitative management should focus on accommodating weakness and promoting mobility to improve
patients’ engagement and minimize the orthopedic complications of progressive weakness. Positioning and
bracing are especially important for both sitting and nonsitting patients to avoid worsening contractures and
scoliosis.
Article 11: Peripheral Neuropathies

Associated With Monoclonal
Gammopathies
Elie Naddaf, MD; Michelle L. Mauermann, MD, FAAN. Continuum (Minneap Minn).
October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1369–1383.
ABSTRACT
PURPOSE OF REVIEW:
Neurologists commonly evaluate patients with a monoclonal gammopathy and peripheral
neuropathy. As both monoclonal gammopathy and peripheral neuropathy are common in the
general population, their coexistence may, in some instances, be purely coincidental. However,
monoclonal gammopathies or underlying lymphoplasmacytic disorders can affect the peripheral

nervous system by various mechanisms. This article discusses how to approach patients with
monoclonal gammopathy and peripheral neuropathy, highlighting clinical and laboratory clues
that may aid in establishing a diagnosis in a timely manner.
RECENT FINDINGS:
From a hematologic standpoint, a monoclonal gammopathy may be of undetermined
significance or can be associated with an underlying myeloma, lymphoplasmacytic lymphoma,
or amyloidosis. Each of these conditions can cause peripheral neuropathy, with varying clinical
and electrodiagnostic profiles. Treatment usually consists of treating the underlying
hematologic disorder. IgM-associated peripheral neuropathy may not require treatment from a
hematologic standpoint, and only anecdotal evidence exists for the use of immunotherapy in
such patients. Therefore, treatment should be determined on a case-by-case basis.
SUMMARY:
Evaluating for an association between a monoclonal gammopathy and a peripheral neuropathy in
a patient depends on the monoclonal gammopathy subtype and the clinical and
electrodiagnostic characteristics of the peripheral neuropathy.
KEY POINTS
• The coexistence of a monoclonal gammopathy and peripheral neuropathy in an individual patient is often
coincidental.
• A monoclonal gammopathy has undetermined significance from a hematologic standpoint when the patient
has a low serum monoclonal protein level (<3 g/dL), less than 10% plasma cells in the bone marrow, and
less than 500 mg/24 hour of M protein in the urine) and no evidence of end organ damage.
• Whereas a monoclonal gammopathy may be of undetermined significance from a hematologic standpoint, it
may still be of clinical significance from a neurologic standpoint.
• IgM peripheral neuropathy usually presents with progressive sensory loss resulting in gait ataxia, with no to
minimal weakness (distal acquired demyelinating symmetric [DADS] phenotype).
• IgM peripheral neuropathy, distal acquired demyelinating symmetric (DADS) phenotype, is a demyelinating
neuropathy with characteristic prolongation of motor distal latencies on electrodiagnostic testing.
• Waldenström macroglobulinemia–associated peripheral neuropathy can look similar to IgM peripheral
neuropathy but with more prominent systemic symptoms and cytopenias.
• Chemotherapy-induced peripheral neuropathy is the most common neuropathy type encountered in
multiple myeloma.
• POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin
changes) neuropathy can mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as
associated features may be easily overlooked.
• The presence of thrombocytosis in a patient with CIDP should prompt evaluation for underlying POEMS.
• Any type of monoclonal gammopathy can be associated with amyloidosis.
• Among all patients with paraproteinemic disorders, patients with immunoglobulin light chain (AL) amyloidosis
appear the sickest and may display cardiorespiratory, gastrointestinal, genitourinary, and systemic
symptoms at presentation.
• Most commonly, patients with AL amyloidosis with peripheral nerve involvement present with generalized
autonomic failure and a painful length-dependent sensory and motor peripheral neuropathy.
• The majority of patients with AL amyloidosis are not autologous stem cell transplantation eligible at
diagnosis; hence, early diagnosis is important.

Issue Overview
Peripheral Nerve and Motor Neuron Disorders, Volume 26, Number 5, October 2020
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Peripheral Nerve and
Motor Neuron Disorders issue, participants will be able to:
 Distinguish between focal, multifocal, and generalized disorders of the peripheral

nervous system using the history, neurologic examination, and carefully selected tests
 Diagnose and manage peripheral neuropathies related to diabetes and other metabolic
disorders
 Diagnose Guillain-Barré syndrome and its subtypes, treat patients using

immunomodulatory and supportive therapies, and use existing prognostication tools to
advise patients and their families about the likelihood and degree of recovery
 Identify, diagnose, and treat the spectrum of chronic acquired demyelinating

polyradiculoneuropathies
 Recognize, diagnose, and treat patients with inherited neuropathies
 Diagnose and manage the spectrum of peripheral neuropathies associated with

autoimmune connective tissue disease and vasculitis
 Diagnose and manage peripheral neuropathies due to vitamin and mineral deficiencies,
toxins, and medications
 Discuss current pharmacologic and nonpharmacologic therapies for the management of

painful polyneuropathy
 Describe clinical patterns, diagnostic evaluation, and management strategies in

amyotrophic lateral sclerosis and discuss current advances in its genetics and
pathophysiology
 Explain the underlying genetics and pathophysiology of spinal muscular atrophy,

differentiate between its clinical phenotypes, appropriately prescribe the US Food and
Drug Administration–approved therapeutics, and provide supportive care
 Describe how to evaluate patients presenting with peripheral neuropathy and a

monoclonal gammopathy and screen for an underlying lymphoplasmacytic disorder

 Perform an evidenced-based and cost-effective diagnostic evaluation for patients with
typical and atypical peripheral neuropathy
 Discuss the importance of fair drug prices, the concept of opportunity cost, and the ways
that expensive drugs can impact patients and society and explain the basic concepts
underlying clinical and economic analyses to estimate the value of drugs
Core Competencies
This Continuum: Lifelong Learning in Neurology Peripheral Nerve and Motor Neuron Disorders
issue covers the following core competencies:
 Patient Care
 Medical Knowledge
 Practice-Based Learning and Improvement
 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Contributors
A. Gordon Smith, MD, FAAN, Guest Editor

Professor and Chair of Neurology, Kenneth and Dianne Wright Distinguished Chair in Clinical
and Translational Research (Neurology), Virginia Commonwealth University, Richmond,
Virginia
Relationship Disclosure: Dr Smith serves as a consultant for Alexion Pharmaceuticals, Inc; Argenx; Disarm
Therapeutics; Eidos Therapeutics; and Regenesis Biomedical, Inc. Dr Smith receives research/grant support from
the National Institutes of Health (U01NS095388, R01DK064814).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Smith reports no disclosure.
Ted M. Burns, MD
Harrison Distinguished Professor of Neurology, University of Virginia, Charlottesville, Virginia
Relationship Disclosure: Dr Burns reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Burns reports no disclosure.
Brian C. Callaghan, MD, MS, FAAN

Associate Professor of Neurology, University of Michigan, Ann Arbor, Michigan
Relationship Disclosure: Dr Callaghan serves on a scientific advisory board for a Patient-Centered Outcomes
Research Institute grant, on the International Diabetes Neuropathy Consortium board for the Peripheral Nerve
Society, on the editorial board of Neurology, and as a consultant for DynaMed. Dr Callaghan has received
research/grant support from the American Academy of Neurology, JDRF, the National Institutes of Health (R01
DK115687), and the US Department of Veterans Affairs (Clinical Science Research and Development Merit
I01CX001504) and provided consulting services for medicolegal cases and the US Vaccine Injury Compensation
Program.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Callaghan reports no disclosure.
Jason L. Crowell, MD
Neurologist, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Jerome H.
Grossman MD Graduate Fellow, Harvard Kennedy School, Cambridge, Massachusetts
Relationship Disclosure: Dr Crowell has received fellowship support from Medtronic.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Crowell reports no disclosure.
Lauren Elman, MD
Associate Professor of Neurology, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, Pennsylvania
Relationship Disclosure: Dr Elman serves on advisory boards for Biogen and Genentech, Inc, and receives
publishing royalties from UpToDate, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Elman discusses the unlabeled/investigational use of
anticholinergics, clonazepam, levetiracetam, mexiletine, mirtazapine, phenytoin, selective serotonin reuptake
inhibitors, steroids, and tricyclic antidepressants for the treatment of amyotrophic lateral sclerosis and other motor
neuron diseases.

Christopher H. Gibbons, MD, MMSc, FAAN
Associate Professor of Neurology, Harvard Medical School, Boston, Massachusetts
Relationship Disclosure: Dr Gibbons has received personal compensation for serving as a scientific advisor for
Lundbeck and Theravance Biopharma and as an associate editor for Autonomic Neuroscience: Basic and Clinical,
research/grant support from Grifols, and publishing royalties from UpToDate, Inc. Dr Gibbons has held stock/stock
options in Cutaneous Neurodiagnostics, LLC, and has given expert medical testimony.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gibbons reports no disclosure.
Kelly Gwathmey, MD
Assistant Professor of Neurology; Chief, Division of Neuromuscular Medicine, Virginia
Commonwealth University, Richmond, Virginia
Relationship Disclosure: Dr Gwathmey has served as a consultant for and received personal compensation for
speaking engagements from Alexion Pharmaceuticals, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gwathmey discusses the unlabeled/investigational

use of azathioprine, bortezomib, corticosteroids (methylprednisolone, prednisone), cyclophosphamide, cyclosporine,
methotrexate, mycophenolate mofetil, and rituximab for the treatment of chronic inflammatory demyelinating
polyradiculoneuropathy and its variants.
Chafic Karam, MD
Associate Professor, Department of Neurology, Hospital of the University of Pennsylvania,
Philadelphia, Pennsylvania
Relationship Disclosure: Dr Karam has served as a deputy editor for Neurology and as a consultant for Acceleron
Pharma, Inc; Akcea Therapeutics; Alnylam Pharmaceuticals, Inc; Argenx; Biogen; CSL Behring; and Sanofi
Genzyme. Dr Karam has received personal compensation for speaking engagements from Akcea Therapeutics;
Alnylam Pharmaceuticals, Inc; CSL Behring; and Sanofi Genzyme and research/grant support from Akcea
Therapeutics and Sanofi Genzyme.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Karam discusses the unlabeled/investigational use of
cyclophosphamide, immunoglobulin, rituximab, and steroids in the treatment of vasculitis and immune-mediated
neuropathy in rheumatologic disorders.
Christopher J. Klein, MD, FAAN

Professor of Neurology, Mayo Clinic, Rochester, Minnesota
Relationship Disclosure: Dr Klein serves on the clinical expert and therapy boards of the Charcot-Marie-Tooth
Association. Dr Klein has received personal compensation for speaking engagements at the Neuropathic Pain
Symposium and research/grant support from the Mayo Clinic Center for Individualized Medicine.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Klein reports no disclosure.
Zachary N. London, MD, FAAN

James W. Albers Collegiate Professor of Neurology and Clinical Professor of Neurology,
University of Michigan Medical School, Ann Arbor, Michigan
Relationship Disclosure: Dr London has received personal compensation for speaking engagements from the
American Academy of Neurology, the American Association of Neuromuscular & Electrodiagnostic Medicine, the
American Clinical Neurophysiology Society, the University of Pennsylvania, and the University of Rochester.
Unlabeled Use of Products/Investigational Use Disclosure: Dr London reports no disclosure.

Michelle L. Mauermann, MD, FAAN
Professor of Neurology, Neuromuscular Division of Neurology, Mayo Clinic College of
Medicine and Science, Rochester, Minnesota
Relationship Disclosure: Dr Mauermann serves on the editorial board of Mayo Clinic Proceedings; receives
research/grant support from Alnylam Pharmaceuticals, Inc, and Ionis Pharmaceuticals, Inc; and receives publishing
royalties from Oxford University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Mauermann discusses the unlabeled/investigational

use of IV immunoglobulin and rituximab for the treatment of IgM neuropathy.
Elie Naddaf, MD
Assistant Professor of Neurology, Mayo Clinic College of Medicine and Science, Rochester,
Minnesota
Relationship Disclosure: Dr Naddaf reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Naddaf discusses the unlabeled/investigational use of
IV immunoglobulin and rituximab for the treatment of IgM neuropathy.

Assistant Professor of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland
Relationship Disclosure: Dr Nance receives research/grant support from AveXis, Inc; Biogen; Catabasis
Pharmaceuticals, Inc; Catalyst Pharmaceuticals, Inc; Cytokinetics, Inc; Santhera Pharmaceuticals; and Scholar Rock.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Nance reports no disclosure.
Amanda C. Peltier, MD, MS

Associate Professor of Neurology; Associate Professor of Medicine, Director of Cardiology,
Heart and Vascular Institute, Vanderbilt University Medical Center, Nashville, Tennessee
Relationship Disclosure: Dr Peltier serves as secretary of the International Diabetes Neuropathy Consortium, on the
board of directors of the American Autonomic Society, and on advisory boards for Akcea Therapeutics; Alnylam
Pharmaceuticals, Inc; and CSL Behring. Dr Peltier has received personal compensation for speaking engagements
from Akcea Therapeutics and CSL Behring and research/grant support from Akcea Therapeutics, CSL Behring, and
the National Institute of Neurological Disorders and Stroke NeuroNEXT.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Peltier discusses the unlabeled/investigational use of
α-lipoic acid, amitriptyline, cannabidiol oil, carbamazepine, nortriptyline, oxcarbazepine, spinal cord stimulators,
valproic acid, and venlafaxine for the treatment of neuropathic pain in polyneuropathy.
Colin Quinn, MD
Assistant Professor of Clinical Neurology, University of Pennsylvania, Philadelphia,
Pennsylvania
Relationship Disclosure: Dr Quinn serves on advisory boards for Acceleron Pharma, Inc, and Amylyx
Pharmaceuticals and as a consultant for Amicus Therapeutics, Inc. Dr Quinn receives research/grant support from
Acceleron Pharma, Inc; Amicus Therapeutics, Inc; and Amylyx Pharmaceuticals.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Quinn discusses the unlabeled/investigational use of
anticholinergics, clonazepam, levetiracetam, mexiletine, mirtazapine, phenytoin, selective serotonin reuptake
inhibitors, steroids, and tricyclic antidepressants for the treatment of amyotrophic lateral sclerosis and other motor
neuron diseases.

Kazim A. Sheikh, MBBS
Professor of Neurology, McGovern Medical School, University of Texas; Director,
Neuromuscular Program, Houston Health Science Center, Houston, Texas
Relationship Disclosure: Dr Sheikh serves on the medical advisory board of the GBS/CIDP Foundation International
and on the editorial board of Scientific Reports. Dr Sheikh has received personal compensation for speaking
engagements from CSL Behring and research/grant support from the Department of Defense (W81XWH-18-1-
0422) and the National Institute of Neurological Disorders and Stroke (R21NS107961).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Sheikh reports no disclosure.
Nathan P. Staff, MD, PhD, FAAN

Associate Professor and Consultant of Neurology, Mayo Clinic, Rochester, Minnesota
Relationship Disclosure: Dr Staff serves as an associate editor of Stem Cell Research & Therapy and receives
research/grant support from BrainStorm Cell Limited; Disarm Therapeutics; the National Institutes of Health (R01
CA 211887); Orion Therapeutics, LLC; and Regenerative Medicine Minnesota (RMM 11215 CT002).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Staff reports no disclosure.
Derek Wood, MD
Neurologist, UW Medicine–Valley Medical Center, Renton, Washington
Relationship Disclosure: Dr Wood reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Wood discusses the unlabeled/investigational use of
α-lipoic acid, amitriptyline, cannabidiol oil, carbamazepine, nortriptyline, oxcarbazepine, spinal cord stimulators,
valproic acid, and venlafaxine for the treatment of neuropathic pain in polyneuropathy.
Self-Assessment and CME Test Writers
Douglas J. Gelb, MD, PhD, FAAN

Professor of Neurology, University of Michigan, Ann Arbor, Michigan
Relationship Disclosure: Dr Gelb receives royalties from MedLink, Oxford University Press, and UpToDate, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gelb reports no disclosure.
D. Joanne Lynn, MD, FAAN

Associate Dean for Student Life, Clinical Professor of Neurology, The Ohio State University
College of Medicine, Columbus, Ohio
Relationship Disclosure: Dr Lynn receives book royalties from Lippincott Williams & Wilkins and holds stock in
Abbott Laboratories; AbbVie Inc; Amgen Inc; Bristol-Myers Squibb Company; CVS Health Corporation; Express
Scripts Holding Company; General Electric; Merck & Co, Inc; and Zimmer Biomet.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Lynn reports no disclosure.
Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning

skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing
neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished authors who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, and comprehensive continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and video material relating to the
issue topic accompanies issues when applicable.
The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
regular and perhaps new study habits, Continuum’s goal of establishing lifelong learning patterns
can be met.

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1128 Editor’s Preface

1130 A Structured Approach to the Diagnosis of Peripheral Nervous

1161 Diabetes and Metabolic Disorders and the Peripheral

1184 Guillain-Barré Syndrome

1205 Chronic Inﬂammatory Demyelinating Polyradiculoneuropathy and

1224 Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies

1257 Peripheral Neuropathies Associated With Vasculitis and

1299 Management of Neuropathic Pain in Polyneuropathy

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1348 Spinal Muscular Atrophy

1369 Peripheral Neuropathies Associated With Monoclonal

1384 Test Utilization and Value in the Evaluation of

1392 Rising Drug Costs for Neurologic Diseases

SELF-ASSESSMENT AND CME

1120 Learning Objectives and Core Competencies

1407 Instructions for Completing Postreading Self-Assessment and CME

1409 Postreading Self-Assessment and CME Test

1421 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

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A. Gordon Smith, MD, FAAN Brian C. Callaghan, MD, MS, FAAN

Distinguished Chair in Clinical

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Christopher J. Klein, MD, FAAN Michelle L. Mauermann,

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Clinical Professor of Neurology,

Jessica Rose Nance, MD

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Self-Assessment and CME Test Writers

Douglas J. Gelb, MD, PhD, FAAN D. Joanne Lynn, MD, FAAN

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Disorders of Peripheral Nerves,

This issue of Continuum is devoted to the diagnosis and management

1128 OCTOBER 2020

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1130 OCTOBER 2020

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u Does it localize to the CNS or to the peripheral nervous system?

CENTRAL OR PERIPHERAL NERVOUS SYSTEM

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disorders of the CNS. In addition to appreciation of upper motor neuron and

TABLE 1-1 Distinguishing Central From Peripheral Nervous System Lesions

Features Consistent With Any Central Nervous System Localization

1132 OCTOBER 2020

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● Features that suggest a

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Principal Muscles Diminished

C6 root Supraspinatus Lateral forearm and hand, first Biceps,

C7 root Tricepsb Centermost portion of the distal Triceps

C8 root Triceps Fourth and fifth digits and medial None

T1 root Abductor pollicis Medial forearm None

1134 OCTOBER 2020